Shunsuke Furuta

Rituximab versus cyclophosphamide in ANCA-associated renal vasculitis: 2-year results of a randomised trial

OBJECTIVES The RITUXVAS trial reported similar remission induction rates and safety between rituximab and cyclophosphamide based regimens for antineutrophil cytoplasm antibody (ANCA)-associated vasculitis at 12 months; however, immunosuppression maintenance requirements and longer-term outcomes after rituximab in ANCA-associated renal vasculitis are unknown. METHODS Forty-four patients with newly diagnosed ANCA-associated vasculitis and renal involvement were randomised, 3:1, to glucocorticoids plus either rituximab (375 mg/m(2)/week×4) with two intravenous cyclophosphamide pulses (n=33, rituximab group), or intravenous cyclophosphamide for 3-6 months followed by azathioprine (n=11, control group). RESULTS The primary end point at 24 months was a composite of death, end-stage renal disease and relapse, which occurred in 14/33 in the rituximab group (42%) and 4/11 in the control group (36%) (p=1.00). After remission induction treatment all patients in the rituximab group achieved complete B cell depletion and during subsequent follow-up, 23/33 (70%) had B cell return. Relapses occurred in seven in the rituximab group (21%) and two in the control group (18%) (p=1.00). All relapses in the rituximab group occurred after B cell return. CONCLUSIONS At 24 months, rates of the composite outcome of death, end-stage renal disease and relapse did not differ between groups. In the rituximab group, B cell return was associated with relapse. TRIAL REGISTRATION NUMBER ISRCTN28528813.

Role of Th2 Cells in IgG4-Related Lacrimal Gland Enlargement

Background: Lacrimal gland enlargement (LGE) is one of the characteristics of Mikulicz’s disease (MD). Recently, marked serum IgG4 elevation and infiltration of IgG4-positive plasmacytes in the enlarged exocrine glands have been reported in MD patients. However, little is known about the role of CD4+ T cells and their cytokines in IgG4-related diseases. The aim of this study was to evaluate the characteristics of CD4+ T cells in patients with IgG4-related diseases. Methods: We investigated the clinical characteristics of 9 patients with LGE and elevated serum IgG4 levels (named IgG4-related LGE). We also examined mRNA expression of cytokines and transcription factors of peripheral blood CD4+ T cells in patients with IgG4-related LGE. Results: All patients with IgG4-related LGE showed elevated serum IgE levels. In addition, 5 of 9 patients with IgG4-related LGE exhibited eosinophilia and asthma-like symptoms. In patients with IgG4-related LGE, mRNA expression of IL-4, IL-5, IL-10 and GATA-3 but not IFN-γ or T-bet was enhanced on CD4+ T cells compared with that in healthy controls. Conclusions: Th2 cells may be involved in the pathogenesis of IgG4-related diseases.

Prediction of Therapeutic Responses to Tocilizumab in Patients With Rheumatoid Arthritis: Biomarkers Identified by Analysis of Gene Expression in Peripheral Blood Mononuclear Cells Using Genome‐Wide DNA Microarray

The aim of this prospective multicenter study was to identify biomarkers that can be used to predict therapeutic responses to tocilizumab in patients with rheumatoid arthritis (RA).

Antineutrophil cytoplasm antibody–associated vasculitis: recent developments

Antineutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV) is a group of vasculitides characterized by small-to-medium-sized blood vessel vasculitis and the presence of ANCA. Although our understanding of the causes of AAV remains limited, new information supporting an autoimmune basis is emerging. This review highlights recent progresses in etiology, pathogenesis, classification, and treatment. A genome-wide association study has confirmed a role for genetic susceptibility in AAV, and links between environmental factors and AAV induction through abnormal neutrophil extracellular traps has been demonstrated. Ongoing international consensus initiatives have revised approaches to the classification of vasculitis that has been enhanced by the analysis of large-scale prospective clinical data sets. New autoantibodies to human lysosome-associated membrane protein-2 antibody, moesin, and plasminogen have been detected in AAV sera and a prognostic classification of renal biopsies developed. Clinical trial networks have extended the evidence base for the treatment of AAV, and rituximab has emerged as an alternative to cyclophosphamide for remission induction. Long-term outcomes following current treatment strategies have been determined and increased risks for cardiovascular and malignant disease reported.

