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Objectives: To assess the best choice of second-line therapy between tumour necrosis factor-inhibitor (TNFi) and biologics of different-mode-ofaction (BDMA-rituximab/tocilizumab/abatacept) in rheumatoid arthritis (RA) by evaluating drug-survival following discontinuation of the first-line TNFi. Methods: This retrospective drug-survival study was performed across two different hospitals by conventional-statistics and machine-learning approach. Results: From a total of 435 patients, 213 (48.9%; TNFi = 122, BDMA = 91) discontinued their second-line biologic {median drug-survival: TNFi, 27 months [95% confidence interval (95%CI) 22-32] vs BDMA, 37 months (95%CI 32-52)}. As a second-line biologic, BDMA was likely to reduce the risk of treatment-discontinuation [hazard-ratio (HR) 0.63, 95%CI 0.48-0.83] compared to TNFi, but only in seropositive-patients (HR 0.52, 95%CI 0.38-0.73), not in seronegative-RA. Drug-survival benefit of BDMA over TNFi was not observed if the seropositive-patients were previously exposed to monoclonal-TNFi (HR 0.77, 95%CI 0.49-1.22) versus soluble-TNFi (etanercept/biosimilars) or if the first-line TNFi was terminated within 23.9 months of initiation (HR 0.97, 95%CI 0.56-1.68). Conclusions: BDMA, as a second-line biologic, is more likely to be sustained in seropositive-patients, particularly without prior exposure to monoclonal-TNFi. The drug-survival benefit of BDMA was not observed in seronegative-patients or if the first-line TNFi was stopped within 2 years. [ABSTRACT FROM AUTHOR]

Objectives: We aimed to evaluate the efficacy and safety of haematopoietic stem cell transplantation (HSCT) in patients with systemic sclerosis. Methods: A systematic literature review and meta-analysis were carried out. We compared survival outcomes using the Kaplan-Meier method with patient-level data between HSCT and intravenous pulse cyclophosphamide. Additionally, the incidence rate of treatment-related deaths with HSCT was pooled using a random-effect model. Results: Of the 2091 articles screened, 22 were included: 3 randomized controlled trials and 19 observational studies. HSCT studies showed significant improvement in the skin thickness score and lung function. Despite treatment-related deaths being higher in HSCT than in intravenous pulse cyclophosphamide, the Kaplan-Meier analysis showed a high survival rate of 2 years post-transplant (log-rank, P = 0.004). The pooled frequency of transplant-related death from 700 systemic sclerosis patients was 6.30% (95% confidence interval 4.21-8.38). However, the estimated frequency of treatment-related deaths has been reducing over the last decade. Conclusions: HSCT is an effective treatment for systemic sclerosis, but the optimal indications must be carefully determined by balancing the risks. [ABSTRACT FROM AUTHOR]

Objectives: To evaluate the efficacy and safety of biosimilars compared with reference biological disease modifying antirheumatic drugs (bDMARDs) in patients with rheumatoid arthritis (RA) as a part of the process of developing the 2020 update of the Japan College of Rheumatology guidelines for the management of RA. Methods: PubMed, Cochrane Library, and Japan Centra Revuo Medicina were searched for articles to conduct a systematic review (SR). The quality of evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation system. Results: Twenty randomized controlled trials were included (biosimilars of infliximab, etanercept, and adalimumab). A meta-analysis revealed that the risk ratios (RRs) and 95% confidence intervals (CIs) of achieving the American College of Rheumatology 50% response (ACR50) at week 24 and serious adverse events (SAEs) for biosimilars compared with the reference bDMARDs were 1.04 (0.98-1.10) and 0.84 (0.61-1.18), respectively. The RRs of achieving ACR50 and SAEs at week 24 were respectively 0.93 (0.69-1.26) and 2.15 (0.55-8.35) in the patients who switched to biosimilars from the reference bDMARDs and 0.92 (0.76-1.12) and 1.41 (0.32-6.15) in those who continued the reference bDMARDs. Conclusion: Biosimilars and reference bDMARDs were equally useful for the management of RA. [ABSTRACT FROM AUTHOR]

Objectives: Rheumatoid arthritis (RA) in patients undergoing immunosuppressive therapy (IS) is sometimes involved with other iatrogenic immunodeficiency-associated lymphoproliferative disorders (LPD). We aimed to clarify the effects of LPD treatment on RA and the current status of RA treatment options after LPD onset and subsequent IS withdrawal. Methods: We retrospectively analyzed data of patients who had RA with LPD and examined the relationship between LPD course and RA treatment as well as that between RA relapse and LPD treatment. Results: LPD patients were categorized into two groups: patients who regressed spontaneously (n=19) and those who needed chemotherapy (n=12). The chemotherapy group had significantly less RA relapse than the spontaneous regression group (p=.041). RA almost relapsed early in the spontaneous regression group and needed treatment for RA. Chemotherapy with rituximab prevented longterm RA relapse, and RA did not relapse for long even after rituximab monotherapy. The total dose of rituximab in monotherapy correlated with the time to RA relapse. Six patients with RA relapse received biologics and had no LPD relapse for more than 1 year. Conclusions: Rituximab in chemotherapy for LPD may help prevent RA relapse with LPD. Large-scale studies are required in the future for verification. [ABSTRACT FROM AUTHOR]

Objectives: To assess the real-world effectiveness of golimumab in Japanese patients with rheumatoid arthritis who had previously received one or more biologic therapies. Methods: A post-hoc analysis of post-marketing surveillance was performed. The clinical response to golimumab was analyzed in 1216 patients who had previously received one or more biologic agents including non-TNF inhibitors with stratification by the number of previous biologic agents. Logistic regression analyses were conducted to identify factors associated with DAS28-CRP response to golimumab. Results: While treatment persistence is comparable, the response to golimumab declined with an increasing number of previous biologic therapies. When stratified by golimumab dose, patients receiving golimumab at 100mg had higher disease activity at baseline with an increasing number of previous bDMARDs, but they still achieved comparable disease activity at 24 weeks regardless of how many bDMARDs had been previously used. Univariate and multivariate analyses both identified concomitant oral corticosteroid therapy as a factor negatively associated with the likelihood of achieving a DAS28-CRP response. Conclusion: Switching to golimumab was effective regardless of how many biologic agents had been previously used, but the response declined with an increasing number of prior biologic agents. A golimumab dose of 100mg was also effective for those who previously received three or more bDMARDs. [ABSTRACT FROM AUTHOR]

