Rheumatoid Arthritis Treatment Has Changed Dramatically Over the Past 3 Decades, but Has the Disease Itself Changed?

It is now well established that if an individual exhibiting the clinical and serological features of early rheumatoid arthritis (RA) accesses appropriate and timely rheumatological care, the trajectory and outcome of this disease has dramatically improved over the last number of decades.¹ The availability of multiple pharmacological and nonpharmacological interventions, coupled with timely management strategies such as treat-to-target, has resulted in a substantial number of patients diagnosed with RA achieving remission or low disease activity at an early stage of their disease. In turn, this has translated into declines in the accrual of irreversible joint damage and functional loss that were the hallmark of this disease as recently as 3 decades ago. Rheumatologists whose practice has spanned this period of time can uniformly attest to this spectacular progress, although there remains a significant minority of patients with RA with refractory disease who continue to have unfavorable outcomes.²

In the context of these dramatic changes in disease trajectory resulting from modern rheumatological care and therapeutics, it is rare to get a glimpse of whether RA itself may have changed over this time frame. Secular trends in how RA initially presents to rheumatologists are reported by Carrier et al in this issue of The Journal of Rheumatology.³ This important work was made possible through the long-term Early Undifferentiated Polyarthritis (EUPA) cohort, established in 1998. The EUPA cohort comprises individuals who presented to a single French Canadian academic center and were diagnosed with RA, either at study enrollment or within 18 months. The baseline assessments at study enrollment included a comprehensive array of demographic, clinical, serological, and radiographic variables, along with validated patient-reported outcome measures. The methodology and metrics used by these researchers has remained largely unchanged over this time frame, allowing for a relatively unbiased assessment of how the patterns of presentation may have changed over 24 years.

The investigators chose to divide the EUPA cohort into thirds based on the time period in which the patients were recruited. The early part of the cohort was recruited between 1998 and 2004; this interval was chosen because it was prior to the general availability of biologics for use in early RA. The second part of the cohort, recruited between 2005 and 2010, was chosen because it was prior to the development and wide application of the 2010 American College of Rheumatology (ACR)/European Alliance of Associations for Rheumatology (EULAR) RA classification criteria⁴ and widespread adoption of treat-to-target guidelines.⁵ The third part of the cohort was the most recent, spanning 2011-2022. The resultant groups are well balanced in terms of the number of patients in each group: 245, 266, 329, respectively. Although this is a reasonable approach to dividing the cohort into groups for comparison, it could be argued that it is unlikely that the availability of biologic therapies had a substantial effect on how patients initially presented to the EUPA cohort, since these therapies require initiation by rheumatologists in most Canadian jurisdictions. The diagnosis of RA in the 2011-2022 cohort was based on the 2010 ACR/EULAR classification criteria,⁴ and these were retrospectively applied to the earlier groups. An alternative approach may have been to simply divide the cohort into 3 equal subgroups, although this is unlikely to have had a major effect on the findings.

In comparing the baseline demographic characteristics of the 3 groups, variables such as age, female sex, and BMI were comparable across the study time periods. These demographic characteristics are also consistent with what is typically observed in other primarily White RA cohorts around the world,^6-8 with the EUPA cohort comprising 99% White, mostly French Canadian, participants. Similar findings for undifferentiated arthritis have been reported.⁹ Importantly, in the Carrier study,³ the percentage of active smokers declined steadily over time, which reflects the overall secular trend in most Western societies. A potentially related variable in the analysis is the increase in the level of formal education over time, which has been repeatedly shown to affect smoking rates.¹⁰

Clinical characteristics at presentation, such as swollen and tender joint counts (SJC/TJC), as well as a spectrum of patient- and physician-reported outcomes related to rheumatic disease, were largely consistent over time. A previous study has suggested reduced baseline disease severity measures, such as inflammation levels and SJC.⁶ Moreover, there appears to be a trend for participants enrolled in clinical trials to have lower baseline levels of systemic inflammation, SJC (but not TJC), and radiographic damage scores compared to earlier trials.¹¹ In contrast to the RA-specific clinical characteristics, Carrier et al³ found that the prevalence of baseline comorbidities, in particular cardiovascular (CV) comorbidities and malignancy, increased over time, as also reported in other large cohort studies.^6,12 Carrier et al speculate that the observed rise of CV disease (CVD) at presentation may relate to increased recognition of CVD and CV risks,³ as recommended by the international Comorbidities in Rheumatoid Arthritis (COMORA) consortium.¹³ Regardless of the cause, comorbidity burden remains high in newly diagnosed RA, affects clinical outcomes, and complicates treatment decisions, highlighting the need for comprehensive comorbidity screening throughout the course of RA.

