Bio

Bio


Mark C. Genovese, MD, is the James W. Raitt Professor of Medicine and Director of the Rheumatology Clinic in the Division of Immunology and Rheumatology at Stanford University Medical Center. He received his bachelor's degree from the University of Notre Dame and his medical degree from the Johns Hopkins University School of Medicine. He completed an internship, residency, and chief residency in the Department of Medicine at Stanford University. He remained at Stanford as a fellow in the Division of Immunology and Rheumatology and subsequently joined the faculty in the same division and serving as the clinic chief. Dr. Genovese has established a clinical research program that is focused on bench-to-bedside translational medicine in autoimmune diseases. He has designed and led numerous investigator-initiated studies and international multi-center trials investigating novel therapies and therapeutic strategies for the treatment of autoimmune disease and arthritis. In addition, he actively collaborates with other investigators on studies of biomarkers, chemokines, cytokines, and cell surface markers associated with disease progression and response to therapy in various autoimmune diseases and arthritis.

Clinical Focus


  • Rheumatology
  • Immunology/Rheumatology

Academic Appointments


Professional Education


  • Board Certification: Rheumatology, American Board of Internal Medicine (1998)
  • Fellowship:Stanford University Medical Center (1998) CA
  • Residency:Stanford University Medical Center (1996) CA
  • Residency:Stanford University Medical Center (1995) CA
  • Internship:Stanford University Medical Center (1993) CA
  • Medical Education:Johns Hopkins University (1992) MD

Research & Scholarship

Current Research and Scholarly Interests


Clinical trials and interventions in the rheumatic diseases including Rheumatoid Arthritis,Systemic Lupus Erythematosus, Systemic Sclerosis, Osteoarthritis.

Clinical Trials


  • Hydroxychloroquine/Atorvastatin in the Treatment of Osteoarthritis (OA) of the Knee Not Recruiting

    The purpose of this study of a combination therapy of hydroxychloroquine and atorvastatin is to learn about the effects in inflammation and pain in patients with Osteoarthritis of the knee. These medications are FDA approved and commercially available.

    Stanford is currently not accepting patients for this trial. For more information, please contact Rosario Villacorta, 650-723-8516.

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  • A Phase II Study Evaluating the Efficacy and Safety of AbGn-168H in Patients With Active Psoriatic Arthritis Not Recruiting

    To evaluate efficacy, safety, tolerability, and immunogenicity of AbGn-168H administered intravenously in patients with active psoriatic arthritis.

    Stanford is currently not accepting patients for this trial.

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  • Evaluation of the Effectiveness and Safety of Two Dosing Regimens of Olokizumab (OKZ), Compared to Placebo and Adalimumab, in Subjects With Rheumatoid Arthritis (RA) Who Are Taking Methotrexate But Have Active Disease Not Recruiting

    The purpose of this study is to determine how safe and effective the study drug Olokizumab is, in patients with Rheumatoid Arthritis (RA) who are already receiving, but not fully responding to treatment with methotrexate (MTX).

    Stanford is currently not accepting patients for this trial.

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  • Switching Anti-TNF-Alpha Agents in Rheumatoid Arthritis (RA) Not Recruiting

    Rheumatoid Arthritis (RA) is a systemic inflammatory autoimmune disorder that leads to inflammation and progressive joint damage affecting 2.5 million people in the United States. The primary purpose of this study is to determine the effectiveness of switching to an alternative Tumor Necrosis Factor (TNF) alpha inhibitor in comparison to continuing treatment with an existing TNF-alpha inhibitor in adults suffering from RA in a setting of inadequate clinical response to etanercept or adalimumab.

    Stanford is currently not accepting patients for this trial.

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  • A Phase 2 Study to Evaluate the Safety, Tolerability, and Activity of Fontolizumab in Subjects With Active Rheumatoid Arthritis Not Recruiting

    To evaluate the efficacy of fontolizumab in subjects with active rheumatoid arthritis as determined by a 50% improvement of an American College of Rheumatology criteria (ACR50) response at Week 14 (Stage A of study).

    Stanford is currently not accepting patients for this trial.

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  • A Pilot Trial of Adalimumab for the Treatment of Osteoarthritis Not Recruiting

    A 12 week trial of Adalimumab in subjects with active erosive inflammatory OA who have ahd an inadequate response to NSAID therapy

    Stanford is currently not accepting patients for this trial.

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Teaching

2016-17 Courses


Publications

All Publications


  • Effects of the oral Janus kinase inhibitor tofacitinib on patient-reported outcomes in patients with active rheumatoid arthritis: results of two Phase 2 randomised controlled trials CLINICAL AND EXPERIMENTAL RHEUMATOLOGY Wallenstein, G. V., Kanik, K. S., Wilkinson, B., Cohen, S., Cutolo, M., Fleischmann, R., Genovese, M. C., Gomez Reino, J., Gruben, D., Kremer, J., Krishnaswami, S., Lee, E. B., Pascual-Ramos, V., Strand, V., Zwillich, S. H. 2016; 34 (3): 430-442
  • Safety and Efficacy of Subcutaneous Golimumab in Patients with Active Rheumatoid Arthritis despite Methotrexate Therapy: Final 5-year Results of the GO-FORWARD Trial. journal of rheumatology Keystone, E. C., Genovese, M. C., Hall, S., Bae, S., Han, C., Gathany, T. A., Xu, S., Zhou, Y., Leu, J. H., Hsia, E. C. 2016; 43 (2): 298-306

    Abstract

    To evaluate the safety and efficacy of golimumab (GOL), a human antitumor necrosis factor antibody, in patients with active rheumatoid arthritis (RA) despite methotrexate (MTX) therapy through 5 years in the GO-FORWARD trial.Patients with active RA despite MTX therapy were randomly assigned to receive placebo + MTX (Group 1), GOL 100 mg + placebo (Group 2), GOL 50 mg + MTX (Group 3), or GOL 100 mg + MTX (Group 4). Patients in groups 1, 2, and 3 with inadequate response could enter early escape at Week 16 to GOL 50 mg + MTX or GOL 100 mg + MTX, and all remaining Group 1 patients crossed over to GOL 50 mg + MTX at Week 24. The blind was maintained through the 52-week database lock, after which treatment adjustments were permitted. Adverse events (AE) were monitored through Week 268. Efficacy was evaluated using the American College of Rheumatology (ACR) 20/50/70 responses and a 28-joint Disease Activity Score using C-reactive protein (DAS28-CRP). Response rates at Week 256 were analyzed by an intent-to-treat analysis.A total of 444 patients were randomized, and 313 received GOL through Week 252; 301 patients completed the safety followup through Week 268. Infections were the most common type of AE; 172 patients (39.6%) had ? 1 serious AE. No unexpected safety signals were observed. At Week 256, ACR20/50/70 responses were achieved by 63.1%, 40.8%, and 24.1%, respectively, of all randomized patients. About 78% of all patients achieved a good or moderate DAS28-CRP response.Improvements in the signs and symptoms of RA were maintained through 5 years. AE through 5 years were consistent with earlier reports of the GO-FORWARD trial; no apparent increased risk was observed over time.

    View details for DOI 10.3899/jrheum.150712

    View details for PubMedID 26669912

  • Safety and Efficacy of Open-label Subcutaneous Ixekizumab Treatment for 48 Weeks in a Phase II Study in Biologic-naive and TNF-IR Patients with Rheumatoid Arthritis. journal of rheumatology Genovese, M. C., Braun, D. K., Erickson, J. S., Berclaz, P., Banerjee, S., Heffernan, M. P., Carlier, H. 2016; 43 (2): 289-297

    Abstract

    To evaluate ixekizumab, an anti-interleukin 17A monoclonal antibody, for safety and effectiveness through 64 weeks in biologic-naive and tumor necrosis factor-inadequate responder (TNF-IR) patients with rheumatoid arthritis.Patients completing the 16-week double-blind period of a phase II study were eligible to enter the open-label extension (OLE) for an additional 48 weeks of ixekizumab treatment. After a treatment hiatus between weeks 10 to 16, 232 biologic-naive and 158 TNF-IR patients entered the OLE with all patients receiving 160 mg ixekizumab at weeks 16, 18, and 20, and then every 4 weeks through Week 64.A total of 201 (87%) biologic-naive and 99 (62%) TNF-IR patients completed the OLE. Treatment-emergent adverse events (AE) occurred in 168 (72%) biologic-naive and 115 (73%) TNF-IR patients during the OLE. Most AE were mild to moderate in severity and did not lead to study discontinuation. Serious AE (SAE) occurred in 17 (7%) biologic-naive patients, including 5 (2%) serious infections and 2 (1%) deaths. SAE occurred in 18 (11%) TNF-IR patients, including 4 (3%) serious infections and 1 (1%) death. No mycobacterial or invasive fungal infections were reported. Clinical responses [American College of Rheumatology (ACR) 20, ACR50, ACR70, and 28-joint Disease Activity Score with C-reactive protein] observed at Week 16 were maintained or improved through Week 64.Ixekizumab was well tolerated, and safety findings in the OLE were consistent overall with those in the double-blind period of this study. Clinical improvements observed with ixekizumab through Week 16 were maintained or improved in patients participating in the OLE through Week 64.NCT00966875.

    View details for DOI 10.3899/jrheum.140831

    View details for PubMedID 26669919

  • Association of HLA-DRB1 alleles with clinical responses to the anti-interleukin-17A monoclonal antibody secukinumab in active rheumatoid arthritis RHEUMATOLOGY Burmester, G. R., Durez, P., Shestakova, G., Genovese, M. C., Schulze-Koops, H., Li, Y., Wang, Y. A., Lewitzky, S., Koroleva, I., Berneis, A. A., Lee, D. M., Hueber, W. 2016; 55 (1): 49-55

    Abstract

    To assess whether preliminary findings of associations between the HLA-DRB1*04 and HLA-DRB1* shared epitope (SE) allelic groups and response to the anti-IL-17A mAb secukinumab in RA were reproducible in an independent RA cohort.Biologic-naïve subjects (n = 100) with RA by 2010 criteria with tender/swollen joint counts (each ?6) and high-sensitivity CRP (hsCRP) >10 mg/l were randomized 2:1 to secukinumab 10 mg/kg i.v. or placebo every 2 weeks until week 10. Potential associations with treatment response to secukinumab at week 12 (DAS28-CRP change from baseline by analysis of covariance, ACR20 response rate by logistic regression) were assessed for HLA-DRB1*04 (primary end point), HLA-DRB1*SE and HLA-DRB1 position 11 V/L (HLA-DRB1*pos11 V/L) allelic groups, and baseline levels of hsCRP, RF and anti-CCP.Secukinumab was significantly more effective than placebo in reducing DAS28-CRP (-2.41 vs -0.71; P < 0.0001) and producing ACR20 responses (87.1% vs 25.0%; P < 0.0001) at week 12. The HLA-DRB1*04 allelic group was not significantly related to secukinumab response vs placebo. For change from baseline in DAS28-CRP, HLA-DRB1*SE (P = 0.003) and HLA-DRB1*pos11 V/L (P = 0.002) allelic groups were associated with positive treatment response. Higher RF levels, but not anti-CCP positivity, were significantly associated with DAS28-CRP reductions (P = 0.015) and ACR20 (P = 0.008) responses. Secukinumab was well tolerated.Secukinumab significantly reduced signs and symptoms of RA vs placebo. As the HLA-DRB1*SE and HLA-DRB1*pos11 V/L results were driven by lack of placebo response in carriers, the hypothesis of clinical utility for HLA-DRB1* allelic groups in RA anti-IL-17A short-term response prediction could not be corroborated.ClinicalTrials.gov; https://clinicaltrials.gov/; NCT01426789.

    View details for DOI 10.1093/rheumatology/kev258

    View details for Web of Science ID 000369074800008

    View details for PubMedID 26268815

  • Sarilumab plus methotrexate improves patient-reported outcomes in patients with active rheumatoid arthritis and inadequate responses to methotrexate: results of a phase III trial. Arthritis research & therapy Strand, V., Kosinski, M., Chen, C., Joseph, G., Rendas-Baum, R., Graham, N. M., van Hoogstraten, H., Bayliss, M., Fan, C., Huizinga, T., Genovese, M. C. 2016; 18: 198-?

    Abstract

    Sarilumab is a human monoclonal antibody directed against the alpha subunit of the interleukin-6 receptor complex. In the MOBILITY phase III randomized controlled trial (RCT), sarilumab?+?methotrexate (MTX) treatment resulted in clinical improvements at 24 weeks that were maintained at 52 weeks in adults with rheumatoid arthritis (RA), who have inadequate response to MTX (MTX-IR). These analyses indicate the effects of sarilumab?+?MTX versus placebo on patient-reported outcomes (PROs) in this RCT.Patients (n?=?1197) were randomized to receive placebo, sarilumab 150 or 200 mg subcutaneously?+?MTX every 2 weeks for 52 weeks; after 16 weeks, patients without ?20 % improvement from baseline in swollen or tender joint counts on two consecutive assessments were offered open-label treatment. PROs included patient global assessment of disease activity (PtGA), pain, health assessment questionnaire disability index (HAQ-DI), Short Form-36 Health Survey (SF-36), and functional assessment of chronic illness therapy-fatigue (FACIT-F). Changes from baseline at weeks 24 and 52 were analyzed using a mixed model for repeated measures. Post hoc analyses included percentages of patients reporting improvements equal to or greater than minimal clinically important differences (MCID) and normative values in the FACIT-F and SF-36. Pearson correlation between observed PRO scores and clinical measures of disease activity was tested at week 24.Both doses of sarilumab?+?MTX vs placebo?+?MTX resulted in improvement from baseline by week 24 in PtGA, pain, HAQ-DI, SF-36 and FACIT-F scores (p?

    View details for DOI 10.1186/s13075-016-1096-9

    View details for PubMedID 27600829

  • Efficacy and Safety of Tabalumab, an Anti-B-Cell-Activating Factor Monoclonal Antibody, in a Heterogeneous Rheumatoid Arthritis Population Results From a Randomized, Placebo-Controlled, Phase 3 Trial (FLEX-O) JCR-JOURNAL OF CLINICAL RHEUMATOLOGY Genovese, M. C., Silverman, G. J., Emery, P., Gupta, R. C., Gill, A., Veenhuizen, M., Xie, L., Komocsar, W. J., Berclaz, P., Lee, C. 2015; 21 (5): 231-238

    Abstract

    The efficacy and safety of 2 different dosing regimens of tabalumab, a monoclonal antibody that neutralizes membrane-bound and soluble B-cell-activating factor (BAFF), were evaluated in patients with rheumatoid arthritis.In this phase 3, multicenter, randomized study, 1004 patients (intention-to-treat population) received subcutaneous 120 mg tabalumab every 4 weeks (120/Q4W), 90 mg tabalumab every 2 weeks (90/Q2W), or placebo over 24 weeks. At baseline, a loading dose double the planned dose (ie, 240 mg, 180 mg, or placebo) was administered. Efficacy analyses were based on a prespecified subset of patients with 5 or more of 68 tender and 5 or more of 66 swollen joints at baseline (efficacy population, n = 849). The primary efficacy end point was ACR20 (20% improvement in American College of Rheumatology criteria) response at week 24.At week 24, there were no differences in ACR20 response rates (120/Q4W = 34.4%, 90/Q2W = 33.5%, placebo = 31.5%) or any other measures of efficacy across the treatment groups. Discontinuations due to adverse events (AE) were 3.4%, 2.7%, and 4.0%; incidence of treatment-emergent AEs were 64.1%, 58.2%, and 58.8%, with 23.2%, 25.9%, and 22.0% treatment-emergent infections; and incidence rates of serious AEs were 3.7%, 2.2%, and 2.8% with 1.1%, 0.3%, and 0.7% serious infections in the 120/Q4W, 90/Q2W, and placebo groups, respectively. Three deaths were reported (120/Q4W, n = 2; 90/Q2W, n = 1). Each tabalumab group had significant decreases versus placebo in CD3-CD20 B cells (P ? 0.05) and in serum immunoglobulins (P ? 0.001).Although tabalumab administration resulted in biologic activity, as demonstrated by changes in B cells and immunoglobulins, targeting BAFF-dependent pathways alone is not sufficient to significantly reduce rheumatoid arthritis disease activity.

    View details for DOI 10.1097/RHU.0000000000000276

    View details for Web of Science ID 000359829100001

    View details for PubMedID 26203826

  • Apremilast in Patients With Active Rheumatoid Arthritis: A Phase II, Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study ARTHRITIS & RHEUMATOLOGY Genovese, M. C., Jarosova, K., Cieslak, D., Alper, J., Kivitz, A., Hough, D. R., Maes, P., Pineda, L., Chen, M., Zaidi, F. 2015; 67 (7): 1703-1710

    Abstract

    To study the efficacy/safety of apremilast, an oral phosphodiesterase 4 inhibitor, compared with placebo in patients with active rheumatoid arthritis (RA) who had an inadequate response to methotrexate (MTX).Patients were randomized 1:1:1 to receive placebo, apremilast 20 mg twice a day, or apremilast 30 mg twice a day. Patients whose swollen and tender joint counts had not improved by ?20% were considered nonresponders at week 16 and were required to enter the protocol-defined early escape. At week 24, patients were transitioned in a blinded manner to receive apremilast 20 mg twice a day if they were initially randomized to receive placebo. Patients who were not initially randomized to receive placebo continued to receive their target apremilast dose. Patients were required to take a stable dose of MTX (7.5-25 mg/week) throughout the study. Magnetic resonance imaging (MRI) was performed in a subset of patients.A total of 237 patients who were receiving MTX therapy were randomized and received ?1 dose of study medication. At week 16, similar proportions of patients receiving placebo (35%), apremilast 20 mg twice a day (28%), and apremilast 30 mg twice a day (34%) met the American College of Rheumatology criteria for 20% improvement in disease activity (the primary efficacy end point). In the MRI substudy, mean change from baseline in total joint damage scores according to the Rheumatoid Arthritis Magnetic Resonance Imaging Scoring system was generally similar with either apremilast dose at week 16. At week 52, no trends were noted for clinical end points by treatment group. Both apremilast doses were generally well tolerated.Apremilast efficacy was not demonstrated in patients who had active RA despite stable MTX therapy.

    View details for DOI 10.1002/art.39120

    View details for Web of Science ID 000357013500004

    View details for PubMedID 25779750

  • Gene expression changes reflect clinical response in a placebo-controlled randomized trial of abatacept in patients with diffuse cutaneous systemic sclerosis ARTHRITIS RESEARCH & THERAPY Chakravarty, E. F., Martyanov, V., Fiorentino, D., Wood, T. A., Haddon, D. J., Jarrell, J. A., Utz, P. J., Genovese, M. C., Whitfield, M. L., Chung, L. 2015; 17
  • Sarilumab Plus Methotrexate in Patients With Active Rheumatoid Arthritis and Inadequate Response to Methotrexate: Results of a Phase III Study. Arthritis & rheumatology Genovese, M. C., Fleischmann, R., Kivitz, A. J., Rell-Bakalarska, M., Martincova, R., Fiore, S., Rohane, P., van Hoogstraten, H., Garg, A., Fan, C., van Adelsberg, J., Weinstein, S. P., Graham, N. M., Stahl, N., Yancopoulos, G. D., Huizinga, T. W., van der Heijde, D. 2015; 67 (6): 1424-1437

    Abstract

    To evaluate the efficacy and safety of sarilumab in combination with methotrexate (MTX) for the treatment of rheumatoid arthritis (RA).Adults with moderate-to-severe RA and an inadequate response to MTX were randomized (1:1:1) to receive sarilumab (doses of 150 mg or 200 mg) or placebo every 2 weeks in conjunction with weekly MTX for 52 weeks. Co-primary end points were the proportion of patients achieving American College of Rheumatology 20% (ACR20) improvement responses at week 24, change from baseline in the Health Assessment Questionnaire (HAQ) disability index (DI) at week 16, and change from baseline in the modified Sharp/van der Heijde score (SHS) of radiographic damage at week 52.Baseline characteristics were similar among the groups. For all 3 co-primary end points, the sarilumab 150 mg and 200 mg groups demonstrated statistically significant improvements as compared with the placebo group (ACR20 response rate at week 24, 58.0%, 66.4%, and 33.4%, respectively [P?3-fold the upper limit of normal occurred in 9.5%, 8.0%, and 2.1% of patients, respectively; in 24 patients, this led to discontinuation of treatment. Elevated total cholesterol levels were observed in 36.8%, 43.0%, and 18.3% of patients, respectively. In patients receiving 150 mg and 200 mg sarilumab, neutrophil counts of 0.5 to <1.0 × 10(9) /liter were observed in 5.1% and 7.8% of patients, respectively, while neutrophil counts of <0.5 × 10(9) /liter were observed in 0.9% and 0.7% of patients, respectively; none of the patients receiving placebo experienced changes in neutrophil counts.In RA patients treated with sarilumab (150 mg or 200 mg every 2 weeks) in combination with MTX, both doses provided sustained clinical efficacy, as shown by significant improvements in symptomatic, functional, and radiographic outcomes. Sarilumab was generally well tolerated. The adverse events observed in this study were consistent with the effects of interleukin-6 signaling blockade.

    View details for DOI 10.1002/art.39093

    View details for PubMedID 25733246

  • Sarilumab Plus Methotrexate in Patients With Active Rheumatoid Arthritis and Inadequate Response to Methotrexate Results of a Phase III Study ARTHRITIS & RHEUMATOLOGY Genovese, M. C., Fleischmann, R., Kivitz, A. J., Rell-Bakalarska, M., Martincova, R., Fiore, S., Rohane, P., van Hoogstraten, H., Garg, A., Fan, C., van Adelsberg, J., Weinstein, S. P., Graham, N. M., Stahl, N., Yancopoulos, G. D., Huizinga, T. W., van der Heijde, D. 2015; 67 (6): 1424-1437

    View details for DOI 10.1002/art.39093

    View details for Web of Science ID 000355328400005

  • Safety and efficacy of baricitinib at 24 weeks in patients with rheumatoid arthritis who have had an inadequate response to methotrexate ANNALS OF THE RHEUMATIC DISEASES Keystone, E. C., Taylor, P. C., Drescher, E., Schlichting, D. E., Beattie, S. D., Berclaz, P., Lee, C. H., Fidelus-Gort, R. K., Luchi, M. E., Rooney, T. P., Macias, W. L., Genovese, M. C. 2015; 74 (2): 333-340

    Abstract

    To investigate baricitinib (LY3009104, formerly INCB028050), a novel, oral inhibitor of JAK1/JAK2 in patients with moderate to severe rheumatoid arthritis (RA) despite treatment with methotrexate.In this phase IIb study, 301 patients were randomised 2:1:1:1:1 to receive once daily doses of placebo or 1, 2, 4 or 8?mg baricitinib for 12?weeks. Patients assigned to 2, 4 and 8 mg baricitinib continued blinded treatment for an additional 12?weeks. Patients assigned to placebo or 1 mg baricitinib were reassigned to 2 mg twice daily or 4 mg once daily baricitinib between weeks 12-24. The primary endpoint was the proportion of patients in the combined 4 and 8 mg groups achieving an American College of Rheumatology 20% (ACR20) response versus placebo at week 12.Significantly more patients in the combined baricitinib 4 and 8 mg groups compared with placebo achieved an ACR20 response at week 12 (76% vs 41%, p<0.001). At week 12, significant differences versus placebo were also observed in patients achieving ACR50, ACR70 and remission as measured by Disease Activity Score for 28-joint counts, Clinical Disease Activity Index and Simplified Disease Activity Index. Patients receiving 2, 4, or 8?mg baricitinib maintained or improved in all measures through 24?weeks. Similar proportions of patients experienced at least one adverse event in the placebo and baricitinib groups. Serious infections developed in three patients receiving baricitinib. No cases of tuberculosis, herpes zoster, opportunistic infections or deaths were reported. Dose-dependent decreases in haemoglobin were observed with baricitinib.Baricitinib improved the signs and symptoms of RA in methotrexate inadequate responders with active disease. Baricitinib was well tolerated with no unexpected safety findings through week 24.NCT01185353.

    View details for DOI 10.1136/annrheumdis-2014-206478

    View details for Web of Science ID 000347458300004

    View details for PubMedID 25431052

  • Gene expression changes reflect clinical response in a placebo-controlled randomized trial of abatacept in patients with diffuse cutaneous systemic sclerosis. Arthritis research & therapy Chakravarty, E. F., Martyanov, V., Fiorentino, D., Wood, T. A., Haddon, D. J., Jarrell, J. A., Utz, P. J., Genovese, M. C., Whitfield, M. L., Chung, L. 2015; 17: 159-?

    Abstract

    Systemic sclerosis is an autoimmune disease characterized by inflammation and fibrosis of the skin and internal organs. We sought to assess the clinical and molecular effects associated with response to intravenous abatacept in patients with diffuse cutaneous systemic.Adult diffuse cutaneous systemic sclerosis patients were randomized in a 2:1 double-blinded fashion to receive abatacept or placebo over 24 weeks. Primary outcomes were safety and the change in modified Rodnan Skin Score (mRSS) at week 24 compared with baseline. Improvers were defined as patients with a decrease in mRSS of ?30% post-treatment compared to baseline. Skin biopsies were obtained for differential gene expression and pathway enrichment analyses and intrinsic gene expression subset assignment.Ten subjects were randomized to abatacept (n = 7) or placebo (n = 3). Disease duration from first non-Raynaud's symptom was significantly longer (8.8 ± 3.8 years vs. 2.4 ± 1.6 years, p = 0.004) and median mRSS was higher (30 vs. 22, p = 0.05) in the placebo compared to abatacept group. Adverse events were similar in the two groups. Five out of seven patients (71%) randomized to abatacept and one out of three patients (33%) randomized to placebo experienced ?30% improvement in skin score. Subjects receiving abatacept showed a trend toward improvement in mRSS at week 24 (-8.6 ± 7.5, p = 0.0625) while those in the placebo group did not (-2.3 ± 15, p = 0.75). After adjusting for disease duration, mRSS significantly improved in the abatacept compared with the placebo group (abatacept vs. placebo mRSS decrease estimate -9.8, 95% confidence interval -16.7 to -3.0, p = 0.0114). In the abatacept group, the patients in the inflammatory intrinsic subset showed a trend toward greater improvement in skin score at 24 weeks compared with the patients in the normal-like intrinsic subset (-13.5 ± 3.1 vs. -4.5 ± 6.4, p = 0.067). Abatacept resulted in decreased CD28 co-stimulatory gene expression in improvers consistent with its mechanism of action. Improvers mapped to the inflammatory intrinsic subset and showed decreased gene expression in inflammatory pathways, while non-improver and placebos showed stable or reverse gene expression over 24 weeks.Clinical improvement following abatacept therapy was associated with modulation of inflammatory pathways in skin.ClinicalTrials.gov NCT00442611. Registered 1 March 2007.

    View details for DOI 10.1186/s13075-015-0669-3

    View details for PubMedID 26071192

  • Effects of Fostamatinib, an Oral Spleen Tyrosine Kinase Inhibitor, in Rheumatoid Arthritis Patients With an Inadequate Response to Methotrexate Results From a Phase III, Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study ARTHRITIS & RHEUMATOLOGY Weinblatt, M. E., Genovese, M. C., Ho, M., Hollis, S., Rosiak-Jedrychowicz, K., Kavanaugh, A., Millson, D. S., Leon, G., Wang, M., van der Heijde, D. 2014; 66 (12): 3255-3264

    Abstract

    This phase III, 52-week study compared fostamatinib with placebo (for 24 weeks) in patients with active rheumatoid arthritis (RA) and an inadequate response to methotrexate (MTX) therapy.Patients taking MTX were randomized (1:1:1) to receive fostamatinib 100 mg twice daily for 52 weeks (group A), fostamatinib 100 mg twice daily for 4 weeks and then 150 mg once daily (group B), or placebo for 24 weeks and then fostamatinib 100 mg twice daily (group C). At week 24, the co-primary end points were change from baseline in the American College of Rheumatology 20% (ACR20) improvement response rates and change in the modified total Sharp/van der Heijde score of radiographic damage (SHS).In this study, 918 patients were randomized and received ?1 dose of study drug (fostamatinib or placebo); the demographic and baseline clinical characteristics were well balanced. Following treatment with both fostamatinib regimens, a statistically significant difference in the ACR20 improvement response was achieved at week 24 as compared with that in patients receiving placebo (49.0% [group A] and 44.4%, [group B] versus 34.2%; P < 0.001 and P = 0.006, respectively), but there was no statistically significant difference in the SHS between either fostamatinib group and placebo (P = 0.25 and P = 0.17, respectively). The most common adverse events in patients in groups A, B, and C were hypertension (15.8%, 15.1%, and 3.9%, respectively) and diarrhea (13.9%, 15.1%, and 3.9%, respectively). Elevated blood pressure (?140/90 mm Hg) occurred at ?1 visit in 44.2%, 41.6%, and 19.3% of patients in each respective group.With the use of either fostamatinib regimen in patients with RA, statistically significant, but not clinically significant, improvements in the ACR20 improvement response over placebo were achieved at 24 weeks, whereas a significant difference in the SHS was not seen. The overall level of response to treatment with fostamatinib was lower than had been observed in the phase II program, but similar adverse events were reported.

    View details for DOI 10.1002/art.38851

    View details for Web of Science ID 000345571200002

    View details for PubMedID 25223724

  • A Phase III, Multicenter, Randomized, Double-blind, Placebo-controlled, Parallel-group Study of 2 Dosing Regimens of Fostamatinib in Patients with Rheumatoid Arthritis with an Inadequate Response to a Tumor Necrosis Factor-alpha Antagonist JOURNAL OF RHEUMATOLOGY Genovese, M. C., van der Heijde, D. M., Keystone, E. C., Spindler, A. J., Benhamou, C., Kavanaugh, A., Fudman, E., Lampl, K., O'Brien, C., Duffield, E. L., Poiley, J., Weinblatt, M. E. 2014; 41 (11): 2120-2128
  • Serum 14-3-3 eta is a Novel Marker that Complements Current Serological Measurements to Enhance Detection of Patients with Rheumatoid Arthritis JOURNAL OF RHEUMATOLOGY Maksymowych, W. P., Naides, S. J., Bykerk, V., Siminovitch, K. A., van Schaardenburg, D., Boers, M., Landewe, R., van der Heijde, D., Tak, P., Genovese, M. C., Weinblatt, M. E., Keystone, E. C., Zhukov, O. S., Abolhosn, R. W., Popov, J. M., Britsemmer, K., van Kuijk, A. W., Marotta, A. 2014; 41 (11): 2104-2113

    Abstract

    Serum 14-3-3? is a novel joint-derived proinflammatory mediator implicated in the pathogenesis of rheumatoid arthritis (RA). In our study, we assessed the diagnostic utility of 14-3-3? and its association with standard clinical and serological measures.A quantitative ELISA was used to assess 14-3-3? levels. Early (n=99) and established patients with RA (n=135) were compared to all controls (n=385), including healthy subjects (n=189). The sensitivity, specificity, positive and negative predictive values of 14-3-3?, and the likelihood ratios (LR) for RA were determined through receiver-operator curve analysis. The incremental value of adding 14-3-3? to anticitrullinated protein antibody (ACPA) and rheumatoid factor (RF) in diagnosing early and established RA was assessed.Serum 14-3-3? differentiated established patients with RA from healthy individuals and all controls (p<0.0001). A serum 14-3-3? cutoff of ?0.19 ng/ml delivered a sensitivity and specificity of 77% and 93%, respectively, with corresponding LR positivity of 10.4. At this cutoff in early RA, 64% of patients with early RA were positive for 14-3-3?, with a corresponding specificity of 93% (LR+ of 8.6), while 59% and 57% were positive for ACPA or RF, respectively. When ACPA, RF, and 14-3-3? positivity were used in combination, 77 of the 99 patients (78%) with early RA were positive for any 1 of the 3 markers. Serum 14-3-3? did not correlate with C-reactive protein, erythrocyte sedimentation rate, or Disease Activity Score, but patients who were 14-3-3?-positive had significantly worse disease.Serum 14-3-3? is a novel RA mechanistic marker that is highly specific, associated with worse disease, and complements current markers, enabling a more accurate diagnosis of RA.

