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Background To analyse the subsequent clinical course of patients with rheumatoid arthritis (RA) who either continued or discontinued biologic agents after hospitalization for infections. Methods We retrospectively reviewed the clinical records of 230 RA patients with 307 hospitalizations for infections under biologic therapy between September 2008 and May 2014 in 15 institutions for up to 18 months after discharge. The risks of RA flares and subsequent hospitalizations for infections from 61 days to 18 months after discharge were evaluated. Results Survival analyses indicated that patients who continued biologic therapy had a significantly lower risk of RA flares (31.4% vs. 60.6%, P P = 0.37). Multivariate analysis showed that discontinuation of biologic therapy, diabetes, and a history of hospitalization for infection under biologic therapy were associated with RA flares. Oral steroid therapy equivalent to prednisolone 5 mg/day or more and chronic renal dysfunction were independent risk factors for subsequent hospitalizations for infections. Conclusions Discontinuation of biologic therapy after hospitalization for infections may result in RA flares. Continuation of biologic therapy is preferable, particularly in patients without immunodeficiency.

Objective.We investigated the association of airway comorbidities with the clinical phenotypes and outcomes of myeloperoxidase (MPO)–antineutrophil cytoplasmic antibodies (ANCA)–positive ANCA-associated vasculitis (AAV).Methods.An AAV patient multicenter cohort trial was established in 13 hospitals in western Japan between 2012 and 2018. We examined 143 of the new-onset MPO-ANCA–positive AAV patients. Their clinical characteristics and comorbidities at disease onset were compared based on clinical phenotypes. Multivariate analysis was performed to identify factors predictive of remission and death.Results.Twenty-seven cases with granulomatosis with polyangiitis (GPA), 10 with eosinophilic GPA (EGPA), 81 with microscopic polyangiitis (MPA), and 25 with unclassified AAV were identified. The average age of MPO-ANCA–positive patients was 71.4 years. Comorbidity (87.4%) and airway comorbidity (70.6%) were frequently observed in these patients. Examination of the clinical phenotypes revealed that the cases of GPA were frequently accompanied by infectious airway comorbidity (upper airway disease, bronchiectasis, pulmonary infections), and most of the cases of MPA and unclassified AAV were accompanied by fibrotic interstitial lung disease (fILD) or emphysema. Among MPO-ANCA–positive patients, infectious airway comorbidity was predictive of both remission (HR 1.58, P = 0.03) and mortality (HR 2.64, P = 0.04), and fILD was predictive of mortality (HR 7.55, P = 0.008). The combination of infectious airway comorbidities and fILD caused the worst survival outcomes in patients.Conclusion.MPO-ANCA–positive AAV was frequently accompanied by airway comorbidities. In addition to fILD, infectious airway comorbidities were closely associated with those clinical phenotypes and outcomes.

Clozapine is the most effective antipsychotic medication for refractory schizophrenia, but it has many possible serious side effects, including antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). However, the rare case reports available have not presented sufficient characteristic features of drug-induced AAV. Herein, we report a case of a 48-year-old Japanese woman with schizophrenia who presented with fever, arthralgia, myalgia and skin rash after 2 years of clozapine treatment. Her C-reactive protein (CRP) level increased, myeloperoxidase ANCA was positive and skin biopsy revealed leukocytoclastic vasculitis. Initially, steroid administration achieved remission, but her symptoms and high CRP levels relapsed every time the steroid dosage was tapered down. Upon discontinuation of clozapine, her symptoms and elevated CRP level immediately improved and the steroid was successfully tapered and discontinued. This outcome suggested that clozapine was the main cause of AAV.

As previous reports regarding rituximab usage for refractory thrombotic thrombocytopenic purpura (TTP) patients with connective tissue diseases (CTD) are limited, it is essential to clarify the clinical effect of early rituximab administration for refractory TTP with CTD in clinical practice. We retrospectively analysed three refractory TTP patients with CTD (plasma exchange [PE]-refractory case (case 2) or cases (case 1 and case 3) with high titers of von Willebrand factor-cleaving protease [ADAMTS13] inhibitor) in a single institution during 2012–2015. The patients were treated with PE/plasma infusion, steroids, and off-label use of rituximab treatment as early administration, at a dosage of 375 mg/m2 weekly with four or eight repeats. Owing to the early diagnosis of refractory TTP with ADAMTS13 activity-deficiency and presence of ADAMTS13 inhibitors (case 1: 2.5, case 2: 1.0, case 3: 6.6), and the subsequent early rituximab treatment combined with PE (case 1: day 1, case 2: day 12, case 3: day ...

