Tamiko Katsumoto

All Publications

• Fenebrutinib versus Placebo or Adalimumab in Rheumatoid Arthritis: A Randomized, Double-Blind, Phase II Trial (ANDES Study). Arthritis & rheumatology (Hoboken, N.J.) Cohen, S., Tuckwell, K., Katsumoto, T. R., Zhao, R., Galanter, J., Lee, C., Rae, J., Toth, B., Ramamoorthi, N., Hackney, J. A., Berman, A., Damjanov, N., Fedkov, D., Jeka, S., Chinn, L. W., Townsend, M. J., Morimoto, A. M., Genovese, M. C. 2020

  Abstract

  OBJECTIVE: To evaluate fenebrutinib, an oral and highly selective non-covalent inhibitor of Bruton's tyrosine kinase (BTK), in patients with active rheumatoid arthritis (RA).METHODS: Patients with RA and inadequate response to methotrexate (cohort 1, n=480) were randomized to fenebrutinib (50 mg once daily, 150 mg once daily, 200 mg twice daily), 40 mg adalimumab every other week, or placebo. Patients with RA and inadequate response to tumor necrosis factor inhibitors (cohort 2, n=98) received fenebrutinib (200 mg twice daily) or placebo. Both cohorts continued methotrexate therapy.RESULTS: In cohort 1, American College of Rheumatology scores (ACR50) at week 12 were similar for fenebrutinib 50 mg once daily and placebo, and higher for fenebrutinib 150 mg once daily (28%) and 200 mg twice daily (35%) than placebo (15%) (p=0.017; p=0.0003). Fenebrutinib 200 mg twice daily and adalimumab (36%) were comparable (p=0.81). In cohort 2, more patients achieved ACR50 with fenebrutinib 200 mg twice daily (25%) than placebo (12%) (p=0.072). The most common adverse events for fenebrutinib included nausea, headache, anemia, and upper respiratory tract infections. Fenebrutinib had significant effects on myeloid and B cell biomarkers (CCL4 and rheumatoid factor). Fenebrutinib and adalimumab caused overlapping as well as distinct changes in B cell and myeloid biomarkers.CONCLUSION: Fenebrutinib demonstrated efficacy comparable to adalimumab in patients with an inadequate response to methotrexate, and safety consistent with existing immunomodulatory therapies for RA. These data support targeting both B and myeloid cells via this novel mechanism for potential efficacy in the treatment of RA.

  View details for DOI 10.1002/art.41275

  View details for PubMedID 32270926

• Efficacy and Safety of Fenebrutinib, a BTK Inhibitor, Compared to Placebo in Rheumatoid Arthritis Patients with Active Disease Despite TNF Inhibitor Treatment: Randomized, Double Blind, Phase 2 Study Cohen, S., Tuckwell, K., Kunder, R., Katsumoto, T., Zhao, R., Berman, A., Damjanov, N., Fedkov, D., Jeka, S., Genovese, M. WILEY. 2019

  View details for Web of Science ID 000507466901352

• FENEBRUTINIB COMPARED TO PLACEBO AND ADALIMUMAB IN PATIENTS WITH INADEQUATE RESPONSE TO EITHER METHOTREXATE THERAPY OR PRIOR TNF THERAPY: PHASE 2 STUDY Cohen, S., Tuckwell, K., Katsumoto, T. R., Zhao, R., Lee, C., Berman, A., Damjanov, N., Fedkov, D., Jeka, S., Genovese, M. C. BMJ PUBLISHING GROUP. 2019: 80–81

  View details for DOI 10.1136/annrheumdis-2019-eular.4469

  View details for Web of Science ID 000472207100239

• Paraneoplastic and Therapy-Related Immune Complications in Thymic Malignancies. Current treatment options in oncology Lippner, E. A., Lewis, D. B., Robinson, W. H., Katsumoto, T. R. 2019; 20 (7): 62

  Abstract

  The thymus is a key organ involved in establishing central immune tolerance. Thymic epithelial tumors (TETs) include thymomas and thymic carcinomas. Thymomas, which are histologically distinct from thymic carcinomas, lead to dysregulated thymopoiesis via decreased thymic epithelial expression of AIRE and MHC Class II, as well as via alterations in thymic architecture, thereby resulting in autoimmune complications that manifest as paraneoplastic disorders (PNDs). Although progress has been made in elucidating the mechanisms underlying thymoma-associated PNDs, there remains a great need to further define the underlying mechanisms and to identify additional immune biomarkers, such as novel antibodies (in "seronegative" cases) to facilitate diagnosis and monitoring of patients. In addition, a better understanding of the pathogenesis of PNDs could lead to improved treatment strategies for both thymomas and their immune complications. In advanced, refractory cases of TETs (both thymoma and thymic carcinoma), additional therapeutic approaches are needed. Immune checkpoint inhibitors have revolutionized the treatment of several malignancies and hold promise in the treatment of TETs; however, the risks for immune-related adverse events (especially for inducing PNDs as well as in the setting of pre-existing PNDs) underscore the need to optimize patient selection and improve clinical management before there can be widespread acceptance of checkpoint inhibitor therapy in patients with TETs.