    View details for DOI 10.3899/jrheum.131446

    View details for Web of Science ID 000344598900006

    View details for PubMedID 25128504

  • Efficacy and safety of olokizumab in patients with rheumatoid arthritis with an inadequate response to TNF inhibitor therapy: outcomes of a randomised Phase IIb study ANNALS OF THE RHEUMATIC DISEASES Genovese, M. C., Fleischmann, R., Furst, D., Janssen, N., Carter, J., Dasgupta, B., Bryson, J., Duncan, B., Zhu, W., Pitzalis, C., Durez, P., Kretsos, K. 2014; 73 (9): 1607-1615

    Abstract

    The aim of this 12-week Phase IIb study was to assess the efficacy and safety of olokizumab (OKZ), a humanised anti-IL6 monoclonal antibody, in patients with rheumatoid arthritis (RA) with moderate-to-severe disease activity who had previously failed tumour necrosis factor (TNF) inhibitor therapy. The dose-exposure-response relationship for OKZ was also investigated.Patients were randomised to one of nine treatment arms receiving placebo (PBO) or OKZ (60, 120 or 240?mg) every 4?weeks (Q4W) or every 2?weeks (Q2W), or 8?mg/kg tocilizumab (TCZ) Q4W. The primary endpoint was change from baseline in DAS28(C-reactive protein, CRP) at Week 12. Secondary efficacy endpoints were American College of Rheumatology 20 (ACR20), ACR50 and ACR70 response rates at Week 12. Exploratory analyses included comparisons of OKZ efficacy with TCZ.Across 221 randomised patients, OKZ treatment produced significantly greater reductions in DAS28(CRP) from baseline levels at Week 12, compared to PBO (p<0.001), at all the OKZ doses tested (60?mg OKZ p=0.0001, 120 and 240?mg OKZ p<0.0001). Additionally, ACR20 and ACR50 responses were numerically higher for OKZ than PBO (ACR20: PBO=17.1-29.9%, OKZ=32.5-60.7%; ACR50: PBO=1.3-4.9%, OKZ=11.5-33.2%). OKZ treatment, at several doses, demonstrated similar efficacy to TCZ across multiple endpoints. Most adverse events were mild or moderate and comparable between OKZ and TCZ treatment groups. Pharmacokinetic/pharmacodynamic modelling demonstrated a shallow dose/exposure response relationship in terms of percentage of patients with DAS28(CRP) <2.6.OKZ produced significantly greater reductions in DAS28(CRP) from baseline at Week 12 compared with PBO. Reported AEs were consistent with the safety profile expected of this class of drug, with no new safety signals identified.NCT01242488.

    View details for DOI 10.1136/annrheumdis-2013-204760

    View details for Web of Science ID 000340723700010

    View details for PubMedID 24641941

  • Long-Term Safety of Subcutaneous Abatacept in Rheumatoid Arthritis Integrated Analysis of Clinical Trial Data Representing More Than Four Years of Treatment ARTHRITIS & RHEUMATOLOGY Alten, R., Kaine, J., Keystone, E., Nash, P., Delaet, I., Genovese, M. C. 2014; 66 (8): 1987-1997

    Abstract

    To investigate the safety of long-term subcutaneous (SC) abatacept treatment using integrated clinical trial data obtained in patients with rheumatoid arthritis refractory to traditional disease-modifying antirheumatic drugs.Data from the double-blind and open-label phases of 5 clinical trials of SC abatacept were pooled. The overall and 6-month incidence rates were calculated as events per 100 patient-years of exposure.This analysis included 1,879 patients with 4,214.6 patient-years of exposure to SC abatacept. The mean ± SD length of exposure was 27.3 ± 9.1 months. The reported incidence rate of serious infections was 1.79 (95% confidence interval [95% CI] 1.42-2.24); the most frequent infections were pneumonia (incidence rate 0.36 [95% CI 0.22-0.59]), urinary tract infection (incidence rate 0.14 [95% CI 0.06-0.32]), and gastroenteritis (incidence rate 0.10 [95% CI 0.04-0.25]). Tuberculosis occurred rarely (incidence rate 0.09 [95% CI 0.04-0.25]). The reported incidence rate of malignancies was 1.32 (95% CI 1.01-1.72), and the most common was solid organ malignancy (incidence rate 0.69 [95% CI 0.48-0.99]). The incidence rate of autoimmune events was 1.37 (95% CI 1.06-1.78), and the most frequent events were psoriasis (incidence rate 0.33 [95% CI 0.20-0.56]) and Sjögren's syndrome (incidence rate 0.24 [95% CI 0.13-0.44]). The reported incidence rate of local injection site reactions was 1.72 (95% CI 1.36-2.17); these events occurred primarily during the first 6 months of treatment, and almost all were of mild or moderate intensity. The incidence rates of serious infections, malignancies, autoimmune events, and injection site reactions did not increase over time.Long-term treatment with SC abatacept was associated with low incidence rates of serious infections, malignancies, and autoimmune events and was well tolerated, with infrequent injection site reactions. These findings are consistent with those related to treatment with intravenous abatacept. Long-term treatment with SC abatacept did not lead to new safety signals over time.

    View details for DOI 10.1002/art.38687

    View details for Web of Science ID 000340375600005

    View details for PubMedID 24782324

  • A Phase II Randomized Study of Subcutaneous Ixekizumab, an Anti-Interleukin-17 Monoclonal Antibody, in Rheumatoid Arthritis Patients Who Were Naive to Biologic Agents or Had an Inadequate Response to Tumor Necrosis Factor Inhibitors ARTHRITIS & RHEUMATOLOGY Genovese, M. C., Greenwald, M., Cho, C., Berman, A., Jin, L., Cameron, G. S., Benichou, O., Xie, L., Braun, D., Berclaz, P., Banerjee, S. 2014; 66 (7): 1693-1704

    Abstract

    To evaluate ixekizumab, an anti-interleukin-17A (anti-IL-17A) monoclonal antibody, in 2 populations of rheumatoid arthritis (RA) patients: biologics-naive patients and patients with an inadequate response to tumor necrosis factor (TNF) inhibitors.In this phase II, randomized, double-blind study, placebo or ixekizumab was administered subcutaneously to 260 biologics-naive patients and 188 patients with an inadequate response to TNF inhibitors at weeks 0, 1, 2, 4, 6, 8, and 10 with concomitant disease-modifying antirheumatic drugs. The primary objective was to determine the dose-response relationship of ixekizumab as measured by the proportion of biologics-naive patients meeting the American College of Rheumatology 20% improvement criteria (ACR20) at week 12.Using a logistic regression model defined a priori, a statistically significant dose-response relationship as measured by ACR20 response rates at week 12 was detected in biologics-naive patients (P = 0.031). For patients with an inadequate response to TNF inhibitors, ACR20 responses at week 12 were significantly better with ixekizumab than placebo (P < 0.05). Decreases in the Disease Activity Score in 28 joints using the C-reactive protein level (DAS28-CRP), Clinical Disease Activity Index (CDAI), and CRP level from baseline were observed at week 12 in the ixekizumab groups in both populations (P < 0.05 versus placebo). Onset of action was rapid in some dose groups in both populations, with improvements in the ACR20, DAS28-CRP, CRP levels, and CDAI observed by day 3 (P < 0.05). Adverse events occurred with similar frequencies overall in the ixekizumab and placebo groups. Infections were more frequent with ixekizumab than placebo (biologics-naive 25% versus 19%; inadequate responders to TNF inhibitors 27% versus 25%). No mycobacterial or invasive fungal infections were reported.Ixekizumab improved RA signs and symptoms in RA patients who were either naive to biologics treatment or had an inadequate response to TNF inhibitors. The safety profile was similar to that of other biologic agents, with no unexpected safety concerns.

    View details for DOI 10.1002/art.38617

    View details for Web of Science ID 000339092800003

    View details for PubMedID 24623718

  • Brodalumab, an Anti-IL17RA Monoclonal Antibody, in Psoriatic Arthritis NEW ENGLAND JOURNAL OF MEDICINE Mease, P. J., Genovese, M. C., Greenwald, M. W., Ritchlin, C. T., Beaulieu, A. D., Deodhar, A., Newmark, R., Feng, J., Erondu, N., Nirula, A. 2014; 370 (24): 2295-2306

    Abstract

    We assessed the efficacy and safety of brodalumab, a human monoclonal antibody against interleukin-17 receptor A (IL17RA), in a phase 2, randomized, double-blind, placebo-controlled study involving patients with psoriatic arthritis.We randomly assigned patients with active psoriatic arthritis to receive brodalumab (140 or 280 mg subcutaneously) or placebo on day 1 and at weeks 1, 2, 4, 6, 8, and 10. At week 12, patients who had not discontinued their participation in the study were offered open-label brodalumab (280 mg) every 2 weeks. The primary end point was 20% improvement in American College of Rheumatology response criteria (ACR 20) at week 12.Of the 168 patients who underwent randomization (57 in the brodalumab 140-mg group, 56 in the brodalumab 280-mg group, and 55 in the placebo group), 159 completed the double-blind phase and 134 completed 40 weeks of the open-label extension. At week 12, the brodalumab 140-mg and 280-mg groups had higher rates of ACR 20 than the placebo group (37% [P=0.03] and 39% [P=0.02], respectively, vs. 18%); they also had higher rates of 50% improvement (ACR 50) (14% [P=0.05] and 14% [P=0.05] vs. 4%). Rates of 70% improvement were not significantly higher in the brodalumab groups. Similar degrees of improvement were noted among patients who had received previous biologic therapy and those who had not received such therapy. At week 24, ACR 20 response rates in the brodalumab 140-mg and 280-mg groups were 51% and 64%, respectively, as compared with 44% among patients who switched from placebo to open-label brodalumab; responses were sustained through week 52. At week 12, serious adverse events had occurred in 3% of patients in the brodalumab groups and in 2% of those in the placebo group.Brodalumab significantly improved response rates among patients with psoriatic arthritis. Larger studies of longer duration are necessary to assess adverse events. (Funded by Amgen; ClinicalTrials.gov number, NCT01516957 .).

    View details for DOI 10.1056/NEJMoa1315231

    View details for Web of Science ID 000337033700009

    View details for PubMedID 24918373

  • Subcutaneous Abatacept for the Treatment of Rheumatoid Arthritis: Longterm Data from the ACQUIRE Trial. journal of rheumatology Genovese, M. C., Tena, C. P., Covarrubias, A., Leon, G., Mysler, E., Keiserman, M., Valente, R., Nash, P., Simon-Campos, J. A., Box, J., Legerton, C. W., Nasonov, E., Durez, P., Delaet, I., Teng, J., Alten, R. 2014; 41 (4): 629-639

    Abstract

    Assess longterm tolerability, safety, and efficacy of subcutaneous (SC) abatacept (ABA) in methotrexate-refractory patients with rheumatoid arthritis (RA).The phase III, multinational Abatacept Comparison of Sub[QU]cutaneous Versus Intravenous in Inadequate Responders to MethotrexatE (ACQUIRE) trial comprised a 6-month, randomized, double-blind (DB) period, in which patients received intravenous (IV) or SC ABA, plus MTX, followed by an open-label, longterm extension (LTE), in which patients received SC ABA, 125 mg/week. Safety and efficacy from the LTE (?3.5 yrs of exposure) are reported.Patients who completed the DB period (1372/1385, 99.1%) entered the LTE; 1134 patients (82.7%) kept taking the treatment at time of reporting. Mean (SD) was 31.9 months (6.8); median (range) exposure was 33.0 (8-44) months. Patients entering the LTE had longstanding, moderate-to-severe disease [mean 7.6 (7.9) yrs and DAS28 (C-reactive protein) 6.2 (0.9)]. Incidence rates (events/100 patient-yrs) were reported for serious adverse events (8.76, 95% CI 7.71, 9.95), infections (44.80, 95% CI 41.76, 48.01), serious infections (1.72, 95% CI 1.30, 2.27), malignancies (1.19, 95% CI 0.86, 1.66), and autoimmune events (1.31, 95% CI 0.95, 1.79). Twenty-seven patients (2%) experienced injection-site reactions; all except 1 were mild. American College of Rheumatology 20, 50, and 70 responses achieved during the DB period were maintained through the LTE, and on Day 981 were 80.2% (95% CI 77.2, 83.2), 63.5% (95% CI 58.2, 68.9), and 39.5% (95% CI 34.0, 44.9) for patients who kept taking SC ABA, and 80.0% (95% CI 77.0, 83.0), 63.2% (95% CI 57.8, 68.7), and 39.2% (95% CI 33.7, 44.7) for those who switched from IV to SC ABA.These findings support SC ABA as a well-tolerated and efficacious longterm treatment for patients with RA and inadequate response to MTX (ClinicalTrials.gov identifier NCT00559585).

    View details for DOI 10.3899/jrheum.130112

    View details for PubMedID 24584926

  • One-year Efficacy and Safety Results of Secukinumab in Patients With Rheumatoid Arthritis: Phase II, Dose-finding, Double-blind, Randomized, Placebo-controlled Study. journal of rheumatology Genovese, M. C., Durez, P., Richards, H. B., Supronik, J., Dokoupilova, E., Aelion, J. A., Lee, S., Codding, C. E., Kellner, H., Ikawa, T., Hugot, S., Ligozio, G., Mpofu, S. 2014; 41 (3): 414-421

    Abstract

    To evaluate the longer-term safety and efficacy of secukinumab, a fully human monoclonal antiinterleukin-17A antibody, in patients with rheumatoid arthritis.In this 52-week, double-blind, placebo-controlled (up to Week 20) study (NCT00928512), patients responding inadequately to disease-modifying antirheumatic drugs (DMARD) or biologics were randomized to receive monthly subcutaneous injections of secukinumab (25, 75, 150, or 300 mg), or placebo. The efficacy and safety results up to Week 20 have been reported previously. Here, efficacy results from Week 20 to 52 and safety results from Week 20 to 60 are presented.Of 237 patients randomized, 174 (73.4%) completed the study. Patients with improved American College of Rheumatology (ACR) and 28-joint Disease Activity Score (DAS28) C-reactive protein (CRP) responses at Week 16 sustained their responses through Week 52. In patients taking 150 mg of secukinumab, responses were improved through Week 52 (ACR50: Week 16 = 45%, Week 52 = 55%; DAS28-CRP ? 2.6: Week 16 = 25%, Week 52 = 40%). The rate of adverse events (AE) from weeks 20 to 60 was 64.8%, with most AE being mild to moderate in severity. The overall rate of infections was 31.9%, most being mild. The most predominant infection was nasopharyngitis, and was not associated with dose or concurrent neutropenia. Serious AE were reported in 21 patients (8.9%). There were 3 reports of malignancies (ovarian, lung, basal cell), and no deaths between weeks 20 and 60.Patients with active RA who failed to respond to DMARD and other biologics showed an improvement after longterm treatment with 150 mg of secukinumab. The frequency of AE remained stable over time and secukinumab had a consistent safety profile over 60 weeks.

    View details for DOI 10.3899/jrheum.130637

    View details for PubMedID 24429175

  • Effects of golimumab, an anti-tumour necrosis factor-alpha human monoclonal antibody, on lipids and markers of inflammation ANNALS OF THE RHEUMATIC DISEASES Kirkham, B. W., Wasko, M. C., Hsia, E. C., Fleischmann, R. M., Genovese, M. C., Matteson, E. L., Liu, H., Rahman, M. U. 2014; 73 (1): 161-169

    Abstract

    To assess the effect of golimumab, with or without methotrexate (MTX), on serum lipids and inflammatory markers of cardiovascular disease (CVD) in patients with rheumatoid arthritis (RA) in two phase 3, randomised, placebo-controlled trials (GO-BEFORE and GO-FORWARD).Patients in GO-BEFORE (n=637, MTX-naïve) and GO-FORWARD (n=444, MTX-inadequate response) were randomised to placebo+MTX, golimumab 100 mg+placebo, golimumab 50 mg+MTX, or golimumab 100 mg+MTX. Subcutaneous injections (placebo and golimumab) were given every 4 weeks. Patients with an insufficient response entered early escape at week 16 (GO-FORWARD) or 28 (GO-BEFORE). All placebo+MTX patients in GO-FORWARD crossed over to golimumab 50 mg+MTX at week 24. Changes from baseline to weeks 14 (GO-FORWARD) or 24 (GO-BEFORE), and 52 in serum lipid levels and inflammatory markers were assessed.At week 14 in the GO-FORWARD trial, total cholesterol (TC), high-density lipoprotein (HDL) and low-density lipoprotein (LDL) increased in golimumab+MTX patients versus MTX-only patients (16.00 vs 2.00 (p<0.001); 3.00 vs 0.00 (p<0.05); 8.00 vs 4.00 (p<0.001); respectively); favourable changes in LDL subfractions were only observed in golimumab-treated patients. At week 24 in GO-BEFORE, TC and LDL increased, and LDL subfractions improved in the MTX-only and golimumab+MTX groups. Inflammatory markers of CVD risk improved significantly with golimumab+MTX versus placebo+MTX in both studies and were generally maintained through week 52. Atherogenic indices were generally stable.While TC and LDL levels increased mildly in RA patients receiving golimumab+MTX, atherogenic indices generally remained stable, favourable changes in LDL subfractions were observed, and inflammatory markers improved.

    View details for DOI 10.1136/annrheumdis-2012-202089

    View details for Web of Science ID 000327835100029

    View details for PubMedID 23300117

  • Effect of Golimumab on Carotid Atherosclerotic Disease Measures and Cardiovascular Events in Inflammatory Arthritides JCR-JOURNAL OF CLINICAL RHEUMATOLOGY Wasko, M. C., Hsia, E. C., Kirkham, B., Touboul, P., Fleischmann, R., Genovese, M. C., Matteson, E. L., Lu, J., Xu, W., Rahman, M. U. 2014; 20 (1): 1-10

    Abstract

    The objective of this study was to assess the effect of golimumab on carotid ultrasound measures and cardiovascular serious adverse events (SAEs) in patients with inflammatory arthritides.An exploratory carotid artery ultrasound substudy was performed in the GO-BEFORE study of methotrexate (MTX)-naive rheumatoid arthritis patients, with ultrasounds performed at weeks 0, 24, and 52 to measure common carotid artery intima-media thickness, distensibility coefficient, interadventitial diameter, and plaque count. Cardiovascular SAEs reported over 2 years of follow-up were assessed in 5 golimumab phase 3 clinical trials of patients with rheumatoid arthritis (GO-BEFORE, GO-FORWARD, and GO-AFTER), psoriatic arthritis (GO-REVEAL), and ankylosing spondylitis (GO-RAISE). In GO-BEFORE and GO-FORWARD, patients received placebo + MTX, golimumab 50 mg + MTX, or golimumab 100 mg +/- MTX at baseline and every 4 weeks; in the other 3 trials, patients received placebo or golimumab 50 or 100 mg.The carotid ultrasound substudy showed inconsistent changes in common carotid artery intima-media thickness in the golimumab + MTX groups over time, and there was large variability in the measurements. Increases in interadventitial diameter were observed in the golimumab 100 mg + placebo group, but not in the golimumab + MTX groups. There were no significant differences in the distensibility coefficient and plaque count between the golimumab and placebo groups. Very few patients overall experienced a cardiovascular SAE, and the incidence of cardiovascular SAEs was not statistically different between the golimumab and placebo groups.The results of the carotid ultrasound substudy were inconclusive, and no increase or decrease in cardiovascular SAEs was observed following 2 years of treatment with golimumab with or without MTX.

    View details for DOI 10.1097/RHU.0000000000000053

    View details for Web of Science ID 000336963500001

    View details for PubMedID 24356481

  • A phase 2 dose-ranging study of subcutaneous tabalumab for the treatment of patients with active rheumatoid arthritis and an inadequate response to methotrexate ANNALS OF THE RHEUMATIC DISEASES Genovese, M. C., Lee, E., Satterwhite, J., Veenhuizen, M., Disch, D., Berclaz, P., Myers, S., Sides, G., Benichou, O. 2013; 72 (9): 1453-1460

    Abstract

    OBJECTIVES: To assess the dose-response relationship, efficacy and safety of tabalumab, a human monoclonal antibody that neutralises membrane-bound and soluble B-cell activating factor (BAFF), in patients with rheumatoid arthritis (RA) with inadequate response to methotrexate (MTX). METHODS: In this phase 2, 24-week, double-blind, placebo-controlled, dose-ranging study, patients with RA (N=158) on stable  MTX were randomised by Bayesian-adaptive method to receive 1, 3, 10, 30, 60, or 120 mg tabalumab or placebo subcutaneously every 4 weeks for 24 weeks. The primary objective was to test for a significant dose-response relationship using a statistical model of the proportion of patients having ?50% improvement in American College of Rheumatology (ACR) criteria (ACR50) at week 24 (prespecified ?=0.10). RESULTS: At week 24, a significant dose-response relationship was observed using ACR50 (p=0.059) and ACR20 (p=0.044) response rates. Using model-estimated data, only 120 mg had significantly higher ACR50 and ACR20 response rates versus placebo (p<0.05). Observed response rates were significantly higher for 120 mg versus placebo as measured by ACR50 at weeks 12 (p=0.039) and 20 (p=0.018), but not week 24, and by ACR20 at weeks 12 (p=0.011) and 24 (p=0.039). Mean DAS28 C-reactive protein  improved with 120 mg at week 24 (p=0.048). Frequency of TEAEs was similar across groups (range 50-69%, p=0.884). Ten (8.2%) tabalumab and 5 (13.9%) placebo patients reported a serious adverse event (SAE). Infections occurred more frequently in patients exposed to tabalumab (30.3% vs 19.4%). Serious infections were reported in 3 (2.5%) tabalumab-treated patients only. CONCLUSIONS: A dose-response relationship was detected with monthly subcutaneous tabalumab. A significant effect was detected with the 120 mg dose with no unexpected safety signals. CLINICAL TRIAL #: NCT00785928.

    View details for DOI 10.1136/annrheumdis-2012-202864

    View details for Web of Science ID 000323161100004

    View details for PubMedID 23599435

  • Tabalumab, an anti-BAFF monoclonal antibody, in patients with active rheumatoid arthritis with an inadequate response to TNF inhibitors ANNALS OF THE RHEUMATIC DISEASES Genovese, M. C., Fleischmann, R. M., Greenwald, M., Satterwhite, J., Veenhuizen, M., Xie, L., Berclaz, P., Myers, S., Benichou, O. 2013; 72 (9): 1461-1468

    Abstract

    OBJECTIVE: To evaluate the efficacy and safety of tabalumab, a monoclonal antibody that neutralises membrane-bound and soluble B-cell activating factor (BAFF), in patients with active rheumatoid arthritis (RA) who showed inadequate response to tumour necrosis factor (TNF) inhibitors. METHODS: Patients on stable methotrexate and with inadequate response to one or more TNF inhibitors were randomised to placebo (n=35), 30 mg tabalumab (n=35) or 80 mg tabalumab (n=30) given intravenously at 0, 3 and 6 weeks. The primary outcome was the proportion of patients achieving an American College of Rheumatology 50% response (ACR50) at week 16 (all tabalumab-treated patients vs placebo). RESULTS: At week 16, no significant differences were observed in the combined tabalumab group versus placebo in ACR50 (12.7% vs 2.9%, p=0.101) or ACR20 response rates (27.0% vs 17.1%, p=0.198). However, significant differences between the combined tabalumab group and placebo were observed at earlier time points for ACR20, ACR50 and Disease Activity Score in 28 joints (DAS28)-C-reactive protein (CRP) reduction. Treatment-emergent adverse events (AEs) were similar with 30 mg tabalumab (65.7%), 80 mg tabalumab (76.7%) and placebo (71.4%), although certain events occurred more often with tabalumab than placebo (eg, infection, anaemia and gastrointestinal events). Serious AEs occurred in two (6.7%) patients receiving 80 mg tabalumab and three (8.6%) receiving placebo, with one serious infection in the placebo group. Initial increases in total and mature B cells were followed by progressive decreases, despite declines in serum tabalumab. CONCLUSIONS: At week 16, the primary end point was not achieved, but an indication of efficacy was observed at earlier time points. Safety findings for tabalumab were consistent with other biological RA therapies. CLINICAL TRIAL REGISTRATION NUMBER: NCT00689728.

    View details for DOI 10.1136/annrheumdis-2012-202775

    View details for Web of Science ID 000323161100005

    View details for PubMedID 23268367

  • Tofacitinib in Combination With Nonbiologic Disease-Modifying Antirheumatic Drugs in Patients With Active Rheumatoid Arthritis A Randomized Trial ANNALS OF INTERNAL MEDICINE Kremer, J., Li, Z., Hall, S., Fleischmann, R., Genovese, M., Martin-Mola, E., Isaacs, J. D., Gruben, D., Wallenstein, G., Krishnaswami, S., Zwillich, S. H., Koncz, T., Riese, R., Bradley, J. 2013; 159 (4): 253-?

    Abstract

    Many patients with rheumatoid arthritis (RA) do not achieve adequate and safe responses with disease-modifying antirheumatic drugs (DMARDs). Tofacitinib is a novel, oral, Janus kinase inhibitor that treats RA.To evaluate the efficacy and safety of tofacitinib in combination with nonbiologic DMARDs.1-year, double-blind, randomized trial (ClinicalTrials.gov: NCT00856544).114 centers in 19 countries.792 patients with active RA despite nonbiologic DMARD therapy.Patients were randomly assigned 4:4:1:1 to oral tofacitinib, 5 mg or 10 mg twice daily, or placebo advanced to tofacitinib, 5 mg or 10 mg twice daily.Primary end points were 20% improvement in American College of Rheumatology (ACR20) criteria; Disease Activity Score for 28-joint counts based on the erythrocyte sedimentation rate (DAS28-4[ESR]) of less than 2.6; DAS28-4(ESR)-defined remission, change in Health Assessment Questionnaire Disability Index (HAQ-DI) score, and safety assessments.Mean treatment differences for ACR20 response rates (month 6) for the 5-mg and 10-mg tofacitinib groups compared with the combined placebo groups were 21.2% (95% CI, 12.2% to 30.3%; P < 0.001) and 25.8% (CI, 16.8% to 34.8%; P < 0.001), respectively. The HAQ-DI scores (month 3) and DAS28-4(ESR) less than 2.6 response rates (month 6) were also superior in the tofacitinib groups versus placebo. The incidence rates of serious adverse events for patients receiving 5-mg tofacitinib, 10-mg tofacitinib, or placebo were 6.9, 7.3, or 10.9 events per 100 patient-years of exposure, respectively. In the tofacitinib groups, 2 cases of tuberculosis, 2 cases of other opportunistic infections, 3 cardiovascular events, and 4 deaths occurred. Neutrophil counts decreased, hemoglobin and low- and high-density lipoprotein cholesterol levels increased, and serum creatinine levels had small increases in the tofacitinib groups.Placebo groups were smaller and of shorter duration. Patients received primarily methotrexate. The ability to assess drug combinations other than tofacitinib plus methotrexate was limited.Tofacitinib improved disease control in patients with active RA despite treatment with nonbiologic DMARDs, primarily methotrexate.Pfizer.

    View details for Web of Science ID 000323421700015

    View details for PubMedID 24026258

  • Golimumab in Patients with Active Rheumatoid Arthritis Despite Methotrexate Therapy: Results Through 2 Years of the GO-FORWARD Study Extension JOURNAL OF RHEUMATOLOGY Keystone, E. C., Genovese, M. C., Hall, S., Miranda, P. C., Bae, S., Palmer, W., Wu, Z., Xu, S., Hsia, E. C. 2013; 40 (7): 1097-1103

    Abstract

    OBJECTIVE: To assess the longterm efficacy and safety of golimumab in patients with active rheumatoid arthritis (RA) despite methotrexate (MTX) therapy. METHODS: We randomized 444 RA patients with inadequate response to MTX (3:3:2:2) to placebo + MTX (Group 1), golimumab 100 mg + placebo (Group 2), golimumab 50 mg + MTX (Group 3), or golimumab 100 mg + MTX (Group 4). Subcutaneous golimumab/placebo was injected every 4 weeks. Patients could escape early (Group 1 added golimumab 50 mg, Group 2 added MTX, Group 3 increased golimumab to 100 mg, Group 4 continued 100 mg) based on Week 16 swollen and tender joint counts. From Week 24, Group 1 patients received golimumab 50 mg + MTX. After the Week 52 database lock, patients in the longterm extension received golimumab 50-100 mg ± MTX. Coprimary endpoints [Week 14 American College of Rheumatology (ACR)20, Week 24 Health Assessment Questionnaire Disability Index (HAQ-DI)] and Week 52 findings have been published; 2-year findings (observed data by randomized group, no imputation) are presented. RESULTS: Of 444 randomized patients, 392 continued from Week 52 (Group 1: n = 116, Group 2: n = 116, Group 3: n = 84, Group 4: n = 76). Clinical improvement was maintained through Week 104; ~75% and 72% of patients randomized to golimumab 50 mg + MTX and 100 mg + MTX achieved ACR20 response, respectively. The majority [88% (105/120)] of golimumab + MTX-treated patients with Week 24 HAQ-DI improvement ? 0.25 maintained improved physical function through Week 104. Group 1 patients with delayed golimumab treatment exhibited more Week 104 radiographic progression (mean change score = 1.15) than golimumab + MTX-randomized patients (0.52). Incidences of serious infections were 2.24, 4.77, 5.78/100 patient-years of followup for golimumab 50 mg + MTX, 100 mg + placebo, and 100 mg + MTX, respectively. CONCLUSION: Clinical improvement was maintained and no new safety signals were identified with 2 years of golimumab + MTX. Golimumab efficacy and safety, including serious infections, will continue to be monitored through 5 years (Clinical Trial No. NCT00264550).

    View details for DOI 10.3899/jrheum.120584

    View details for Web of Science ID 000321993800012

    View details for PubMedID 23678153

  • Novel small molecule therapeutics in rheumatoid arthritis RHEUMATOLOGY Kelly, V., Genovese, M. 2013; 52 (7): 1155-1162

    Abstract

    A new wave of emerging therapies for the treatment of autoimmune and inflammatory diseases is under development. These therapies interrupt intracellular signalling through kinase inhibition. By interrupting one or more kinases it is possible to modulate the function of cellular structures such as surface receptors, signalling proteins and transcription of nuclear proteins and thus influence the behaviour of the cell types targeted. With these advances comes the significant potential to develop highly effective orally bioavailable therapeutics. The targets generating the greatest enthusiasm at this time for the treatment of autoimmune and inflammatory diseases include Janus-associated kinase, spleen tyrosine kinase, phosphodiesterase-4, Bruton's tyrosine kinase and phosphatidylinositol-3 kinase. Ultimately human trials will help us understand the potential risks and benefits of these novel approaches across a number of diseases.

    View details for DOI 10.1093/rheumatology/kes367

    View details for Web of Science ID 000321061200003

    View details for PubMedID 23297340

  • Longterm Safety and Efficacy of Tocilizumab in Patients with Rheumatoid Arthritis: A Cumulative Analysis of Up to 4.6 Years of Exposure JOURNAL OF RHEUMATOLOGY Genovese, M. C., Rubbert-Roth, A., Smolen, J. S., Kremer, J., Khraishi, M., Gomez-Reino, J., Sebba, A., Pilson, R., Williams, S., van Vollenhoven, R. 2013; 40 (6): 768-780

    Abstract

    OBJECTIVE: To assess the longterm safety and efficacy of tocilizumab (TCZ) in patients with moderate to severe rheumatoid arthritis (RA). METHODS: Patient data were from 5 randomized controlled TCZ trials (n = 4211), their open-label extension phases (n = 3512), and a drug interaction study (n = 23). All randomly assigned patients, regardless of previous RA treatment, were analyzed. Measures of safety included number of adverse events (AE), serious AE (SAE), AE leading to treatment discontinuation, laboratory tests, and deaths. Efficacy measures included American College of Rheumatology (ACR) 20/50/70 responses, tender joint count (TJC), swollen joint count (SJC), ACR core set components, and low disease activity (LDA) or Disease Activity Score in 28 joints (DAS28) remission. ACR/European League Against Rheumatism (EULAR) disease remission was a posthoc exploratory analysis. RESULTS: Total duration of observation was 12,293 patient-years (PY). No new safety signals were identified; infections were the most common AE and SAE. The rate of serious infections was 4.5/100 PY. Improvements from baseline in clinical efficacy, measured as ACR20/50/70 responses, TJC, SJC, ACR core set components, and LDA and DAS28 remission, were generally sustained through at least 216 weeks of followup. ACR/EULAR disease remission was attained by 16.5% (Boolean) and 22.7% (index) of patients at Week 216. CONCLUSION: TCZ has to date been studied for up to 4.6 years (240 weeks) of treatment in patients with RA. Our analysis reveals a longer-term safety profile consistent with previous observations, no new safety signals, and durable efficacy of TCZ in a large clinical trial program.

    View details for DOI 10.3899/jrheum.120687

    View details for Web of Science ID 000320009600006

    View details for PubMedID 23457383

  • Efficacy and safety of secukinumab in patients with rheumatoid arthritis: a phase II, dose-finding, double-blind, randomised, placebo controlled study. Annals of the rheumatic diseases Genovese, M. C., Durez, P., Richards, H. B., Supronik, J., Dokoupilova, E., Mazurov, V., Aelion, J. A., Lee, S., Codding, C. E., Kellner, H., Ikawa, T., Hugot, S., Mpofu, S. 2013; 72 (6): 863-869

    Abstract

    To assess the safety and efficacy of secukinumab, a fully human monoclonal anti-interleukin-17A antibody, in patients with rheumatoid arthritis (RA).Patients (n=237) with inadequate response to methotrexate were randomly assigned to receive monthly subcutaneous injections of secukinumab 25 mg, 75 mg, 150 mg, 300 mg or placebo. The primary endpoint was the American College of Rheumatology 20% response (ACR20) at week 16.Demographics and baseline characteristics were comparable across all treatment groups. The primary efficacy endpoint was not achieved: the proportion of ACR20 responders at week 16 with secukinumab 25-300 mg was 36.0-53.7% versus placebo (34%). Disease activity score in 28 joints (DAS28)-C-reactive protein (CRP) was a secondary endpoint and clinically relevant decreases with secukinumab 75-300 mg were reported versus placebo. Serum high sensitivity CRP levels at week 16 were significantly reduced with secukinumab 75 mg, 150 mg and 300 mg doses versus placebo. The safety profile of secukinumab was consistent with that seen with other biological agents. Most adverse events (AE) were mild to moderate in severity. Infections were slightly more frequent with secukinumab than placebo. Six serious AE were reported: secukinumab 75 mg (one), secukinumab 300 mg (four) and placebo (one).ACR20 response rates differed between secukinumab 75 mg, 150 mg and 300 mg doses and placebo; however, the primary efficacy endpoint was not achieved. Greater decreases in DAS28 were observed with secukinumab 75 mg, 150 mg and 300 mg than placebo. There were no unexpected safety signals and no specific organ-related toxicities. Further trials with secukinumab in the treatment of RA are warranted.

