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We conducted a Japanese GWAS for systemic sclerosis (SSc) comprising 1,428 cases and 112,599 controls, the largest Asian GWAS for SSc ever, and identified three novel signals. The lead SNP in FCGR/FCRL region had a strong effect size (OR 2.05, P = 4.9×10−11). The complete LD SNP, rs10917688, was found in a cis-regulatory element and a part of binding motifs for IRF8. IRF8 was a significant locus in the European GWAS and rs10917688 showed an association only in the presence of the risk allele of IRF8 in Japanese. rs10917688 was marked with H3K4me1 in primary B cells, and the heritability was enriched in active histone marks of primary B cells. A meta-analysis with the latest European GWAS found additional 30 significant loci including three novel signals. PRS constructed with the effect sizes of the meta-analysis indicated potential portability of genetic associations beyond populations (AUC: 0.593). The fitting of PRS was improved by further prioritizing the top 5% SNPs of IRF8 biding sites in B cells, underscoring common genetic architecture across populations and critical roles of B cells and IRF8 for SSc development.

ObjectivesThis study aimed to clarify the usefulness of screening for malignancies using CT before the initiation of biologic and targeted synthetic DMARDs (b/tsDMARDs) in patients with active RA.MethodsWe examined 2192 patients with RA who underwent plain CT scans prior to the initiation of b/tsDMARDs. The sensitivity for detecting malignancy was measured and compared with that of regular screening (physical examination and X-ray). We then evaluated the clinical characteristics, prognosis and treatment of patients with RA with concomitant malignancies. Additionally, we determined the incidence rate of malignancy in patients with RA who were initiated on b/tsDMARDs after CT screening.ResultsOf the 2192 patients, 33 (1.5%) were diagnosed with malignancy after CT screening. Whereas regular screening detected only seven malignancies, CT screening further detected 26 (including 19 at the early stage). On the other hand, 86% of the malignancies detectable by regular screening were at an advanced stage. Patients diagnosed with early-stage malignancies received RA treatments that included b/tsDMARDs after curative resection; 80% of these patients achieved low disease activity after 1 year. This rate was comparable to the patients without malignancy detection after screening (70%). The 5 year incidence of malignancy after the initiation of b/tsDMARDs after CT screening was lower than that of the RA cohort without CT screening (standardized incidence ratio: 0.35).ConclusionScreening in patients with RA using CT before the initiation of b/tsDMARDs allows for the early detection and treatment of malignancy, resulting in safer and more stable b/tsDMARD treatments.

We had two cases of trisomy 8-positive myelodysplastic syndrome (MDS) with incomplete Behçet’s disease (BD) in which the remissions of both diseases were maintained by allogeneic stem cell transplantation (allo-SCT). Among MDS with BD patients, sometimes it is difficult to control the symptoms of BD with standard therapies such as corticosteroids and tumor necrosis factor (TNF) inhibitors. Although there should be careful consideration regarding indications for transplantation, our two cases, in which refractory BD was completely controlled by allo-SCT, suggest that allo-SCT can be one of the treatment options for higher-risk MDS with BD patients.

Objective MCTD manifests with microvasculopathy and overlapping clinical features of SLE, SSc and idiopathic inflammatory myopathies (IIM). The aim of this study was to investigate the clinical significance of microvasculopathy in patients with MCTD using nailfold videocapillaroscopy (NVC). Methods Fifty patients with newly diagnosed and untreated MCTD were enrolled in this multicentre, prospective and observational study. Clinical features and NVC findings were assessed at baseline and after 1 year post-intervention, along with disease controls [SLE (n = 40), SSc (n = 70) and IIM (n = 50)]. Results All MCTD patients presented Raynaud’s phenomenon and were positive for anti-U1 RNP antibodies, and 22.0% (11/50) had pulmonary arterial hypertension (PAH). The prevalence of NVC scleroderma patterns in MCTD was 38.0%, which was lower than SSc (88.6%) but higher than SLE (10.0%). In addition, when we divided MCTD patients into two groups by presence or absence of NVC scleroderma patterns, we found a higher prevalence of PAH in patients with NVC scleroderma patterns. Namely, NVC scleroderma patterns were observed in all MCTD patients with PAH, and in 21.0% of those without PAH. After intensive immunosuppressive therapy, NVC scleroderma patterns disappeared in half of the MCTD patients but were not changed in SSc patients. Conclusions MCTD differed from SLE, SSc and IIM in terms of the prevalence and responsiveness of NVC scleroderma patterns to immunosuppressive therapy. Detection of nailfold microvascular abnormalities in MCTD could contribute to predicting PAH and help us to understand further aspects of the pathogenesis of MCTD.

Objective To clarify the efficacy and safety of intravenous abatacept for glandular and extraglandular involvements in Sjögren’s syndrome (SS) associated with rheumatoid arthritis (RA). Materials and methods We performed an open-label, prospective, 1-year, observational multicenter study (ROSE and ROSE II trials). The primary endpoint was the remission rate as measured by SDAI at 52 weeks. The secondary endpoints included the changes in the Saxon’s test, Schirmer’s test, ESSDAI and ESSPRI. Adverse events and adherence rates were also analyzed. Results 68 patients (36 in ROSE and 32 in ROSE II, all women) were enrolled. SDAI decreased significantly from 23.6 ± 13.2 at baseline to 9.9 ± 9.5 at 52 weeks. Patients with SDAI remission increased from 0 (0 weeks) to 19 patients (27.9%) at 52 weeks. Saliva volume increased significantly at 24 weeks. Tear volume increased significantly at 52 weeks. Both ESSDAI and ESSPRI were significantly decreased at 12 weeks, and these responses were maintained up to 52 weeks. The rate of adherence to abatacept over the 52-week period was 83.8%. Twenty-two adverse events occurred in 15 patients. Conclusion Abatacept ameliorated both glandular and extraglandular involvements, as well as the systemic disease activities and patient-reported outcomes based on composite measures, in SS associated with RA.

