The DAS28 is routinely used in rheumatology practice to monitor the disease trajectory in RA. In this study of an early RA cohort managed with a T2T approach, we identified three distinct subgroups of patients with different disease trajectories over 12 months by clustering each component of the DAS28 (the overall score, and both the objective and subjective components of the score). Of the 121 study participants, at 52 weeks, nearly half of them were in disease remission (the ‘Responders’ group), and the other half of the study cohort continued to have moderate-to-high disease activity, with 26% in the ‘Partial Responders’ group and 26% in the ‘Non-Responders’ group. When we examined the components of the DAS28, both ‘Responders’ and ‘Partial Responders’ groups had similar DAS28 objective component mean scores at baseline and at 52 weeks, and yet, these two subgroups had different disease trajectories. In fact, the relatively high total mean DAS28-ESR scores for the ‘Partial Responders’ group at baseline and at 52 weeks were largely driven by the reporting of high DAS28 subjective component scores, as highlighted by the consistently higher proportions of the DAS28-P index throughout the study period when compared to both ‘Responders’ and ‘Non-Responders’ groups. Despite receiving similar T2T therapy, these findings in the ‘Partial Responders’ group reflect ongoing patient-reported concerns about their disease trajectories disproportionate to the underlying disease inflammation and support the use of the DAS28-P index as a predictor of persistent non-inflammatory pain in early RA.
In our study, both ‘Partial Responders’ and ‘Non-Responders’ groups reported similar worsening of disease impact throughout the study period, when compared to the ‘Responders’ group, as demonstrated in the mHAQ scores, the level of fatigue and helplessness scores. Apart from the higher level of fatigue in the ‘Partial Responders’ group, both ‘Partial Responders’ and ‘Non-Responders’ groups were indistinguishable at baseline, even in the DAS28 subjective component scores. Evidently, these two subgroups differed in the trajectories of the DAS28 objective component scores and the DAS28-P proportion indices. Again, according to the DAS28-P index, these findings suggest a predominance of non-inflammatory pain mechanisms in the ‘Partial Responders’ group and failure of treatment and ongoing active disease in the ‘Non-Responders’ group at baseline and throughout the study. This further validates the role of DAS28-P index as a discriminatory measure of non-inflammatory pain and disease impact throughout the treatment course in early RA. Other concomitant chronic pain conditions, such as osteoarthritis and fibromyalgia, could be confounders for persistent pain in this study cohort, and although beyond the scope of our study, their contribution to non-inflammatory pain in early RA would be relevant in any future analysis.
Overtreatment is a potential risk in the modern treatment era for patients diagnosed with early RA, especially in the T2T approach(22). In this study, there was a substantial increase in both the methotrexate mean dose and the proportions of leflunomide users in both ‘Partial Responders’ and ‘Non-Responders’ groups. In detail, dose increments for both of these DMARDs were seen at week 16, a typical time period for deciding any change in dosing, and subsequently the doses were gradually up-titrated to the maximum recommended target doses, as dictated by the serial DAS28 scores. Similarly, despite the analysis of only a subset of the study cohort, the cumulative dose of glucocorticoid use in the ‘Non-Responders’ group was substantively higher compared to the other two subgroups. Consequently, these subgroups with disproportionate dose titration and disease activity could be at risk of DMARD-related toxicity in the intermediate- and long-term. Likewise, a recent study by Wallace and colleague revealed two thirds of established rheumatoid arthritis patients had persistent glucocorticoid use, especially in those with high fibromyalgianess(23). In addition, escalation to biologic DMARDs in these subgroups may occur, which may result in higher societal and health care cost and unnecessary immunosuppression. Future studies examining the use of conventional synthetic DMARDs beyond a 1-year period and the timing of switching to biologic DMARD in these subgroups of early RA cohort may help to further characterize the impact of the ‘treat-to-target’ treatment approach in those with persistent non-inflammatory pain in RA.
Furthermore, in our study, despite not achieving the DAS28 indicative of low disease activity/disease remission, the ‘Partial Responders’ group had the lowest joint erosion scores serially over 3 years, demonstrating no progression of erosive disease. This is consistent with their low levels of disease inflammation following treatment, as reflected by the overall DAS28 objective component score. This finding underscores the risk of unnecessary overtreatment in a ‘partially-responsive’ subgroup of patients with early RA, in whom additional immunosuppressive agents will not alleviate non-inflammatory symptoms. Adjuvant interventions that target non-inflammatory pain rather than relying on immunosuppressive therapies are likely warranted in this group of patients with suboptimal disease control despite no objective evidence of ongoing inflammation(24, 25).
From the patient’s perspective, disease remission comprises both resolution of disease inflammation and alleviation of symptoms related to the disease. Although the PGA within the DAS28 has been considered the cornerstone of determining the patient-reported disease remission, the role of PGA remains contentious. A recent large individual patient data meta-analysis evaluating the impact of PGA in the definition of disease remission and as a predictor of radiographic damage in RA concluded that the current DAS28 remission definition that includes the PGA, is better than a definition that excludes PGA for predicting a good functional outcome but reduces the predictive accuracy for radiological outcomes, raising concerns for risk of overtreatment.(26). In a large multinational study using the METEOR database of patients on biologic DMARDs for RA, the PGA remained high in those in remission, with the danger of further unnecessary immunosuppression(27). Ferreira and colleagues have proposed a dual T2T strategy, which comprises the management of disease inflammation (biologic remission) and the management of disease impact (symptom remission) to guide treatment in RA(28). For biologic remission, alongside the dual T2T, the author recommended the use of 3-variable remission – SJC, TJC and CRP(29). For symptom remission, the author suggested further validation of the PGA with the use of the Rheumatoid Arthritis Impact of Disease (RAID) score(29). This additional patient-reported measure in early RA may provide early insight at the start of DMARD initiation, with early adjuvant interventions to be provided to those who are likely to have persistent non-inflammatory pain.
Our study has some strengths and limitations. Our study examined patients who were definitively diagnosed with early RA as they were recruited through strict RCT inclusion criteria. We were able to differentiate patients with persistent pain (the ‘Partial Responders’ group) from the ‘Non-Responders’ group, a difference that was not shown in the previous study using the DAS28-P index(10). It included a relatively small cohort of patients with early RA. Irrespective, we had adequate study size and repeated measures to provide representative subgroups of patients with different trajectories to evaluate the utility of DAS28-P index as predictor of treatment response in the first year after diagnosis of RA. In addition, the study participants were mainly recruited from a single-center rheumatology unit, which may introduce selection bias in terms of the residency of the patients and their corresponding education levels and socio-economic status.
In summary, in this well-characterized early RA cohort managed with a T2T approach within the first year, the use of the DAS28-P index in predicting those with non-inflammatory pain at the start of the DMARD initiation and throughout the year is useful. Additional clinical assessment and communication, as well as a shared decision-making framework between the patients and the treating clinicians are warranted, when there is a suspicion of ongoing non-inflammatory pain despite adequate control of disease inflammation.