  View details for DOI 10.1007/s11864-019-0661-2

  View details for PubMedID 31227926

• Absence of Pharmacokinetic Interactions Between the Bruton's Tyrosine Kinase Inhibitor Fenebrutinib and Methotrexate. The Journal of pharmacology and experimental therapeutics Jones, N. S., Winter, H., Katsumoto, T. R., Florero, M., Murray, E., Walker, H., Singh, N., Chinn, L. 2019

  Abstract

  Fenebrutinib (GDC-0853) is an orally administered small molecule inhibitor of Bruton's tyrosine kinase being investigated for treatment of rheumatoid arthritis (RA) in patients with inadequate responses to methotrexate (MTX). This study interrogated the potential for pharmacokinetic drug interactions between fenebrutinib and MTX. Eighteen healthy male subjects enrolled in the study. They received a single oral dose of MTX (7.5 mg) on Day 1 followed by a 13-day washout period. Subsequently, on Days 15 to 20, subjects received 200 mg fenebrutinib twice daily. On Day 21, subjects received a 7.5 mg dose of MTX and a 200 mg dose of fenebrutinib under fasting conditions. The geometric mean ratios of MTX AUC and Cmax on Day 21 relative to Day 1 (90% CI) were 0.96 (0.88-1.04) and 1.05 (0.94-1.18), respectively. The geometric mean ratios of fenebrutinib AUC and Cmax for Day 21 relative to Day 20 (90% CI) were 1.03 (0.95-1.11) and 1.02 (0.90-1.15), respectively. The combination treatment was well tolerated, with an adverse event profile similar to that reported in other methotrexate trials. These results indicate that there is no clinically significant pharmacokinetic interaction between fenebrutinib and MTX. SIGNIFICANCE STATEMENT: N/A.

  View details for DOI 10.1124/jpet.119.257089

  View details for PubMedID 31371481

• Outcome of participants with nephrotic syndrome in combined clinical trials of lupus nephritis. Lupus science & medicine Gomez Mendez, L. M., Cascino, M. D., Katsumoto, T. R., Brakeman, P., Brunetta, P., Jayne, D., Dall'Era, M., Rovin, B., Garg, J. 2019; 6 (1): e000308

  Abstract

  The outcome of participants with nephrotic syndrome in clinical trials of lupus nephritis has not been studied in detail.Collated data from two randomised controlled trials in lupus nephritis, Lupus Nephritis Assessment of Rituximab (LUNAR) and A Study to Evaluate Ocrelizumab in Patients With Nephritis due to Systemic Lupus Erythematosus (BELONG) were analysed. Nephrotic syndrome was defined as albumin <3 g/dL and urine protein/creatinine ratio ≥3.5 g/g at start of trial. Renal response was defined as a first morning urine protein/creatinine ratio ≤0.5 g/g in addition to ≤25% increase in creatinine from trial entry assessed at week 48. Logistic regression was used to evaluate the association of nephrotic syndrome with renal response while adjusting for treatment received and ACE inhibitor or angiotensin receptor blocker use.28 (26%) participants with nephrotic syndrome achieved renal response as compared with 130 (52.5%) of those without (p<0.001). Having nephrotic syndrome at baseline significantly lowered the likelihood of achieving renal response (OR 0.32, 95 % CI 0.19 to 0.54, p<0.001). 125 (80%) participants achieved resolution of their nephrotic syndrome in a median time of 16 weeks.Nephrotic syndrome at baseline decreases the likelihood of renal response at 1 year. Longer clinical trials or better short-term predictors of long-term outcomes may better assess the effect of novel therapeutic approaches on subjects with nephrotic syndrome.

  View details for DOI 10.1136/lupus-2018-000308

  View details for PubMedID 31080631

  View details for PubMedCentralID PMC6485211

• Peripheral Blood B Cell Depletion after Rituximab and Complete Response in Lupus Nephritis. Clinical journal of the American Society of Nephrology : CJASN Gomez Mendez, L. M., Cascino, M. D., Garg, J., Katsumoto, T. R., Brakeman, P., Dall'Era, M., Looney, R. J., Rovin, B., Dragone, L., Brunetta, P. 2018; 13 (10): 1502–9

