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A novel patient cluster in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) may be identified in Japan. We performed multiple correspondence and cluster analysis regarding 427 clinically diagnosed AAV patients excluding eosinophilic granulomatosis with polyangiitis. Model 1 included the ANCA phenotype, items of the Birmingham Vasculitis Activity Score, and interstitial lung disease; model 2 included serum creatinine (s-Cr) and C-reactive protein (CRP) levels with model 1 components. In seven clusters determined in model 1, the ANCA-negative (n = 8) and proteinase 3-ANCA-positive (n = 41) groups emerged as two distinct clusters. The other five myeloperoxidase-ANCA-positive clusters were characterized by ear, nose, and throat (ENT) (n = 47); cutaneous (n = 36); renal (n = 256), non-renal (n = 33); and both ENT and cutaneous symptoms (n = 6). Four clusters in model 2 were characterized by myeloperoxidase-ANCA negativity (n = 42), without s-Cr elevation ( 10 mg/dL) (n = 71), or s-Cr elevation (≥ 1.3 mg/dL) without high CRP (≤ 10 mg/dL) (n = 157). Overall, renal, and relapse-free survival rates were significantly different across the four clusters in model 2. ENT, cutaneous, and renal symptoms may be useful in characterization of Japanese AAV patients with myeloperoxidase-ANCA. The combination of s-Cr and CRP levels may be predictive of prognosis.

BackgroundEffective prognostic markers are needed for antineutrophil cytoplasmic antibody-associated vasculitis (AAV). This study evaluated the clinical associations of serum vascular endothelial growth factor-A (sVEGF-A) and sVEGF-A165b (an antiangiogenic isoform of VEGF-A) concentrations with time to remission of AAV in a nationwide Japanese prospective follow-up cohort.MethodsWe collected samples from patients with AAV who were enrolled in the nationwide Japanese cohort study (RemIT-JAV-RPGN). We measured sVEGF-A and sVEGF-A165b concentrations using enzyme-linked immunosorbent assays in 57 serum samples collected 6 months before and after initiation of AAV treatment. Patients were classified based on AAV disease subtypes: microscopic polyangiitis, granulomatosis with polyangiitis and eosinophilic granulomatosis with polyangiitis (EGPA).ResultsResults revealed significant reductions in sVEGF-A and sVEGF-A165b concentrations in patients with microscopic polyangiitis and EGPA, respectively. However, despite the comparable concentrations of sVEGF-A and sVEGF-A165b during the 6 months of treatment in granulomatosis with polyangiitis patients, correlation analysis revealed that the differences in log2-transformed concentrations of sVEGF-A and sVEGF-A165b were inversely correlated with time to remission in granulomatosis with polyangiitis patients.ConclusionThese results suggest that sVEGF-A and -A165b can serve as potential markers of time to remission in patients with granulomatosis with polyangiitis.

Objective To investigate the long-term efficacy and safety of the IL-6 receptor antibody tocilizumab in patients with Takayasu arteritis (TAK). Methods Patients completing the randomized, double-blind, placebo-controlled period of the TAKT (Takayasu arteritis Treated with Tocilizumab) trial were followed up during open-label extended treatment with weekly s.c. tocilizumab 162 mg for up to 96 weeks or longer, with oral glucocorticoid tapering performed at the investigators’ discretion. Endpoints of the extension analysis included steroid-sparing effects of tocilizumab, imaging data, patient-reported outcomes (36-Item Short Form Health Survey) and safety. Results All 36 patients enrolled in the double-blind period entered the open-label extension; 28 patients received tocilizumab for 96 weeks. The median glucocorticoid dose was 0.223 mg/kg/day at the time of relapse before study entry, 0.131 mg/kg/day (interquartile range 0.099, 0.207) after 48 weeks and 0.105 mg/kg/day (interquartile range 0.039, 0.153) after 96 weeks. Overall, 46.4% of patients reduced their dose to Conclusion These results in patients with Takayasu arteritis provide evidence of a steroid-sparing effect and improvements in well-being during long-term treatment with once-weekly tocilizumab 162 mg, with no new safety concerns. Trial registration JAPIC Clinical Trials Information, http://www.clinicaltrials.jp/user/cteSearch_e.jsp, JapicCTI-142616.

Objective Interstitial pneumonia is common and has high short-term mortality in patients with PM and DM despite glucocorticoid (GC) treatment. Retrospective studies suggested that the early use of immunosuppressive drugs with GCs might improve its short-term mortality. Methods A multicentre, single-arm, 52-week-long clinical trial was performed to test whether the initial combination treatment with tacrolimus (0.075 mg/kg/day, adjusted for the target whole-blood trough levels between 5 and 10 ng/ml) and GCs (0.6–1.0 mg/kg/day of prednisolone followed by a slow taper) improves short-term mortality of PM/DM-interstitial pneumonia patients. The primary outcome was overall survival. We originally intended to compare, by using propensity-score matching, the outcome data of clinical trial patients with that of historical control patients who were initially treated with GCs alone. Results The 52-week survival rate with the combination treatment (N = 26) was 88.0% (95% CI, 67.3, 96.0). Safety profiles of the combination treatment were consistent with those known for tacrolimus and high-dose GCs individually. Serious adverse events occurred in 11 patients (44.0%), which included four opportunistic infections. Only 16 patients, including only 1 deceased patient, were registered as historical controls, which precluded meaningful comparative analysis against the clinical trial patients. Conclusion Our study provided findings which suggest that initial treatment with tacrolimus and GCs may improve short-term mortality of PM/DM-interstitial pneumonia patients with manageable safety profiles. This was the first prospective clinical investigation conducted according to the Good Clinical Practice Guideline of the International Conference on Harmonization for the treatment of this potentially life-threatening disease. Trial registration ClinicalTrials.gov, http://clinicaltrials.gov, NCT00504348.

Objectives: To investigate the safety, effectiveness, and risk-benefit balance of intravenous abatacept (ABA) in non-elderly (

Using an expert- and data-driven methodology, we have constructed the first clinical practice guidelines (CPGs) for adult Still's disease (ASD) after complete systematic review (SR) of the literature based upon the Medical Information Network Distribution Service (Minds) procedure.The CPG committee for ASD organized by the Research Team for Autoimmune Diseases, the Research Program for Intractable Disease of the Japanese Ministry of Health, Labour, and Welfare has developed CPG for ASD 2017, according to the procedure proposed by Minds. The CPG development process includes (1) clarification of the purpose of CPG, (2) organization of the steering committee, (3) organization of the CPG committee and secretariat, (4) defining the scope (setting of clinical questions (CQs)), (5) SR, (6) development of recommendations, (7) drafting the CPG, (8) external evaluation and public comments, and (9) release. Because we wanted to construct CPG for ASD to encompass both adult-onset Still's disease (AOSD) and adult patients with systemic juvenile idiopathic arthritis (sJIA), we also included SR data from sJIA in this study.Twenty-six CQs were selected and roughly divided into the following items: (1) clinical findings (CQs 1-4), (2) laboratory findings (CQs 5-8), (3) complications (CQs 9-13), (4) treatment with oral medicine (CQs 14-19), (5) treatment with biological reagents (CQs 20-23), and (6) treatments for sJIA (CQs 25-26). Recommendations and the strength of the recommendations for these CQs were decided by a modified Delphi method.We have developed the first published CPG for ASD including AOSD and sJIA, which includes 26 CQs and recommendations. This guideline will help rheumatologists, non-specialized physicians, other healthcare providers, medical and health-related students, and patients and their family members to understand and treat ASD.

