安岡 秀剛

OBJECTIVES: We established a multicentre prospective registry of patients with systemic sclerosis (SSc) in Japan to evaluate the outcomes in the modern treatment era. This report presents the baseline characteristics of patients enrolled in the registry. METHODS: Adult SSc patients were prospectively enrolled from 20 medical centres across Japan. Baseline data, including demographics, organ involvement, autoantibody profiles, and patient-reported outcomes, were collected using a dedicated electronic data capture system. RESULTS: A total of 835 patients were eligible for analysis. The cohort was predominantly female (85.1%), with a median age of 64 years at enrolment, and 35.0% had diffuse cutaneous SSc. Autoantibodies included anticentromere (38.9%), anti-topoisomerase I (topo I; 33.5%), anti-RNA polymerase III (RNAP III; 12.4%), and anti-U1 RNP (12.9%). Interstitial lung disease (ILD) was the most common organ manifestation (56.0%), followed by upper gastrointestinal (GI) involvement (42.5%), heart involvement (5.3%), pulmonary hypertension (3.4%), scleroderma renal crisis (1.9%), and lower GI involvement (1.2%). Patients with anti-topo I had the worst patient global assessment, whereas those with anti-RNAP III patients had the worst physician global assessment. CONCLUSIONS: This prospective registry captures real-world data on SSc patients, providing a valuable resource for understanding the clinical spectrum and outcomes in contemporary practice in Japan.

OBJECTIVES: This study aimed to explore the potential of plasma micro-ribonucleic acids (miRNAs) in predicting joint damage in patients with rheumatoid arthritis (RA). METHODS: This subanalysis of the MIRACLE study, a randomised, open-label, non-inferiority trial, explored and compared the efficacy and safety of treatment with adalimumab (ADA), an anti-tumour necrosis factor (TNF) α, plus a maximum tolerated dose of methotrexate (MTX) with a reduced dose of MTX in early RA. Plasma levels of miRNAs (miR-143-3p, miR-146a-5p, miR-155-5p, miR-182-5p, miR-21-5p, and miR-221-3p) and serum levels of inflammatory cytokines (interleukin-6 [IL-6], vascular endothelial growth factor [VEGF]) and matrix metalloprotease-3 (MMP-3) were measured at 24 weeks. Their association with joint destruction assessed by the modified total Sharp score [mTSS] over the 24-week period were analysed. RESULTS: A total of 134 patients who showed an inadequate response to MTX and started treatment with ADA were included in the analyses. Logistic regression analyses revealed that higher plasma levels of miR-143-3p, miR-146a-5p, miR-21-5p, and miR-221-3p were significantly associated with increases in mTSS >0.5 points during the observation period. In particular, positive correlation was derived from the progression of joint space narrowing. In contrast, MMP-3, VEGF, and IL-6 levels were not associated with joint destruction. Cartilage damage occurred mainly in patients treated with reduced dose of MTX. CONCLUSIONS: Higher circulating miRNA levels predicted subsequent cartilage damage in early RA treated with a TNF inhibitor in addition to MTX. Thus, the MTX dose at ADA initiation should not be reduced in patients with high microRNA levels.

OBJECTIVES: The usefulness of methotrexate-polyglutamates (MTX-PGs) concentration for management of rheumatoid arthritis has been debated. We aimed to clarify the association of MTX-PGs concentration with efficacy and safety in MTX-naïve patients initiating MTX in a prospective interventional clinical trial. METHODS: The MIRACLE trial enrolled 300 MTX-naïve patients. Oral MTX was initiated and increased to the maximum tolerated dose by week 12. Patients who did not achieve remission according to the Simplified Disease Activity Index at week 24 were randomised to either the continued dose or reduced dose group and were started on subcutaneous adalimumab. We measured the concentrations of MTX-PGs in erythrocytes using liquid chromatography-tandem mass spectrometry and analysed the association of these concentrations with efficacy and safety. RESULTS: The mean concentration of total MTX-PGs increased with an increasing dose of MTX and continued to elevate for another 12 weeks after the dose was fixed. At week 24, the total MTX-PGs concentration was 110.5 (SD 43.8) nmol/L with MTX dose of 12.6 (3.0) mg/week (0.23 (0.07) mg/kg/week). During MTX monotherapy, the higher MTX-PGs concentration was an independent factor for lower disease activity; however, this association disappeared after adalimumab initiation in patients with continued MTX dose. Hepatotoxicity was related to the higher MTX-PGs concentration regardless of adalimumab use. The total MTX-PGs concentration was significantly elevated by lower estimated glomerular filtration rate, serum albumin and body mass index. CONCLUSIONS: The MIRACLE trial demonstrated that higher total MTX-PGs concentration in erythrocytes is related to the higher efficacy and lower safety of MTX. TRIAL REGISTRATION NUMBER: NCT03505008.