Reduced-dose versus high-dose glucocorticoids added to rituximab on remission induction in ANCA-associated vasculitis: predefined 2-year follow-up study.

OBJECTIVES: The LoVAS trial reported non-inferiority in remission induction rates between the reduced-dose and conventional high-dose glucocorticoid regimens plus rituximab for antineutrophil cytoplasm antibody (ANCA)-associated vasculitis at 6 months; however, maintenance glucocorticoid requirements and long-term outcomes are unknown. METHODS: A total of 140 patients with new-onset ANCA-associated vasculitis without severe glomerulonephritis or alveolar haemorrhage were randomised to receive reduced-dose prednisolone (0.5 mg/kg/day) plus rituximab (375 mg/m2/week×4) or high-dose prednisolone (1 mg/kg/day) plus rituximab. After achieving remission, patients received the rituximab maintenance therapy (1 g/6 months). RESULTS: A total of 134 patients were analysed. Among patients who achieved remission with the protocolised treatments, the majority of patients in the reduced-dose group (89.7%) and 15.5% in the high-dose group discontinued prednisolone (median time to withdrawal, 150 and 375 days, respectively). During 24-month trial period, two patients in the reduced-dose group (2.8%) died, while five patients in the high-dose group (7.6%) died (p=0.225). Relapse occurred in nine patients in the reduced-dose group (13.0%) (two major and seven minor) and five in the high-dose group (7.6%) (two major and three minor) (p=0.311). Serious adverse events (SAEs) were less frequent in the reduced-dose group (36 events in 19 patients, 27.5%) than in the high-dose group (54 events in 30 patients, 46.2%) (p=0.025). CONCLUSION: At 24 months, frequencies of relapse did not differ between the groups, and SAEs were less frequent in the reduced-dose group due to the lower event rate in the 6-month induction phase. The bias to myeloperoxidase-ANCA positivity (85.8%) in the trial population should be noted. TRIAL REGISTRATION NUMBER: NCT02198248.

Short-term and long-term outcomes of patients with anti-melanoma differentiation-associated gene 5 antibody-positive dermatomyositis.

OBJECTIVES: Anti-melanoma differentiation-associated gene 5 (MDA5) antibody-positive dermatomyositis (MDA5-DM) is a subtype of dermatomyositis characterized by frequent interstitial lung disease and reduced muscle involvement. This study aimed to determine the short-term and long-term outcomes of patients with MDA5-DM. METHODS: Information on baseline characteristics, treatments, and short-term and long-term outcomes of patients with MDA5-DM including survival, relapse, and the titer of anti-MDA5 antibody, was retrospectively collected. Descriptive statistics regarding clinical outcomes were calculated, and a comparison of clinical parameters between patients with and without relapse was performed. The short-term survival according to the use of Janus kinase inhibitors (JAKi) was also assessed. RESULTS: A total of 154 patients with MDA5-DM were included in the study. Forty patients (25.9%) died during the remission induction phase, with respiratory failure being the most common cause of mortality. Among the 114 patients who survived the remission induction phase, the 5-year cumulative survival and relapse-free survival rates were 96.8% and 77.4%, respectively, and 7.9% of patients achieved complete drug-free remission. Fifty-four patients achieved normalization of anti-MDA5 antibody titers and only two of them relapsed after normalization. In the severe patients, the 6-month survival rate became significantly higher after the emergence of the JAKi treatment compared with before its existence (p= 0.03). CONCLUSIONS: Although relapse often occurs, the long-term survival of MDA5-DM patients who survived the remission induction phase is generally favorable. The status of the anti-MDA5 antibody is associated with relapse. JAKi may improve the survival of refractory patients with severe MDA5-DM.

Effect of Reduced-Dose vs High-Dose Glucocorticoids Added to Rituximab on Remission Induction in ANCA-Associated Vasculitis: A Randomized Clinical Trial.