To evaluate the performance of the 2012 Systemic Lupus International Collaborating Clinics criteria (SLICC-12) on classifying systemic lupus erythematosus (SLE) in an uncontrolled multi-centered study with real-life scenario of the patients in Japan.This study comprised 495 patients with SLE or non-SLE rheumatic diseases and allied conditions from 12 institutes in Japan. Chart review of each patient was performed by the 27 expert rheumatologists and diagnosis of 487 cases reached to the consensus. Value of the SLICC-12 on SLE classification was analyzed comparing with the 1997 revised American College of Rheumatology SLE classification criteria (ACR-97) employing the expert-consented diagnoses.Compared to the ACR-97, the SLICC-12 had a higher sensitivity (ACR-97 vs. SLICC-12: 0.88 vs. 0.99, p .01) and comparable specificity (0.85 vs. 0.80). The rate of misclassification (0.14 vs. 0.11) or the area under the receiver operating characteristic curves (0.863 vs. 0.894) was not statistically different. In the cases that diagnoses corresponded in high rates among experts, both criteria showed high accordance of SLE classification over 85% with the expert diagnoses.Although employment of SLICC-12 for the classification for SLE should be carefully considered, the SLICC-12 showed the higher sensitivity on classifying SLE in Japanese population.

A 69-year-old woman was admitted to our hospital due to a two-week history of low-grade fever, dry cough and erythematous eruptions. Physical examination revealed facial erythema, Gottron’s papules...

Objective The objective of this study was to confirm the efficacy of low-dose mizoribine (MZR), an inhibitor of inosine monophosphate dehydrogenase, as part of synchronized methotrexate (MTX) therapy for rheumatoid arthritis (RA) patients with an inadequate response to various combination therapies of MTX, other synthetic disease-modifying anti-rheumatic drugs (DMARDs) and biological DMARDs. Methods Low-dose MZR was administered to 56 uncontrolled RA patients being treated with MTX and various biological DMARDs. The observation period was 12 months, and the disease activity was evaluated based on the Disease Activity Score in 28 joints (DAS28)-ESR, Simplified Disease Activity Index (SDAI) and serum MMP-3 level. Results All of the disease activity indices were significantly improved within three months, and the serum MMP-3 levels were also significantly decreased around four months after starting low-dose MZR therapy. No patients experienced any adverse effects. Conclusion The present preliminary findings suggest that low-dose MZR therapy with MTX should be considered for the treatment of RA patients with an inadequate response to various combination therapies including MTX, other synthetic DMARDs and biological DMARDs or in whom increasing the dose of MTX is difficult for reasons such as adverse effects and complications.

Background The detection of leukocyte-derived CD11b (α subunit of integrin Mac-1) and CD163 (scavenger receptor) in urine may reflect renal inflammation in antineutrophil cytoplasmic antibody-associated glomerulonephritis (ANCA-GN). The objective of this study was to evaluate the clinical significance of urinary CD11b (U-CD11b) and CD163 (U-CD163) in ANCA-GN. Methods U-CD11b and U-CD163 were examined using enzyme-linked immunosorbent assay in ANCA-GN urine samples from our institutional cohort (n = 88) and a nationwide cohort (n = 138), and their association with renal histology was subsequently analyzed. Logistic regression analyses were performed on a nationwide ANCA cohort to determine the associations of the two urinary molecules with renal remission failure at 6 months or with yearly estimated glomerular filtration rate (eGFR) slope over a 24-month observation period. Results U-CD11b and U-CD163 were significantly associated with cellular crescent formation and leukocyte accumulation in glomerular crescents. With regard to interstitial inflammation, both levels of U-CD11b and U-CD163 at diagnosis remarkably increased in ANCA-GN compared with the levels observed in nonglomerular kidney disorders including nephrosclerosis, immunoglobulin G4-related disease and tubulointerstitial nephritis; however, the presence of U-CD11b alone was significantly correlated with tubulointerstitial leukocyte infiltrates. Although neither U-CD11b nor U-CD163 at diagnosis was associated with remission failure at 6 months, multivariate analysis demonstrated that the baseline U-CD11b levels were significantly associated with the increase in eGFR following immunosuppressive therapy. Conclusions Although both U-CD11b and U-CD163 reflect renal leukocyte accumulation, U-CD11b at diagnosis provides additional clinical value by predicting the recovery rate after the treatment of ANCA-GN.

The study aims to confirm the feasibility of new oral triple combination therapy using methotrexate (MTX), mizoribine (MZR), and tacrolimus (TAC) in patients with rheumatoid arthritis (RA) by in vitro and clinical analyses. Triple therapy with a combination of MTX, MZR, and TAC was used for an in vitro study with osteoclasts and a prospective clinical study in order to show the efficacy of these agents against refractory RA. In particular, low-dose TAC or MZR was added to treat 14 patients with RA that was resistant to MTX + MZR or MTX + TAC dual therapy. The combination of three pharmacological agents showed statistically significant differences to reduce differentiation induction and activity of osteoclasts compared with single and double agents. In clinical use, triple therapy showed a statistically significant difference in the improvement of Disease Activity Score-28-erythrocyte sedimentation rate and the Simple Disease Activity Index score at around 8 months. Additionally, the serum matrix metalloproteinase-3 level significantly decreased. No patients dropped out because of adverse effects. Based on this in vitro and prospective clinical study, oral triple therapy might be effective against refractory RA. Furthermore, this therapy might be safe and economical for clinical practice.