  Abstract

  Incomplete peripheral blood B cell depletion after rituximab in lupus nephritis might correlate with inability to reduce tubulointerstitial lymphoid aggregates in the kidney, which together could be responsible for inadequate response to treatment. We utilized data from the Lupus Nephritis Assessment with Rituximab (LUNAR) study to characterize the variability of peripheral blood B cell depletion after rituximab and assess its association with complete response in patients with lupus nephritis.We analyzed 68 participants treated with rituximab. Peripheral blood B cell depletion was defined as 0 cells/µl, termed "complete peripheral depletion," assessed over 78 weeks. Logistic regression was used to estimate the association between characteristics of complete peripheral depletion and complete response (defined as urine protein-to-creatinine ratio <0.5 mg/mg, and normal serum creatinine or an increase in creatinine <15%, if normal at baseline), assessed at week 78.A total of 53 (78%) participants achieved complete peripheral depletion (0 cells/µl) in a median time of 182 days (interquartile range, 80-339).The median duration of complete peripheral depletion was 71 days (interquartile range, 14-158). Twenty-five (47%) participants with complete peripheral depletion achieved complete response, compared with two (13%) without. Complete peripheral depletion was associated with complete response (unadjusted odds ratio [OR], 5.8; 95% confidence interval [95% CI], 1.2 to 28; P=0.03). Longer time to achieving complete peripheral depletion was associated with a lower likelihood of complete response (unadjusted OR, 0.89; 95% CI, 0.81 to 0.98; P=0.02). Complete peripheral depletion lasting >71 days (the median) was associated with complete response (unadjusted OR, 4.1; 95% CI, 1.5 to 11; P=0.008).There was substantial variability in peripheral blood B cell depletion in patients with lupus nephritis treated with rituximab from the LUNAR trial. Achievement of complete peripheral depletion, as well as the rapidity and duration of complete peripheral depletion, were associated with complete response at week 78.This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2018_09_06_CJASNPodcast_18_10_.mp3.

  View details for DOI 10.2215/CJN.01070118

  View details for PubMedID 30089664

• Safety, Pharmacokinetics, and Pharmacodynamics in Healthy Volunteers Treated With GDC-0853, a Selective Reversible Bruton's Tyrosine Kinase Inhibitor. Clinical pharmacology and therapeutics Herman, A. E., Chinn, L. W., Kotwal, S. G., Murray, E. R., Zhao, R., Florero, M., Lin, A., Moein, A., Wang, R., Bremer, M., Kokubu, S., Serone, A. P., Hanze, E. L., Viberg, A., Morimoto, A. M., Winter, H. R., Katsumoto, T. R. 2018; 103 (6): 1020–28

  Abstract

  GDC-0853 is a small molecule inhibitor of Bruton's tyrosine kinase (BTK) that is highly selective and noncovalent, leading to reversible binding. In double-blind, randomized, and placebo-controlled phase I healthy volunteer studies, GDC-0853 was well tolerated, with no dose-limiting adverse events (AEs) or serious AEs. The maximum tolerated dose was not reached during dose escalation (≤600 mg, single ascending dose (SAD) study; ≤250 mg twice daily (b.i.d.) and ≤500 mg once daily, 14-day multiple ascending dose (MAD) study). Plasma concentrations peaked 1-3 hours after oral administration and declined thereafter, with a steady-state half-life ranging from 4.2-9.9 hours. Independent assays demonstrated dose-dependent BTK target engagement. Based on pharmacokinetic/pharmacodynamic (PK/PD) simulations, a once-daily dosing regimen (e.g., 100 mg, q.d.) is expected to maintain a high level of BTK inhibition over the dosing interval. Taken together, the safety and PK/PD data support GDC-0853 evaluation in rheumatoid arthritis, lupus, and other autoimmune or inflammatory indications.

  View details for DOI 10.1002/cpt.1056

  View details for PubMedID 29484638

• Brief Report: Whole-Exome Sequencing for Identification of Potential Causal Variants for Diffuse Cutaneous Systemic Sclerosis. Arthritis & rheumatology (Hoboken, N.J.) Mak, A. C., Tang, P. L., Cleveland, C., Smith, M. H., Kari Connolly, M., Katsumoto, T. R., Wolters, P. J., Kwok, P. Y., Criswell, L. A. 2016; 68 (9): 2257–62

  Abstract

  Scleroderma is a genetically complex autoimmune disease with substantial phenotypic heterogeneity. Previous genome-wide association studies have identified common genetic variants associated with disease risk, but these studies are not designed to capture rare or potential causal variants. Our goal was to identify rare as well as common genetic variants in patients with diffuse cutaneous systemic sclerosis (dcSSc) through whole-exome sequencing (WES) in order to identify potential causal variants.We generated WES data for 32 dcSSc patients with or without interstitial lung disease (ILD) and for 17 healthy "in-house" controls. Variants were annotated and filtered by quality, minor allele frequency, and deleterious effects on gene function. We applied a gene burden test to identify novel dcSSc and dcSSc-associated ILD candidate genes that were enriched with deleterious variants in cases compared to in-house controls as well as controls from the 1000 Genomes Project (n = 130).We identified 70 genes that were enriched with deleterious variants in dcSSc patients. Two of them (BANK1 and TERT) were in pathways previously implicated in SSc or ILD pathogenesis or known susceptibility loci. Newly identified genes (COL4A3, COL4A4, COL5A2, COL13A1, and COL22A1) were significantly enriched in the extracellular matrix-related pathway, which is relevant to the fibrotic features of dcSSc, and in the DNA repair pathway (XRCC4).This study demonstrates the value of WES for the identification of novel gene variants and pathways that may contribute to scleroderma risk and/or severity. The candidate genes we discovered are potential targets for in-depth functional studies.