    View details for DOI 10.1136/annrheumdis-2012-201601

    View details for PubMedID 22730366

  • Efficacy and Safety of Belimumab in Patients with Rheumatoid Arthritis: A Phase II, Randomized, Double-blind, Placebo-controlled, Dose-ranging Study JOURNAL OF RHEUMATOLOGY Stohl, W., Merrill, J. T., McKay, J. D., Lisse, J. R., Zhong, Z. J., Freimuth, W. W., Genovese, M. C. 2013; 40 (5): 579-589

    Abstract

    To evaluate the efficacy/safety of belimumab in patients with rheumatoid arthritis (RA).Patients fulfilling American College of Rheumatology (ACR) criteria for RA for ? 1 year who had at least moderate disease activity while receiving stable disease-modifying antirheumatic drug (DMARD) therapy and failed ? 1 DMARD were randomly assigned to placebo or belimumab 1, 4, or 10 mg/kg, administered intravenously on Days 1, 14, and 28, and then every 4 weeks for 24 weeks (n = 283). This was followed by an optional 24-week extension (n = 237) in which all patients received belimumab. Primary efficacy endpoint was the Week 24 ACR20 response.Week 24 ACR20 responses with placebo and belimumab 1, 4, and 10 mg/kg were 15.9%, 34.7% (p = 0.010), 25.4% (p = 0.168), and 28.2% (p = 0.080), respectively. Patients taking any belimumab dose who continued with belimumab in the open-label extension had an ACR20 response of 41% at 48 weeks. A similar ACR20 response (42%) at 48 weeks was seen in patients taking placebo who switched in the extension to belimumab 10 mg/kg. Greater response rates were observed in patients who at baseline were rheumatoid factor-positive, anticitrullinated protein antibody-positive, or tumor necrosis factor inhibitor-naive, or had elevated C-reactive protein levels, Disease Activity Score 28 > 5.1, or low B lymphocyte stimulator levels (< 0.858 ng/ml). Adverse event rates were similar across treatment groups.In this phase II trial, belimumab demonstrated efficacy and was generally well tolerated in patients with RA who had failed previous therapies. [ClinicalTrials.gov identifier NCT00071812].

    View details for DOI 10.3899/jrheum.120886

    View details for Web of Science ID 000319171900008

    View details for PubMedID 23547209

  • Immunogenicity, Safety, and Efficacy of Abatacept Administered Subcutaneously With or Without Background Methotrexate in Patients With Rheumatoid Arthritis: Results From a Phase III, International, Multicenter, Parallel-Arm, Open-Label Study ARTHRITIS CARE & RESEARCH Nash, P., Nayiager, S., Genovese, M. C., Kivitz, A. J., Oelke, K., Ludivico, C., Palmer, W., Rodriguez, C., Delaet, I., Elegbe, A., Corbo, M. 2013; 65 (5): 718-728

    Abstract

    To evaluate the impact of concomitant methotrexate (MTX) on subcutaneous (SC) abatacept immunogenicity, and to assess safety and efficacy.This phase III, open-label study had a 4-month short-term (ST) period and an ongoing long-term extension (LTE) period. Rheumatoid arthritis patients were stratified to receive SC abatacept (125 mg/week) with (combination) or without MTX (monotherapy), with no intravenous loading dose; patients receiving monotherapy could add MTX in the LTE period. Immunogenicity (percentage of anti-abatacept antibody-positive patients) was assessed. ST and LTE period data are reported, including efficacy through LTE month 14 and safety through LTE month 20.Ninety-six of 100 enrolled patients completed the ST period; 3.9% (combination) and 4.1% of patients (monotherapy) developed transient immunogenicity, and no patients were antibody positive at month 4. Serious adverse events (SAEs) were reported in 3.9% (combination) and 6.1% of patients (monotherapy); 5.9% (combination) and 8.2% of patients (monotherapy) experienced SC injection reactions, and all were mild in intensity. Mean 28-joint Disease Activity Score (DAS28) changes were -1.67 (95% confidence interval [95% CI] -2.06, -1.28; combination) and -1.94 (95% CI -2.46, -1.42; monotherapy) at month 4. Ninety patients entered and were treated in the LTE period; 83.3% (75 of 90) remained ongoing at month 24. One LTE-treated patient (1.1%) developed immunogenicity, 14.4% of patients experienced SAEs, and no SC injection reactions were reported. For patients entering the LTE period, mean DAS28 changes from baseline were -1.84 (95% CI -2.23, -1.34; combination) and -2.86 (95% CI -3.46, -2.27; monotherapy) at month 18.SC abatacept did not elicit immunogenicity associated with loss of safety or efficacy, either with or without MTX.

    View details for DOI 10.1002/acr.21876

    View details for Web of Science ID 000318114700008

    View details for PubMedID 23097311

  • Effects of Fostamatinib (R788), an Oral Spleen Tyrosine Kinase Inhibitor, on Health-related Quality of Life in Patients with Active Rheumatoid Arthritis: Analyses of Patient-reported Outcomes from a Randomized, Double-blind, Placebo-controlled Trial JOURNAL OF RHEUMATOLOGY Weinblatt, M. E., Kavanaugh, A., Genovese, M. C., Jones, D. A., Musser, T. K., Grossbard, E. B., Magilavy, D. B. 2013; 40 (4): 369-378

    Abstract

    To assess the influence of fostamatinib on patient-reported outcomes (PRO) in patients with active rheumatoid arthritis and an inadequate response to methotrexate (MTX).Patients taking background MTX (N = 457) were enrolled in a phase II clinical trial (NCT00665925) and randomized equally to placebo, fostamatinib 100 mg twice daily (bid), or fostamatinib 150 mg once daily (qd) for 24 weeks. Self-administered PRO measures included pain, patient's global assessment (PtGA) of disease activity, physical function, health-related quality of life (HRQOL), and fatigue. Mean change from baseline and a responder analysis of the proportion of patients achieving a minimal clinically important difference were determined.At Week 24, there were statistically significant improvements in pain, PtGA, physical function, fatigue, and the physical component summary of the Medical Outcomes Study Short Form-36 (SF-36) for fostamatinib 100 mg bid compared with placebo. Mean (standard error) changes from baseline in the fostamatinib 100 mg bid group versus the placebo group were -31.3 (2.45) versus -17.8 (2.45), p < 0.001 for pain; -29.1 (2.26) versus -16.7 (2.42), p < 0.001 for PtGA; -0.647 (0.064) versus -0.343 (0.062), p < 0.001 for physical function; 7.40 (1.00) versus 4.50 (0.94), p < 0.05 for fatigue; 8.52 (0.77) versus 4.90 (0.78), p < 0.01 for SF-36 physical component score; and 3.99 (0.93) versus 3.71 (0.99), p = 0.83 for SF-36 mental component score. Patients receiving fostamatinib 150 mg qd showed improvements in some PRO, including physical function.Patients treated with fostamatinib 100 mg bid showed significant improvements in HRQOL outcomes.

    View details for DOI 10.3899/jrheum.120923

    View details for Web of Science ID 000317540600007

    View details for PubMedID 23378467

  • Tabalumab in Rheumatoid Arthritis Patients With an Inadequate Response to Methotrexate and Naive to Biologic Therapy: A Phase II, Randomized, Placebo-Controlled Trial ARTHRITIS AND RHEUMATISM Genovese, M. C., Bojin, S., Biagini, I. M., Mociran, E., Cristei, D., Mirea, G., Georgescu, L., Sloan-Lancaster, J. 2013; 65 (4): 880-889

    Abstract

    Tabalumab, a fully human IgG4 monoclonal antibody, neutralizes soluble and membrane-bound BAFF. The aim of this study was to examine the tolerability and efficacy of tabalumab in patients with active rheumatoid arthritis receiving methotrexate.In this randomized, double-blind, placebo-controlled, parallel, multiple-dose study, patients who were naive to biologic therapy received infusions of tabalumab (30, 60, or 160 mg) or placebo at weeks 0, 3, and 6 in combination with methotrexate and were evaluated for 24 weeks. The primary efficacy end point was the percentage of patients meeting American College of Rheumatology 20% improvement criteria (achieving an ACR20 response) at week 16.At week 16, the percentages of patients achieving an ACR20 response in the 30-mg (57.6%), 60-mg (67.6%), and 160-mg (51.5%) groups were significantly greater than the percentage of patients achieving an ACR20 response in the placebo group (29.4%; P<0.05). There were initial transient increases from baseline in the frequency of CD20+ and IgD+/CD27- B cells, followed by reductions, although B cells were not completely depleted. Also, the frequency of IgD-/CD27+ B cells increased in all tabalumab groups compared with the placebo group and returned toward baseline levels by the end of the study. The incidence of adverse events was similar across all treatment groups; no deaths occurred. Serum IgM levels decreased significantly in all tabalumab groups combined compared with the placebo group. There were no significant decreases in serum IgG or IgA levels in the tabalumab groups compared with the placebo group.Tabalumab treatment significantly reduces the signs and symptoms of rheumatoid arthritis and has a safety profile similar to that seen with placebo treatment.

    View details for DOI 10.1002/art.37820

    View details for Web of Science ID 000316962000006

    View details for PubMedID 23359344

  • Tocilizumab as Monotherapy or in Combination With Nonbiologic Disease-Modifying Antirheumatic Drugs: Twenty-Four-Week Results of an Open-Label, Clinical Practice Study ARTHRITIS CARE & RESEARCH Weinblatt, M. E., Kremer, J., Cush, J., Rigby, W., Teng, L. L., Devenport, J., Singh, N., Lepley, D., Genovese, M. C. 2013; 65 (3): 362-371

    Abstract

    To assess the safety and tolerability of tocilizumab (TCZ) as monotherapy or in combination with nonbiologic disease-modifying antirheumatic drugs (DMARDs) in patients with moderate to severe rheumatoid arthritis (RA) who had an inadequate response at study entry to their current treatment with biologic agents or DMARDs.This 24-week, multicenter, open-label, phase IIIb study conducted in the US enrolled 886 patients. Treatments were allocated to patients based on their current therapy at study entry. Patients receiving monotherapy with biologic agents were assigned to TCZ 8 mg/kg monotherapy. All other patients were randomized to either TCZ 4 mg/kg + DMARDs or TCZ 8 mg/kg + DMARDs. The primary end point was the number and percentage of patients with serious adverse events (SAEs) during 24 weeks of TCZ treatment. Efficacy assessments were evaluated as secondary outcomes. Data were analyzed descriptively.Overall, 69 patients (7.8%) reported ?1 SAEs. The rate of SAEs per 100 person-years was 28.3 (95% confidence interval [95% CI] 23.1-34.4) overall and was similar across treatment groups: 29.1 (95% CI 21.0-39.2), 30.3 (95% CI 22.2-40.2), and 20.6 (95% CI 10.3-36.9) in the TCZ 4/8 mg/kg + DMARDs, TCZ 8 mg/kg + DMARDs, and TCZ 8 mg/kg monotherapy groups, respectively. The most common SAEs were infections (i.e., pneumonia [1.0%] and cellulitis [0.9%]). In addition, American College of Rheumatology response rates and reductions in mean Disease Activity Score based on a 28-joint count were generally similar among treatment groups.The safety findings in this study were consistent with the previously identified safety profile of TCZ. TCZ had an AE profile consistent with prior randomized blinded studies and was effective when administered as either monotherapy or in combination with DMARDs for the treatment of RA.

    View details for DOI 10.1002/acr.21847

    View details for Web of Science ID 000316907700004

    View details for PubMedID 22972745

  • Effects of sclerostin antibody on healing of a non-critical size femoral bone defect JOURNAL OF ORTHOPAEDIC RESEARCH Jawad, M. U., Fritton, K. E., Ma, T., Ren, P., Goodman, S. B., Ke, H. Z., Babij, P., Genovese, M. C. 2013; 31 (1): 155-163

    Abstract

    Sclerostin is a glycoprotein secreted by osteocytes and inhibits osteoblastogenesis via inhibition of Wnt signaling. We hypothesized that sclerostin antibody (Scl-AbIII) would accelerate the healing of a murine femoral non-critical size bone defect model. A unilateral and unicortical 0.8?mm-sized drill hole was made in the proximal femoral shaft of adult female nude mice. One group of mice received subcutaneous injections of Scl-AbIII and a second group received vehicle only. Reporter MC3T3 osteoprogenitor cells were injected via the tail vein 3 days after surgery to monitor systemic trafficking of exogenous osteoprogenitors. Bioluminescence imaging (BLI), microcomputed tomography (microCT), micropositron emission tomography (microPET) and histological analysis were used to compare the bone healing responses to Scl-AbIII treatment. Bone mineral density (BMD) significantly increased at the defect site after week 1, and was significantly higher in the treatment compared with the control group at all time points. This finding was also confirmed on histological analysis by increased deposition of new woven bone. MicroPET scanning showed a trend for greater activity in the control group at day 21 compared with the Scl-AbIII group, indicating early bone maturation following treatment with Scl-AbIII. Whereas the BLI signals derived from the injected osteoprogenitor cells showed no differences between vehicle and Scl-AbIII treated groups, systemic migration of MC3T3 cells to the bone defect was clearly identified in both groups using immunohistochemistry. Systemic administration of Scl-AbIII resulted in earlier healing and maturation of a non-critical size bone defect. These findings underscore the potential use of Scl-AbIII for treatment of complicated fractures, non-unions, and other clinical scenarios.

    View details for DOI 10.1002/jor.22186

    View details for Web of Science ID 000311568700022

    View details for PubMedID 22887736

  • Subcutaneous Abatacept: Long-Term Data From the Acquire Trial Genovese, M. C., Pacheco-Tena, C., Covarrubias, A., LEON, G., Mysler, E., Keiserman, M., Valente, R., Nash, P., Simon-Campos, J. A., Box, J., Legerton, C., Nasonov, E., Durez, P., Delaet, I., Alten, R. WILEY-BLACKWELL. 2012: S201-S201
  • Prolonged Exposure to Subcutaneous and Intravenous Abatacept in Patients with Rheumatoid Arthritis Does Not Affect Rates of Infection, Malignancy and Autoimmune Events: Results From Pooled Clinical Trial Data. Genovese, M. C., Hochberg, M. C., Cohen, R. B., Weinblatt, M. E., Kaine, J., Keystone, E., Nash, P., Delaet, I., Alten, R. WILEY-BLACKWELL. 2012: S725-S725
  • Longterm Safety and Efficacy of Abatacept Through 5 Years of Treatment in Patients with Rheumatoid Arthritis and an Inadequate Response to Tumor Necrosis Factor Inhibitor Therapy JOURNAL OF RHEUMATOLOGY Genovese, M. C., Schiff, M., Luggen, M., Le Bars, M., Aranda, R., Elegbe, A., DougadoS, M. 2012; 39 (8): 1546-1554

    Abstract

    To evaluate abatacept safety and efficacy over 5 years in patients with rheumatoid arthritis (RA) who had inadequate response to anti-tumor necrosis factor (TNF) therapy in the ATTAIN trial.Patients completing the 6-month, double-blind (DB) placebo-controlled period were eligible to enter the longterm extension (LTE), where all patients received abatacept every 4 weeks (?10 mg/kg, according to weight range). Safety, efficacy, physical function, and health-related quality of life were monitored throughout.In total, 317 patients (218 DB abatacept, 99 DB placebo) entered the LTE; 150 (47.3%) completed it. Overall incidences of serious adverse events, infections, serious infections, malignant neoplasms, and autoimmune events did not increase during the LTE versus the DB period. American College of Rheumatology responses with abatacept at Month 6 were maintained over 5 years. At Year 5, among patients who received abatacept for 5 years and had available data, 38/103 (36.9%) achieved low disease activity as defined by the 28-joint Disease Activity Score (DAS28)/C-reactive protein (CRP); 23/103 (22.3%) achieved DAS28/CRP-defined remission. Health Assessment Questionnaire response was achieved by 62.5% of patients remaining on treatment at Year 5; mean improvements from baseline in physical component summary and mental component summary scores were 7.34 and 6.42, respectively. High proportions of patients maintained efficacy and physical function benefits or improved their disease state at each timepoint throughout the LTE, if remaining on abatacept treatment.Safety remained consistent, and abatacept efficacy was maintained from 6 months to 5 years, demonstrating the benefits of switching to abatacept in this difficult-to-treat population of patients with RA previously failing anti-TNF therapy.

    View details for DOI 10.3899/jrheum.111531

    View details for Web of Science ID 000307795800010

    View details for PubMedID 22798265

  • Effect of Golimumab on Patient-reported Outcomes in Rheumatoid Arthritis: Results from the GO-FORWARD Study JOURNAL OF RHEUMATOLOGY Genovese, M. C., Han, C., Keystone, E. C., Hsia, E. C., Buchanan, J., Gathany, T., Murphy, F. T., Wu, Z., Parasuraman, S., Rahman, M. U. 2012; 39 (6): 1185-1191

    Abstract

    To evaluate the effect of golimumab on physical function, general health, and fatigue in patients with active rheumatoid arthritis (RA) despite methotrexate (MTX) therapy.In the multicenter, randomized, placebo-controlled GO-FORWARD study, 444 adults with active RA despite MTX received subcutaneous placebo + MTX (crossover to golimumab 50 mg at Week 24), golimumab 100 mg + placebo, golimumab 50 mg + MTX, or golimumab 100 mg + MTX every 4 weeks. Physical function and general health were assessed using the Health Assessment Questionnaire-Disability Index (HAQ-DI) and Physical and Mental Component Summary (PCS, MCS) scores of the Medical Outcomes Study Short Form-36 questionnaire (SF-36), respectively, through Week 52. Fatigue was measured through Week 24 using the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) questionnaire.Mean improvements from baseline in HAQ-DI, SF-36 PCS, and FACIT-Fatigue scores (Weeks 14 and 24) were significantly greater for golimumab 50 mg + MTX and 100 mg + MTX versus placebo + MTX. Significantly greater proportions of patients treated with golimumab + MTX achieved clinically meaningful improvements from baseline to Weeks 14 and 24 in HAQ-DI, PCS, and FACIT-Fatigue scores. Mean improvements in SF-36 PCS (Week 14), MCS (Week 24), and FACIT-Fatigue (Weeks 14 and 24) scores were significantly greater for golimumab 100 mg + placebo versus placebo + MTX. Mean improvements from baseline in HAQ-DI, SF-36 PCS, and MCS scores through Week 24 were sustained through Week 52.Patients with active RA despite MTX had significant improvement in physical function, general health, and fatigue following golimumab + MTX therapy; improvements in physical function and general health were maintained through Week 52. (Clinical Trials Registration NCT00264550).

    View details for DOI 10.3899/jrheum.111195

    View details for Web of Science ID 000304893800015

    View details for PubMedID 22505702

  • SAFETY PROFILE OF SUBCUTANEOUS ABATACEPT FOCUSING ON CLINICALLY RELEVANT EVENTS IN PATIENTS WITH RHEUMATOID ARTHRITIS AND UP TO 4.5 YEARS OF EXPOSURE Alten, R., Kaine, J. L., Keystone, E., Nash, P. T., Delaet, I., Qi, K., Genovese, M. C. OXFORD UNIV PRESS. 2012: 127-128
  • Phase IIb dose-ranging study of the oral JAK inhibitor tofacitinib (CP-690,550) or adalimumab monotherapy versus placebo in patients with active rheumatoid arthritis with an inadequate response to disease-modifying antirheumatic drugs ARTHRITIS AND RHEUMATISM Fleischmann, R., Cutolo, M., Genovese, M. C., Lee, E. B., Kanik, K. S., Sadis, S., Connell, C. A., Gruben, D., Krishnaswami, S., Wallenstein, G., Wilkinson, B. E., Zwillich, S. H. 2012; 64 (3): 617-629

    Abstract

    To compare the efficacy, safety, and tolerability of 5 doses of oral tofacitinib (CP-690,550) or adalimumab monotherapy with placebo for the treatment of active rheumatoid arthritis (RA) in patients with an inadequate response to disease-modifying antirheumatic drugs.In this 24-week, double-blind, phase IIb study, patients with RA (n = 384) were randomized to receive placebo, tofacitinib at 1, 3, 5, 10, or 15 mg administered orally twice a day, or adalimumab at 40 mg injected subcutaneously every 2 weeks (total of 6 injections) followed by oral tofacitinib at 5 mg twice a day for 12 weeks. The primary end point was the responder rate according to the American College of Rheumatology 20% improvement criteria (ACR20) at week 12.Treatment with tofacitinib at a dose of ?3 mg twice a day resulted in a rapid response with significant efficacy when compared to placebo, as indicated by the primary end point (ACR20 response at week 12), achieved in 39.2% (3 mg; P ? 0.05), 59.2% (5 mg; P < 0.0001), 70.5% (10 mg; P < 0.0001), and 71.9% (15 mg; P < 0.0001) in the tofacitinib group and 35.9% of patients in the adalimumab group (P = 0.105), compared with 22.0% of patients receiving placebo. Improvements were sustained at week 24, according to the ACR20, ACR50, and ACR70 response rates as well as classifications of remission according to the 3-variable Disease Activity Score in 28 joints (DAS28) using C-reactive protein and the 4-variable DAS28 using the erythrocyte sedimentation rate. The most common treatment-emergent adverse events (AEs) in patients across all tofacitinib treatment arms (n = 272) were urinary tract infection (7.7%), diarrhea (4.8%), headache (4.8%), and bronchitis (4.8%).Tofacitinib monotherapy at ?3 mg twice a day was efficacious in the treatment of patients with active RA over 24 weeks and demonstrated a manageable safety profile.

    View details for DOI 10.1002/art.33383

    View details for Web of Science ID 000300835900005

    View details for PubMedID 21952978

  • Safety and efficacy of ocrelizumab in patients with rheumatoid arthritis and an inadequate response to at least one tumor necrosis factor inhibitor: Results of a forty-eight-week randomized, double-blind, placebo-controlled, parallel-group phase III trial ARTHRITIS AND RHEUMATISM Tak, P. P., Mease, P. J., Genovese, M. C., Kremer, J., Haraoui, B., Tanaka, Y., Bingham, C. O., Ashrafzadeh, A., Travers, H., Safa-Leathers, S., Kumar, S., Dummer, W. 2012; 64 (2): 360-370

    Abstract

    To evaluate the safety and efficacy of ocrelizumab plus methotrexate (MTX) or leflunomide (LEF) in patients with active rheumatoid arthritis (RA) and an inadequate response to tumor necrosis factor ? inhibitors.This was a multicenter randomized, double-blind, placebo-controlled, parallel-group study that continued over 48 weeks. Patients receiving stable doses of MTX or LEF were randomized to receive 2 infusions of placebo (n = 277), ocrelizumab 200 mg (n = 278), or ocrelizumab 500 mg (n = 285) on days 1 and 15 as well as at weeks 24 and 26. Coprimary end points were the proportion of patients with response according to the American College of Rheumatology 20% improvement criteria (ACR20) at weeks 24 and 48. Secondary end points included the change from baseline in the modified Sharp/van der Heijde score (SHS) and the ACR50/70 responses.ACR20 responses were 22.0% in the placebo group, 42.2% in the ocrelizumab 200 mg group, and 47.9% in the ocrelizumab 500 mg group at 24 weeks and 19.5%, 48.7%, and 50.7%, respectively, at 48 weeks (P < 0.0001 versus placebo for each comparison at each time point). At 48 weeks, patients receiving both doses of ocrelizumab showed significantly improved ACR50 and ACR70 responses of ~3-fold versus placebo. Only those in the ocrelizumab 500 mg group showed statistically significant (P = 0.0017) inhibition of joint damage progression (mean change in the SHS) relative to placebo (61% inhibition) at 48 weeks. Overall adverse events and infections during the 48 weeks of study were comparable in all treatment groups. Serious infections were observed more frequently in patients taking ocrelizumab (5.1% and 4.3%) than in those taking placebo (2.5%).Patients in both of the ocrelizumab groups met the clinical primary efficacy end points. Inhibition of change in the SHS was statistically significant at 48 weeks for those in the ocrelizumab 500 mg group. The rate of serious infections in this trial was higher for both ocrelizumab doses as compared with placebo.

    View details for DOI 10.1002/art.33353

    View details for Web of Science ID 000299625700006

    View details for PubMedID 22389919

  • Exploratory analyses of the association of MRI with clinical, laboratory and radiographic findings in patients with rheumatoid arthritis ANNALS OF THE RHEUMATIC DISEASES Emery, P., van der Heijde, D., Ostergaard, M., Conaghan, P. G., Genovese, M. C., Keystone, E. C., Fleischmann, R., Hsia, E. C., Xu, W., Xu, S., Rahman, M. U. 2011; 70 (12): 2126-2130

    Abstract

    Evaluate relationships between MRI and clinical/laboratory/radiographic findings in rheumatoid arthritis (RA).637 methotrexate-naive patients (GO-BEFORE) and 444 patients with active RA despite methotrexate (GO-FORWARD) were randomly assigned to subcutaneous placebo + methotrexate, golimumab 100mg + placebo, golimumab 50mg + methotrexate, or golimumab 100mg + methotrexate every-4-weeks. In GO-BEFORE(n=318) and GO-FORWARD(n=240) substudies, MRI of dominant wrist/metacarpophalangeal joints were scored for synovitis, bone oedema and bone erosion (RA MRI scoring (RAMRIS) system). Relationships between RAMRIS scores and serum C-reactive protein (CRP), 28-joint count disease activity score (DAS28-CRP) and van der Heijde modified Sharp (vdH-S) scores were assessed.Baseline and weeks 24/28 DAS28-CRP, CRP, and vdH-S generally correlated well with baseline and week 24 RAMRIS synovitis, oedema and erosion scores. Early (week 4) CRP changes correlated with later (week 12) RAMRIS synovitis/oedema change scores; earlier (week 12) changes in some RAMRIS scores correlated with later (weeks 24/28) changes in vdH-S. Significant correlations between RAMRIS change scores and clinical/radiographic change scores were weak.MRI and clinical/laboratory/radiographic measures generally correlated well. Associations between earlier changes in CRP and later changes in RAMRIS synovitis/osteitis were observed. Changes in MRI and clinical/radiographic measures did not correlate well, probably because MRI is more sensitive than radiographs and more objective than DAS28-CRP.

    View details for DOI 10.1136/ard.2011.154500

    View details for Web of Science ID 000297571900011

    View details for PubMedID 21926186

  • Assessment by MRI of inflammation and damage in rheumatoid arthritis patients with methotrexate inadequate response receiving golimumab: results of the GO-FORWARD trial ANNALS OF THE RHEUMATIC DISEASES Conaghan, P. G., Emery, P., Ostergaard, M., Keystone, E. C., Genovese, M. C., Hsia, E. C., Xu, W., Rahman, M. U. 2011; 70 (11): 1968-1974

    Abstract

    To evaluate golimumab's effect on MRI-detected inflammation and structural damage in patients with active rheumatoid arthritis (RA) despite methotrexate (MTX).Patients (n=444) were randomly assigned to placebo plus MTX, golimumab 100 mg plus placebo, golimumab 50 mg plus MTX, or golimumab 100 mg plus MTX (subcutaneous injections every 4 weeks). A subset of 240 patients participated in an MRI substudy. MRIs (1.5T+contrast enhancement) of the dominant wrist and metacarpophalangeal (MCP) joints were obtained at baseline and weeks 12 and 24. Images were scored by two independent, blinded readers for synovitis (0-9 wrist only (n=240), 0-21 wrist+MCP (n=223)), bone oedema (osteitis) (0-69) and bone erosions (0-230) using the OMERACT Rheumatoid Arthritis MRI Scoring system.Significant improvements in synovitis and bone oedema (osteitis) were observed in the combined golimumab plus MTX groups versus placebo plus MTX at week 12 (-1.77 vs -0.15, p<0.001 wrist+MCP and -2.00 vs 0.19, p=0.003, respectively) and week 24 (-1.91 vs -0.38, p<0.001 wrist+MCP and -1.74 vs 0.71, p=0.004, respectively). Fewer than 10% of patients had a substantial degree of erosive progression (most showed no progression) across all treatment groups (including the control group), precluding adequate evaluation of golimumab's effect on bone erosions.Golimumab plus MTX significantly improved MRI-detected synovitis and osteitis (prognosticators of future structural damage) versus placebo plus MTX at weeks 12 and 24. The effect of golimumab on bone erosions could not be determined by semi-quantitative scoring in these RA patients with minimal progression of bone erosions.

    View details for DOI 10.1136/ard.2010.146068

    View details for Web of Science ID 000295399700015

    View details for PubMedID 21784729

  • Subcutaneous Abatacept Versus Intravenous Abatacept A Phase IIIb Noninferiority Study in Patients With an Inadequate Response to Methotrexate ARTHRITIS AND RHEUMATISM Genovese, M. C., Covarrubias, A., LEON, G., Mysler, E., Keiserman, M., Valente, R., Nash, P., Simon-Campos, J. A., PORAWSKA, W., Box, J., Legerton, C., Nasonov, E., Durez, P., Aranda, R., Pappu, R., Delaet, I., Teng, J., Alten, R. 2011; 63 (10): 2854-2864

    Abstract

    To compare the efficacy and safety of subcutaneous (SC) and intravenous (IV) abatacept.In this phase IIIb double-blind, double-dummy, 6-month study, patients with rheumatoid arthritis (RA) and inadequate responses to methotrexate were randomized to receive 125 mg SC abatacept on days 1 and 8 and weekly thereafter (plus an IV loading dose [?10 mg/kg] on day 1) or IV abatacept (?10 mg/kg) on days 1, 15, and 29 and every 4 weeks thereafter. The primary end point for determining the noninferiority of SC abatacept to IV abatacept was the proportion of patients in each group meeting the American College of Rheumatology 20% improvement criteria (achieving an ACR20 response) at month 6. Other efficacy end points, immunogenicity, and safety were also assessed.Of 1,457 patients, 693 of 736 (94.2%) treated with SC abatacept and 676 of 721 (93.8%) treated with IV abatacept completed 6 months. At month 6, 76.0% (95% confidence interval 72.9, 79.2) of SC abatacept-treated patients versus 75.8% (95% confidence interval 72.6, 79.0) of IV abatacept-treated patients achieved an ACR20 response (estimated difference between groups 0.3% [95% confidence interval -4.2, 4.8]), confirming noninferiority of SC abatacept to IV abatacept. Onset and magnitude of ACR responses and disease activity and physical function improvements were comparable between the SC and IV abatacept-treated groups. The proportions of adverse events (AEs) and serious AEs over 6 months were 67.0% and 4.2%, respectively, in the SC abatacept-treated group and 65.2% and 4.9%, respectively, in the IV abatacept-treated group, with comparable frequencies of serious infections, malignancies, and autoimmune events between groups. SC injection site reactions (mostly mild) occurred in 19 SC abatacept (IV placebo)-treated patients (2.6%) and 18 IV abatacept (SC placebo)-treated patients (2.5%). Abatacept-induced antibodies occurred in 1.1% of SC abatacept-treated patients and 2.3% of IV abatacept-treated patients.SC abatacept provides efficacy and safety comparable with that of IV abatacept, with low immunogenicity and high retention rates, consistent with the established IV abatacept profile. Rates of injection site reactions were low. SC abatacept will provide additional treatment options, such as an alternative route of administration, for patients with RA.