Rheumatoid arthritis (RA) is a systemic inflammatory disease in which the predominant symptom is polyarthritis that follows a chronic and progressive clinical course characterized by destructive synovitis and various immune disorders. Striking progress in RA treatment was achieved with the emergence of monoclonal antibodies to target cytokines. However, drug choices are limited for many patients due to resistance to multidrug antirheumatic therapy, concomitant disease, and infection. We evaluated the efficacy of treatment in 85 patients with RA for whom leukocytapheresis (LCAP) was initiated at our hospital between 2006 and 2015. All patients continued drug therapy and were treated with LCAP once a week for up to 5 weeks. The clinical response was evaluated at the completion of LCAP series and 4 weeks later using the American College of Rheumatology (ACR) criteria and the 28-joint disease activity score (DAS28) of European League Against Rheumatism (EULAR). The tender joint counts, swollen joint counts, and C-reactive protein (CRP) levels decreased remarkably. DAS28-CRP was significantly improved by LCAP. And furthermore, the efficacy lasted at least 4 weeks after the completion of LCAP. These results suggest that LCAP is a beneficial and are consistent with several trials' reported effect of LCAP. This treatment can contribute to improvements in activities of daily living (ADLs) and long-term outcome by improving swollen and tender joint counts and CRP levels even in refractory patients for whom the use of conventional disease-modifying antirheumatic drugs (DMARDs) and biopharmaceuticals is problematic. LCAP might be a promise therapy to refractory RA.

To clarify the mechanisms underlying lupus nephritis (LN) amelioration following bortezomib treatment.Bortezomib was administered subcutaneously every 3 days to NZB/W F1 mice, and the serum anti-double stranded (ds) deoxyribonucleic acid (DNA) antibody titers and proteinuria levels were measured. The renal samples and the splenocytes were examined histologically or used for real-time quantitative reverse transcription-polymerase chain reaction analysis after 18 weeks of treatment. Serum cytokine and anti-dsDNA antibody levels were measured using flow cytometry and enzyme-linked immunoassays every 3 weeks. Transforming growth factor (TGF)-β, angiotensin II type-1 receptor (AT1R), and type I collagen expression levels in the glomeruli were evaluated using immunohistochemistry.Bortezomib reduced the serum anti-dsDNA antibody titers and the proteinuria levels. It prevented inflammatory cell infiltrations into and the deposition of immunoglobulin G within the glomeruli. Bortezomib reduced the interferon-γ, interleukin (IL)-4, and IL-10 levels in the serum and the ribonucleic acid expression levels for these cytokines within the splenocytes. Bortezomib prevented type I collagen synthesis by downregulating TGF-β and AT1R expression in the glomeruli.Bortezomib exerts multiple immunosuppressive effects and thus ameliorates LN. Furthermore, bortezomib can prevent glomerulosclerosis formation in NZB/W F1 mice through suppressive effects on the renin-angiotensin system.

Objectives: To determine which grade of ultrasound (US) synovitis corresponds to clinically involved joints in rheumatoid arthritis (RA) and develops a new US-adjusted composite measure. Methods: Clinical and US examinations were performed on 137 patients with RA (28 joints). Synovial effusion, hypertrophy, and blood flow were semiquantitatively graded from 0 to 3 using gray scale (GS) and power Doppler (PD) modes. We calculated US-adjusted simple disease activity index (SDAI) and assessed feasibility, and external validity by comparing with erythrocyte sedimentation rate (ESR), and modified health assessment questionnaires (MHAQ). Results: GS ≥2 and PD ≥0 corresponds to clinically swollen joints, and GS ≥2 and PD ≥1 corresponds to tender joints. The US-adjusted SDAI showed the highest correlation when US-determined swollen joints were defined as PD ≥2 with ESR, and GS ≥3 and PD ≥2 with MHAQ. A feasible US-adjusted SDAI examining only clinically involved joints still showed a higher correlation with ESR and MHAQ than SDAI. Conclusion: Our composite measure complemented by US only for clinically involved joints is feasible and reliable for monitoring disease activity.

OBJECTIVE: To compare disease severity classification systems for six-month outcome prediction in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). METHODS: Patients with newly diagnosed AAV from 53 tertiary institutions were enrolled. Six-month remission, overall survival, and end-stage renal disease (ESRD)-free survival were evaluated. RESULTS: According to the European Vasculitis Study Group (EUVAS)-defined disease severity, the 321 enrolled patients were classified as follows: 14, localized; 71, early systemic; 170, generalized; and 66, severe disease. According to the rapidly progressive glomerulonephritis (RPGN) clinical grading system, the patients were divided as follows: 60, grade I; 178, grade II; 66, grade III; and 12, grade IV. According to the Five-Factor Score (FFS) 2009, 103, 109, and 109 patients had ≤1, 2, and ≥3 points, respectively. No significant difference in remission rates was found in any severity classification. The overall and ESRD-free survival rates significantly differed between grades I/II, III, and IV, regardless of renal involvement. Severe disease was a good predictor of six-month overall and ESRD-free survival. The FFS 2009 was useful to predict six-month ESRD-free survival but not overall survival. CONCLUSIONS: The RPGN grading system was more useful to predict six-month overall and ESRD-free survival than the EUVAS-defined severity or FFS 2009.

Previous reports indicate that serum anti-microtubule-associated protein 2 (MAP-2) antibodies are common in sera from patients with neuropsychiatric systemic lupus erythematosus (NPSLE). Differential diagnosis of NPSLE is occasionally difficult because of differential diagnosis which can mimic NPSLE. Therefore, specific biomarkers for NPSLE are needed. We conducted this study to clarify whether cerebrospinal fluid (CSF) anti-MAP-2 antibodies are a useful diagnostic biomarker for NPSLE.Enzyme-linked immunosorbent assay was conducted to measure CSF concentrations of anti-MAP-2 and anti-ribosomal P antibodies and of IL-6 in NPSLE patients (n = 24) and non-NPSLE controls (n = 17). The non-NPSLE controls consisted of systemic lupus erythematosus patients with neuropsychiatric symptoms caused by non-NPSLE conditions (n = 10) and patients with other connective tissue diseases (n = 7).Significantly higher anti-MAP-2 antibody titers were found in the CSF of patients with NPSLE versus non-NPSLE controls. The prevalence of anti-MAP-2 antibodies was 33.3% (8/24) in NPSLE patients when a positive cutoff value was 3 standard deviations above the mean optical density of non-NPSLE controls. None of the controls had anti-MAP-2 antibodies in their CSF. Both anti-ribosomal P antibody titers and concentration of IL-6 in the CSF were significantly higher in patients with NPSLE having anti-MAP-2 antibodies than in patients with non-NPSLE controls.Anti-MAP-2 antibodies could be detected in the CSF of 33.3% of patients with NPSLE, and its presence was highly specific for NPSLE. We propose that CSF anti-MAP-2 antibodies are a novel and useful diagnostic biomarker for NPSLE.