Objectives: To assess the real-world effectiveness of golimumab in Japanese patients with rheumatoid arthritis who had previously received first-line biologic therapy. Methods: A post-hoc analysis of post-marketing surveillance was performed. The effectiveness of golimumab was assessed in 731 patients with an inadequate response to first-line biologic therapy stratified by their prior biologic agents. Outcome variables included DAS28-CRP, DAS28-ESR, SDAI and CDAI, and medication persistence. Logistic regression analyses were conducted to identify factors associated with the likelihood of achieving a DAS28-CRP response (good/moderate) after 24 weeks of golimumab treatment. Results: Patients demonstrated significant improvement in the clinical signs and symptoms of rheumatoid arthritis at 24 weeks, as indicated by the reduction of DAS28-CRP (D0.87), DAS28-ESR (D0.85), SDAI (D7.32), and CDAI (D6.98) scores. This result was consistent across the subgroups stratified by previous biologic therapy. Multivariate analysis failed to identify any factors associated with response to golimumab. Conclusion: In the real-world clinical setting, switching to golimumab was effective for Japanese patients with an inadequate response to first-line biologic therapy regardless of the biologic agent, including both TNF and non-TNF inhibitors. [ABSTRACT FROM AUTHOR]

Objectives This study aimed to evaluate the efficacy of add-on iguratimod (IGU) in patients with rheumatoid arthritis (RA patients) who inadequately respond to either tocilizumab (TCZ) or tumor necrosis factor alpha inhibitors (TNFi). Methods Twenty-three RA patients treated with TCZ (the TCZ group) and 23 RA patients treated with TNFi (the TNFi group) were enrolled in this 24-week retrospective study from our multicenter registry. All inadequate responders to either TCZ or TNFi received add-on IGU. Baseline demographics and disease activity at 24 weeks after initiating add-on IGU were compared between the two groups. Results Baseline clinical disease activity index (CDAI) values in the TCZ group and TNFi group were 14.1 and 11.8 (p = .24 between the two groups). At 24 weeks, CDAI values in the TCZ group and TNFi group were 5.1 and 7.5 (p = .002 and .002 compared to baseline, respectively) and ΔCDAI values were -9.0 and -4.3 (p =.007 between the two groups). Multiple linear regression analysis revealed that add-on IGU in the TCZ group was associated with greater improvement in CDAI relative to the TNFi group. Conclusion Add-on IGU was more effective in inadequate responders to TCZ than in inadequate responders to TNFi. [ABSTRACT FROM AUTHOR]

Objectives We evaluated long-term control of rheumatoid arthritis (RA) in Japanese paid workers (PWs) and house workers (HWs) treated with subcutaneous tocilizumab (TCZ-SC) and explored factors affecting response to TCZ-SC regarding work productivity. Methods This study collected data from patients with RA in the TCZ-SC +/- conventional synthetic disease-modifying antirheumatic drugs group. Factors affecting the response to tocilizumab regarding work productivity were explored using logistic regression. Differences in quality-adjusted life years (QALYs) between with/without response were analysed by a linear regression. Results Data were analysed for 357/360 patients. Patients with a ≥ 75% improvement in activity impairment (AI) were considered responders. EuroQol-5 Dimension (EQ-5D), six-item Kessler psychological distress scale score (K6), Health Assessment Questionnaire Disability Index (HAQ-DI), and the patient's disease global health by visual analogue scale were significant contributors to TCZ-SC response based on improvements in AI. Work Functioning Impairment Scale, presenteeism, EQ-5D, K6, and HAQ-DI significantly contributed to the improvement of overall work impairment in PWs. Shorter disease duration also was related to TCZ-SC response based on AI improvements. Responders had significantly larger mean QALYs than non-responders (difference = 0.2614; p < .001). Conclusions These real-world clinical data support long-term work productivity control with TCZ-SC for biologic-naïve HWs and PWs with RA. [ABSTRACT FROM AUTHOR]

Objectives: To assess the middle-term outcome of iguratimod (IGU) in rheumatoid arthritis (RA) patients. Methods: Sixty-nine RA patients (14 males and 55 females, mean age of 64.0 years) receiving IGU-containing therapies were enrolled. We divided these patients into three groups based on the treatment at the baseline: an IGU group, a methotrexate (MTX) plus IGU group, and a biologics plus IGU group. The baseline characteristics and clinical course were evaluated over three years. Predictive factors associated with the achievement of low disease activity (LDA) were statistically analyzed. Results: The survival rate of IGU therapy at 3 years was 40.6%. The disease activity was significantly decreased in the IGU group and MTX plus IGU group compared with the baseline. Furthermore, 38 patients (55.1%) were in remission or had LDA at 3 years. The patient gender, use of prednisolone (PSL) and DAS28-CRP at baseline were the factors associated with the achievement of remission or LDA at three years. Conclusion: IGU was effective without MTX or bDMARDs as well as in combination with MTX. A female gender, no use of PSL and a low DAS28-CRP at the initiation of IGU were associated with clinical remission or LDA achievement at three years. [ABSTRACT FROM AUTHOR]

