Unincreased mortality of patients with early rheumatoid arthritis compared to the general population in the past 17 years: Analyses from the IORRA cohort.

OBJECTIVES: The aim of this article is to investigate the mortality rate of patients with early rheumatoid arthritis (RA) over the past 17 years. METHODS: Japanese patients with early RA enrolled in the Institute of Rheumatology, Rheumatoid Arthritis cohort from 2001 to 2012 were classified into Groups A (2001-06) and B (2007-12). The standardized mortality ratio (SMR) and 5-year survival rate were calculated. RESULTS: Groups A and B had 1609 and 1608 patients, of which 167 and 178 patients were lost during follow-up and 47 and 45 deaths were confirmed, respectively. The SMR (95% confidence intervals) for Groups A and B were 0.81 (0.59-1.08) and 0.78 (0.57-1.04), respectively, with the condition that all untraceable patients were alive. Assuming that the mortality rate of untraceable patients was twice as high as that of the general population, the SMR was 0.90 (0.68-1.19) for Group A and 0.92 (0.68-1.23) for Group B. The 5-year survival rates were 96.9% and 97.0% for Groups A and B, respectively. CONCLUSIONS: The 5-year mortality of patients with early RA has been comparable to that of the general Japanese population. The 5-year survival rate has been stable over the past 17 years.

Impact of interstitial lung disease on clinical remission and unfavourable events of rheumatoid arthritis: results from the IORRA cohort.

OBJECTIVES: We aimed to examine the impact of concomitant interstitial lung disease (ILD) on achieving clinical remission and the occurrence of unfavourable clinical events in patients with RA. METHODS: Among the participants in the Institute of Rheumatology, Rheumatoid Arthritis (IORRA) cohort from 2011 to 2012, patients not achieving remission of 28-joint disease activity score (DAS28) at baseline and those with chest CT images were enrolled. Based on the chest CT images, the patients were divided into two groups: the ILD group and non-ILD group. The associations among the presence of ILD with time to achieving DAS28 remission and development of death, hospitalized infection, major adverse cardiac events (MACE), or malignancy within 5 years were evaluated using time-dependent Cox regression models. RESULTS: We enrolled 287 patients in the ILD group and 1235 in the non-ILD group. DAS28 remission was achieved at least once in 55.7% and 75.0% of the ILD and non-ILD groups within 5 years, respectively. Presence of ILD was significantly associated with failure to achieve DAS28 remission (adjusted hazard ratio [aHR]: 0.71; 95% CI: 0.58, 0.89). ILD was also a significant factor associated with death (aHR: 3.24; 95% CI: 2.08, 5.03), hospitalized infection (aHR 2.60; 95% CI: 1.77, 3.83), MACE (aHR: 3.40; 95% CI: 1.76, 6.58), and lung cancer (aHR: 16.0; 95% CI: 3.22, 79.2), but not with malignant lymphoma (aHR: 2.27; 95% CI: 0.59, 8.81). CONCLUSION: Concomitant ILD was a significant factor associated with failure to achieve clinical remission and the occurrence of the unfavourable clinical events in patients with RA.

Evaluation of RABBIT risk score in Japanese patients with rheumatoid arthritis starting first bDMARDs: a validation study using the IORRA cohort data.

OBJECTIVE: To examine the ability of the Rheumatoid Arthritis Observation of Biologic Therapy (RABBIT) risk score to predict the occurrence of serious infections in Japanese patients with rheumatoid arthritis (RA), after initiating their first biologic disease-modifying antirheumatic drug (bDMARD). METHODS: We used data from the Institute of Rheumatology, Rheumatoid Arthritis (IORRA) cohort from 2008 to 2020. Patients with RA who were started on their first bDMARDs were included. Those with missing data required to calculate the score were excluded. A receiver operating characteristic (ROC) curve was used to evaluate the discriminatory ability of the RABBIT score. RESULTS: A total of 1,081 patients were enrolled. During the one-year observational period, 23 (1.7%) patients had serious infections; the most frequent one was bacterial pneumonia (n=11, 44%). The median RABBIT score in the serious infection group was significantly higher than that in the non-serious infection group (2.3 [1.5-5.4] vs 1.6 [1.2-2.5], p<0.001). The area under the ROC curve for the occurrence of serious infections was 0.67 (95% confidence interval 0.52-0.79), suggesting that the score had low accuracy. CONCLUSION: Our present study revealed that the RABBIT risk score did not have sufficient discriminatory ability for predicting the development of severe infections in Japanese patients with rheumatoid arthritis after initiating their first bDMARD.

