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.

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.

TAp63, a methotrexate target in CD4+ T cells, suppresses Foxp3 expression and exacerbates autoimmune arthritis.

Methotrexate (MTX) is a standard, first-line therapy for rheumatoid arthritis (RA); however, its precise mechanisms of action other than antifolate activity are largely unknown. We performed DNA microarray analyses of CD4+ T cells in patients with RA before and after MTX treatment and found that TP63 was the most significantly downregulated gene after MTX treatment. TAp63, an isoform of TP63, was highly expressed in human IL-17-producing Th (Th17) cells and was suppressed by MTX in vitro. Murine TAp63 was expressed at high levels in Th cells and at lower levels in thymus-derived Treg cells. Importantly, TAp63 knockdown in murine Th17 cells ameliorated the adoptive transfer arthritis model. RNA-Seq analyses of human Th17 cells overexpressing TAp63 and those with TAp63 knockdown identified FOXP3 as a possible TAp63 target gene. TAp63 knockdown in CD4+ T cells cultured under Th17 conditions with low-dose IL-6 increased Foxp3 expression, suggesting that TAp63 balances Th17 cells and Treg cells. Mechanistically, TAp63 knockdown in murine induced Treg (iTreg) cells promoted hypomethylation of conserved noncoding sequence 2 (CNS2) of the Foxp3 gene and enhanced the suppressive function of iTreg cells. Reporter analyses revealed that TAp63 suppressed the activation of the Foxp3 CNS2 enhancer. Collectively, TAp63 suppresses Foxp3 expression and exacerbates autoimmune arthritis.

Fibroblast growth factor receptor 1 as a potential marker of terminal effector peripheral T helper cells in rheumatoid arthritis patients.

OBJECTIVES: RA is an autoimmune disease characterized by destructive polyarthritis. CD4+ T cells are pivotal to its pathogenesis, and our previous study revealed the expression of fibroblast growth factor receptor 1 (FGFR1) is modulated by MTX treatment in CD4+ T cells of RA patients; however, the roles of FGFR1 in CD4+ T cells in the pathogenesis of RA is unclear. Therefore, in this study, we aimed to characterize FGFR1-positive CD4+ T cells in RA patients. METHODS: The abundance of FGFR1-positive CD4+ T cells in peripheral blood and synovium was determined. Single-cell RNA sequencing (scRNA-seq) was performed on synovial CD4+ T cells to characterize FGFR1-positive cells. In addition, T cell activation status and cytokine production were determined using flow cytometry. RESULTS: The percentage of FGFR1-positive CD4+ T cells in the peripheral blood was higher in RA patients than in healthy controls (P =0.0035). They were also present in the synovium of active RA patients. The results of scRNA-seq revealed that peripheral Th (Tph) cells preferentially expressed FGFR1. Additionally, these FGFR1-positive Tph cells displayed a terminal effector cell phenotype. Consistent with this finding, FGFR1-positive CD4+ T cells in peripheral blood expressed IL-21 and IFN-γ. CONCLUSION: Our study provides evidence that FGFR1 marks terminal effector Tph cells in patients with RA.

Prognosis of spontaneous pneumomediastinum occurring in dermatomyositis or polymyositis patients with interstitial lung disease according to antimelanoma differentiation-associated gene 5 antibody status: a retrospective cohort study.