  View details for DOI 10.1002/art.39721

  View details for PubMedID 27111861

  View details for PubMedCentralID PMC5568050

• Cut to the quick. Journal of hospital medicine Su, R., Katsumoto, T. R., George, V., Gundling, K., Hollander, H. 2013; 8 (2): 110–13

  View details for DOI 10.1002/jhm.2000

  View details for PubMedID 23288681

• Prevalence and clinical significance of circulating autoantibodies in idiopathic pulmonary fibrosis. Respiratory medicine Lee, J. S., Kim, E. J., Lynch, K. L., Elicker, B., Ryerson, C. J., Katsumoto, T. R., Shum, A. K., Wolters, P. J., Cerri, S., Richeldi, L., Jones, K. D., King, T. E., Collard, H. R. 2013; 107 (2): 249–55

  Abstract

  The clinical significance of circulating autoantibodies in idiopathic pulmonary fibrosis is unclear. The objective of this study was to determine the frequency and clinical significance of circulating autoantibodies in idiopathic pulmonary fibrosis.We measured an extensive panel of autoantibodies (including rheumatoid factor, anti-cyclic citrullinated peptide, and anti-nuclear antibodies by immunofluorescence) associated with connective tissue disease or vasculitis in a cohort of well-characterized patients with idiopathic pulmonary fibrosis (n = 67). The prevalence of circulating autoantibodies was compared between idiopathic pulmonary fibrosis patients and healthy controls (n = 52). We compared the clinical characteristics of patients with and without circulating autoantibodies, and analyzed the relationship between autoantibody positivity and transplant-free survival time.Positive autoantibodies were found in 22% of patients with IPF and 21% of healthy controls. There were no differences in the types of autoantibodies found between patients with idiopathic pulmonary fibrosis and healthy controls. Among patients with idiopathic pulmonary fibrosis, there were no significant differences in clinical characteristics between those with and without circulating autoantibodies. The presence of circulating autoantibodies was associated with longer transplant-free survival time on adjusted analysis, however the significance varied depending on which statistical model was used (HR 0.22-0.47, p value 0.02-0.17).The frequency of circulating autoantibodies in patients with idiopathic pulmonary fibrosis is no different compared to healthy controls, but may be associated with longer survival.

  View details for DOI 10.1016/j.rmed.2012.10.018

  View details for PubMedID 23186614

  View details for PubMedCentralID PMC3543473

• The phosphatase CD148 promotes airway hyperresponsiveness through SRC family kinases. The Journal of clinical investigation Katsumoto, T. R., Kudo, M., Chen, C., Sundaram, A., Callahan, E. C., Zhu, J. W., Lin, J., Rosen, C. E., Manz, B. N., Lee, J. W., Matthay, M. A., Huang, X., Sheppard, D., Weiss, A. 2013; 123 (5): 2037–48

  Abstract

  Increased airway smooth muscle (ASM) contractility and the development of airway hyperresponsiveness (AHR) are cardinal features of asthma, but the signaling pathways that promote these changes are poorly understood. Tyrosine phosphorylation is tightly regulated by the opposing actions of protein tyrosine kinases and phosphatases, but little is known about whether tyrosine phosphatases influence AHR. Here, we demonstrate that genetic inactivation of receptor-like protein tyrosine phosphatase J (Ptprj), which encodes CD148, protected mice from the development of increased AHR in two different asthma models. Surprisingly, CD148 deficiency minimally affected the inflammatory response to allergen, but significantly altered baseline pulmonary resistance. Mice specifically lacking CD148 in smooth muscle had decreased AHR, and the frequency of calcium oscillations in CD148-deficient ASM was substantially attenuated, suggesting that signaling pathway alterations may underlie ASM contractility. Biochemical analysis of CD148-deficient ASM revealed hyperphosphorylation of the C-terminal inhibitory tyrosine of SRC family kinases (SFKs), implicating CD148 as a critical positive regulator of SFK signaling in ASM. The effect of CD148 deficiency on ASM contractility could be mimicked by treatment of both mouse trachea and human bronchi with specific SFK inhibitors. Our studies identify CD148 and the SFKs it regulates in ASM as potential targets for the treatment of AHR.

