Introduction
(Article introduction authored by Conquest Editorial Team)
Over the past two decades, treatment options for rheumatoid arthritis (RA) have evolved significantly. Methotrexate (MTX), biologic disease-modifying antirheumatic drugs (bDMARDs), and targeted synthetic antirheumatic drugs (tsDMARDs) like Janus kinase inhibitors (JAKis) have notably enhanced disease management for RA patients.
Clinical evidence from randomized controlled trials supports their efficacy in improving disease activity, functional disability, and joint prognosis. However, long-term efficacy and safety beyond study periods or in patient groups excluded from trials remain uncertain.
Observational cohort studies, like the Kyoto University Rheumatoid Arthritis Management Alliance (KURAMA) cohort, provide valuable real-world data.
KURAMA, established in 2011 with 4418 registered patients by 2022, tracks treatment outcomes longitudinally, including disease activity, disability, adverse events, and conducts annual surveys assessing joint health, osteoporosis, frailty, and mental status. Additionally, KURAMA maintains a biobank of RA-related specimens. Over the period from 2012 to 2021, the Japanese Ministry of Health, Labour and Welfare approved two bDMARDs (certolizumab pegol, sarilumab) and five JAKis (tofacitinib, baricitinib, upadacitinib, peficitinib, filgotinib).
This study aims to analyze the 10-year experience of the KURAMA cohort during this period, examining how treatment strategies and outcomes have evolved alongside advances in therapeutic options.
Materials and methods
The study analyzed annual trends in managing rheumatoid arthritis (RA) by collecting clinical data from 2012 to 2021. It included disease activity, functional disability, and medication usage. For patients on b/tsDMARDs, data were recorded before and after treatment initiation.
Missing values were excluded, and propensity score matching was used to address confounding factors, with CTLA4-Ig patients as the reference group.
Mixed-effects models were employed for time-series analysis, with transformations applied to certain variables. Statistical analyses were conducted using Python and R libraries, and graphs were generated accordingly. This approach provided insights into the effectiveness of RA treatments over the study period.
Results
Changes in RA patient background and RA treatment trends from 2012 to 2021
From 2012 to 2021, a total of 1156 patients participated annually in rheumatoid arthritis (RA) surveys, totaling 5070 patients cumulatively. The mean age of RA patients increased from 62.9 in 2012 to 65.9 in 2021, with less than 20% of patients
younger than 60 years old in 2021, reflecting Japan’s aging society. The percentage of patients treated with MTX remained over 60% throughout the period, decreasing slightly from 70.8% in 2012 to 64.3% in 2021.
Meanwhile, glucocorticoid (GC) usage decreased from 40.5% to 18.6%, while biologic/targeted synthetic disease-modifying antirheumatic drug (b/tsDMARD) usage increased from 29.5% to 53.2%, indicating a shift towards more intensive treatment for RA patients over the past decade. (Fig 1)
Treatment outcomes of b/tsDMARDs in the KURAMA cohort
Due to the increasing utilization of biologic/targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) and their favorable outcomes observed in the KURAMA cohort from 2012 to 2021, particularly with the approval of new b/tsDMARDs, the study delved into analyzing real-world treatment responses to these drugs using longitudinal observational data.
Between 2012 and 2021, 1816 new prescriptions were recorded, with 820 for b/tsDMARD-naïve patients and 996 for b/tsDMARD-switching patients.
Trends in b/tsDMARD initiation categorized by mode of action (MOA) revealed consistency in IL-6 receptor inhibitors (IL6Ri) usage over the decade, while TNF inhibitors (TNFi) and CTLA4-Ig prescriptions declined. Conversely, the prescription of Janus kinase inhibitors (JAKis) increased notably, especially in switch cases.
Concomitant usage of methotrexate (MTX) varied across different b/tsDMARDs, with TNFi showing the highest usage in both naïve and switched patients.
Effectiveness comparisons of b/tsDMARDs, evaluating disease activity and functional disability measures, revealed that all MOAs achieved low disease activity or remission at specific time points.
Propensity score matching, with CTLA4-Ig as the reference group, highlighted significant improvements with TNFi and IL6Ri compared to CTLA4-Ig, particularly in disease activity measures, in naïve patients. However, outcomes were comparable across all MOAs in switched cases.