Objective: To perform a postmarketing surveillance study evaluating the safety and effectiveness of abatacept in Japanese patients with rheumatoid arthritis (RA). Methods: Safety and effectiveness data were collected for all RA patients (at 772 sites) treated with intravenous abatacept between September 2010 and June 2011. Patients were treated by the approved dosing regimen according to the package insert. Treatment effectiveness was evaluated at baseline and at weeks 4, 12, and 24 using Disease Activity Score 28 (DAS28) according to erythrocyte sedimentation rate or serum C-reactive protein concentrations. Results: Overall, 3882 and 3016 abatacept-naïve RA patients were included in safety and effectiveness analyses, respectively. Adverse drug reactions (ADRs) were reported for 15.66% of patients and serious ADRs were detected for 2.52% of patients. The incidence of serious infections was 1.03% and these were mainly attributed to different types of bacterial pneumonia. Disease activity improved significantly over 6 months. Separate multivariate analysis identified predictors of severe ADR, and severe infections and factors predictive of clinically meaningful DAS28 improvement after 6 months of treatment with abatacept. Conclusions: Abatacept was efficacious and well tolerated in a clinical setting. No new safety concerns were detected.

Background:Systemic lupus erythematosus (SLE) is a chronic autoimmune disease of unknown etiology that affects mostly young women. Multiorgan complications and prolonged treatment significantly cause physical and mental stress in patients. Improving patients’ quality of life (QOL) in SLE treatment is essential. We examined the treatment effects on disease activity and QOL of SLE patients.Objectives:In recent years, lupus low disease activity state (LLDAS) has been proposed as a treatment target for SLE. Patients who achieve LLDAS have a low recurrence rate for lupus and a low risk of serious complications (1). The aim of this study is to investigate whether achieving LLDAS reduces not only recurrence rate and complications of SLE but also improves patients’ QOL.Methods:A total of 104 SLE patients were enrolled in our prospective SLE registry study (Juntendo, Multi-center, Prospective cohort for investigation of clinical course and outcome in SLE: JUMP) conducted at our institution. SLE was diagnosed using the American College of Rheumatology (ACR) 1982 criteria (revised in 1997). QOL was evaluated using the standard version of the 36-item short form health survey version 2 (SF36v2). Participants were divided into the LLDAS achievement and non-achievement groups, and the characteristics of each group including results of SF36v2 were examined.Results:This study included 104 SLE patients, 94 female and 10 male, and the average age and disease duration were 46.4±13.8 and 14.5±11.3 years, respectively. The average corticosteroid dose was 8.0±17.4 mg/day in terms of prednisolone, and anti-dsDNA antibody titer was 16.8±38.5 IU/ml. Of the 104 patients, 57 achieved LLDAS. The subscale’s standard scoring using SF36v2 for role physical (RP) was 78.9±24.0 and 64.6±27.6 (P50. However, in the LLDAS non-achievement group, all categories were Conclusion:Results of examining the association between LLDAS and QOL using SF36v2 in SLE patients showed that patients who achieved LLDAS had significantly better standard statistical scores in many subscale categories. Thus, LLDAS achievement as a treatment target for SLE patients greatly contributes to improving patients’ QOL.References:[1]Franklyn K, et al. Definition and initial validation of a Lupus Low Disease Activity State (LLDAS).Ann Rheum Dis. 2016 Sep;75(9):1615-21.Disclosure of Interests:None declared

Objectives: We evaluated the long-term (52 weeks) safety and effectiveness of iguratimod (IGU) in patients with rheumatoid arthritis (RA). Methods: This multicenter, prospective, observational study included all evaluable RA patients who received IGU since its market launch in 2012. We evaluated adverse events (AEs); adverse drug reactions (ADRs); ADRs of special interest, including liver and renal dysfunctions, interstitial lung disease, gastrointestinal and blood disorders, and infection; and change in Disease Activity Score 28-C-reactive protein (DAS28-CRP) at week 52. Results: Safety and effectiveness were analyzed in 2666 and 1614 patients, respectively. The incidences of AEs, serious AEs, ADRs, and serious ADRs were 46.92, 7.35, 38.26, and 4.58%, respectively. The incidence of ADRs peaked at approximately 4 weeks of treatment. Subsequently, the ADR incidence did not increase over time. Improvement of RA activity was shown up to week 52. Conclusion: Long-term treatment with IGU in patients with RA resulted in a tolerable safety profile and an improvement in RA activity. IGU could be considered a useful treatment option for patients with RA. Trial registration:ClinicalTrials.gov identifier: NCT01850966.

We previously reported the importance of connective tissue growth factor (CTGF) in rheumatoid arthritis (RA). CTGF contains four distinct modules connected in tandem, namely insulin-like growth factor-binding protein (IGFBP)-like, von Willebrand factor (vWF) type C repeat, thrombospondin type 1 (TSP-1) repeat, and carboxyl-terminal (CT) modules. The relationships between each of these modules of CTGF and RA remain unknown. Here, we analyzed how inhibition of each CTGF module affects the pathophysiology of RA. We conducted stimulation and suppression experiments on synovial cells (MH7A) obtained from patients with RA. Moreover, we examined angiogenesis by means of a tube-formation assay performed using human umbilical vein endothelial cells (HUVECs), and we used tartrate-resistant acid phosphatase (TRAP) staining to analyze osteoclastogenesis. Our results showed that M-CSF/RANKL-mediated osteoclastogenesis was enhanced when CTGF was added, but the effect of CTGF was neutralized by mAbs against CTGF modules 1-4. Furthermore, CTGF treatment of HUVECs induced formation of tubular networks, which resulted in acceleration of the angiogenesis of RA synoviocytes, and quantification showed that this tubular-network formation was also disrupted by anti-CTGF module 1-4 mAbs. Lastly, TNF-α enhanced the expression of CTGF and matrix metalloproteinase-3 (MMP3) in MH7A cells, and this enhancement was potently neutralized by mAbs against CTGF modules 1, 3 and 4. Thus, our results indicate that not only a mAb against CTGF but also mAbs against each specific module of CTGF might serve as potential therapeutic agents in the treatment of RA.

Objectives: This 12-week, randomized, double-blind, placebo-controlled, multicenter phase 1/2 study (NCT01449071) assessed the safety, pharmacokinetics, and pharmacodynamics of epratuzumab in Japanese patients with moderate-to-severe systemic lupus erythematosus despite standard of care.Methods: Twenty patients were randomized 1:1:1:1:1 to placebo or one of four epratuzumab dose regimens (100 mg every other week [Q2W], 400 mg Q2W, 600 mg every week [QW], or 1200 mg Q2W) administered during an initial 4-week dosing period. Adverse events (AEs), pharmacokinetics and pharmacodynamics were assessed.Results: Nineteen of 20 patients completed the study. All placebo patients and 13 of 16 epratuzumab patients reported ≥1 AE, 2 of 16 epratuzumab patients reported a serious AE. Cmax and AUCτ increased proportionally with dose after first and last infusion, t1/2 was similar across groups (∼13 days). Epratuzumab treatment was associated with decreased CD22 mean fluorescence intensity in total B cells (CD19+CD22+) and unswitched memory B cells (CD19+IgD+CD27+). Small-to-moderate decreases were observed in total B cell (CD20+) count.Conclusions: Epratuzumab was well-tolerated, with no new safety signals identified. The pharmacokinetics appeared linear after first and last infusions. Treatment with epratuzumab was associated with CD22 downregulation and with small-to-moderate decreases in total B cell count.