Difficult-to-treat rheumatoid arthritis (dt-RA) is an emerging concept defined as persistency of signs and/or symptoms despite prior treatment. However, whether this refractoriness affects effectiveness and tolerance to next treatment is not fully understood. This study aimed to find cut-off values for a definition of dt-RA with respect to responsiveness to newly used biologic and targeted synthetic disease-modifying anti-rheumatic drugs (b/tsDMARDs).A retrospective cohort study was conducted using the FIRST registry. An inadequate response to current b/tsDMARDs was defined as clinical disease activity index10 at week 22 or termination of treatment within 22 weeks due to insufficient efficacy. Cut-off values were defined according to the number of past failures to DMARDs and current dose of glucocorticoid. Responsiveness to newly used b/tsDMARDs were compared with respect to above versus below cut-off values.Failures to ≥2 conventional synthetic DMARDs (csDMARDs) and ≥4 b/tsDMARDs as well as ≥3mg/day of glucocorticoid were independent cut-off values associated with poor responsiveness to newly used b/tsDMARD treatment. Concomitant use of glucocorticoid was significantly correlated with an increased hazard of infection. Failures to ≥2 csDMARDs was associated with less improvement in inflammatory symptoms, while that to ≥4 b/tsDMARDs was associated with less improvement in health assessment questionnaire and global health as well.We propose cut-off values of ≥2 failures to csDMARDs and/or ≥4 b/tsDMARDs as a definition of dt-RA with respect to responsiveness to use of b/tsDMARDs.

The patient was a 73-year-old woman who had hair loss, purpura, and numbness of the soles for past 1 year. Three months prior, she was diagnosed with interstitial lung disease (ILD) and was admitted to our department. She was diagnosed with systemic lupus erythematosus (SLE) based on positive antinuclear antibodies 1280× (speckled type), hair loss, low white blood cell count, positive anti-cardiolipin and anti-ds-DNA antibodies, and lupus retinopathy. In addition, the patient was also diagnosed with immunoglobulin G (IgG)4-related disease (IgG4RD) based on high serum IgG4 levels, ILD, urine occult blood, protein, and cast, and renal histological findings showed endocapillary proliferative glomerulonephritis, increased IgG4 positive plasma cells, and characteristic storiform fibrosis. High-dose glucocorticoid therapy, hydroxychloroquine, and belimumab were administered, which improved the SLE symptoms of lupus retinopathy and peripheral neuropathy, as well as the IgG4RD symptoms of ILD and urinary findings. Herein, we report a rare case of simultaneous onset of IgG4-related nephropathy with active glomerular lesions and SLE, in which renal histology, including fluorescent antibodies, was crucial for diagnosis.

Anti-PM/Scl antibodies are associated with the overlap syndrome of systemic sclerosis and dermatomyositis/polymyositis (SSc-DM/PM), and are found in 50% of SSc-DM/PM cases in Europe and the USA, whereas they are rare in Japan. We report a case of an 80-year-old Japanese female with SSc-amyopathic dermatomyositis overlap syndrome, who developed scleroderma renal crisis, a complication of SSc. She had positive antinuclear antibodies in a discrete-speckled and nucleolar pattern and anti-centromere antibodies and anti-PM/Scl antibodies were confirmed by enzyme-linked immunosorbent assay and immunoprecipitation, respectively. The incidence rate of SRC in SSc patients varies significantly depending on the specificity of autoantibodies, with the highest incidence of ∼50% in anti-RNA polymerase III antibody positive patients, followed by ∼10% in anti-PM/Scl and lower incidence of 0.45% in anti-centromere antibody-positive cases. Anti-PM/Scl antibodies are uncommon in Japanese patients presumably due to its strong association with certain human leucocyte antigen haplotype that is rare in Japanese. Clinical significance of anti-PM/Scl antibodies in Japanese patients will need to be clarified with accumulation of cases in future studies.

Granulomatosis with polyangiitis (GPA) is characterized by necrotizing granulomatous lesions and is classified as ANCA-associated vasculitis (AAV). We herein report a case of GPA that was remitted by resection of a pulmonary lesion without immunosuppressive therapy. We detected activated neutrophils and neutrophil extracellular traps (NET) formation in resected lung tissue by immunofluorescence. Activated neutrophils and NETs might be involved in the pathophysiology of AAV and induce the vicious cycle of ANCAs and NETs. In cases of GPA with no other severe lesions, the reevaluation of the disease activity after diagnostic resection is crucial for considering the need for immunosuppressive therapy.

Objectives To develop an illustrative tool presenting visualized rheumatoid arthritis (RA) symptoms using pictures to promote better understanding between patients and physicians. Methods A tool named ‘Okomarigoto Sheet’ was developed through an internet survey of patients with RA and certified rheumatologists by repeated in-person interviews. Results An internet survey on the reality of communication between patients with RA and physicians in 200 patients and 200 certified rheumatologists revealed various local and systemic symptoms of RA and difficulties in sharing those symptoms between patients and physicians during a short consultation. Interviews from patients and certified rheumatologists suggested that illustrations of symptoms would be helpful for better communication between them; therefore, an illustrative tool presenting visualized RA symptoms was drafted. The draft illustrations were refined through multiple rounds of interviews with the patients. The final version of the tool was discussed and evaluated at a joint meeting of patients and rheumatologists. Conclusions A picture sheet presenting RA symptoms was developed. Future prospective studies should evaluate the usefulness of the sheet in clinical practice to promote better communication between patients and physicians.

Tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS) is an autoinflammatory periodic fever syndrome associated with heterozygous mutations in TNFRSF1A, which encodes TNF receptor type I (TNFR1). Although possible proinflammatory mechanisms have been proposed, most previous studies were performed using in vitro overexpression models, which could lead to undesirable inflammatory responses due to artificial overexpression. It is crucial to reproduce heterozygous mutations at physiological expression levels; however, such studies remain limited. In this study, we generated TRAPS mutant mice and analyzed their phenotypes. Three Tnfrsf1a mutant strains were generated by introducing T79M, G87V, or T90I mutation. T79M is a known mutation responsible for TRAPS, whereas G87V is a TRAPS mutation that we have reported, and T90I is a variant of unknown significance. Using these murine models, we investigated whether TRAPS mutations could affect the inflammatory responses in vivo and in vitro. We found that none of the mutant mice exhibited detectable inflammatory phenotypes under standard housing conditions for 1 year. Interestingly, TRAPS mutant (T79M and G87V) mice had reduced mortality rates after the administration of lipopolysaccharide (LPS) and D-galactosamine, which induce TNFα-dependent lethal hepatitis. Moreover, TRAPS mutations strongly suppressed the development of TNFα-mediated arthritis when crossed with human TNFα transgenic mice. In in vitro primary bone marrow-derived macrophage cultures, the T79M and G87V mutations attenuated the inflammatory responses to TNFα compared with the wild-type, whereas these mutations did not alter the responsiveness of these cells to LPS. The T90I mutant macrophages behaved similarly to wild type in response to LPS and TNFα. The TNFR1 levels were increased in whole-cell lysates of TRAPS mutant macrophages, whereas the cell surface expression of TNFR1 was significantly decreased in TRAPS mutant macrophages. Taken together, TRAPS mutations did not augment the inflammatory responses to TNFα and LPS; instead, they suppressed the response to TNFα via decreased cell surface expression of TNFR1. The stimulation of lymphotoxin-α, adenosine triphosphate, and norepinephrine in primary macrophages or various stimuli in murine splenocytes did not induce detectable inflammatory responses. In conclusion, TRAPS mutations suppressed responsiveness to TNFα, and TRAPS-associated inflammation is likely induced by unconfirmed disease-specific proinflammatory factors.

A 43-year-old-woman admitted to our department because of abdominal pain, abdominal distension, pain on both inner thighs and blurred vision lasting for 3 months. Pancytopenia and positive anti-dou...

Objective To investigate clinical characteristics and time course of lymphoproliferative disorders (LPDs) in rheumatoid arthritis (RA) patients after methotrexate (MTX) discontinuation, in those who achieved spontaneous regression (SR). Methods We retrospectively reviewed clinical data from RA patients with LPDs obtained from eight institutions between 2000 and 2017 and compared clinical and pathological findings between SR and non-SR groups. Results Among 232 RA patients with LPDs, 216 were treated with MTX at the onset of LPD and 144 (66.7%) achieved SR after MTX discontinuation. Higher MTX doses, high titers of anti-CCP antibodies (>13.5 U/mL), and lower LDH and soluble IL-2 receptor levels were associated with SR. Lymphocyte count was decreased at LPD onset and increased at 2 weeks after MTX discontinuation in the SR group. Epstein–Barr virus-positive mucocutaneous ulcer, reactive lymphoid hyperplasia and unclassifiable B-cell lymphoma, were more frequent in the SR than in the non-SR group. In multivariable analysis, diffuse large B-cell lymphomas was an independent predictive factor for non-SR. In the patients with SR, 73.9% achieved partial or complete regression as early as 2 weeks after MTX discontinuation. Conclusion SR and non-SR in RA patients with LPDs after MTX discontinuation were associated with certain clinical characteristics.

Objectives To clarify factors affecting 5-year survival rates and relapse rates after spontaneous regression (SR) of lymphoproliferative disorders (LPDs) in patients with rheumatoid arthritis (RA). Methods This retrospective longitudinal study comprised 232 patients with RA diagnosed with LPDs between January 2000 and March 2017 at eight hospitals in Japan. The Kaplan-Meier method was used to analyze survival and the Cox proportional hazard model was applied to identify predictive factors. Results Among all patients, 1-, 2- and 5-year overall survival rates were 89.5%, 86.1%, and 78.2%, respectively. Multivariable analysis revealed four 5-year survival risk factors assessed at diagnosis: age above 70 years (p = .002), deep lymphadenopathy and/or more than one extranodal lesion (p = .008), Eastern Cooperative Oncology Group/Zubrod performance status of 2–4 (p = .004), and classic Hodgkin lymphoma (CHL) histology (p = .047). Among 143 patients who achieved SR, 2- and 5-year relapse rates were 14.2% and 24.9%, respectively. CHL histology (p = .003) and serum soluble interleukin-2 receptor levels exceeding 2000 IU/L (p = .014) were associated with post-SR relapse-free survival. Blood lymphocyte counts were significantly lower at relapse than at 3–6 months prior (p Conclusion Assessment of the above risk factors and routine inspection of blood lymphocyte counts could aid in the care management of LPDs in RA.

ObjectiveIncreasing numbers of patients are developing rheumatoid arthritis (RA) at an older age, and optimal treatment of patients with elderly-onset RA (EORA) is attracting greater attention. This study aimed to analyze the efficacy and safety of biologic/targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) in EORA and non-EORA elderly patients.MethodsA cohort of patients with RA treated with b/tsDMARDs were retrospectively analyzed. Only patients aged ≥ 60 years were included. Among them, patients who developed RA aged ≥ 60 years were categorized as EORA, whereas those aged < 60 years were categorized as non-EORA elderly. Disease activity was compared between the EORA and non-EORA elderly groups.ResultsIn total, 1040 patients were categorized as EORA and 710 as non-EORA elderly. There were no significant differences in characteristics at baseline between the 2 groups. The proportion of patients with low and high disease activity was comparable at Weeks 2, 22, and 54 between the EORA and the non-EORA elderly group. There were no significant differences in the reasons for the discontinuation of b/tsDMARDs between the 2 groups. Elderly RA onset did not affect changes in Clinical Disease Activity Index (CDAI) and Health Assessment Questionnaire–Disability Index, nor did it affect the reasons for b/tsDMARD discontinuation between the 2 groups. The trajectory analysis on CDAI responses to b/tsDMARDs for 54 weeks identified 3 response patterns. The proportion of patients categorized into each group and CDAI response trajectories to b/tsDMARDs were very similar between EORA and non-EORA elderly patients.ConclusionCDAI response patterns to b/tsDMARDs and HR of adverse events were similar between EORA and non-EORA elderly patients.

