Published papers

Summary Background The use of proton pump inhibitors for prevention of nonsteroidal anti-inflammatory drug (NSAID)-induced gastrointestinal adverse events is well documented. However, data regarding the efficacy and safety of this approach in Japan are scarce. Aim To evaluate the efficacy and tolerability of esomeprazole in preventing NSAID-induced peptic ulcers in Japanese at-risk patients. Methods Male and female Japanese adult patients (aged ≥20 years) with endoscopically confirmed history of peptic ulcers who required long-term oral NSAID therapy for a chronic inflammatory condition were randomised to 24 weeks' treatment with esomeprazole 20 mg once daily or matching placebo. The primary end point was the Kaplan-Meier estimated proportion of ulcer-free patients. Results Overall, 343 patients were randomised to treatment (esomeprazole, n = 175; placebo, n = 168). The Kaplan-Meier estimated ulcer-free rate over the 24-week treatment period was significantly higher (log-rank P < 0.001) in esomeprazole-treated patients (96.0%; 95% CI 92.8, 99.1) than in placebo recipients (64.4%; 95% CI 56.8, 71.9). Esomeprazole was effective at preventing peptic ulcers in both Helicobacter pylori-positive and -negative patients (96.3% vs. 95.5% of patients ulcer-free, respectively); however, in the placebo group, the proportion of ulcer-free patients at 24 weeks was markedly lower among H. pylori-positive than -negative patients (59.7% vs. 69.9%). The NSAID type did not seem to affect the estimated ulcer-free rate with esomeprazole. Treatment with esomeprazole was well tolerated. Conclusion Esomeprazole 20 mg once daily is effective and safe in preventing ulcer recurrence in Japanese patients with a definite history of peptic ulcers who were taking an NSAID (identifier: NCT00542789). © 2012 Blackwell Publishing Ltd.

Objectives: To understand the status of mizoribine use in patients with lupus nephritis (LN) and to collect safety- and efficacy-related data on 2-year treatment with mizoribine. Methods: A continuous survey was conducted between March 2010 and July 2015. Results: The analysis set included 559 patients (mean age 39.5 years, females 82.6%, mean duration of systemic lupus erythematosus (SLE) 8.4 years, mean duration of LN 5.9 years). Renal function was satisfactory for 6 months, but worsened from 12 months, with significant worsening at 24 months. By the ACR 2006 remission criteria (eGFR >60), at 24 months, 26.5% of patients achieved complete remission, and 63.3% achieved complete or partial remission. The urine protein to creatinine ratio decreased significantly. The SLE Disease Activity Index 2000 score decreased significantly at 12 and 24 months. Overall, 98 (17.5%) patients experienced 124 adverse drug reactions (ADRs); 3.6% experienced serious ADRs. Mizoribine was used with a steroid in 99.3% and an immunosuppressant in 51.2%; tacrolimus was used in 43.8%. The oral steroid dosage decreased from baseline to 24 months. The incidence of ADRs was not significantly different with concomitant tacrolimus use. Conclusions: The results suggest that long-term mizoribine is safe and effective, even when used with tacrolimus.

Rationale: Dialysis-related amyloidosis (DRA) can present rheumatic manifestations in patients on long-term hemodialysis. Typical articular symptoms with DRA involve carpal-tunnel syndrome, effusion in large joints, spondyloarthropathy, or cystic bone lesions, which are usually with non-inflammatory processes. Patient concerns: A 64-year-old man on hemodialysis for >30 years was admitted because of intermittent fever, polyarthritis, and elevated serum C-reactive protein (CRP) level, which was continuous for 2 years. Several antibiotics were ineffective for 3 months before his admission. On physical examination, joint swelling was observed at bilateral wrists, knees, ankles, and hip joints. Laboratory tests revealed elevation of serum inflammatory markers and β2-microglobulin (β2-MG). Synovial fluid showed predominant infiltration of polymorphonuclear leukocytes and the increase of β2-MG level. Diagnosis: Significant deposition of β2-MG with inflammatory cell infiltration was found in biopsied samples from synovium, skin, and ileum. Interventions: We decided to switch to the hemodialysis column with membrane that can effectively absorb β2-MG in circulation. Outcomes: The relief of symptoms and a decrease of CRP level by changing the membrane lead to the final diagnosis of DRA. Lessons: Our case demonstrates that DRA arthropathy can be inflammatory and destructive, and also develop systemic inflammatory signs and symptoms. In such cases, aggressive absorption of β2-MG in circulation might help the amelioration of symptoms.

