Subgrouping of Patients With Rheumatoid Arthritis Based on Pain, Fatigue, Inflammation, and Psychosocial Factors

Rheumatoid arthritis (RA) is the most common systemic rheumatic disease, affecting approximately 1.5 million adults in the United States (1). Historically, physicians have focused on the inflammatory components of the disease (e.g. synovitis), whereas RA patients have cited pain, fatigue, sleep problems and other quality of life outcomes as their main priorities (2). Both patients and physicians frequently assume that these symptoms are correlated with heightened systemic inflammation. However, many studies indicate significant discordance between inflammation, pain and fatigue among RA patients (3, 4). In a prospective observational cohort of established RA patients experiencing sustained inflammatory disease remission, 12% continued to report clinically significant pain (≥ 4 on a 10-point numeric rating scale) (5). A study including 2,096 RA patients in a clinical setting and 14,607 RA patients from a survey-based cohort reported weak correlations of 0.07–0.11 between fatigue and measures of inflammation (6). Similarly, van Hoogmoed found no association between fatigue and either the erythrocyte sedimentation rate or C-reactive protein (CRP) among 228 RA outpatients in the Netherlands (7). These observations suggest that patient-reported outcomes, such as pain, fatigue and sleep problems, should not automatically be attributed to inflammation in an inflammatory disease population, such as RA. Central, non-inflammatory pain conditions, such as fibromyalgia, tend to be associated with high levels of pain, fatigue and sleep problems (8, 9). Compared to the general population (10, 11), the prevalence of non-inflammatory pain conditions is significantly higher in RA, with 15–25% of RA patients also meeting criteria for fibromyalgia and an additional 7–15% meeting criteria for chronic widespread pain (12, 13). Thus, while it is not debated that RA is an inflammatory condition, many patients with RA also have features characteristic of non-inflammatory centralized pain conditions (e.g., fatigue, sleep disturbances). The objective of this study was to determine whether subgroups of RA patients could be characterized by a latent construct, representing the involvement of central, non-inflammatory pain processes. The latent construct was defined by grouping individuals based on the presence or absence of symptoms indicative of aberrant central nervous system involvement (e.g., fatigue, sleep problems, negative mood, catastrophic attributions and perception of overall illness burden) using cluster analysis. Whereas factor analysis aggregates variables into patterns based on correlations, cluster analysis categorizes individuals into non-overlapping subgroups (14). Cluster analysis is particularly valuable in identifying subgroups which differ in underlying pathogenic mechanisms and clinical outcomes (15). The identification of clinically distinct phenotypes within a heterogeneous population of RA patients would be the first step in understanding the pathogenic mechanisms underlying each symptom cluster and, ultimately, identifying potential targets for treatment. The variables used in this cluster analysis were markers of central pain processes, similar to those included in a previous cluster analysis examining the role of central, non-inflammatory pain in osteoarthritis (16). We hypothesized the presence of at least three subgroups: one group comprised of RA patients with well-controlled disease, minimal fatigue and low psychosocial distress; a second group of RA patients with active inflammatory joint pain and moderate levels of psychosocial distress, and a third group of RA patients with low swollen joint counts and high levels of pain, fatigue and other symptoms characteristic of a chronic, non-inflammatory, pain syndrome. This hypothesis was based on clinical observations, as well as studies in other painful chronic conditions. These studies have reported similar subgroups consisting of: a) participants predominantly affected by peripheral pain generators (e.g., joint inflammation and/or mechanical/structural markers), and b) participants in whom inflammation and/or mechanical factors appear to have minimal impact compared to the influence of central, non-inflammatory pain processes(16, 17). Additional subgroups may also exist. For example, other studies have described a group with high levels of depression but low levels of other symptoms (16, 17). However, given the low levels of depression in our patient population (18), we did not expect to identify this group in this cluster analysis.