Objectives To identify the optimal treatment for rheumatoid arthritis (RA) after the regression of lymphoproliferative disorders (LPDs). Methods The subjects were 232 patients with RA who developed LPD between 2000 and 2017 at seven hospitals participating in the LPD-WG study. Kaplan-Meier and Cox proportional regression analyses were performed to determine the factors associated with the rate of LPD relapse and the retention of biological disease-modifying antirheumatic drugs (bDMARDs). Results Treatment for RA was resumed in 138 patients after spontaneous regression of LPD after the discontinuation of methotrexate and in 52 patients after chemotherapy for LPD (persistent-LPD). LPD relapses occurred in 23 patients. Not DMARDs use but Hodgkin’s lymphoma was identified as a risk factor for LPD relapse. In 88 RA patients treated with bDMARDs [tocilizumab, 39 patients; abatacept 20 patients; tumor necrosis factor inhibitor, 29 patients], the one-year retention rate was 67.8%. The risk factors for discontinuation of bDMARDs were persistent-LPD, non-diffuse large B-cell lymphomas (non-DLBCL), and a high clinical disease activity index (CDAI). Tocilizumab showed the highest retention rate among bDMARDs, particularly in DLBCL. Conclusion Although any bDMARD could be used in patients after LPD regression, effectiveness and risk for relapse should be carefully assessed for each LPD subtype.

Tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS) is an autoinflammatory periodic fever syndrome associated with heterozygous mutations in

BackgroundShort-term mortality and incidence of cerebrovascular and cardiovascular events (C-CVE) during hospitalization of patients with severe herpes zoster (HZ) have not been sufficiently investigated. We aimed to investigate short-term prognosis and incidence of C-CVE associated with HZ in hospitalized patients.MethodsThis retrospective cohort study from April 2016 to March 2018 included HZ inpatient cases selected from the Diagnosis Procedure Combination database—a Japanese nationwide inpatient database. HZ and C-CVE were diagnosed based on the 10th revision of the International Classification of Diseases and Injuries codes. The definition of primary exposure was that treatments were initiated within 7 days of admission, and antivirals were administered for ≥7 days. Main Outcomes were in-hospital deaths and C-CVE onset after hospitalization.ResultsAmong 16,811,501 in-hospital cases registered from 1,208 hospitals, 29,054 cases with HZ were enrolled. The median age was 71.0 years, 15,202 cases (52.3%) were female, and the HZ types were the central nervous system (n=9,034), disseminated (n=3,051), and ophthalmicus (n=1,069) types. There were 301 (1.0%) in-hospital deaths and 385 (1.3%) post-hospitalization onset of C-CVE. The 30-day in-hospital survival rates with or without underlying disease were 96.8% and 98.5%, respectively. Age ≥75 years (hazard ratio [HR], 2.18; 95% confidence interval [CI], 1.55–3.05), liver cirrhosis or hepatic failure (HR, 5.93; 95% CI, 2.16–16.27), chronic kidney disease (HR, 1.82; 95% CI, 1.24–2.68), heart failure (HR, 1.65; 95% CI, 1.22–2.24), and old cerebrovascular events (HR, 1.92; 95% CI, 1.10–3.34) were associated with poor short-term prognosis. Age ≥75 years (odds ratio [OR], 1.70; 95% CI, 1.29–2.24), diabetes (OR, 1.50; 95% CI, 1.19–1.89), dyslipidemia (OR, 1.95; 95% CI, 1.51–2.51), hyperuricemia (OR, 1.63; 95% CI, 1.18–2.27), hypertension (OR, 1.76; 95% CI, 1.40–2.20), heart failure (OR, 1.84; 95% CI, 1.32–2.55), and glucocorticoid administration (OR, 1.59; 95% CI, 1.25–2.01) were associated with increased risks for in-hospital C-CVE onset.ConclusionsThe underlying diseases that could influence the short-term mortality of severe HZ were identified. Glucocorticoid is a possible risk factor for the in-hospital onset of C-CVE after severe HZ development.

We herein report five patients with nasal mucosa and sinus involvement who were diagnosed with immunoglobulin G4-related disease (IgG4-RD). In all cases, the lacrimal, parotid, and submandibular glands were swollen; biopsies of these glands were risky, so the labium and nasal mucosa were instead targeted. All patients tested positive through these biopsies, suggesting alternative sites for confirming IgG4-RD. These five patients had first been diagnosed and unsuccessfully treated for allergic rhinitis or chronic sinusitis. After the IgG4-RD diagnosis, they were administered corticosteroid therapy, which drastically improved the nasal mucosa and sinus involvement. When refractory allergic rhinitis or sinusitis is detected, IgG4-RD should be considered.

A 62-year-old woman was admitted to our hospital because of fever, renal dysfunction, eosinophilia, and the presence of MPO-ANCA. Based on the renal pathological examination which showed granuloma lesion with eosinophils and crescentic glomerulonephritis, eosinophilic granulomatosis with polyangiitis (EGPA) was diagnosed. On the other hand, laboratory examination showed elevated serum IgG4 levels and renal pathological examination showed marked lymphoplasmacytic infiltration and fibrosis surrounding nest "Bird's eye pattern," which were characteristic of IgG4-related kidney disease (IgG4-RKD). Because there are cases when EGPA has clinical features of IgG4-RKD, we should be careful about diagnoses of IgG4-RKD in patients with EGPA.

Mixed connective tissue disease (MCTD) involves various clinical manifestations, and pulmonary hypertension (PH) is an important organ dysfunction defining the prognosis of MCTD. The pathology of PH is heterogeneous. Here, we present 2 cases of MCTD complicated by PH that had contrasting clinical courses. The first case involved a 54-year-old woman with Raynaud's phenomenon and dyspnoea on exertion. She was diagnosed with MCTD accompanied by pulmonary arterial hypertension (PAH) and was treated with ambrisentan and tadalafil in addition to high-dose glucocorticoid (GC) therapy and rituximab therapy. After treatment, her PH resolved. The second case involved a 64-year-old woman with Raynaud's phenomenon and dyspnoea on exertion. She was similarly diagnosed with MCTD accompanied by PAH and was treated with ambrisentan and tadalafil in addition to high-dose GC therapy and cyclophosphamide pulse therapy. However, she showed exacerbation of her respiratory condition and manifestation of pulmonary veno-occlusive disease (PVOD). Thus, the treatment was discontinued, and subsequently, her condition improved and eventually returned to that before treatment. The findings suggest that the presence or absence of latent PVOD might be an important factor for predicting the therapeutic responsiveness of MCTD-associated PH. Evaluation of chest radiography findings, computed tomography findings, percent vital capacity, and percent carbon monoxide diffusion capacity might be useful for predicting prognosis and might aid in treatment. PVOD could be underlying in patients with CTD-PH. When the complication of PVOD is suggested by chest CT or pulmonary function test, we need a careful introduction with pulmonary vasodilators. So, combination therapy of pulmonary vasodilators should not be applied in all patients with CTD-PH since underlying PVOD could deteriorate the patient's condition.

