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Objectives To investigate the association between decreased serum IgG levels caused by remission-induction immunosuppressive therapy of antineutrophil cytoplasmic antibody-associated vasculitis (AAV) and the development of severe infections. Methods We conducted a retrospective cohort study of patients with new-onset or severe relapsing AAV enrolled in the J-CANVAS registry, which was established at 24 referral sites in Japan. The minimum serum IgG levels up to 24 weeks and the incidence of severe infection up to 48 weeks after treatment initiation were evaluated. After multiple imputations for all explanatory variables, we performed the multivariate analysis using a Fine–Gray model to assess the association between low IgG (the minimum IgG levels Results Of 657 included patients (microscopic polyangiitis, 392; granulomatosis with polyangiitis, 139; eosinophilic granulomatosis with polyangiitis, 126), 111 (16.9%) developed severe infections. The minimum serum IgG levels were measured in 510 patients, of whom 77 (15.1%) had low IgG. After multiple imputations, the confounder-adjusted hazard ratio of low IgG for the incidence of severe infections was 1.75 (95% confidence interval: 1.03–3.00). The RCS revealed a U-shaped association between serum IgG levels and the incidence of severe infection with serum IgG 946 mg/dl as the lowest point. Subgroup analysis showed no obvious heterogeneity between treatment regimens. Conclusion Regardless of treatment regimens, low IgG after remission-induction treatment was associated with the development of severe infections up to 48 weeks after treatment initiation.

Objectives Histopathological synovitis scoring is useful for assessing activity in patients with rheumatoid arthritis (RA) at sampling, but it is unclear whether it can be a predictor of future drug treatment. The purpose of this study was to examine whether histopathological synovitis score is a predictor of postoperative requirement for additional or alternative drug treatment after total knee arthroplasty (TKA). Methods Thirty patients with RA in whom synovial samples were obtained during TKA were included. Patients were divided into the drug treatment enhanced group (EG), which included patients who needed additional or alternative drug treatment within 1 year after TKA, and the drug treatment maintenance group (MG). The Rooney synovitis score (RSS) was compared between groups. Logistic regression analysis was performed to clarify prognostic factors for postoperative drug treatment change. Results The total RSS was significantly higher in the EG than in the MG (29.3 vs 15.1; P Conclusions Histopathological synovitis scoring may predict requirement for additional or alternative drug treatment in patients with RA after TKA.

Objective Recent studies suggest that the knee is frequently involved in PMR. In this study, we aimed to determine whether the US assessment of the shoulder and knee discriminates between PMR and other differential diagnoses and improves the accuracy of the 2012 EULAR/ACR provisional classification criteria for PMR. Methods We consecutively enrolled 81 untreated patients who received a diagnosis of PMR. These patients were divided into two groups based on the final diagnosis made at 1-year follow-up: PMR-definite group (n = 60) and PMR-mimic group (n = 21). We also enrolled age/sex-matched untreated RA patients with shoulder pain from an independent cohort (RA group, n = 60). All patients underwent comprehensive US assessment of the shoulder and knee for synovitis, bursitis, tenosynovitis, tendinitis and ligament inflammation at baseline. Results US scores for tenosynovitis, tendinitis and ligament inflammation better discriminated the PMR-definite group from the PMR-mimic and RA groups than do those for synovitis or bursitis. Among logistic regression models to identify US variables that were associated with the PMR-definite group, the best fitted model included two US variables: the bilateral involvement of the shoulder (long head of biceps, supraspinatus or subscapularis tendon) and the bilateral involvement of the knee (popliteus tendon or medial or lateral collateral ligament). Incorporating these two items into the 2012 EULAR/ACR provisional classification criteria numerically increased the accuracy to classify the PMR-definite group. Conclusion US assessment of the tendon/ligament-related lesions in the shoulder and knee may improve the accuracy of the 2012 EULAR/ACR provisional classification criteria for PMR.

Membranous nephropathy (MN) with anti-neutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis (ANCA-GN) is seen infrequently. Previous reports of patients with ANCA-GN with MN showed that the most frequent ANCA subtype was myeloperoxidase-ANCA. We herein present a 73-year-old woman with scleritis, hematuria, proteinuria, and positive serum proteinase 3 (PR3)-ANCA. She underwent a renal biopsy and was diagnosed with MN and ANCA-GN. Immunofluorescence staining for PR3 colocalized with IgG along the glomerular basement membrane were observed. Oral prednisolone and intravenous rituximab therapy immediately improved her symptoms and urinalysis abnormalities. PR3-ANCA may be involved in the pathogenesis of MN via the formation of immune complexes.

