MHC-DRB alleles with amino acids Val11, Phe13, and the shared epitopes promote collagen-induced arthritis and a rapid IgG1 response in Filipino cynomolgus macaques.

Macaques are useful animal models for studying the pathogenesis of rheumatoid arthritis (RA) and the development of anti-rheumatic drugs. The purpose of this study was to identify the major histocompatibility complex (MHC) polymorphisms associated with the pathology of collagen-induced arthritis (CIA) and anti-collagen IgG induction in a cynomolgus macaque model, as MHC polymorphisms affect the onset of CIA in other animal models. Nine female Filipino cynomolgus macaques were immunized with bovine type II collagen (b-CII) to induce CIA, which was diagnosed clinically by scoring the symptoms of joint swelling over 9 weeks. MHC polymorphisms and anti-b-CII antibody titers were compared between symptomatic and asymptomatic macaques. Four of 9 (44%) macaques were defined as the CIA-affected group. Anti-b-CII IgG in the affected group increased in titer approximately 3 weeks earlier compared with the asymptomatic group. The mean plasma IgG1 titer in the CIA-affected group was significantly higher (p < 0.05) than that of the asymptomatic group. Furthermore, the cynomolgus macaque MHC (Mafa)-DRB1*10:05 or Mafa-DRB1*10:07 alleles, which contain the well-documented RA-susceptibility five amino acid sequence known as the shared epitope (SE) in positions 70 to 74, with valine at position 11 (Val11, V11) and phenylalanine at position 13 (Phe13, F13), were detected in the affected group. In contrast, no MHC polymorphisms specific to the asymptomatic group were identified. In conclusion, the presence of V11 and F13 along with SE in the MHC-DRB1 alleles seems essential for the production of IgG1 and the rapid induction of severe CIA in female Filipino cynomolgus macaques.

Epidemiological characteristics of rheumatoid arthritis in Japan: Prevalence estimates using a nationwide population-based questionnaire survey.

Objectives: To elucidate the epidemiological characteristics of patients with rheumatoid arthritis (RA) in Japan using data from the Comprehensive Survey of Living Conditions, a nationwide questionnaire survey conducted in 2016.Methods: In total, 222,365 men and 245,251 women aged ≥16 years were included in the study. RA patients were defined as those who reported 'currently receiving treatment for RA at hospitals, clinics, or a facility for Japanese traditional massage, acupuncture, moxibustion, or judo-orthopedics.' The number of RA patients was estimated from the age-specific prevalence and total Japanese population in 2016. Further, the prevalence of individuals experiencing difficulties in activities of daily living due to health problems and those with mental distress as evaluated by K6 Scale was examined.Results: The estimated number and prevalence of RA in Japan with 95% confidence interval was 822 (768-880) thousand and 0.75% (0.70-0.80%). The population peaked in the late 60s, and the prevalence continued increasing until the early 80s, regardless of sex. Compared with non-RA participants, RA patients were more likely to experience difficulties in activities and to be distressed.Conclusion: High prevalence of RA in older age and mental and physical burden among RA patients were confirmed.

Risk of opportunistic infections in patients with antineutrophil cytoplasmic antibody-associated vasculitis, using a Japanese health insurance database.

AIM: Opportunistic infections (OIs) adversely affect outcomes in patients with antineutrophil cytoplasmic antibody-associated vasculitis (AAV). This study aimed to identify the incidence proportion of risk factors for OIs in patients with AAV who were on remission-induction therapy, using a Japanese health insurance database. METHOD: This retrospective longitudinal population-based study was conducted using claims data provided by Medical Data Vision Co., Ltd. We defined individuals as AAV cases receiving remission-induction therapy if they met all of the following criteria: (a) having OIs with at least 1 specified International Statistical Classification of Diseases and Related Health Problems, 10th Revision code (M300, M301, M313, or M318); (b) receiving at least 1 prescription of oral corticosteroids (CS) with prednisolone (PSL)-equivalent dosage ≥30 mg/d, CS pulse therapy, immunosuppressive agents or rituximab during hospitalization between April 2008 and April 2017; and (c) at least 7 days of hospitalization while on the above-mentioned therapies. We calculated incidence and proportion of OIs during the year following remission-induction therapy and the adjusted odds ratio (OR) using a logistic regression model. RESULTS: We included 2299 patients with AAV in this study. OIs occurred in 460 patients (20.0%), with the most frequently occurring OI being cytomegalovirus infection (n = 122, 6.5%). After adjusting for covariates, age by decade (OR 1.24, 95% CI: 1.12-1.36), daily PSL dose per 10 mg (OR 1.16, 95% CI: 1.08-1.25), and CS pulse therapy (OR 1.29, 95% CI: 1.04-1.60) were found to be significantly associated with occurrence of OIs. CONCLUSION: Older age and corticosteroid use were found to be significant risk factors for OIs in patients with AAV on remission-induction therapy, using a health insurance database.