To identify predictive factors for lymphoproliferative disorders (LPDs) that persist after methotrexate (MTX) withdrawal (Persistent-LPD) and the optimal treatment for rheumatoid arthritis (RA) after LPD regression.Among 3666 patients with RA treated with MTX in our department from 2006 to 2017, 26 cases of LPD that regressed after MTX withdrawal (Regressive-LPD) and 25 cases of Persistent-LPD were compared. Multivariate logistic analysis was performed to identify predictive factors for Persistent-LPD. Retention rates of biological disease-modifying antirheumatic drugs (bDMARDs) were calculated using the Kaplan-Meier Method.In Persistent-LPD, the incidence of diffuse large B-cell lymphoma was higher (76%). The overall 2-year survival rate was 83.9%: 95.8% for Regressive-LPD and 71.0% for Persistent-LPD. The International Prognostic Index (IPI) risk classification was useful for predicting Persistent-LPD. bDMARDs were introduced in 38 RA patients after LPD regression. Unadjusted retention rate of bDMARDs in the 51 LPD patients was significantly lower than that in the 1668 non-LPD RA patients in our bDMARD cohort (controls) (Risk assessment using IPI predicted Persistent-LPD. After LPD regression, non-TNFi tended to have higher retention rates.

Protein-losing enteropathy (PLE) is a rare organ disorder that can develop as a complication of systemic lupus erythematosus (SLE). Here, we report the case of a 59-year-old woman with SLE who experienced recurrent PLE resulting from different pathological conditions. The patient was diagnosed with SLE in X-14. In X-12, she was hospitalised due to persistent diarrhoea, generalised oedema, abdominal distension, dyspnoea on exertion, and hypoalbuminemia. A thrombus was noted in the superior mesenteric vein extending from the main trunk of the portal vein. She was diagnosed with PLE resulting from portal vein thrombosis caused by SLE, and her condition improved with anticoagulant therapy. In X-1, she developed diarrhoea and hypoalbuminemia again and was diagnosed with PLE associated with SLE. The symptoms promptly ameliorated with immunosuppressive therapy. Because PLE associated with SLE can be caused by various pathological conditions, appropriate therapeutic intervention based on the underlying condition is crucial.

Background Rheumatoid arthritis (RA) patients present with abnormal methylation patterns in their fibroblast-like synoviocytes (FLS). Given that DNA demethylation is critical for producing DNA methylation patterns, we hypothesized that DNA demethylation may facilitate RA progression. Therefore, we designed this study to examine the role of DNA dioxygenase family, Ten-Eleven translocation (TET1/2/3), in the pathological process of RA. Methods Synovial tissues and FLS were obtained from patients with RA and Osteoarthritis. K/BxN serum-induced arthritis was induced in Wild-type (WT) and TET3 heterozygous-deficient (TET3+/−) C57BL/6 mice. Results We found that both TET3 and 5-hydroxymethylcytosine (5hmC) were upregulated in synovitis tissues from RA patients and confirmed this upregulation in the cultured FLS derived from synovitis tissues. Tumor necrosis factor α (TNFα) upregulated TET3 and 5hmC levels in cultured FLS, and the stimulated FLS exhibited high cell mobility with increased transcription of cellular migration-related factors such as C-X-C motif chemokine ligand 8 (CXCL8) and C-C motif chemokine ligand 2 (CCL2) in a TET3-dependent manner. In addition, TET3 haploinsufficiency lowered RA progression in a mouse model of serum-induced arthritis. Conclusions Based on these findings, we can assume that TET3-mediated DNA demethylation acts as an epigenetic regulator of RA progression.

Vascular calcification is characterized by mineral deposition in the vasculature, which is triggered by chronic systemic inflammation, including psoriasis. Psoriasis is an IL-17A-mediated inflammatory skin disease that is associated with exacerbated vascular calcification and high cardiovascular mortality. Although previous studies have shown that IL-17A induces vascular dysfunction in murine psoriasis models, it has not been clarified whether IL-17A induces vascular calcification. In this study, we investigated the potential vascular calcification-inducing effect of IL-17A in an ex vivo culture system.Thoracic and abdominal aortas from mice were cultured in a medium supplemented with inorganic phosphate and were treated with inflammatory cytokines (IL-1β, TNF-α, IL-6, and IL-17A). Vascular calcification was determined using micro-computed tomography (CT) and histological analyses.IL-1β, TNF-α, and IL-6 did not significantly promote vascular calcification, whereas IL-17A significantly accelerated vascular calcification of the aorta, as indicated by the increased mineralized volume based on micro-CT analysis. Micro-CT and histological analyses also revealed that the promoting effect of IL-17A on vascular calcification was concentration dependent.IL-17A significantly promoted vascular calcification in ex vivo cultured aortas, which suggests that this mechanism is involved in the increased risk of cardiovascular events in IL-17A-mediated inflammatory diseases.

We performed an autopsy on a patient with systemic sclerosis who developed uncontrollable pulmonary hypertension due to pulmonary tumour thrombotic microangiopathy (PTTM) caused by gastric carcinoma. The case was of a 62-year-old woman with systemic sclerosis who was admitted to the intensive care unit (ICU) with severe pulmonary hypertension accompanied by respiratory insufficiency. Pulmonary hypertension could not be controlled despite aggressive medical treatment including vasodilators. Approximately 10 days after admission, a unilateral pleural effusion developed. Thoracentesis was performed, and cytology examination of the pleural fluid revealed carcinomatous pleurisy. Because of the presence of a known gastric carcinoma, PTTM was clinically diagnosed. Although chemotherapy was administered, she died 33 days after ICU admission. An autopsy revealed diffuse fibrocellular intimal thickening of the peripheral pulmonary arterioles, which indicated PTTM. In patients with connective tissue disease complicated with pulmonary hypertension, it is necessary to differentiate not only pulmonary arterial hypertension but also other pathological conditions such as PTTM.