ObjectivesSpontaneous 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.MethodsDermatomyositis/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).ResultsA 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).ConclusionSPNM 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.

ObjectiveWe 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).MethodsOne 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.ResultsAmong 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).ConclusionEighteen 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.

ObjectiveRecently, podocytes have been recognised not only as a physical barrier to prevent urinary protein loss but also as producers of proinflammatory cytokines. However, the roles of podocytes in the pathogenesis of lupus nephritis (LN) remain largely unknown. This study aims to determine the roles of suppressor of cytokine signalling (SOCS) family members expressed in glomeruli in the regulation of LN.MethodsWe investigated the expression of SOCS family members in glomeruli in murine lupus model induced by repeated epicutaneous administration of the TLR7/8 agonist imiquimod. We also investigated the roles of SOCS3 expressed in podocytes in the imiquimod-induced glomerulonephritis and systemic autoimmunity by using podocyte-specific SOCS3-deficient mice (podocin-Cre x SOCS3fl/fl mice (SOCS3-cKO mice)). Finally, we investigated the expression of proinflammatory cytokines and chemokines in SOCS3-deficient podocyte cell lines.ResultsqPCR analysis revealed that among SOCS family members, SOCS3 was preferentially induced in glomeruli on epicutaneous administration of imiquimod and that interleukin 6 (IL-6) induced SOCS3 expression in podocyte cell lines. SOCS3-cKO mice exhibited severe glomerulonephritis, high levels of serum creatinine and urine albumin and decreased survival rate compared with control SOCS3-WT mice. Levels of anti-double-strand DNA antibody, SOCS (GC) formation and the numbers of follicular helper T (Tfh) cells and GC B cells in the spleen were higher in SOCS3-cKO mice than those in SOCS3-WT mice. Serum IL-6 levels and expression of IL-6 mRNA in glomeruli were also elevated in SOCS3-cKO mice. IL-6-induced IL-6 expression was enhanced in SOCS3-deficient podocyte cell lines compared with that in SOCS3-sufficient podocyte cell lines.ConclusionSOCS3 expressed in podocytes plays protective roles for the development of glomerulonephritis and inhibits autoantibody production in the imiquimod-induced lupus model presumably by suppressing IL-6 production of podocytes.

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.

This study researched the efficacy of rituximab (RTX) in patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated hypertrophic pachymeningitis (HP).Eight patients were identified by retrospective chart review from local registries at four hospitals in Japan. All patients met the Chapel Hill 2012 Consensus Conference definitions of ANCA-associated vasculitis and had disease complicated with HP. We assessed the dose of glucocorticoids, C-reactive protein (CRP) levels, Birmingham vasculitis activity score (BVAS) and contrast-enhanced magnetic resonance imaging (MRI) findings of HP before and after RTX administration.Three of eight patients were female. The median age was 68 years. No patients had HP at onset of vasculitis. Two patients had a relapse of HP before RTX administration. RTX was used as the initial treatment for HP in three patient. The daily dose of glucocorticoids, CRP levels and BVAS decreased from baseline to 6 months after RTX treatment in all patients. Evaluation of HP by contrast-enhanced MRI showed improvement in seven of eight cases. All of seven patients achieved sustained remission at 6 months after RTX treatment. No serious adverse events were observed in any patient.Our case series highlights the efficacy of RTX in patients with difficult-to-treat ANCA-associated HP. Future prospective studies are warranted to establish B-cell depletion therapy by RTX as a treatment option for ANCA-associated HP.

