Published papers

© © Author(s) (or their employer(s)) 2018. Objective To evaluate the efficacy and safety of tocilizumab, an interleukin-6 receptor antibody, in patients with adult-onset Still's disease. Methods In this double-blind, randomised, placebo-controlled phase III trial, 27 patients with adult-onset Still's disease refractory to glucocorticoids were randomised to tocilizumab at a dose of 8 mg/kg or placebo given intravenously every 2 weeks during the 12-week, double-blind phase. Patients received open-label tocilizumab for 40 weeks subsequently. The primary outcome was American College of Rheumatology (ACR) 50 response at week 4. The secondary outcomes included ACR 20/50/70, systemic feature score, glucocorticoid dose and adverse events at each point. Results In the full analysis set, ACR50 response at week 4 was achieved in 61.5% (95% CI 31.6 to 86.1) in the tocilizumab group and 30.8% (95% CI 9.1 to 61.4) in the placebo group (p=0.24). The least squares means for change in systemic feature score at week 12 were -4.1 in the tocilizumab group and -2.3 in the placebo group (p=0.003). The dose of glucocorticoids at week 12 decreased by 46.2% in the tocilizumab group and 21.0% in the placebo group (p=0.017). At week 52, the rates of ACR20, ACR50 and ACR70 were 84.6%, 84.6% and 61.5%, respectively, in both groups. Serious adverse events in all participants who received one dose of tocilizumab were infections, aseptic necrosis in the hips, exacerbation of adult-onset Still's disease, drug eruption and anaphylactic shock. Conclusion The study suggests that tocilizumab is effective in adult-onset Still's disease, although the primary endpoint was not met and solid conclusion was not drawn.

Objectives. To confirm the safety and effectiveness of adalimumab and to evaluate the influence of the concomitant use of methotrexate (MTX). Methods. Postmarketing surveillance of 7740 Japanese rheumatoid arthritis (RA) patients was performed. All patients who received adalimumab in the registration period were followed for 28 weeks after starting treatment for safety and 24 weeks for effectiveness. Effectiveness was measured by duration of morning stiffness, swollen and tender joint counts (28 joints), patient global assessment of disease activity, erythrocyte sedimentation rate and serum C-reactive protein. Results. Comparable rates of adverse drug reactions (ADRs) were reported in this study and in the interim analysis. Age, pulmonary disease history or comorbidity, co-existing diabetes mellitus, concomitant MTX at doses of > 8 mg/week and concomitant glucocorticoids at doses of > 5 mg/day were risk factors for infections. All mean values of effectiveness measurements improved. Relatively lower disease activity at baseline, biologic-naïve, concomitant MTX use and early RA stage/low functional class were background factors contributing to the effectiveness. The combination of adalimumab with MTX improved the response to adalimumab treatment. Conclusion. Adalimumab, especially with concomitant use of MTX, provided significant improvement in disease activity, without any unexpected ADRs in Japanese RA patients. © 2014 Japan College of Rheumatology.

Objective: To determine the effect of methotrexate (MTX) on plasma levels of interleukin (IL)-6 and tumor necrosis factor (TNF)-α and to investigate their associations with clinical and radiographic responses in patients with early rheumatoid arthritis (RA). Methods: Sixty-two untreated RA patients with the disease duration of ≤36 months in whom MTX was initiated were consecutively identified in our prospective RA cohort and included in this study. Concomitant use of prednisolone and synthetic disease-modifying anti-rheumatic drugs with MTX was allowed, but patients who used biological agents were excluded. Plasma IL-6 and TNF-α levels were measured at the time of diagnosis (baseline) and 1 year later. The relationships of the clinical and radiographic data with plasma levels of IL-6 and TNF-α were analyzed. Results: The median age of the patients was 57 years, 49 patients were female, and the median disease duration was 3 months. Forty-six (74.2 %) patients were anti-cyclic citrullinated protein antibody-positive. Serum C-reactive protein (CRP), plasma IL-6, and DAS28 decreased significantly (p <0.001) after MTX treatment, but plasma TNF-α did not. Radiographic progression was significantly correlated with disease activity score and plasma IL-6 levels but not with CRP or TNF-α after MTX treatment. Patients with plasma IL-6 level above 4.03 pg/ml showed clinically relevant radiographic progression with a sensitivity of 91.7 % and a specificity of 88.0 %. Conclusion: In this early RA cohort, we demonstrated a significant (p <0.001) reduction of plasma IL-6, but not TNF-α, during MTX treatment. The post-treatment IL-6 level was a strong indicator of radiographic progression. © 2013 Clinical Rheumatology.