Objective To compare the outcome of various treatment de-escalation regimens in patients with RA who achieved sustained remission. Methods At period 1, 436 RA patients who were treated with MTX and bDMARDs and had maintained DAS28(ESR) at Results Based on shared decision-making, 81.4% elected de-escalation of treatment and 48.4% selected de-escalation of MTX. At end of period 1, similar proportions of patients maintained DAS28(ESR) Conclusions After achieving sustained remission by combination treatment of MTX/bDMARDs, disease control was achieved comparably by continuation, dose reduction or discontinuation of MTX and dose reduction of bDMARDs at end of year 1. Subsequent de-escalation of MTX had no impacts on disease control but decreased adverse events in year 2.

Objectives To clarify the effectiveness and safety of induction therapy with mycophenolate mofetil (MMF) in patients with lupus nephritis (LN). Methods Patients with LN administered MMF (n = 35) or intravenous cyclophosphamide pulse therapy (IVCY) (n = 25) plus high-dose corticosteroids between July 2015 and June 2020 were included. MMF was increased from 2 to 3 g/day, with no adverse events (AEs). The primary endpoint was the 6 month renal remission rate. Secondary endpoints were retention rate and AEs. Results There were no significant differences in age, sex, disease duration, renal histological type, SLE disease activity index, and urine protein creatinine ratio between the two groups. Twenty-six patients (74%) continued with MMF therapy, whereas 12 (48%) completed six IVCY courses. The retention rate was significantly higher in the MMF than in the IVCY group (p = 0.048). Twenty-four and 14 patients in MMF and IVCY groups, respectively, achieved renal remission with insignificant differences. Grade 3 or higher AEs were observed in 8 and 14 patients in the MMF and IVCY groups, respectively (p = 0.014). Conclusions The efficacy of high-dose MMF was comparable to that of IVCY in Japanese patients with proliferative LN, with fewer AEs and a higher retention rate than IVCY, suggesting the high tolerability of MMF.

We present the case of a 54-year-old woman with a long history of pulmonary hypertension associated with mixed connective tissue disease. She was being treated with pulmonary vasodilators, including epoprostenol and bosetan, but her mean pulmonary arterial pressure (mPAP) gradually worsened. Although her mPAP began to improve with adding sildenafil, ascites occurred. Discontinuing newly initiated drugs and starting diuretics improved her ascites. This suggested that an intensification of the treatment with vasodilators might have led to ascites (on a background of a probable arteriovenous shunt formation) in this patient with a long history of pulmonary hypertension.

We encountered a 60-year-old female patient who died of cerebral hemorrhage caused by disseminated aspergillosis during massive steroid therapy for overlap syndrome of systemic lupus erythematosus (SLE) and systemic sclerosis (SSc) and performed autopsy. Histologically, necrotizing vasculitis accompanied by Aspergillus hyphae was noted in the arterial wall of the region with cerebral hemorrhage and an abscess containing Aspergillus clumps was present in the lung, therefor we considered the cerebral hemorrhage caused by disseminated aspergillosis. For immunocompromised patients, it is desirable to perform treatment taking the possibility of deep mycosis into consideration, and when it is suspected, early therapeutic intervention may be useful.

Case 1. A 23-year-old female with polyarthralgia, facial erythema, pleuritis, carditis, nephropathy and cytopenia, the diagnosis of systemic lupus erythematosus (SLE) was established. She did not have abdominal pain, but abdominal ultrasonography and CT scan demonstrated acute acalculous cholecystitis (AAC) due to SLE. AAC was improved with glucocorticoid therapy. Case 2. A 26-year-old female with cytopenia, anti ds-DNA antibody, low complements, nephropathy and pleuritis, the diagnosis of SLE was established. She was hospitalized due to epigastralgia and high fever, abdominal ultrasonography and CT scan demonstrated pericholecystic edoema without gallstones. AAC was diagnosed and which was thought to be developed in accordance with active SLE. Reports of AAC in patients with SLE are rare and it sometimes difficult to diagnose because the findings of abdominal symptoms or immunological abnormalities are not specific. Because of the high risk of morbidity, surgical intervention remains as mainstay ...

In this article, we implemented a regression model and conducted experiments for predicting disease activity using data from 1929 rheumatoid arthritis patients to assist in the selection of biologics for rheumatoid arthritis. On modelling, the missing variables in the data were completed by three different methods, mean value, self-organizing map and random value. Experimental results showed that the prediction error of the regression model was large regardless of the missing completion method, making it difficult to predict the prognosis of rheumatoid arthritis patients.

Chronic Non-bacterial Osteomyelitis (CNO) is an autoinflammatory bone disorder that causes non-bacterial and non-neoplastic osteomyelitis. CNO appeared to the long bone, clavicle, pelvis, and spine on children commonly. This time, we report a case with osteomyelitis of the mandible for the adult-onset. A 25-year-old woman presented pustulosis palmaris/pustular psoriasis after the extraction of the lower right tooth 1 year before hospitalisation. She felt pain and swelling of the right jaw and an antibiotic, NSAIDs, and glucocorticoids were ineffective. The cortical osteotomy of right mandibular bone was carried out 2 months before hospitalisation, but the symptom was not improved and she was admitted to our hospital. For pustular psoriasis with CNO, we treated her with adalimumab and the pain and swelling in her right jaw disappeared immediately. One and two years after the treatment, osteolytic and sclerotic bone lesion and osteomyelitis were improved in both Computed Tomography (CT) and Magnetic Resonance Imaging (MRI). An anti-TNF-α antibody may be an effective therapy for CNO resistant to conventional treatment.