Objective. To examine the relationship between MRI structural damage and repair and plasma inflammatory cytokines in patients with RA. Methods. A total of 88 newly diagnosed, untreated RA patients were enrolled. Contrast MRI of the dominant hand and X-rays of the hands and feet were performed at baseline and 1 year later. MR images were evaluated using RA MRI scoring, and X-raywere assessed by the modified total Sharp score. Erosion progression was defined as changes in RA MRI scoring erosion or modified total Sharp score erosion of >0.5. Erosion repair was defined as erosion score changes of less than -0.5. Plasma levels of 10 cytokines were measured by electrochemiluminescence assay. Results. Progression of bone erosion and repair were observed more frequently in MRI than in X-rays (erosion, 52% vs 26%, P < 0.001; repair, 26% vs 15%, P = 0.003, respectively). Baseline IL-6 levels and seropositivity were independent relevant factors for MRI erosion progression, with IL-6 having stronger effect than seropositivity. A receiver operating characteristic curve identified the baseline IL-6 level of 7.6 pg/ml for predicting erosion progression during 1 year, with an area under the curve of 0.82; higher IL-6 levels resulted in more erosion progression. Baseline low IL-6 was also an independent predictor for MRI erosion repair. Conclusion. In newly diagnosed, untreated RA patients, baseline plasma IL-6 levels are responsible for 1-year MRI bone erosion progression and repair.

Objectives The selectivity index has been proposed in predicting the response to immunosuppressive therapy in nephrotic syndrome and other primary kidney disorders. The aim of this study was to elucidate the predictive value of the selectivity index for the treatment response and renal outcome in patients with lupus nephritis. Methods Forty-four patients with lupus nephritis with selectivity index available at the time of renal biopsy were divided into two groups according to the cut-off value of the selectivity index determined by a receiver operating characteristics curve to differentiate treatment responders from non-responders. The baseline characteristics, overall response rate and renal functional outcome were studied retrospectively, and compared between the two groups. Prognostic factors for achieving remission were identified. Results The cut-off value of the selectivity index was 0.167. The low selectivity index (<0.167) and the high selectivity index (≥0.167) group included 24 and 20 patients, respectively. The overall response rate was significantly higher (88% vs. 50%, P = 0.007) and the rate of progression to end-stage renal disease was lower in the low selectivity index group (0% vs. 15%, P = 0.049). More patients in the high selectivity index group had chronic lesions on renal biopsy (P = 0.002). The selectivity index was the prognostic factor for achieving overall response based on a multivariate analysis (P = 0.020). Conclusions A selectivity index ≥0.167 was a strong predictor for a poor treatment response and the presence of chronic lesions on renal biopsy. Further exploration with a larger cohort and longer follow-up period is warranted.

We treated a patient with relapsing polychondritis (RP) who presented with intermittent oculomotor and abducens nerve palsies as the first manifestation. Ear swelling and laryngeal edema emerged 7 months later, which led us to diagnose him with RP. Moderate doses of glucocorticoid resolved all symptoms. Our experience with RP accompanied by oculomotor nerve palsy suggests that RP should be considered in patients with cranial nerve palsies so that they may be promptly diagnosed and treated.

Objectives: To compare the efficacy and safety of certolizumab pegol (CZP) with and without loading dose (LD) in a post-hoc analysis of two Japanese clinical studies. Methods: Data from the double-blind trials (DBT) J-RAPID and HIKARI, and their open-label extension (OLE) studies, were used. Patients randomized to CZP 200 mg every 2 weeks (Q2W) groups starting with LD (400 mg Weeks 0/2/4; LD group; J-RAPID: n = 82, HIKARI: n = 116) and patients randomized to placebo groups who subsequently started CZP Q2W without LD in the OLEs (No-LD group; J-RAPID: n = 61, HIKARI: n = 99) were analyzed. Efficacy and pharmacokinetics were assessed during 24 weeks. Adverse events were reported from all studies. Results: In both trials, the LD groups showed more rapid initial ACR20/50/70 kinetics, and maintained higher ACR50/70 responses until 24 weeks, compared with the No-LD groups. Anti-CZP antibody development was less frequent in the LD groups (J-RAPID: 1.2% versus 4.9%; HIKARI: 17.2% versus 27.3%). Similar safety profiles were reported between LD and No-LD groups (any AEs: 281.8 versus 315.7 [J-RAPID], 282.6 versus 321.3 [HIKARI] [incidence rate/100 patient-years]). Conclusions: Despite limitations, including comparing DBT and OLE studies, these results suggest that a CZP LD improves clinical response in active rheumatoid arthritis without altering the safety profile.