  View details for DOI 10.1172/JCI66397

  View details for PubMedID 23543053

  View details for PubMedCentralID PMC3635736

• Outcomes in systemic sclerosis-related lung disease after lung transplantation. Transplantation Sottile, P. D., Iturbe, D., Katsumoto, T. R., Connolly, M. K., Collard, H. R., Leard, L. A., Hays, S., Golden, J. A., Hoopes, C., Kukreja, J., Singer, J. P. 2013; 95 (7): 975–80

  Abstract

  Lung disease is the leading cause of death in systemic sclerosis (SSc). The diagnosis of SSc-related lung disease (SSc-LD) is often a contraindication to lung transplantation (LT) due to concerns that extrapulmonary involvement will yield worse outcomes. We sought to evaluate posttransplantation outcomes in persons with SSc-LD with esophageal involvement compared with persons with nonconnective tissue disease-related interstitial lung disease (nCTD-ILD).From 1998 to 2012, persons undergoing LT for SSc-LD were age and gender matched in a 2:1 fashion to controls undergoing LT for nCTD-ILD. Esophageal function was assessed by pH testing and manometry. We defined esophageal dysfunction as the presence of a DeMeester score >14 or dysmotility more severe than "mild nonspecific disorder". The primary outcome was posttransplantation survival. Secondary outcomes included freedom from bronchiolitis obliterans syndrome (fBOS) and rates of acute rejection. Survival and fBOS were estimated with Kaplan-Meier methods. Acute rejection was compared with Student's t test.Survival was similar in 23 persons with SSc-LD and 46 controls who underwent LT (P = 0.47). For the SSc-LD group, 1- and 5-year survival was 83% and 76% compared with 91% and 64% in the nCTD-ILD group, respectively. There were no differences in fBOS (P = 0.83). Rates of acute rejection were less in SSc-ILD (P = 0.05). Esophageal dysfunction was not associated with worse outcomes (P>0.55).Persons with SSc-LD appear to have similar survival and fBOS as persons transplanted for nCTD-ILD. The risk of acute rejection after transplantation may be reduced in persons with SSc-LD. Esophageal involvement does not appear to impact outcomes.

  View details for DOI 10.1097/TP.0b013e3182845f23

  View details for PubMedID 23545509

  View details for PubMedCentralID PMC3616420

• Treatment of systemic sclerosis complications: what to use when first-line treatment fails--a consensus of systemic sclerosis experts. Seminars in arthritis and rheumatism Walker, K. M., Pope, J. 2012; 42 (1): 42–55

  Abstract

  There is a need for standardization in systemic sclerosis (SSc) management.SSc experts (n = 117) were sent 3 surveys to gain consensus for SSc management.First-line therapy for scleroderma renal crisis (SRC) was an angiotensin-converting enzyme inhibitor (ACEi). For SRC there were not many differences between treating mild or severe SRC. In general, Second-line was to add either a calcium channel blocker (CCB) or angiotensin receptor blocker (ARB) and then an alpha-blocker (66% agreed). Endothelin receptor agonists (ERAs) were the first treatment in mild pulmonary arterial hypertension (PAH) (72%), followed by adding a phosphodiesterase-5 inhibitor (PDE5i) (77%) and then a prostanoid (73%). For severe PAH, initial treatment was 1 of the following: a prostanoid (49%), combination of a ERA and a PDE5i (18%), or combination of a ERA and a prostanoid (16%) (71% agreed). For mild Raynaud's phenomenon (RF), after a CCB and adding a PDE5i (35%), trying an ARB (32%) and finally a prostanoid (23%) was suggested. For more severe RF, 54% agreed on adding a PDE5i (45%) or prostanoid (32%) to a CCB. In the prevention of digital ulcers (DU), initial treatment was a CCB (73%), then adding a PDE5i, then use of a ERA, and then a prostanoid (44% agreed). In interstitial lung disease/pulmonary fibrosis, for induction, usually intravenous cyclophosphamide and mycophenolate mofetil (MMF) or azathioprine were chosen. For maintenance, MMF was chosen by three-fourths (56% agreed). For gastroesophageal reflux disease, >50% would exceed the maximum recommended proton pump inhibitor dose if required (72% agreed). For skin involvement after methotrexate, MMF was usually chosen (37% agreement). For SSC-related inflammatory arthritis, methotrexate therapy (60%) was followed by adding corticosteroids (37%) or hydroxychloroquine (31%) (62% agreed).Discrepancies in drug choices occurred in treatment after first line in SSc. Not all algorithms had good agreement. This study provides some guidance for SSc management.