Importance: The current standard induction therapy for antineutrophil cytoplasm antibody (ANCA)-associated vasculitis is the combination of high-dose glucocorticoids and cyclophosphamide or rituximab. Although these regimens have high remission rates, they are associated with considerable adverse events presumably due to high-dose glucocorticoids. Objective: To compare efficacy and adverse events between a reduced-dose glucocorticoid plus rituximab regimen and the standard high-dose glucocorticoid plus rituximab regimen in remission induction of ANCA-associated vasculitis. Design, Setting, and Participants: This was a phase 4, multicenter, open-label, randomized, noninferiority trial. A total of 140 patients with newly diagnosed ANCA-associated vasculitis without severe glomerulonephritis or alveolar hemorrhage were enrolled between November 2014 and June 2019 at 21 hospitals in Japan. Follow-up ended in December 2019. Interventions: Patients were randomized to receive reduced-dose prednisolone (0.5 mg/kg/d) plus rituximab (375 mg/m2/wk, 4 doses) (n = 70) or high-dose prednisolone (1 mg/kg/d) plus rituximab (n = 70). Main Outcomes and Measures: The primary end point was the remission rate at 6 months, and the prespecified noninferiority margin was -20 percentage points. There were 8 secondary efficacy outcomes and 6 secondary safety outcomes, including serious adverse events and infections. Results: Among 140 patients who were randomized (median age, 73 years; 81 women [57.8%]), 134 (95.7%) completed the trial. At 6 months, 49 of 69 patients (71.0%) in the reduced-dose group and 45 of 65 patients (69.2%) in the high-dose group achieved remission with the protocolized treatments. The treatment difference of 1.8 percentage points (1-sided 97.5% CI, -13.7 to ∞) between the groups met the noninferiority criterion (P = .003 for noninferiority). Twenty-one serious adverse events occurred in 13 patients in the reduced-dose group (18.8%), while 41 occurred in 24 patients in the high-dose group (36.9%) (difference, -18.1% [95% CI, -33.0% to -3.2%]; P = .02). Seven serious infections occurred in 5 patients in the reduced-dose group (7.2%), while 20 occurred in 13 patients in the high-dose group (20.0%) (difference, -12.8% [95% CI, -24.2% to -1.3%]; P = .04). Conclusions and Relevance: Among patients with newly diagnosed ANCA-associated vasculitis without severe glomerulonephritis or alveolar hemorrhage, a reduced-dose glucocorticoid plus rituximab regimen was noninferior to a high-dose glucocorticoid plus rituximab regimen with regard to induction of disease remission at 6 months. Trial Registration: ClinicalTrials.gov Identifier: NCT02198248.

Development of a Kidney Prognostic Score in a Japanese Cohort of Patients With Antineutrophil Cytoplasmic Autoantibody Vasculitis.

Introduction: Glomerulonephritis is frequent in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and crucial to disease outcomes. We conducted a detailed assessment of renal pathology in Japanese patients with AAV, and developed a new score that would predict renal outcome. Methods: Two hundred twenty-one patients who were diagnosed with AAV and underwent a kidney biopsy were enrolled. Data on glomerular, tubular, interstitial, and vascular lesions from kidney biopsies were analyzed; the 3 established classification and prognostic scoring systems (Berden Classification, Mayo Clinic/RPS Chronicity Score [MCCS], and ANCA Renal Risk Score [ARRS]) were validated. Further, we developed a new prognostic score by including variables relevant for Japanese patients with ANCA-glomerulonephritis. Results: Median follow-up was 60 months (interquartile range: 6-60). End-stage kidney disease (ESKD) risk prediction by the MCCS and the ARRS was confirmed. Moreover, our analysis identified 4 items with significant ESKD risk prediction capacity, namely percentage of cellular, fibrocellular, and fibrous crescents; and sclerotic glomeruli. Based on our findings, we created a score evaluating the percentage of these lesions to total glomeruli, the Percentage of ANCA Crescentic Score (PACS). The area under the receiver operating characteristic (ROC) curve evaluating PACS was 0.783. The PACS had a comparable performance as the ARRS in predicting ESKD. The optimal PACS cut-off for ESKD risk over 60 months was 43%. In addition, the percentage of cellular crescents and presence of interstitial inflammation were independent predictors of kidney function recovery. Conclusion: We developed a new score predicting renal prognosis using histopathological data of Japanese patients with ANCA-glomerulonephritis. Studies are needed to validate our results in international cohorts.

Prevalence and risk factors of osteonecrosis of the femoral head in patients with ANCA-associated vasculitis: a multicentre cohort study.

OBJECTIVE: We aimed to determine the prevalence and risk factors for osteonecrosis of the femoral head (ONFH) in a multicentre cohort of patients with antineutrophil cytoplasmic antibody-associated vasculitis (AAV). METHODS: One hundred and eighty-six AAV patients who underwent radiographs and MRI screening of bilateral hip joints at more than 6 months after initial remission induction therapy (RIT) were retrospectively assessed for the presence of ONFH. RESULTS: Among 186 AAV patients, 33 (18%) were diagnosed with ONFH. Among the patients with ONFH, 55% were asymptomatic and 64% had bilateral ONFH. Seventy-six per cent of ONFH joints were in precollapse stages (stage ≤2), whereas 24% of ONFH joints were in collapse stages (stage ≥3). Moreover, 56% of the precollapse stage joints were already at risk of future collapse (type ≥C-1). Even in asymptomatic ONFH patients, 39% of the precollapse stage joints were type ≥C-1. Prednisolone dose of ≥20 mg/day on day 90 of RIT was an independent risk factor for ONFH in AAV patients (OR 1.072, 95% CI 1.017 to 1.130, p=0.009). Rituximab use was a significant beneficial factor against ONFH (p=0.019), but the multivariate analysis rejected its significance (p=0.257). CONCLUSION: Eighteen per cent of AAV patients developed ONFH, and two-thirds of the ONFH joints were already in collapse stages or at risk of future collapse. Prednisolone dose of ≥20 mg/day on day 90 of RIT was an independent risk factor for ONFH. A rapid reduction of glucocorticoids in RIT and early detection of precollapse ONFH by MRI may decrease and intervene ONFH development in AAV patients.