Objectives: To assess the influence of golimumab dosage and disease activity on joint destruction in patients with active rheumatoid arthritis (RA) in the GO-FORTH study. Methods: Efficacy was compared among groups given basal methotrexate plus placebo, golimumab (50 mg), or golimumab (100 mg) with stratification by high (HDA) or moderate (MDA) baseline disease activity and by high or low baseline C-reactive protein (CRP). Results: Among HDA or high CRP patients, the mean change of the total Sharp score was 3.48 and 3.41 in the placebo group, 1.94 and 2.71 in the 50 mg group, and 0.39 and 1.15 in the 100 mg group, respectively. The percentage of progression-free patients with HDA or high CRP was 40.4% and 40.0%, 43.1% and 38.2%, and 69.8% and 61.5%, respectively. Among MDA or low CRP patients, both golimumab doses showed similar prevention of joint destruction. Among HDA or high CRP patients, a shorter disease duration and higher TSS/disease duration ratio were associated with joint destruction. Conclusion: Both doses of golimumab (50 or 100 mg) prevented joint destruction in MDA or low CRP patients, but 100 mg was better for HDA or high CRP patients with a shorter disease duration or higher TSS/disease duration ratio.

The aim of this study is to investigate the renal outcomes of anti-neutrophil cytoplasmic antibody (ANCA)-associated crescentic glomerulonephritis in patients with normal estimated glomerular filtration rate (eGFR) at diagnosis. Twenty-seven patients with biopsy-proven ANCA-associated crescentic glomerulonephritis were retrospectively recruited and were divided into 12 with normal eGFR (≥60 ml/min/1.73 m2) and 15 with low eGFR (2) at baseline. Clinical and renal pathological findings at diagnosis and renal outcomes for up to 3 years were compared between the two groups. Two patients in the low eGFR group died of severe bacterial pneumonia. In the normal eGFR group, the following characteristics were observed: younger age at diagnosis (p = 0.04), diagnosis of granulomatosis polyangiitis (GPA) (p <0.01), and lower frequency of cyclophosphamide treatment (p = 0.03). On renal pathological analysis, the normal eGFR group had a significantly lower proportion of cellular crescent formation (p = 0.01), fibrinoid necrosis (p = 0.01), interstitial fibrosis (p = 0.02), and tubular atrophy (p = 0.02). As a result, the two groups did not significantly differ in remission rates, relapse rates, Birmingham vasculitis score, vasculitis damage index, or eGFR on 3-year follow-up. Patients with biopsy-proven ANCA-associated glomerulonephritis and normal eGFR at diagnosis have poor renal outcomes and may require standard intensive immunosuppressive treatment to prevent accrual of damage.

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.

T cells are considered to develop through three stages, from naïve T (Tn) into central memory T (Tcm) and finally into effector memory T (Tem). Among the subsets of Tn, stem cell memory T (Tscm) were recently found to be the least developed memory subset. While this subset was revealed to possess self-reproducibility and multipotentiality, little is known about the relationship between development and polarity. We conducted transcriptome analysis of human CD4+ T subsets and found that Tscm was a clearly distinct subset, located between Tn and Tcm. Surface antigen analysis and differentiation assay showed that the flexibility of polarity and the cytokine production progressively changed as the differentiation of CD4+ T cells advanced. Interestingly, we found that most cells of the CD45RO-CCR7+CCR6+ subset, hitherto considered the naïve precursor of Th17, were in fact Tscm. These findings may advance our understanding of the highly heterogeneous human helper T cells.

Objective. To investigate the probability of clinical remission (REM) or low disease activity (LDA) after 1 year of infliximab (IFX) therapy based on disease activity at 3 months in patients with rheumatoid arthritis (RA). Methods. Methotrexate-refractory patients with RA received 3 mg/kg of IFX at weeks 0, 2, and 6, followed by 3 mg/kg, 6 mg/kg, or 10 mg/kg every 8 weeks from Week 14 (W14) to Week 46. Correlation of disease activity at W14 with disease activity at W54 and probability of REM/LDA at W54 were analyzed in each dosing group. Results. Disease activities at W14 were significantly correlated with both disease activity at W54 and probability of REM/LDA at W54 in patients continuing 3 mg/kg as well as in those receiving 6 mg/kg or 10 mg/kg therapy from W14. Results showed that, if approximate REM or LDA had not been achieved by W14, ≥ 50% of patients continuing 3 mg/kg therapy would not be able to achieve REMor LDAatW54. However, even in patients with high or moderate disease activity atW14, dose escalation to 6 mg/kg or 10 mg/kg enabled many to achieve REM/LDA. Conclusion. Disease activity at W14 in standard-dose IFX therapy enabled the prediction of longterm clinical response at continued standard dose, as well as subsequent escalated-dose regimens. Disease activity at W14 was hypothesized to be an important index for IFX treatment strategy.