T-bet and signal transducer and activator of transcription (STAT) 6 are critical factors for helper T-cell differentiation in humans and mice. Additionally, polymorphisms in TBX21 (T-bet) and STAT6 are associated with the susceptibility of allergic diseases. However, precise mechanisms of the reciprocal regulation between T-bet and STAT6 in allergy remain unclear. To determine the reciprocal regulation in vivo, we investigated the phenotype of T-bet/STAT6 double-deficient (T-bet−/− STAT6−/−) mice. Unexpectedly, T-bet−/− STAT6−/− mice but not T-bet−/− mice or STAT6−/− mice spontaneously developed severe dermatitis. Not only eosinophils and mast cells but also CD4+ T cells infiltrated into the skin of T-bet−/− STAT6−/− mice. Adoptive transfer of CD4+ T cells of T-bet−/− STAT6−/− mice into severe combined immunodeficient mice induced the accumulation of eosinophils and mast cells in the skin, whereas depletion of CD4+ T cells ameliorated the dermatitis in T-bet−/− STAT6−/− mice. Comprehensive transcriptome analyses revealed that IL-9 expression was enhanced in T-bet−/− STAT6−/− CD4+ T cells. Indeed, IL-9 neutralization ameliorated the dermatitis in T-bet−/− STAT6−/− mice. T-bet−/− STAT6−/− CD4+ T cells expressed functional thymic stromal lymphopoietin receptors and produced large amounts of IL-9 on thymic stromal lymphopoietin stimulation. These results indicate that T-bet and STAT6 coordinately suppress atopic dermatitis–like skin inflammation, possibly by inhibiting thymic stromal lymphopoietin–dependent IL-9 production in CD4+ T cells.

Numerous studies have clarified the immunological mechanisms of contact hypersensitivity (CHS). In addition, we have recently shown that M2 macrophages play key roles in the development of CHS by producing matrix metalloproteinase-12 (MMP-12). However, regulatory mechanisms of the elicitation phase in CHS remain largely unknown. To determine the roles of suppressor of cytokine signaling (SOCS) family members in M2 macrophages in the regulation of CHS, we investigated the expression of SOCS family members in M2 macrophages at the inflammatory sites of CHS. Transcriptome analysis revealed that among SOCS family members, SOCS3 was highly expressed in M2 macrophages at the site of CHS, and SOCS3 induction was reduced by IFN-? neutralization. 2,4-Dinitrofluorobenzene-induced CHS was significantly enhanced and prolonged in mice lacking SOCS3 expression in monocytes/macrophages (SOCS3(?/?) mice) compared with that in control mice. Importantly, expression of MMP-12 in M2 macrophages was significantly increased in SOCS3(?/?) mice at the site of CHS, and deletion of the MMP-12 gene reduced the exacerbated CHS in SOCS3(?/?) mice. Finally, IFN-? inhibited IL-4-induced MMP-12 expression in a SOCS3-dependent manner. Taken together, these results suggest that SOCS3 expressed in M2 macrophages is involved in the attenuation and/or resolution of CHS, presumably by suppressing MMP-12 production.

Objective Renal involvement in anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitis is associated with significant morbidity and higher mortality rates. This study examined clinical manifestations associated with renal involvement in ANCA-associated vasculitis within a large, international cross-sectional cohort. Methods Univariate and multivariate analyses were performed to identify clinical factors associated with renal disease, which was defined as i) a serum-creatinine >30% above normal and a fall in creatinine-clearance >25%; or ii) haematuria attributable to active vasculitis. Results The study cohort include 1230 patients from 31 countries; 723 (58.8%) presented with renal involvement: microscopic polyangiitis (82.2%), granulomatosis with polyangiitis (58.6%), and eosinophilic granulomatosis with polyangiitis (26.4%). The following clinical and laboratory factors were more common among patients with renal disease: age (OR 1.01, 95% CI 1.01–1.02), fever (OR 1.97, 95% CI 1.35–2.88), fatigue (OR 1.55, 95% CI 1.14–2.10), weight loss (OR 1.62, 95% CI 1.23–2.12), polyarthritis (OR 1.39, 95% CI 1.02–1.89), petechiae/purpura (OR 1.47, 95% CI 1.06–2.05), pulmonary haemorrhage (OR 5.23, 95% CI 1.39–19.63), gastrointestinal symptoms (OR 2.19, 95% CI 1.34–3.58), seizures (OR 3.42, 95% CI 1.26–9.30), lower serum albumin (OR 2.42, 95% CI 1.64–3.57), higher CRP (OR 2.06, 95% CI 1.04–4.06), low serum C3 at baseline (OR 3.86, 95% CI 1.30–11.53), myeloperoxidase- (OR 7.97, 95% CI 2.74–23.20) and proteinase 3-ANCA (OR 3.40, 95% CI 1.22–9.50). The following clinical factors were less common among patients with renal disease: mononeuritis multiplex (OR 0.63, 95% CI 0.41–0.98), proptosis/exophthalmos (OR 0.19, 95% CI 0.06–0.59), nasal polyps (OR 0.32, 95% CI 0.19–0.55), septal defect/perforation (OR 0.29, 95% CI 0.14–0.60), respiratory distress/pulmonary fibrosis/asthma (OR 0.08, 95% CI 0.04–0.19), and wheeze/obstructive airway disease (OR 0.29, 95% CI 0.16–0.52). Conclusion In this large international study, several clinical and laboratory factors were identified as associated with renal involvement in ANCA-associated vasculitis.