Tocilizumab (TCZ) is an interleukin-6 (IL-6) inhibitor used for the treatment of rheumatoid arthritis (RA). It was developed in 2008, and its effectiveness is supported by evidence from all over the world based on its first decade of use. Although the overall efficacy and safety profiles of TCZ are similar to those of tumor necrosis factor (TNF) inhibitors, TCZ displays certain differences. The most notable advantage of TCZ is its usefulness as a monotherapy. Additionally, TCZ is favorable in the improvement of systemic inflammatory symptoms such as anemia and fatigue. The low immunogenicity of TCZ contributes favorably to long-term drug retention. Due to frequent relapse after TCZ cessation, TCZ use should be tapered beyond remission. During TCZ therapy, C-reactive protein (CRP) is unable to recognize disease activity and the severity of infection. The most common adverse events (AEs) are infection and abnormalities in laboratory findings including dyslipidemia, neutropenia, thrombocytopenia, and abnormality of liver enzymes. TCZ obscures the symptoms of infection. Therefore, stealth infections without obvious CRP elevation can sometimes cause severe damage to patients. Lower intestinal perforation is an uncommon but serious AE in TCZ therapy. Further clinical investigations will continue to refine the IL-6 inhibitory strategy. [ABSTRACT FROM AUTHOR]

Objectives: The objective of this study is to compare the effectiveness of biological disease-modifying antirheumatic drugs (bDMARDs) by analyzing claims data of 13 Japanese national university hospitals. Methods: We evaluated 4970 cases of rheumatoid arthritis treated with bDMARDs from the Clinical Information Statistical Analysis database, which has collected and integrated 13 Japanese national university hospitals' claims data for 10 years. We surveyed the medications and calculated the retention rates of bDMARDs using the Kaplan-Meier method and differentiated the effectiveness between the two bDMARDs by comparing the retention rates after switching from one drug to another. Results: Of the 4970 cases, 1364 switched bDMARDs at least once. Tocilizumab (TCZ) reported the highest retention rate, whereas abatacept (ABT) revealed a similar rate compared with only naïve cases. The retention rate curves were higher in cases on TCZ that switched from the other bDMARDs than those in the reversed cases. Following TCZ, ABT and etanercept indicated better results than the other bDMARDs. Conclusion: We could compare the effectiveness among bDMARDs by differentiating the retention rates from big claims data. TCZ reported higher retention rates in both naïve and switched cases than other bDMARDs. [ABSTRACT FROM AUTHOR]

Objectives: The objective of this study is to evaluate the safety and effectiveness of subcutaneous tocilizumab (TCZ-SC) in a real-world clinical setting in Japan. Methods: This single arm, 26-week prospective observational study enrolled patients with RA who were either TCZ naïve or switched from TCZ-IV to TCZ-SC (TCZ-IV-SC group) (UMIN Clinical Trials Registry UMIN000011102). All patients received TCZ-SC 162 mg every 2 weeks and data were collected until week 26 or discontinuation. Results: Overall 784 (78.1%) were TCZ naïve and 219 (21.8%) were in the TCZ-IV-SC group. 70.9% received disease-modifying antirheumatic drugs at baseline. Adverse events (AEs) and serious AEs occurred in 28.2% and 4.9% of patients, respectively (TCZ-naïve: 29.5% and 5.2%; TCZ-IV-SC: 23.2% and 4.1%). Infections and infestations were the most common AEs (7.4%) and serious AEs (1.7%). Two TCZ-naïve patients died. TCZ-naïve patients had an improvement in median Clinical Disease Activity Index (CDAI) score and mean Disease Activity Score in 28 joints as measured by erythrocyte sedimentation rate (DAS28-ESR) from baseline to week 26. The TCZ-IV-SC group had similar median CDAI scores and mean DAS28-ESR over 26 weeks. Conclusions: There were no unexpected safety signals with TCZ-SC. TCZ-SC was effective in reducing disease activity in TCZ-naïve patients and maintaining remission in TCZ-IV-SC patients. [ABSTRACT FROM AUTHOR]

Objectives: In this study, iguratimod (IGU) was added to rheumatoid arthritis (RA) patients inadequately responding to 24-week or longer treatment with biological disease-modifying antirheumatic drug (bDMARDs), its effectiveness was assessed, and factors contributing to remission were evaluated. Methods: RA patients who fulfilled the following criteria were included: (i) ≤24-week of bDMARDs; (ii) 2.6

Objective: To determine the efficacy and safety of subcutaneous tocilizumab (TCZ-SC) monotherapy every week (qw) versus every other week (q2w) in patients with rheumatoid arthritis who had an inadequate response to TCZ-SC q2w. Methods: Adult patients in Japan with inadequate response to TCZ-SC q2w were randomized to either TCZ-SC 162mg qw monotherapy or TCZ-SC 162mg q2w monotherapy for 12 weeks (double-blind). The primary endpoint was the change from baseline in adjusted Disease Activity Score 28-erythrocyte sedimentation rate (DAS28-ESR) at week 12. Efficacy, safety and pharmacokinetics were assessed. Results: TCZ-SC qw was superior to TCZ-SC q2w for adjusted mean change in DAS28-ESR from baseline to week 12. The difference in the change in DAS28-ESR between TCZ-SC qw and q2w was ≤1.21 (95%CI:≤2.13, ≤0.30, p=.0108). A higher proportion of patients receiving TCZ-SC qw achieved DAS28-ESR remission/low disease activity than TCZ-SC q2w. Adverse events were 71.4% and 66.7% for TCZ-SC qw and q2w, respectively; infection was the most common event with one fatal case with TCZ-SC qw. Conclusions: In patients with inadequate response to TCZ-SC q2w, shortening the dosing interval to qw improved efficacy with acceptable tolerability. Occurrence of infection for both TCZ q2w and qw is important and needs careful attention. [ABSTRACT FROM AUTHOR]