    View details for DOI 10.1002/art.30463

    View details for Web of Science ID 000295293000004

    View details for PubMedID 21618201

  • Safety Profile of Subcutaneous Abatacept Focusing on Clinically Relevant Events in Patients with Rheumatoid Arthritis (RA) and up to 4.5 Years of Exposure. Alten, R., Kaine, J. L., Keystone, E., Nash, P. T., Delaet, I., Qi, K., Genovese, M. C. WILEY-BLACKWELL. 2011: S150-S151
  • Subcutaneous (SC) Abatacept (ABA) Versus Intravenous (IV) ABA in Patients (pts) with Rheumatoid Arthritis: Long-Term Data From the ACQUIRE (Abatacept Comparison of Sub[QU]cutaneous versus Intravenous in Inadequate Responders to MethotrexatE) Trial. Genovese, M. C., Covarrubias Cobos, A., Leon, G., Mysler, E. F., Keiserman, M. W., Valente, R. M., Nash, P. T., Simon Campos, J. A., Porawska, W., Box, J. H., Legerton, C. W., Nasonov, E. L., Durez, P., Pappu, R., Delaet, I., Teng, J., Alten, R. WILEY-BLACKWELL. 2011: S150-S150
  • Atacicept in Patients With Rheumatoid Arthritis and an Inadequate Response to Tumor Necrosis Factor Antagonist Therapy Results of a Phase II, Randomized, Placebo-Controlled, Dose-Finding Trial ARTHRITIS AND RHEUMATISM Genovese, M. C., Kinnman, N., de La Bourdonnaye, G., Rossi, C. P., Tak, P. P. 2011; 63 (7): 1793-1803

    Abstract

    To assess the efficacy, safety, and biologic activity of atacicept in patients with rheumatoid arthritis (RA) in whom the response to treatment with tumor necrosis factor antagonists was inadequate.The Atacicept for Reduction of Signs and Symptoms in Rheumatoid Arthritis Trial (AUGUST I) was a multicenter, phase II, double-blind, placebo-controlled dose-finding study involving 256 patients randomized 1:1:1:1 to receive atacicept (25 mg, 75 mg, or 150 mg) or placebo twice weekly for 4 weeks, then weekly for 21 weeks, with a 13-week treatment-free followup period (week 38). The primary end point was a response at week 26 according to the American College of Rheumatology criteria for 20% improvement in disease severity, using the C-reactive protein level.No statistically significant differences were observed in the efficacy end points at week 26 (P = 0.410 for overall treatment effect). However, atacicept significantly reduced immunoglobulin and rheumatoid factor (RF) levels, but not anti-citrullinated protein antibody levels, in a dose-dependent manner, with levels returning toward baseline values during followup. The effects of treatment on IgG-RF and IgA-RF were more pronounced than the effects on total IgG and IgA. Adverse events (AEs), including serious AEs, leading to withdrawal were more common among patients treated with atacicept compared with placebo. AEs were variable in nature, and no dose-dependent trends were observed. The frequency of infection-related AEs was similar across treatments. No notable effect of treatment on immunization status (protective versus nonprotective titer) was observed after initiation of treatment.This study did not meet the primary efficacy end point. However, clear biologic activity consistent with the proposed mechanism of action was observed. The results suggest that decreasing the expression of RF may not be sufficient to induce clinical improvement in RA. The safety of atacicept was considered acceptable in this patient population.

    View details for DOI 10.1002/art.30373

    View details for Web of Science ID 000292809700007

    View details for PubMedID 21452293

  • THE EFFICACY AND SAFETY OF SUBCUTANEOUS (SC) ABATACEPT (ABA) WITH OR WITHOUT MTX IN PATIENTS WITH ACTIVE RA Nash, P., Nayiager, S., Genovese, M., Rodriguez, C., Delaet, I., Elegbe, A., Corbo, M., Bamford, T. WILEY-BLACKWELL. 2011: 15-15
  • The Effects of Golimumab on Radiographic Progression in Rheumatoid Arthritis Results of Randomized Controlled Studies of Golimumab Before Methotrexate Therapy and Golimumab After Methotrexate Therapy ARTHRITIS AND RHEUMATISM Emery, P., Fleischmann, R., van der Heijde, D., Keystone, E. C., Genovese, M. C., Conaghan, P. G., Hsia, E. C., Xu, W., Baratelle, A., Beutler, A., Rahman, M. U. 2011; 63 (5): 1200-1210

    Abstract

    To evaluate the effects of golimumab on radiographic progression in patients with rheumatoid arthritis (RA).Methotrexate (MTX)-naive patients (in the Golimumab Before Employing Methotrexate as theFirst-Line Option in the Treatment of Rheumatoid Arthritis of Early Onset [GO-BEFORE] study; n = 637)and patients with active RA despite MTX therapy (in the Golimumab in Active Rheumatoid Arthritis Despite Methotrexate Therapy [GO-FORWARD] study; n =444) were randomly assigned to receive placebo plus MTX (group 1), golimumab 100 mg plus placebo (group 2), golimumab 50 mg plus MTX (group 3), or golimumab 100 mg plus MTX (group 4). Golimumab orplacebo was administered subcutaneously every 4 weeks. Radiographs of the hands and feet were taken at baseline, week 28, and week 52 in the GO-BEFORE study and at baseline, week 24 (week 16 for patients who entered early escape), and week 52 in the GO-FORWARD study. Radiographs were scored by 2 independent readers in each study using the van der Heijde modification of the Sharp score.In the GO-BEFORE study, the mean ± SD changes in the modified Sharp score from base line to week 52 (control period) were 1.4 ± 4.6 in group 1, 1.3 ± 6.2 in group 2 (P = 0.266), 0.7 ± 5.2 in group 3 (P = 0.015), and 0.1 ± 1.8 in group 4 (P = 0.025). In the GO-FORWARD study, changes from baseline to week 24 (control period) were 0.6 ± 2.4 in group 1, 0.3 ± 1.6 in group 2 (P = 0.361), 0.6 ± 2.7 in group 3 (P = 0.953), and 0.2 ± 1.3 in group 4 (P = 0.293).Golimumab in combination with MTX inhibited radiographic progression significantly better than did MTX alone in the GO-BEFORE study. Radiographic progression in the GO-FORWARD study was minimal in all treatment arms, precluding an adequate assessment of the effect of golimumab on radiographic progression in this study.

    View details for DOI 10.1002/art.30263

    View details for Web of Science ID 000290609800007

    View details for PubMedID 21305524

  • THE EFFICACY AND SAFETY OF SUBCUTANEOUS (SC) ABATACEPT (ABA) IS CONSISTENT WITH THE ESTABLISHED INTRAVENOUS (IV) PROFILE IN A STUDY OF 1457 PATIENTS WITH RA AND AN INADEQUATE RESPONSE TO MTX (MTX-IR) Nash, P., Genovese, M., COVARRUBIAS, J., LEON, G., Mysler, E., Keiserman, M., Valante, R., Simon, J., PORAWSKA, W., Box, J., Leggerton, C., Nasonov, E., Durez, P., Aranda, R., Pappau, R., Delaet, I., Teng, J., Alten, R., Bamford, T. WILEY-BLACKWELL. 2011: 16-16
  • A 24-Week, Randomized, Double-Blind, Placebo-Controlled, Parallel Group Study of the Efficacy of Oral SCIO-469, a p38 Mitogen-activated Protein Kinase Inhibitor, in Patients with Active Rheumatoid Arthritis JOURNAL OF RHEUMATOLOGY Genovese, M. C., Cohen, S. B., Wofsy, D., Weinblatt, M. E., Firestein, G. S., Brahn, E., Strand, V., Baker, D. G., Tong, S. E. 2011; 38 (5): 846-854

    Abstract

    To evaluate the efficacy, safety, and tolerability of oral SCIO-469, a p38 MAPK inhibitor that blocks tumor necrosis factor-?, interleukin-1ß, and cyclooxygenase-2 synthesis in patients with active rheumatoid arthritis (RA).Patients were randomized to receive SCIO-469 at either 30 or 60 mg three times daily in an immediate-release (IR) formulation or at 100 mg once daily in an extended-release (ER) formulation, or placebo for 24 weeks. The primary endpoint was American College of Rheumatology (ACR)20 response at Week 12. Safety was monitored through Week 26.Overall, 302 patients were randomized: 76 to placebo, 75 to 30 mg IR, 73 to 60 mg IR, and 78 to 100 mg ER. There were no significant differences in ACR20 responses at Week 12 between SCIO-469 and placebo. Declines in C-reactive protein and erythrocyte sedimentation rate during early treatment did not persist to Week 12 and were not a consequence of decreased SCIO-469 plasma levels. The 60 mg IR regimen showed a dose-limiting toxicity manifested by elevations in alanine aminotransferase. Adverse events were common in all groups (79.7% and 86.7% through 13 and 26 weeks, respectively). Twenty-one patients reported 28 serious adverse events (SAE). SAE were more common with IR SCIO-469 than with placebo (7% vs 4%) but were not reported with ER SCIO-469.In all regimens tested, SCIO-469 showed no greater efficacy compared to placebo in patients with RA. The transient effect of SCIO-469 on acute-phase reactants suggests a complex role of p38 MAPK in inflammation.

    View details for DOI 10.3899/jrheum.100602

    View details for Web of Science ID 000290780700010

    View details for PubMedID 21285160

  • Abatacept in the Treatment of Patients With Psoriatic Arthritis ARTHRITIS AND RHEUMATISM Mease, P., Genovese, M. C., Gladstein, G., Kivitz, A. J., Ritchlin, C., Tak, P. P., Wollenhaupt, J., Bahary, O., Becker, J., Kelly, S., Sigal, L., Teng, J., Gladman, D. 2011; 63 (4): 939-948

    Abstract

    To assess the safety and efficacy of abatacept, a selective T cell costimulation modulator, in patients with psoriatic arthritis (PsA).In this 6-month, multicenter, randomized, double-blind, placebo-controlled, phase II study, 170 PsA patients with a psoriasis target lesion (TL) ?2 cm who had previously taken disease-modifying antirheumatic drugs (DMARDs), including anti-tumor necrosis factor (anti-TNF) agents, were randomized (1:1:1:1) to receive placebo or abatacept at doses of 3 mg/kg, 10 mg/kg, or 30/10 mg/kg (2 initial doses of 30 mg/kg, followed by 10 mg/kg) on days 1, 15, and 29 and then once every 28 days thereafter. The primary end point was the American College of Rheumatology 20% criteria for improvement (ACR20 response) on day 169. Other key end points were magnetic resonance imaging (MRI) scores for joint erosion, osteitis, and synovitis, scores on the Health Assessment Questionnaire (HAQ) and the Short Form-36 (SF-36) health survey, the investigator's global assessment of psoriasis, the TL score, and the Psoriasis Area and Severity Index (PASI) score.Proportions of patients achieving an ACR20 response were 19%, 33%, 48%, and 42% in the placebo, the abatacept 3 mg/kg, the abatacept 10 mg/kg, and the abatacept 30/10 mg/kg groups, respectively. Compared with placebo, improvements were significantly higher for the abatacept 10 mg/kg (P = 0.006) and 30/10 mg/kg (P = 0.022) groups, but not for 3 mg/kg group (P = 0.121). All abatacept regimens resulted in improved MRI, HAQ, and SF-36 scores, with 10 mg/kg showing the greatest improvements. Improvements in the TL and PASI scores were observed in all abatacept arms; a response according to the investigator's global assessment was seen only with 3 mg/kg of abatacept. The safety profiles were similar among the treatment arms.The results of this study suggest that 10 mg/kg of abatacept, the approved dosage for rheumatoid arthritis and juvenile idiopathic arthritis, may be an effective treatment option for PsA.

    View details for DOI 10.1002/art.30176

    View details for Web of Science ID 000289421100013

    View details for PubMedID 21128258

  • SAFETY, EFFICACY AND HEALTH-RELATED QUALITY OF LIFE THROUGH 5 YEARS OF ABATACEPT TREATMENT IN PATIENTS WITH RHEUMATOID ARTHRITIS AND AN INADEQUATE RESPONSE TO ANTI-TUMOUR NECROSIS FACTOR THERAPY Genovese, M. C., Schiff, M., Luggen, M., Le Bars, M., Becker, J., Aranda, R., Li, T., Elegbe, A., DougadoS, M. OXFORD UNIV PRESS. 2011: 123-123
  • Safety and Efficacy of Etanercept Beyond 10 Years of Therapy in North American Patients With Early and Longstanding Rheumatoid Arthritis ARTHRITIS CARE & RESEARCH Weinblatt, M. E., Bathon, J. M., Kremer, J. M., Fleischmann, R. M., Schiff, M. H., Martin, R. W., Baumgartner, S. W., Park, G. S., Mancini, E. L., Genovese, M. C. 2011; 63 (3): 373-382

    Abstract

    To evaluate the long-term safety and efficacy of etanercept therapy in rheumatoid arthritis (RA) patients.Adult patients with early RA or longstanding RA received etanercept in open-label extension studies following initial double-blind trials of etanercept.Of 558 early RA patients and 714 longstanding RA patients who received at least 1 dose of etanercept, a total of 194 early RA patients and 217 longstanding RA patients were treated with 25 mg of etanercept twice weekly through 10 years. Five opportunistic infections were reported: in early RA, 1 Candida septicemia; in longstanding RA, 1 herpes zoster, 1 atypical mycobacterium infection, 1 meningoencephalitis (unspecified), and 1 fungal sepsis (unspecified). Twenty-nine cases of sepsis occurred (10 early RA, 19 longstanding RA). Occurrence of all malignancies was similar to that expected in the general population, but the occurrence of lymphomas was higher than expected in the general population. Fourteen lymphomas (7 early RA, 7 longstanding RA) and 2 cases of demyelinating disease (1 early RA, 1 longstanding RA) were reported. Deaths occurred in 18 early RA patients and 43 longstanding RA patients. Both patient groups showed sustained improvement in American College of Rheumatology responses, swollen joint counts, Health Assessment Questionnaire disability index scores, and C-reactive protein levels.Etanercept maintained therapeutic benefits beyond 10 years of therapy in both early RA and longstanding RA patients, suggesting that etanercept is well tolerated and effective as a long-term, continuous therapy for the treatment of RA, with a favorable risk/benefit ratio.

    View details for DOI 10.1002/acr.20372

    View details for Web of Science ID 000288095800009

    View details for PubMedID 20957659

  • An Oral Syk Kinase Inhibitor in the Treatment of Rheumatoid Arthritis A Three-Month Randomized, Placebo-Controlled, Phase II Study in Patients With Active Rheumatoid Arthritis That Did Not Respond to Biologic Agents ARTHRITIS AND RHEUMATISM Genovese, M. C., Kavanaugh, A., Weinblatt, M. E., Peterfy, C., DiCarlo, J., White, M. L., O'Brien, M., Grossbard, E. B., Magilavy, D. B. 2011; 63 (2): 337-345

    Abstract

    To assess the efficacy and safety of R788 (fostamatinib disodium), an inhibitor of spleen tyrosine kinase (Syk), in patients with active rheumatoid arthritis (RA) that did not respond to biologic therapies.A total of 219 patients with active RA in whom treatment with biologic agents had failed were enrolled in a 3-month multicenter, randomized, double-blind, placebo-controlled trial of R788. The primary end point was the percentage of patients who met the American College of Rheumatology 20% improvement criteria (achieved an ACR20 response) at month 3. Secondary end points included changes in inflammation and damage, as assessed by magnetic resonance imaging (MRI), and changes in the Disease Activity Score.The ACR20 response in the R788 100 mg twice daily group was 38%, versus 37% in the placebo group, at month 3. No significant differences were achieved in the ACR20, ACR50, or ACR70 response levels at 3 months. There were differences between the groups from baseline to month 3 in the secondary end points C-reactive protein (CRP) level and synovitis score on MRI. There were baseline differences in steroid use, prior biologic use, and synovitis score on MRI between the R788 group and the placebo group that may have affected the outcomes. A high placebo response rate was seen in this trial, and exploratory analysis suggested that this may in part have been driven by patients who entered the trial with an elevated erythrocyte sedimentation rate but normal CRP level.Our findings indicate that there were no differences in the primary end point between the R788 and placebo groups. Differences were observed between the R788 and placebo groups in secondary end points, particularly in those patients who entered the study with an elevated CRP level.

    View details for DOI 10.1002/art.30114

    View details for Web of Science ID 000287202600007

    View details for PubMedID 21279990

  • An Oral Spleen Tyrosine Kinase (Syk) Inhibitor for Rheumatoid Arthritis. NEW ENGLAND JOURNAL OF MEDICINE Weinblatt, M. E., Kavanaugh, A., Genovese, M. C., Musser, T. K., Grossbard, E. B., Magilavy, D. B. 2010; 363 (14): 1303-1312

    Abstract

    Spleen tyrosine kinase (Syk) is an important modulator of immune signaling. The objective of this phase 2 study was to evaluate the efficacy and safety of R788, an oral inhibitor of Syk, in patients with active rheumatoid arthritis despite methotrexate therapy.We enrolled 457 patients who had active rheumatoid arthritis despite long-term methotrexate therapy in a 6-month, double-blind, placebo-controlled trial. The primary outcome was the American College of Rheumatology (ACR) 20 response (which indicates at least a 20% reduction in the number of both tender and swollen joints and improvement in at least three of five other criteria) at month 6.R788, at a dose of 100 mg twice daily and at a dose of 150 mg once daily, was significantly superior to placebo at month 6 (ACR 20 response rates of 67% and 57%, respectively, vs. 35%; P<0.001 for the comparison of both doses with placebo). It was also significantly superior with respect to ACR 50, which indicates at least a 50% improvement (43% and 32% vs. 19%; P<0.001 for the comparison of the 100-mg dose with placebo, P=0.007 for the comparison of the 150-mg dose with placebo) and ACR 70 (28% and 14% vs. 10%; P<0.001 for the comparison of the 100-mg dose with placebo, P=0.34 for the comparison of the 150-mg dose with placebo). A clinically significant effect was noted by the end of the first week of treatment. Adverse effects included diarrhea (in 19% of subjects taking the 100-mg dose of R788 vs. 3% of those taking placebo), upper respiratory infections (14% vs. 7%), and neutropenia (6% vs. 1%). R788 was associated with an increase in systolic blood pressure of approximately 3 mm Hg between baseline and month 1, as compared with a decrease of 2 mm Hg with placebo; 23% of the patients taking R788 vs. 7% of the patients receiving placebo required the initiation of or a change in antihypertensive therapy.In this phase 2 study, a Syk inhibitor reduced disease activity in patients with rheumatoid arthritis; adverse events included diarrhea, hypertension, and neutropenia. Additional studies will be needed to further assess the safety and efficacy of Syk-inhibition therapy in patients with rheumatoid arthritis. (Funded by Rigel; ClinicalTrials.gov number, NCT00665925.)

    View details for DOI 10.1056/NEJMoa1000500

    View details for Web of Science ID 000282271500004

    View details for PubMedID 20879879

  • Continued inhibition of structural damage over 2 years in patients with rheumatoid arthritis treated with rituximab in combination with methotrexate ANNALS OF THE RHEUMATIC DISEASES Cohen, S. B., Keystone, E., Genovese, M. C., Emery, P., Peterfy, C., Tak, P. P., Cravets, M., Shaw, T., Hagerty, D. 2010; 69 (6): 1158-1161

    Abstract

    Rituximab inhibited structural damage at 1 year in patients with rheumatoid arthritis (RA) who had had a previous inadequate response to tumour necrosis factor (TNF) inhibitors.To assess structural damage progression through 2 years.Intention-to-treat patients with one post-baseline radiograph (rituximab n=281; placebo n=187) received background methotrexate (MTX) and were randomised to rituximab (2 x 1000 mg infusions, 2 weeks apart) or placebo; patients were eligible for rituximab re-treatment every 6 months. By week 104, 82% of the placebo population had received > or = 1 dose of rituximab. Radiographic end points included the change in total Sharp score (TSS), erosion and joint space narrowing scores at week 104.At week 104, significantly lower changes in TSS (1.14 vs 2.81; p<0.0001), erosion score (0.72 vs 1.80; p<0.0001) and joint space narrowing scores (0.42 vs 1.00; p<0.0009) were observed with rituximab plus MTX vs placebo plus MTX. Within the rituximab group, 87% who had no progression of joint damage at 1 year remained non-progressive at 2 years.Rituximab plus MTX demonstrated significant and sustained effects on joint damage progression in patients with RA and a previously inadequate response to TNF inhibitors.

    View details for DOI 10.1136/ard.2009.119222

    View details for Web of Science ID 000278017700039

    View details for PubMedID 20439295

  • Golimumab in patients with active rheumatoid arthritis despite methotrexate therapy: 52-week results of the GO-FORWARD study ANNALS OF THE RHEUMATIC DISEASES Keystone, E., Genovese, M. C., Klareskog, L., Hsia, E. C., Hall, S., Miranda, P. C., Pazdur, J., Bae, S., Palmer, W., Xu, S., Rahman, M. U. 2010; 69 (6): 1129-1135

    Abstract

    To evaluate the efficacy and safety of golimumab to 52 weeks in patients with active rheumatoid arthritis despite methotrexate.Patients were randomly assigned to receive placebo plus methotrexate (group 1), golimumab 100 mg plus placebo (group 2), golimumab 50 mg plus methotrexate (group 3) and golimumab 100 mg plus methotrexate (group 4). At week 16, patients in groups 1, 2 and 3 who had less than 20% improvement in tender and swollen joints entered early escape. At week 24, patients in group 1 who had not entered early escape crossed over to 50 mg golimumab plus methotrexate.At week 16, 31%, 27% and 17% of patients in groups 1, 2 and 3, respectively, entered early escape. At week 52, 44%, 45%, 64% and 58% of patients in groups 1, 2, 3 and 4, respectively, achieved 20% improvement in the American College of Rheumatology criteria; and 34%, 31%, 42% and 53%, respectively, achieved low disease activity (< or = 3.2) according to the 28-joint disease activity score. Patients in group 4 appeared to have an increased risk of serious adverse events and serious infections.The results of various outcome measures showed that the response rates achieved by patients receiving golimumab to 24 weeks were sustained to 52 weeks. The safety profile appeared to be consistent with the known safety profile of tumour necrosis factor inhibitors.

    View details for DOI 10.1136/ard.2009.116319

    View details for Web of Science ID 000278017700032

    View details for PubMedID 20444749

  • LY2439821, a Humanized Anti-Interleukin-17 Monoclonal Antibody, in the Treatment of Patients With Rheumatoid Arthritis A Phase I Randomized, Double-Blind, Placebo-Controlled, Proof-of-Concept Study ARTHRITIS AND RHEUMATISM Genovese, M. C., Van den Bosch, F., ROBERSON, S. A., Bojin, S., Biagini, I. M., Ryan, P., Sloan-Lancaster, J. 2010; 62 (4): 929-939

    Abstract

    We undertook this study to evaluate safety, tolerability, pharmacokinetics, pharmacodynamics, and efficacy of LY2439821, a humanized anti-interleukin-17 (anti-IL-17) monoclonal antibody, in a first in-human trial in rheumatoid arthritis (RA) patients taking oral disease-modifying antirheumatic drugs (DMARDs).This randomized, double-blind, placebo-controlled study consisted of 2 parts. In part A, 20 patients received 1 intravenous (IV) dose of LY2439821 (0.06, 0.2, 0.6, or 2.0 mg/kg, escalating) or placebo followed by 8 weeks of evaluation. End points included safety, tolerability, and pharmacokinetics. In part B, 77 patients received 1 IV dose of LY2439821 (0.2, 0.6, or 2.0 mg/kg) or placebo every 2 weeks for a total of 5 doses, with a total evaluation period of 16 weeks. End points included safety, tolerability, pharmacokinetics/pharmacodynamics, and efficacy (Disease Activity Score in 28 joints [DAS28] and percentages of patients meeting American College of Rheumatology 20%, 50%, or 70% improvement criteria [achieving an ACR20, ACR50, or ACR70 response]). The primary efficacy end point was the DAS28 at week 10.Baseline characteristics were similar across all groups. Changes in the DAS28 were significantly greater in the 0.2 mg/kg, 2.0 mg/kg, and all-LY2439821-combined groups (-2.3, -2.4, and -2.3, respectively) than in the placebo group (-1.7) at week 10 (P < or = 0.05), and these differences were significant as early as week 1. Percentages of ACR20, ACR50, and ACR70 responses as well as improvements in the ACR core set of measures were greater in LY2439821-treated patients than in placebo-treated patients at multiple time points. There was no apparent dose-response relationship in treatment-emergent adverse events.LY2439821 added to oral DMARDs improved signs and symptoms of RA, with no strong adverse safety signal noted. This first evaluation of LY2439821 supports neutralization of IL-17 as a potential novel goal for the treatment of RA.

    View details for DOI 10.1002/art.27334

    View details for Web of Science ID 000279432300003

    View details for PubMedID 20131262

  • Comparison of tocilizumab monotherapy versus methotrexate monotherapy in patients with moderate to severe rheumatoid arthritis: the AMBITION study ANNALS OF THE RHEUMATIC DISEASES Jones, G., Sebba, A., Gu, J., Lowenstein, M. B., CALVO, A., Gomez-Reino, J. J., Siri, D. A., Tomsic, M., Alecock, E., Woodworth, T., Genovese, M. C. 2010; 69 (1): 88-96

    Abstract

    The anti-interleukin (IL) 6 receptor antibody tocilizumab inhibits signalling of IL6, a key cytokine in rheumatoid arthritis (RA) pathogenesis.To evaluate through the AMBITION study the efficacy and safety of tocilizumab monotherapy versus methotrexate in patients with active RA for whom previous treatment with methotrexate/biological agents had not failed.This 24-week, double-blind, double-dummy, parallel-group study, randomised 673 patients to either tocilizumab 8 mg/kg every 4 weeks, or methotrexate, starting at 7.5 mg/week and titrated to 20 mg/week within 8 weeks, or placebo for 8 weeks followed by tocilizumab 8 mg/kg. The primary end point was the proportion of patients achieving American College of Rheumatology (ACR) 20 response at week 24.The intention-to-treat analysis demonstrated that tocilizumab was better than methotrexate treatment with a higher ACR20 response (69.9 vs 52.5%; p<0.001), and 28-joint Disease Activity Score (DAS28) <2.6 rate (33.6 vs 12.1%) at week 24. Mean high-sensitivity C-reactive protein was within the normal range from week 12 with tocilizumab, whereas levels remained elevated with methotrexate. The incidence of serious adverse events with tocilizumab was 3.8% versus 2.8% with methotrexate (p = 0.50), and of serious infections, 1.4% versus 0.7%, respectively. There was a higher incidence of reversible grade 3 neutropenia (3.1% vs 0.4%) and increased total cholesterol > or =240 mg/dl (13.2% vs 0.4%), and a lower incidence of alanine aminotransferase elevations >3x-<5x upper limit of normal (1.0% vs 2.5%), respectively.Tocilizumab monotherapy is better than methotrexate monotherapy, with rapid improvement in RA signs and symptoms, and a favourable benefit-risk, in patients for whom treatment with methotrexate or biological agents has not previously failed.

    View details for DOI 10.1136/ard.2008.105197

    View details for Web of Science ID 000272594100017

    View details for PubMedID 19297346

  • Association of serum markers with improvement in clinical response measures after treatment with golimumab in patients with active rheumatoid arthritis despite receiving methotrexate: results from the GO-FORWARD study ARTHRITIS RESEARCH & THERAPY Visvanathan, S., Rahman, M. U., Keystone, E., Genovese, M., Klareskog, L., Hsia, E., Mack, M., Buchanan, J., Elashoff, M., Wagner, C. 2010; 12 (6)

    Abstract

    The goal of this study was to identify serum markers that are modulated by treatment with golimumab with or without methotrexate (MTX) and are associated with clinical response.Sera were collected at weeks 0 and 4 from a total of 336 patients (training dataset, n = 100; test dataset, n = 236) from the GO-FORWARD study of patients with active rheumatoid arthritis despite MTX. Patients were randomly assigned to receive placebo plus MTX; golimumab, 100 mg plus placebo; golimumab, 50 mg plus MTX; or golimumab, 100 mg plus MTX. Subcutaneous injections were administered every 4 weeks. Samples were tested for select inflammatory, bone, and cartilage markers and for protein profiling using multianalyte profiles.Treatment with golimumab with or without MTX resulted in significant decreases in a variety of serum proteins at week 4 as compared with placebo plus MTX. The American College of Rheumatology (ACR) 20, ACR 50, and Disease Activity Score (DAS) 28 responders showed a distinct biomarker profile compared with nonresponding patients.ACR 20 and ACR 50 responders among the golimumab/golimumab + MTX-treated patients had a distinct change from baseline to week 4 in serum protein profile as compared with nonresponders. Some of these changed markers were also associated with multiple clinical response measures and improvement in outcome measures in golimumab/golimumab + MTX-treated patients. Although the positive and negative predictive values of the panel of markers were modest, they were stronger than C-reactive protein alone in predicting clinical response to golimumab.http://ClinicalTrials.gov identification number: NCT00264550.

    View details for DOI 10.1186/ar3188

    View details for Web of Science ID 000287517000021

    View details for PubMedID 21083889

  • Safety of biological therapies following rituximab treatment in rheumatoid arthritis patients ANNALS OF THE RHEUMATIC DISEASES Genovese, M. C., Breedveld, F. C., Emery, P., Cohen, S., Keystone, E., Matteson, E. L., Baptiste, Y., Chai, A., Burke, L., Reiss, W., Sweetser, M., Shaw, T. M. 2009; 68 (12): 1894-1897

    Abstract

    To assess the safety of biological disease-modifying antirheumatic drugs (DMARD) in rheumatoid arthritis (RA) patients following rituximab.RA patients who participated in an international rituximab clinical trial programme were included. Patients who had received one or more rituximab courses and entered safety follow-up (SFU) were permitted additional biological DMARD. Serious infection events (SIE) were collected.Of 185 of 2578 patients who entered SFU and received another biological DMARD, 88.6% had peripheral B-cell depletion at the time of initiation of another biological agent. Thirteen SIE (6.99 events/100 patient-years) occurred following rituximab but before another biological DMARD and 10 SIE (5.49 events/100 patient-years) occurred following another biological DMARD. SIE were of typical type and severity for RA patients. 153 had received one or more tumour necrosis factor inhibitor(s). No fatal or opportunistic infections occurred.In this analysis, treatment with biological DMARD after rituximab was not associated with an increased serious infection rate. Sample size with limited follow-up restricts definitive conclusions.

    View details for DOI 10.1136/ard.2008.101675

    View details for Web of Science ID 000271730700017

    View details for PubMedID 19155233

  • Epitope-Specific Immunotherapy of Rheumatoid Arthritis Clinical Responsiveness Occurs With Immune Deviation and Relies on the Expression of a Cluster of Molecules Associated With T Cell Tolerance in a Double-Blind, Placebo-Controlled, Pilot Phase II Trial ARTHRITIS AND RHEUMATISM Koffeman, E. C., Genovese, M., Amox, D., Keogh, E., Santana, E., Matteson, E. L., Kavanaugh, A., Molitor, J. A., Schiff, M. H., Posever, J. O., Bathon, J. M., Kivitz, A. J., Samodal, R., Belardi, F., Dennehey, C., Van den Broek, T., van Wijk, F., Zhang, X., Zieseniss, P., Le, T., Prakken, B. A., Cutter, G. C., Albani, S. 2009; 60 (11): 3207-3216

    Abstract

    Induction of immune tolerance to maintain clinical control with a minimal drug regimen is a current research focus in rheumatoid arthritis (RA). Accordingly, we are developing a tolerization approach to dnaJP1, a peptide part of a pathogenic mechanism that contributes to autoimmune inflammation in RA. We undertook this study to test 2 hypotheses: 1) that mucosal induction of immune tolerance to dnaJP1 would lead to a qualitative change from a proinflammatory phenotype to a more tolerogenic functional phenotype, and 2) that immune deviation of responses to an inflammatory epitope might translate into clinical improvement.One hundred sixty patients with active RA and with immunologic reactivity to dnaJP1 were enrolled in a pilot phase II trial. They received oral doses of 25 mg of dnaJP1 or placebo daily for 6 months.The dnaJP1 peptide was safe and well-tolerated. In response to treatment with dnaJP1, there was a significant reduction in the percentage of T cells producing tumor necrosis factor alpha and a corresponding trend toward an increased percentage of T cells producing interleukin-10. Coexpression of a cluster of molecules (programmed death 1 and its ligands) associated with T cell regulation was also found to be a prerequisite for successful tolerization in clinical responders. Analysis of the primary efficacy end point (meeting the American College of Rheumatology 20% improvement criteria at least once on day 112, 140, or 168) showed a difference between treatment groups that became significant in post hoc analysis using generalized estimating equations. Differences in clinical responses were also found between treatment groups on day 140 and at followup. Post hoc analysis showed that the combination of dnaJP1 and hydroxychloroquine (HCQ) was superior to the combination of HCQ and placebo.Tolerization to dnaJP1 leads to immune deviation and a trend toward clinical efficacy. Susceptibility to treatment relies on the coexpression of molecules that can down-regulate adaptive immunity.