A previously healthy 44-year-old male presented with fever, abdominal pain, liver dysfunction and lymphadenopathy. He was diagnosed as having acute cytomegalovirus (CMV) infection with elevated CMV-IgG and IgM, and observed with supportive therapy. He was admitted to our hospital with prolonged fever lasting for a month. Enhanced CT revealed multiple thromboses in the right pulmonary artery and superior mesenteric vein. Follow-up CT after one week revealed new-onset thromboses in the left pulmonary artery and common iliac vein. Screening tests for thrombophilia were negative. His symptoms were improved with anticoagulant therapy with intravenous heparin, followed by oral warfarin. He was discharged on admission day 28 with good condition. Follow-up CT after 6 months revealed complete resolution of the thromboses. Anticoagulant therapy was stopped after 9 months, and he has been well without recurrence. Though vascular thrombosis is a rare complication, we must be alert to the signs and symptoms of thrombosis in patients with acute CMV infection.

Objective To elucidate the clinical and genetic features of patients with TNFRSF1A variants in Japan using data obtained from a nationwide survey conducted by the Ministry of Health, Labor, and Welfare of Japan study group for tumor necrosis factor receptor–associated periodic syndrome (TRAPS). Methods Inquiries were sent to 2,900 departments of internal medicine and pediatrics in all hospitals with more than 200 beds in Japan, asking whether they had patients in whom TRAPS was suspected. Genetic tests for TNFRSF1A, MEFV, and MVK were performed on 169 patients. Cell surface expression of TNFRSF1A variants was assessed using 293T cells. Results Ten patients from 10 independent families were found to have TNFRSF1A variants. We collected clinical and genetic information on 41 additional patients with TNFRSF1A variants and symptoms of inflammation from 23 independent families; 17 of these patients had not been described in the literature. The common clinical features of Japanese patients were fever of >38°C (100% of patients), arthralgia (59%), and rash (55%). The prevalence of abdominal pain (36%), myalgia (43%), and amyloidosis (0%) was significantly lower in Japanese patients than in Caucasian patients. The most common variant was T61I (appearing in 49% of patients), and it was identified in 7 of 363 healthy controls. Defects in cysteine residues and the T50M variant were associated with decreased cell surface expression, while other variants, including T61I, were not. Conclusion Patients with TNFRSF1A variants are very rare in Japan, as in other countries, but there are a number of clinical and genetic differences between Japanese and Caucasian patients. The pathogenic significance of the T61I variant remains unclear.

Tumor necrosis factor receptor-associated periodic syndrome (TRAPS) is a representative of autoinflammatory diseases. We conducted a nationwide survey for patients with TNFRSF1A variants in Japan. We obtained clinical and genetic features of 51 patients from 33 independent families. The most common variant was T61I (appearing in 49% of patients), and it was identified in 7 of 363 healthy controls. The common clinical features of Japanese patients were fever of >38 °C (100% of patients), arthralgia (59%), and rash (55%). The prevalence of abdominal pain (36%), myalgia (43%), and amyloidosis (0%) was significantly lower in Japanese patients than in Caucasian patients. Patients with TNFRSF1A variants are very rare in Japan, as in other countries, but there are a number of clinical and genetic differences between Japanese and Caucasian patients.

Progranulin (PGRN), a pleiotropic growth factor, has emerged as an immunoregulatory molecule. Because the roles of PGRN in dermatomyositis (DM) are still unknown, we investigated whether serum PGRN levels are associated with disease activity and prognosis in DM patients, particularly in those with DM complicated with interstitial lung disease (ILD). The serum levels of PGRN were measured by enzyme-linked immunosorbent assay in patients with DM (n =57; acute/subacute interstitial pneumonia (A/SIP): n =17, chronic interstitial pneumonia (CIP): n =24, without ILD: n =16), polymyositis (PM, n =21; including 6 with ILD) and normal healthy controls (NHCs, n =60). We assessed the correlation between the serum PGRN levels and the activity indexes of ILD or prognosis in DM patients with ILD. Serum PGRN levels were significantly higher in DM patients than in PM patients (P =0.0025) and in NHCs (P

Early diagnosis is crucial for effective treatment of Wegener’s granulomatosis, although this disease shows only atypical symptoms in the primary stage. This report describes a patient suspected of having a malignancy based on integrated 18F-fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT), which showed increased uptake in pulmonary nodules and nasopharyngeal mucosa. Integrated PET/CT is therefore considered to be useful to confirm the distribution and determine the optimal site for biopsy.