Comparison of phenotype and outcome in microscopic polyangiitis between europe and Japan.

Objective. There are differences between Europe and Japan in the incidence and antineutrophil cytoplasmic antibody (ANCA) serotype of patients with microscopic polyangiitis (MPA). However, differences in phenotype or outcome have not been explored. We aimed to identify differences in phenotype and outcome of MPA between Europe and Japan. Methods. Sequential cohorts of patients with MPA and renal limited vasculitis were collected from European and Japanese centers (n = 147 and n = 312, respectively). Trial databases from the European Vasculitis Society and the Japanese patients with Myeloperoxidase (MPO)-ANCA-Associated Vasculitis (JMAAV) trial were studied (n = 254 and n = 48, respectively). We evaluated baseline characteristics including ANCA status and organ involvement, treatment, survival, and renal survival. Differences in survival and renal survival were studied using multivariate analysis. Results. The non-trial cohorts showed patients with MPA in Japan had a higher age at onset, more frequent MPO-ANCA positivity, lower serum creatinine, and more frequent interstitial pneumonitis than those in Europe (all p < 0.01). Comparisons between the trial databases demonstrated similar results. Cumulative patient survival and renal survival rates were not different between Europe and Japan (p = 0.71 and p = 0.38, respectively). Multivariate analysis identified age at onset, serum creatinine, gastrointestinal, and respiratory involvement as factors with higher risk of death. For endstage renal failure, serum creatinine and use of plasma exchange were identified as factors with higher risk, and immunosuppressant use as lower risk factors. Conclusion. Phenotypes in patients with MPA were different between Europe and Japan. However, the outcomes of patient survival and renal survival were similar.

Overlapping and Distinct Roles of STAT4 and T-bet in the Regulation of T Cell Differentiation and Allergic Airway Inflammation

T-bet and STAT4 play critical roles in helper T cell differentiation, especially for Th1 cells. However, it is still unknown about the relative importance and redundancy of T-bet and STAT4 for Th1 differentiation. It is also unknown about their independent role of T-bet and STAT4 in the regulation of allergic airway inflammation. In this study, we addressed these issues by comparing T-bet-deficient (T-bet−/−) mice, STAT4−/− mice, and T-bet- and STAT4-double-deficient (T-bet−/−STAT4−/−) mice on the same genetic background. Th1 differentiation was severely decreased in T-bet−/− mice and STAT4−/− mice as compared with that in wild-type mice, but Th1 differentiation was still observed in T-bet−/− mice and STAT4−/− mice. However, Th1 cells were hardly detected in T-bet−/−STAT4−/− mice. In contrast, the maintenance of Th17 cells was enhanced in T-bet−/− mice but was reduced in STAT4−/− mice and T-bet−/−STAT4−/− mice. In vivo, Ag-induced eosinophil and neutrophil recruitment into the airways was enhanced in T-bet−/− mice but was attenuated in STAT4−/− mice and T-bet−/−STAT4−/− mice. Ag-induced IL-17 production in the airways was also diminished in STAT4−/− mice and T-bet−/−STAT4−/− mice. These results indicate that STAT4 not only plays an indispensable role in T-bet-independent Th1 differentiation but also is involved in the maintenance of Th17 cells and the enhancement of allergic airway inflammation.

Clinical Features and Radiological Findings in Large Vessel Vasculitis: Are Takayasu Arteritis and Giant Cell Arteritis 2 Different Diseases or a Single Entity?