Background Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis presents with various symptoms. ANCA-associated hypertrophic pachymeningitis (HP) is a very rare pathology. Objectives This study aimed to investigate the efficacy of rituximab (RTX) against patients with ANCA-related HP. Methods Seven patients were identified by retrospective chart review from local registries at four Hospitals in Japan. All patients met Chapel Hill 2012 Consensus Conference definitions of ANCA–associated vasculitis and were complicated with HP. We assessed the dose of prednisolone, CRP, and MRI findings of HP before and after RTX administration. Results Three female and 4 male were evaluated. Median age was 66 years-old. Four cases had HP at the onset of vasculitis. Relapse of HP before RTX administration was found in 2 cases. RTX was used as an initial treatment in one patient. Daily dose of prednisolone and CRP were significantly decreased from baseline levels 24 weeks after RTX treatment. Evaluation of HP by contrast MRI showed improvement in six of seven cases. No relapse after RTX treatment was observed during the follow-up period of 24 weeks. Severe adverse effects were not found in any patients. Conclusions Our case series highlight the efficacy of RTX against patients with difficult-to-treat ANCA-related HP. Future studies in this context in a prospective manner are definitely required to establish the B-cell depletion therapy by RTX as a treatment option for ANCA-related HP. References [1] Shimojima Y, Kishida D, Hineno A, et al. Hypertrophic pachymeningitis is a characteristic manifestation of granulomatosis with polyangiitis: A retrospective study of anti-neutrophil cytoplasmic antibody-associated vasculitis. Int J Rheum Dis2017;20:489–496. [2] Aman S, Susheel K, Ajay W, et al. Successful treatment of hypertrophic pachymeningitis in refractory Wegener’s granulomatosis with rituximab. Clin Rheumatol2010;29:107–110. Disclosure of Interest None declared

Background It is unknown which joint arthritis the inflammatory markers such as CRP or MMP-3 reflect. Objectives We analysed the association between joint regions with ultrasound-determined synovitis and systemic inflammatory markers. Methods We enrolled 152 patients with untreated arthritis and performed musculoskeletal ultrasound on 40 joints and determined a semiquantitative grade for power Doppler (PD) signals. We analysed the associations between PD scores in 8 joint regions and CRP/MMP-3 levels using multiple linear regression models with forced entry method. Results Mean age was 55 years and 112 patients were female. Median CRP and MMP-3 were 0.36 mg/dl and 65.7 ng/ml. Median total PD score was 2. Standard regression coefficients for 8 joint regions were −0.009 for MCPs, 0.05 for PIPs, 0.372 for wrists, 0.183 for elbows, 0.628 for shoulders, 0.377 for knees, 0.261 for ankles, and −0.0131 for MTPs in a regression model to explain CRP using PD scores as dependent variables. Standard regression coefficients for the same joint regions were −5.134,–4.449, 24.061, 27.839, 22.508, 64.108, 36.501, and 2.539 to explain MMP-3. Conclusions Systemic inflammatory markers such as CRP and MMP-3 do not accurately reflect the inflammation in small joints. Conversely, it is necessary to weight the large joints for the global ultrasound synovitis score to represent the severity of systemic inflammation. References [1] Kawashiri SY, Kawakami A, Iwamoto N, et al. The power Doppler ultrasonography score from 24 synovial sites or 6 simplified synovial sites, including the metacarpophalangeal joints, reflects the clinical disease activity and level of serum biomarkers in patients with rheumatoid arthritis. Rheumatology (Oxford)2011May;50(5):962–5. [2] Gorai M, Ogasawara M, Matsuki Y, et al. Weighting with the Lansbury articular index improves the correlation of ultrasound score with serum matrix metalloproteinase-3 level in rheumatoid arthritis patients. Mod Rheumatol2014Nov;24(6):915–9. Disclosure of Interest None declared

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.