Effect of denosumab on Japanese patients with rheumatoid arthritis: a dose-response study of AMG 162 (Denosumab) in patients with RheumatoId arthritis on methotrexate to Validate inhibitory effect on bone Erosion (DRIVE)-a 12-month, multicentre, randomised, double-blind, placebo-controlled, phase II clinical trial.

OBJECTIVES: To evaluate efficacy and safety of three different regimens of denosumab, a fully human monoclonal antibody to receptor activator of nuclear factor kappa B (RANK) ligand (RANKL), for Japanese patients with rheumatoid arthritis (RA). METHODS: In this multicentre, randomised, placebo-controlled phase II study, 350 Japanese patients with RA between 6 months and <5 years, stratified by glucocorticoid use and rheumatoid factor status, were randomly assigned to subcutaneous injections of placebo or denosumab 60 mg every 6 months (Q6M), every 3 months (Q3M) or every 2 months (Q2M). All patients basically continued methotrexate treatment and had a supplement of calcium and vitamin D throughout the study. The primary endpoint was change in the modified Sharp erosion score from baseline to 12 months. RESULTS: Denosumab significantly inhibited the progression of bone erosion at 12 months compared with the placebo, and the mean changes of the modified Sharp erosion score at 12 months from baseline were 0.99, 0.27 (compared with placebo, p=0.0082), 0.14 (p=0.0036) and 0.09 (p<0.0001) in the placebo, Q6M, Q3M and Q2M, respectively. Secondary endpoint analysis revealed that denosumab also significantly inhibited the increase of the modified total Sharp score compared with the placebo, with no obvious evidence of an effect on joint space narrowing for denosumab. As shown in previous studies, denosumab increased bone mineral density. No apparent difference was observed in the safety profiles of denosumab and placebo. CONCLUSIONS: Addition of denosumab to methotrexate has potential as a new therapeutic option for patients with RA with risk factors of joint destruction. TRIAL REGISTRATION NUMBER: JapicCTI-101263.

Analysis of direct medical and nonmedical costs for care of rheumatoid arthritis patients using the large cohort database, IORRA.

OBJECTIVES: Our goal was to determine the annual direct medical and nonmedical costs for the care of patients with rheumatoid arthritis (RA) using data from a large cohort database in Japan. METHODS: Direct medical costs [out of pocket to hospitals and pharmacies and for complementary and alternative medicine (CAM)] and nonmedical costs (caregiving, transportation, self-help devices, house modifications) were determined for RA patients who were participants in the Institute of Rheumatology, Rheumatoid Arthritis (IORRA) studies conducted in October 2007 and April 2008. Correlations between these costs and RA disease activity, disability level, and quality of life (QOL) were assessed. RESULTS: Data were analyzed from 5,204 and 5,265 RA patients in October 2007 and April 2008, respectively. The annual direct medical costs were JPY132,000 [out of pocket to hospital (US$1 = JPY90 in 2007)], JPY84,000 (out of pocket to pharmacy), and JPY146,000 (CAM). Annual direct nonmedical costs were JPY105,000 (caregiving), JPY22,000 (transportation), JPY30,000 (self-help devices), and JPY188,000 (house modifications). Based on the utilization rate for each cost component, the annual medical and nonmedical costs for each RA patient were JPY262,136 and JPY61,441, respectively. Costs increased with increasing RA disease activity and disability level or worsening quality of life (QOL). CONCLUSIONS: Based on the IORRA database, patients with RA bear heavy economic burdens that increase as the disease is exacerbated. The results also suggest that the increase in medical and nonmedical costs may be ameliorated by the proactive control of disease activity.

One third of Japanese patients with rheumatoid arthritis use complementary and alternative medicine.

We investigated the prevalence and predictors of complementary and alternative medicine (CAM) use by patients with rheumatoid arthritis (RA) in Japan. A cross-sectional descriptive study was performed using the database from a large observational cohort of RA patients in the Institute of Rheumatology, Tokyo Women's Medical University. Logistic regression analysis was carried out to reveal predictive factors for CAM use. Among 3815 RA patients, 1321 (34.6%; 174 males, 1147 females) used at least one type of CAM. Health foods, including dietary supplements, were the most commonly used. CAM was more frequently used by female patients (odds ratio: 0.578; 95% confidence interval [CI] = 0.451-0.740). A multiple logistic regression analysis revealed that sex (odds ratio: 0.489; 95% CI = 0.333-0.718) and degree of satisfaction with disease-modifying antirheumatic drugs (DMARDs) (odds ratio: 0.899; 95% CI = 0.852-0.948) were significant independent predictive factors for CAM use. The serum C-reactive protein level and erythrocyte sedimentation rate showed no significant associations with CAM use. Approximately 35% of RA patients used CAM in Japan. Female patients and patients dissatisfied with DMARDs used CAM more frequently, regardless of their disease activity.