    View details for DOI 10.1002/art.24916

    View details for Web of Science ID 000271781400008

    View details for PubMedID 19877047

  • The 6-month safety and efficacy of abatacept in patients with rheumatoid arthritis who underwent a washout after anti-tumour necrosis factor therapy or were directly switched to abatacept: the ARRIVE trial ANNALS OF THE RHEUMATIC DISEASES Schiff, M., Pritchard, C., Huffstutter, J. E., Rodriguez-Valverde, V., Durez, P., Zhou, X., Li, T., Bahrt, K., Kelly, S., Le Bars, M., Genovese, M. C. 2009; 68 (11): 1708-1714

    Abstract

    To assess the safety, tolerability and efficacy of abatacept in patients with rheumatoid arthritis (RA) who had failed anti-tumour necrosis factor (TNF) therapy and were switched to abatacept directly or after completing washout.In this international, 6-month, open-label trial, patients had active RA, an inadequate response to anti-TNF therapy for 3 months or longer and a disease activity score in 28 joints (DAS28 (C-reactive protein; CRP) of 5.1 or greater. "Washout" patients discontinued anti-TNF therapy 2 months or longer pre-screening; "direct-switch" patients began abatacept ( approximately 10 mg/kg) at their next scheduled anti-TNF therapy dose.1046 patients were treated (449 washout, 597 direct-switch; baseline characteristics were similar between groups). At 6 months, adverse events (AE; 78.0% vs 79.2%), serious AE (11.1% vs 9.9%) and discontinuations due to AE (3.8% vs 4.0%) and serious AE (2.0% vs 1.3%) were comparable in washout versus direct-switch patients. There were no opportunistic infections. At 6 months, in washout versus direct-switch patients, similar clinically meaningful improvements were seen in DAS28 (CRP) (> or =1.2 unit improvement, 59.5% vs 53.6%, respectively; low disease activity state, 22.5% vs 22.3%; DAS28-defined remission, 12.0% vs 13.7%), physical function (health assessment questionnaire disability index > or =0.22 improvement; 46.3% vs 47.1%) and health-related quality of life (mean change in short-form 36 scores: physical component summary, 5.5 vs 6.1; mental component summary, 4.8 vs 5.4).Abatacept demonstrated acceptable safety and tolerability and clinically meaningful efficacy over 6 months in patients with inadequate response to anti-TNF therapy. Results were comparable with or without a washout, supporting direct switching from anti-TNF therapy to abatacept as an option in clinical practice. Trial registration number: NCT00124982.

    View details for DOI 10.1136/ard.2008.099218

    View details for Web of Science ID 000270700900010

    View details for PubMedID 19074911

  • First Report of Idiopathic Granulomatous Mastitis Treated with Methotrexate Monotherapy JOURNAL OF RHEUMATOLOGY Schmajuk, G., Genovese, M. C. 2009; 36 (7): 1559-1560

    View details for DOI 10.3899/jrheum.090091

    View details for Web of Science ID 000267847700039

    View details for PubMedID 19567642

  • Less Radiographic Progression with Adalimumab Plus Methotrexate Versus Methotrexate Monotherapy Across the Spectrum of Clinical Response in Early Rheumatoid Arthritis JOURNAL OF RHEUMATOLOGY Emery, P., Genovese, M. C., van Vollenhoven, R., Sharp, J. T., Patra, K., Sasso, E. H. 2009; 36 (7): 1429-1441

    Abstract

    To determine the relationship between radiographic progression and clinical response for adalimumab plus methotrexate (MTX) versus either monotherapy in patients with early rheumatoid arthritis (RA) in the PREMIER study.Patients with early RA who received adalimumab plus MTX (n = 240), adalimumab (n = 222), or MTX (n = 216) were grouped by American College of Rheumatology (ACR) response, 28-joint Disease Activity Score (DAS28), or remission-like state [tender joint count (TJC) = 0; DAS28 < 2.6; swollen joint count = 0; ACR100] at 26 and 104 weeks. Radiographic progression was assessed by cumulative probability plots, mean changes in total Sharp score (DeltaTSS), and percentages of progressors (DeltaTSS > 0.5).Across the spectrum of clinical outcomes, including ACR20 nonresponses and remission-like responses, therapy with adalimumab plus MTX permitted less radiographic progression at Weeks 26 and 104 than MTX monotherapy. Adalimumab monotherapy was generally intermediate. A strong, proportional relationship was observed between clinical response and radiographic efficacy only for MTX monotherapy. The monotherapies approximated the radiographic efficacy of adalimumab plus MTX only among remission-like responders, although progression was significantly greater with MTX monotherapy versus adalimumab plus MTX for patients with TJC = 0. Concurrent clinical (DAS28 < 2.6) and radiographic (DeltaTSS

    View details for DOI 10.3899/jrheum.081018

    View details for Web of Science ID 000267847700014

    View details for PubMedID 19369462

  • Golimumab, a human antibody to tumour necrosis factor alpha given by monthly subcutaneous injections, in active rheumatoid arthritis despite methotrexate therapy: the GO-FORWARD Study ANNALS OF THE RHEUMATIC DISEASES Keystone, E. C., Genovese, M. C., Klareskog, L., Hsia, E. C., Hall, S. T., Miranda, P. C., Pazdur, J., Bae, S., Palmer, W., ZRUBEK, J., Wiekowski, M., Visvanathan, S., Wu, Z., Rahman, M. U. 2009; 68 (6): 789-796

    Abstract

    The phase III GO-FORWARD study examined the efficacy and safety of golimumab in patients with active rheumatoid arthritis (RA) despite methotrexate therapy.Patients were randomly assigned in a 3 : 3 : 2 : 2 ratio to receive placebo injections plus methotrexate capsules (group 1, n = 133), golimumab 100 mg injections plus placebo capsules (group 2, n = 133), golimumab 50 mg injections plus methotrexate capsules (group 3, n = 89), or golimumab 100 mg injections plus methotrexate capsules (group 4, n = 89). Injections were administered subcutaneously every 4 weeks. The co-primary endpoints were the proportion of patients with 20% or greater improvement in the American College of Rheumatology criteria (ACR20) at week 14 and the change from baseline in the health assessment questionnaire-disability index (HAQ-DI) score at week 24.The proportion of patients who achieved an ACR20 response at week 14 was 33.1% in the placebo plus methotrexate group, 44.4% (p = 0.059) in the golimumab 100 mg plus placebo group, 55.1% (p = 0.001) in the golimumab 50 mg plus methotrexate group and 56.2% (p<0.001) in the golimumab 100 mg plus methotrexate group. At week 24, median improvements from baseline in HAQ-DI scores were 0.13, 0.13 (p = 0.240), 0.38 (p<0.001) and 0.50 (p<0.001), respectively. During the placebo-controlled portion of the study (to week 16), serious adverse events occurred in 2.3%, 3.8%, 5.6% and 9.0% of patients and serious infections occurred in 0.8%, 0.8%, 2.2% and 5.6%, respectively.The addition of golimumab to methotrexate in patients with active RA despite methotrexate therapy significantly reduced the signs and symptoms of RA and improved physical function.

    View details for DOI 10.1136/ard.2008.099010

    View details for Web of Science ID 000266917100006

    View details for PubMedID 19066176

  • Efficacy of a p38 mitogen activated protein kinase inhibitor in mitigating an established inflammatory reaction to polyethylene particles in vivo. Journal of biomedical materials research. Part A Ma, T., Ren, P., Larsen, D. M., Suenaga, E., Zilber, S., Genovese, M., Smith, R. L., Goodman, S. B. 2009; 89 (1): 117-123

    Abstract

    The inhibitor of p38 mitogen-activated protein kinase (MAPK) is of interest in the nonoperative treatment of periprosthetic osteolysis due to wear particles. Previous studies demonstrated that an oral p38 MAPK inhibitor did not suppress bone formation when given during the initial phase of tissue differentiation. However, the oral p38 MAPK inhibitor also did not curtail the foreign body and chronic inflammatory response to particles when given simultaneously. The purpose of the current study was to examine the efficacy of a p38 MAPK inhibitor, SCIO-323, on mitigating an established inflammatory reaction that parallels the clinical situation more closely. The Bone Harvest Chamber was implanted in rabbits and submicron polyethylene particles were placed in the chamber for 6 weeks. The contents of the chambers were harvested every 6 weeks. Oral treatment with the SCIO-323 included delivery for 3 weeks and stopping for 3 weeks, delivery for 3 weeks after an initial 3-week delay, and delivery for 6 weeks continuously. Administration of the SCIO-323 continuously for 6 weeks with/without the presence of particles, or for the initial 3 of 6 weeks had minor effects on bone ingrowth. After establishing a particle-induced chronic inflammatory reaction for 3 weeks, administration of SCIO-323 for a subsequent 3 weeks suppressed net bone formation. The activity of osteoclast-like cells remained low among all treatments when compared with the first control. Using the present model, the oral p38 MAPK inhibitor was ineffective in improving bone ingrowth in the presence of polyethylene particles.

    View details for DOI 10.1002/jbm.a.31957

    View details for PubMedID 18431764

  • Efficacy of a p38 mitogen activated protein kinase inhibitor in mitigating an established inflammatory reaction to polyethylene particles in vivo JOURNAL OF BIOMEDICAL MATERIALS RESEARCH PART A Ma, T., Ren, P., Larsen, D. M., Suenaga, E., Zilber, S., Genovese, M., Smith, R. L., Goodman, S. B. 2009; 89A (1): 117-123
  • RAPID AND SIGNIFICANT REDUCTION IN DISEASE ACTIVITY WITH TOCILIZUMAB IN COMBINATION WITH SIX DIFFERENT DMARDS IN RHEUMATOID ARTHRITIS PATIENTS WITH AN INADEQUATE RESPONSE TO DISEASE-MODIFYING ANTI-RHEUMATIC DRUGS: THE TOWARD STUDY Gomez-Reino, J. J., Nasonov, E. L., McKay, J. D., Mysler, E. F., da Silva, N., Alecock, E., Woodworth, T., Genovese, M. C. OXFORD UNIV PRESS. 2009: I89-I89
  • RAPID AND SIGNIFICANT REDUCTION OF DAS28 FOLLOWING TOCILIZUMAB TREATMENT IN PATIENTS WITH RHEUMATOID ARTHRITIS INADEQUATELY RESPONDING TO DISEASE-MODIFYING ANTI-RHEUMATIC DRUGS Smolen, J. S., Mysler, E. F., Rubbert-Roth, A., Gomez-Reino, J., Alten, R., Law, A., Woodworth, T., Genovese, M. OXFORD UNIV PRESS. 2009: I91-I91
  • Inhibition of p38: Has the Fat Lady Sung ARTHRITIS AND RHEUMATISM Genovese, M. C. 2009; 60 (2): 317-320

    View details for DOI 10.1002/art.24264

    View details for Web of Science ID 000263276400002

    View details for PubMedID 19180514

  • Rituximab inhibits structural joint damage in patients with rheumatoid arthritis with an inadequate response to tumour necrosis factor inhibitor therapies ANNALS OF THE RHEUMATIC DISEASES Keystone, E., Emery, P., Peterfy, C. G., Tak, P. P., Cohen, S., Genovese, M. C., Dougados, M., Burmester, G. R., Greenwald, M., Kvien, T. K., Williams, S., Hagerty, D., Cravets, M. W., Shaw, T. 2009; 68 (2): 216-221

    Abstract

    To determine if treatment with a B cell-targeted therapy can inhibit the progression of structural joint damage in patients with rheumatoid arthritis (RA), exhibiting an inadequate response to tumour necrosis factor (TNF) inhibitors.In this phase III study, patients with an inadequate response to a TNF inhibitor and receiving methotrexate were randomised to rituximab or placebo. Radiographs were obtained at baseline, week 24 and week 56 after randomisation. Patients with an inadequate response to their randomised therapy could receive rescue medication from week 16. From week 24, eligible patients from both treatment arms could receive open-label rituximab. Patients were analysed according to their original treatment group. Radiographs were scored using the Genant-modified Sharp method. The primary radiographic endpoint was change in total Genant-modified Sharp score at week 56.Rituximab treatment caused significant reduction in joint damage progression compared with placebo. The mean change from baseline in the total Genant-modified Sharp score at week 56 was significantly lower for patients treated with rituximab than for patients treated with placebo (1.00 vs 2.31; p = 0.005), and was supported by changes in erosion score (0.59 and 1.32 for rituximab plus methotrexate vs placebo plus methotrexate, respectively; p = 0.011) and joint space narrowing score (0.41 and 0.99, respectively; p<0.001).This study provides the first evidence that a B cell-targeted therapy-rituximab-can significantly inhibit the progression of structural joint damage in patients with RA with long-standing, active and treatment-resistant disease.

    View details for DOI 10.1136/ard.2007.085787

    View details for Web of Science ID 000262394000011

    View details for PubMedID 18388156

  • Blood autoantibody and cytokine profiles predict response to anti-tumor necrosis factor therapy in rheumatoid arthritis ARTHRITIS RESEARCH & THERAPY Hueber, W., Tomooka, B. H., Batliwalla, F., Li, W., Monach, P. A., Tibshirani, R. J., Van Vollenhoven, R. F., Lampa, J., Saito, K., Tanaka, Y., Genovese, M. C., Klareskog, L., Gregersen, P. K., Robinson, W. H. 2009; 11 (3)

    Abstract

    Anti-TNF therapies have revolutionized the treatment of rheumatoid arthritis (RA), a common systemic autoimmune disease involving destruction of the synovial joints. However, in the practice of rheumatology approximately one-third of patients demonstrate no clinical improvement in response to treatment with anti-TNF therapies, while another third demonstrate a partial response, and one-third an excellent and sustained response. Since no clinical or laboratory tests are available to predict response to anti-TNF therapies, great need exists for predictive biomarkers.Here we present a multi-step proteomics approach using arthritis antigen arrays, a multiplex cytokine assay, and conventional ELISA, with the objective to identify a biomarker signature in three ethnically diverse cohorts of RA patients treated with the anti-TNF therapy etanercept.We identified a 24-biomarker signature that enabled prediction of a positive clinical response to etanercept in all three cohorts (positive predictive values 58 to 72%; negative predictive values 63 to 78%).We identified a multi-parameter protein biomarker that enables pretreatment classification and prediction of etanercept responders, and tested this biomarker using three independent cohorts of RA patients. Although further validation in prospective and larger cohorts is needed, our observations demonstrate that multiplex characterization of autoantibodies and cytokines provides clinical utility for predicting response to the anti-TNF therapy etanercept in RA patients.

    View details for DOI 10.1186/ar2706

    View details for Web of Science ID 000269019300042

    View details for PubMedID 19460157

  • Interleukin-6 Receptor Inhibition With Tocilizumab Reduces Disease Activity in Rheumatoid Arthritis With Inadequate Response to Disease-Modifying Antirheumatic Drugs The Tocilizumab in Combination With Traditional Disease-Modifying Antirheumatic Drug Therapy Study ARTHRITIS AND RHEUMATISM Genovese, M. C., McKay, J. D., Nasonov, E. L., Mysler, E. F., da Silva, N. A., Alecock, E., Woodworth, T., Gomez-Rein, J. J. 2008; 58 (10): 2968-2980

    Abstract

    To examine the efficacy and safety of the humanized anti-interleukin-6 receptor antibody tocilizumab combined with conventional disease-modifying antirheumatic drugs (DMARDs) in patients with active rheumatoid arthritis (RA).A total of 1,220 patients were randomized (2:1 ratio) in the phase III, double-blind, placebo-controlled, multicenter TOWARD (Tocilizumab in Combination With Traditional DMARD Therapy) study. Patients remained on stable doses of DMARDs and received tocilizumab 8 mg/kg or placebo (control group) every 4 weeks for 24 weeks.At week 24, the proportion of patients achieving a response according to the American College of Rheumatology criteria for 20% improvement (ACR20) was significantly greater in the tocilizumab plus DMARD group than in the control group (61% versus 25%; P<0.0001). Secondary end points including 50% or 70% improvement (ACR50/70), the Disease Activity Score in 28 joints (DAS28), DAS28 remission responses (DAS28<2.6), European League Against Rheumatism responses, and systemic markers such as the C-reactive protein and hemoglobin levels showed superiority of tocilizumab plus DMARDs over DMARDs alone. Seventy-three percent of patients in the tocilizumab group had >or=1 adverse event (AE), compared with 61% of patients in the control group. AEs leading to withdrawal from the study were infrequent (4% of patients in the tocilizumab group and 2% of those in the control group). Serious AEs occurred in 6.7% and 4.3% of patients in the tocilizumab and control groups, respectively, and serious infections occurred in 2.7% and 1.9%, respectively. Elevations in the alanine aminotransferase level, from normal at baseline to >3-fold the upper limit of normal, occurred in 4% of patients in the tocilizumab group and 1% of those in the control group, and elevated total cholesterol levels were observed in 23% and 6% of patients, respectively. Sixteen patients started lipid-lowering therapy during the study. Grade 3 neutropenia occurred in 3.7% of patients receiving tocilizumab and none of the patients in the control group, and no grade 4 neutropenia was reported.Tocilizumab combined with any of the DMARDs evaluated was safe and effective in reducing articular and systemic symptoms in patients with an inadequate response to these agents.

    View details for DOI 10.1002/art.23940

    View details for Web of Science ID 000260024400007

    View details for PubMedID 18821691

  • Ocrelizumab, a humanized anti-CD20 monoclonal antibody, in the treatment of patients with rheumatoid arthritis - A phase I/II randomized, blinded, placebo-controlled, dose-ranging study ARTHRITIS AND RHEUMATISM Genovese, M. C., Kaine, J. L., Lowenstein, M. B., Del Giudice, J., Baldassare, A., Schechtman, J., Fudman, E., Kohen, M., Gujrathi, S., Trapp, R. G., Sweiss, N. J., Spaniolo, G., Dummer, W. 2008; 58 (9): 2652-2661

    Abstract

    Ocrelizumab, a humanized anti-CD20 monoclonal antibody, was studied in a first-in-human trial in rheumatoid arthritis (RA) patients receiving concomitant methotrexate (MTX).The ACTION trial was a combined phase I/II study of placebo plus MTX versus ocrelizumab plus MTX in 237 RA patients (intent-to-treat population). During phase I, 45 patients were treated with 1 of 5 escalating doses of study drug (infusions on days 1 and 15, 10-1,000 mg per each infusion). An additional 192 patients were randomized during phase II. Eligible patients had active disease, an inadequate response to treatment with at least MTX, rheumatoid factor positivity, and elevated levels of acute-phase reactants. The total study duration was 72 weeks. B cell pharmacodynamics over time was investigated.Baseline demographics were similar among the treatment groups. Based on the entire 72-week data set, the incidence of serious adverse events in the ocrelizumab-treated patients was 17.9%, as compared with 14.6% in placebo-treated patients. The incidence of serious infections was 2.0% in all ocrelizumab-treated patients and 4.9% in placebo-treated patients. Infusion-associated adverse events were mostly grade 1 or grade 2 and were more frequent around the time of the first infusion. No serious infusion-associated adverse events were reported in the ocrelizumab group. Evidence of clinical activity was observed at all doses evaluated. Peripheral B cell depletion after infusion was rapid at all doses, with earlier repletion of B cells at doses of 10 mg and 50 mg. Human anti-human antibodies were detected in 19% and 10%, respectively, of those receiving 10 mg and 50 mg of ocrelizumab, compared with 0-5% of those receiving 200, 500, and 1,000 mg.Ocrelizumab therapy in combination with MTX was well tolerated. Doses of 200 mg (2 infusions) and higher showed better clinical responses, better reduction of C-reactive protein levels, and very low immunogenicity.

    View details for DOI 10.1002/art.23732

    View details for Web of Science ID 000259244000009

    View details for PubMedID 18759293

  • Golimumab administered subcutaneously every 4 wks in patients with active rheumatoid arthritis despite methotrexate: Wk 24 results of the randomized, double-blind, placebo-controlled, GO-FORWARD study Keystone, E., Genovese, M. C., Klareskog, L., Hsia, E. C., Livingston, J., Wiekowski, M., Hall, S. T., Miranda, P., Pazdur, J., Bae, S. C., Palmer, W., Wu, Z., Rahman, M. U. WILEY-BLACKWELL. 2008: S618-S619
  • IL-6 receptor inhibition with tocilizumab reduces disease activity in patients with rheumatoid arthritis with inadequate response to a range of DMARDs: The TOWARD study Genovese, M., Brown, J. P., McKay, J., Nasonov, E., Mysler, E., da Silva, N., Alecock, E., Gomez-Reino, J. J RHEUMATOL PUBL CO. 2008: 1187-1187
  • Targeted inhibition of IL-6 signaling with tocilizumab improves quality of life and function in patients with rheumatoid arthritis with inadequate response to a range of DMARDs Gomez-Reino, J. J., Nair, B., FAIRFAX, M. J., Pavelka, K., Alecock, E., Woodworth, T., Genovese, M. J RHEUMATOL PUBL CO. 2008: 1216-1216
  • Efficacy and safety of the selective co-stimulation modulator abatacept following 2 years of treatment in patients with rheumatoid arthritis and an inadequate response to anti-tumour necrosis factor therapy ANNALS OF THE RHEUMATIC DISEASES Genovese, M. C., Schiff, M., Luggen, M., Becker, J., Aranda, R., Teng, J., Li, T., Schmidely, N., Le Bars, M., Dougados, M. 2008; 67 (4): 547-554

    Abstract

    To evaluate the safety and efficacy of abatacept during 2 years of the ATTAIN (Abatacept Trial in Treatment of Anti-TNF INadequate responders) trial in patients with rheumatoid arthritis.Patients completing the 6-month, double-blind period were eligible to enter the long-term extension; patients received abatacept approximately 10 mg/kg, plus disease-modifying antirheumatic drugs. Safety and efficacy (American College of Rheumatology (ACR) criteria responses, DAS28 (C-reactive protein), HAQ-DI, SF-36, Medical Outcomes Study Sleep Problems Index, fatigue VAS) were assessed through 2 years.317 patients (218 from the abatacept and 99 from the placebo group) entered and 222 (70%) completed 18 months of long-term extension treatment. The incidence and type of adverse events were consistent between the double-blind and cumulative (double-blind plus long-term extension) periods. Rates of serious adverse events were 25.6 and 23.4 per 100 patient-years in the double-blind versus cumulative period. At 6 months and 2 years, using non-responder analyses, ACR responses in abatacept-treated patients were: ACR 20, 59.4% and 56.2%; ACR 50, 23.5% and 33.2%; ACR 70, 11.5% and 16.1%; HAQ-DI responses were 54.4% and 47.9%. At 6 months and 2 years, using post-hoc as-observed analyses, the percentage of patients (95% confidence interval) achieving DAS28 (C-reactive protein) low disease activity score (< or = 3.2) and DAS28 (C-reactive protein)-defined remission (< 2.6) increased from 18.3% (13.0, 23.5) to 32.0% (24.6, 39.4) and 11.1% (6.8, 15.3) to 20.3% (13.9, 26.6). Clinically meaningful improvements in SF-36, pain, fatigue and sleep problems were also maintained throughout the 2 years of abatacept treatment.No unique safety observations were reported during open-label exposure. Improvements in the signs and symptoms of rheumatoid arthritis, physical function and health-related quality of life observed after 6 months, were maintained throughout the 2 years in this population with difficult-to-treat disease.NCT00124982.

    View details for DOI 10.1136/ard.2007.074773

    View details for Web of Science ID 000254121100022

    View details for PubMedID 17921185

  • Quality of life and functional improvements with the IL-6 receptor inhibitor tocilizumab in patients with active rheumatoid arthritis despite DMARD therapy: The toward study Gomez-Reino, J. J., FAIRFAX, M. J., Pavelka, K., Alecock, E., Woodworth, T., Laughton, J., Eves, D., Genovese, M. C. OXFORD UNIV PRESS. 2008: II49-II49
  • Safety of TNF inhibitors (TNF-is) and non-biologic DMARDs in rheumatoid arthritis (RA) patients (pts) previously treated with Rituximab (RTX) Genovese, M., van Vollenhoven, R., Breedveld, F., Emery, P., Moreland, L., Keystone, E., Matteson, E., Baptiste, Y., Burke, L., Reiss, W., Sweetser, M., Shaw, T. INFORMA HEALTHCARE. 2008: 44-44
  • Longitudinal Evaluation of the Occurrence of MRI-Detectable Bone Marrow Edema in Osteoarthritis of the Knee ACTA RADIOLOGICA Brem, M. H., Schlechtweg, P. M., Bhagwat, J., Genovese, M., Dillingham, M. F., Yoshioka, H., Lang, P. 2008; 49 (9): 1031-1037

    Abstract

    Bone marrow edema (BME) is a condition detectable with magnetic resonance imaging (MRI) and is present in different stages of osteoarthritis (OA). Its pathogenesis is still not completely known.To evaluate the longitudinal occurrence and persistence of BME in early OA of the knee.Twenty-three patients (eight females, 15 males; mean age 55.5+/-10.3 years) were scanned with a 1.5T MR imaging unit (sagittal fat-suppressed intermediate-weighted fast spin echo; 4-mm section thickness, 1-mm intersection gap, 256 x 192 matrix, 120-mm field of view). Images were obtained in all 23 patients at two time points (TPs) and in 12 patients at three TPs. Images were evaluated by two readers independently; discrepancies in image grading were reviewed and evaluated in consensus. A four-point image-grading scale was used (absence of BME to severe BME). Four main anatomical regions were evaluated (medial femur, lateral femur, medial tibia, lateral tibia), which were subcategorized into anterior, central, and posterior regions.One hundred five areas of BME in the 23 patients were found at all three TPs. In 16 areas, the BME was consistent at the same location over time, in seven locations the BME became larger, in six areas the BME became smaller, and in 16 locations it could not be detected in follow-up MRIs. In one case, the BME was smaller at TP2 but increased at TP3. In eight cases, only at the last time point could a BME be detected.BME is not a static phenomenon but changes over time. Correlation to physical activity and local inflammatory reaction should be evaluated.

    View details for DOI 10.1080/02841850802339413

    View details for Web of Science ID 000260053900011

    View details for PubMedID 18720084

  • Targeted inhibition of IL-6 signalling withtocilizumab improves quality of life and function in patients with rheumatoid arthritis with inadequate response to a range of DMARDs Gomez-Reino, J. J., FAIRFAX, M. J., Pavelka, K., Alecock, E., Woodworth, T., Genovese, M. WILEY-LISS. 2007: 4234-4234
  • Reduced B lymphocyte and immunoglobulin levels after atacicept treatment in patients with systemic lupus erythematosus ARTHRITIS AND RHEUMATISM Dall'Era, M., Chakravarty, E., Wallace, D., Genovese, M., Weisman, M., Kavanaugh, A., Kalunian, K., Dhar, P., Vincent, E., Pena-Rossi, C., Wofsy, D., Serono, M. 2007; 56 (12): 4142-4150

    View details for DOI 10.1002/art.23047

    View details for Web of Science ID 000251781200031

  • IL-6 receptor inhibition with tocilizumab reduces disease activity in patients with rheumatoid arthritis with inadequate response to a range of DMARDs: The TOWARD study Genovese, M., McKay, J., Nasonov, E., Myster, E., da Silva, N., Alecock, E., Woodworth, T., Gomez-Reino, J. WILEY-LISS. 2007: 4309-4310
  • Efficacy results from pivotal clinical trials with abatacept CLINICAL AND EXPERIMENTAL RHEUMATOLOGY Rozelle, A. L., Genovese, M. C. 2007; 25 (5): S30-S34

    Abstract

    Rheumatoid arthritis (RA) is a prevalent systemic disease that causes significant joint dysfunction and disability. Dramatic improvements in the management of RA have been achieved with the use of biologic therapies aimed at cytokines, and B and T lymphocytes. Abatacept, a soluble receptor-IgG fusion protein that interferes with T-cell co-stimulation, has now been shown to improve symptoms, signs and function in RA, while also slowing radiographic progression. The degree of improvement in these measures is comparable to that seen with other biologic agents.Abatacept is effective in a range of RA patients that are encountered in clinical practice, namely methotrexate-inadequate responders, as well patients with inadequate responses to tumor necrosis factor inhibitors and patients with co-morbidities common in an aging population. When used for up to 2 years, abatacept appears to be safe and remains efficacious, although there is a trend toward increased infection rates when used in combination with other biologic therapies, as well as a trend toward more adverse events when used in a background of chronic obstructive pulmonary disease. Backed by these data, ongoing extensions of these trials, and additional new studies, abatacept represents the first co-stimulation modulator approved for RA, and is a welcome addition to the biologic therapies available for the management of this disease.

    View details for Web of Science ID 000251248100005

    View details for PubMedID 17977486

  • Safety of TNF inhibitors in rheumatoid arthritis patients previously treated with rituximab Breedveld, F. C., Khraishi, M. M., Genovese, M., Emery, P., Moreland, L. W., Keystone, E., Matteson, E. L., Burke, L., Agarwal, S., Kim, D., Cooper, S. J RHEUMATOL PUBL CO. 2007: 1602-1602
  • A pilot study of tumor necrosis factor inhibition in erosive/inflammatory osteoarthritis of the hands JOURNAL OF RHEUMATOLOGY Magnano, M. D., Chakravarty, E. F., Broudy, C., Chung, L., Kelman, A., Hillygus, J., Genovese, M. C. 2007; 34 (6): 1323-1327

    Abstract

    To determine if anti-tumor necrosis factor (TNF) therapy (adalimumab) can safely improve symptoms of erosive/inflammatory osteoarthritis (EOA).This was an open-label pilot trial in 12 patients with EOA. Patients > 45 years old with EOA of the hands defined by > or = 2 tender and > or = 2 swollen joints (distal interphalangeal, proximal interphalangeal, first carpometacarpal) despite nonsteroidal antiinflammatory drug therapy were eligible. Patients were excluded for autoimmune arthritis, recent disease modifying antirheumatic drug use, prior use of anti-TNF therapy, infection, malignancy, or poorly controlled medical conditions. All patients received adalimumab 40 mg every other week for 12 weeks. Safety was assessed 4 weeks after the final dose. Primary endpoints included safety and American College of Rheumatology (ACR) response.Patients were predominantly female with a mean age of 60 years and 12 years of arthritis. All patients completed the study and safety followup. Adverse events were mild without necessitating discontinuation of study drug. After 12 weeks, there was a statistically significant improvement in the number of swollen joints compared to baseline (p < 0.01). One patient achieved an ACR20 response and 42% achieved an OMERACT-OARSI response. Although we detected no statistically significant improvement in the number of tender joints, grip strength, disability, pain, or global disease assessments, trends suggested modest improvement in all efficacy measures.This small open-label study of patients with EOA demonstrated that adalimumab was well tolerated. Treatment with adalimumab for 3 months did not significantly improve the signs and symptoms of EOA and most patients did not achieve an ACR20. Trends suggested improvement and individual patients had some benefit. Factors limiting interpretation of this study include the lack of a control group, outcomes chosen, number of patients treated, and the duration of treatment.

    View details for Web of Science ID 000247116600019

    View details for PubMedID 17516620

  • Proteomic analysis of secreted proteins in early rheumatoid arthritis: anti-citrulline autoreactivity is associated with up regulation of proinflammatory cytokines ANNALS OF THE RHEUMATIC DISEASES Hueber, W., Tomooka, B. H., Zhao, X., Kidd, B. A., Drijfhout, J. W., Fries, J. F., van Venrooij, W. J., Metzger, A. L., Genovese, M. C., Robinson, W. H. 2007; 66 (6): 712-719

    Abstract

    To identify peripheral blood autoantibody and cytokine profiles that characterise clinically relevant subgroups of patients with early rheumatoid arthritis using arthritis antigen microarrays and a multiplex cytokine assay.Serum samples from 56 patients with a diagnosis of rheumatoid arthritis of <6 months' duration were tested. Cytokine profiles were also determined in samples from patients with psoriatic arthritis (PsA) and ankylosing spondylitis (n = 21), and from healthy individuals (n = 19). Data were analysed using Kruskal-Wallis test with Dunn's adjustment for multiple comparisons, linear correlation tests, significance analysis of microarrays (SAM) and hierarchical clustering software.Distinct antibody profiles were associated with subgroups of patients who exhibited high serum levels of tumour necrosis factor (TNF)alpha, interleukin (IL)1beta, IL6, IL13, IL15 and granulocyte macrophage colony-stimulating factor. Significantly increased autoantibody reactivity against citrullinated epitopes was observed in patients within the cytokine "high" subgroup. Increased levels of TNFalpha, IL1alpha, IL12p40 and IL13, and the chemokines eotaxin/CCL11, monocyte chemoattractant protein-1 and interferon-inducible protein 10, were present in early rheumatoid arthritis as compared with controls (p<0.001). Chemokines showed some of the most impressive differences. Only IL8/CXCL8 concentrations were higher in patients with PsA/ankylosing spondylitis (p = 0.02).Increased blood levels of proinflammatory cytokines are associated with autoantibody targeting of citrullinated antigens and surrogate markers of disease activity in patients with early rheumatoid arthritis. Proteomic analysis of serum autoantibodies, cytokines and chemokines enables stratification of patients with early rheumatoid arthritis into molecular subgroups.