OBJECTIVES: Spontaneous pneumomediastinum (SPNM) historically has been considered a poor prognostic factor in dermatomyositis/polymyositis patients complicated with interstitial lung disease (ILD). However, there is a lack of actual data regarding the association between SPNM occurrence and mortality in dermatomyositis/polymyositis patients. This study aimed to assess the association between SPNM occurrence and mortality in myositis patients with ILD according to antimelanoma differentiation-associated gene 5 (MDA5) antibody status. METHODS: Dermatomyositis/polymyositis patients with ILD who were hospitalised at five Japanese hospitals from 2016 to 2020 were included in this retrospective observational study. We collected data about baseline characteristics including myositis-specific autoantibodies, treatments, SPNM and death within 1 year from therapy initiation or strengthening. Baseline characteristics and outcomes were compared between patients with and without SPNM (the SPNM group and the non-SPNM group, respectively). RESULTS: A total of 119 patients were analysed. SPNM occurred in 23 patients, and 15 patients died. Fifteen patients with SPNM were anti-MDA5 antibody positive. The mortality rate was significantly higher in the SPNM group (34.8%) than in the non-SPNM group (7.3%) (p=0.001). All deaths in the SPNM group occurred in anti-MDA5 antibody-positive patients (8/15), whereas none of the anti-MDA5 antibody-negative patients in the SPNM group died (0/8). In anti-MDA5 antibody-positive patients, the mortality rate was significantly higher in patients with SPNM occurrence (53.3%) than in those without SPNM occurrence (4.0%) (p=0.001). CONCLUSION: SPNM occurred more frequently in anti-MDA5 antibody-positive than in anti-MDA5 antibody-negative myositis patients. SPNM occurrence was associated with higher mortality risk, especially in anti-MDA5 antibody-positive patients.

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.

Clinical significance of cytomegalovirus (CMV) pp65 antigenemia in the prediction of CMV infection during immunosuppressive therapy for rheumatic disease.

To investigate the risk factors for CMV infection and to clarify the cut-off count of CMV pp65 antigenemia predicting clinical symptoms related to CMV infection in patients with rheumatic disease. We retrospectively analyzed 261 patients with rheumatic disease who were treated with immunosuppressive therapy. CMV infection was defined as positive > 1 CMV-positive cell per two slides (CMV pp65 antigenemia C10/C11). Patients with CMV infection were divided into two groups based on the presence of antiviral treatment for CMV disease. We determined a cut-off value of CMV-positive cells for the diagnosis of CMV disease. CMV infection was observed in 141 cases (54%). In a multivariate analysis, CMV infection was associated with three following factors: Age > 60 years (OR 1.87 [95% CI 1.04-3.36]); lymphocyte counts < 1000/µL (OR 3.34 [95% CI 1.88-6.05]); steroid pulse therapy (OR 2.60 [95% CI 1.27-5.55]). The cut-off level of CMV pp65 antigenemia indicating CMV disease was five positive cells average two slides by using receiver operating characteristic curve analysis (AUC 0.95, sensitivity 0.94, specificity 0.80). Age > 60 years, lymphocytopenia (< 1000/µL) and steroid pulse therapy are risk factors of CMV infection. We recommend that CMV pp65 antigenemia of > 5 cells average two slides (C10/C11) in patients with rheumatic disease should be the treated with antiviral drugs.

Latent class analysis of 216 patients with adult-onset Still's disease.

BACKGROUND: Adult-onset Still's disease (AOSD) is a rare systemic autoinflammatory disease which encompasses patients with heterogenous presentation and a wide range of clinical courses. In this study, we aimed to identify potential subgroups of AOSD and reveal risk factors for relapse. METHODS: We included a total of 216 AOSD patients who received treatment in nine hospitals between 2000 and 2019. All patients fulfilled the Yamaguchi classification criteria. We retrospectively collected information about baseline characteristics, laboratory tests, treatment, relapse, and death. We performed latent class analysis and time-to-event analysis for relapse using the Cox proportional hazard model. RESULTS: The median age at disease onset was 51.6 years. The median follow-up period was 36.8 months. At disease onset, 22.3% of the patients had macrophage activation syndrome. The median white blood cell count was 12,600/µL, and the median serum ferritin level was 7230 ng/mL. Systemic corticosteroids were administered in all but three patients (98.6%) and the median initial dosage of prednisolone was 40mg/day. Ninety-six patients (44.4%) were treated with concomitant immunosuppressants, and 22 (10.2%) were treated with biologics. Latent class analysis revealed that AOSD patients were divided into two subgroups: the typical group (Class 1: 71.8%) and the elderly-onset group (Class 2: 28.2%). During the follow-up period, 13 of 216 patients (6.0%) died (12 infections and one senility), and 76 of 216 patients (35.1%) experienced relapses. Overall and relapse-free survival rates at 5 years were 94.9% and 57.3%, respectively, and those rates were not significantly different between Class 1 and 2 (p=0.30 and p=0.19). Time-to-event analysis suggested higher neutrophil count, lower hemoglobin, and age ≥65 years at disease onset as risk factors for death and age ≥65 years at disease onset as a risk factor for relapse. CONCLUSIONS: AOSD patients were divided into two subgroups: the typical group and the elderly-onset group. Although the survival of patients with AOSD was generally good, the patients often experienced relapses. Age ≥65 years at disease onset was the risk factor for relapse.