Mycophenolate mofetil (MMF) is used as one of the standard induction/maintenance protocols for lupus nephritis (LN). However, MMF has not been approved for treating LN in any country, resulting in worldwide off-label use of this immunosuppressant. In order to clarify the real-world use of MMF as a treatment for LN in Japan, Japan College of Rheumatology surveyed the use of MMF in daily clinical practice.Adult patients with LN who visited enrolled hospitals from October 2008 to September 2013 were surveyed for the initial, maximum, and maintenance doses of MMF. The safety and efficacy of MMF were retrospectively evaluated.One hundred and thirty-seven LN patients including 116 females were enrolled. The median of initial, maximum, and maintenance doses of MMF were 1.0 g/day, 1.5 g/day, and 1.0 g/day, respectively. Sixty-one adverse events were reported in 39 patients during the follow-up period. Median urine protein level decreased from 1.89 g/gCr to 0.21 g/gCr, meanC3 level increased from 66.4 mg/dl to 80.3 mg/dl, and median anti-DNA antibody titer decreased from 40.6 IU/ml to 10.6 IU/ml.MMF was commonly used for the treatment of adult LN patients with acceptable efficacy and safety in Japan.

Connective tissue disease-associated interstitial pneumonia (CTD-IP) significantly affects the mortality of patients with CTD. The purpose of the present study is to identify causes and risk factors for death during hospitalization for immunosuppressive treatment of CTD-IP.A multicenter, retrospective study was conducted that collected data from patients with CTD who had been hospitalized for commencing or intensifying immunosuppressive treatment of CTD-IP using a standardized case report form. Risk factors were identified using the Cox proportional hazard regression model.A total of 322 CTD-IP patients were enrolled with rheumatoid arthritis (n = 84), systemic lupus erythematosus (n = 13), polymyositis (n = 33), dermatomyositis (n = 69), systemic sclerosis (n = 55), mixed connective tissue disease (n = 21), microscopic polyangiitis (n = 19), and overlap syndrome (n = 28). Of the 42 patients who died during hospitalization, 22 died from CTD-IP, 15 from CTD-IP and pulmonary infection, 2 from pulmonary infection, and 3 from other causes. Age ≥ 65 years and development of pulmonary infections after commencing or intensifying immunosuppressive treatments were identified as risk factors for death during hospitalization after adjusting for covariates.Careful consideration of the benefit-risk balance of immunosuppressive treatment for CTD-IP is indispensable for improving the short-term vital prognosis of these patients.

Objective.The aim was to elucidate the prognosis and risk factors associated with relapse during longterm remission maintenance therapy for antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV).Methods.Patients with newly diagnosed AAV (n = 156) were registered in the Remission Induction Therapy in Japanese patients with ANCA-associated Vasculitides (RemIT-JAV) study, and among them, 83 patients who achieved remission were enrolled and followed up for 24 additional months in our nationwide, prospective cohort study (Co-RemIT-JAV; registration number UMIN 000006373). Patterns of maintenance therapy, effectiveness, and safety were evaluated from months 25 to 48 after the RemIT-JAV. The primary outcome measure was the rate of relapse. Secondary outcome measures included overall and renal survival, risk factors associated with relapse, and incidence rates of serious infections.Results.The patients comprised 35 men and 48 women aged 65.3 ± 12.6 years. Between months 25 and 48, the survival rate was 95% (79/83). Causes of death included 1 thyroid cancer, 1 infection, and 2 unknown reasons. Four patients had developed endstage renal disease (ESRD) by Month 24; 1 developed ESRD beyond Month 25. The relapse rate was 24% (20/83) from months 25 to 48. Multivariable analysis revealed that oral prednisolone ≤ 2.5 mg/day at Month 24 was a significant risk factor for relapse between months 25 and 48 (HR = 3.1, 95% CI 1.1–8.5).Conclusion.One-quarter of patients with AAV relapsed during maintenance therapy, and relapse was associated with the dose of oral prednisolone 24 months after the initiation of remission induction therapy in Japan.

Objectives This study aims to analyze the distribution and clinicopathological characteristics of anti-aminoacyl-transfer ribonucleic acid (tRNA) synthetase (ARS) antibodies in rheumatoid arthritis patients. Patients and methods We retrospectively studied the anti-ARS antibody levels in 228 RA patients' (44 males, 184 females; mean age 62.9±14.0 years; range 23 to 88 years) sera from their medical charts. We determined the association with anti-cyclic citrullinated peptide antibody levels, interstitial lung disease (ILD), rheumatoid factor, and methotrexate or biological disease modifying antirheumatic drug treatments. Results Anti-ARS antibodies were detected in 14 RA patients (6.1%). ILD complications were significantly higher among anti-ARS antibody-positive patients (57.1% vs 22.4%, p

Background Mucosal-associated invariant T (MAIT) cells are innate-like lymphocytes that express a semi-invariant TCRα chain (Vα7.2-Jα33 in humans). MAIT cells are restricted by the MHC-related molecule-1 (MR1) and uniquely recognize vitamin B metabolites presented by MR1. Like other innate-like lymphocytes, MAIT cells are also activated by cytokines in the absence of exogenous antigens. Human MAIT cells are abundant and constitute approximately 5% of peripheral blood T cells, suggesting possible roles of MAIT cells in various types of immune responses. Objectives We aimed to investigate whether MAIT cells are involved in systemic lupus erythematous (SLE). Methods Peripheral blood was collected from SLE patients and healthy volunteers. Informed consent was obtained from all individuals according to institutional ethical guidelines. Disease activity was measured based on the SLE disease activity index (SLEDAI) and a SLEDAI score ≥5 was defined as active disease. Peripheral blood mononuclear cells (PBMC) were stained with anti-human monoclonal antibodies against CD3, γδTCR, Vα7.2TCR, CD161, CD95 (Fas) and CD69, and then analyzed by FACS. CD19 + B cells or CD14 + monocytes were isolated from PBMC of healthy controls (HC) or SLE patients by using magnetic cell sorting. MAIT cells from healthy controls were co-cultured with B cells or monocytes in the presence of MR1 ligand (MR1L), and the expression of CD69 on MAIT cells was evaluated by FACS. Cytokine levels in plasma samples and culture supernatants were measured by ELISA and Bioplex assay. PBMC were cultured in the presence of various cytokines, and CD69 expression on MAIT cells was analyzed by FACS. Results The frequency of MAIT cells was markedly reduced in SLE. Reduced numbers of MAIT cells were not attributable to the downregulation of surface markers, but were partially due to the enhanced cell death of MAIT cells, possibly by activation-induced cell death. The CD69 expression levels on MAIT cells in SLE correlated with disease activity. Monocytes from patients with SLE exhibited increased ability to induce MAIT cell activation, and the profound MAIT cell activating capacity of lupus monocytes was associated with enhanced IL-12 production in the culture supernatants. The plasma concentration of IL-6, IL-18 and IFNα positively correlated with the expression levels of CD69 on MAIT cells in SLE. MAIT cells were activated by cytokines including IFNα, IL-15, and IL-12 plus IL-18 in the absence of exogenous antigens. Conclusions These results suggest that MAIT cells reflect the pathological condition of SLE and their activated status correlates with disease activity. References Miyazaki Y, et al. Mucosal-associated invariant T cells regulate Th1 response in multiple sclerosis. Int. Immunol. 2011;23:529–35. Chiba A, et al. Mucosal-associated invariant T cells promote inflammation and exacerbate disease in murine models of arthritis. Arthritis Rheum. 2012; 64:153–61. Hayashi E, et al. Involvement of Mucosal-associated Invariant T cells in Ankylosing Spondylitis. J Rheumatol. 2016; 43: 1695–703. Disclosure of Interest None declared