Trends in risks of malignancies in Japanese patients with rheumatoid arthritis: Analyses from a 14-year observation of the IORRA cohort.

OBJECTIVES: The aim is to investigate the trends in risks of overall and site-specific malignancies in patients with rheumatoid arthritis (RA). METHODS: Among Japanese patients with RA enrolled in the Institute of Rheumatology, Rheumatoid Arthritis cohort, all malignancies that occurred from 2000 to 2013 were extracted. The standardized incidence ratios and 95% confidence intervals for overall and site-specific malignancies were calculated during three periods: pre-biologics, 2000-04; early biologics, 2005-09; and recent biologics, 2010-13. Risk factors for overall and specific malignancies were analysed using time-dependent Cox regression models. RESULTS: Among 11,299 patients with RA (68,483 person-years), 507 malignancies were confirmed. Similar risks were observed versus the general Japanese population for overall malignancies throughout the three periods, with standardized incidence ratios (95% confidence intervals) of 0.96 (0.80-1.14) in the pre-biologics period, 0.95 (0.82-1.09) in the early biologics period, and 0.87 (0.75-1.01) in the recent biologics period. A significantly increased risk for malignant lymphoma was observed throughout the observation period (standardized incidence ratio 4.61, 95% confidence interval 3.58-5.85). The disease activity was a significant risk factor for overall malignancies and lung cancer. CONCLUSIONS: Despite the expanding use of methotrexate and biologics, there were no increases in malignancy risk in Japanese patients with RA.

Cost-consequence of abatacept as first-line therapy in Japanese rheumatoid arthritis patients using IORRA real-world data.

OBJECTIVES: To investigate the cost-effectiveness of abatacept (ABA) as first-line (1L) therapy in Japanese rheumatoid arthritis (RA) patients using data from the Institute of Rheumatology, Rheumatoid Arthritis database. METHODS: A decision-analytic model was used to estimate the cost per American College of Rheumatology response of at least 50% improvement (ACR50) responder and per patient in Clinical Disease Activity Index (CDAI) and Simplified Disease Activity Index (SDAI) remission from a Japanese healthcare payers' perspective over a 2-year time horizon. Clinical characteristics of patients on ABA-1L were matched with those of patients on ABA second or later line (2L+) or tumour necrosis factor inhibitor (TNFi)-1L directly or using propensity scores. Resource utilisation and medical costs were calculated from the Japan Medical Data Center claims database. Parameter uncertainty was addressed by sensitivity and subgroup analyses (age, treatment duration, Japanese version of Health Assessment Questionnaire [J-HAQ] score). RESULTS: Incremental costs per member per month (ΔPMPM) for ABA-1L versus TNFi-1L and ABA-2L+ were -1,571 Japanese Yen (JPY) and 81 JPY, respectively. For ABA-1L versus TNFi-1L, ΔPMPM by ACR50 response was -11,715 JPY and by CDAI and SDAI remission 11,602 JPY and 47,003 JPY, respectively. Corresponding costs for ABA-1L were lower for all outcome parameters versus those for ABA-2L+. Scenario analyses showed that ABA-1L was cost-effective over TNFi-1L in patients <65 years for any outcome. Furthermore, ABA-1L was cost-effective over ABA-2L+ for all outcomes in patients with age <65 years, disease duration <5 years and J-HAQ ≥1.5. CONCLUSIONS: ABA-1L demonstrated a favourable cost-effectiveness profile in RA patients, accruing savings for the Japanese healthcare payers.

Impact of concomitant chronic kidney disease on hospitalised infections and remission in patients with rheumatoid arthritis: results from the IORRA cohort.