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.

Granulomatosis with polyangiitis complicated with refractory optic neuritis and maxillary osteomyelitis.

We report a case of a 61-year-old man with granulomatosis with polyangiitis (GPA) complicated with refractory optic neuritis and maxillary osteomyelitis. He had been treated with prednisolone (PSL) as cryptogenic organizing pneumonia in the respiratory department for 2 years. Afterward, he complained tenderness of paranasal sinuses and rapidly progressive visual loss of the left eye. Although both MPO-ANCA and PR3-ANCA were negative, he was diagnosed as GPA based on the American College of Rheumatology 1990 criteria. Ophthalmologic and oral examination revealed left optic neuritis and destructive maxillary bone. Magnetic resonance imaging (MRI) showed the optic neuritis and inflammation around the optic nerve. This finding suggested that the direct spread of inflammation from paranasal sinuses caused the optic neuritis. In a short time, increasing a dose of PSL and administration of intravenous cyclophosphamide were initiated. Antibiotics were also administered to treat sinusitis. Although his visual acuity of the left eye deteriorated to no light perception temporarily, it finally improved after treatment and findings of MRI were also improved. In contrast, destruction of maxilla bone had been progressing. This is a rare case of GPA complicated with optic neuritis due to sinusitis and maxillary osteomyelitis.

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.

Serum periostin levels serve as a biomarker for both eosinophilic airway inflammation and fixed airflow limitation in well-controlled asthmatics.

OBJECTIVE: Periostin, a matricellular protein, is produced from airway epithelial cells and lung fibroblasts by IL-13. It has been suggested that periostin is involved in allergic inflammation and fibrosis. However, the usefulness of serum periostin measurement in the assessment of airway inflammation and remodeling and management of asthmatic patients is still debated. We aimed to determine whether serum periostin levels reflect eosinophilic airway inflammation and airway remodeling in asthma. METHODS: We examined the relationship of serum periostin levels with clinical features, biomarkers for eosinophilic airway inflammation, fraction of exhaled nitric oxide (FeNO) levels and blood eosinophil counts, and pulmonary functions in 235 well-controlled asthmatic patients on inhaled corticosteroids (ICS) treatment. RESULTS: Serum periostin levels were positively correlated with blood eosinophil counts (%) and age (r = 0.36 and 0.23, respectively), and were negatively correlated with body weight and FEV1/FVC (%) (r = -0.24 and - 0.23, respectively) in well-controlled asthmatic patients on ICS treatment (daily dose of 453 µg equivalent to fluticasone propionate). Blood eosinophil counts and serum periostin levels were similarly associated with increased FeNO levels (≥40 ppb) in the asthmatics. Serum periostin levels were better associated with fixed airflow limitation (FEV1/FVC ratio <70%) than FeNO levels, blood eosinophil counts or total IgE levels in the asthmatics. Multivariate analysis showed that fixed airflow limitation was significantly associated with high serum periostin levels (≥97 ng/ml) (Odds ratio 3.2). CONCLUSIONS: Serum periostin levels serve as a biomarker for both eosinophilic airway inflammation and fixed airflow limitation in well-controlled asthmatics on ICS treatment.

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.

Diffuse Cerebral Vasoconstriction in a Intravascular Lymphoma Patient with a High Serum MPO-ANCA Level.

An 87-year-old woman presented with a 3-month history of fever, edema of the lower legs, and gait disturbance. A laboratory examination revealed high serum levels of myeloperoxidase-specific antineutrophil cytoplasmic antibody (MPO-ANCA). Although microscopic polyangiitis was initially suspected and treated, the patient subsequently developed transient hemiparesis and disturbed consciousness. Brain magnetic resonance imaging/angiography revealed infarct-like lesions, pachymeningeal involvement, and diffuse cerebral vasoconstriction. A random skin biopsy confirmed the histological diagnosis of intravascular lymphoma. Diffuse cerebral vasoconstriction and a high serum MPO-ANCA level have rarely been reported in patients with intravascular lymphoma. Endothelial damage due to immune-mediated mechanisms, tumor derived factors, or the direct interaction of lymphoma cells with endothelial cells may commonly predispose patients to both cerebral vasoconstriction and the development of ANCAs.