  View details for DOI 10.1016/j.semarthrit.2012.01.003

  View details for PubMedID 22464314

• Blocking TGFβ via Inhibition of the αvβ6 Integrin: A Possible Therapy for Systemic Sclerosis Interstitial Lung Disease. International journal of rheumatology Katsumoto, T. R., Violette, S. M., Sheppard, D. 2011; 2011: 208219

  Abstract

  Interstitial lung disease (ILD) is a commonly encountered complication of systemic sclerosis (SSc) and accounts for a significant proportion of SSc-associated morbidity and mortality. Its pathogenesis remains poorly understood, and therapies that treat SSc ILD are suboptimal, at best. SSc ILD pathogenesis may share some common mechanisms with other fibrotic lung diseases, in which dysregulation of lung epithelium can contribute to pathologic fibrosis via recruitment or in situ generation and activation of fibroblasts. TGFβ, a master regulator of fibrosis, is tightly regulated in the lung by the integrin αvβ6, which is expressed at low levels on healthy alveolar epithelial cells but is highly induced in the setting of lung injury or fibrosis. Here we discuss the biology of αvβ6 and present this integrin as a potentially attractive target for inhibition in the setting of SSc ILD.

  View details for DOI 10.1155/2011/208219

  View details for PubMedID 22013449

  View details for PubMedCentralID PMC3195527

• The pathogenesis of systemic sclerosis. Annual review of pathology Katsumoto, T. R., Whitfield, M. L., Connolly, M. K. 2011; 6: 509–37

  Abstract

  Systemic sclerosis (SSc), also known as scleroderma, is a rare connective tissue disease characterized by vascular and immune dysfunction, leading to fibrosis that can damage multiple organs. Its pathogenesis is complex and poorly understood. Two major clinical subtypes are the limited and diffuse forms. Research into SSc has been hampered by its rarity, its clinical heterogeneity, and the lack of mouse models that accurately recapitulate the disease. Clinical and basic studies have yielded some mechanistic clues regarding pathogenesis. Recent insights gained through the use of microarrays have revealed distinctive subsets of SSc within and beyond the limited and diffuse subsets. In this review, we discuss potential mechanisms underlying the vascular, autoimmune, and fibrotic points of dysregulation. Proper categorization of SSc patients for research studies by use of microarrays or other biomarkers is critical, as disease heterogeneity may explain some of the inconsistencies of prior studies.

  View details for DOI 10.1146/annurev-pathol-011110-130312

  View details for PubMedID 21090968

• Expert agreement on EULAR/EUSTAR recommendations for the management of systemic sclerosis. The Journal of rheumatology Walker, K. M., Pope, J. 2011; 38 (7): 1326–28

  Abstract

  The European League Against Rheumatism/EULAR Scleroderma Trials and Research group (EULAR/EUSTAR) has published recommendations for the management of systemic sclerosis (SSc). Members of the Scleroderma Clinical Trials Consortium and the Canadian Scleroderma Research Group were surveyed regarding their level of agreement with the recommendations.A survey containing the 14 EULAR/EUSTAR recommendations asked participants to indicate their level of agreement with each on a 10-point scale, from 0 (not at all) to 9 (completely agree). The survey was sent to 117 people, and 66 replies were received (56% response rate).Exceptions to generally high agreement included the use of iloprost and bosentan for digital vasculopathy, methotrexate for skin involvement, and bosentan and epoprostenol for pulmonary arterial hypertension (PAH; all < 69% agreement, defined as ≥ 7 rating). Vasculopathy and PAH treatment had differences in agreement between North America and Europe (p < 0.006). Respondents who were EULAR/EUSTAR recommendation authors shared a similar level of agreement compared to those who were not, except for the use of proton pump inhibitors for the prevention of SSc-related gastroesophageal reflux disease, esophageal ulcers, and strictures.EULAR/EUSTAR recommendations were relatively well accepted among SSc experts. Overall reduced agreement may be due to the modest efficacy of some agents (such as methotrexate for the skin). Some regional disagreement is likely because of access differences.

  View details for DOI 10.3899/jrheum.101262

  View details for PubMedID 21459952

• Activation of the innate immune receptor Dectin-1 upon formation of a 'phagocytic synapse'. Nature Goodridge, H. S., Reyes, C. N., Becker, C. A., Katsumoto, T. R., Ma, J., Wolf, A. J., Bose, N., Chan, A. S., Magee, A. S., Danielson, M. E., Weiss, A., Vasilakos, J. P., Underhill, D. M. 2011; 472 (7344): 471–75

  Abstract

  Innate immune cells must be able to distinguish between direct binding to microbes and detection of components shed from the surface of microbes located at a distance. Dectin-1 (also known as CLEC7A) is a pattern-recognition receptor expressed by myeloid phagocytes (macrophages, dendritic cells and neutrophils) that detects β-glucans in fungal cell walls and triggers direct cellular antimicrobial activity, including phagocytosis and production of reactive oxygen species (ROS). In contrast to inflammatory responses stimulated upon detection of soluble ligands by other pattern-recognition receptors, such as Toll-like receptors (TLRs), these responses are only useful when a cell comes into direct contact with a microbe and must not be spuriously activated by soluble stimuli. In this study we show that, despite its ability to bind both soluble and particulate β-glucan polymers, Dectin-1 signalling is only activated by particulate β-glucans, which cluster the receptor in synapse-like structures from which regulatory tyrosine phosphatases CD45 and CD148 (also known as PTPRC and PTPRJ, respectively) are excluded (Supplementary Fig. 1). The 'phagocytic synapse' now provides a model mechanism by which innate immune receptors can distinguish direct microbial contact from detection of microbes at a distance, thereby initiating direct cellular antimicrobial responses only when they are required.