Objective. To assess real-world safety, tolerability, and effectiveness of etanercept monotherapy, etanercept plus methotrexate (MTX), or etanercept plus other disease-modifying antirheumatic drugs (DMARD) in Japanese patients with active rheumatoid arthritis (RA) despite previous treatment with DMARD. Methods. In this 24-week, all-cases postmarketing surveillance study, adverse events (AE) were coded using the Medical Dictionary for Regulatory Activities. Effectiveness was assessed every 4 weeks using the 28-joint Disease Activity Score and the European League Against Rheumatism response criteria. Results. Of 13,861 patients (81% women) in the analysis, 3616, 2506, and 7739, respectively, were classified into etanercept monotherapy (ETN-mono), etanercept plus DMARD other than MTX (ETN + DMARD), and etanercept plus MTX (ETN + MTX) groups. Rates of AE and serious AE (SAE) in the ETN + MTX group were lower than in other groups. Risk of SAE or serious infections was not significantly increased with higher versus lower MTX doses at baseline or with concomitant use of salazosulfapyridine or bucillamine in ETN + DMARD versus ETN-mono groups. A greater likelihood of achieving clinical remission was seen with ETN + MTX versus ETN-mono (OR 1.36; 95% CI, 1.16-1.60; p < 0.001). Higher MTX dose at baseline was associated with a higher remission rate (> 8 mg vs 0 to ≤ 4 mg, OR 1.47, 95% CI 1.07-2.00, p = 0.016; 6 to ≤ 8 mg vs 0 to ≤ 4 mg, OR 1.27, 95% CI 1.01-1.60, p = 0.038). Conclusion. Combination therapies with etanercept plus MTX or other DMARD were reasonably well tolerated, and ETN + MTX at higher doses was more effective than ETN-mono in Japanese patients with RA. © 2013. All rights reserved.

Background: Non-steroidal anti-inflammatory drugs (NSAIDs) are an effective and common treatment for chronic pain disorders, but long-term use is associated with risk of potentially life-threatening gastrointestinal adverse events (AEs). The proton pump inhibitor esomeprazole has been found to be effective for gastroprotection in NSAID users, but few long-term studies have been conducted in Japan.Methods: This was an open-label, multicentre, single-arm, prospective 1-year study of treatment with esomeprazole (20 mg once daily) in Japanese patients (aged ≥20 years) with endoscopic evidence of previous peptic ulcer and receiving daily oral NSAID therapy (at a stable dose) for a chronic condition. Eligibility was not dictated by type of oral NSAID. The primary objective was to determine long-term safety and tolerability of esomeprazole. Efficacy for prevention of peptic ulcers was also determined (Kaplan-Meier method). All statistical analyses were descriptive.Results: A total of 130 patients (73.1% women, mean age 62.1 years, 43.8% Helicobacter pylori-positive) received treatment with esomeprazole in addition to long-term NSAID therapy (most commonly for rheumatoid arthritis [n=42] and osteoarthritis [n=34]). Loxoprofen, meloxicam and diclofenac were the most commonly used NSAIDs; cyclo-oxygenase (COX)-2 selective agents were used by 16.2% of patients (n=21). Long-term compliance with esomeprazole (capsule counts) was >75% for the majority of patients. Although 16.9% of patients (n=22) experienced AEs judged to be possibly related to treatment with esomeprazole, they were mostly mild and transient. The most commonly reported possibly treatment-related AEs were abnormal hepatic function, headache, increased γ-glutamyltransferase levels and muscle spasms (2 patients each). Overall, 95.9% (95% confidence interval: 92.3, 99.4) of patients remained ulcer free at 1 year.Conclusion: Long-term treatment with esomeprazole (20 mg once daily) is well tolerated and efficacious for preventing ulcer recurrence in Japanese NSAID users with a history of peptic ulcer.Trial registration: ClinicalTrials.gov identifier NCT00595517. © 2013 Sugano et al.; licensee BioMed Central Ltd.

