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Intestinal mucosal injury that develops as a complication of tocilizumab (TCZ) is usually associated with diverticulosis. We herein report a rare case of TCZ-induced intestinal mucosal injury in the absence of diverticulosis. A 74-year-old woman suffering from rheumatoid arthritis started taking TCZ. Six months later, she complained of hematochezia and abdominal pain. Colonoscopy revealed multiple ulcers spreading from the cecum to the transverse colon but no diverticulosis. These lesions were cured at three months after the discontinuation of TCZ. We should consider TCZ as a risk factor for intestinal mucosal injury, even if patients have no history of intestinal disease associated with diverticulosis.

Objectives: To investigate the efficacy of suppressing joint destruction with subcutaneous tocilizumab (TCZ-SC) for Japanese rheumatoid arthritis (RA) patients in the real-world clinical setting. Methods: This 1-year prospective, multicenter study included 110 RA patients in whom TCZ-SC was newly initiated. Primary endpoint was the change from baseline in vdH-modified total Sharp score (mTSS) at week 52. Structural remission was defined as yearly mTSS of 0.5 or less. Disease activity was evaluated using the disease activity score (DAS28-ESR) and clinical disease activity index (CDAI). Results: At baseline, the patients' mean age was 58.6 years, and the mean disease duration was 10.6 years. The proportion of patients who were naïve for biologics was 44.5%, and 64.5% concomitantly received methotrexate. The yearly mTSS showed significant improvement from 9.41 before TCZ-SC initiation to -0.15 after 52 weeks. The structural remission rate was 76.1%. After 52 weeks, the DAS28-ESR and CDAI remission rates were 52% and 21%, respectively. Although the previous usage of biologics and baseline disease activity significantly affected the clinical remission, no factors with significant effects on structural remission were identified. Conclusion: These findings support the efficacy of TCZ-SC in suppressing disease activity as well as joint destruction over a 1-year period.

Aim: The purpose of this study was to assess 5-year changes in physical function and factors associated with improvement among patients with rheumatoid arthritis (RA) in daily clinical practice, focusing on the effect of treatments, including biologic agents, in the early stage of disease course., Methods: The National Database of Rheumatic Diseases by iR-net in Japan (NinJa) was searched for patients with disease duration ≤ 2 years and modified health assessment questionnaire (mHAQ) > 0 between 2004 and 2007, so that 510 patients were included in the final analysis. Multivariate-logistic regression analyses were used to identify predictors of 5-year mHAQ disability score improvement., Results: Median mHAQ score was 0.40 at baseline and decreased to a median 0.17 after 5 years. Seventy-four percent of the patients were treated with methotrexate (MTX) and 25% with biologic agents, with early use of biologic agents (within 2 years of RA onset) increasing over time. Multivariate analyses identified higher baseline Disease Activity Score of 28 joints - C-reactive protein and early use of MTX (within 1 year of RA onset) and of biologic agents (within 2 years) as significantly associated with improved mHAQ; odds ratios of the early treatment were 1.83 (P = 0.01) for MTX and 2.23 (P = 0.04) for biologic agents, respectively., Conclusion: Five-year mHAQ improved in early RA patients in the NinJa database. In daily clinical management of RA, likewise in clinical trials, early administration of MTX or biologic agents is able to improve physical function outcome., (© 2016 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.)