A 30-year-old female patient had been administered 5-mg/day prednisolone for systemic lupus erythematosus. She developed hypertension, dyslipidemia, moon face, central obesity, hypertrichosis, and impaired glucose tolerance. Although iatrogenic Cushing syndrome was initially suspected, we made a diagnosis of Cushing syndrome caused by a right adrenal adenoma, on the basis of the endocrine function test result and imaging findings. After surgery, the Cushingoid signs disappeared. Autoimmune diseases are often treated with corticosteroids; therefore, a differential diagnosis of primary Cushing syndrome should be made adequately.

ObjectivesB cells play an important pathological role in RA. In this study, we investigated the role of metabolic regulator mTOR in B cells and its relevance to the pathology of RA.MethodsPeripheral blood mononuclear cells were isolated from 31 normal subjects and 86 RA patients and the gated B cells were assessed for mTOR phosphorylation and chemokine receptor expression. In vitro studies on peripheral blood B cells isolated from the control and RA patients investigated the molecular mechanisms.ResultsHigher concentrations of CXCL10 (CXCR3 ligands) and lower percentages of CXCR3+ memory B cells were present in the peripheral blood of RA patients relative to the control. RA patients with high CXCL10 concentrations had smaller percentage of CXCR3+ memory B cells and high disease activity. One-year treatment with TNF inhibitors increased the percentage of CXCR3+ memory B cells and reduced serum CXCL10 concentrations. mTOR phosphorylation in B cells was further enhanced in RA patients, compared with the control, and was selectively enhanced in CXCR3+ memory B cells. mTOR phosphorylation in CXCR3+ memory B cells correlated with disease activity. In vitro, mTOR phosphorylation in B cells enhanced IL-6 production and increased RANKL expression.ConclusionmTOR activation in CXCR3+ memory B cells of RA patients is associated with disease activity, mediated through IL-6 production and RANKL expression. The obtained results also suggest that TNF inhibitors mediate an impact on the association between CXCL10 and mTOR activated CXCR3+ memory B cells.

Objective To describe the clinicopathological characteristics of lymphoproliferative disorders (LPDs) in patients with rheumatoid arthritis (RA). Methods In this multicenter case series, we retrospectively reviewed the medical records of RA patients who were newly diagnosed as having LPDs with or without biopsy confirmation between 2000 and 2017 in eight hospitals in Japan. Results We included 232 patients with LPDs. The median age was 67 years (interquartile range [IQR], 60–73 years), and 77.1% were female. At the time of LPD diagnosis, 94.8% and 62.6% of the patients were methotrexate users and in remission or had low RA disease activity, respectively; lymphadenopathy and extranodal involvement were present in 77.1% and 51.9%, respectively. Major extranodal sites were the lungs and oral/oropharyngeal mucosa. The most common LPD pathological subtype was diffuse large B-cell lymphoma (40.5%), followed by classic Hodgkin lymphoma (10.8%), Epstein–Barr virus-positive mucocutaneous ulcer (7.7%), and reactive lymphoid hyperplasia (6.2%). The clinical and laboratory characteristics varied across the pathological subtypes. Conclusion LPD occurred mainly in methotrexate users, while RA disease activity did not seem to be associated with LPD development. Although the clinical manifestations vary among pathological subtypes, manifestations of LPD in patients with RA can include lymphadenopathy, extranodal mass, and mucocutaneous ulcer.

Background Difficult-to-treat rheumatoid arthritis (dt-RA) is an emerging concept, the definition of which has been proposed based on global consensus. This study aimed to establish an evidence-based definition of dt-RA with respect to responsiveness to newly used biologic and targeted synthetic disease-modifying anti-rheumatic drugs (b/tsDMARDs). Methods A retrospective cohort study was conducted using the FIRST registry. An inadequate response to current b/tsDMARDs was defined as clinical disease activity index (CDAI) >10 at week 22 or termination of treatment within 22 weeks due to insufficient efficacy. Cut-off values were defined according to the number of past failures to DMARDs and dose of glucocorticoid. Responsiveness to newly used b/tsDMARDs were compared with respect to above- versus below- cut-off values. Hazards of treatment cessation within 22 weeks due to adverse events were also compared using the same thresholds. Results The cut-off values associated with significant differences in responsiveness to b/tsDMARD treatment were ≥ 2 failures to conventional synthetic DMARD (csDMARD) treatment and ≥ 4 failures to b/tsDMARD treatment. Three or more failures to csDMARDs and concomitant use of glucocorticoid were significantly correlated with an increased hazard ratio of infection. Further analysis using clinical variables revealed that refractoriness to ≥ 2 previous csDMARDs was weakly associated with less improvement in ESR titre, while refractoriness to ≥ 4 previous b/tsDMARDs was associated with less improvement in HAQ. For both cut-offs, significant but weak association with GH was also observed. Conclusions We propose cut-off values of ≥ 2 failures to csDMARDs and/or ≥ 4 b/tsDMARDs to define dt-RA with respect to responsiveness to use of b/tsDMARDs.

We herein report a 65-year-old man with elevated serum IgG4 levels, enlarged thyroid, and renal dysfunction, mimicking IgG4-related disease (IgG4-RD). The definitive diagnosis of IgG4-RD was not established because a tissue biopsy revealed no IgG4-positive cell infiltration or fibrosis. The presence of an M peak in the β fraction, Bence Jones protein in urine, and progressive anemia suggested multiple myeloma (MM). The κ/λ ratio was >100, tumor plasma cells were present at >20% in bone marrow, and immunostaining revealed IgG4-positive plasma cells; therefore, he was diagnosed with IgG4-type MM. Patients with elevated IgG4 levels with no significant mass lesions should undergo systemic examinations to exclude malignancy.