Objectives: Several biological disease-modifying antirheumatic drugs (bDMARDs) are currently available for the treatment of rheumatoid arthritis (RA). Increasing evidence indicates that second-line bDMARDs are effective for inadequate responders to first-line bDMARDs. However, all previous studies investigated the use of tumor necrosis factor inhibitors (TNFi) as a first-line bDMARD, while investigated the efficacy of second-line bDMARDs after the use of tocilizumab (TCZ), a non-TNFi, as a first-line bDMARD. Thus, we investigated the efficacy of golimumab (GLM) as a second-line bDMARD after treatment with TCZ as a first-line bDMARD. Methods: The final study population consisted of 26 patients (inadequate responders to TCZ; TCZ group) with moderate or high disease activity (DAS28-ESR 3.2) at week 24 of treatment with TCZ as a first-line bDMARD or whose DAS28-ESR score worsened after starting TCZ treatment. These patients could be followed for another 52 weeks or more after the subsequent switch to GLM treatment. For comparison, 19 patients treated with TNFi as a firstline bDMARD and inadequate response to TNFi (TNFi group) were included. Results: The DAS28-ESR score at week 52 after the start of treatment with GLM improved significantly compared with baseline in the TCZ and TNFi groups. However, the TCZ group showed significantly better improvement. Patients in both groups had significantly improved treatment outcomes according to European League Against Rheumatism response criteria, but there was no statistically significant difference among them. The retention rate at week 52 after the start of treatment with GLM was significantly higher in the TCZ group than in the TNFi group (81% vs. 68%, respectively). In addition, no difference was found in the progression of bone destruction determined by the change in van der Heijde modified total Sharp scoring system scores between groups. Conclusions: GLM was an effective therapeutic option for inadequate responders to TCZ. [ABSTRACT FROM AUTHOR]

Objectives: To compare the utility of QuantiFERON-TB Gold in tube (QFT-GIT) and T-SPOT.TB assays to detect past tuberculosis infection in Japanese rheumatoid arthritis patients receiving methotrexate. Methods: We compared the sensitivities and specificities, the rates of indeterminate results, and the rates of positive results in patients with total and CD4-positive lymphocyte counts of both assays simultaneously performed on 68 rheumatoid arthritis patients receiving methotrexate, in whom 33 had evidence of past tuberculosis infection by chest computed tomography and the other had neither history of tuberculosis exposure nor abnormalities in chest computed tomography. Results: The sensitivities, specificities, and the rates of indeterminate results of QFT-GIT were 21.2%, 100%, and 4.4%, and those of T-SPOT.TB were 21.9%, 100%, and 1.5%, respectively. The overall agreement of both assays was good (= 0.68). In patients with past tuberculosis infection, there are significant positive linear trends in positive rates of both assays across ranges of larger numbers of total and CD4-positive lymphocyte counts. Conclusions: Both assays were equally useful with high specificities, but may falsely identify past tuberculosis infection owing to low sensitivities. In patients with low total and CD4-positive lymphocyte counts, both assays might give higher rates of false negative results. [ABSTRACT FROM AUTHOR]

Objectives: To investigate the use of tocilizumab (TCZ) in pregnant patients with active rheumatoid arthritis (RA) refractory to anti-tumour necrosis factor (TNF) agents. Methods: We retrospectively analysed the medical records of pregnant women with active RA treated between July 2008 and January 2015 by the Division of Maternal Medicine at our hospital. Inclusion criteria for this case series included active RA refractory to anti-TNF agents and exposure to TCZ at the time of conception. Results: Our review of 28 patient hospital records identified four patients who met the inclusion criteria. All four patients had active synovitis before starting treatment with TCZ. Successful TCZ therapy allowed them to plan to become pregnant. When pregnancy was confirmed, TCZ was terminated as soon as possible in all patients. Three patients delivered full-term infants without any adverse outcomes. One patient had a partial molar pregnancy and miscarried during gestational week 11. Two patients remained in clinical remission with low-dose prednisolone (PSL) or no treatment for RA during pregnancy. Conclusions: TCZ may be a good alternative therapy for RA patients with symptoms that are hard to control with TNF blockers who desire to bear children. [ABSTRACT FROM AUTHOR]

Objectives: This phase II, dose-ranging, double-blind, placebo-controlled, randomized study (NCT01463059) evaluated efficacy and safety of olokizumab (OKZ), a humanized antiinterleukin 6 monoclonal antibody, in Asian patients with moderately-to-severely active rheumatoid arthritis (RA) who had previously failed anti-TNF therapy. Methods: Patients were randomized to one of six treatment arms: placebo or OKZ (60 mg/120 mg/240mg every four weeks [Q4W]; or 60 mg/120mg every two weeks [Q2W]); stratified by country and number of prior anti-TNFs. Primary efficacy variable was Week 12 change from baseline (CFB) in DAS28 CRP for 4-week cumulative dose groups of OKZ and placebo; secondary efficacy variables were Week 12 ACR20/ACR50/ACR70 response rates. Patients continued MTX treatment from baseline, without additional csDMARDs. Results: Of 119 randomized patients, 88.2% completed the study. Greater improvements in DAS28(CRP) mean CFB at Week 12 were observed in all OKZ 4-week cumulative dose groups (60 mg/120 mg/240 mg) versus placebo (p<0.0001). Week 12 ACR20/ACR50 response rates were higher in all OKZ cumulative dose groups versus PBO (p<0.05). Incidences of adverse events were similar across OKZ 4-week cumulative dose groups (76.9-84.4%) and placebo (82.8%) with no deaths. Conclusions: OKZ demonstrated improvements in efficacy variables versus placebo in Asian patients with moderately-to-severely active RA who had previously failed anti-TNF therapy. The safety profile was as expected for this class of drug. [ABSTRACT FROM AUTHOR]

Objectives. To evaluate the subclinical articular involvement in patients with primary Sjögren's syndrome (pSS) using musculoskeletal ultrasound (MSUS), and to correlate the findings with laboratory results and clinical manifestations. Methods. Forty-eight consecutive patients with pSS were enrolled. The bilateral metacarpophalangeal, proximal interphalangeal, and interphalangeal joints were examined using MSUS, and the synovial hypertrophy and power Doppler signal were recorded for each joint using semiquantitative scores (0 = normal, 1 = mild change compared with undamaged joint, 2 = moderate change, and 3 = severe change). Results. Mild or moderate synovial hypertrophy was found in 151 (15.7%) and 2 (0.2%) out of 960 hand joints, respectively, and power Doppler signals were present in 19 (2.0%) of the 960 joints. While anti-centromere antibody (ACA) was found in 10 patients (20.8%), none of the patients with MSUS-confirmed synovitis was positive for ACA. No other autoantibodies, laboratory tests, or clinical manifestations correlated with MSUS-confirmed synovitis. Conclusion. MSUS is useful for detecting subclinical synovitis in pSS patients. MSUS showed that ACA-positive pSS patients had a low prevalence of synovitis. [ABSTRACT FROM AUTHOR]