Background Recent phase II study demonstrated that autologous hematopoietic stem cell transplantation (auto-HSCT) is more effective than conventional intravenous cyclophosphamide in the treatment of severe systemic sclerosis (SSc). However, the long-term results of CD34-selectiod or unmanipulated auto-HSCT for SSc has not been investigated. Objectives The aim of this study is to investigate the long-term results of auto-HSCT for severe SSc and to compare efficacy of CD34-selected auto-HSCT with that of unmanipulated auto-HSCT. Methods Nineteen patients (4 male and 15 female) with severe SSc were enrolled. Peripheral blood stem cells (PBSCs) were mobilized with cyclophosphamide (CY, 4 g/m 2 ) and G-CSF. After collecting PBSCs more than 2×10 6 CD34+cells/kg by apheresis, CD34+ cells were immunologically selected in 11 patients. All of the patients were treated with high-dose CY (200 mg/kg) and received CD34-selected (n=11; a group with CD34-selection) or unmanipulated (n=8; a group without CD34-selection) auto-HSCT. Immune reconstitution was evaluated serially by analyzing lymphocyte subpopulations for 36 months after HSCT. Results There was no treatment-related mortality. As toxicity, there were a variety of post-transplant infections such as adenoviral hemorrhagic cystitis, herpes zoster and cytomegaloviral antigenemia. Sclerosis of the skin was markedly improved in all of the patients within 6 months and the improvement was sustained for 60 months after auto-HSCT. Vital capacity was significantly increased at 48 months after HSCT and KL-6, a marker for interstitial pneumonia (IP), was significantly decreased in patients with IP during 12-60 months after HSCT. A titer of anti-Scl-70 was significantly decreased during 1-60 months after HSCT. Progression-free and overall 5-year survivals were 68 and 95%, respectively. Interestingly, the reduction of the skin scores was significantly greater and viral infections were more frequent in the patients with CD34-selection than those without. Effect of auto-HSCT on interstitial pneumonia, and the recovery of lymphocyte subpopulations after auto-HSCT were not significantly different between two groups. Conclusions Auto-HSCT had long-term effects on skin sclerosis and IP, resulting in improved prognosis in patients with severe SSc. CD34-selected auto-HSCT had greater effect on skin sclerosis than unmanipulated auto-HSCT. References Tsukamoto H, Nagafuji K, Horiuchi T, et al. A Phase I-II Trial of Autologous Peripheral Blood Stem Cell Transplantation in the Treatment of Refractory Autoimmune Disease. Ann Rheum Dis. 65: 508-14, 2006. Tsukamoto H, Nagafuji K, Horiuchi T, et al. Analysis of immune reconstitution after autologous CD34+ stem/progenitor cell transplantation for systemic sclerosis: predominant reconstitution of Th1 CD4+ T cells. Rheumatology 2011; 50: 944-52. Disclosure of Interest None Declared

Background Autologous stem cell transplantation for international scleroderma (ASTIS) trial demonstrated that autologous hematopoietic stem cell transplantation (auto-HSCT) is more effective than conventional intravenous cyclophosphamide in the treatment of severe systemic sclerosis (SSc). However, there is paucity of the study showing the long-term efficacy of auto-HSCT for severe SSc. Objectives The aim of this study is to investigate seven-year follow-up results of auto-HSCT for severe SSc. Methods Nineteen patients (4 male and 15 female) with severe SSc were enrolled. Peripheral blood stem cells (PBSCs) were mobilized with cyclophosphamide (CY, 4 g/m 2 ) and G-CSF. After collecting PBSCs more than 2x 10 6 CD34+cells/kg by apheresis, CD34+ cells were immunologically selected in 11 patients. All of the patients were treated with high-dose CY (200 mg/kg) and received CD34-selected (n=11; a group with CD34-selection) or unmanipulated (n=8; a group without CD34-selection) auto-HSCT. Immune reconstitution was evaluated serially by analyzing lymphocyte subpopulations for 36 months after HSCT. Results There was no treatment-related mortality. As toxicity, there were a variety of post-transplant infections such as adenoviral hemorrhagic cystitis, herpes zoster and cytomegaloviral antigenemia. Sclerosis of the skin was markedly improved in all of the patients within 6 months and the improvement was sustained for 84 months after auto-HSCT. Vital capacity was significantly increased at 48 and 60 months after HSCT and KL-6, a marker for interstitial pneumonia (IP), was significantly decreased in patients with IP during 12-84 months after HSCT. A titer of anti-Scl-70 was significantly decreased during 1-84 months after HSCT. Five and seven years after auto-HSCT, the overall survival was 89 and 78%, and the progression-free survival was 65 and 57%, respectively. Interestingly, the reduction of the skin scores was significantly greater and viral infections were more frequent in the patients with CD34-selection than those without. Effect of auto-HSCT on interstitial pneumonia, and the recovery of lymphocyte subpopulations after auto-HSCT were not significantly different between two groups. Conclusions Auto-HSCT was effective in the treatment of SSc and the effect was sustained for 7 years. References Tsukamoto H, Nagafuji K, Horiuchi T, et al. A Phase I-II Trial of Autologous Peripheral Blood Stem Cell Transplantation in the Treatment of Refractory Autoimmune Disease. Ann Rheum Dis. 65: 508-14, 2006. Tsukamoto H, Nagafuji K, Horiuchi T, et al. Analysis of immune reconstitution after autologous CD34+ stem/progenitor cell transplantation for systemic sclerosis: predominant reconstitution of Th1 CD4+ T cells. Rheumatology 2011; 50: 944-52. Disclosure of Interest None Declared