    View details for DOI 10.1136/ard.2006.054924

    View details for Web of Science ID 000246594700002

    View details for PubMedID 16901957

  • A pilot trial of rituximab in the treatment of patients with dermatomyositis ARCHIVES OF DERMATOLOGY Chung, L., Genovese, M. C., Fiorentino, D. F. 2007; 143 (6): 763-767

    Abstract

    Dermatomyositis is an autoimmune disease that is associated with muscle and skin inflammation. Using quantitative scales, we sought to evaluate the effects of rituximab therapy on muscle strength and skin disease in patients with dermatomyositis.An open-label trial of rituximab therapy was conducted in 8 adult patients with dermatomyositis. Patients received 2 infusions of rituximab (1 g each) 2 weeks apart without peri-infusional steroids. The primary outcome was partial remission at week 24 (prespecified reduction in elevated creatine phosphokinase levels, muscle strength deficit (Manual Muscle Test), or skin disease (Dermatomyositis Skin Severity Index). After the first infusion of rituximab, all patients achieved sustained depletion of peripheral B cells. One patient withdrew at week 16 owing to a lack of treatment efficacy. Three patients (38%) achieved partial remission at week 24, in each case by improvement in muscle strength. Muscle enzyme levels and skin scores at week 24 were not significantly changed from those at baseline. Rituximab infusions were well tolerated, with no serious infectious complications. One patient died of metastatic cancer 9 months after his last infusion.Depletion of peripheral B cells had modest effects on muscle disease and limited effects on skin disease in our cohort of patients with dermatomyositis.

    View details for Web of Science ID 000247207400012

    View details for PubMedID 17576943

  • Safety and efficacy of adalimumab in treatment of patients with psoriatic arthritis who had failed disease modifying antirheumatic drug therapy JOURNAL OF RHEUMATOLOGY Genovese, M. C., Mease, P. J., Thomson, G. T., Kivitz, A. J., Perdok, R. J., Weinberg, M. A., Medich, J., Sasso, E. H. 2007; 34 (5): 1040-1050

    Abstract

    To demonstrate the safety and efficacy of adalimumab for the treatment of active psoriatic arthritis (PsA) in patients with an inadequate response to disease modifying antirheumatic drugs (DMARD).In a placebo controlled, double-blind, randomized, multicenter study, patients were treated for 12 weeks with subcutaneous injections of adalimumab 40 mg every other week (eow) or placebo, followed by a period of open-label treatment with adalimumab 40 mg eow. The primary efficacy endpoint was the percentage of patients who met the American College of Rheumatology (ACR20) core criteria at Week 12. Secondary efficacy measures included the modified Psoriatic Arthritis Response Criteria (PsARC) and assessments of disability, psoriatic lesions, and quality of life. For missing data, nonresponder imputation was used for ACR and PsARC scores and last observation carried forward for other measures.A total of 100 patients received study drug (51 adalimumab, 49 placebo). At Week 12, an ACR20 response was achieved by 39% of adalimumab patients versus 16% of placebo patients (p = 0.012), and a PsARC response was achieved by 51% with adalimumab versus 24% with placebo (p = 0.007). At Week 12, measures of skin lesions and disability were statistically significantly improved with adalimumab. After Week 12, open-label adalimumab provided continued improvement for adalimumab patients and initiated rapid improvement for placebo patients, with ACR20 response rates of 65% and 57%, respectively, observed at Week 24. Serious adverse events had similar frequencies during therapy with placebo (4.1%), blinded adalimumab (2.0%), and open-label adalimumab (3.1%). No serious infections occurred during adalimumab therapy.In this study of patients who had active PsA and a previous, inadequate response to DMARD therapy, adalimumab was well tolerated and significantly reduced the signs, symptoms, and disability of PsA during 12 weeks of blinded and 12 weeks of open-label therapy. Adalimumab also improved psoriasis in these patients.

    View details for Web of Science ID 000246230700024

    View details for PubMedID 17444593

  • Selective tyrosine kinase inhibition by imatinib mesylate for the treatment of autoimmune arthritis JOURNAL OF CLINICAL INVESTIGATION Paniagua, R. T., Sharpe, O., Ho, P. P., Chan, S. M., Chang, A., Higgins, J. P., Tomooka, B. H., Thomas, F. M., Song, J. J., Goodman, S. B., Lee, D. M., Genovese, M. C., Utz, P. J., Steinman, L., Robinson, W. H. 2006; 116 (10): 2633-2642

    Abstract

    Tyrosine kinases play a central role in the activation of signal transduction pathways and cellular responses that mediate the pathogenesis of rheumatoid arthritis. Imatinib mesylate (imatinib) is a tyrosine kinase inhibitor developed to treat Bcr/Abl-expressing leukemias and subsequently found to treat c-Kit-expressing gastrointestinal stromal tumors. We demonstrate that imatinib potently prevents and treats murine collagen-induced arthritis (CIA). We further show that micromolar concentrations of imatinib abrogate multiple signal transduction pathways implicated in RA pathogenesis, including mast cell c-Kit signaling and TNF-alpha release, macrophage c-Fms activation and cytokine production, and fibroblast PDGFR signaling and proliferation. In our studies, imatinib attenuated PDGFR signaling in fibroblast-like synoviocytes (FLSs) and TNF-alpha production in synovial fluid mononuclear cells (SFMCs) derived from human RA patients. Imatinib-mediated inhibition of a spectrum of signal transduction pathways and the downstream pathogenic cellular responses may provide a powerful approach to treat RA and other inflammatory diseases.

    View details for DOI 10.1172/JCI28546

    View details for Web of Science ID 000240965700013

    View details for PubMedID 16981009

  • Selective tyrosine kinase inhibition by imatinib mesylate for the treatment of autoimmune arthritis. Robinson, W. H., Paniagua, R. T., Ho, P. P., Chan, S. M., Sharpe, O., Utz, P. J., Genovese, M. C. WILEY-BLACKWELL. 2006: S356-S357
  • A pilot study of TNF inhibition in Erosive/Inflammatory osteoarthritis of the hands. Magnano, M. D., Chakravarty, E. F., Broudy, C., Chung, L., Kelman, A., Hillygus, J. J., Genovese, M. C. WILEY-BLACKWELL. 2006: S674-S674
  • Rituximab for rheumatoid arthritis refractory to anti-tumor necrosis factor therapy - Results of a multicenter, randomized, double-blind, placebo-controlled, phase III trial evaluating primary efficacy and safety at twenty-four weeks ARTHRITIS AND RHEUMATISM Cohen, S. B., Emery, P., Greenwald, M. W., DougadoS, M., Furie, R. A., Genovese, M. C., Keystone, E. C., Loveless, J. E., Burmester, G., Cravets, M. W., Hessey, E. W., Shaw, T., Totoritis, M. C. 2006; 54 (9): 2793-2806

    Abstract

    To determine the efficacy and safety of treatment with rituximab plus methotrexate (MTX) in patients with active rheumatoid arthritis (RA) who had an inadequate response to anti-tumor necrosis factor (anti-TNF) therapies and to explore the pharmacokinetics and pharmacodynamics of rituximab in this population.We evaluated primary efficacy and safety at 24 weeks in patients enrolled in the Randomized Evaluation of Long-Term Efficacy of Rituximab in RA (REFLEX) Trial, a 2-year, multicenter, randomized, double-blind, placebo-controlled, phase III study of rituximab therapy. Patients with active RA and an inadequate response to 1 or more anti-TNF agents were randomized to receive intravenous rituximab (1 course, consisting of 2 infusions of 1,000 mg each) or placebo, both with background MTX. The primary efficacy end point was a response on the American College of Rheumatology 20% improvement criteria (ACR20) at 24 weeks. Secondary end points were responses on the ACR50 and ACR70 improvement criteria, the Disease Activity Score in 28 joints, and the European League against Rheumatism (EULAR) response criteria at 24 weeks. Additional end points included scores on the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), Health Assessment Questionnaire (HAQ) Disability Index (DI), and Short Form 36 (SF-36) instruments, as well as Genant-modified Sharp radiographic scores at 24 weeks.Patients assigned to placebo (n = 209) and rituximab (n = 311) had active, longstanding RA. At week 24, significantly more (P < 0.0001) rituximab-treated patients than placebo-treated patients demonstrated ACR20 (51% versus 18%), ACR50 (27% versus 5%), and ACR70 (12% versus 1%) responses and moderate-to-good EULAR responses (65% versus 22%). All ACR response parameters were significantly improved in rituximab-treated patients, who also had clinically meaningful improvements in fatigue, disability, and health-related quality of life (demonstrated by FACIT-F, HAQ DI, and SF-36 scores, respectively) and showed a trend toward less progression in radiographic end points. Rituximab depleted peripheral CD20+ B cells, but the mean immunoglobulin levels (IgG, IgM, and IgA) remained within normal ranges. Most adverse events occurred with the first rituximab infusion and were of mild-to-moderate severity. The rate of serious infections was 5.2 per 100 patient-years in the rituximab group and 3.7 per 100 patient-years in the placebo group.At 24 weeks, a single course of rituximab with concomitant MTX therapy provided significant and clinically meaningful improvements in disease activity in patients with active, longstanding RA who had an inadequate response to 1 or more anti-TNF therapies.

    View details for DOI 10.1002/art.22025

    View details for Web of Science ID 000240872900010

    View details for PubMedID 16947627

  • Sustained efficacy and safety through 2 years in patients with rheumatoid arthritis (RA) in the long-term extension of the ATTAIN trial. Genovese, M. C., Schiff, M., Luggen, M., Becker, J., Aranda, R., McCann, T., Schmidely, N., Le Bars, M., Dougados, M. WILEY-BLACKWELL. 2006: S244-S244
  • Safety of TNF inhibitors in rheumatoid arthritis patients previously treated with rituximab Breedveld, F. C., Van Vollenhoven, R. F., Genovese, M., Emery, P., Moreland, L. W., Keystone, E., Matteson, E. L., Burke, L., Agarwal, S., Kim, D., Cooper, S. TAYLOR & FRANCIS AS. 2006: 11-11
  • Safety of TNF inhibitors in rheumatoid arthritis patients previously treated with rituximab Breedveld, F. C., Genovese, M., Emery, P., Moreland, L. W., Keystone, E., Matteson, E. L., Burke, L., Agarwal, S., Kim, D., Cooper, S. BMJ PUBLISHING GROUP. 2006: 178-179
  • Effect of etanercept on fatigue in patients with recent or established rheumatoid arthritis ARTHRITIS & RHEUMATISM-ARTHRITIS CARE & RESEARCH Moreland, L. W., Genovese, M. C., Sato, R., Singh, A. 2006; 55 (2): 287-293

    Abstract

    To assess the long-term impact of etanercept on fatigue in patients with recent-onset (mean duration 11 months) or established (mean duration 12 years) rheumatoid arthritis (RA).Patients participating in either of 2 multicenter, randomized, double-blind clinical trials were included. In one trial, patients with recent-onset RA received either etanercept 25 mg twice weekly or methotrexate in a double-blind fashion for 12 months, then open label for 12 months. All patients then received open-label etanercept. In the second trial, patients with established RA received etanercept 25 mg or placebo twice weekly for 6 months in a double-blinded fashion, then open-label etanercept. Up to 46 months of followup data were included. Fatigue was measured regularly using the Health Assessment Questionnaire vitality domain.Patients with recent-onset RA who received etanercept had a significantly faster improvement in fatigue than those receiving methotrexate in the first 2 months. Subsequently, patients receiving etanercept and methotrexate had 23-29% and 17-24% reductions in fatigue scores, respectively. In the group with established RA, patients who received etanercept had significantly greater reductions in fatigue than those receiving placebo during the blinded period. Patients initially receiving etanercept sustained a mean fatigue reduction of 25-36% for the entire followup. Patients achieving clinically meaningful improvement in fatigue were more likely to meet the American College of Rheumatology improvement criteria.Etanercept therapy reduces fatigue in patients with recent-onset or established RA. Improvement in fatigue was sustained for up to 46 months, and correlated with other RA-relevant outcomes.

    View details for DOI 10.1002/art.21838

    View details for Web of Science ID 000236830400018

    View details for PubMedID 16583424

  • Long-term experience with etanercept in the treatment of rheumatoid arthritis in elderly and younger patients - Patient-reported outcomes from multiple controlled and open-label extension studies DRUGS & AGING Schiff, M. H., Yu, E. B., Weinblatt, M. E., Moreland, L. W., Genovese, M. C., White, B., Singh, A., Chon, Y., Woolley, J. M. 2006; 23 (2): 167-178

    Abstract

    The impact of long-term therapy for rheumatoid arthritis (RA) in elderly (> or = 65 years of age) and younger (< 65 years of age) patients, especially on patient-reported outcomes, has not been well studied. We evaluated patient-reported outcomes in elderly patients treated with etanercept, in contrast to outcomes in younger patients, using data from multiple controlled and open-label extension studies of patients with early RA (ERA; < or = 3 years) and late RA (LRA; disease-modifying antirheumatic drug [DMARD]-refractory RA).This post hoc analysis included adult patients with RA enrolled in controlled, double-blind studies (up to 2 years) and subsequent open-label extension studies (up to 4 years). Patients were evaluated according to age at baseline of the original study. Patients may have received etanercept, placebo or methotrexate during the blinded treatment phases, but all patients had been receiving etanercept 25 mg twice weekly for at least 4 years. Both ERA and LRA extension studies are ongoing. Patient-reported outcome assessments included improvement in Health Assessment Questionnaire-Disability Index (HAQ-DI), proportions of patients achieving an improvement in HAQ-DI > or = 0.22 points, patients exhibiting worsening of HAQ-DI and patients achieving an HAQ-DI score of 0.Elderly patients, with either ERA or LRA, had significantly worse baseline mean HAQ-DI scores than younger patients (p < 0.05, Student's t-test) in most studies, indicating greater disability. Improvement in HAQ-DI was greatest during the first 3 months after starting etanercept treatment in the controlled phase and appeared to be sustained over 3-6 months in patients with early or DMARD-refractory RA. Across the various controlled trials, mean improvements from baseline in HAQ-DI ranged from 0.39 to 0.92 points in elderly patients and from 0.57 to 1.00 points in younger patients. Patients with ERA and LRA, regardless of age group, maintained their improvement in HAQ-DI throughout the open-label extension trials for up to a total of 6 years of etanercept therapy. Change from baseline in HAQ-DI was moderately correlated with 28-joint Disease Activity Score within each age group across the multiple trials.Both elderly and younger patients with RA treated with etanercept exhibited similar and rapid improvements in functional status during controlled studies, and these improvements were sustained during open-label extension trials.

    View details for Web of Science ID 000237272800006

    View details for PubMedID 16536638

  • A randomized, blinded, parallel group, placebo controlled pilot study evaluating the effect of PVAC treatment in patients with diffuse systemic sclerosis JOURNAL OF RHEUMATOLOGY Genovese, M. C., Chakravarty, E. F., Boyle, D. L., Tutuncu, Z., Thorburn, C. M., Halilhodzic, M., KROLL, S., Baughman, J., Stewart, S., Kavanaugh, A. 2005; 32 (12): 2345-2350

    Abstract

    Systemic sclerosis (SSc) is a disorder characterized by progressive thickening of the skin; there is no effective therapy. PVAC, a potential therapeutic agent derived from delipidated, deglycolipidated Mycobacterium vaccae, has shown effects on cutaneous disease in animal models of SSc. We evaluated the safety and possible biologic effect of intradermal injections of PVAC in patients with diffuse SSc.Eighteen patients enrolled in this double blind, placebo controlled, randomized, 24 week pilot study. All patients met criteria for diffuse SSc without evidence of significant renal dysfunction, pulmonary fibrosis, pulmonary hypertension, or congestive heart failure. Patients received 8 intradermal injections of 15 microg PVAC, 50 microg PVAC, or placebo at 3 week intervals. The primary efficacy endpoint was the change in Modified Rodnan Skin Score (MRSS) at Week 24. Each of the active drug arms was compared to placebo.Baseline demographic and disease characteristics were similar across the 3 treatment groups. The median age was 48 years and 14 of 18 (78%) patients were female. The regimens were well tolerated with no reported serious adverse events; however, grade 1 or 2 injection site reactions occurred in the majority of patients receiving PVAC. The MRSS improved by 20.6% in the 15 microg PVAC arm, while it worsened by 29.8% in the placebo arm and by 16.7% in the 50 microg arm. Change in physician and patient global assessments followed similar trends.In this pilot study, use of PVAC in patients with SSc appeared safe and was associated with a trend toward improved skin scores in the 15 microg treatment group. Additional evaluation of this therapeutic approach is warranted.

    View details for Web of Science ID 000233857500014

    View details for PubMedID 16331761

  • Computer-assisted pattern recognition of autoantibody results CLINICAL AND DIAGNOSTIC LABORATORY IMMUNOLOGY Binder, S. R., Genovese, M. C., Merrill, J. T., Morris, R. I., Metzger, A. L. 2005; 12 (12): 1353-1357

    Abstract

    Immunoassay-based anti-nuclear antibody (ANA) screens are increasingly used in the initial evaluation of autoimmune disorders, but these tests offer no "pattern information" comparable to the information from indirect fluorescence assay-based screens. Thus, there is no indication of "next steps" when a positive result is obtained. To improve the utility of immunoassay-based ANA screening, we evaluated a new method that combines a multiplex immunoassay with a k nearest neighbor (kNN) algorithm for computer-assisted pattern recognition. We assembled a training set, consisting of 1,152 sera from patients with various rheumatic diseases and non-diseased patients. The clinical sensitivity and specificity of the multiplex method and algorithm were evaluated with a test set that consisted of 173 sera collected at a rheumatology clinic from patients diagnosed by using standard criteria, as well as 152 age- and sex-matched sera from presumably healthy individuals (sera collected at a blood bank). The test set was also evaluated with a HEp-2 cell-based enzyme-linked immunosorbent assay (ELISA). Both the ELISA and multiplex immunoassay results were positive for 94% of the systemic lupus erythematosus (SLE) patients. The kNN algorithm correctly proposed an SLE pattern for 84% of the antibody-positive SLE patients. For patients with no connective tissue disease, the multiplex method found fewer positive results than the ELISA screen, and no disease was proposed by the kNN algorithm for most of these patients. In conclusion, the automated algorithm could identify SLE patterns and may be useful in the identification of patients who would benefit from early referral to a specialist, as well as patients who do not require further evaluation.

    View details for DOI 10.1128/CDLI.12.12.1353-1357.2005

    View details for Web of Science ID 000234061400001

    View details for PubMedID 16339056

  • Management of co-morbidities and general medical conditions in patients with rheumatoid arthritis. Current rheumatology reports Magnano, M. D., Genovese, M. C. 2005; 7 (5): 407-415

    Abstract

    Rheumatologists, in addition to providing subspecialty care, are frequently called to treat general medical conditions in their patients with rheumatoid arthritis (RA). Co-morbid medical problems are common in the RA population and may require a different approach from standard practice recommendations. In this paper, we review the evaluation and treatment of cardiovascular disease, chronic kidney disease, gastrointestinal disease, depression, and metabolic bone disease in patients with RA. Appreciation of the unique interaction between arthritis and common medical co-morbidities may have a significant impact on management and outcomes of RA.

    View details for PubMedID 16174493

  • Abatacept for rheumatoid arthritis refractory to tumor necrosis factor alpha inhibition NEW ENGLAND JOURNAL OF MEDICINE Genovese, M. C., Becker, J., Schiff, M., Luggen, M., Sherrer, Y., Kremer, J., Birbara, C., Box, J., Natarajan, K., Nuamah, I., Li, T., Aranda, R., Hagerty, D. T., Dougados, M. 2005; 353 (11): 1114-1123

    Abstract

    A substantial number of patients with rheumatoid arthritis have an inadequate or unsustained response to tumor necrosis factor alpha (TNF-alpha) inhibitors. We conducted a randomized, double-blind, phase 3 trial to evaluate the efficacy and safety of abatacept, a selective costimulation modulator, in patients with active rheumatoid arthritis and an inadequate response to at least three months of anti-TNF-alpha therapy.Patients with active rheumatoid arthritis and an inadequate response to anti-TNF-alpha therapy were randomly assigned in a 2:1 ratio to receive abatacept or placebo on days 1, 15, and 29 and every 28 days thereafter for 6 months, in addition to at least one disease-modifying antirheumatic drug. Patients discontinued anti-TNF-alpha therapy before randomization. The rates of American College of Rheumatology (ACR) 20 responses (indicating a clinical improvement of 20 percent or greater) and improvement in functional disability, as reflected by scores for the Health Assessment Questionnaire (HAQ) disability index, were assessed.After six months, the rates of ACR 20 responses were 50.4 percent in the abatacept group and 19.5 percent in the placebo group (P<0.001); the respective rates of ACR 50 and ACR 70 responses were also significantly higher in the abatacept group than in the placebo group (20.3 percent vs. 3.8 percent, P<0.001; and 10.2 percent vs. 1.5 percent, P=0.003). At six months, significantly more patients in the abatacept group than in the placebo group had a clinically meaningful improvement in physical function, as reflected by an improvement from baseline of at least 0.3 in the HAQ disability index (47.3 percent vs. 23.3 percent, P<0.001). The incidence of adverse events and peri-infusional adverse events was 79.5 percent and 5.0 percent, respectively, in the abatacept group and 71.4 percent and 3.0 percent, respectively, in the placebo group. The incidence of serious infections was 2.3 percent in each group.Abatacept produced significant clinical and functional benefits in patients who had had an inadequate response to anti-TNF-alpha therapy.

    View details for Web of Science ID 000231841900006

    View details for PubMedID 16162882

  • Antigen microarray profiling of autoantibodies in rheumatoid arthritis ARTHRITIS AND RHEUMATISM Hueber, W., Kidd, B. A., Tomooka, B. H., Lee, B. J., Bruce, B., Fries, J. F., Sonderstrup, G., Monach, P., Drijfhout, J. W., van Venrooij, W. J., Utz, P. J., Genovese, M. C., Robinson, W. H. 2005; 52 (9): 2645-2655

    Abstract

    Because rheumatoid arthritis (RA) is a heterogeneous autoimmune disease in terms of disease manifestations, clinical outcomes, and therapeutic responses, we developed and applied a novel antigen microarray technology to identify distinct serum antibody profiles in patients with RA.Synovial proteome microarrays, containing 225 peptides and proteins that represent candidate and control antigens, were developed. These arrays were used to profile autoantibodies in randomly selected sera from 2 different cohorts of patients: the Stanford Arthritis Center inception cohort, comprising 18 patients with established RA and 38 controls, and the Arthritis, Rheumatism, and Aging Medical Information System cohort, comprising 58 patients with a clinical diagnosis of RA of <6 months duration. Data were analyzed using the significance analysis of microarrays algorithm, the prediction analysis of microarrays algorithm, and Cluster software.Antigen microarrays demonstrated that autoreactive B cell responses targeting citrullinated epitopes were present in a subset of patients with early RA with features predictive of the development of severe RA. In contrast, autoimmune targeting of the native epitopes contained on synovial arrays, including several human cartilage gp39 peptides and type II collagen, were associated with features predictive of less severe RA.Proteomic analysis of autoantibody reactivities provides diagnostic information and allows stratification of patients with early RA into clinically relevant disease subsets.

    View details for DOI 10.1002/art.21269

    View details for Web of Science ID 000232115700009

    View details for PubMedID 16142722

  • Selective co-stimulation modulation with abatacept leads to improvements in ACR responses in patients with an inadequate response to etanercept, infliximab or both: The ATTAIN trial. Dougados, M., Kavanagh, A., Espinoza, L., Sibilia, J., Aranda, R., Becker, J. C., White, A., Genovese, M., Schiff, M., Luggen, M. WILEY-BLACKWELL. 2005: S137-S138
  • The impact of disease duration on improvements in ACR responses and remission following abatacept treatment in patients with an inadequate response 2 to anti-TNF therapy in the ATTAIN trial. Genovese, M., Luggen, M., Kremer, J., Sany, J., Aranda, R., Becker, J. C., White, A., Schiff, M., Dougados, M. WILEY-BLACKWELL. 2005: S137-S137
  • Efficacy of abatacept following wash-out of anti-TNF therapy in rheumatoid arthritis patients in the ATTAIN (Abatacept Trial in Treatment of Anti-TNF INadequate Responders) trial: Current versus prior discontinuation. Genovese, M., Schiff, M., Luggen, M., Aranda, R., Becker, J. C., White, A., Dougados, M. WILEY-BLACKWELL. 2005: S560-S561
  • Abatacept leads to significant improvements in all American college of rheumatology core components in patients with an inadequate response to anti-TNF therapy in the attain trial Schiff, M., Dougados, M., Luggen, M., Espinoza, L., Nuamah, I., Aranda, R., Becker, J., Genovese, M. BMJ PUBLISHING GROUP. 2005: 435-436
  • Beneficial effects of the selective CO-stimulation modulator abatacept on biomarkers of rheumatoid arthritis immunopathology in patients with an inadequate response to methotrexate or TNF-inhibitor treatment Emery, R., Westhovens, R., LEON, G., Nuamah, I., Ge, Z., Aranda, R., Becker, J., Genovese, M., Dougados, M. BMJ PUBLISHING GROUP. 2005: 432-433
  • Longterm safety, efficacy, and radiographic outcome with etanercept treatment in patients with early rheumatoid arthritis JOURNAL OF RHEUMATOLOGY Genovese, M. C., Bathon, J. M., Fleischmann, R. M., Moreland, L. W., Martin, R. W., Whitmore, J. B., Tsuji, W. H., Leff, J. A. 2005; 32 (7): 1232-1242

    Abstract

    To evaluate safety, efficacy, and radiographic progression in patients with early rheumatoid arthritis (RA) undergoing longterm treatment with etanercept.Patients with early RA (disease duration of 3 years or less) who had completed a 2-year efficacy study comparing etanercept and methotrexate (MTX) were followed in an extension where they received 25 mg etanercept twice weekly. Safety was summarized descriptively and compared with data from the efficacy study. Efficacy and radiographic progression were assessed using American College of Rheumatology response criteria, disease activity scores, and Total Sharp Score (TSS).Rates of serious adverse events and serious infections did not increase with longterm exposure to etanercept, and were similar to rates reported for the blinded portion of the efficacy study. Efficacy was sustained in patients who completed 5 years of etanercept treatment at the time of this report (N = 201), even in those who decreased or discontinued use of MTX or corticosteroids. No radiographic progression (change in TSS < or = 0) was seen in 55% of patients with 5-year radiographs; negative change (TSS < 0) was seen in 11%.Etanercept treatment in patients with early RA was generally well tolerated for up to 5 years. The results indicate sustained efficacy and decreased rate of radiographic progression. The rate of radiographic progression was low compared with other studies, emphasizing the benefit gained in patients with early aggressive RA who undergo longterm treatment with etanercept.

    View details for Web of Science ID 000230532000012

    View details for PubMedID 15996057

  • Factors that predict prematurity and preeclampsia in pregnancies that are complicated by systemic lupus erythematosus AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY Chakravarty, E. F., Colon, I., Langen, E. S., Nix, D. A., El-Sayed, Y. Y., Genovese, M. C., Druzin, M. L. 2005; 192 (6): 1897-1904

    Abstract

    The purpose of this study was to describe the outcomes of a 10-year cohort of pregnancies in patients with systemic lupus erythematosus and to evaluate clinical and laboratory markers for adverse outcomes.We reviewed all pregnancies in patients with systemic lupus erythematosus who were seen at Stanford University from 1991 to 2001. Univariate analyses were performed to identify potential risk factors for adverse outcomes.Sixty-three pregnancies in 48 women were identified. Approximately 35% of the pregnancies occurred in women with previous renal disease and 10% in women with previous central nervous system disease. Flares occurred in 68% of the pregnancies, the majority of which were mild to moderate. Preeclampsia complicated 12 pregnancies. Factors that were associated with premature delivery included prednisone use at conception (relative risk, 1.8), the use of antihypertensive medications (relative risk, 1.8), and a severe flare during pregnancy (relative risk, 2.0). Thrombocytopenia was associated with an increased risk of preeclampsia (relative risk, 3.2).Flares, most of which were mild to moderate, occurred most of the pregnancies in our cohort of patients with systemic lupus erythematosus. Thrombocytopenia, hypertension, and prednisone use may be predictive factors for particular adverse outcomes.

    View details for DOI 10.1016/j.ajog.2005.02.063

    View details for Web of Science ID 000230037600034

    View details for PubMedID 15970846

  • Biologic therapies in clinical development for the treatment of rheumatoid arthritis JCR-JOURNAL OF CLINICAL RHEUMATOLOGY Genovese, M. C. 2005; 11 (3): S45-S54

    Abstract

    The therapeutic objective in patients with rheumatoid arthritis (RA) is reduction of disease activity with an ultimate goal of disease remission. Limitations of currently available disease-modifying antirheumatic drugs and biologic therapies suggest that there remains an unmet need for agents that advance these goals in a greater proportion of patients. Progress in our understanding of the regulatory molecules and pathways that mediate the immune and inflammatory responses necessary for the initiation and perpetuation of RA has led to the identification of new targets for therapy. It is expected that the therapeutic modulation of these targets, which include proinflammatory cytokines, T and B cells, adhesion molecules, chemokines, and intra- and extracellular signaling pathways, can provide new treatment strategies in patients with RA and other autoimmune disorders. Toward this end, a series of novel agents with diverse mechanisms of action are in development. Although many of these agents are still beyond the clinical horizon, several of them have shown promise in recent trials. This article reviews a few of the many treatment strategies currently being evaluated, which are hoped to lead to greater benefits and better disease management in the clinical setting.

    View details for DOI 10.1097/01.rhu.0000166625.65114.5f

    View details for Web of Science ID 000230136100003

    View details for PubMedID 16357750

  • Temporal effects of a COX-2-selective NSAID on bone ingrowth. Journal of biomedical materials research. Part A Goodman, S. B., Ma, T., Mitsunaga, L., Miyanishi, K., Genovese, M. C., Smith, R. L. 2005; 72 (3): 279-287

    Abstract

    The effects of a short course of a COX-2 inhibitor on bone healing when the drug is discontinued are unknown. We examined the effects of rofecoxib on bone ingrowth over a 6-week period using a well-defined animal model. The Bone Harvest Chamber was implanted bilaterally in mature rabbits. After osseointegration of the chamber, the following treatments were given for 6 weeks each, followed by a harvest in each case: control-no drug; oral rofecoxib (12.5 mg/day) for the first 2 of 6 weeks; washout period-no drug; oral rofecoxib for the last 2 of 6 weeks; washout period-no drug; rofecoxib given continuously for all 6 weeks. Harvested specimens were snap-frozen, cut into serial 6-microm sections, and stained with hematoxylin and eosin and alkaline phosphatase (osteoblast marker), and processed using immunohistochemistry to identify the vitronectin receptor (osteoclast-like cells). Rofecoxib given continuously for 6 weeks yielded statistically less bone ingrowth compared to the control treatment. Rofecoxib given during the initial or final 2 weeks of a 6-week treatment did not appear to interfere with bone ingrowth. This suggests that the effects of COX-2 inhibitors on bone are less profound when the drug is administered for a short period of time.

    View details for PubMedID 15666361

  • Temporal effects of a COX-2-selective NSAID on bone ingrowth JOURNAL OF BIOMEDICAL MATERIALS RESEARCH PART A Goodman, S. B., Ma, T., Mitsunaga, L., Miyanishi, K., Genovese, M. C., Smith, R. L. 2005; 72A (3): 279-287
  • Fibrinogen-induced arthritis in mice as a novel model for rheumatoid arthritis. Ho, P. P., Tomooka, B. H., Higgins, J. P., Lee, L. Y., Genovese, M., Robinson, W. H. ACADEMIC PRESS INC ELSEVIER SCIENCE. 2005: S32-S32
  • A multicentre, randomised, double blind, placebo controlled phase II study of subcutaneous interferon beta-1a in the treatment of patients with active rheumatoid arthritis ANNALS OF THE RHEUMATIC DISEASES van Holten, J., Pavelka, K., Vencovsky, J., Stahl, H., Rozman, B., Genovese, M., Kivitz, A. J., Alvaro, J., Nuki, G., Furst, D. E., Herrero-Beaumont, G., McInnes, I. B., Musikic, P., Tak, P. P. 2005; 64 (1): 64-69

    Abstract

    To assess the efficacy of interferon beta (IFN beta) in combination with methotrexate in treatment of patients with rheumatoid arthritis.209 patients with active rheumatoid arthritis, who had been on methotrexate for at least six months and at a stable dose for four weeks before study entry, were randomised in double blind fashion to receive placebo (0.05 ml or 0.5 ml), IFN beta 2.2 microg (0.05 ml), or IFN beta 44 microg (0.5 ml), given subcutaneously three times weekly for 24 weeks. The primary efficacy measure was a change in radiological scores at week 24. The secondary endpoint was the proportion of patients who met the ACR 20% improvement criteria at the end of the study. Synovial biopsy specimens were obtained before and after treatment from a subset of patients. Immunohistochemistry was used to detect the presence of inflammatory cells and the results were measured by digital image analysis. Collagen crosslinks were measured in urine at different times throughout the study.Analysis of radiological scores and clinical variable showed no changes in any of the groups, and there were no differences between the groups. On microscopic analysis of synovial tissue there was no significant change in the scores for infiltration by inflammatory cells after IFN beta treatment. Urinary levels of collagen crosslinks were unchanged between the treatment groups.At the doses tested, treatment with IFN beta three times weekly in combination with methotrexate did not have a clinical or radiological effect in patients with rheumatoid arthritis.