Long-term use of biologic agents does not increase the risk of serious infections in elderly patients with rheumatoid arthritis.

This study aimed to determine whether the long-term use of biologic agents increases serious infections in elderly patients with rheumatoid arthritis (RA) and to determine the risk factors of serious infections in biologics-treated elderly RA patients. We retrospectively analyzed the incidence rate of serious infections that required hospitalization between biologics-treated and non-biologic disease-modifying antirheumatic drug (DMARD)-treated elderly RA patients (aged over 65 years). We examined the risk factors for serious infections in biologics-treated elderly RA patients. We found that, during a 3-year observation period, the incidence rate of serious infections was not significantly different between biologics-treated and non-biologic DMARD-treated elderly RA patients [8.0 (95% CI 4.7-13.5) and 6.3 (95% CI 4.1-9.5) events per 100 person-years of follow-up, respectively, P = 0.78]. The time to the first serious infection did not significantly differ between the two groups by the analysis of the Kaplan-Meier curves, either (P = 0.46). We then found that prednisolone doses alone were significantly associated with serious infections in biologics-treated elderly RA patients. Furthermore, we found that prednisolone at 1-4 mg/day was associated with serious infections in biologics-treated patients, but not non-biologic DMARD-treated patients. On the other hand, prednisolone at greater than 5 mg/day was associated with serious infections in both biologics-treated and non-biologics-treated patients. We show that there is not a significant difference between the incidence of serious infections between biologics group and non-biologics group in elderly RA patients (≧65 years) and that even very low-dose glucocorticoid use (prednisolone 1-4 mg/day) is a risk factor for serious infections in biologics-treated elderly RA patients.

Sarcoidosis Presenting Addison's Disease.

We herein describe a second Japanese case of sarcoidosis presenting Addison's disease. A 52-year-old man was diagnosed with sarcoidosis based on clinical and laboratory findings, including bilateral hilar lymphadenopathy and elevated levels of serum angiotensin-converting enzyme and lysozyme, as well as the presence of noncaseating epithelioid granulomas. The patient also exhibited general fatigue, pigmentation, weight loss, hypotension and hyponatremia, suggestive of chronic adrenocortical insufficiency. An endocrine examination confirmed primary adrenocortical insufficiency. This case suggests the direct involvement of sarcoid granuloma in the adrenal glands.

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.

OBJECTIVE: 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. METHODS: We retrospectively identified 167 consecutive hospital-based patients with MPA in 3 hospitals in Japan. We longitudinally collected clinical information for 150 of these patients, for whom CT images obtained before treatment were available. We then determined the presence of 22 imaging components of lung abnormalities in these patients. RESULTS: The vast majority of patients (97%) had at least 1 lung abnormality on chest CT images, including interstitial lung lesions (66%), airway lesions (66%), pleural lesions (53%), and emphysematous lesions (37%). In multivariate analyses, ground-glass opacity was associated with the Birmingham Vasculitis Activity Score, whereas 3 of 4 airway lesions were associated with myeloperoxidase-antineutrophil cytoplasmic antibodies. Latent class analysis identified a distinct group of patients with airway-predominant lung lesions. Airway lesions such as bronchiolitis and bronchovascular bundle thickening were among the components that showed improvement within 3 months of the initial treatment. An idiopathic pulmonary fibrosis pattern was the only chest CT variable that was independently associated with shorter survival. CONCLUSION: Abnormalities in a wide range of anatomic areas, including the whole airway, can be identified in the lungs of patients with MPA before treatment. The prevalence, clustering patterns, and responsiveness to treatment of individual lung abnormalities provide groundwork for informing future studies to understand the pathophysiology of MPA.

Helios Enhances Treg Cell Function in Cooperation With FoxP3.