This interim analysis of postmarketing surveillance data for adalimumab-treated rheumatoid arthritis (RA) patients summarizes safety and effectiveness during the first 24 weeks of therapy for the first 3,000 patients treated in Japan (June 2008-December 2009). Patient eligibility for antitumor necrosis factor therapy was based on the Japanese College of Rheumatology treatment guidelines and Japanese labeling. All patients were screened for tuberculosis. Approximately 50% of the population was biologic näve, 66% received concomitant methotrexate (MTX), and 72% received concomitant glucocorticoids. The overall incidence rate of adverse events was 31% (5.5% serious) and that of adverse drug reactions (ADRs) was 27% (4.1% serious). Incidence rates of ADRs and serious ADRs were similar regardless of prior biologic therapy or concomitant MTX use but were significantly higher in patients receiving glucocorticoids compared with those not receiving glucocorticoids. Bacterial/bronchial pneumonia occurred in 1.2% of patients; Interstitial pneumonia, 0.6%; Pneumocystis jirovecii pneumonia, 0.3%; tuberculosis, 0.13%; and administration-site reactions, 6.1%. Mean 28-joint Disease Activity Scores decreased significantly after 24 weeks from 5.29 to 3.91. All subgroups showed significant improvement, particularly the biologic-naïve patients receiving concomitant MTX. No new safety concerns were identified. ADR Incidence rates were similar to those of other biologic agents approved for RA. © Japan College of Rheumatology 2011.

The aim is to investigate the relationship of duration of rheumatoid arthritis (RA) with safety and effectiveness of etanercept (ETN) in Japan. Post-marketing surveillance data for 7,099 patients treated with ETN were analyzed. Baseline characteristics, treatment effectiveness, incidence of adverse events (AEs), and serious AEs (SAEs) in relation to duration of RA were studied. At baseline, patients with RA for longer duration were older, weighed less, had more comorbidities, allergies, and corticosteroid use, but smoked less and had less morning stiffness. By 2-5 years with RA, more than half of the patients had advanced to Steinbrocker radiographic stage III or IV. Methotrexate (MTX) was the most commonly used pretreatment disease-modifying antirheumatic drug; however, concomitant MTX use and its dose were lower among patients with longer duration of RA. Remission rates (26.6%) were greatest among patients having RA for <2 years. Less AEs and SAEs were observed among patients with shorter duration of RA. These results suggest that RA treatment in Japan in the era pre-biologics may not have been adequate to control disease activity and prevent joint destruction. Patients with shorter duration of RA may have better physical status which allows the opportunity to treat more intensively putting a higher percentage of patients in remission and possibly decreasing exposure to SAEs. © Springer-Verlag 2011.

Finding an effective treatment strategy for rheumatoid arthritis (RA) patients who have not benefited from previous tumor necrosis factor-α antagonist treatment is important for minimizing RA disease activity and improving patient outcomes. The aim of this study was to compare the safety and effectiveness of etanercept in patients with and without infliximab (IFX) treatment experience. Patients (n = 7,099) from a large postmarketing observational study of etanercept use in Japan were divided into 2 cohorts based on previous IFX use (pre-IFX and non-IFX). Baseline characteristics were assessed in each cohort. Adverse events (AEs) and European League Against Rheumatism (EULAR) responses were monitored every 4 weeks for 24 weeks. At baseline, pre-IFX patients were younger and had fewer comorbidities and a shorter RA duration than non-IFX patients. During the study, pre-IFX patients received concomitant methotrexate more often than non-IFX patients. The incidence of AEs and serious AEs were significantly lower in pre-IFX patients, as was the percentage of patients who discontinued treatment. Both cohorts had significant improvement (P<0.001) in EULAR responses at the end of the treatment period. This study demonstrated that etanercept was effective and well tolerated in active RA patients with and without prior IFX treatment. © Springer-Verlag 2011.