Prognostic factors of Pneumocystis pneumonia in patients with systemic autoimmune diseases.

OBJECTIVE: Pneumocystis pneumonia (PCP) is one of the most common opportunistic infections. In systemic autoimmune disease patients receiving immunosuppressive treatments, low lymphocyte count, old age and coexisting lung disease have been known as risk factors for the occurrence of PCP. However, factors relevant to prognosis of PCP have not been fully studied. METHODS: A total of 95 sequential patients who developed PCP during immunosuppressive treatment for systemic autoimmune diseases was identified from five Japanese centres. We retrospectively assessed baseline characteristics, immunosuppressive treatment prior to the onset of PCP, treatment for PCP and survival. Univariate and multivariate analyses were performed to identify prognostic factors. RESULTS: Forty-two deaths (44.2%) were observed in this study. Age at the diagnosis of PCP was higher in non-survivors than in survivors (74 years vs. 64 years, p = 0.008). Non-survivors more frequently had lung involvement than did survivors (47.6% vs. 13.2%, p<0.001). Median lymphocyte count at the diagnosis of PCP was lower in non-survivors than in survivors (499/µl vs. 874/µl, p = 0.002). Multivariate analysis identified lower lymphocyte count, older age and coexisting lung disease at the diagnosis of PCP as independent risk factors for death. Those risk factors for death were similar to the known risk factors for the occurrence of PCP. CONCLUSION: Although PCP can occur even in patients without these risk factors, our data demonstrate that the overall prognosis of PCP in such patients is good. Given that the standard prophylactic treatment against PCP has safety issues, the risk-stratified use of prophylactic treatment may be advisable.

Longterm Outcomes of 188 Japanese Patients with Eosinophilic Granulomatosis with Polyangiitis.

OBJECTIVE: Patients with eosinophilic granulomatosis with polyangiitis (EGPA) frequently experience relapses, which lead to cumulative organ damage. In this retrospective observational study, we aimed to reveal the risk factors for relapse in EGPA. METHODS: A total of 188 Japanese patients with EGPA diagnosed between 1996 and 2015 were identified from medical records in 10 hospitals. The diagnosis was based on the American College of Rheumatology 1990 criteria or Lanham's criteria. Baseline characteristics, treatments, asthma exacerbation, and relapses were evaluated by retrospective chart review. RESULTS: The median followup period was 56 months. The median age at disease onset was 59.7 years. At the disease onset, 95.2% of the patients had a history of bronchial asthma and 44.7% were positive for antineutrophil cytoplasmic antibodies. The cumulative survival and relapse-free survival rates at 5 years were 89.6% and 64.0%, respectively. Multivariate analysis with 2 models, proportional hazards, and competing risk models, was performed to identify the factors associated with relapse. The proportional hazards model identified azathioprine (AZA) maintenance therapy and high eosinophil counts at onset as independent factors with lower relapse risks, and high immunoglobulin E (IgE) levels at onset as a risk factor for relapse. The competing risk model identified no statistically significant factors. CONCLUSION: Although potential benefit of AZA maintenance therapy in preventing relapse of EGPA was suggested by the proportional hazards model, there was a discrepancy in the results between the models. Eosinophil counts and IgE levels at onset were also identified as candidates of factors associated with relapse in EGPA.

Low-dose glucocorticoids plus rituximab versus high-dose glucocorticoids plus rituximab for remission induction in ANCA-associated vasculitis (LoVAS): protocol for a multicentre, open-label, randomised controlled trial.