Conventional synthetic disease-modifying anti-rheumatic drugs, including methotrexate, may not be tolerated by all patients with rheumatoid arthritis (RA), and limited international data for etanercept (ETN) monotherapy are available. The aim of this review was to summarize the clinical program for ETN monotherapy in Japanese patients with RA, which has included a pharmacokinetic study, clinical trials for registration, long-term studies, and once-weekly dosing studies. Pharmacokinetic results showed that serum concentrations of ETN were linear with dose levels and were similar to other international studies. Across interventional studies, 652 Japanese patients with active RA were treated with ETN. In the registration studies, ETN treatment led to consistent improvement in American College of Rheumatology 20/50/70 scores, European League Against Rheumatism Good Response, Disease Activity Score 28 erythrocyte sedimentation rate remission, and Health Assessment Questionnaire disability index. In the long-term studies, efficacy was maintained for up to 180 weeks. Similar results were seen in the once-weekly studies. Across the studies, more than 870 patient-years of exposure to ETN were recorded. Discontinuations owing to lack of efficacy or adverse events were modest and no new safety signals were recorded. These studies demonstrated that ETN monotherapy is efficacious and well-tolerated in Japanese patients with RA.

OBJECTIVE: The aim of this study was to identify cold-associated autoantibodies in patients with RP secondary to CTDs.METHODS: Indirect immunofluorescence staining was performed on non-permeabilized cold-stimulated normal human dermal microvascular endothelial cells (dHMVECs), using patients' sera. Cold-induced alterations in cell surface proteomes were analysed by isobaric tag for relative and absolute quantitation (iTRAQ) analysis. Serological proteome analysis (SERPA) was applied to screen cold-associated autoantigens. The prevalence of the candidate autoantibody was determined by ELISA in 290 patients with RP secondary to CTDs (SSc, SLE or MCTD), 10 patients with primary RP and 27 healthy controls.RESULTS: Enhanced cell surface immunoreactivity was detected in cold-stimulated dHMVECs when incubated with sera from patients with secondary RP. By iTRAQ analysis, many proteins, including heterogeneous nuclear ribonucleoprotein K (hnRNP-K), were found to be increased on the cell surface of dHMVECs after cold stimulation. By the SERPA approach, hnRNP-K was identified as a candidate autoantigen in patients with secondary RP. Cold-induced translocation of hnRNP-K to the cell surface was confirmed by immunoblotting and flow cytometry. By ELISA analysis, patients with secondary RP show a significantly higher prevalence of anti-hnRNP-K autoantibody (30.0%, 61/203) than patients without RP (9.2%, 8/87, P = 0.0001), patients with primary RP (0%, 0/10, P = 0.0314) or healthy controls (0%, 0/27, P = 0.0001).CONCLUSION: By comprehensive proteomics, we identified hnRNP-K as a novel cold-associated autoantigen in patients with secondary RP. Anti-hnRNP-K autoantibody may potentially serve as a biomarker for RP secondary to various CTDs.

Copyright © 2017 the Author(s). Published by Wolters Kluwer Health, Inc. Introduction: Polymyositis (PM) is a type of autoimmune, inflammatory myopathy. IgG4-related disease (IgG4-RD) is a recently recognized disease entity characterized by elevated serum IgG4 levels and IgG4 + plasma-cell infiltration of various organs. However, several reports have described cases of other diseases that present with those features, suggesting the importance of careful differential diagnosis. Herein, we report the first case of PM with elevated serum IgG4 levels and IgG4 + plasma cells in the muscles, mimicking IgG4-RD. A 73-year-old woman visited our hospital because of proximal muscle weakness of both thighs. Her blood test showed high levels of serum creatinine kinase, aldolase, and IgG4. Magnetic resonance imaging of the thighs showed muscle edema. Needle electromyography showed findings typical of myositis. Histological analysis of her left quadriceps revealed infiltration of IgG4 + plasma cells as well as CD8 + T cells. Scattered necrotic and regenerating muscle fibers with no specific findings for IgG4-RD (storiform fibrosis and obliterative phlebitis) were typical for PM. We diagnosed her condition as PM and treated her with 40 mg/day of prednisolone that decreased levels of muscle enzymes and improved muscle weakness. Conclusion: Our case indicated that PM could present with high serum IgG4 levels and IgG4 + plasma-cell infiltration, mimicking IgG4-RD. Although the mechanism of IgG4 elevation in such PM is unclear, our case highlights the necessity to recognize that high serum IgG4 levels and IgG4 + plasma-cell infiltration in organs are not specific for IgG4-RD.

© 2017 Japan College of Rheumatology. Rheumatoid arthritis (RA) is a chronic inflammatory disorder characterized by progressive joint destruction. Recent studies have indicated the critical involvement of osteoclasts in bone destruction in RA. The osteoclast differentiation factor receptor activator of NF-κB ligand (RANKL), which belongs to the tumor necrosis factor superfamily, plays a critical role in osteoclast differentiation and bone destruction in RA. Denosumab, an antibody against human RANKL, efficiently suppressed the progression of bone erosion in RA patients in randomized controlled studies, and is considered as a putative therapeutic option for preventing bone destruction in RA.