Retention rates of b/tsDMARDs, indicating treatment success, were examined through Kaplan‒Meier analysis, showing no significant differences in naïve patients but significantly better retention rates with IL6Ri in switched patients.
The Sankey diagram summarized MOA choices when initiating or switching b/tsDMARDs, illustrating varying trends in MOA selection based on previous treatment.
Overall, the study provided insights into real-world treatment outcomes of b/tsDMARDs across different MOAs, shedding light on their efficacy and retention rates in clinical practice. (Fig 2)
Statistical implications of the annual trends in disease activity and functional disability
To know the statistical implications of observed trends in DAS28-CRP, CDAI, and HAQ from 2012 to 2021, we used a mixed-effect model for adjusting patient-specific characteristics. The annual changes in CDAI and HAQ were statistically significant, but not DAS28-CRP. Patients’ demographic data such as age, stage, and class significantly affected HAQ, and b/tsDMARDs, MTX, and GC use were significantly associated with DAS28-CRP and CDAI. b/tsDMARDs use was also associated with HAQ .
Discussions
The study analyzed RA treatment trends and outcomes in the KURAMA cohort from 2012 to 2021. It showed changes in medication usage, treatment responses, and disease activity over the decade, reflecting the evolving landscape of RA management. Notably, the introduction of new b/tsDMARDs impacted treatment strategies. TNFi initially showed efficacy in naïve patients, while IL6Ri demonstrated better long-term outcomes. IL6Ri also had superior drug retention rates.
However, individual patient circumstances and potential confounding factors were not considered, and the study may not encompass all RA patients treated at the hospital.
Overall, the findings underscore the evolving efficacy of b/tsDMARDs and their impact on real-world RA management.
Conclusions
In summary, we reviewed the real-world transition of therapeutic strategies and their outcomes in the 10-year history of the KURMA cohort. The disease activity and functional disability metrics of patients with RA improved over a decade with increased use of b/tsDMARDs.
References
1. Rantapää-Dahlqvist S de Jong BA Berglin E et al. Antibodies against cyclic citrullinated peptide and IgA rheumatoid factor predict the development of rheumatoid arthritis. Arthritis Rheum. 2003; 48: 2741-2749
2. Nielen MM van Schaardenburg D Reesink HW et al. Specific autoantibodies precede the symptoms of rheumatoid arthritis: a study of serial measurements in blood donors. Arthritis Rheum. 2004; 50: 380-386
3. Nam JL Hensor EMA Hunt L Conaghan PG Wakefield RJ Emery P Ultrasound findings predict progression to inflammatory arthritis in anti-CCP antibody-positive patients without clinical synovitis.
Ann Rheum Dis. 2016; 75: 2060-2067
4. van Steenbergen HW Mangnus L Reijnierse M Huizinga TW van der Helm-van Mil AH Clinical factors, anticitrullinated peptide antibodies and MRI-detected subclinical inflammation in relation to progression from clinically suspect arthralgia to arthritis.
Ann Rheum Dis. 2016; 75: 1824-1830
5. Gerlag DM Raza K van Baarsen EGM et al. EULAR recommendations for terminology and research in individuals at risk of rheumatoid arthritis (RA): report from the Study Group for Risk Factors for RA.
Ann Rheum Dis. 2012; 71: 638
6. Smolen JS Landewé RBM Bergstra SA et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2022 update.
Ann Rheum Dis. 2023; 82: 3-18
7.Linsley PS Ledbetter JA The role of the CD28 receptor during T cell responses to antigen. Annu Rev Immunol. 1993; 11: 191-212
8.Kremer JM Westhovens R Leon M et al. Treatment of rheumatoid arthritis by selective inhibition of T-cell activation with fusion protein CTLA4Ig. N Engl J Med. 2003; 349: 1907-1915
9.Westhovens R Robles M Ximenes AC et al. Clinical efficacy and safety of abatacept in methotrexate-naive patients with early rheumatoid arthritis and poor prognostic factors. Ann Rheum Dis. 2009; 68: 1870-1877