Background Granulin (GRN) is a soluble cofactor for TLR9 signaling and enhances the interaction between TLR9 and CpG-DNA. TLR9 is involved in the pathogenesis of systemic lupus erythematosus (SLE) via this DNA-containing immune complex. The roles of progranulin (PGRN) and GRN in SLE are still unknown. Objectives To determine if serum PGRN levels are elevated in patients with SLE and are correlated with disease activity and to investigate the role of PGRN in the pathogenesis of SLE. Methods The serum levels of PGRN and IL-6 were measured by ELISA in patients with SLE (n=68; active (SLEDAI score ≥6): n=46, inactive: n=22; female: n=58, male: n=10, median age=37 years), age- and sex-matched rheumatoid arthritis (RA, n=20) and normal healthy controls (NHCs, n=32). We assessed the correlation between the serum PGRN levels and an established disease activity index. The sera from the patients with high PGRN titers (>80 ng/ml) at the initial evaluation were reevaluated after the disease was ameliorated by treatment (n=15). We also measured the IL-6 secreted by peripheral blood mononuclear cells (PBMCs) from healthy donors stimulated with 1) CpG-B in the presence or absence of recombinant human PGRN (rhPGRN) 2) lupus serum in the presence or absence of an anti-PGRN antibody. Results The serum PGRN levels were significantly higher in the SLE patients (median: 87.6 ng/ml) than in the RA patients (54.2 ng/ml, P=0.0082) and NHCs (44.5 ng/ml, P in vitro (respectively, P Conclusions These findings indicate that PGRN is associated with global activities of lupus. PGRN may play a role in the pathogenesis of SLE by affecting the TLR9 signaling elicited by immune complexes and could therefore be a therapeutic target for SLE. References Park B, Buti L, Lee S, et al. Granulin is a soluble cofactor for toll-like receptor 9 signaling. Immunity 2011;34:505-513. Disclosure of Interest None Declared

Background Recently, it has been reported that granulin (GRN) and/or progranulin (PGRN), precursor of GRN, is a soluble cofactor for TLR9 signaling [1]. We reported that serum PGRN levels are associated with SLE global activity and PGRN may have a role in the pathogenesis via increased cytokine production [2]. TLR9 is also involved in the pathological condition of dermatomyositis (DM). Moreover, DM is occasionally complicated with interstitial lung disease (ILD). However, the roles of PGRN and GRN in DM are still unknown. Objectives To determine if serum PGRN levels are elevated in DM patients, in particular, complicated with ILD and are associated with severity and prognosis. Methods The serum levels of PGRN were measured by ELISA in patients with DM (n=50; acute/subacute interstitial pneumonia (A/SIP), defined as a rapidly progressive ILD within 3 months from the onset of symptoms: n=13, chronic interstitial pneumonia (CIP): n=20, without ILD: n=17), polymyositis (PM, n=21) and normal healthy controls (NHCs, n=60). We assessed the correlation between the serum PGRN levels and the activity indexes of ILD. The sera from some of the patients were reevaluated after the disease was ameliorated by treatment (n=6). Moreover, we calculated the cumulative survival rate for 6 months in DM patients with ILD, which is classified two groups, serum PGRN levels > or =200 ng/ml and Results The serum PGRN levels were significantly higher in the DM patients (median: 100 ng/ml) than in the PM patients (60.4 ng/ml, P=0.0028) and NHCs (48.3 ng/ml, P or =200 ng/ml (60%) than that in the group with serum PGRN levels Conclusions These findings indicate that PGRN is associated with severity and prognosis of DM with ILD. PGRN may play a role in the pathogenesis of DM by affecting the TLR9 signaling and could be a useful biomarker. References Park B, Buti L, Lee S, et al. Granulin is a soluble cofactor for toll-like receptor 9 signaling. Immunity 2011;34:505-513. Tanaka A, Tsukamoto H, Mitoma H, et al. Serum progranulin levels are elevated in patients with systemic lupus erythematosus, reflecting disease activity. Arthritis Res Ther 2012;14(6):R244. Disclosure of Interest None Declared