Objectives: To investigate the safety, effectiveness, and risk-benefit balance of intravenous abatacept (ABA) in non-elderly (<65 years: NEG) and elderly (≥65 years: EG) rheumatoid arthritis patients. Methods: This sub-analysis of an all-cases postmarketing surveillance in Japan assessed safety in all enrolled patients and effectiveness in those with Disease Activity Score 28 based on C-reactive protein (DAS28-CRP) measurements at ≥2 time points including baseline. Risk-benefit was evaluated based on infections and DAS28-CRP improvement >1.2. Results: The NEG and EG of the safety analysis set comprised 2,170 and 1,712 patients, respectively; corresponding 6-month ABA retention rates were 80.2% and 77.1%. The NEG had fewer adverse drug reactions (14.5% vs. 17.2%, p =.021) and infections (4.8% vs. 7.2%, p =.002) than the EG. DAS28-CRP changed similarly between groups. The proportion of patients with low-risk/high-benefit and high-risk/low-benefit were 33.1% and 6.9% (NEG) and 29.7% and 9.0% (EG). Low-risk/high-benefit patients were younger, had shorter disease duration and fewer comorbidities, and were with less use of oral glucocorticoid and prior biologics, more use of methotrexate and higher DAS28-CRP than high-risk/low-benefit patients at baseline. Conclusion: ABA was well tolerated and similarly efficacious in the EG and NEG. Identification of factors related to low-risk/high-benefit may aid appropriate patient selection.

Background: Lymphoproliferative disorder (LPD), including malignant lymphoma, is a relatively rare but life-threatening complication in RA patients under methotrexate (MTX) therapy. Spontaneous regression of LPD after MTX withdrawal is regarded as a distinct characteristic in part of such LPDs. Objective: The present study aimed to investigate the immunological difference in regressive LPD and persistent LPD. Methods: We studied RA patients who developed LPD during MTX administration (n = 35) and clinically matched controls (n = 35). The time of MTX cessation was defined as week 0, and LPD patients were divided into two groups according to LPD status at week 12: regressive group (n = 22) and persistent group (n = 13). Flow cytometric analysis of whole blood samples and serum cytokine assays were conducted for LPD (n = 10) and control patients (n = 10) at weeks 0, 4, and 12. Results: There was a significant decrease in peripheral lymphocytes and the proportion of T helper 1 cells (Th1 cells), effector memory CD8+ T cells (EMCD8+ T) and Epstein-Barr virus (EBV)-specific CD8+ T cells at the time of LPD diagnosis, and a significant increase after MTX cessation was observed in the regressive group but not in the persistent group. The expansion of Th1 cells and EMCD8+ T cells significantly correlated with an increase in serum interferon (IFN)-γ concentration. Conclusion: Changes in Th1 cells, EMCD8+ T cells and EBV-specific CD8+ T cells, which coincided with an increase in IFN-γ, were significantly different between regressive LPD and persistent LPD after MTX cessation.