INTRODUCTION: Antineutrophil cytoplasm antibody-associated vasculitis (AAV) is a form of systemic vasculitis. The current standard induction therapy with the combination of high-dose glucocorticoids and cyclophosphamide or rituximab has high remission rates of 80%-90%. However, it is also associated with various side effects, including death due to infection or cardiovascular disease. There is an unmet medical need of a new therapy to reduce side effects. METHODS AND ANALYSIS: This is a phase IV multicentre, open-label, randomised controlled trial that aims to evaluate the efficacy and safety of a new remission induction regimen with the combination of low-dose glucocorticoids and rituximab. Newly diagnosed patients with AAV will be assessed for eligibility at 34 tertiary rheumatology/nephrology centres in Japan. One hundred and forty patients will be randomised (1:1) to receive low-dose prednisolone (0.5 mg/kg daily) plus rituximab (375 mg/m2 weekly) or high-dose prednisolone (1 mg/kg daily) plus rituximab. The trial consists of remission induction and maintenance phases. The primary endpoint of the study is the remission rate at 6 months (induction phase). Relapse and long-term safety profile will also be assessed until 24 months (maintenance phase). ETHICS AND DISSEMINATION: The protocol was first approved by the Institutional Review Board of Chiba University Hospital (reference number: G25051), and then approved by each participating site. The trial was registered at the University hospital Medical Information Network (UMIN) clinical registry (UMIN000014222) and ClinicalTrials.gov registry (NCT02198248). The Low-dose Glucocorticoid Vasculitis Induction Study (LoVAS) trial is currently ongoing and is due to finish in September 2019. The findings of this trial will be disseminated to participants through peer-reviewed publications and presented at national and international conferences in accordance with the Consolidated Standards of Reporting Trials (CONSORT) Statement. TRIAL REGISTRATION NUMBER: UMIN000014222; NCT02198248.

Severity and Diurnal Improvement of Morning Stiffness Independently Associate with Tenosynovitis in Patients with Rheumatoid Arthritis.

BACKGROUND AND OBJECTIVES: Although morning stiffness has long been recognized as a characteristic feature of rheumatoid arthritis (RA), it is no more included in the 2010 ACR/EULAR Classification Criteria or in the current major instruments for evaluating disease activity of RA. In this cross-sectional study, we aimed to determine the independent value and the optimal measurement of morning stiffness by clarifying the associations between morning stiffness and synovial inflammation. PATIENTS AND METHODS: We enrolled 76 consecutive RA patients who underwent musculoskeletal ultrasound examination and agreed to participate in the study. In addition to asking the duration of morning stiffness, we asked patients to complete a diagram which represents the time course of their morning stiffness in the dominant hand. Based on this diagram, we calculated the severity and the diurnal improvement of morning stiffness. We also determined the activity of intra-articular synovitis in 11 joints and tenosynovitis in 8 tendons/tendon compartments in the same hand by using power Doppler (PD) ultrasound with a semiquantitative score (0-3). RESULTS: For intra-articular synovitis, swollen/tender joint counts more strongly correlated with total PD scores (ρ = 0.379-0.561, p ≤ 0.001) than did any parameters of morning stiffness (ρ = 0.217-0.314, p = 0.006-0.021). For tenosynovitis, however, the severity on awakening and the improvement of morning stiffness more strongly correlated with total PD scores (ρ = 0.503-0.561, p < 0.001) than did swollen/tender joint counts (ρ = 0.276-0.388, p = 0.001-0.016). Multivariate analyses identified the severity on awakening and the improvement but not the duration of morning stiffness as factors that independently associate with the total tenosynovial PD score. CONCLUSIONS: Our data demonstrate a pathophysiological link between morning stiffness and tenosynovitis and also give an insight into the optimal measurement of morning stiffness. Our data support an independent value of evaluating morning stiffness in the management of RA.

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.

OBJECTIVE: 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). METHODS: We recruited patients with RA who were treated with tocilizumab for the first time, and determined therapeutic responses at 6 months. In the training cohort (n = 40), gene expression in peripheral blood mononuclear cells (PBMCs) at baseline was analyzed using genome-wide DNA microarray, with 41,000 probes derived from 19,416 genes. In the validation cohort (n = 20), expression levels of the candidate genes in PBMCs at baseline were determined using real-time quantitative polymerase chain reaction (qPCR) analysis. RESULTS: We identified 68 DNA microarray probes that showed significant differences in signal intensity between nonresponders and responders in the training cohort. Nineteen putative genes were selected, and a significant correlation between the DNA microarray signal intensity and the qPCR relative expression was confirmed in 15 genes. In the validation cohort, a significant difference in relative expression between nonresponders and responders was reproduced for 3 type I interferon response genes (IFI6, MX2, and OASL) and MT1G. Receiver operating characteristic curve analysis of models incorporating these genes showed that the maximum area under the curve was 0.947 in predicting a moderate or good response to tocilizumab in the validation cohort. CONCLUSION: Using genome-wide DNA microarray analyses, we identified candidate biomarkers that can be used to predict therapeutic responses to tocilizumab in patients with RA. These findings suggest that type I interferon signaling and metallothioneins are involved in the pathophysiology of RA.