    View details for DOI 10.1136/ard.2003.020347

    View details for Web of Science ID 000225800100014

    View details for PubMedID 15242865

  • Pharmacologic modulation of periprosthetic osteolysis CLINICAL ORTHOPAEDICS AND RELATED RESEARCH Goodman, S. B., Trindade, M., Ma, T., Genovese, M., Smith, R. L. 2005: 39-45

    Abstract

    Wear and periprosthetic osteolysis of total joint replacements continue to be the most important problems in arthroplasty surgery. Despite the introduction of improved technologies including alternative bearing surfaces for TJRs, wear is inevitable because of relative movement at different interfaces and processes such as electrolysis and material degradation. Worn, clinically failing implants need to be followed closely and revised when appropriate. However, early wear and minor osteolysis do not result necessarily in progressive failure of the prosthesis. Indeed such cases may be followed up clinically and radiographically to establish the functional and biologic sequelae of wear and the timeline of these events. This scenario provides an opportunity to modulate the adverse biologic reaction associated with wear particles that includes chronic inflammation, the foreign body response, and periprosthetic bone destruction. Currently, immunological events associated with wear particles are becoming understood more clearly. Strategies to mitigate adverse processes associated with wear debris include local or systemic administration of immune modulators, signaling molecules, anti-inflammatory agents and growth factors, and altering osteoclast function. Ultimately, prevention of accelerated wear and periprosthetic osteolysis will be achieved with improved bearing surfaces and prosthetic designs.

    View details for DOI 10.1097/01/blo.0000149998.88218.05

    View details for Web of Science ID 000226145500005

    View details for PubMedID 15662302

  • Efficacy and safety of abatacept (CTLA41g), a selective co-stimulation modulator, in rheumatoid arthritis patients not responding adequately to anti-TNF-alpha therapy: Results of the phase III ATTAIN (Abatacept trial in treatment of Anti-TNF INadequate responders) Genovese, M., Luggen, M., Schiff, M., Sherrer, Y., Nuamah, I., Aranda, R., Becker, J. C., Dougados, M. WILEY-BLACKWELL. 2004: 4103-4103
  • Magnetic resonance imaging of articular cartilage of the knee: Comparison between fat-suppressed three-dimensional SPGR imaging, fat-suppressed FSE imaging, and fat-suppressed three-dimensional DEFT imaging, and correlation with arthroscopy JOURNAL OF MAGNETIC RESONANCE IMAGING Yoshioka, H., Stevens, K., Hargreaves, B. A., Steines, D., Genovese, M., Dillingham, M. F., Winalski, C. S., Lang, P. 2004; 20 (5): 857-864

    Abstract

    To compare signal-to-noise ratios (S/N) and contrast-to-noise ratios (C/N) in various MR sequences, including fat-suppressed three-dimensional spoiled gradient-echo (SPGR) imaging, fat-suppressed fast spin echo (FSE) imaging, and fat-suppressed three-dimensional driven equilibrium Fourier transform (DEFT) imaging, and to determine the diagnostic accuracy of these imaging sequences for detecting cartilage lesions in osteoarthritic knees, as compared with arthroscopy.Two sagittal fat-suppressed FSE images (repetition time [TR] / echo time [TE], 4000/13 [FSE short TE] and 4000/39 [FSE long TE]), sagittal fat-suppressed three-dimensional SPGR images (60/5, 40 degrees flip angle), and sagittal fat-suppressed echo-planar three-dimensional DEFT images (400/21.2) were acquired in 35 knees from 28 patients with osteoarthritis of the knee. The S/N efficiencies (S/Neffs) of cartilage, synovial fluid, muscle, meniscus, bone marrow, and fat tissue, and the C/N efficiencies (C/Neffs) of these structures were calculated. Kappa values, exact agreement, sensitivity, specificity, positive predictive value, and negative predictive value were determined by comparison of MR grading with arthroscopic results.The synovial fluid S/Neff on fat-suppressed FSE short TE images, fat-suppressed FSE long TE images, and fat-suppressed three-dimensional DEFT images showed similar values. Fat-suppressed three-dimensional DEFT images showed the highest fluid-cartilage C/Neff of all sequences. All images showed fair to good agreement with arthroscopy (kappa, 0.615 in FSE short TE, 0.601 in FSE long TE, 0.583 in three-dimensional SPGR, and 0.561 in three-dimensional DEFT). Although the sensitivity of all sequences was high (100% in FSE short TE, FSE long TE, and DEFT; 96.7% in SPGR), specificity was relatively low (67.6% in FSE short TE and FSE long TE; 85.3% in SPGR; 58.3% in DEFT). The peripheral area of bone marrow edema or whole area of bone marrow edema on fat-suppressed FSE images was demonstrated as low or iso-signal intensity on fat-suppressed three-dimensional DEFT images.Fat-suppressed three-dimensional SPGR imaging and fat-suppressed FSE imaging showed high sensitivity and high negative predictive values, but relatively low specificity. The Kappa value and exact agreement was the highest on fat-suppressed FSE short TE images. Fat-suppressed three-dimensional DEFT images showed results similar to the conventional sequences.

    View details for DOI 10.1002/jmri.20193

    View details for Web of Science ID 000224762700017

    View details for PubMedID 15503323

  • Effects of prasterone on disease activity and symptoms in women with active systemic lupus erythematosus - Results of a multicenter randomized, double-blind, placebo-controlled trial ARTHRITIS AND RHEUMATISM Petri, M. A., Mease, P. J., Merrill, J. T., Lahita, R. G., Iannini, M. J., Yocum, D. E., GINZLER, E. M., Katz, R. S., Gluck, O. S., Genovese, M. C., van Vollenhoven, R., Kalunian, K. C., Manzi, S., Greenwald, M. W., Buyon, J. P., Olsen, N. J., Schiff, M. H., Kavanaugh, A. F., Caldwell, J. R., Ramsey-Goldman, R., St Clair, E. W., Goldman, A. L., Egan, R. M., Polisson, R. P., Moder, K. G., Rothfield, N. F., Spencer, R. T., Hobbs, K., Fessler, B. J., Calabrese, L. H., Moreland, L. W., Cohen, S. B., Quarles, B. J., Strand, V., GURWITH, M., Schwartz, K. E. 2004; 50 (9): 2858-2868

    View details for DOI 10.1002/art.20427

    View details for Web of Science ID 000223799200017

  • Demyelination and inhibition of tumor necrosis factor (TNF) CLINICAL AND EXPERIMENTAL RHEUMATOLOGY Magnano, M. D., Robinson, W. H., Genovese, M. C. 2004; 22 (5): S134-S140

    Abstract

    The development of tumor necrosis factor alpha (TNFalpha) inhibitor therapy is arguably the most significant achievement in the treatment of rheumatic diseases to date. One serious potential side effect associated with these agents is the onset of neurologic signs and symptoms. In this paper we will examine the relationship of TNFalpha antagonism and demyelinating disease. Reviewing early laboratory and animal models, we discuss the mechanism of TNFalpha in central nervous system (CNS) injury and repair. Two negative studies of TNFa inhibitor therapy in the treatment of refractory multiple sclerosis (MS) are considered. From the manufacturers' clinical development programs and post-marketing adverse event reporting data, we report the current incidence of demyelinating symptoms associated with each of the commercially available anti-TNFa agents. Comparing these reports to the incidence of MS in society as a whole, we find the rate of new cases of neurologic disease in exposed patients is not different from the rate of expected cases. Finally we explore arguments that support and refute a potential biologic relationship between TNFa neutralization and demyelinating disease.

    View details for Web of Science ID 000224406600021

    View details for PubMedID 15552527

  • Arthritis antigen microarray analysis reveals associations of distinct autoantibody profiles with markers of disease activity and severity in RA. Hueber, W., Kidd, B., Lee, B. J., Genovese, M., Bruce, B., Fries, J., van Venrooij, W., Robinson, W. H. WILEY-BLACKWELL. 2004: S651-S651
  • A randomized, blinded, parallel group, placebo-controlled, pilot study evaluating the effect of Pvac treatment in patients with diffuse systemic sclerosis Genovese, M. C., Boyle, D., Chakravarty, E., Tutuncu, Z., Thorburn, C., Halilhodzic, M., KROLL, S., Stewart, S., Baughman, J., Kavanaugh, A. WILEY-BLACKWELL. 2004: S636-S636
  • Combination leflunomide and methotrexate (MTX) therapy for patients with active rheumatoid arthritis failing MTX monotherapy: Open-label extension of a randomized, double-blind, placebo controlled trial JOURNAL OF RHEUMATOLOGY Kremer, J., Genovese, M., Cannon, G. W., Caldwell, J., Cush, J., Furst, D. E., Luggen, M., Keystone, E. D., Bathon, J., Kavanaugh, A., Ruderman, E., Coleman, P., Curtis, D., Kopp, E., Kantor, S., Weisman, M., Waltuck, J., Lindsley, H. B., Markenson, J., Crawford, B., Fernando, I., Simpson, K., Strand, V. 2004; 31 (8): 1521-1531

    Abstract

    To obtain additional safety and efficacy data on leflunomide (LEF) treatment in combination with methotrexate (MTX) therapy in an open-label extension study in patients with rheumatoid arthritis (RA).Following a 24 week, randomized, double-blind trial of adding placebo (PLA) or LEF to stable MTX therapy, patients could enter a 24 week extension. Subjects randomized to LEF and MTX continued treatment [(LEF/LEF) + MTX]. Subjects randomized to PLA and MTX switched to LEF (10 mg/day, no loading dose) and MTX [(PLA/LEF) + MTX]. The double-blind regarding initial randomization was maintained.For subjects in the extension phase, American College of Rheumatology 20% (ACR20) responder rates for the (LEF/LEF) + MTX group were maintained from Week 24 (57/96, 59.4%) to Week 48 (53/96, 55.2%). ACR20 responder rates improved in patients switched to LEF from PLA at Week 24 [(PLA/LEF) + MTX] from 25.0% (24/96) at Week 24 to 57.3% (55/96) at Week 48. Patients in the extension who switched from PLA to LEF without a loading dose exhibited a lower incidence of elevated transaminases compared to patients initially randomized to LEF. Diarrhea and nausea were less frequent during the open-label extension in patients who did not receive a LEF loading dose.Response to therapy was maintained to 48 weeks of treatment in patients who continued to receive LEF and MTX during the extension. Importantly, ACR20 response rates after 24 weeks of LEF therapy were similar between patients switched from PLA to LEF without loading dose, and those who received a loading does of LEF (100 mg/day x 2 days) at randomization. Fewer adverse events were reported in patients switched to LEF without a loading dose.

    View details for Web of Science ID 000223004900010

    View details for PubMedID 15290730

  • The efficacy of switching from etanercept to infliximab in patients with rheumatoid arthritis JOURNAL OF RHEUMATOLOGY Hansen, K. E., Hildebrand, J. P., Genovese, M. C., Cush, J. J., Patel, S., Cooley, D. A., Cohen, S. B., Gangnon, R. E., Schiff, M. H. 2004; 31 (6): 1098-1102

    Abstract

    To describe the degree of clinical benefit in patients with rheumatoid arthritis (RA) who receive infliximab therapy after lack of efficacy with etanercept.In a retrospective study among 6 centers primarily designed to assess the safety of infliximab in combination with leflunomide, a standardized chart review form was used to collect data on 93 patients with RA. During that study, it was noted that some of these patients had switched from etanercept to infliximab. In this study, we compared the response of subjects switching from etanercept to infliximab (n = 20) to that of subjects receiving infliximab with no prior tumor necrosis factor (TNF) therapy (n = 73).The swollen and tender joint count, patient and physician global assessments, morning stiffness, and C-reactive protein all improved substantially in both groups, with no statistical difference in the degree of benefit between the groups. At the time of chart review, switchers had received a statistically higher dose of infliximab than controls (4.4 vs 3.19 mg/kg; p = 0.006) with a total of 5.7 and 5 infusions, respectively.In this retrospective study, previous lack of efficacy with etanercept did not predict lack of efficacy with infliximab. Indeed, the degree of clinical improvement was similar in both groups, although switchers were receiving a higher dose of infliximab at the time of chart review. Our findings suggest that clinical response may differ between anti-TNF agents, and lack of response to one agent may not predict a lack of response to another.

    View details for Web of Science ID 000221823500015

    View details for PubMedID 15170921

  • Associations between rheumatoid arthritis and malignancy RHEUMATIC DISEASE CLINICS OF NORTH AMERICA Chakravarty, E. F., Genovese, M. C. 2004; 30 (2): 271-?

    Abstract

    There are many complex associations between rheumatoid arthritis(RA) and malignancy. Patients with rheumatic diseases on the whole appear to be at increased risk for the development of certain malignancies. The data from several studies are persuasive that the presence of RA conveys an increased risk for the development of lymphoproliferative disorders and may convey a decreased risk for the development of malignancies of the digestive tract. Understanding the complex interrelationships between RA and malignancy will lead to more accurate diagnosis of underlying pathology, more effective treatment of symptoms and underlying disease, and appropriate surveillance for the development of later complications.

    View details for DOI 10.1016/j.rdc.2004.01.007

    View details for Web of Science ID 000221971000004

    View details for PubMedID 15172040

  • Combination therapy with etanercept and anakinra in the treatment of patients with rheumatoid arthritis who have been treated unsuccessfully with methotrexate ARTHRITIS AND RHEUMATISM Genovese, M. C., Cohen, S., Moreland, L., Lium, D., Robbins, S., Newmark, R., Bekker, P. 2004; 50 (5): 1412-1419

    Abstract

    To determine the potential for additive or synergistic effects of combination therapy with the selective anti-tumor necrosis factor alpha agent etanercept and the anti-interleukin-1 agent anakinra.Two hundred forty-four patients in whom rheumatoid arthritis (RA) was active despite methotrexate therapy were treated with subcutaneous etanercept only (25 mg twice weekly), full-dosage etanercept (25 mg twice weekly) plus anakinra (100 mg/day), or half-dosage etanercept (25 mg once weekly) plus anakinra (100 mg/day) for 6 months in a double-blind study at 41 centers in the US. Patients had never previously received anticytokine therapy. Patient response was measured with the American College of Rheumatology (ACR) core set criteria, a health-related quality-of-life questionnaire, and the Disease Activity Score. Safety was assessed by the number of adverse events and clinical laboratory values. Plasma concentrations of both agents and antibody formation against both agents were also assessed.Combination therapy with etanercept plus anakinra provided no treatment benefit over etanercept alone, regardless of the regimen, but was associated with an increased safety risk. Thirty-one percent of the patients treated with full-dosage etanercept plus anakinra achieved an ACR 50% response, compared with 41% of the patients treated with etanercept only. This result was not statistically significant (P = 0.914). The incidence of serious infections (0% for etanercept alone, 3.7-7.4% for combination therapy), injection-site reactions, and neutropenia was increased with combination therapy. Combination therapy had no effect on the pharmacokinetics or immunogenicity of either agent.Combination therapy with etanercept and anakinra provides no added benefit and an increased risk compared with etanercept alone and is not recommended for the treatment of patients with RA.

    View details for DOI 10.1002/art.20221

    View details for Web of Science ID 000221340900008

    View details for PubMedID 15146410

  • Treatment of rheumatoid arthritis with etanercept RHEUMATIC DISEASE CLINICS OF NORTH AMERICA Genovese, M. C., Kremer, J. M. 2004; 30 (2): 311-?

    Abstract

    Etanercept is effective in the treatment of rheumatoid arthritis (RA)when used as monotherapy and in combination with methotrexate(MTX). Radiographic progression of disease was slowed significantly when the drug was used for a 24-month period and was statistically significantly better than MTX. In addition to its use in RA,etanercept is approved by the U.S. Food and Drug Administration for other rheumatologic conditions, including psoriatic arthritis,ankylosing spondylitis, and juvenile chronic arthritis.

    View details for DOI 10.1016/j.rdc.2004.01.004

    View details for Web of Science ID 000221971000007

    View details for PubMedID 15172043

  • The safety and efficacy of leflunomide in combination with infliximab in rheumatoid arthritis ARTHRITIS & RHEUMATISM-ARTHRITIS CARE & RESEARCH Hansen, K. E., Cush, J., Singhal, A., Cooley, D. A., Cohen, S., Patel, S. R., Genovese, M., Sundaramurthy, S., Schiff, M. 2004; 51 (2): 228-232

    Abstract

    To report the safety and efficacy of leflunomide (LEF) in combination with infliximab (INF) for the treatment of rheumatoid arthritis.In an open, multicenter, retrospective study, data were collected on the safety and efficacy of LEF and INF.Eighty-eight patients received the combination of LEF and INF for an average of 6.6 months and a total exposure of 581 patient-months. The mean duration of LEF was 17 +/- 9 months (range 3-32 months; median 18.5 months) with an average of 4.8 INF infusions per patient. In all but 3 subjects, LEF was used initially and INF was added later. Infusion reactions occurred in 3 patients (0.7% of all infusions). A total of 34% of subjects experienced adverse events and in 6 (6.8% of the group) these were deemed serious. Ten infections occurred when patients were taking the combination; 9 patients recovered fully and 1 died of bacterial pneumonia. A lifetime smoker developed lung cancer and another patient was found to have colon cancer.The adverse events noted within the combination therapy group were in keeping with the known risks of each drug when used individually. Limited data were available on efficacy, but a general improvement in disease control was noted with the combination of drugs, which for most patients involved the addition of INF to previous use of LEF.

    View details for DOI 10.1002/art.20228

    View details for Web of Science ID 000220764600012

    View details for PubMedID 15077264

  • Unlocking the "PAD" lock on rheumatoid arthritis ANNALS OF THE RHEUMATIC DISEASES Utz, P. J., Genovese, M. C., Robinson, W. H. 2004; 63 (4): 330-332

    View details for DOI 10.1136/ard.2003.015990

    View details for Web of Science ID 000220198000002

    View details for PubMedID 15020322

  • Articular cartilage of knee: Normal patterns at MR imaging that mimic disease in healthy subjects and patients with osteoarthritis RADIOLOGY Yoshioka, H., Stevens, K., Genovese, M., Dillingham, M. F., Lang, P. 2004; 231 (1): 31-38

    Abstract

    To evaluate normal magnetic resonance (MR) imaging findings that may mimic articular cartilage diseases in healthy subjects and patients with osteoarthritis of the knee.Sagittal fat-suppressed intermediate-weighted fast spin-echo (FSE) (repetition time msec/echo time [TE] msec, 4,000/13), sagittal T2-weighted FSE (4,000/39), and sagittal fat-suppressed three-dimensional (3D) spoiled gradient-echo (SPGR) (60/5, 40 degrees flip angle) MR images were acquired in 28 patients and four volunteers. FSE images with a TE of 13 msec were considered "short-TE images"; those with a TE of 39 msec were considered "long-TE images." Presence of normal MR imaging appearance of articular cartilage was determined by one author. Contrast between cartilage and adjacent structures (meniscus, joint capsule, synovial fluid, muscle) was calculated in posterior regions of the femoral condyle on images obtained with each sequence; Wilcoxon signed rank testing was performed.The following appearances were observed in patients with knee osteoarthritis (on short-TE FSE, long-TE FSE, and SPGR MR images, respectively): (a) ambiguity of surface contour in posterior region of the femoral condylar cartilage (in zero, zero, and 20 patients), (b) linear area of high signal intensity in deep zone adjacent to subchondral bone of femoral condyle (in zero, zero, and 26 patients), (c) pseudolaminar appearance in posterior region of femoral condylar cartilage (in seven, nine, and 24 patients), (d) truncation artifact in patellofemoral compartment (in seven, six, and 27 patients), (e) susceptibility artifact on cartilage surface caused by air or metal (in three, three, and 11 patients), (f) decreased signal intensity in distal part of trochlear cartilage (in 28, 28, and 28 patients), (g) cartilage thinning adjacent to the anterior horn of the lateral meniscus (in 19, 19, and 21 patients), and (h) focal cartilage flattening in posterior region of femoral condyle (in 16, 16, and nine patients). Cartilage-meniscus and cartilage-synovial fluid contrast was significantly higher on fat-suppressed FSE than on fat-suppressed 3D SPGR MR images (P <.001).Fat-suppressed FSE and 3D SPGR MR images showed nonuniform signal intensity arising from articular cartilage and cartilage thinning, both of which could mimic disease.

    View details for DOI 10.1148/radiol.2311020453

    View details for Web of Science ID 000220394300006

    View details for PubMedID 15068938

  • A randomized, controlled trial of interferon-beta-1a (Avonex(R)) in patients with rheumatoid arthritis: a pilot study [ISRCTN03626626]. Arthritis research & therapy Genovese, M. C., Chakravarty, E. F., Krishnan, E., Moreland, L. W. 2004; 6 (1): R73-R77

    Abstract

    The objective of this study was to evaluate the safety and possible efficacy of IFN-beta-1a for the treatment of patients with rheumatoid arthritis (RA). Twenty-two patients with active RA were enrolled in a phase II randomized, double-blind, placebo-controlled trial of 30 microg IFN-beta-1a by weekly self-injection for 24 weeks. The primary outcome of the study was safety. Secondary outcomes included the proportion of patients achieving an American College of Rheumatology (ACR) 20 response at 24 weeks. There were no significant differences in adverse events reported in the two groups. Fewer than 20% of patients in each arm of the study achieved an ACR 20 response at 24 weeks (P = 0.71). Sixty-nine percent of patients receiving IFN-beta and 67% receiving placebo terminated the study early, most of them secondary to a perceived lack of efficacy. Overall, IFN-beta-1a had a safety profile similar to that of placebo. There were no significant differences in the proportion of patients achieving an ACR 20 response between the two groups.

    View details for PubMedID 14979940

  • A randomized, controlled trial of interferon-beta-1a (Avonex (R)) in patients with rheumatoid arthritis: a pilot study [ISRCTN03626626] ARTHRITIS RESEARCH & THERAPY Genovese, M. C., Chakravarty, E. F., Krishnan, E., Moreland, L. W. 2004; 6 (1): R73-R77

    View details for DOI 10.1186/ar1026

    View details for Web of Science ID 000187021500012

  • Interleukin 1 receptor antagonist inhibits localized bone formation in vivo JOURNAL OF RHEUMATOLOGY Ma, T., Miyanishi, K., Trindade, M. C., Genovese, M., Regula, D., Smith, R. L., Goodman, S. B. 2003; 30 (12): 2547-2552

    Abstract

    To test the in vivo effects of interleukin 1 receptor antagonist (IL-1ra) on bone formation and tissue ingrowth using an implantable bone ingrowth chamber that can be infused with test solutions.The bone ingrowth chamber was implanted in the proximal tibia of 10 mature NZW rabbits unilaterally. After an initial osseointegration period, the chambers were emptied of tissue and infused with either 0.05% bovine serum albumin (BSA) in phosphate buffered saline (PBS) or an IL-1ra solution for 4-week periods, which were separated by 4-week periods of no infusion. Tissue samples harvested from each chamber were snap-frozen and examined by histology and immunohistochemistry.The chambers were filled with longitudinally-oriented woven bone in a fibrovascular stroma during periods of infusion of 0.05% BSA in PBS or during periods without infusion. In contrast, infusion of IL-1ra for 4 weeks prevented tissue ingrowth in 4 of 6 chambers, and in 2 chambers exhibiting tissue ingrowth, bone formation was decreased. Bone formation remained at a lower level during the subsequent two 4-week periods without infusion after IL-1ra was discontinued, compared to samples prior to the IL-1ra treatment.The results showed that tissue ingrowth and bone formation were suppressed in an in vivo model by continuous infusion of IL-1ra at an early phase of tissue regeneration and differentiation.

    View details for Web of Science ID 000187441800008

    View details for PubMedID 14719192

  • Synovial proteome microarrays identify deiminated proteins as targets of the autoantibody response in Rheumatoid Arthritis Hueber, W., Lee, B. J., Genovese, M. C., Bruce, B., van Venrooij, W. J., Smolen, J. S., Steinman, L., Utz, P. J., Robinson, W. H. WILEY-BLACKWELL. 2003: S429-S429
  • The Early Rheumatoid Arthritis (ERA) Trial comparing the efficacy and safety of etanercept and methotrexate CLINICAL AND EXPERIMENTAL RHEUMATOLOGY Bathon, J. M., Genovese, M. C. 2003; 21 (5): S195-S197

    Abstract

    The Early Rheumatoid Arthritis (ERA) trial compared monotherapy with etanercept or methotrexate in patients with early erosive rheumatoid arthritis. Over the initial period of 12, and subsequently 24, months both treatments were associated with a profound reduction in radiographic progression of joint damage, as well as a reduction in signs and symptoms of disease. Etanercept showed slight superiority to methotrexate in reducing subsequent radiographic erosions and in the rapidity of the clinical response. Both therapies proved to be safe and well tolerated and, importantly, the relative safety and tolerance of a rapidly escalated dosing regimen for methotrexate was demonstrated. In summary, early aggressive treatment of RA is associated with clinical and radiographic benefit that can be demonstrated after a relatively short period of treatment.

    View details for Web of Science ID 000185970100035

    View details for PubMedID 14969076

  • COX-2 selective inhibitors and bone INTERNATIONAL JOURNAL OF IMMUNOPATHOLOGY AND PHARMACOLOGY Goodman, S. B., Ma, T., Genovese, M., Smith, R. L. 2003; 16 (3): 201-205

    Abstract

    Non-steroidal anti-inflammatory drugs (NSAIDs) are widely prescribed medications for relief of pain and inflammation. Recent animal studies using models of fracture healing and bone ingrowth suggest that NSAIDs (both non-selective NSAIDs and selective COX-2 inhibitors) adversely affect these bone-related processes. The dose and time-relationships of these medications and their resulting effects on bone have not yet been fully elucidated. Furthermore, whether COX-2 inhibitors and non-selective NSAIDs lead to clinically relevant adverse effects on bone healing in humans is unknown.

    View details for Web of Science ID 000186975200003

    View details for PubMedID 14611721

  • CTLA4IG (BMS-188667) in a phase IIB, multi-center, randomized, double-blind, placebo controlled study in rheumatoid arthritis patients receiving etanercept: Association between clinical response and key biomarkers Schiff, M., Genovese, M., Nuamah, I., Becker, J., Weinblatt, M. BMJ PUBLISHING GROUP. 2003: 178-178
  • Imaging of the articular cartilage in osteoarthritis of the knee joint: 3D spatial-spectral spoiled gradient-echo vs. fat-suppressed 3D spoiled gradient-echo MR imaging JOURNAL OF MAGNETIC RESONANCE IMAGING Yoshioka, H., Alley, M., Steines, D., Stevens, K., Rubesova, E., Genovese, M., Dillingham, M. F., Lang, P. 2003; 18 (1): 66-71

    Abstract

    To compare three-dimensional (3D) spatial-spectral (SS) spoiled gradient-recalled acquisition in the steady state (SPGR) imaging with fat-suppressed 3D SPGR sequences in MR imaging of articular cartilage of the knee joint in patients with osteoarthritis.MR images of six patients with osteoarthritis of the knee were prospectively examined with a 1.5T MR scanner. For quantitative analyses, the signal-to-noise ratios, contrast-to-noise ratios, and contrast of cartilage and adjacent structures including meniscus, synovial fluid, muscle, fat tissue, and bone marrow were measured.In patients with osteoarthritis, 3DSS-SPGR images demonstrated higher spatial resolution and higher mean signal-to-noise (S/N) ratios (cartilage, 24.9; synovial fluid, 12.3; muscle, 20.7; meniscus, 21.6), with shorter acquisition times (7 minutes 20 seconds), when compared to fat-suppressed 3D SPGR images (cartilage, 22.3; synovial fluid, 10.8; muscle, 16.7; meniscus, 13.4).3DSS-SPGR imaging is a promising method for evaluating cartilage pathology in patients with osteoarthritis of the knee and has the potential to replace fat-suppressed 3D SPGR imaging.

    View details for DOI 10.1002/jmri.10320

    View details for Web of Science ID 000183899500008

    View details for PubMedID 12815641

  • Modulation of bone ingrowth and tissue differentiation by local infusion of interleukin-10 in the presence of ultra-high molecular weight polyethylene (UHMWPE) wear particles. Journal of biomedical materials research. Part A Goodman, S., Trindade, M., Ma, T., Lee, M., Wang, N., Ikenou, T., Matsuura, I., Miyanishi, K., Fox, N., Regula, D., Genovese, M., Klein, J., Bloch, D., Smith, R. L. 2003; 65 (1): 43-50

    Abstract

    Interleukin-10 (IL-10) is a cytokine that plays a major role in suppressing the inflammatory response, particularly cell-mediated immunity that is characteristic of the TH1 response. The purpose of this study was to determine whether local infusion of IL-10 could mitigate the suppression of bone ingrowth associated with polyethylene wear particles. Drug test chambers were implanted in the proximal tibia of 20 mature New Zealand White rabbits. The DTC provided a continuous 1 x 1 x 5-mm canal for tissue ingrowth. After a 6-week period for osseointegration, the DTC was then connected to an osmotic diffusion pump. IL-10 at doses of 0.1-100 ng/mL (0.25 microL/h) was infused with or without ultra-high molecular weight polyethylene particles (0.5 +/- 0.2 microm diameter, 10(12) particles/mL) present in the chamber for a 3- or 6-week period. The tissue in the chamber was harvested after each treatment; sections were stained with hematoxylin and eosin for morphometric analysis. Osteoclast-like cells were identified by immunohistochemical staining using a monoclonal antibody directed against the alpha chain of the vitronectin receptor, CD51. Osteoblasts were identified using alkaline phosphatase staining. In dose-response studies, infusion of 1 ng/mL IL-10 yielded the greatest bone ingrowth in the presence of particles. The addition of polyethylene particles evoked a marked foreign body reaction and fibrosis; bone ingrowth was significantly suppressed (p = 0.0003). Bone ingrowth was increased by over 48% with infusion of IL-10 for the final 3 weeks of a 6-week ultra-high molecular weight polyethylene particle exposure compared with particles alone (p = 0.027). IL-10 is a cytokine that plays a major role in suppressing the inflammatory response, especially cell-mediated immunity that is characteristic of the TH1 response. Local infusion of immune-modulating cytokines such as IL-10 may prove to be useful in abating particle-induced periprosthetic osteolysis.

    View details for PubMedID 12635153

  • Modulation of bone ingrowth and tissue differentiation by local infusion of interleukin-10 in the presence of ultra-high molecular weight polyethylene (UHMWPE) wear particles JOURNAL OF BIOMEDICAL MATERIALS RESEARCH PART A Goodman, S., Trindade, M., Ma, T., Lee, M., Wang, N., Ikenou, T., Matsuura, I., Miyanishi, K., Fox, N., Regula, D., Genovese, M., Klein, J., Bloch, D., Smith, R. L. 2003; 65A (1): 43-50
  • Allele and antigen-specific treatment of rheumatoid arthritis: A double blind, placebo controlled phase 1 trial JOURNAL OF RHEUMATOLOGY Kavanaugh, A., Genovese, M., Baughman, J., Kivitz, A., Bulpitt, K., Olsen, N., Weisman, M., Matteson, E., Furst, D., van Vollenhoven, R., Anderson, J., Cohen, S., Wei, N., Meijerink, J., Jacobs, C., Mocci, S. 2003; 30 (3): 449-454

    Abstract

    Human cartilage glycoprotein 39 (HC gp-39) appears to be a relevant autoantigen in patients with rheumatoid arthritis (RA). Administration of major histocompatibility complex (MHC) Class II complexed antigens without requisite costimulatory signals can induce immunologic tolerance. We evaluated the safety, pharmacokinetics, and preliminary efficacy of AG4263 in patients with RA. AG4263 is a soluble complex of native HLA-DR4 (beta*0401) complexed to Org 36601, a 13-mer peptide derived from HC gp-39 (also referred to as CDP263).Thirty-one HLA-DRB1*0401 positive patients with persistent RA disease activity despite concurrent methotrexate were randomized to 7 infusions of AG4263 (n = 24) or placebo (n = 7) over 6 weeks. The initial dose of 0.5 micro g/kg was escalated in subsequent cohorts to a maximum of 150 micro g/kg. Safety analyses included recording of adverse events and measurement of CD4/CD8 counts, reactivity to recall antigens, and development of antibodies to HLA-DR4. Efficacy was assessed using the Paulus 20 criteria.Treatment was well tolerated, with injection site reaction the most common adverse event. There was no loss of reactivity to recall antigens, change in cell counts, or antibodies to HLA-DR. The mean half-life of AG4263 was 12.5 h. Some evidence of clinical response was seen; responses were more common among patients receiving the highest doses of AG4263 and among those with baseline T cell reactivity to CDP263.AG4263 was safe, well tolerated, and without evidence of generalized immune suppression. Along with the observed trend toward clinical efficacy, the results suggest that this therapeutic approach warrants further investigation in patients with RA.