© Copyright CLINICAL AND EXPERIMENTAL RHEUMATOLOGY 2018. Objective. To identify risk factors of relapse in IgG4-related disease (IgG4-RD) during glucocorticoid (GC) tapering. Methods. A total of 27 consecutive patients with IgG4-RD (7 with and 20 without relapse) treated with GC for more than 6 months were enrolled. Baseline characteristics were compared in patients with and without relapse. Longitudinal analysis was also performed. Results. Patients with relapse had significantly higher levels of serum IgG4 (816.0 vs. 346.5 mg/dL, p=0.048) and number of organs involved (5 vs. 3, p=0.008) and lower levels of serum IgA (82 vs. 176 mg/dL, p=0.002) at baseline, compared to patients without relapse. The most useful cut-off value of baseline serum IgG4 to predictive relapse was 813 mg/dl with a sensitivity of 57.1% and a specificity of 95.0%. In longitudinal analysis, serum IgG4 decreased at 6 months after treatment in both groups, but was elevated at relapse in patients with relapse, while remaining low in those without relapse. Conclusion. Higher levels of serum IgG4 at baseline were associated with relapse in IgG4-RD. Re-elevation of serum IgG4 levels during GC treatment reflected disease relapse.

Objective: Fractalkine (CX3CL1/FKN) is a chemokine that regulates chemotaxis and adhesion of CX3C chemokine receptor 1 (CX3CR1)-expressing inflammatory cells. We conducted the first phase 1/2, open-label, multiple ascending dose study of E6011, a humanized anti-FKN monoclonal antibody, in Japanese rheumatoid arthritis (RA) patients (clinicaltrial.gov identifier: NCT02196558). Methods: Active RA patients with an inadequate response or intolerance to methotrexate or tumor necrosis factor (TNF) inhibitor received E6011 at week 0, 1, 2, and thereafter every 2 weeks for 12 weeks. Results: Twelve, 15, and 10 subjects were enrolled in the 100, 200, and 400 mg cohorts, respectively. No severe adverse events (AEs) or deaths occurred, and no major differences were observed in the incidence or severity of AEs across the cohorts. Serum E6011 concentrations increased dose dependently. American College of Rheumatology (ACR) 20, 50, and 70 responses at week 12 were 75.0%, 33.3%, and 8.3% in the 100 mg cohort; 66.7%, 20.0%, and 13.3% in the 200 mg cohort; and 60.0%, 30.0%, and 20.0% in the 400 mg cohort, respectively. Conclusions: E6011 appeared to be safe and well tolerated in RA patients during this 12-week treatment period, suggesting that E6011 has an effective clinical response in active RA patients.

Objectives: Post-marketing surveillance (PMS) was conducted to assess the safety and effectiveness of tacrolimus (TAC) add-on therapy for patients with rheumatoid arthritis (RA) and an inadequate response to biological disease-modifying anti-rheumatic drugs (DMARDs). Methods: Patients with RA from 180 medical sites across Japan were registered centrally with an electronic investigation system. The observational period was 24 weeks from the first day of TAC administration concomitantly with biological DMARDs. Results: Safety and effectiveness populations included 624 and 566 patients, respectively. Patients were predominantly female (81.1%), with a mean age of 61.9 years. Overall, 125 adverse drug reactions (ADRs) occurred in 94 patients (15.1%), and 15 serious ADRs occurred in 11 patients (1.8%). These incidences were lower compared with previously reported incidences after TAC treatment in PMS, and all of the observed ADRs were already known. A statistically significant improvement was observed in the primary effectiveness variable of Simplified Disease Activity Index after TAC treatment; 62.7% of patients achieved remission or low disease activity at week 24. Conclusions: TAC is well tolerated and effective when used as an add-on to biological DMARDs in Japanese patients with RA who do not achieve an adequate response to biological DMARDs in a real-world clinical setting.