Objectives To investigate the duration of remission and low disease activity (LDA) after cessation of tocilizumab (TCZ) treatment in rheumatoid arthritis patients who showed remission or LDA as assessed by DAS28 in response to preceding TCZ monotherapy, and to explore the factors contributing to prolonged efficacy duration. Methods Disease activity was monitored for 56 weeks. The rate of continued efficacy was estimated by Kaplan-Meier curves. Results A total of 187 patients were eligible. At baseline of this study, median disease duration was 7.8 years, preceding TCZ treatment period was 4.0 years and DAS28 was 1.5. The rate of continued LDA at 52 weeks was 13.4 % according to the Kaplan-Meier estimate. 19 patients (10 %) were completely drug-free and 17 patients (9.1 %) fulfilled DAS28 remission at 52 weeks. Multivariate Cox regression analysis identified low serum IL-6 and normalisation of MMP-3 levels at cessation of TCZ as independent predictive markers for longer duration of LDA. In patients with low serum IL-6 (<12.9 pg/mL) and normal MMP-3 levels, the rate of continued LDA reached 38.0 % at 52 weeks. Conclusions TCZ monotherapy may induce biologics-free remission or LDA without concomitant use of synthetic DMARDs. Serum levels of IL-6 and MMP-3 are useful markers for identifying patients who could discontinue TCZ without acute disease flare. [ABSTRACT FROM AUTHOR]

Objectives To evaluate the safety and efficacy of retreatment with tocilizumab (TCZ) in patients who had participated in the DREAM study ( Drug free remission/low disease activity after cessation of tocilizumab [Actemar] monotherapy study) and had experienced loss of efficacy. Methods Patients were retreated with TCZ or other disease modifying antirheumatic drugs (DMARDs). Disease activity was measured using the 28-joint disease activity score (DAS28) for 12 weeks. Results A total of 164 eligible patients, including 161 who experienced loss of efficacy within 52 weeks of the DREAM study, resumed treatment: 157 with TCZ and 7 with DMARDs and/or infliximab. Of TCZ-treated patients, 88.5 % (139 patients) achieved DAS28 <2.6 within 12 weeks, whereas among patients treated with DMARDs and/or infliximab only 14.3 % (1 patient) achieved DAS28 <2.6. Adverse events were observed in 70 TCZ-treated patients (44.0 %), but no serious infusion reactions were observed. Conclusions Retreatment with TCZ was well-tolerated and effective in patients who had responded to the preceding TCZ monotherapy but had experienced loss of efficacy after cessation of TCZ. [ABSTRACT FROM AUTHOR]

Objective: Tocilizumab (TCZ) is effective in patients with rheumatoid arthritis (RA) who are refractory to anti-tumor-necrosis-factor (anti-TNF) biologics. The Rheumatoid Arthritis Society Disease Activity Score in 28 Joints (DAS28) is used to evaluate the response to TCZ. However, DAS28 is inappropriate marker because TCZ normalizes C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) in the early stage of treatment. The aim of our study was to test the usefulness of magnetic resonance imaging (MRI)-based markers of response to TCZ treatment. Methods: Nine patients with RA who were refractory to anti-TNF inhibitors (six to infliximab, one to etanercept, one to adalimumab, and one to both) were assessed. MRI images of both hands were obtained by low-field extremity MRI at baseline, 20, and 44 weeks of treatment, in addition to assessment with DAS28-ESR. The effect of TCZ on RA was examined by compact MRI score (cMRIS). Results: All patients showed good or moderate response to TCZ treatment, as evaluated by significant reduction in DAS28-ESR at both 20 and 44 weeks ( p < 0.001, each, relative to baseline). In contrast, MRI-based indexes (e.g., cMRIS, synovitis, edema, erosion scores) improved significantly at 44 weeks but not at 20 weeks. Conclusion: Differences in response to TCZ therapy were determined based on the method of evaluation, suggesting that MRI-based markers are potentially useful for evaluating RA response to TCZ therapy. [ABSTRACT FROM AUTHOR]

Objective: To evaluate perioperative changes in rheumatoid arthritis (RA) patients treated with tocilizumab. Methods: We collected RA cases with tocilizumab and orthopaedic surgery from 1999 to 2010. Incidences of postoperative infections, delayed wound healing, and RA symptom flare-ups were extracted from the data for comparison with patients without these postoperative events. We also evaluated the changes in C-reactive protein (CRP) and body temperature in patients without postoperative complications with normal CRP before surgery, i.e., patients without postoperative events in whom the tocilizumab level was maintained, for each duration to discontinuation before surgery. Results: A total of 161 cases ( n = 122) were collected. The patients had mean age of 56.9 years, and mean disease duration of 12.8 years at operation. Joint replacement surgery was performed in 89 cases. Three patients had postoperative infections (two superficial and one organ/space surgical-site infection), 20 had delayed wound healing, and 36 had RA symptom flare-ups. Delayed wound healing occurred most commonly in patients who underwent spinal surgery ( P = 0.0061, versus patients without delayed wound healing). CRP levels were high when tocilizumab was restarted in patients with RA symptom flare-ups ( P = 0.0010, versus patients without RA symptom flare-ups). Increased postoperative CRP was observed in patients without postoperative events when the duration from final tocilizumab infusion to surgery was long. The changes in body temperature showed a similar trend to CRP. Conclusions: Although it has been demonstrated that infection rates in patients treated with tocilizumab are by no means high, incidence of delayed wound healing was significantly higher in cases with surgical interventions such as foot and spinal surgeries. Many patients treated with tocilizumab remained in a normal range of CRP even during the perioperative period. For prevention of perioperative complications, observation of postoperative conditions and surgical wounds, and subjective symptoms of patients are considered important. [ABSTRACT FROM AUTHOR]