Since the original description by Zone et al in 1994, the disease entity and target antigens in linear IgA/IgG bullous dermatosis (LAGBD) have not been clarified in 20 years. To determine autoantibodies and autoantigens in a new LAGBD case which showed atypical clinical and histopathological findings without apparent mucosal involvement. We performed various indirect immunofluorescence and immunoblotting studies. Indirect immunofluorescence of 1M NaCl-split skin showed IgG and IgA reactivity with both epidermal and dermal sides. Immunoblotting studies using various antigen sources revealed circulating IgG and IgA antibodies reactive with laminin-332, laminin-γ1 and integrin α6β4 in various patterns. Absorption study using recombinant proteins of laminin-γ1 indicated that the patient serum reacted with different epitopes between laminin-γ1 and laminin-γ2. This study presented for the first time a LAGBD patient with IgG and IgA antibodies to various laminins and integrins.

Objective.To describe pulmonary involvement at time of diagnosis in antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV), as defined by computed tomography (CT).Methods.Patients with thoracic CT performed on or after the onset of AAV (n = 140; 75 women; granulomatosis with polyangiitis, n = 79; microscopic polyangiitis MPA, n = 61) followed at a tertiary referral center vasculitis clinic were studied. Radiological patterns of pulmonary involvement were evaluated from the CT studies using a predefined protocol, and compared to proteinase 3 (PR3)-ANCA and myeloperoxidase (MPO)-ANCA specificity.Results.Of the patients, 77% had an abnormal thoracic CT study. The most common abnormality was nodular disease (24%), of which the majority were peribronchial nodules, followed by bronchiectasis and pleural effusion (19%, each), pulmonary hemorrhage and lymph node enlargement (14%, each), emphysema (13%), and cavitating lesions (11%). Central airways disease and a nodular pattern of pulmonary involvement were more common in PR3-ANCA–positive patients (p < 0.05). Usual interstitial pneumonitis (UIP) and bronchiectasis were more prevalent in MPO-ANCA–positive patients (p < 0.05). Alveolar hemorrhage, pleural effusion, lymph node enlargement, and pulmonary venous congestion were more frequent in MPO-ANCA–positive patients.Conclusion.Pulmonary involvement is frequent and among 140 patients with AAV who underwent a thoracic CT study, almost 80% have pulmonary abnormalities on thoracic CT. Central airway disease occurs exclusively among patients with PR3-ANCA while UIP were mainly seen in those with MPO-ANCA. These findings may have important implications for the investigation, management, and pathogenesis of AAV.

Alternatively activated macrophages (M2 macrophages) play key roles in the suppression of Th1 cell responses and the orchestration of tissue repair. However, recent studies have shown that M2 macrophages have potentials to produce high levels of proinflammatory cytokines such as IL-1β, IL-6, and TNF-α, suggesting that M2 macrophages may exacerbate inflammation in some settings. In this regard, we have recently shown that large numbers of M2 macrophages accumulate in the sites of hapten-induced contact hypersensitivity (CHS), an animal model of allergic contact dermatitis, and that M2 macrophages exacerbate hapten-induced CHS by producing matrix metalloproteinase 12 (MMP12). We have also shown that suppressor of cytokine signaling-3 (SOCS3), a member of SOCS family proteins that are cytokine-inducible negative regulators of the JAK/STAT signaling pathways, is highly and preferentially expressed in M2 macrophages in hapten-induced CHS and that SOCS3 expressed in M2 macrophages is involved in the attenuation of CHS by suppressing MMP12 production. These findings underscore the importance of M2 macrophage-derived MMP12 in the development of CHS, and suggest that inhibition of M2 macrophages or MMP12 could be a potential therapeutic strategy for the treatment of allergic contact dermatitis.