Background Mucosal-associated invariant T (MAIT) cells are innate-like lymphocytes constituting a large proportion of peripheral blood T cells expressing αβ T-cell receptor in humans. In this study, we aimed to investigate their involvement in systemic lupus erythematosus (SLE). Methods Peripheral blood MAIT cells from patients with SLE were assessed for their frequency, activation markers, and cell death by flow cytometry. The correlation between plasma cytokine levels and CD69 expression on MAIT cells was analyzed. The major histocompatibility complex class I-related protein MR1-restricted antigen-presenting capacity of antigen-presenting cells was investigated. Cytokine-mediated activation of MAIT cells in the absence of exogenous antigens was also examined. Results The frequency of MAIT cells was markedly reduced in SLE. The reduced number of MAIT cells was not attributable to the downregulation of surface markers, but it was partially due to the enhanced cell death of MAIT cells, possibly by activation-induced cell death. The CD69 expression levels on MAIT cells in SLE correlated with disease activity. Moreover, monocytes from patients with SLE exhibited increased ability to induce MAIT cell activation. The plasma concentration of interleukin (IL)-6, IL-18, and interferon (IFN)-α positively correlated with the expression levels of CD69 on MAIT cells in SLE. MAIT cells were activated by cytokines, including IFN-α, IL-15, and IL-12 plus IL-18, in the absence of exogenous antigens. Conclusions These results suggest that MAIT cells reflect the pathological condition of SLE and that their activated status correlates with presence of disease.

We have shown that connective tissue growth factor (CTGF) plays an important role in the pathogenesis of rheumatoid arthritis (RA). Insulin-like growth factor binding proteins (IGFBPs) are modules of CTGF. IGFBPs bind IGF-I and IGF-II. IGF-I plays a role in the regulation of immunity, bone metabolism and inflammation. Therefore, we investigated how the IGF system is associated with RA disease progression.Serum samples were collected from RA patients. IGF-I and IGFBP-3 production were evaluated by enzyme-linked immunosorbent assay, real-time RT-PCR and indirect immunofluorescence microscopy. Osteoclastogenesis was evaluated using tartrate-resistant acid phosphatase staining, a bone resorption assay and osteoclast-specific enzyme production. Angiogenesis was examined by a tube formation assay using human umbilical vein endothelial cells.The serum concentrations of IGFBP-3 in RA patients were greater than those in normal controls. IGF-I and IGFBP-3 were produced primarily by macrophages in the RA synovium. Furthermore, tumor necrosis factor-α could induce aberrant IGF-I and IGFBP-3 production in synovial fibroblasts. IGF-I and IGFBP-3 promoted the induction of osteoclast generation and morphological changes, in combination with M-colony stimulating factor and the receptor activator of NF-κB ligand. In addition, IGF-I and IGFBP-3 induced angiogenesis, as determined by the tube formation assay. These effects were neutralized by anti-IGF-IR monoclonal antibody (mAb).These results indicate that aberrant IGF-I and IGFBP-3 production plays a role in abnormal osteoclastic activation and angiogenesis in RA. This work supports future clinical exploration of anti-IGF-IR mAb in drug repositioning as a new treatment for RA.

To determine the real-world safety and effectiveness of iguratimod (IGU) for rheumatoid arthritis (RA), a 52-week, Japanese, post-marketing surveillance study was conducted. An interim analysis at week 24 was performed.This study included all RA patients who received IGU following its introduction to the market. All adverse events (AEs) and adverse drug reactions (ADRs) were collected. Effectiveness was evaluated by the change in Disease Activity Score 28-C-reactive protein (DAS28-CRP) from baseline to week 24.Safety was analyzed in 2679 patients. The overall incidences of AEs, ADRs, and serious ADRs were 38.41, 31.65, and 3.21%, respectively; the most commonly reported serious ADRs were pneumonia/bacterial pneumonia, interstitial lung disease, and Pneumocystis jiroveci pneumonia. Concomitant glucocorticoid use and comorbid conditions associated with respiratory disease were identified as risk factors for serious infections. Pulmonary alveolar hemorrhage and increased international normalized ratio of prothrombin time were observed with concomitant use of IGU and warfarin. The DAS28-CRP decreased from baseline to week 24.Although a safety concern was identified with concomitant use of IGU and warfarin, this real-world study showed no other new safety concerns and similar effectiveness to clinical trials. IGU is a new therapeutic option for RA patients.

Objective.Systemic lupus erythematosus (SLE) occurs predominantly in women, and sex hormones play an important role in SLE. Variation in the second-to-fourth digit ratio (2D4D ratio) is attributed to sex hormone exposure. Therefore, we evaluated the relationship between sex hormones and SLE by measuring 2D4D ratios.Methods.We measured 2D4D ratios in 100 patients with SLE and 200 normal healthy controls (NHC).Results.Patients with SLE had a lower 2D4D ratio than NHC.Conclusion.Our study suggests that patients with SLE have experienced high prenatal testosterone and low prenatal estrogen. To our knowledge, this is the first study evaluating the association between 2D4D ratio and SLE.