    View details for Web of Science ID 000181372100006

    View details for PubMedID 12610799

  • Multiplex autoantibody profiling using 'synovial proteome' microarrays identifies citrulline-modified peptides as major targets of the autoimmune response in rheumatoid arthritis Hueber, W., Lee, B. J., Genovese, M., van Venrooij, W., Steinman, L., Utz, P. J., Robinson, W. H. BIOMED CENTRAL LTD. 2003: S31-S31

    View details for DOI 10.1186/ar900

    View details for Web of Science ID 000220116700101

  • Rheumatic syndromes associated with malignancy CURRENT OPINION IN RHEUMATOLOGY Chakravarty, E., Genovese, M. C. 2003; 15 (1): 35-43

    Abstract

    The relation between rheumatic syndromes and an underlying malignancy is a complex one. As a result of autoimmunity, an aberrant immune response, or the use of immunomodulatory drugs, many of the rheumatic diseases appear to pose an increased risk for the development of malignancy. Unfortunately, for many of the same reasons, the presence of an underlying malignancy can result in the development of features of rheumatic disease. Awareness of the associations between rheumatic syndromes and malignancy will aid the clinician in the accurate diagnosis of underlying pathology, more effective treatment of both the symptoms and underlying disease, and appropriate surveillance for the development of later complications.

    View details for Web of Science ID 000180055000007

    View details for PubMedID 12496508

  • Concomitant leflunomide therapy in patients with active rheumatoid arthritis despite stable doses of methotrexate - A randomized, double-blind, placebo-controlled trial ANNALS OF INTERNAL MEDICINE Kremer, J. M., Genovese, M. C., Cannon, G. W., Caldwell, J. R., Cush, J. J., Furst, D. E., Luggen, M. E., Keystone, E., Weisman, M. H., Bensen, W. M., Kaine, J. L., Ruderman, E. M., Coleman, P., Curtis, D. L., Kopp, E. J., Kantor, S. M., Waltuck, J., Lindsley, H. B., Markenson, J. A., Strand, V., Crawford, B., Fernando, I., Simpson, K., Bathon, J. M. 2002; 137 (9): 726-733

    Abstract

    Disease-modifying antirheumatic drugs may confer greater benefits when combined with the antimetabolite methotrexate.To evaluate the efficacy and safety of leflunomide versus placebo when added to ongoing, stable-dose methotrexate therapy in patients with persistently active rheumatoid arthritis.24-week, multicenter, randomized, double-blind, placebo-controlled trial.20 centers in the United States and Canada.Patients with persistent rheumatoid arthritis, as defined by American College of Rheumatology (ACR) criteria, despite receiving methotrexate for at least 6 months.Leflunomide or matching placebo added to existing methotrexate therapy.The primary efficacy variable was the rate of achievement of 20% improvement in ACR criteria (ACR20) at the end of the study. The Health Assessment Questionnaire Disability Index was assessed at each visit, and the Medical Outcomes Study 36-Item Short Form was completed as an end point analysis.In the leflunomide and placebo groups, 46.2% and 19.5% of patients, respectively, met ACR20 criteria at 24 weeks (P < 0.001). Clinical improvement was demonstrated by statistically significant mean changes in individual components of the ACR20 response criteria. Discontinuation rates were similar in both treatment groups (23.1% in the leflunomide group and 24.8% in the placebo group), as were the overall incidences of adverse events (89.2% vs. 89.5%, respectively). Adverse events were predominantly mild or moderate.Combination therapy with leflunomide and methotrexate provides statistically significant clinical benefit in patients with active rheumatoid arthritis who are receiving methotrexate therapy. Leflunomide plus methotrexate is generally well tolerated and can be used safely with appropriate liver enzyme and hematologic monitoring.

    View details for Web of Science ID 000179052400003

    View details for PubMedID 12416946

  • COX-2 selective NSAID decreases bone ingrowth in vivo JOURNAL OF ORTHOPAEDIC RESEARCH Goodman, S., Ma, T., Trindade, M., Ikenoue, T., Matsuura, I., Wong, N., Fox, N., Genovese, M., Regula, D., Smith, R. L. 2002; 20 (6): 1164-1169

    Abstract

    Whether non-steroidal anti-inflammatory drug (NSAID)-induced suppression of bone ingrowth is due to cyclooxygenase-1 (COX-1) inhibition, cyclooxygenase-2 (COX-2) inhibition, or through a yet unidentified pathway is unknown. In this study, the effects of a non-specific COX-1 and COX-2 inhibitor, versus a specific COX-2 inhibitor on bone ingrowth and tissue differentiation are examined in vivo. Harvest chambers were implanted unilaterally in the tibiae of eight mature, New Zealand white rabbits. After a 6-week period for osseointegration of the chamber, the following oral treatments were given for 4 weeks each, followed by a harvest in each case: drinking water with no NSAID (control 1), Naproxen sodium--a COX-1 and COX-2 non-specific inhibitor at a dose of 110 mg/kg/day in the drinking water, drinking water with no NSAID (control 2), and Rofecoxib-a COX-2 inhibitor at a dose of 12.5 mg/day inserted directly into the rabbit's mouth. Harvested specimens were snap frozen, cut into serial 6 microm sections and stained with hematoxylin and eosin for general morphological characterization, and alkaline phosphatase (osteoblast marker). Sections were also processed for immunoperoxidase staining using monoclonal antibodies to identify cells expressing the vitronectin receptor (osteoclast-like cells). With drinking water alone, the percentage of bone ingrowth averaged 24.8 +/- 2.9% and 29.9 +/- 4.5% respectively. Naproxen sodium in the drinking water and oral Rofecoxib decreased bone ingrowth significantly (15.9 +/- 3.3%. p = 0.031 and 18.5 +/- 2+/-4%, p = 0.035 compared to drinking water respectively). Both Naproxen sodium (p = 0.026) and Rofecoxib (p = 0.02) decreased the number of CD51 positive osteoclast-like cells per section compared with drinking water alone. Rofecoxib decreased the area of osteoblasts per section area (p = 0.014) compared to controls, although the value for Naproxen sodium did not reach statistical significance. The results of the present study suggest that bone formation is suppressed by oral administration of an NSAID which contains a COX-2 inhibitor. COX-2 inhibitors currently taken for arthritis and other conditions may potentially delay fracture healing and bone ingrowth.

    View details for Web of Science ID 000179400800005

    View details for PubMedID 12472224

  • Central nervous system lupus and pregnancy: 11-year experience at a single center. journal of maternal-fetal & neonatal medicine El-Sayed, Y. Y., Lu, E. J., Genovese, M. C., Lambert, R. E., Chitkara, U., Druzin, M. L. 2002; 12 (2): 99-103

    Abstract

    To describe the pregnancy outcomes in women with central nervous system (CNS) manifestations of lupus.Between 1991 and 2002, the outcome of five pregnancies in four patients with CNS lupus were retrospectively reviewed. All patients had an established history of systemic lupus erythematosus (SLE), and either a history of CNS lupus or active CNS lupus. Pregnancy outcomes assessed included term and preterm birth, intrauterine growth restriction, abnormal antepartum testing, perinatal mortality, pre-eclampsia and other maternal morbidities.Evidence of active CNS lupus symptoms developed in three of the five pregnancies. Two pregnancies were complicated by early onset pre-eclampsia, abnormal antepartum testing and extreme prematurity, with one subsequent neonatal death. The remaining three pregnancies had good neonatal outcomes, but were complicated by severe maternal post-pregnancy exacerbations, and the eventual death of one patient.CNS lupus in pregnancy represents an especially severe manifestation of SLE, and may involve great maternal and fetal risks.

    View details for PubMedID 12420839

  • Etanercept versus methotrexate in patients with early rheumatoid arthritis - Two-year radiographic and clinical outcomes ARTHRITIS AND RHEUMATISM Genovese, M. C., Bathon, J. M., Martin, R. W., Fleischmann, R. M., Tesser, J. R., Schiff, M. H., Keystone, E. C., Wasko, M. C., Moreland, L. W., Weaver, A. L., Markenson, J., Cannon, G. W., Spencer-Green, G., Finck, B. K. 2002; 46 (6): 1443-1450

    Abstract

    To compare the clinical and radiographic outcomes in patients with rheumatoid arthritis (RA) who received monotherapy with either etanercept or methotrexate (MTX) for 2 years and to assess the safety of this therapy.In the Enbrel ERA (early rheumatoid arthritis) trial, 632 patients with early, active RA were randomized to receive either twice-weekly subcutaneous etanercept (10 mg or 25 mg) or weekly oral MTX (mean dosage 19 mg per week) for at least 1 year in a double-blind manner. Following the blinded phase of the trial, 512 patients continued to receive the therapy to which they had been randomized for up to 1 additional year, in an open-label manner. Radiograph readers remained blinded to treatment group assignment and the chronologic order of images.At 24 months, more 25-mg etanercept patients than MTX patients met American College of Rheumatology 20% improvement criteria (72% and 59%, respectively; P = 0.005), and more had no increase in total score and erosion scores on the Sharp scale (P = 0.017 and P = 0.012, respectively). The mean changes in total Sharp score and erosion score in the 25-mg etanercept group (1.3 and 0.66 units, respectively) were significantly lower than those in the MTX group (3.2 and 1.86 units, respectively; P = 0.001). Significantly more patients in the 25-mg etanercept group (55%) than in the MTX group (37%) had at least 0.5 units of improvement in the Health Assessment Questionnaire disability index (P < 0.001). Fewer patients in the etanercept group than in the MTX group experienced adverse events or discontinued treatment because of adverse events.Etanercept as monotherapy was safe and was superior to MTX in reducing disease activity, arresting structural damage, and decreasing disability over 2 years in patients with early, aggressive RA.

    View details for DOI 10.1002/art.10308

    View details for Web of Science ID 000176199200004

    View details for PubMedID 12115173

  • Long-term followup of patients treated with total lymphoid irradiation for lupus nephritis ARTHRITIS AND RHEUMATISM Genovese, M. C., Uhrin, Z., Bloch, D. A., Oehlert, J., Sibley, R. K., Myers, B., Strober, S. 2002; 46 (4): 1014-1018

    Abstract

    To describe the long-term survival, renal condition, and morbidity outcomes in patients who received total lymphoid irradiation (TLI) for the treatment of lupus nephritis.Twenty-one patients with biopsy-proven, diffuse membranoproliferative glomerulonephritis and significant proteinuria of >2.5 grams/day received TLI from 1980 to 1987 at Stanford University Medical Center. All patients had previously failed to respond to treatment with high-dose corticosteroids or therapy with corticosteroids plus immunosuppressive agents (azathioprine, cyclophosphamide, or chlorambucil).The mean duration of followup since TLI was 10.7 years. Fifteen of 21 patients (71%) remained alive at the time of this assessment. Nine of the 21 patients (43%) survived without developing end-stage renal disease (ESRD). The probability of long-term survival without ESRD and without need for additional immunosuppressive agents after TLI was 19% (4 of 21). Factors predicting renal failure at the time of TLI included elevated creatinine levels, increased interstitial fibrosis on renal biopsy, and increased fractional excretion of immunoglobulin and albumin. Malignancies were found in 4 patients, and opportunistic infections occurred in 7 patients.Overall, patients with lupus nephritis treated with TLI do not appear to have better 10-year survival with lower incidence of ESRD compared with patients in published series treated with conventional immunosuppressive therapies. However, in this series of patients, treatment with conventional immunosuppressive therapies had been unsuccessful and given the limited number of adverse events and the efficacy seen in some patients, TLI appears to be a reasonable therapeutic option for the treatment of severe lupus nephritis among patients who fail to respond under standard cytotoxic regimens.

    View details for Web of Science ID 000174946500022

    View details for PubMedID 11953979

  • Autoantigen microarrays for multiplex characterization of autoantibody responses NATURE MEDICINE Robinson, W. H., DiGennaro, C., Hueber, W., Haab, B. B., KAMACHI, M., Dean, E. J., Fournel, S., Fong, D., Genovese, M. C., de Vegvar, H. E., Skriner, K., Hirschberg, D. L., Morris, R. I., Muller, S., Pruijn, G. J., van Venrooij, W. J., Smolen, J. S., Brown, P. O., Steinman, L., Utz, P. J. 2002; 8 (3): 295-301

    Abstract

    We constructed miniaturized autoantigen arrays to perform large-scale multiplex characterization of autoantibody responses directed against structurally diverse autoantigens, using submicroliter quantities of clinical samples. Autoantigen microarrays were produced by attaching hundreds of proteins, peptides and other biomolecules to the surface of derivatized glass slides using a robotic arrayer. Arrays were incubated with patient serum, and spectrally resolvable fluorescent labels were used to detect autoantibody binding to specific autoantigens on the array. We describe and characterize arrays containing the major autoantigens in eight distinct human autoimmune diseases, including systemic lupus erythematosus and rheumatoid arthritis. This represents the first report of application of such technology to multiple human disease sera, and will enable validated detection of antibodies recognizing autoantigens including proteins, peptides, enzyme complexes, ribonucleoprotein complexes, DNA and post-translationally modified antigens. Autoantigen microarrays represent a powerful tool to study the specificity and pathogenesis of autoantibody responses, and to identify and define relevant autoantigens in human autoimmune diseases.

    View details for Web of Science ID 000174139500036

    View details for PubMedID 11875502

  • Expression of the chemokine receptors CCR4, CCR5, and CXCR3 by human tissue-infiltrating lymphocytes AMERICAN JOURNAL OF PATHOLOGY Kunkel, E. J., Boisvert, J., Murphy, K., Vierra, M. A., Genovese, M. C., Wardlaw, A. J., Greenberg, H. B., Hodge, M. R., Wu, L. J., BUTCHER, E. C., Campbell, J. J. 2002; 160 (1): 347-355

    Abstract

    Differential expression of adhesion molecules and chemokine receptors has been useful for identification of peripheral blood memory lymphocyte subsets with distinct tissue and microenvironmental tropisms. Expression of CCR4 by circulating memory CD4(+) lymphocytes is associated with cutaneous and other systemic populations while expression of CCR9 is associated with a small intestine-homing subset. CCR5 and CXCR3 are also expressed by discrete memory CD4(+) populations in blood, as well as by tissue-infiltrating lymphocytes from a number of sites. To characterize the similarities and differences among tissue-infiltrating lymphocytes, and to shed light on the specialization of lymphocyte subsets that mediate inflammation and immune surveillance in particular tissues, we have examined the expression of CCR4, CXCR3, and CCR5 on CD4(+) lymphocytes directly isolated from a wide variety of normal and inflamed tissues. Extra-lymphoid tissues contained only memory lymphocytes, many of which were activated (CD69(+)). As predicted by classical studies, skin lymphocytes were enriched in CLA expression whereas intestinal lymphocytes were enriched in alpha(4)beta(7) expression. CCR4 was expressed at high levels by skin-infiltrating lymphocytes, at lower levels by lung and synovial fluid lymphocytes, but never by intestinal lymphocytes. Only the high CCR4 levels characteristic of skin lymphocytes were associated with robust chemotactic and adhesive responses to TARC, consistent with a selective role for CCR4 in skin lymphocyte homing. In contrast, CXCR3 and CCR5 were present on the majority of lymphocytes from each non-lymphoid tissue examined, suggesting that these receptors are unlikely to determine tissue specificity, but rather, may play a wider role in tissue inflammation.

    View details for Web of Science ID 000173231700038

    View details for PubMedID 11786428

  • Rules of chemokine receptor association with T cell polarization in vivo JOURNAL OF CLINICAL INVESTIGATION Kim, C. H., Rott, L., Kunkel, E. J., Genovese, M. C., Andrew, D. P., Wu, L. J., BUTCHER, E. C. 2001; 108 (9): 1331-1339

    Abstract

    Current concepts of chemokine receptor (CKR) association with Th1 and Th2 cell polarization and effector function have largely ignored the diverse nature of effector and memory T cells in vivo. Here, we systematically investigated the association of 11 CKRs, singly or in combination, with CD4 T cell polarization. We show that Th1, Th2, Th0, and nonpolarized T cells in blood and tissue can express any of the CKRs studied but that each CKR defines a characteristic pool of polarized and nonpolarized CD4 T cells. Certain combinations of CKRs define populations that are markedly enriched in major subsets of Th1 versus Th2 cells. For example, although Th0, Th1, and Th2 cells are each found among blood CD4 T cells coordinately expressing CXCR3 and CCR4, Th1 but not Th2 cells can be CXCR3(+)CCR4(-), and Th2 but only rare Th1 cells are CCR4(+)CXCR3(-). Contrary to recent reports, although CCR7(-) cells contain a higher frequency of polarized CD4 T cells, most Th1 and Th2 effector cells are CCR7(+) and thus may be capable of lymphoid organ homing. Interestingly, Th1-associated CKRs show little or no preference for Th1 cells except when they are coexpressed with CXCR3. We conclude that the combinatorial expression of CKRs, which allow tissue- and subset-dependent targeting of effector cells during chemotactic navigation, defines physiologically significant subsets of polarized and nonpolarized T cells.

    View details for Web of Science ID 000172051100016

    View details for PubMedID 11696578

  • Demyelinating and neurologic events reported in association with tumor necrosis factor alpha antagonism - By what mechanisms could tumor necrosis factor alpha antagonists improve rheumatoid arthritis but exacerbate multiple sclerosis? ARTHRITIS AND RHEUMATISM Robinson, W. H., Genovese, M. C., Moreland, L. W. 2001; 44 (9): 1977-1983

    View details for Web of Science ID 000172491200004

    View details for PubMedID 11592357

  • Treatment of rheumatoid arthritis with total lymphoid irradiation - Long-term survival ARTHRITIS AND RHEUMATISM Uhrin, Z., Wang, B. W., Matsuda, Y., Strober, S., Genovese, M. C. 2001; 44 (7): 1525-1528

    Abstract

    Total lymphoid irradiation (TLI) has been used to treat rheumatoid arthritis (RA) since the 1970s. This study reviews long-term (15-20-year) mortality outcomes of patients treated with TLI for RA at Stanford University Medical Center and compares these outcomes with those in patients treated with disease-modifying antirheumatic drugs (DMARDs).Fifty-three patients with RA were treated with full-dose TLI at Stanford University Medical Center. All had failed previous therapy with gold salts and penicillamine. One hundred six control patients were selected from the Arthritis, Rheumatism, and Aging Medical Information Systems database and were matched with the patients for age, sex, disease duration, and mean Health Assessment Questionnaire (HAQ) score. Survival was analyzed using Kaplan-Meier methods and Cox proportional hazards regression.No significant difference in age and sex was found between TLI-treated patients and controls. TLI-treated patients had more education (mean 13.4 years versus 11.8 years; P = 0.016) and received more DMARDs prior to TLI (mean 2.1 versus 1.3; P = 0.0001). TLI-treated patients had lower mean HAQ scores at the time of TLI (2.0 versus 2.4; P = 0.0002). TLI had no significant overall effect on survival in treated patients compared with controls (P = 0.62). The survival curves appeared to cross over at approximately 11 years of followup, with better early survival in the TLI group and better late survival in the control group. There was a total of 25 deaths in the TLI group. There were 45 deaths in the control group, with causes of death available for 20 patients. There were 3 patients with lymphoma and 2 with myelodysplastic syndrome in the TLI group, and none in the control group. The most common cause of death in both groups was infection.TLI had no significant effect on overall survival, with trends toward higher early mortality in controls and trends toward higher late mortality in TLI-treated patients. Overall, there was no difference in mortality, but it appears that there may have been more lymphoproliferative malignancies in the TLI cohort. We would recommend that TLI be used cautiously for patients with refractory RA in whom the benefits outweigh the risks.

    View details for Web of Science ID 000172491000008

    View details for PubMedID 11465702

  • Combination therapy of leflunomide (LEF) & methotrexate (MTX) is effective & well tolerated in RA patients inadequately responding to MTX alone Kremer, J. M., Genovese, M., Cannon, G. W., Caldwell, J. R., Cush, J. J., Bathon, J. J RHEUMATOL PUBL CO. 2001: 105-105
  • Bonzo/CXCR6 expression defines type 1-polarized T-cell subsets with extralymphoid tissue homing potential JOURNAL OF CLINICAL INVESTIGATION Kim, C. H., Kunkel, E. J., Boisvert, J., Johnston, B., Campbell, J. J., Genovese, M. C., Greenberg, H. B., BUTCHER, E. C. 2001; 107 (5): 595-601

    Abstract

    Chemokine receptor expression is finely controlled during T-cell development. We show that newly identified chemokine receptor Bonzo/CXCR6 is expressed by subsets of Th1 or T-cytotoxic 1 (Tc1) cells, but not by Th2 or Tc2 cells, establishing Bonzo as a differential marker of polarized type 1 T cells in vitro and in vivo. Priming of naive T cells by dendritic cells induces expression of Bonzo on T cells. IL-12 enhances this dendritic cell-dependent upregulation, while IL-4 inhibits it. In blood, 35-56% of Bonzo+ CD4 T cells are Th1 cells, and 60-65% of Bonzo+ CD8 T cells are Tc1 cells, while few Bonzo+ cells are type 2 T cells. Almost all Bonzo+ Tc1 cells contain preformed granzyme A and display cytotoxic effector phenotype. Most Bonzo+ T cells lack L-selectin and/or CCR7, homing receptors for lymphoid tissues. Instead, Bonzo+ T cells are dramatically enriched among T cells in tissue sites of inflammation, such as rheumatoid joints and inflamed livers. Bonzo may be important in trafficking of effector T cells that mediate type 1 inflammation, making it a potential target for therapeutic modulation of inflammatory diseases.

    View details for Web of Science ID 000167337800009

    View details for PubMedID 11238560

  • Current management of rheumatoid arthritis HOSPITAL PRACTICE Genovese, M. C., Davis, J. S. 2001; 36 (2): 21-?

    View details for Web of Science ID 000166876100003

    View details for PubMedID 11220358

  • CCR7 expression and memory T cell diversity in humans JOURNAL OF IMMUNOLOGY Campbell, J. J., Murphy, K. E., Kunkel, E. J., Brightling, C. E., Soler, D., Shen, Z. M., Boisvert, J., Greenberg, H. B., Vierra, M. A., Goodman, S. B., Genovese, M. C., Wardlaw, A. J., BUTCHER, E. C., Wu, L. J. 2001; 166 (2): 877-884

    Abstract

    CCR7, along with L-selectin and LFA-1, mediates homing of T cells to secondary lymphoid organs via high endothelial venules (HEV). CCR7 has also been implicated in microenvironmental positioning of lymphocytes within secondary lymphoid organs and in return of lymphocytes and dendritic cells to the lymph after passage through nonlymphoid tissues. We have generated mAbs to human CCR7, whose specificities correlate with functional migration of lymphocyte subsets to known CCR7 ligands. We find that CCR7 is expressed on the vast majority of peripheral blood T cells, including most cells that express adhesion molecules (cutaneous lymphocyte Ag alpha(4)beta(7) integrin) required for homing to nonlymphoid tissues. A subset of CD27(neg) memory CD4 T cells from human peripheral blood is greatly enriched in the CCR7(neg) population, as well as L-selectin(neg) cells, suggesting that these cells are incapable of homing to secondary lymphoid organs. Accordingly, CD27(neg) T cells are rare within tonsil, a representative secondary lymphoid organ. All resting T cells within secondary lymphoid organs express high levels of CCR7, but many activated cells lack CCR7. CCR7 loss in activated CD4 cells accompanies CXC chemokine receptor (CXCR)5 gain, suggesting that the reciprocal expression of these two receptors may contribute to differential positioning of resting vs activated cells within the organ. Lymphocytes isolated from nonlymphoid tissues (such as skin, lung, or intestine) contain many CD27(neg) cells lacking CCR7. The ratio of CD27(neg)/CCR7(neg) cells to CD27(pos)/CCR7(pos) cells varies from tissue to tissue, and may correlate with the number of cells actively engaged in Ag recognition within a given tissue.

    View details for Web of Science ID 000166259600023

    View details for PubMedID 11145663

  • A comparison of etanercept and methotrexate in patients with early rheumatoid arthritis NEW ENGLAND JOURNAL OF MEDICINE Bathon, J. M., Martin, R. W., Fleischmann, R. M., Tesser, J. R., Schiff, M. H., Keystone, E. C., Genovese, M. C., Wasko, M. C., Moreland, L. W., Weaver, A. L., Markenson, J., Finck, B. K. 2000; 343 (22): 1586-1593

    Abstract

    Etanercept, which blocks the action of tumor necrosis factor, reduces disease activity in patients with long-standing rheumatoid arthritis. Its efficacy in reducing disease activity and preventing joint damage in patients with active early rheumatoid arthritis is unknown.We treated 632 patients with early rheumatoid arthritis with either twice-weekly subcutaneous etanercept (10 or 25 mg) or weekly oral methotrexate (mean, 19 mg per week) for 12 months. Clinical response was defined as the percent improvement in disease activity according to the criteria of the American College of Rheumatology. Bone erosion and joint-space narrowing were measured radiographically and scored with use of the Sharp scale. On this scale, an increase of 1 point represents one new erosion or minimal narrowing.As compared with patients who received methotrexate, patients who received the 25-mg dose of etanercept had a more rapid rate of improvement, with significantly more patients having 20 percent, 50 percent, and 70 percent improvement in disease activity during the first six months (P<0.05). The mean increase in the erosion score during the first 6 months was 0.30 in the group assigned to receive 25 mg of etanercept and 0.68 in the methotrexate group (P= 0.001), and the respective increases during the first 12 months were 0.47 and 1.03 (P=0.002). Among patients who received the 25-mg dose of etanercept, 72 percent had no increase in the erosion score, as compared with 60 percent of patients in the methotrexate group (P=0.007). This group of patients also had fewer adverse events (P=0.02) and fewer infections (P= 0.006) than the group that was treated with methotrexate.As compared with oral methotrexate, subcutaneous [corrected] etanercept acted more rapidly to decrease symptoms and slow joint damage in patients with early active rheumatoid arthritis.

    View details for Web of Science ID 000165511000001

    View details for PubMedID 11096165

  • A novel chemokine ligand for CCR10 and CCR3 expressed by epithelial cells in mucosal tissues. Journal of immunology Pan, J., Kunkel, E. J., Gosslar, U., Lazarus, N., Langdon, P., Broadwell, K., Vierra, M. A., Genovese, M. C., BUTCHER, E. C., Soler, D. 2000; 165 (6): 2943-2949

    Abstract

    Mucosae-associated epithelial chemokine (MEC) is a novel chemokine whose mRNA is most abundant in salivary gland, with strong expression in other mucosal sites, including colon, trachea, and mammary gland. MEC is constitutively expressed by epithelial cells; MEC mRNA is detected in cultured bronchial and mammary gland epithelial cell lines and in epithelia isolated from salivary gland and colon using laser capture microdissection, but not in the endothelial, hemolymphoid, or fibroblastic cell lines tested. Although MEC is poorly expressed in skin, its closest homologue is the keratinocyte-expressed cutaneous T cell-attracting chemokine (CTACK; CCL27), and MEC supports chemotaxis of transfected lymphoid cells expressing CCR10, a known CTACK receptor. In contrast to CTACK, however, MEC also supports migration through CCR3. Consistent with this, MEC attracts eosinophils in addition to memory lymphocyte subsets. These results suggest an important role for MEC in the physiology of extracutaneous epithelial tissues, including diverse mucosal organs.

    View details for PubMedID 10975800

  • Cutting edge: A novel chemokine ligand for CCR10 and CCR3 expressed by epithelial cells in mucosal tissues JOURNAL OF IMMUNOLOGY Pan, J. L., Kunkel, E. J., Gosslar, U., Lazarus, N., Langdon, P., Broadwell, K., Vierra, M. A., Genovese, M. C., BUTCHER, E. C., Soler, D. 2000; 165 (6): 2943-2949
  • Lymphocyte CC chemokine receptor 9 and epithelial thymus-expressed chemokine (TECK) expression distinguish the small intestinal immune compartment: Epithelial expression of tissue-specific chemokines as an organizing principle in regional immunity JOURNAL OF EXPERIMENTAL MEDICINE Kunkel, E. J., Campbell, J. J., Haraldsen, G., Pan, J. L., Boisvert, J., Roberts, A. I., Ebert, E. C., Vierra, M. A., Goodman, S. B., Genovese, M. C., Wardlaw, A. J., Greenberg, H. B., Parker, C. M., Butcher, E. C., Andrew, D. P., Agace, W. W. 2000; 192 (5): 761-767

    Abstract

    The immune system has evolved specialized cellular and molecular mechanisms for targeting and regulating immune responses at epithelial surfaces. Here we show that small intestinal intraepithelial lymphocytes and lamina propria lymphocytes migrate to thymus-expressed chemokine (TECK). This attraction is mediated by CC chemokine receptor (CCR)9, a chemoattractant receptor expressed at high levels by essentially all CD4(+) and CD8(+) T lymphocytes in the small intestine. Only a small subset of lymphocytes in the colon are CCR9(+), and lymphocytes from other tissues including tonsils, lung, inflamed liver, normal or inflamed skin, inflamed synovium and synovial fluid, breast milk, and seminal fluid are universally CCR9(-). TECK expression is also restricted to the small intestine: immunohistochemistry reveals that intense anti-TECK reactivity characterizes crypt epithelium in the jejunum and ileum, but not in other epithelia of the digestive tract (including stomach and colon), skin, lung, or salivary gland. These results imply a restricted role for lymphocyte CCR9 and its ligand TECK in the small intestine, and provide the first evidence for distinctive mechanisms of lymphocyte recruitment that may permit functional specialization of immune responses in different segments of the gastrointestinal tract. Selective expression of chemokines by differentiated epithelium may represent an important mechanism for targeting and specialization of immune responses.

    View details for Web of Science ID 000089265000016

    View details for PubMedID 10974041

  • A double-blind, placebo-controlled, clinical trial of dehydroepiandrosterone in severe systemic lupus erythematosus LUPUS van Vollenhoven, R. F., Park, J. L., Genovese, M. C., West, J. P., McGuire, J. L. 1999; 8 (3): 181-187

    Abstract

    To determine if dehydroepiandrosterone (DHEA) is beneficial in severe systemic lupus erythematosus (SLE).A double-blinded, placebo-controlled, randomized clinical trial in 21 patients with severe and active SLE, manifestated primarily by nephritis, serositis or hematological abnormalities. In addition to conventional treatment with corticosteroids +/- immunosuppressives, patients received DHEA 200 mg/d vs. placebo for 6 months, followed by a 6-month open label period. The primary outcome was a prospectively defined responder analysis, based on a quantitatively specified improvement of the principal severe lupus manifestation at 6 months.Nineteen patients were available for evaluation at 6 months. Baseline imbalance between the groups was noted, with the DHEA group having greater disease activity at baseline (P<0.05 by physician's global assessment). Eleven patients were responders: 7/9 patients on DHEA vs. 4/10 patients on placebo (P<0.10). Of the secondary outcomes, mean improvement in SLE disease activity index (SLE-DAI) score was greater in the DHEA group (-10.3+/-3.1 vs. -3.9+/-1.4. P<0.07). Bone mineral density at the lumbo-sacral spine showed significant reduction in the placebo group, but was maintained in the DHEA group.DHEA therapy, when added to conventional treatment for severe SLE, may at most have a small added benefit with respect to lupus outcomes, but baseline imbalances in the study population limit the generalizability of the results. DHEA appears to have a protective effect with respect to corticosteroid-induced osteopenia in such patients.

    View details for Web of Science ID 000080473900004

    View details for PubMedID 10342710

  • Joint and soft-tissue injection - A useful adjuvant to systemic and local treatment POSTGRADUATE MEDICINE Genovese, M. C. 1998; 103 (2): 125-?

    Abstract

    Joint and soft-tissue injection can augment systemic and local conservative treatment and have long-lasting benefits. Inflammatory and crystalline arthritis, synovitis, tendinitis, bursitis, and many other conditions respond well to injection. Corticosteroid preparations should be chosen on the basis of solubility and potency desired and the size of structure to be injected. Injections should not be made directly into a ligament or tendon and should be limited to every third or fourth month. With attention to the usual cautions required with corticosteroid use and avoidance of contraindications (e.g., bacteremia, fracture), injection is usually safe and effective, particularly as a bridging technique to long-term therapy.

    View details for Web of Science ID 000071888100014

    View details for PubMedID 9479311

  • Running and osteoarthritis of the knee: A 12 year longitudinal study. Lane, N. E., Oehlert, J., Ward, M., Genovese, M., Bloch, D., Fries, J. F. WILEY-BLACKWELL. 1997: 1242-1242
  • Fever, rash, and arthritis in a woman with silicone gel breast implants WESTERN JOURNAL OF MEDICINE Genovese, M. C. 1997; 167 (3): 149-158

    View details for Web of Science ID A1997XW74200003

    View details for PubMedID 9308407

  • Lemierre's syndrome SOUTHERN MEDICAL JOURNAL Lee, B. K., LOPEZ, F., Genovese, M., Loutit, J. S. 1997; 90 (6): 640-643

    Abstract

    Lemierre's syndrome is an acute medical condition characterized by anaerobic oropharyngeal infection leading to septic thrombophlebitis of the internal jugular vein. The illness is often complicated by septic pulmonary emboli and distant metastatic infections. Treatment consists of surgical drainage of purulent collections and long-term intravenous antibiotic therapy. Although Lemierre's syndrome is rare, it is potentially fatal and remains an important entity for clinicians to recognize and treat appropriately.

    View details for Web of Science ID A1997XE84400013

    View details for PubMedID 9191743

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