In this cohort study, LORA patients had a similar time to remission to YORA patients after adjusting for other prognostic factors (HR of 1.10, 95% CI 0.90 to 1.34). For those patients who reached remission, LORA patients were more likely to be on a less intensive DMARD regimen such as using a single csDMARD without a biologic or JAK inhibitor.
In our study, LORA patients had a higher proportion of males, a lower proportion of RF or anti-CCP positivity, and higher inflammatory markers compared to YORA patients. These findings were similar to other published studies [5, 8, 13].
Previous studies have shown conflicting results on the prognosis of LORA patients compared to YORA patients. LORA patients had a better prognosis in some older studies [6, 7] and a worse prognosis in more recent studies [8,9,10,11]. For example, in a large multicenter French cohort study of 698 patients with early RA, 118 LORA patients (age >60 years) had an adjusted odds ratio of 0.33 (95% CI 0.16 to 0.71) for remission at 1 year using SDAI, compared to YORA patients (age <45 years), suggesting a worse prognosis for LORA . Whereas, in a US cohort study of 422 patients with RA onset within 2 years, the remission rates using the American Rheumatism Association (ARA) criteria in 214 LORA patients (age ≥65 years), and 186 YORA patients (age <65 years) were 46% and 20%, respectively, suggesting a better prognosis for LORA .
For studies that reported disease activity based on DAS28, the mean area under the curve was 47.7 in LORA patients versus 44.8 in YORA patients (P<0.01) at 1 year in a cohort of 750 RA patients . In another study, LORA had a lower response to therapy based on DAS28 <3.2 at 6 months with an odds ratio of 0.28 (95% CI 0.08 to 0.98) in 140 patients with early RA . Finally, in a cohort of 229 patients with early RA, although DAS28 was higher at baseline in LORA (mean of 5.0 vs. 4.0 p<0.001), the DAS28 was not significantly different between the two groups at the end of the 2-year follow-up (mean of 2.5 vs. 2.3 p=0.07) . Our study results are consistent with this last study , which had a large sample of patients with early RA with a long follow-up.
In contrast to these studies, our study results provide an estimate showing a similar prognosis between LORA and YORA patients. The different results may be related to differences in the definition of LORA, the time point with respect to the disease course at enrolment, criteria for remission, the geographic location and sample size. Compared to other studies, our study defined LORA as being a diagnosis in the same or next calendar year and a widely accepted remission criteria based on DAS28. As well, our study has a larger sample size than the aforementioned studies allowing for a more precise estimate. The use of different measures for disease activity and remission makes comparison difficult across studies. The most commonly used measures of disease activity include DAS28, Clinical Disease Activity Index (CDAI) and SDAI . The DAS28, CDAI and SDAI cut-offs do not translate into the same clinical information . Even CDAI and SDAI had significant disagreements when applied to the same patients . Of these three composite measures, the DAS28 is the oldest instrument that has been extensively validated and most widely used in clinical practice as well as research [20,21,22].
The results of this study have important implications to the management of LORA. When deciding on the initial treatment regimen for LORA, it is likely not necessary to start combination DMARDs or a biologic/JAK inhibitor, because many LORA patients were able to reach remission while on csDMARD. This validates the current practice pattern where LORA patients are typically not treated with combination DMARD or a biologic [23, 24]. However, the goal of treatment for LORA should be the same for YORA, given that LORA patients were just as likely as YORA patients to reach remission on follow-up in our study. Therefore, if LORA patients are still not at remission at follow-up, treatment should be escalated in the same aggressive manner as YORA patients so that they may reach remission. For example, in a study of 197 patients with LORA, patients that adhered to a treat-to-target strategy targeting low disease activity with escalation of therapy were more likely to have sustained remission by SDAI (42.2% vs. 14.5% p<0.001) as well as less progression of joint destruction and better physical function during 3 years of follow-up . Based on observational cohort studies and randomized controlled trials, the effectiveness and safety of biologic DMARDs are likely similar in elderly patients . Therefore, clinicians should not hesitate to escalate and add a biologic or JAK inhibitor for LORA patients who have been treated with csDMARDs and have not reached remission.
A higher proportion of LORA patients were initiated on glucocorticoids in our study. LORA patients may have more active disease at baseline based on higher inflammatory markers and joint erosions, prompting the rheumatologist to treat with glucocorticoid for early disease control. Interestingly, a higher proportion of LORA patients were maintained on glucocorticoids at remission. Similarly, in a large observational cohort of 4202 patients, prednisone use was much higher in LORA patients than in YORA patients (41.0% vs. 37.6% P=0.025) . Prolonged glucocorticoid therapy can have potential adverse effects . This presents an opportunity to improve the care of LORA. Once LORA patients reach remission, the rheumatologist should re-evaluate the treatment regimen and readjust the regimen if necessary to make it safer in the long term.
Our study has several strengths. First, this is one of the largest studies to date describing the prognosis of LORA patients over time. The large sample size allowed for more precise estimates. Second, this study has detailed data on clinical characteristics, treatment and outcome over a long period of follow-up. The data collection is prospective, rigorous and complete.
Our study also has several weaknesses. First, there may be residual confounding due to the observational nature of the study. However, we used a Cox proportional hazards model to adjust for other important prognostic factors. The significant predictors and correlation with prognosis in the final multivariable models were consistent with the important predictors of remission in a previous systematic review . One significant predictor was the number of comorbidities, which may bias the assessment of disease activity. It is not possible to ascertain how much of disease activity is attributable to comorbidities versus RA. Thus, patients may have persistent symptoms due to comorbidities when their RA is actually in remission. This would underestimate the remission rate in LORA patients who had more comorbidities. Second, in an ideal inception cohort, all patients should be recruited at the onset of symptoms. This is not feasible in a cohort study. Nevertheless, our criteria of enrolment date at the same or next calendar year relative to the diagnosis of RA was more stringent than previous studies [6, 27] and should be representative of patients with early and active RA. Third, there may be variations in the treatment of LORA patients across centres and over time. In the 2011/2012 Canadian Rheumatology Association guidelines on pharmacotherapy of RA , there is no special consideration for LORA and this serves as general guidance for Canadian rheumatologists. Our study findings are representative of real-world data on the management of LORA patients.