  View details for DOI 10.1038/nature10071

  View details for PubMedID 21525931

  View details for PubMedCentralID PMC3084546

• Structurally distinct phosphatases CD45 and CD148 both regulate B cell and macrophage immunoreceptor signaling. Immunity Zhu, J. W., Brdicka, T., Katsumoto, T. R., Lin, J., Weiss, A. 2008; 28 (2): 183–96

  Abstract

  The receptor-type protein tyrosine phosphatase (RPTP) CD148 is thought to have an inhibitory function in signaling and proliferation in nonhematopoietic cells. However, its role in the immune system has not been thoroughly studied. Our analysis of CD148 loss-of-function mice showed that CD148 has a positive regulatory function in B cells and macrophages, similar to the role of CD45 as a positive regulator of Src family kinases (SFKs). Analysis of CD148 and CD45 doubly deficient B cells and macrophages revealed hyperphosphorylation of the C-terminal inhibitory tyrosine of SFKs accompanied by substantial alterations in B and myeloid lineage development and defective immunoreceptor signaling. Because these findings suggest the C-terminal tyrosine of SFKs is a common substrate for both CD148 and CD45 phosphatases and imply a level of redundancy not previously appreciated, a reassessment of the function of CD45 in the B and myeloid lineages based on prior data from the CD45-deficient mouse is warranted.

  View details for DOI 10.1016/j.immuni.2007.11.024

  View details for PubMedID 18249142

  View details for PubMedCentralID PMC2265106

• Granulocyte/macrophage colony-stimulating factor and accessory cells modulate radioprotection by purified hematopoietic cells. The Journal of experimental medicine Katsumoto, T. R., Duda, J., Kim, A., Wardak, Z., Dranoff, G., Clapp, D. W., Shannon, K. 2005; 201 (6): 853–58

  Abstract

  Granulocyte/macrophage colony-stimulating factor (GM-CSF) promotes the survival, proliferation, and differentiation of myeloid lineage cells and regulates chemotaxis and adhesion. However, mice in which the genes encoding GM-CSF (Gmcsf) or the beta common subunit of the GM-CSF receptor (betac) are inactivated display normal steady-state hematopoiesis. Here, we show that host GM-CSF signaling strongly modulates the ability of donor hematopoietic cells to radioprotect lethally irradiated mice. Although bone marrow mononuclear cells efficiently rescue Gmcsf mutant recipients, fetal liver cells and Sca1(+) lin(-/dim) marrow cells are markedly impaired. This defect is partially attributable to accessory cells that are more prevalent in bone marrow. In contrast, Gmcsf-deficient hematopoietic stem cells demonstrate normal proliferative potentials. Short-term survival is also impaired in irradiated betac mutant recipients transplanted with fetal liver or bone marrow. These data demonstrate a nonredundant function of GM-CSF in radioprotection by donor hematopoietic cells that may prove relevant in clinical transplantation.

  View details for DOI 10.1084/jem.20041504

  View details for PubMedID 15781578

  View details for PubMedCentralID PMC2213101

• Polymerized liposome assemblies: Bifunctional macromolecular selectin inhibitors mimicking physiological selectin ligands BIOCHEMISTRY Bruehl, R. E., Dasgupta, F., Katsumoto, T. R., Tan, J. H., Bertozzi, C. R., Spevak, W., Ahn, D. J., ROSEN, S. D., Nagy, J. O. 2001; 40 (20): 5964-5974

  Abstract

  Monomeric sialyl Lewis(X) (sLe(x)) and sLe(x)-like oligosaccharides are minimal structures capable of supporting selectin binding in vitro. However, their weak binding interactions do not correlate with the high-affinity binding interactions witnessed in vivo. The polyvalent display of carbohydrate groups found on cell surface glycoprotein structures may contribute to the enhanced binding strength of selectin-mediated adhesion. Detailed biochemical analyses of physiological selectin ligands have revealed a complicated composition of molecules that bind to the selectins in vivo and suggest that there are other requirements for tight binding beyond simple carbohydrate multimerization. In an effort to mimic the high-affinity binding, polyvalent scaffolds that contain multicomponent displays of selectin-binding ligands have been synthesized. Here, we demonstrate that the presentation of additional anionic functional groups in the form of sulfate esters, on a polymerized liposome surface containing a multimeric array of sLe(x)-like oligosaccharides, generates a highly potent, bifunctional macromolecular assembly. This assembly inhibits L-, E-, and P-selectin binding to GlyCAM-1, a physiological ligand better than sLe(x)-like liposomes without additional anionic charge. These multivalent arrays are 4 orders of magnitude better than the monovalent carbohydrate. Liposomes displaying 3'-sulfo Lewis(X)-like oligosaccharides, on the other hand, show slight loss of binding with introduction of additional anionic functional groups for E- and P-selectin and negligible change for L-selectin. The ability to rapidly and systematically vary the composition of these assemblies is a distinguishing feature of this methodology and may be applied to the study of other systems where composite binding determinants are important for high-affinity binding.