Objective: To determine whether tofacitinib can be discontinued in patients with RA who achieve low disease activity (LDA)., Methods: RA patients with LDA after tofacitinib treatment in a phase III and long-term extension study were enrolled in this multicentre, non-randomized, open, prospective, observational study. The decision of discontinuation or continuation of tofacitinib was determined based on patient-physician decision making with informed consent. The primary endpoint was the proportion of patients who remained tofacitinib-free at post-treatment week 52. Clinical outcome was compared between those who continued and those who discontinued tofacitinib. The last observation carried forward method was used for patients who could not discontinue tofacitinib before week 52., Results: Of 64 patients, 54 discontinued and 10 continued tofacitinib therapy. At post-treatment week 52, 20 of the 54 patients (37%) of the discontinuation group remained tofacitinib-free without disease flare. Disease activity at post-treatment week 52 was higher in the discontinuation group than the continuation group. Among the discontinuation group, the RF titre at baseline was significantly lower in patients who remained tofacitinib-free than those who did not (40 vs 113 U/ml). In fact, a higher proportion of patients with lower RF remained tofacitinib-free at week 52 compared with those with higher RF at baseline. In patients who could not achieve tofacitinib-free status, re-initiation of tofacitinib or other biologics improved disease activity., Conclusion: It is possible to discontinue tofacitinib without flare in about a third of patients with RA. A low RF predicts maintenance of LDA after discontinuation of tofacitinib., (© The Author 2017. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com)

Aims: To analyse the clinicopathological characteristics and prognosis of 40 rheumatoid arthritis (RA) patients with methotrexate (MTX)-associated large B cell lymphoproliferative disorders (MTX-BLPD)., Methods and Results: Soluble interleukin 2 receptor titres (median 1500 U/ml) in 40 patients with MTX-BLPD were lower than those of 24 RA patients with non-MTX- associated (non-MTX) BLPD (5731 U/ml) and 15 with control diffuse large B cell lymphoma (DLBCL, 5918 U/ml) (P < 0.01). Using in-situ hybridization, Epstein-Barr virus (EBV) was detected in tumour cells of 25 of 40 RA patients with MTX-BLPD (63%). Immunohistologically, BCL2 expression was detected in 35% of patients with MTX-BLPD, which was lower than 93% of control DLBCL patients (P < 0.01). Eleven patients with EBV(+) MTX-BLPD (44%) showed remission after MTX withdrawal. In RA patients with clinical stage III/IV BLPD, 15 with rituximab (R)+ cytotoxic therapies pursued better prognosis than 10 with R- cytotoxic therapies (P < 0.05). Among the 15 patients, seven with MTX-BLPD showed better overall survival than nine control DLBCL patients (P < 0.01)., Conclusions: In RA patients with MTX-BLPD, immunosuppression by MTX, EBV infection and low BCL2 expression in tumour cells may play roles in tumorigenesis and tumour regression. R+ cytotoxic therapies as well as MTX withdrawal were highly effective in these patients., (© 2014 John Wiley & Sons Ltd.)

Introduction: In rheumatoid arthritis (RA) patients receiving immunosuppressive treatments, vaccination against Streptococcus pneumoniae is recommended. The objective of the study was to evaluate the effects of tacrolimus (TAC) on immune response following administration of a 23-valent pneumococcal polysaccharide vaccine (PPSV23) in patients with established RA., Methods: Patients with RA (n = 133) were vaccinated with PPSV23. Patients were classified into TAC (n = 29), methotrexate (MTX) (n = 55), control (n = 35), and TAC/MTX (n = 14) treatment groups. We measured the concentrations of pneumococcal serotypes 6B and 23F by using an enzyme-linked immunosorbent assay and determined antibody functionality by using a multiplexed opsonophagocytic killing assay, reported as the opsonization index (OI), before and 4 to 6 weeks after vaccination. A positive antibody response was defined as at least a twofold increase in the IgG concentration or as at least a 10-fold increase in the OI., Results: IgG concentrations and OIs were significantly increased in all treatment groups after PPSV23 vaccination. The TAC treatment group appears to respond in a manner similar to that of the RA control group in terms of 6B and 23F serotype concentration and function. In contrast, the MTX group had the lowest immune response. Patients who received a combination of TAC and MTX (TAC/MTX) also had a diminished immune response compared with those who received TAC alone., Conclusions: TAC monotherapy does not appear to impair PPSV23 immunogenicity in patients with RA, whereas antibody production and function may be reduced when TAC is used with MTX. Thus, PPSV23 administration during ongoing TAC treatment should be encouraged for infection-prone TAC-treated patients with rheumatic diseases., Trial Registration: University Hospital Medical Information Network Clinical Trials Registry: UMIN000009566. Registered 12 December 2012.