OBJECTIVE: Helios+FoxP3+CD4+ (Helios+) Treg cells are believed to be involved in the regulation of various autoimmune diseases; however, the regulatory mechanisms underlying the development of Helios+ Treg cells remain uncertain. This study was undertaken to elucidate the regulatory mechanisms of Helios expression in CD4+ T cells and its roles in transforming growth factor ß (TGFß)-induced Treg cell function. METHODS: We examined the expression of Helios in CD4+ T cells in patients with rheumatoid arthritis by DNA microarray analysis before and after treatment with biologic agents. We also examined the effect of interleukin-6 (IL-6) and TGFß on Helios expression in CD4+ T cells in humans and mice. The effect of forced expression of Helios on murine induced Treg cell function was also examined. The role of FoxP3 in the induction and function of Helios was assessed by using CD4+ T cells from FoxP3-deficient scurfy mice. RESULTS: Tocilizumab, but not tumor necrosis factor (TNF) inhibitors or abatacept, increased Helios expression in CD4+ T cells in patients with a good response. IL-6 inhibited the TGFß-induced development of Helios+ induced Treg cells in both humans and mice. Both cell-intrinsic FoxP3 expression and TGFß signaling were required for Helios induction in murine induced Treg cells. The forced expression of Helios enhanced the expression of various Treg cell-related molecules and the suppressive function in murine induced Treg cells. Helios-mediated enhancement of the suppressive function of induced Treg cells was obvious in FoxP3-sufficient CD4+ T cells but not in FoxP3-deficient CD4+ T cells. CONCLUSION: Our findings indicate that Helios enhances induced Treg cell function in cooperation with FoxP3.

Sox5 and c-Maf cooperatively induce Th17 cell differentiation via RORγt induction as downstream targets of Stat3.

Stat3 signaling is essential for the induction of RORγt and subsequent Th17 cell differentiation. However, the downstream targets of Stat3 for RORγt expression remain largely unknown. We show here that a novel isoform of Sox5, named Sox5t, is induced in Th17 cells in a Stat3-dependent manner. In vivo, T cell-specific Sox5-deficient mice exhibit impaired Th17 cell differentiation and are resistant to experimental autoimmune encephalomyelitis and delayed-type hypersensitivity. Retrovirus-mediated induction of Sox5 together with c-Maf induces Th17 cell differentiation even in Stat3-deficient CD4(+) T cells but not in RORγt-deficient CD4(+) T cells, indicating that Sox5 and c-Maf induce Th17 cell differentiation as downstream effectors of Stat3 and as upstream inducers of RORγt. Moreover, Sox5 physically associates with c-Maf via the HMG domain of Sox5 and DNA-binding domain of c-Maf, and Sox5 together with c-Maf directly activates the promoter of RORγt in CD4(+) T cells. Collectively, our results suggest that Sox5 and c-Maf cooperatively induce Th17 cell differentiation via the induction of RORγt as downstream targets of Stat3.

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.

OBJECTIVE: 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. METHODS: We examined gene expression profiles of CD4+ T cells by DNA microarray analysis before and after treatment with an anti-IL-6 receptor antibody, tocilizumab (TCZ), in RA patients who exhibited good clinical responses to the treatment. Using murine CD4+ T cells, we then examined the roles of a newly identified molecule whose expression was significantly reduced in CD4+ T cells by TCZ therapy. We also examined the effect of the forced expression of the molecule on retinoic acid receptor-related orphan nuclear receptor γt (RORγt)-induced IL-17A production in CD4+ T cells and on RORγt-induced IL-17A promoter activation. RESULTS: We identified AT-rich-interactive domain- containing protein 5A (ARID-5A) as a new molecule down-regulated by IL-6 blockade in the form of TCZ therapy. IL-6 induced the expression of ARID-5A in CD4+ T cells during Th17 cell differentiation by a STAT-3-dependent mechanism, whereas IL-6-induced ARID-5A expression was not affected by the absence of RORγt, a lineage-specifying transcription factor of Th17 cells. Furthermore, ARID-5A physically associated with RORγt through its N-terminal region and inhibited RORγt-induced Th17 cell differentiation. CONCLUSION: ARID-5A is a lineage-specific attenuator of Th17 cell differentiation and may be involved in the pathogenesis of RA.