OBJECTIVES: To investigate the impact of concomitant chronic kidney disease (CKD) on unfavourable clinical events and remission in Japanese patients with rheumatoid arthritis (RA). METHODS: We included 5103 patients with RA and CKD from the Institute of Rheumatology Rheumatoid Arthritis (IORRA) cohort in 2012. CKD stages were classified into four groups: CKD with normal eGFR ≥60 ml/min/1.73 m2 and proteinuria; mild CKD, eGFR ≥45 to < 60; moderate CKD, eGFR ≥30 to < 45; and severe CKD, eGFR <30. We assessed the association between concomitant CKD and the occurrence of unfavourable clinical events or achieving remission during a 5-year observational period. RESULTS: Of the 5103 patients with RA, 686 (86.6%) had CKD. Concomitant CKD was associated with hospitalised infections [adjusted hazard ratio (aHR) 1.52, 95% confidence interval (CI) 1.07-2.13, p = .02], especially in the moderate to severe CKD group (aHR 1.93, 95% CI 1.12-3.13, p = .02). Of all subjects, 2407 (47.2%) had active RA at baseline and 401 (16.7%) had CKD. Concomitant CKD was also associated with the failure of achieving remission (aHR 0.82, 95% CI 0.68-0.99, p = .04). CONCLUSIONS: Concomitant CKD was a risk factor for hospitalised infections in Japanese patients with RA and failure of achieving remission in patients with active RA.

Differences in patients' population and efficacy/effectiveness of biologic disease-modifying antirheumatic drugs between randomized controlled trials and real-world settings in patients with rheumatoid arthritis - using the IORRA cohort.

OBJECTIVES: To evaluate the differences in patients' population and efficacy/effectiveness of biological disease-modifying antirheumatic drugs (bDMARDs) between randomized controlled trials (RCTs) and clinical practice in patients with rheumatoid arthritis. METHODS: We reviewed inclusion criteria in Phase II or III RCTs of bDMARDs conducted in Japan. The Institute of Rheumatology, Rheumatoid Arthritis study participants during the period when each RCT was conducted (Cohort A) and new bDMARD users at our institute in 2016 (Cohort B) were assessed for the fulfilment of the inclusion criteria. The effectiveness of bDMARDs in our cohort and their efficacy in RCTs were compared using the inverse-variance method. RESULTS: Nineteen RCTs were selected. The mean proportions of patients fulfilling all inclusion criteria of each RCT in Cohorts A and B were 2.3% and 7.6%, respectively. The pooled proportion ratios (95% confidence interval) for achieving the American College of Rheumatology 20 (ACR20), ACR50, ACR70, and disease activity score 28 remission in non-eligible cases for eight RCTs versus all corresponding RCTs were 0.38 (0.30-0.51), 0.41 (0.30-0.57), 0.54 (0.35-0.82), and 1.28 (1.10-1.56), respectively. CONCLUSIONS: Few rheumatoid arthritis patients fulfilled the inclusion criteria of the RCTs in clinical settings. There was a difference in the efficacy/effectiveness of bDMARDs between RCTs and clinical practice.

Risk of herpes zoster in patients with rheumatoid arthritis in the biologics era from 2011 to 2015 and its association with methotrexate, biologics, and corticosteroids.

OBJECTIVES: To elucidate the incidence and risk factors of herpes zoster (HZ) in patients with rheumatoid arthritis (RA) in the biologics era. METHODS: We determined the rate of HZ occurrence among the RA patients that participated in the Institute of Rheumatology, Rheumatoid Arthritis surveys from 2011 to 2015, by assessing medical records. The standardised incidence rate per 1000 patient-years with a 95% confidence interval (CI) was calculated, and risk factors for HZ were analysed using a time-dependent Cox regression analysis. RESULTS: Among 7815 patients (female, 84.7%) contributing to 25,863 patient-years of observation, 340 HZ events in 309 patients were confirmed. The standardised incidence rate (95% CI) per 1000 patient-years was 8.5 (6.9-10.5) in total, 6.0 (3.7-9.2) in men, and 11.0 (8.7-13.7) in women. Risk factors for HZ were age per 10 years (hazard ratio 1.14, 95% CI 1.03-1.26, p < .05), Japanese version of the Health Assessment Questionnaire (J-HAQ) score of 0.5-1.5 (versus J-HAQ = 0; 1.51, 1.09-2.10, p < .05), methotrexate use (1.58, 1.06-2.36, p < .05), and biologic use (1.88, 1.44-2.47, p < .01). CONCLUSIONS: In the era when biologics were frequently used and corticosteroid use and doses were decreasing, methotrexate and biologics increased the risk for HZ.