© 2017, International League of Associations for Rheumatology (ILAR). To identify risk factors for the recurrence of interstitial lung disease (ILD) in patients with polymyositis (PM)/dermatomyositis (DM). Forty-four PM/DM-ILD patients who had been treated with glucocorticoid and/or immunosuppressive agents as a remission induction therapy were enrolled. The patients were first classified into two groups: the early recurrence group that recurred within 52 weeks, and the non-early recurrence group, which was further classified into the late recurrence group that recurred after 52 weeks, and the non-recurrence group. The characteristics and treatment regimen between the groups were compared. Recurrence was experienced by 15 of 44 patients. The pulmonary vital capacity of the early recurrence group was significantly lower than the non-early recurrence group (46 vs 76%, p = 0.0003), and 60% of the early recurrence group was treated with glucocorticoid alone as a maintenance therapy in contrast to 10% in the non-early recurrence group (p = 0.004). The late recurrence was only related with a positivity for autoantibodies against aminoacyl-tRNA synthetases (anti-ARS antibodies, odds ratio 8.4, p = 0.02), but calcineurin inhibitors tended to decrease the relapse incidence in patients with anti-ARS antibodies. Low pulmonary vital capacity at disease onset and anti-ARS antibodies positivity are the risk factors for the recurrence of ILD with PM/DM. Calcinuerin inhibitors are important in preventing relapse.

Objective. To clarify the safety of biologics in elderly patients with rheumatoid arthritis. Methods. Biologics were analyzed for safety in relation to age in 309 patients. Results. Young (< 65 yrs old, n = 174), elderly (65-74 yrs old, n = 86), and older elderly patients (? 75 yrs old, n = 49) were enrolled. Although the incidence of adverse events causing treatment withdrawal was significantly higher in elderly and old elderly compared with young patients, no difference was found between elderly and older elderly patients. Pulmonary complications were independent risk factors. Conclusion. Old patients require special attention, although the safety of biologics in those ? 75 years old and 65-74 was comparable.

© 2016 Japan College of Rheumatology. Published by Informa UK Limited, trading as Taylor & Francis Group. Objectives: This study aimed to evaluate the safety of CT-P13 in patients with rheumatoid arthritis (RA) during long-term treatment or after switching from innovator infliximab (IFX). Methods: Patients who completed 54 weeks of treatment in a phase I/II study (PI/II) received CT-P13 at an initial dose of 3 mg/kg at Week 62, with dose increases permitted up to 10 mg/kg. The primary endpoint was adverse event (AE) incidence. Results: Thirty-four of 38 patients in the maintenance group and 29 of 33 in the switch group reported at least one AE. Safety profiles in both groups were similar to those in PI/II. Eleven of 28 patients who were positive for anti-drug antibodies (ADA) at Week 62 discontinued the study before Week 110. Forty-one of 43 ADA-negative patients remained negative, and 10 of 28 ADA-positive patients became negative during the study. The mean DAS28 (ESR) at Week 134 was 3.166 in the maintenance group and 3.955 in the switch group. Conclusions: CT-P13 was well tolerated in patients who maintained the treatment after 54 weeks and in patients who switched to CT-P13 after 54 weeks of IFX treatment. The study also demonstrated a stable clinical efficacy of CT-P13 in RA patients.

© 2017 The Authors Infliximab, an inhibitor of TNF-α, is one of the most widely used biological disease-modifying antirheumatic drugs. Recent studies indicated that baseline serum TNF-α could be considered as a key indicator for optimal dosing of infliximab for RA treatment to achieve the clinical response and its sustained remission. The Remission induction by Raising the dose of Remicade in RA (RRRR) study is an open-label, parallel group, multicenter randomized controlled trial to compare the proportions of clinical remission based on the simplified disease activity index (SDAI) after 1 year of treatment and its sustained remission rate after another 1 year between the investigational treatment strategy (for which the dose of infliximab was chosen based on the baseline serum TNF) and the standard strategy of 3 mg/kg per 8 weeks of infliximab administration in infliximab-naïve patients with RA showing an inadequate response to MTX. The primary endpoint is the proportion of patients who kept discontinuation of infliximab 1 year after discontinued infliximab at the time of 54 weeks after the first administration of infliximab. The secondary endpoints are the proportion of clinical remission based on SDAI and changes in SDAI from baseline at each time point, other clinical parameters, quality of life measures and adverse events. Target sample size of randomized patients is 400 patients in total. The main results of the RRRR study are expected to be published at the end of 2017.