  View details for Web of Science ID 000168932900013

  View details for PubMedID 11352731

• Ligation of L-selectin on T lymphocytes activates beta1 integrins and promotes adhesion to fibronectin. Journal of immunology (Baltimore, Md. : 1950) Giblin, P. A., Hwang, S. T., Katsumoto, T. R., Rosen, S. D. 1997; 159 (7): 3498–3507

  Abstract

  Lymphocyte recirculation is dependent on families of adhesion molecules expressed on lymphocytes and their sequential interaction with ligands expressed on high endothelial venules in secondary lymphoid organs such as peripheral lymph nodes. By binding its carbohydrate-based ligands, L-selectin initiates this cascade of molecular interactions, supporting the rolling of lymphocytes along high endothelial venules. Subsequent activation of lymphocyte integrins leads to cell arrest followed by lymphocyte extravasation. Here, we demonstrate stimulated adhesion of PBL and Jurkat T cells to immobilized fibronectin following treatment with (1) GlyCAM-1, a physiologic ligand for L-selectin, and (2) cross-linked anti-L-selectin mAbs. We also utilize a solution binding assay to detect early changes in integrin activity, including affinity modulation and/or integrin clustering, and distinguish these from later postreceptor binding events such as changes in cell shape and spreading. With the Jurkat cell line, GlyCAM-1 and fucoidin (an L-selectin ligand mimetic) induce the binding of soluble fibronectin. In contrast, stimulation through the Jurkat TCR fails to promote binding to soluble ligand even though TCR cross-linking markedly enhances adhesion to immobilized fibronectin. These data suggest that L-selectin and the TCR promote adhesion through distinct mechanisms. Finally, we demonstrate that beta1 integrins are preferentially activated on naive T cells through the L-selectin pathway. Together with our previous studies showing similar activation of beta2 integrins on the naive T cell subset, these data suggest that signals delivered though L-selectin participate in the preferential recruitment of these cells to peripheral lymph nodes.

  View details for PubMedID 9317149

• L-selectin-carbohydrate interactions: Relevant modifications of the Lewis x trisaccharide BIOCHEMISTRY Sanders, W. J., Katsumoto, T. R., Bertozzi, C. R., ROSEN, S. D., Kiessling, L. L. 1996; 35 (47): 14862-14867

  Abstract

  Protein-carbohydrate interactions are known to mediate cell-cell recognition and adhesion events. Specifically, three carbohydrate binding proteins termed selectins (E-, P-, and L-selectin) have been shown to be essential for leukocyte rolling along the vascular endothelium, the first step in the recruitment of leukocytes from the blood into inflammatory sites or into secondary lymphoid organs. Although this phenomenon is well-established, little is known about the molecular-level interactions on which it depends. All three selectins recognize sulfated and sialylated derivatives of the Lewis x [Le(x):Gal beta 1-->4(Fuc alpha 1-->3)GlcNAc] and Lewis a [Le(a): Gal beta 1-->3(Fuc alpha 1-->4)GlcNAc] trisaccharide cores with affinities in the millimolar range, and it is believed that variants of these structures are the carbohydrate determinants of selectin recognition. Recently it was shown that the mucin GlyCAM-1, a secreted physiological ligand for L-selectin, is capped with sulfated derivatives of sialyl Lewis x [sLe(x): Sia alpha 2-->3Gal beta 1-->4(Fuc alpha 1-->3)GlcNAc] and that sulfation is required for the high-affinity interaction between GlyCAM-1 and L-selectin. To elucidate the important sites of sulfation on Le(x) with respect to L-selectin recognition, we have synthesized six sulfated Le(x) analogs and determined their abilities to block binding of a recombinant L-selectin-Ig chimera to immobilized GlyCAM-1. Our results suggest that 6-sulfo sLe(x) binds to L-selectin with higher affinity than does sLe(x) or 6'-sulfo sLe(x) and that sulfation of sLe(x) capping groups on GlyCAM-1 at the 6-position is important for L-selectin recognition.

  View details for Web of Science ID A1996VV23700024

  View details for PubMedID 8942649