Successful discontinuation of biological disease-modifying antirheumatic drugs in patients with rheumatoid arthritis in real-world settings.

OBJECTIVES: To analyze the proportion of successful biological disease-modifying antirheumatic drugs (bDMARDs) discontinuation and related factors in patients with rheumatoid arthritis (RA) in clinical settings. METHODS: Among 1775 RA patients who started bDMARDs between 2003 and 2012, 43 patients with DAS28-ESR <3.2 at the time of bDMARD discontinuation were extracted. Patients were divided into two groups (bio-free success: BS and bio-free failure: BF groups) based on bDMARD usage and disease activity 1 year after discontinuation. We evaluated the proportion of bio-free success and assessed factors related to bio-free success. RESULTS: Twenty-five patients (58.1%: BS group) maintained discontinuation of bDMARDs and DAS28-ESR <3.2 at 1 year after discontinuation. The median DAS28-ESR at bDMARD initiation was lower in the BS group than in the BF group (3.95 vs 5.04; p = .04). The BS group experienced a larger decrease in average glucocorticoid (GC) dose during bDMARD use than the BF group (-3.0 mg/day vs 0 mg/day; p = .01). CONCLUSION: bDMARDs were discontinued without flare up of RA in 58.1% of patients with RA in clinical settings. A lower DAS28-ESR at initiation and reduction of GC dose before discontinuation of bDMARD were important factors associated with bio-free success.

Tumour necrosis factor inhibitor-induced myositis in a patient with ulcerative colitis.

Tumour necrosis factor (TNF) inhibitors are known to induce autoimmune diseases, such as lupus-like syndrome; in rare cases, TNF inhibitor-induced myositis has been reported. This report documents the case of a male patient with ulcerative colitis (UC) complicated by TNF inhibitor-induced myositis. After UC diagnosis and treatment with azathioprine and infliximab, he was evaluated for a recent 5-month history of muscle weakness and pain. Laboratory tests revealed elevated muscle enzymes, such as serum creatine kinase (CK) and aldolase. He also tested positive for anti-nuclear antibodies and anti-double stranded DNA antibodies. High-intensity signals in his quadriceps on magnetic resonance image (MRI) and fibrillation potentials in his proximal muscles on electromyography were demonstrated. Muscle biopsy revealed the endomysial infiltration of mononuclear cells surrounding myofibers. Eventually, the patient fulfilled the classification criteria for idiopathic inflammatory myopathies. Although an adverse drug reaction of infliximab had been speculated, his muscle involvements did not improve in 6 weeks from the last administration of infliximab; therefore, treatment with prednisolone was initiated. Subsequently, his muscle symptoms ameliorated, and his serum CK levels returned to normal. Repeat MRI revealed a complete resolution of the signal intensity, and he reported no symptoms of UC or myositis while prednisolone was tapered without resumption of infliximab. Clinicians should consider the diagnosis of drug-induced myositis if muscle symptoms develop in patients treated with TNF inhibitors.

Successful delivery in a patient with clinically amyopathic dermatomyositis during pregnancy despite first-trimester acute exacerbation of interstitial lung disease.

A 37-year-old woman with rheumatoid arthritis and interstitial lung disease (ILD) developed clinically amyopathic dermatomyositis (CADM) after achieving pregnancy through in vitro fertilization. She was given oral prednisolone, which improved her respiratory status, and delivered a healthy baby at 35 weeks' gestation. There are few reports of successful outcomes for CADM during pregnancy; to the best of our knowledge, this is the first report of successful delivery in a patient with both CADM and ILD.

[Rheumatic diseases and sex differences].

