A Challenging Target: Persistent Pain During the Remission State in Rheumatoid Arthritis Patients

Pain is an important symptom in patients with rheumatoid arthritis (RA) and can cause various physical and psychological impairments [1]. Despite recent advances in disease-modifying anti-rheumatic drugs (DMARDs) and the treat-to-target approaches for improved management of inflammation, rheumatologists often encounter patients in the clinic with complaints of moderate to severe pain [2]. In this point, a study by Kim et al. [3] reported in the previous issue of the Journal of Rheumatic Diseases provides important implications of using a multi-dimensional approach to pain management in RA patients.

Pain in RA patients is caused due to several underlying mechanisms. In addition to the inflammatory pain caused by local and systemic cytokine effects, arthritis pain results from simple mechanical stimulations such as weight-bearing and joint movement (nociceptive pain). Changes in the articular environment due to structural joint damage and chronic inflammation can increase neuronal innervation or sensitize peripheral nociceptors at the joint site (peripheral pain sensitization) [4]. Recent studies using functional magnetic resonance imaging have shown increased and modulated cortical responses to pain stimuli in the central nervous system, suggesting a role of central processing in RA-associated pain (central pain sensitization) [5,6]. Moreover, RA patients have a higher prevalence of mood disorders including depression and anxiety compared to healthy individuals, and the psychological distress has been associated with increased levels of pain [7].

The pain characteristics described in RA patients may include symptoms such as aches, shooting or sharp pain, among others, which may be temporary, constant, or weight bearing-related [8]. An appropriate description of pain obtained from the clinical history and physical examination may aid in elucidation of each pain mechanism underlying RA, or indicate the mechanisms triggered by separate comorbid conditions, including osteoarthritis, fibromyalgia, carpal tunnel syndrome, and depression. Imaging plays a supportive role in measuring disease activity of RA and detecting comorbidities [9]. Plain radiography can detect osteopenia, joint space narrowing, erosion, and osteophytes; however, it is not sensitive so to be better at diagnosing late-stage disease. In recent years, musculoskeletal ultrasonography has emerged as an imaging modality for measuring disease states in RA and osteoarthritis with greater sensitivity and specificity compared to plain radiography. A negative result obtained by musculoskeletal ultrasonography may also be suggestive of other etiologies of pain including fibromyalgia.

Persistent or residual pain accompanying an inflammatory remission state is one of the most significant unmet needs in RA patients. In a previous study, Lee et al. [10] mentioned that approximately 47 percent of RA patients with low levels of inflammation reported moderate to high levels of pain, and that fatigue, pain catastrophe, and sleep disturbance were presented as relevant factors, indicating chronic widespread pain syndrome. Considering the disease duration, about 60% of established RA patients complained of dissatisfaction with pain treatment; however, persistent pain is still known to affect approximately one-third of early RA patients despite a good clinical response [11]. Vergne-Salle et al. [2] showed that despite the high proportion of RA patients on biological DMARDs treatment (83%), 38.4% of patients continue to report moderate to severe pain, which is primarily associated with anxiety and depression scores as well as RA activity scores.

Using the Korean College of Rheumatology Biologics and Targeted Therapy (KOBIO) registry data, Kim et al. [3] reported that 21.5% of RA patients complained of persistent moderate to severe pain despite clinical remission while being managed with biological or targeted synthetic DMARDs. Further, foot erosions, neurological disorders, and corticosteroid use were independent risk factors for moderate-to-severe pain in these patients on multivariate regression analysis. This study explored the prevalence and risk factors for persistent pain in Korean RA patients in remission, suggesting the importance of a physicians’ evaluation of the causes of pain using a multi-angle approach for appropriate therapeutic planning based on the underlying pain mechanisms. No association was found between persistent pain and mental illness, such as depression or anxiety as predicted, since knowledge about these factors were not accurately collected in the KOBIO registry, as mentioned by the authors. Interestingly, despite the small number of cases, the use of Janus kinase inhibitors was inversely associated with moderate to severe pain. This is consistent with the results of a previous study [12] wherein, baricitinib monotherapy displayed superior pain-reducing ability compared to adalimumab monotherapy and tocilizumab monotherapy. However, the exact mechanisms underlying the potential differences between the efficacies of various DMARDs in pain modulation are still unknown.

In conclusion, persistent pain in RA patients, despite remission, remains clinically challenging. In these patients, a multi-dimensional evaluation, including clinical symptoms and signs, laboratory tests, imaging, and comorbidities, should be performed to identify the dominant and most appropriate pain mechanism. This could prevent inappropriate treatment escalation with DMARDs and provide a personalized pain management. Thus, further research is required for development of simplified tools in order to assess various aspects of the pain in RA and to provide guidance to the physicians.

Funding Statement

FUNDING None.