A 69-year-old man with sensorineural hearing loss and iritis was diagnosed with atypical Cogan's syndrome. He had several systematic manifestations: aortitis, meningitis, panniculitis and seronegative arthritis. Remission induced by treatment with high doses of prednisolone was followed by relapse within 1 year. Although his condition was resistant to various immunosuppressive drugs, including methotrexate, cyclosporine, azathioprine and adalimumab, his symptoms, inflammatory response and quality of life measures were successfully improved by tocilizumab, a humanized anti-interleukin-6 receptor antibody. [ABSTRACT FROM AUTHOR]

We investigated the influence of antibodies against infliximab and etanercept on the serum trough levels of these agents and the influence of these antibodies on the effectiveness of treatment in patients with rheumatoid arthritis treated with these agents. Forty patients treated with infliximab for 54 weeks and 40 patients treated with etanercept for 32 weeks were enrolled. They were divided into responder and non-responder groups. Serum trough levels of and antibodies against these agents were measured by enzyme-linked immunosorbent assay or radioimmunoassay. Of the 40 patients treated with infliximab, 14 (35%) had anti-infliximab antibodies. Serum trough levels were significantly lower in the non-responder group (14 patients) than in the responder group (26 patients) 6 weeks after initiation of infliximab ( p < 0.05). Conversely, titers of anti-infliximab antibody were significantly higher in the non-responder group than in the responder group between 6 and 38 weeks after initiation of infliximab ( p < 0.05). Anti-etanercept antibodies were not detected in any patients on etanercept. Serum trough levels of etanercept were not significantly different between the responder (31 patients) and non-responder groups (9 patients). It seems that the appearance of anti-infliximab antibodies might decrease infliximab serum concentrations and, thereby, reduce the agent's effectiveness. The clinical efficacy of etanercept does not appear to be affected by the serum concentrations if it is administered at standard doses. [ABSTRACT FROM AUTHOR]

A retrospective study of 39 rheumatoid arthritis (RA) patients with an inadequate response to infliximab was conducted. The responses of subjects switching from infliximab to tocilizumab ( n = 23) were compared to those of subjects switching to etanercept ( n = 16). Disease activity was assessed by the Disease Activity Score 28-CRP ([C-reactive protein] DAS28-CRP), the Simplified Disease Activity Index (SDAI), and the Clinical Disease Activity Index (CDAI). Twenty-two patients completed 48 weeks of tocilizumab treatment, and 15 patients completed 48 weeks of etanercept treatment. In both treatment groups, 1 patient each discontinued treatment because of lack of efficacy. No serious adverse events occurred during the study, and no patients in either group withdrew due to adverse events. At week 48, there was a significant reduction from baseline in DAS28-CRP, SDAI, and CDAI values after switching to either tocilizumab or etanercept, and there was no significant difference in efficacy, as measured by the DAS28-CRP, SDAI, and CDAI, between the two treatment groups ( p = 0.12, 0.76, and 0.86, respectively). These results suggest that safety and tolerability were similar for both treatments. A switch from infliximab to either tocilizumab or etanercept in patients with RA who have not responded to infliximab is a feasible, well-tolerated treatment option. [ABSTRACT FROM AUTHOR]

We aimed to demonstrate the incidence of serious respiratory infections in patients with rheumatoid arthritis (RA) treated with tocilizumab (TCZ) monotherapy. We analyzed the incidence of serious respiratory infections in 601 RA patients enrolled in TCZ clinical trials and their extension studies (TCZ cohort) and in 601 age- and sex-standardized RA patients treated in daily clinical practice at Tokyo Women's Medical University (IORRA subsample cohort). The rates of serious respiratory infections were 1.77 per 100 patient-years from 1999 to 2008 in the TCZ cohort and 0.53 per 100 patient-years from 2000 to 2009 in the IORRA subsample cohort. With the IORRA subsample cohort regarded as a standard population, the standardized incidence ratio (SIR) of serious respiratory infection in the TCZ cohort was 3.64 [95% confidence interval (CI) 2.56-5.01], standardized for age and sex; 2.35 (95% CI 1.66-3.24), standardized for age sex, and corticosteroid use; 1.85 (95% CI 1.30-2.55), standardized for age sex, and pre-existing pulmonary involvement; and 2.41 (95% CI 1.68-3.34) standardized for age sex, and disease activity. The risk of serious respiratory infection in the TCZ cohort was approximately double that in the IORRA subsample cohort after standardizing for corticosteroid use, pre-existing pulmonary involvement, or disease activity. This is comparable to the risk reported when tumor necrosis factor (TNF) inhibitors are used. [ABSTRACT FROM AUTHOR]

We aimed to clarify the degree of improvement in disease control following early treatment of rheumatoid arthritis (RA) in daily clinical practice in 2006 compared to that in 2001. Using a large observational Japanese RA cohort (IORRA), we analyzed changes in clinical parameters, including disease activity assessed by the disease activity score 28 (DAS28) and physical disability assessed by the Japanese version of the Health Assessment Questionnaire (J-HAQ), which occurred within 2 years of cohort inception. All patients had enrolled in the IORRA cohort within 1 year of RA onset, in either 2001 (2001-cohort) or 2006 (2006-cohort). For both cohorts, changes in clinical features over 2 years were compared by Fisher's exact test or the Wilcoxon test. The 2001-cohort included 71 patients and the 2006-cohort included 56 patients. Over the 2-year period for each cohort, DAS28 significantly decreased from 3.9 to 3.5 in the 2001-cohort ( p < 0.001) and from 4.1 to 3.1 in the 2006-cohort ( p < 0.0001), and J-HAQ significantly decreased from 0.62 to 0.49 ( p < 0.02) in the 2001-cohort and from 0.71 to 0.41 ( p < 0.001) in the 2006-cohort. Greater improvement in disease activity over 2 years occurred in the 2006-cohort than in the 2001-cohort ( p < 0.05). Better disease control was obtained following changes in RA treatment strategy that occurred in Japan between 2001 and 2006. [ABSTRACT FROM AUTHOR]