Objective We have shown that connective tissue growth factor (CTGF) plays an important role in the pathogenesis of rheumatoid arthritis (RA). This study was undertaken to evaluate the effects of blockade of the CTGF pathway on the development of collagen-induced arthritis (CIA) in mice. Methods Arthritis was induced in DBA/1J mice by immunization with a combination of type II collagen (CII) and Freund's complete adjuvant. We evaluated the development of arthritis in mice with CIA left untreated versus treated with neutralizing anti-CTGF monoclonal antibody (mAb). Results Inhibition of CTGF in mice treated with neutralizing anti-CTGF mAb significantly ameliorated arthritis compared to the untreated mice with CIA. Serum levels of matrix metalloproteinase 3 were reduced by anti-CTGF mAb treatment. Moreover, blockade of CTGF decreased interleukin-17 expression on purified CD4+ T lymphocytes. Although the expression of the retinoic acid receptor–related orphan receptor γt gene was not suppressed by anti-CTGF mAb treatment, that of interferon regulatory factor 4 (IRF-4) and IκBζ (Nfkbiz), which are other important molecules for the differentiation of Th17 cells, was suppressed. In addition, blockade of CTGF inhibited pathologic proliferation of T lymphocytes in response to CII restimulation in vitro. Moreover, aberrant osteoclastogenesis in mice with CIA was restored by anti-CTGF mAb treatment. Conclusion Our findings indicate that blockade of CTGF prevents the progression of arthritis in mice with CIA. Anti-CTGF mAb treatment suppresses pathologic T cell function and restores aberrant osteoclastogenesis in mice with CIA. CTGF may become a new target for the treatment of RA.

To clarify the clinical features of systemic lupus erythematosus (SLE) patients, factors associated with flares, and changes over time.Patients having SLE with a visiting history were entered into the Juntendo University Database of Erythematosus. We included 423 cases in the long-term follow-up analysis, and 383 cases were followed for 10 years after the initiation of any therapeutic intervention (comparative analysis: 1973-1982, 82 cases; 1983-1992, 141, and 1993-2002, 160). We assessed changes in the patients' background characteristics, disease symptoms, flare rates, etc.Among the 423 cases, the mean follow-up period was 25.9 years, and mean number of flares was 0.51. Of those, 31.9% had ≥1 flares. Thrombocytopenia at onset contributed to the flares. For disease symptoms at onset, a recent trend in increasing thrombocytopenia was observed. The combination rate of immunosuppressive agents for diseases other than lupus nephritis was slightly increased, and there was no improvement until the first flare or in the flare rate.Thrombocytopenia at onset is predictive factor for flares. Since SLE is a diverse disease with varying symptoms at recurrence, the treatment guidelines should be improved for thrombocytopenia from a long-term perspective.

To determine mortality and its predictive factors in elderly Japanese patients with severe microscopic polyangiitis (MPA).This retrospective single-center study determined the mortality of 52 patients with MPA who were admitted to our geriatric medical center from 2002 to 2014. The variables at baseline, including patient demographics, clinical characteristics, and treatment, were analyzed for their association with mortality.Mean age at onset of MPA was 73.2 years, and the one-year survival rate was 65.9%. Relapse was observed in 32.7%. Among variables at diagnosis, age, cardiomyopathy, central nervous system (CNS) involvement, alveolar hemorrhage, disease severity, the 1996 Five-Factor Score (FFS), and the 2009 FFS were associated with mortality in univariate analysis. Cardiomyopathy, CNS involvement, age 65 years, disease severity, Birmingham Vasculitis Activity Score, the 1996 FFS, and the 2009 FFS were associated with relapse-free survival in univariate analysis.We investigated mortality and relapse-free survival and their predictive factors in elderly Japanese patients with severe MPA. Age, disease severity, the 1996 FFS, and the 2009 FFS at diagnosis were prognostic factors for both mortality and relapse-free survival.

CD146, a transmembrane glycoprotein member of the immunoglobulin superfamily, acts as an adhesion molecule that helps maintain the cell monolayer. Human endothelial cells expressing CD146 are involved in angiogenesis and inflammation. Recently, we developed a sandwich ELISA for detecting soluble CD146 (sCD146) in human serum specimens. The aim of this study is to determine serum levels of sCD146 in patients with systemic sclerosis (SSc) and to examine the relationship between sCD146 levels and clinical manifestations. We quantified serum sCD146 levels in 47 serum samples from patients fulfilling criteria for SSc, 23 serum samples from patients fulfilling criteria for rheumatoid arthritis (RA), and 25 healthy controls. We also investigated the relationship between sCD146 levels and various clinical characteristics with SSc patients. Levels of sCD146 were significantly higher in the 47 patients with SSc than in the 25 healthy controls and 23 patients with RA (12.50 vs. 6.91 vs. 9.95 ng/ml; p

Leukocytapheresis (LCAP) is a safe, unique therapy pertaining to intractable rheumatoid arthritis (RA) even in cases of drug allergy or infectious states. To investigate how to represent LCAP efficacy, we have conducted gene expression analyses from the peripheral blood of RA patients treated with non-woven polyethylene terephthalate filters. Peripheral blood samples were collected immediately before and after treatment from eight RA patients who received LCAP. Among these patients, all of them achieved 20% improvement in the core set of the American College of Rheumatology (ACR20), and thus, they were confirmed as LCAP responders. Gene expression analysis was done with a high-resolution DNA microarray. The results of each of the two groups' gene expression values (immediately before and after LCAP) were calculated using Welch's t-test. Calculations were performed with a statistical software R.basic package: if the P-value was less than 0.05, this was seen as a significant change. In a comparison of 25,370 gene expressions, the number of genes showing a P-value < 0.05 in the upregulating group was 2110, and in the downregulating group it was 1864. The results of pathway analysis using the MetaCore program indicate that gene groups work for cytoskeletal remodeling are upregulated, and genes related to immune responses, such as antigens presenting via major histocompatibility complex class I and II, are downregulated just after LCAP. These findings may relate to LCAP efficacy for RA patients, but this needs further investigation.

Objective Fetal congenital complete heart block (CHB) is irreversible and is associated with significant mortality and morbidity. Anti-SS-A antibodies in the maternal sera are involved in its pathogenesis; however, the predictive value of the antibody titer and its role in prediction of this complication are controversial. The aim of this study was to determine the predictive value of maternal anti-SS-A antibodies on the development of fetal CHB. Methods A retrospective chart review was performed for 189 cases of positive anti-SS-A antibodies determined by the double immunodiffusion (DID) method, and included 17 patients that developed fetal CHB. The relationship between the appearance of CHB and the anti-SS-A antibodies titer was examined. Results An anti-SS-A antibodies titer of 1:32 or higher was identified by analyzing the receiver-operating characteristics (area under curve 0.72) curve. An anti-SS-A antibodies titer of 32 or more times greater than the upper limit by DID was a risk factor for fetal CHB (odds ratio 27.77, 95 % confidence interval (CI) 1.91‐21.02, P \ 0.05) in the multivariate analysis. Among 107 cases of anti-SS-A antibodies titers of 1:32 or higher, 65 patients (60.7 %) were treated with oral steroids. Of these, four patients had CHB (6.2 %). This rate of CHB was significantly lower (P \ 0.01) than the rate in patients not treated with steroids. Conclusion An anti-SS-A antibodies titer of 1:32 or higher in the maternal sera by DID was an independent risk factor for fetal CHB. In these patients, either antenatally administered prednisolone or betamethasone, was associated with a lower risk of fetal CHB.