Objective: To evaluate the longterm safety and efficacy of subcutaneous tocilizumab (TCZ-SC) as monotherapy in patients with rheumatoid arthritis (RA)., Methods: Of 346 patients who received 24 weeks of double-blind treatment with either TCZ-SC monotherapy, 162 mg every 2 weeks (q2w); or intravenous TCZ (TCZ-IV) monotherapy, 8 mg/kg every 4 weeks; 319 patients continued to receive TCZ-SC q2w in the 84-week open-label extension (OLE) of the MUSASHI study (JAPICCTI-101117). Efficacy, safety, and immunogenicity were evaluated for all patients treated with TCZ during 108 weeks., Results: The proportions of patients who achieved American College of Rheumatology 20/50/70 responses, low disease activity [28-joint Disease Activity Score (DAS28) ≤ 3.2], or remission (DAS28 < 2.6) at Week 24 were maintained until Week 108. The incidences of adverse events and serious adverse events were 498.3 and 16.9 per 100 patient-years (PY), respectively. The overall safety of TCZ-SC monotherapy was similar to that of TCZ-IV monotherapy. Rates of injection site reactions (ISR) through 108 weeks remained similar to rates through 24 weeks. ISR were mild and did not cause any patient withdrawals. No serious hypersensitivity events (including anaphylactic reactions) occurred. Anti-TCZ antibodies were present in 2.1% of patients treated with TCZ-SC monotherapy., Conclusion: TCZ-SC monotherapy maintained a favorable safety profile and consistent efficacy throughout the 108-week study. Like TCZ-IV, TCZ-SC could provide an additional treatment option for patients with RA.

Objectives: To examine the long-term safety of intravenous (IV) abatacept treatment in Japanese patients with rheumatoid arthritis (RA) and an inadequate response to methotrexate (MTX) or other conventional or biologic disease-modifying antirheumatic drugs., Methods: This Phase III, open-label, long-term study (NCT00484289) comprised Japanese patients with RA who had completed abatacept Phase I or Phase II studies, and new patients intolerant to MTX. Patients from Phase I and Phase II studies received a weight-tiered dosing equivalent of 10 mg/kg abatacept, with MTX at doses up to 8 mg/week; newly enrolled patients received weight-tiered 10 mg/kg abatacept monotherapy. Safety and efficacy were assessed., Results: A total of 217 patients (Phase I, n = 13; Phase II, n = 178; newly enrolled, n = 26) were treated with IV abatacept for a mean of 3 years. Serious adverse events occurred in 67/217 (30.9%) patients. Most adverse events were mild or moderate. For all cohorts combined, American College of Rheumatology 20% response rates ranged from 61.3 to 81.8% for as-observed and last observation carried forward analyses over 192 weeks. Following initial response, clinical and functional outcomes were maintained for up to 3 years., Conclusions: In Japanese patients with RA, IV abatacept with and without background MTX showed tolerable safety and sustained efficacy over 3 years.

Objectives: This study aimed to evaluate the remission in rheumatoid arthritis (RA) patients treated with tocilizumab (TCZ), based on prospectively registered data in clinical practice., Methods: We studied 114 consecutive RA patients treated with TCZ for an average of 3.5 years. Remission was evaluated by using the EULAR criteria and the new ACR/EULAR Boolean-based criteria., Results: Among 114 patients (average age 52.2 years; average disease duration 10.6 years), 76 (67 %) had previously received anti-TNF biologics. Mean baseline DAS28-ESR of 5.4 and improved to 2.4 at 36 months. Overall, DAS28-ESR <2.6 was attained by 66.7 %, while ACR/EULAR remission was attained by 35.1 %. ACR/EULAR remission rate was significantly higher in the patients who were biologics-naïve and had good response at the first month. Among 23 patients who completed the treatment for 3 years and had ACR/EULAR remission at 1 year, 15 (65 %) remained in the remission and 16 (70 %) had a DAS28-ESR <2.6 at the final follow-up. The retention rate at 36 months was 68.2 %., Conclusions: In patients with RA, TCZ is highly effective for both biologics-naïve patients and patients previously exposed to biologics, achieving a high remission rate and drug continuation rate (68.2 %) in clinical practice.