Recently a concept of "sex differences" in medicine has been spreading. It is well known that autoimmune diseases, especially rheumatoid arthritis or systemic lupus erythematosus mostly affect women, and it is clear that there is a strong sex differences in many rheumatic diseases. Sex difference influences to progression or prognosis of the disease. Although the mechanisms of sex difference are not clear, the influence of sex hormones or sex chromosomes which gives immune system is partially elucidated. In addition, sex hormones may become the future new treatment target, and progress in the study regarding this event is expected in the future.

Chronological changes in baseline disease activity of patients with rheumatoid arthritis who received biologic DMARDs between 2003 and 2012.

BACKGROUND/PURPOSE: The use of biologic disease-modifying anti-rheumatic drugs (DMARDs) for rheumatoid arthritis (RA) has been increasing since 2003. In this study, we evaluated changes in the characteristics of patients receiving biologic DMARDs daily, in Japan. METHODS: The characteristics of all RA patients who received any biologic DMARD at the Institute of Rheumatology, Tokyo Women's Medical University, within 1 year after its approval in Japan, were retrospectively evaluated. The periods of patient enrollment for each biologic agent were: infliximab (IFX), 2003-2004; etanercept (ETN), 2005-2006; tocilizumab (TCZ), 2008-2009; adalimumab (ADA), 2008-2009; abatacept (ABT), 2010-2011; and golimumab (GLM), 2011-2012. We retrospectively collected individual patient characteristics, concomitant medication usage, and disease activity assessed by disease activity score 28 (DAS28) at the time of administration, from the medical records. The retention rate for each agent at 6 months after treatment initiation was also assessed. RESULTS: The numbers of patients who received each biologic DMARD at our institute within 1 year after its approval were: IFX, 49; ETN, 50; TCZ, 62; ADA, 52; ABT, 40; and GLM, 77. From 2003 to 2012, the proportion of patients with prior use of any biologic DMARD increased, as did concomitant use and dose of methotrexate (MTX); however, corticosteroid use and doses decreased. DAS28, at the time of treatment initiation, gradually decreased. At the time of IFX administration, 75% and 25% of patients had high and moderate disease activity respectively, compared to 25% and 58% respectively, of patients who received GLM. No significant difference was observed in the retention rate of biologic DMARDs at 6 months (range, 75.0% to 89.6%). CONCLUSION: Baseline disease activity of RA patients who received biologic DMARDs between 2003 and 2012 has changed from high to moderate in daily practice in Japan.

Assessment of the effectiveness of golimumab 50-mg and 100-mg regimens in patients with rheumatoid arthritis in daily practice.

OBJECTIVES: To assess the effectiveness of the golimumab (GLM) 50-mg and 100-mg regimens in patients with rheumatoid arthritis (RA) in daily practice. METHODS: We retrospectively analyzed RA patients who started GLM between September 2011 and July 2012. Patients were divided into three groups: a 50-mg group; a 50/100-mg group (had a dose increase to 100 mg); and a 100-mg group (started GLM at 100 mg). We assessed Disease Activity Score 28 (DAS28) and treatment continuation rate. Risk factors associated with time to discontinuation of the 50-mg regimen were determined with proportional hazards analysis. RESULTS: We analyzed 74 patients: 43 in the 50-mg group, 23 in the 50/100-mg group, and 8 in the 100-mg group. DAS28 improved from 4.0 ± 1.0, 4.8 ± 1.0, and 4.7 ± 1.9, respectively, at baseline to 2.4 ± 1.2, 3.3 ± 1.5, and 2.5 ± 0.7, respectively, at week 52. Treatment continuation rates at week 52 were 73.7%, 60.9%, and 87.5%, respectively. In the 50/100-mg group, the mean DAS28 improved significantly from 4.4 ± 1.2 before to 3.6 ± 1.3 12 weeks after the dose increase. Oral corticosteroid therapy ≥ 5 mg/day, previous use of two biologic agents, and DAS28 > 5.1 at initiation of GLM were significantly associated with discontinuation of the 50-mg regimen. CONCLUSIONS: Both GLM 50-mg and 100-mg regimens are effective in patients with RA in daily practice.