To characterize primary failure to infliximab and determine the efficacy of switching to tocilizumab in patients with rheumatoid arthritis (RA), we examined 24 RA patients who had started on infliximab therapy (3 mg/kg) as their first biological agent. Nine of the 24 patients were found to be primary nonresponders, defined as patients who had never achieved a 20% clinical improvement according to the American College of Rheumatology criteria (ACR20) during induction therapy. The remaining 15 patients had achieved an ACR20 response to infliximab, without any relapses, for at least the first 14 weeks. A higher baseline health assessment questionnaire score was markedly associated with primary unresponsiveness to infliximab ( p = 0.0005). Six of the 9 primary nonresponders showed rapid clearance of infliximab: their trough concentrations of infliximab were under 1 μg/ml. The other 3 were classified as exhibiting the residual type of unresponsiveness, which was defined as unresponsiveness in patients who maintained serum infliximab levels above 1 μg/ml. Human antichimeric antibody was not detected in the rapid-clearance nonresponders. Dose escalation (5 mg/kg) was insufficiently effective. Primary nonresponders to infliximab were started on tocilizumab therapy (8 mg/kg, every 4 weeks), and their responses were assessed after 24 weeks of this second attempt at therapy. All the nonresponders, except for a single rapid-clearance patient, had achieved an ACR20 clinical improvement at the time of assessment. In conclusion, primary nonresponders to infliximab can be classified into rapid-clearance and residual types, based on their trough concentrations of infliximab, but both types of nonresponders seem to benefit from an early decision to discontinue infliximab therapy and switch to tocilizumab. [ABSTRACT FROM AUTHOR]

We evaluated the efficacy of tocilizumab (TCZ) in patients with rheumatoid arthritis (RA) by the clinical disease activity index (CDAI) and disease activity score (DAS) 28-erythrocyte sedimentation rate (ESR). Thirty-two RA patients received 8 mg/kg of TCZ intravenously every 4 weeks for 48 weeks. The therapeutic response was also evaluated in 30 RA patients treated with 3 mg/kg of infliximab (IFX) for 46 weeks. We compared the therapeutic course of TCZ with IFX in order to evaluate the efficacy of TCZ therapy. A strong positive correlation between CDAI and DAS28-ESR was observed at baseline, whereas their associations dropped significantly within the first 2 months. The association recovered to the baseline by IFX, but still remained low in TCZ. Although a decrement of DAS28-ESR was prominent in TCZ as compared with IFX, that of CDAI was significant in the early phase and even in the latter in patients treated by IFX. The present study revealed that DAS28-ESR may not be sufficient to estimate RA disease activity treated by TCZ, probably due to the significant effect toward inhibition of acute phase reactants by TCZ. CDAI is suggested to be an important alternate of composite measure in these cases. [ABSTRACT FROM AUTHOR]

Tocilizumab, a humanized monoclonal antibody to the interleukin 6 (IL-6) receptor, was approved for use as rheumatoid arthritis (RA) therapy in Japan in 2008, but its efficacy and tolerability in daily practice has not yet been reported. We report the results of a multicenter retrospective study on the efficacy and safety of tocilizumab involving all patients ( n = 229) who were started on tocilizumab therapy at three rheumatology institutes in Japan from April 2008 through to March 2009. Tocilizumab was infused every 4 weeks at a dose of 8 mg/kg according to the drug labeling. Among the 229 patients, 55% concomitantly received methotrexate (MTX) and 63% had previously received anti-tumor necrosis factor (TNF) therapy. Average disease activity score (DAS) 28 of all 229 patients significantly decreased from 5.70 to 3.25 after 24 weeks of therapy. A European League Against Rheumatism (EULAR) good response and DAS28 remission was achieved in 57.4 and 40.7% of the patients, respectively, at 24 weeks. White blood cell counts significantly decreased and liver enzymes and total cholesterol slightly but significantly increased; however, liver enzyme levels did not increase in patients without MTX. Tocilizumab was discontinued in 47 cases (20.5%) due to lack of efficacy (5.2%), adverse events (11.4%), and other reasons (3.9%). The overall retention rate at 24 weeks was 79.5%. Based on these results, we conclude that tocilizumab therapy in daily rheumatology practice appears to be highly efficacious and well tolerated among active RA patients, including the anti-TNF therapy-refractory population. Tocilizumab infusion is therefore applicable not only as an alternative approach for anti-TNF therapy-resistant patients, but also as primary biologic therapy for active RA patients. [ABSTRACT FROM AUTHOR]

tocilizumab (TCZ) greatly inhibits inflammatory markers, methods of evaluating rheumatoid arthritis (RA) disease activity that include inflammatory markers may overestimate the effect of TCZ treatment. We have evaluated the impact of inflammatory markers on the efficacy of TCZ by comparing the efficacy indicated by the 28-joint disease activity score using erythrocyte sedimentation rate (DAS28-ESR) with that indicated by the clinical and simplified disease activity indexes (CDAI and SDAI, respectively) and the American College of Rheumatology (ACR) core set criteria in a double-blind study of TCZ-the SATORI study. The Spearman correlation coefficient between DAS28-ESR and CDAI was comparable between that at week 24 and that at baseline [correlation coefficient at baseline and week 24 was 0.823 ( p < 0.0001) and 0.818 ( p < 0.0001), respectively]. A large difference between the DAS28 remission rate and CDAI remission rate was observed at week 24. However, these results are comparable to those of a previous study conducted with non-TCZ-treated patients. Moreover, the same results were obtained in the comparison between the DAS28-ESR and SDAI, even though the SDAI includes an inflammatory parameter as a component. These results confirm that the DAS28-ESR has a validity comparable to that of other methods in terms of evaluating the RA treatment efficacy of TCZ, despite its strong inflammatory marker-inhibiting effects. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

