Bio

Clinical Focus


  • Rheumatology
  • Immunology/Rheumatology

Academic Appointments


Professional Education


  • 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 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.

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Teaching

2013-14 Courses


Publications

Journal Articles


  • 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

  • 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

  • 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

  • Efficacy and safety of belimumab in patients with rheumatoid arthritis: a phase II, randomized, double-blind, placebo-controlled, dose-ranging Study. The 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): 579-89

    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 PubMedID 23547209

  • 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

  • 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. Y., Myers, S., Benichou, O. 2012

    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 PubMedID 23268367

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

    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 Web of Science ID 000263981300011

    View details for PubMedID 18431764

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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 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

  • 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

  • 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

  • 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

  • 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; 72A (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 DOI 10.1002/jbm.a.30231

    View details for Web of Science ID 000227223200005

    View details for PubMedID 15666361

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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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