Objective. Although several miRNAs have been shown to regulate autoimmune pathogenesis by affecting lymphocyte function, the roles of miRNAs in the pathogenesis of SSc remain unclear. Therefore the purpose of this study was to identify miRNAs that play a role in the pathogenesis of SSc by quantitative PCR screening of serum miRNAs. Methods. Ninety-five miRNAs that were predicted to target SSc-related genes [IL-4, TGF-b, CTGF, PDGFB, PDGF receptor (PDGFR) a/b and COL1A2) by in silico analyses were selected. The expression of these miRNAs in sera of SSc patients and healthy controls was measured by quantitative PCR. Involvement of miR-30b, which was most strongly down-regulated in SSc patients, in the regulation of PDGFR-b expression was examined by transfection experiments and 3 0 -untranslated region (3 0 -UTR) target luciferase assays. The expression of miR-30b in skin was evaluated in a bleomycin-induced dermal fibrosis model in mice and in SSc patients. Results. Nineteen of 95 miRNAs were significantly decreased in the sera of SSc patients. Among them, miR-30b was most strongly down-regulated in SSc patients (P = 0.00006) and the levels of miR-30b were inversely correlated with modified Rodnan skin scores. Transfection of a miR-30b mimic repressed PDGFR-b expression in dermal fibroblasts and the activity of a luciferase reporter containing 3 0 -UTR of PDGFR-b. Moreover, the expression of miR-30b was down-regulated in bleomycin-treated sclerotic skin and in affected skin in SSc patients. Conclusion. Down-regulation of miR-30b might be involved in the pathogenesis of SSc.

Objective The 2010 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) classification criteria for rheumatoid arthritis (RA) refer to a possible use of ultrasound “for confirmation of the clinical findings.” We undertook this study to determine the optimized definition of ultrasound-detected synovitis for the 2010 ACR/EULAR criteria and to assess the impact of its use on the accuracy of RA classification. Methods One hundred nine patients with musculoskeletal symptoms for ≤3 years were enrolled in the study. Patients underwent clinical, laboratory, radiographic, and comprehensive ultrasonographic assessments at baseline and received routine management from expert rheumatologists who were blinded to the ultrasound findings. Results Sensitivity and specificity of the 2010 ACR/EULAR criteria using different definitions of synovitis to identify patients who developed a disease requiring methotrexate (MTX) treatment within 1 year were 58.5% and 79.4%, respectively, for clinical synovitis (tenderness or swelling), 78.0% and 79.4%, respectively, for ultrasound-detected synovitis with a gray-scale (GS) imaging score ≥1 (GS ≥1 ultrasound synovitis), and 56.1% and 93.7%, respectively, for GS ≥2 ultrasound synovitis or a synovial power Doppler (PD) signal score ≥1 (GS ≥2/PD ≥1 ultrasound synovitis). Receiver operating characteristic curve analysis for the criteria scores revealed the largest area under the curve with GS ≥2/PD ≥1 ultrasound synovitis. Conclusion Ultrasound assessment improves the accuracy of the 2010 ACR/EULAR criteria for identifying patients with a disease requiring MTX treatment. Our data provide preliminary but vital information for the methodology to confirm the presence of synovitis using ultrasound in the 2010 ACR/EULAR criteria.

In the past decade, mechanisms underlying allergic contact dermatitis have been intensively investigated by using contact hypersensitivity (CHS) models in mice. However, the regulatory mechanisms, which could be applicable for the treatment of allergic contact dermatitis, are still largely unknown. To determine the roles of B and T lymphocyte attenuator (BTLA), a CD28 family coinhibitory receptor, in hapten-induced CHS, BTLA-deficient (BTLA(-/-)) mice and littermate wild-type (WT) mice were subjected to DNFB-induced CHS, severe combined immunodeficient (SCID) mice were injected with CD4(+) T cells, and CD8(+) T cells from either WT mice or BTLA(-/-) mice were subjected to CHS. BTLA(-/-) mice showed enhanced DNFB-induced CHS and proliferation and IFN-γ production of CD8(+) T cells as compared with WT mice. SCID mice injected with WT CD4(+) T cells and BTLA(-/-) CD8(+) T cells exhibited more severe CHS as compared with those injected with WT CD4(+) T cells and WT CD8(+) T cells. On the other hand, SCID mice injected with BTLA(-/-) CD4(+) T cells and WT CD8(+) T cells exhibited similar CHS to those injected with WT CD4(+) T cells and WT CD8(+) T cells. Finally, to evaluate the therapeutic potential of an agonistic agent for BTLA on CHS, the effects of an agonistic anti-BTLA antibody (6A6) on CHS were examined. In vivo injection of 6A6 suppressed DNFB-induced CHS and IFN-γ production of CD8(+) T cells. Taken together, these results suggest that stimulation of BTLA with agonistic agents has therapeutic potential in CHS.