We retrospectively analyzed in 54 consecutively enrolled Japanese patients with rheumatoid arthritis (RA) and lymphoproliferative disease (LPD) relevant clinicopathological characteristics, in particular paying attention to treatment with methotrexate (MTX). Between the 28 patients treated with MTX (MTX-treated group) and the 26 who were not (non-MTX group), there was no difference in age, interval between onset of RA and LPD, and lymphoma stage. Immunohistochemical analysis showed that in the MTX-treated group, 15 (53 %) patients had mature B-cell LPD, eight (29 %) mature T/NK-cell LPD, and five (18 %) had Hodgkin lymphoma. In the non-MTX group, 22 (84 %) had mature B-cell LPD, 2 (8 %) had mature T/NK-cell LPD, and 2 (8 %) had Hodgkin lymphoma. The frequency of mature T/NK-cell LPD was significantly higher in the MTX-treated group (p < 0.05). Of the eight patients in the MTX-treated group with mature T/NK-cell LPD, two had large granular lymphocytic leukemia and the other six had a variety of different histological types with frequent CD8 but not CD56 expression. Epstein-Barr virus (EBV) infection was significantly higher in the MTX-treated group (p < 0.05); evidence of latent type II EBV infection was found in four of the eight patients with mature T/NK-cell LPD. Withdrawal of MTX led to complete remission in seven patients with mature T/NK-cell LPD irrespective of EBV infection. Our findings highlight that mature T/NK-cell LPD is a frequent complication in RA patients treated with MTX. EBV infection may play a role in the pathogenesis of T/NK-cell LPD, as well as B-cell LPD and Hodgkin lymphoma in MTX-treated RA patients.

Objective: The objective of this study was to assess the response to abatacept at doses of 2 mg/kg and 10 mg/kg compared to placebo in patients with active rheumatoid arthritis (RA) with an inadequate clinical response to methotrexate (MTX)., Methods: In this multicenter, placebo-controlled, double-blind, parallel-group, dose-response study, 195 Japanese patients with active RA with an inadequate response to MTX were randomized 1:1:1 to receive 10 mg/kg or 2 mg/kg abatacept plus MTX, or placebo plus MTX, for 24 weeks., Results: Abatacept demonstrated a dose-response relationship when given at 2 and 10 mg/kg. Based on the American College of Rheumatology criteria (20, 50, and 70 %), the responses to 10 mg/kg abatacept were significantly greater than those to placebo at week 24 (p < 0.001). Smaller yet statistically significant responses were also seen in the 2 mg/kg abatacept group. Overall rates of adverse events, serious adverse events, and treatment discontinuations because of adverse events were comparable in all three groups., Conclusions: Abatacept (2 mg/kg and 10 mg/kg) showed a dose-response relationship in Japanese patients with active RA with an inadequate clinical response to MTX. Administration of abatacept in combination with MTX for 24 weeks was well tolerated.

What Is Known and Objective: Tumour necrosis factor-α (TNF-α)-blocking agents are increasingly used in the management of refractory rheumatoid arthritis (RA). Although effective, they are associated with rare but potentially fatal adverse effects, including interstitial lung disease (ILD). In patients with pre-existing ILD, eternacept (ETN) monotherapy is often regarded as a suitable choice. Other anti-TNF-α blockers such as infliximab and adalimumab, are used in combination therapy with methotrexate (MTX) in most of the cases. We report on a case of fatal exacerbation of ILD in a patient given ETN monotherapy and review the literature on ETN-associated ILD., Methods: We report on a case of a 75-year-old male with RA who developed severe ILD after the introduction of ETN, and we undertook a literature search to identify other reports of similar cases. We then critically assessed those reports., Results and Discussion: In addition to our case, 11 other patients have been reported to have developed ILD in association with the use of ETN. Six patients had pre-existing ILD. Although four patients received MTX, eight patients developed severe ILD without MTX. Ten patients recovered after termination of ETN, although two patients died., What Is New and Conclusion: Although ETN is often regarded as safe for patients with ILD, our case and the literature reports suggest that caution is still required., (© 2010 Blackwell Publishing Ltd.)