A 71-year-old woman was diagnosed with rheumatoid arthritis in 2002. Treatment was started with methotrexate and she was switched to adalimumab in 2006. In May 2008, she started complaining of swelling of the left axilla and the left elbow lymph nodes, and adalimumab was discontinued in December. Her lymphadenopathy did not resolve and she was admitted to hospital with fever in May 2009. Subsequent laboratory examinations showed that serum alkaline phosphatase, gamma-glutamyl transpeptidase, C-reactive protein, and soluble interleukin-2 receptor levels were 3,078 IU/l, 510 IU/l, 20 mg/dl, and 7,290 U/ml, respectively. Gallium scintigraphy showed high-intensity areas in the above-mentioned lymph nodes. She suddenly progressed to jaundice and died of pulmonary edema on the 25th day of hospitalization. Autopsy indicated large atypical cells with a distorted nucleus that had multiplied in the above-mentioned lymph nodes. On immunohistochemical staining these cells showed positive staining for CD15, CD30, PAX-5, Epstein-Barr virus (EBV) early small RNA (EBER), and LMP-1. Reactivation of EBV was diagnosed via EBV antibodies and an EBV DNA determination. We considered that she had developed EBV-associated lymphoproliferative disorders due to immunodeficiency caused by adalimumab administration. Reactivation of EBV associated with adalimumab and the relationship of this reactivation to malignant lymphoma have been rarely reported.

Female patients have a higher prevalence of rheumatoid arthritis (RA) than male patients, suggesting that female sex hormones contribute to the disease pathogenesis. We herein report the findings of our study, which was conducted to clarify the role of estrogen in the pathogenesis of RA.Cultured human synovial fibroblasts from a patient with RA were treated with 17β-estradiol (E(2)). The effects of E(2) against cellular activation and apoptosis were evaluated. To identify the disease-related genes altered by E(2) treatment, the changes in the gene expression of the cells stimulated with and without E(2) were evaluated using a microarray analysis.We found that E(2)-mediated cellular activation signaling through extracellular signal-regulated kinase (ERK)-1/2. E(2) possessed a suppressive effect for apoptosis and a promotive effect for tumor necrosis factor (TNF)-α-induced matrix metalloproteinase (MMP)-3 production on the synovial fibroblasts. A microarray analysis revealed that E(2) profoundly upregulated CC motif chemokine ligand 13 (CCL13) gene expression.E(2) could mediate cellular activation signaling through ERK-1/2 on the synovial fibroblasts. The present data suggest that E(2) has adverse effects on the pathogenesis of RA as a result of unregulated cell death, increased TNF-α-induced MMP-3 production, and CCL13 overproduction, subsequently resulting in the disease progression of RA.

There was no standard or report for the treatment of rheumatoid arthritis (RA) patients on hemodialysis with Salazosulfapyridine (SASP). We examined the pharmacokinetics of SASP and its metabolites in RA patient on hemodialysis. Hemodialysis was started 2 h after administration of SASP at a dose of 250 or 500 mg. Blood samples were took 8 times during the observation period. The concentration of SASP and its metabolites (SP, Ac-SP) in blood sample were measured. There was no difference for the concentration of SASP before and after hemodialysis. Results showed SASP was nondialyzable, but SP and AC-SP were dialyzable. At a dose of 500 mg, AUC0-∞ of SASP and SP were higher than healthy volunteer. Therapy with SASP for hemodialysis RA should be started at a lower dose for adverse event risk.

We conducted a study to evaluate the effect of various anticoagulant agents on large-volume leukocytapheresis using the new Cellsorba CS-180S Filter filled with a changed solution of sodium pyrosulfite and sodium carbonate. We conducted the study on a total of 12 cases of rheumatoid arthritis. As the anticoagulant agents we used sodium citrate, nafamostat mesilate and low molecular weight heparin. The new Cellsorba CS-180S was safely used with the various blood anticoagulant agents. Also, through adjustment of the sodium citrate percentage to the blood flow volume, it is hypothesized that it is possible to increase the neutrophil removal rate.

To retrospectively evaluate the efficacy and safety of combination therapy with tacrolimus (TAC) and other disease-modifying antirheumatic drugs (DMARDs). One hundred fifteen rheumatoid arthritis (RA) patients treated with tacrolimus were enrolled in this retrospective analysis. We collected clinical information, including patient background, treatment efficacy (evaluated using the DAS score), and adverse events observed. Multiple logistic regression analysis was conducted to analyze factors contributing to clinical response and adverse effects. The disease activity score of 28 joints (DAS28) improved significantly at 24 weeks, and continuation rate at 1 year was 57.9%. There was no difference in continuation rate between different DMARD combinations, and not only methotrexate (MTX) but also bucillamine (BUC) and salazosulfapyridine (SSZ) were effective combination partners with TAC. No serious adverse events were observed, and no different inefficacy or safety was observed between non-elderly (

Thrombotic thrombocytopenia purpura (TTP) caused by a deficiency in ADAMTS-13 activity is considered to involve a subset of thrombotic microangiopathy (TMA). Although concept of TTP is included under the umbrella of TMA, discrimination of TTP from TMA is occasionally difficult in an autoimmune disorder. Herein, we report a case with TTP associated with systemic lupus erythematosus (SLE). In this case, it was difficult to discriminate TTP from TMA and the measurement of ADAMTS-13 activity was useful for obtaining an accurate diagnosis. SLE patients having thrombocytopenia in complication with anemia should be considered a monitoring of ADAMTS-13 activity even though the patients lacked symptoms of TTP related to the microvascular coagulation.

Eosinophilic granulomatosis with polyangiitis (EGPA) is a disorder characterized by extravascular granulomas, hypereosinophilia, and pulmonary and systemic small-vessel vasculitis. Bowel perforation is a rare but often fatal complication of EGPA. In the present report, we describe a case of small intestinal perforation in a patient with EGPA. Through various examinations, we confirmed the presence of EGPA, and the patient responded well to steroid therapy. However, as the patient's condition subsequently worsened, the small intestine was consequently resected. The patient's overall condition improved thereafter. Thus, we believe that careful attention should be paid to intestinal symptoms and perforation in patients with EGPA.