At the time of enrollment in the EUPA cohort, one-quarter of the patients were already using disease-modifying antirheumatic drugs (DMARDs), including methotrexate, and this seemed consistent over time. In contrast, the proportion of patients on oral corticosteroids (CS) had almost doubled from 18% in the 1998-2004 group to 33% in the 2011-2022 group. Of potential relevance is the finding that the duration of symptoms prior to inclusion in the cohort had also become progressively longer. Does this reflect an increasing need for primary healthcare providers to use CS as bridge therapy while waiting for patients to receive rheumatological care? This is not clear from the data presented, as there was little mention of any changes in the access to care models over the study period. Alternatively, the increased oral CS use may relate to other disease features not readily captured by SJC/TJC or inflammatory markers, which have clearly not increased in parallel over time. Of note, parenteral CS use, particularly joint injections, was not reported. Seronegative patients tend to have more atypical arthritis patterns, and it is possible that diagnostic uncertainty may limit aggressive DMARD use and, in turn, increase use of CS. Of note, in this regard, Carrier et al report increased CS use, particularly in the patient subset who were seronegative.³ Despite recommendations for CS use to be limited to short-term bridge therapy, the relatively high and sometimes persistent use of oral CS has been similarly reported by a larger Canadian cohort.¹⁴

Arguably, the most important findings in this study by Carrier et al relate to a decline in the level of RA autoantibodies, inflammatory markers, and radiographic erosions at baseline.³ Together, these observations led the investigators to conclude that RA is becoming more seronegative, milder, and less destructive at presentation. The declining rates of seropositivity have also been reported in a previous population-based study.¹⁵ At face value, it is difficult to argue with these conclusions, but the biological basis for these changing patterns is more complex. For example, the data presented do not suggest any differences in the immunogenetic predisposition to RA, as the frequency of shared epitope (SE)–encoding HLA-DRB1 alleles and protective DERAA-encoding alleles is comparable over time. It is well established that SE predisposes individuals primarily to seropositive RA, with a strong gene-environment interaction between SE and smoking.¹⁶ The data presented show that the only major change over time was a dramatic reduction in the proportion of SE-negative nonsmokers who presented with seropositive RA. It is thus difficult to attribute declining autoantibody levels solely to declines in smoking rates, especially as lifetime exposure to smoking was high and stable over time in the cohort. Other environmental exposures hypothesized to be associated with seropositive RA were not evaluated in this study, including exposures to environmental toxins,¹⁷ the presence of periodontal disease, and subtle alterations in the mucosal microbiomes,¹⁸ all of which may have changed over the study period. It had already been demonstrated, even at the time of establishment of the EUPA cohort, that higher socioeconomic status is associated with reduced exposures to these environment factors and, in turn, is also associated with reduced risk of developing seropositive RA.¹⁹

Carrier et al should be commended for their persistence and tenacity in studying the secular trends in RA presentation over an extended time frame.³ Nevertheless, an important limitation of these findings is their generalizability to other populations. For example, we have shown that in Indigenous North American populations, RA continues to present at a young age with severe, primarily seropositive, disease.^20,21 Moreover, it is associated with highly unfavorable outcomes such as early mortality, despite access to the impressive therapeutic armamentarium currently available to all rheumatologists. Having said this, an evolving secular trend in RA presentation toward milder, more seronegative, less erosive RA, that is accompanied by more comorbidities such as CVD, has important implications for the diagnosis, management, and prognosis of early RA. Both rheumatology teams and primary healthcare providers will need to recognize these changing patterns in RA presentation. The alarming increase in the early and persistent use of oral CS will need to be addressed, as this is now known to contribute independently to CV risk in patients with RA, even at low doses.^22,23 New models of care need to be considered, in which primary healthcare providers work with members of rheumatology care teams to address the increasing comorbidities at RA presentation, particularly CVD, as suggested by others.²⁴ RA therapy has dramatically changed, but the disease itself has also changed. Models of healthcare delivery need to adapt.

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