While there are no recommended treatments specifically for RA-associated fatigue, a great deal of progress has been made in recent years in this area. Numerous mechanisms and pathways that potentially underlie RA-associated fatigue have been identified. Various studies have demonstrated significant and positive correlations between fatigue, pain, and mood in patients with RA, and, importantly, these symptoms are increasingly recorded in clinical trials in the form of patient-reported outcomes.

IL-6 is a pleiotropic inflammatory cytokine of particular interest in RA-associated pain and fatigue. IL-6 signaling is regulated in accordance with the sleep-wake cycle, but it is also directly influenced by sleep itself. One line of evidence relates to hypothalamic-pituitary-adrenal (HPA) axis abnormality, which has been associated with the development of fatigue in many different diseases. Tumor necrosis factor alpha (TNF-α), interleukin 1β, and IL-6 can stimulate the HPA axis alone or synergistically, and, among these, IL-6 plays one of the more dominant roles in the immune stimulation of the HPA axis, particularly during chronic inflammatory stress, such as in RA.

Patient-reported data using the Functional Assessment of Chronic Illness Therapy – Fatigue (FACIT-F) are available for both of the anti–IL-6 agents approved for clinical use for RA in the United States—sarilumab and tocilizumab—and these data are summarized as follows:

• In the MOBILITY study, patients receiving sarilumab demonstrated a significant improvement in FACIT-F scores at as early as 2 weeks that were sustained through 52 weeks, compared with placebo.
• In the TARGET study, patients receiving sarilumab plus conventional synthetic disease-modifying antirheumatic drugs reported a significant improvement in FACIT-F scores versus placebo at both 12 and 24 weeks.
• In the OPTION study, patients experienced a significant reduction of fatigue with tocilizumab 4 mg/kg and 8 mg/kg every 4 weeks plus methotrexate compared with placebo plus methotrexate at 24 weeks.
• In the TAMARA study, tocilizumab reduced fatigue within 4 weeks, and improvement continued over 24 weeks. 

Experience with anti-TNF therapy is also instructive with regard to RA-associated fatigue. Anti-TNF agents of the type used in RA do not cross the blood-brain barrier. They do, however, reduce fatigue in adequate responders, as measured using the 36-Item Short Form Health Survey vitality scale. Druce and colleagues have suggested this may occur through central mechanisms, whereby effects on fatigue and pain occur through a common underlying construct, in the absence of alterations in markers of peripheral inflammation. Although anti-TNF therapy has certainly been a major advancement over the last 2 decades, it is a challenge to achieve a deep remission, even for the majority of patients—particularly for those who have established disease. About one-third of patients do not have the gratifying response to anti-TNF therapy that is more typical of the remainder of the population. And, despite achieving clinical remission of their arthritis, many patients with RA do not achieve complete remission of their fatigue.

In summary, patient-reported data from clinical trials are crucial in understanding the effects of biologic and targeted synthetic therapies on domains as complex and interconnected as fatigue and pain. IL-6 is clearly not the only cytokine of importance in RA-associated fatigue; however, for a variety of reasons, IL-6 inhibition is conceptually very appealing in this area.