Introduction
(Article introduction authored by Conquest Editorial Team)
A variety of disease-modifying antirheumatic drugs (DMARDs) are now available for treating rheumatoid arthritis (RA), including biologic DMARDs (bDMARDs) such as TNF inhibitors, abatacept, interleukin-6 inhibitors, and rituximab, as well as targeted synthetic DMARDs (tsDMARDs) like Janus kinase inhibitors. Both bDMARDs and tsDMARDs have demonstrated efficacy in suppressing disease activity, improving physical function, and preventing irreversible joint damage in RA.
International guidelines from organizations like the American College of Rheumatology (ACR) and the European Alliance of Associations for Rheumatology (EULAR) provide recommendations for managing RA, which are largely followed by national societies like the Swedish Society of Rheumatology (SSR). SSR guidelines focus on treatment choice in early RA based on disease activity and prognostic factors, although other factors may also influence treatment decisions in clinical practice.
A systematic literature review identified various factors associated with initiating bDMARDs in RA patients, categorized into clusters including patient-related, disease-related, treatment-related, healthcare staff-related, and healthcare system-related factors. However, the relative importance of these factors was not analyzed. This study aims to investigate factors associated with initiating bDMARDs or tsDMARDs at the time of RA diagnosis, focusing on patient-related, disease-related, and treatment-related factors. Understanding these factors may help guide treatment decisions in early RA patients in the modern therapy era, although such factors may vary over time or among different ethnic populations and healthcare systems.
Methods
This retrospective cohort study was conducted in the Region of Skåne in southern Sweden, where healthcare is tax-funded and provides equal access to public care for all citizens. Private care is also available through agreements with regional health authorities or private insurances.
Patients with early rheumatoid arthritis (RA) diagnosed at Skåne University Hospital outpatient clinics between 2012 and 2016 were included if they met specific criteria, such as confirmed RA diagnosis, age ≥18 years, symptom duration <12 months at diagnosis, and fulfillment of established classification criteria for RA. Patients starting their first biologic or targeted synthetic DMARD (bDMARD/tsDMARD) in a clinical trial were excluded.
Clinical data were collected from medical records, while treatment information was obtained from the Swedish Rheumatology Register and case record reviews. Comorbidity data were retrieved from the Skåne Healthcare Register.
Statistical analysis involved crude and multivariable Cox proportional hazard regression models to examine the relationship between baseline characteristics and the time to start of bDMARD/tsDMARD. Factors with p<0.20 in crude models were considered for inclusion in multivariable analyses.
Proportional hazard assumptions were tested, and potential predictors for starting bDMARD/tsDMARD within the first 3 years after diagnosis were assessed using logistic regression analysis. Multiple imputation was performed for variables with <80% complete data, and exploratory analyses were conducted stratified by age at diagnosis to understand the relationship between age and treatment initiation.
Results
A total of 367 patients diagnosed with early rheumatoid arthritis (RA) between 2012 and 2016 were identified. Excluding 37 patients who participated in a clinical trial, 330 patients (mean age 59.2 years; 74% women; 67% anticitrullinated protein antibody (ACPA) positive) were included in the study. Baseline characteristics, including clinical features at RA diagnosis, level of formal education, prevalent comorbidities, Charlson Comorbidity Index (CCI), country of birth, and family background, are detailed in table 1.
Predictors of bDMARD treatment:
In univariable analyses, higher age at rheumatoid arthritis (RA) diagnosis was linked with a reduced likelihood of initiating a biologic disease-modifying antirheumatic drug (bDMARD) (HR 0.63 per standard deviation; 95% CI 0.54 to 0.74).
Positive anticitrullinated protein antibody (ACPA) and rheumatoid factor (RF), along with baseline disease activity indicated by the tender joint count (but not by C-reactive protein or estimated sedimentation rate), were associated with subsequent initiation of bDMARD treatment.
Additionally, a higher level of formal education and absence of comorbidities were predictive of starting a bDMARD in the univariable analyses.
Predictors of bDMARD treatment: multivariable analyses
In age-adjusted analyses, rheumatoid factor (RF), tender and swollen joint counts, and Disease Activity Score-28 for Rheumatoid Arthritis (DAS28)-CRP-3 were associated with the initiation of a first biologic disease-modifying antirheumatic drug (bDMARD).
However, the level of education and comorbidities did not predict the initiation of bDMARD in age-adjusted analyses. The association with age remained significant in models adjusted for each of the other covariates separately.
In the final multivariable model, lower age, positive anticitrullinated protein antibody (ACPA), and a high number of tender joints at diagnosis were all independently predictive of bDMARD treatment initiation, while country of birth was not an independent predictor.
Predictors of bDMARD treatment within 3 years from RA diagnosis
In univariable logistic regression analyses, age, joint indices, Health Assessment Questionnaire (HAQ), Disease Activity Score-28 for Rheumatoid Arthritis (DAS28)-CRP-3, country of birth, and absence of major comorbidities were significant baseline predictors of initiating biologic disease-modifying antirheumatic drug (bDMARD) treatment within the first 3 years after diagnosis. There was no association with C-reactive protein (CRP) or erythrocyte sedimentation rate (ESR) in these models. In age-adjusted analyses, joint indices, HAQ, DAS28-CRP-3, birth outside Europe, and CRP remained significant predictors. Lower age and higher tender joint counts were the only significant predictors of initiating bDMARD treatment ≤3 years after diagnosis in multivariable logistic regression analysis.
Additional analyses using multiple imputation of missing data showed that disease severity measures (DAS28-CRP, HAQ, and Visual Analogue Scale (VAS) pain) were associated with subsequent initiation of bDMARD treatment.
In exploratory analyses stratified by age, the highest incidence of initiating bDMARD treatment per 100 person-years was observed in the youngest age category (19–48 years), with a gradual decrease in likelihood with higher quartiles of age at diagnosis.
Discussion
In this study, older patients with rheumatoid arthritis (RA) were less likely to initiate biologic disease-modifying antirheumatic drugs (bDMARDs) early, while patients who were positive for anticitrullinated protein antibody (ACPA) and those with extensive joint involvement at diagnosis were more likely to receive early bDMARD treatment.
These findings were consistent with previous studies indicating that most patients who start a bDMARD do so within the first few years after diagnosis. However, the incidence of bDMARD initiation was substantially lower in older patients compared to younger ones, suggesting age-related disparities in treatment initiation.
The lower prescription rate of bDMARDs in older patients may reflect concerns about infection risks associated with these medications, highlighting the need for careful consideration of alternative treatment strategies in this population. Extensive joint involvement, particularly a higher number of tender joints, was associated with early bDMARD initiation, emphasizing the importance of clinical assessment in treatment decision-making.
Conclusion
Younger patients with RA, and those with positive ACPA and extensive joint involvement at baseline, were more likely to receive early treatment with bDMARDs. These associations were not explained by differences in level of formal education, comorbidities or ethnicity, suggesting that other aspects of age may influence treatment decisions in early RA.
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