We present safety and efficacy data from Japanese clinical studies on monotherapy with tocilizumab (TCZ), a humanized anti-interleukin 6 receptor monoclonal antibody, in which 601 patients with moderate to severe rheumatoid arthritis, with a total of 2188 patient-years (pt-yr) exposure, were enrolled. The median treatment duration was 3.8 years. The incidence of adverse events (AEs), including abnormal laboratory test results, was calculated as 465.1 per 100 pt-yr. The most common serious adverse events (SAEs) were infections (6.22 per 100 pt-yr). There was no increase in the frequency of AEs or SAEs with long-term treatment. Abnormalities in the laboratory test results, such as increases in lipid parameters or abnormal liver function parameters, were common, but most were mild and there were no SAEs related to them. At baseline, 546 patients (90.8%) were taking corticosteroids; of these, 77.8% were able to decrease their corticosteroid dose during the study period, while 35.2% discontinued corticosteroids altogether. In the patients treated longer than 5 years, 91.3, 73.0, and 51.3% met the ACR20, ACR50, and ACR70 response criteria, respectively, and 59.7% met the DAS remission criterion (DAS28 <2.6) at 5 years. In conclusion, based on these results, TCZ has shown good tolerability and high efficacy during long-term treatment. [ABSTRACT FROM AUTHOR]

We evaluated the short-term effects of the anti-interleukin-6 (IL-6) receptor antibody tocilizumab (TCZ) in six patients with rheumatoid arthritis (RA) who had been refractory to tumor necrosis factor (TNF) antagonist therapy. All subjects were considered to be secondary nonresponders to TNF antagonists as decided by each physician. The Disease Activity Score of 28 Joints (DAS28) appeared to improve slowly by TCZ compared with TNF antagonist therapy, but significantly decreased at 24 weeks. One patient achieved DAS28 remission [DAS28–erythrocyte sedimentation rate (ESR) <2.60, and 5 of 6 patients showed good or moderate clinical response. The change in the clinical Disease Activity Index was similar to that of the DAS28–ESR. The serum level of matrix metalloproteinase-3 (MMP-3), a marker for synovial overgrowth, also significantly decreased after the treatment (518 ± 567 at baseline, 141 ± 90 ng/ml at 24 weeks, p < 0.05). One patient discontinued TCZ because of tuberculous peritonitis. Although physicians need to watch for infectious adverse events, these data indicate that TCZ is effective for treating RA patients refractory to TNF antagonists. [ABSTRACT FROM AUTHOR]

The introduction of biological agents targeting tumor necrosis factor-alpha (TNF-α) has brought about a paradigm shift in the treatment of rheumatoid arthritis (RA). Although these anti-TNF agents have excellent efficacy against RA, a substantial number of patients still show inadequate responses. In Western countries, such patients are already being treated with new classes of antirheumatic drugs such as abatacept and rituximab. Tocilizumab (TCZ) is a humanized monoclonal antibody developed in Japan against the human interleukin-6 (IL-6) receptor. TCZ does not only alleviate the signs and symptoms of RA but also seems to prevent progressive bone and joint destruction. However, there is a concern that TCZ might increase the risk of adverse events such as infections since IL-6 plays a pivotal role in the immune system. Calculating the relative risks of specific adverse outcomes with TCZ use remains difficult, due to insufficient patient numbers enrolled in clinical trials to date. This review presents tentative guidelines for the use of TCZ for RA patients prepared by the Japan College of Rheumatology and based on results of clinical trials in Japan and Western countries. The guidelines are intended as a guide for postmarketing surveillance and clinical practice, and will be revised periodically based on the surveillance. [ABSTRACT FROM AUTHOR]

Musculoskeletal sonography (MSUS) has played a growing role in the diagnosis and management of rheumatic diseases, enabling the imaging of synovitis, bone erosion, and cartilage damage in the early phase of arthritis. “Dynamic” evaluation of tendons and help in guiding needle positioning in interventional manoeuvres are some of the other reasons for its success. MSUS, particularly when coupled with power Doppler (PD) examination, has recently been shown to be an efficient tool for monitoring disease activity and progression in rheumatoid arthritis, spondyloarthritis, crystal-related arthropathy, and osteoarthritis, with general consensus on its interesting results. More specifically, the PD signal has proved to be a simple and promising tool for short-term monitoring of synovial vascularity changes induced by steroids or biological agents in RA patients. MSUS has some limits, because of the physical properties of US and the quality of the equipment; it is, moreover, an operator-related imaging technique, with few standardized protocols. Future goals should be standardization of the examining approach in grey scale and Doppler ultrasound (US), including use of new equipment (3D US), extensive use in other fields (i.e. connective tissue diseases and vasculitis), and possible new applications (e.g. thoracic US). [ABSTRACT FROM AUTHOR]

Although corticosteroids and immunosuppressants are widely used for the treatments of systemic lupus erythematosus (SLE), safer and more effective therapies are prerequisite. We and others have reported that anti-CD20 antibody rituximab targeting B cells are effective for refractory SLE and, therefore, safety and clinical efficacy of rituximab in SLE was evaluated by a multicenter phase I/II clinical trial. An open-label, multicenter study of 15 patients with active and refractory SLE (total British Isles Lupus Assessment Group [BILAG] score 8 to 17) was conducted. Rituximab was administered to 5 SLE patients as 4 infusions of 500 mg/body every week and to 10 SLE patients as 2 infusions of 1000 mg/body every other week. Assessment of safety, infusion reactions and adverse effects was used as the primary outcome for clinical tolerability and was evaluated by 28 weeks. Rituximab was well tolerated, with most experiencing no significant adverse effects. B cells rapidly reduced in all patients and remained low until 6 months post-treatment. Four patients developed human antichimeric antibodies without affecting efficacy of rituximab. Changes in routine safety laboratory tests clearly related to rituximab were not observed. Nine among 14 evaluable patients achieved the major or partial clinical response of BILAG score and prednisolone dose significantly decreased at the 28 weeks. Rituximab therapy appears to be safe for the treatment of active SLE patients and holds significant therapeutic promise, at least for the majority of patients experiencing profound B-cell depletion. [ABSTRACT FROM AUTHOR]