Objectives B cell depletion by rituximab (RTX) is an effective treatment for anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV). However, peripheral B cell phenotypes and the selection criteria for RTX therapy in AAV remain unclear. Methods Phenotypic characterization of circulating B cells was performed by 8-color flow cytometric analysis in 54 newly diagnosed AAV patients (20 granulomatosis with polyangiitis and 34 microscopic polyangiitis). Patients were considered eligible to receive intravenous cyclophosphamide pulse (IV-CY) or RTX. All patients also received high-dose glucocorticoids (GC). We assessed circulating B cell phenotypes and evaluated the efficacy after 6 months of treatment. Results There were no significant differences in the rate of clinical improvement, relapses, or serious adverse events between patients receiving RTX and IV-CY. The rate of Birmingham Vasculitis Activity Score (BVAS) improvement at 6 months tended to be higher in the RTX group than in the IV-CY group. The proportion of effector or class-switched memory B cells increased in 24 out of 54 patients (44%). The proportions of peripheral T and B cell phenotypes did not correlate with BVAS at baseline. However, among peripheral B cells, the proportion of class-switched memory B cells negatively correlated with the rate of improvement in BVAS at 6 months after treatment initiation (r = − 0.28, p = 0.04). Patients with excessive B cell differentiation were defined as those in whom the proportion of class-switched memory B cells or IgD−CD27− B cells among all B cells was > 2 SDs higher than the mean in the HCs. The rate of BVAS remission in patients with excessive B cell differentiation was significantly lower than that in patients without. In patients with excessive B cell differentiation, the survival rate, the rate of BVAS-remission, and dose reduction of GC were significantly improved in the RTX group compared to those in the IV-CY group after 6 months of treatment. Conclusions The presence of excessive B cell differentiation was associated with treatment resistance. However, in patients with circulating B cell abnormality, RTX was effective and increased survival compared to IV-CY. The results suggest that multi-color flow cytometry may be useful to determine the selection criteria for RTX therapy in AAV patients.

Background. The effectiveness and safety of biological disease-modifying antirheumatic drugs (bDMARDs) by age group (Methods. Data of patients who were treated with tumor necrosis factor inhibitors (TNFi), abatacept (ABA), and tocilizumab (TCZ) between February 2011 and April 2017 were retrospectively collected from an observational registry of RA patients. A total of 1,362 patients were enrolled, of which 695 were aged Results. In patients aged versus TCZ, p = 0.017; TNFi versus TCZ, p = 0.002). In patients aged 65–74 years, three-year retention rates of TNFi, ABA, and TCZ were 44%, 53%, and 60%, respectively (TCZ versus TNFi, p = 0.034). In patients aged ≥75 years, three-year retention rates for TNFi, ABA, and TCZ were 38%, 63%, and 58%, respectively (ABA versus TNFi, p = 0.017).Conclusions. We found that the effectiveness and safety of TCZ were maximized in patients aged

Background The effectiveness and safety of biological disease-modifying antirheumatic drugs (bDMARDs) by age group ( Methods Data of patients who were treated with tumor necrosis factor inhibitors (TNFi), abatacept (ABA), and tocilizumab (TCZ) between February 2011 and April 2017 were collected from a prospective observational registry of RA patients. A total of 1362 patients were enrolled, of which 695 were aged Results In patients aged p = 0.017; TNFi versus TCZ, p = 0.002). In patients aged 65–74 years, 3-year retention rates of TNFi, ABA, and TCZ were 44%, 53%, and 60%, respectively (TCZ versus TNFi, p = 0.034). In patients aged ≥ 75 years, 3-year retention rates for TNFi, ABA, and TCZ were 38%, 63%, and 58%, respectively (ABA versus TNFi, p = 0.017). Conclusions We found that the effectiveness and safety of TCZ were maximal in patients aged

To update and revise the diagnostic criteria for mixed connective tissue disease (MCTD) issued by the Japan Research Committee of the Ministry of Health, Labor, and Welfare (MHLW), a round table discussion by experts from rheumatology, dermatology, and pediatric medicine was conducted in multiple occasions.The definition of MCTD, and items included in the diagnostic criteria were generated by consensus method and evaluation using clinical data of typical and borderline cases of MCTD, by applying to the diagnostic criteria for MCTD proposed in 1996 and 2004 by the Research Committee of MHLW.To the end, all committee members reached consensus. Then, the criteria were assessed in an independent validation cohort and tested against preexisting criteria. The revised criteria facilitate an understanding of the overall picture of this disease by describing the concept of MCTD, common manifestations, immunological manifestation and characteristic organ involvement. Conditions with characteristic organ involvement include pulmonary arterial hypertension, aseptic meningitis and trigeminal neuropathy. Even if the overlapping manifestations are absent, MCTD can be diagnosed based on the presence of the characteristic organ involvement. Furthermore, the criteria were validated for applicability in actual clinical cases, and public comments were solicited from the Japan College of Rheumatology and other associated societies.After being reviewed through public comments, the revised diagnostic criteria have been finalized.

An 81-year-old man was admitted with bilateral pleural effusion. A clinical examination showed lymphocytic pleura effusion and elevated serum IgG4 levels, so that IgG4-related disease was suggested, whereas tuberculous pleurisy was suspected because of high adenosine deaminase (ADA) levels in the pleural effusion. A surgical pleural biopsy revealed that there were large numbers of IgG4-positive cells and IgG4/IgG positive cell ratio exceeded 40% in several sites. Accordingly, we diagnosed IgG4-related pleuritis and treated with the patient with glucocorticoid therapy. The ADA levels in pleural effusion can increase in IgG4-related pleuritis, and it is therefore important to perform a pleural biopsy.

The aim of this study was to compare the clinical outcome of patients with rheumatoid arthritis seen in routine clinical practice treated with either TNF inhibitors or abatacept. To overcome potential bias, both propensity score matching and Inverse Probability of Treatment Weighting were used for patient selection. The propensity score matching procedure selected 315 matched pairs of patients who were treated with TNF inhibitors or abatacept. At week 52, SDAI in TNF inhibitors was lower than abatacept. In contrast, analysis of biologics-naive patients using the propensity-score matching (n = 150; in each group) showed comparable clinical efficacy. Consistent results were obtained by the use of Inverse Probability of Treatment Weighting (581 patients treated with TNF inhibitors and 353 patients treated with abatacept). The predictors of response to each treatment were different; abatacept appeared to benefit patients with high baseline RF titers while TNF inhibitors appeared to benefit patients with low baseline HAQ-DI.