We retrospectively observed the clinical efficacy and safety of tocilizumab (TCZ) in 74 patients with rheumatoid arthritis (RA) at 13 hospitals, without any restrictions on disease duration or stage, treatment history, and other influencing factors. TCZ was infused by the approved method, and disease activity was evaluated every 4 weeks until week 24 using a joint disease activity score (DAS28). Remission and treatment response were categorised using European League Against Rheumatism (EULAR) definitions. We also analysed the impact of previous treatment with other biologics and of concomitant methotrexate (MTX) therapy on the efficacy of TCZ. At week 24, the DAS28 had improved from 5.5 to 2.7 and the EULAR remission rate was 55.2%. Good and moderate responses according to the EULAR criteria were obtained in 61 and 36% of the patients, respectively. The biologic-naïve group had a significantly better DAS28 (2.1 vs. 2.8) and a significantly higher "good" response rate (86% vs. 54%) than the biologic-exposed group. Although the TCZ + MTX treatment group and the TCZ monotherapy group had a good response rate of 71 and 48%, respectively, the difference was not significant. Based on these results, we conclude that TCZ is able to significantly alleviate disease symptoms in a wide range of patients with RA in a normal clinical context.

The appearance of tumor necrosis factor blockers changes the treatment goal of rheumatoid arthritis (RA) to include not only the inhibition of bone destruction, but also the induction of remission. We, herein, report two cases with RA that showed a prolonged remission after the discontinuation of etanercept. The two cases were 27 and 38 years of age, and their disease durations were 6 and 14 months, respectively. Their disease activity score 28 (DAS28) before treatment were 4.43 and 5.07, respectively. Case two was resistant to infliximab as determined by previous treatment with this therapy. Both cases showed a dramatic clinical response and discontinued etanercept in the 15th month and the 14th month after the start of treatment, respectively. No exacerbation of arthritis was evident after the discontinuation of etanercept as supported by the maintenance of DAS28 at less than 2.6. Moreover, after the discontinuation of etanercept, radiographic progression was not evident and decreased modified Sharp scores were observed for at least 1 year in both cases. These findings indicate that clinical and radiographic remission is possible in some patients with RA after the discontinuation of etanercept.

A 47-year-old man was admitted to our hospital in January, 2006 because of a huge cutaneous ulcer in his lower limb. He was diagnosed with polyarteritis nodosa due to the cutaneous ulcer, mononeuritis multiplex, muscular pain, elevated serum CRP level and from histological findings of a skin biopsy. He was initially treated with 60 mg/day of prednisolone, followed by 1000 mg/day of intravenous cyclophosphamide (IVCY) therapy. In June, skin grafting to the cutaneous ulcer was carried out, although the graft did not survive. He revealed therapy-resistance to high dose corticosteroid and IVCY therapy, and so was treated with intravenous high dose immunoglobulin therapy. Serum CRP level then decreased and in October skin grafting was once again undertaken, this time the graft successfully survived. In December, serum CRP level increased again and cutaneous ulcer relapsed, thus he was treated with leukocyte apheresis therapy, although it was ineffective. In February 2007, he subsequently received rituximab (375 mg/m(2)/week x 3). Then, serum CRP level decreased rapidly, and cutaneous ulcer also improved. Recently the efficacy of rituximab against rheumatoid arthritis, systemic lupus erythematosus, polymyositis/dermatomyositis and ANCA-associated vasculitis has been recognized. This case suggests that rituximab is also effective against corticosteroid-resistant polyarteritis nodosa.