Objective. Takayasu arteritis (TAK) and giant cell arteritis (GCA) are 2 major variants of large vessel vasculitis (LVV). The frequent involvement of large vessels in GCA has raised the possibility that TAK and GCA should be regarded as 1 disease. By detailed phenotyping of a single-center cohort, we aimed to define the differences between TAK and GCA. Methods. Forty-five patients (23 TAK, 22 GCA) were identified. Baseline characteristics, clinical symptoms, laboratory data, enhanced computed tomography/magnetic resonance imaging, treatments, and clinical courses were retrospectively assessed with descriptive statistics. In addition, latent class analysis of the 45 patients was performed to explore phenotypic differences. Results. Patients with GCA had more frequent headache (p < 0.01), higher C-reactive protein levels (p = 0.01), and higher erythrocyte sedimentation rates (p = 0.03) than did patients with TAK at diagnosis. With the exception of subdiaphragmatic lesions, the distributions of vessel lesions were not different between TAK and GCA. However, focusing on subclavian and carotid arteries, long tapered-type stenotic lesions were more frequent in GCA than in TAK (p < 0.01). The proportion of patients without relapse was higher in GCA (60%) than in TAK (22%, p = 0.01). Latent class analysis also divided patients with LVV into 2 separate groups consistent with TAK and GCA. Conclusion. The differences observed in clinical symptoms, inflammatory markers, radiological findings, and clinical courses suggested that TAK and GCA were 2 different diseases. Latent class analysis supported these results. The shape of stenotic lesions in the subclavian and carotid arteries is a useful discriminator between TAK and GCA.

Emerging therapies in antineutrophil cytoplasm antibody-associated vasculitis.

Purpose of reviewThe current standard therapy for antineutrophil cytoplasm antibody-associated vasculitis (AAV), high-dose glucocorticoid and cyclophosphamide followed by azathioprine, has improved the disease prognosis. However, there are still unmet needs. For example, reducing relapse risk and glucocorticoid toxicity. Newer therapies are needed. Recent findingsPotential newer drugs are emerging following a better understanding of disease mechanisms and the availability of targeted therapies to B cells, T cells, proinflammatory cytokines and complement. Rituximab, an anti-CD20 monoclonal antibody, has proven efficacy in remission induction therapy for AAV, and two trials with rituximab as remission maintenance therapy are ongoing. Clinical trials evaluating mycophenolate mofetil as remission induction therapy, gusperimus, belimumab and complement factor C5a inhibition are also ongoing, and many other potential candidates are being investigated both clinically and experimentally. SummaryB-cell therapy is now an established treatment in AAV and several other therapies are under evaluation. However, the unmet need in vasculitis therapy remains large and newer therapies either alone or in combination will need to both improve efficacy and permit reductions in glucocorticoid and immunosuppressive exposure.

AT-Rich–Interactive Domain–Containing Protein 5A Functions as a Negative Regulator of Retinoic Acid Receptor–Related Orphan Nuclear Receptor γt–Induced Th17 Cell Differentiation

The proinflammatory cytokines tumor necrosis factor α and interleukin‐6 (IL‐6) and the Th17 cell cytokine IL‐17A are implicated in the pathogenesis of rheumatoid arthritis (RA), and the blockade of these cytokines by biologic agents provides clinical benefits for RA patients. We undertook this study to clarify the mechanisms underlying the efficacy of IL‐6 blockade in RA and to find a novel target for treatment of RA.

Prevalence and Responsiveness to Treatment of Lung Abnormalities on Chest Computed Tomography in Patients With Microscopic Polyangiitis: A Multicenter, Longitudinal, Retrospective Study of One Hundred Fifty Consecutive Hospital-Based Japanese Patients.

To determine the prevalence of lung abnormalities on chest computed tomography (CT) in patients with microscopic polyangiitis (MPA), to assess the responsiveness of such abnormalities to initial treatment, and to assess associations between these abnormalities and patient and disease characteristics and mortality.