Abstract
BackgroundFatigue is a common symptom of systemic autoimmune rheumatic disease (SARD). Patients with SARD have a protracted pre-clinical phase during which progressive immunologic derangements occur culminating in disease. In this study, we sought to determine when fatigue develops and whether its presence correlates with inflammatory factors or predicts disease progression.MethodsAnti-nuclear antibody (ANA)-negative healthy controls (HCs) and ANA-positive participants with no criteria, at least one clinical criteria (undifferentiated connective tissue disease, UCTD), or meeting SARD classification criteria were recruited. Fatigue was assessed using a modified version of the FACIT-F questionnaire and the presence of fibromyalgia determined using a questionnaire based on the modified 2010 ACR criteria. Peripheral blood expression of five IFN-induced genes was quantified by NanoString and the levels of IL-1β, IL-6, or TNF-α by ELISA.ResultsFatigue was as prevalent and severe in individuals lacking SARD criteria as it was in UCTD and SARD. Overall, ~ 1/3 of ANA+ subjects met fibromyalgia criteria, with no differences between sub-groups. Although fatigue was more severe in these individuals, those lacking fibromyalgia remained significantly more fatigued than ANA− HC. However, even in these subjects, fatigue correlated with the widespread pain index and symptom severity scores on the fibromyalgia questionnaire. Fatigue was not associated with elevated cytokine levels in any of the ANA+ sub-groups and did not predict imminent disease progression.ConclusionsFatigue is common in ANA+ individuals lacking sufficient criteria for a SARD diagnosis, correlates with fibromyalgia-related symptoms, and is not associated with inflammation or predictive of disease progression.
Highlights
Fatigue is a common symptom of systemic autoimmune rheumatic disease (SARD)
Participants were stratified into three groups based upon their initial assessment: (1) asymptomatic individuals, who lacked any clinical symptoms of SARD; (2) Undifferentiated connective tissue disease (UCTD) patients that had at least one clinical symptom of SARD but insufficient criteria to be classified as SARD; and (3) early SARD patients meeting classification criteria for a SARD (1997 ACR classification criteria for systemic lupus erythematosus (SLE) [31], 2013 ACR-EULAR classification criteria for systemic sclerosis (SSc) [32], or the revised AmericanEuropean consensus criteria for Sjogren’s disease (SjD) [33]) and that were within 2 years of diagnosis
Because many of the subjects suffered from fibromyalgia, and this may have led to anti-nuclear antibody (ANA) testing in the case of absence of SARD symptoms/criteria (ANS), we examined whether the fatigue was related to fibromyalgia, using the modified 2010 ACR criteria [35]
Summary
Fatigue is a common symptom of systemic autoimmune rheumatic disease (SARD). Patients with SARD have a protracted pre-clinical phase during which progressive immunologic derangements occur culminating in disease. Fatigue is a common feature of the anti-nuclear antibody (ANA)-positive systemic autoimmune rheumatic diseases (SARDs), including systemic lupus erythematosus (SLE), Sjogren’s disease (SjD), systemic sclerosis (SSc), dermatomyositis, and mixed connective tissue disease [1,2,3,4,5]. It can be as disabling as other symptoms of organ dysfunction in these conditions and has a significant negative impact on the quality of life of affected patients [5,6,7,8,9]. This clinical course is likely seen in other SARD, since it is not uncommon for individuals to present with insufficient symptoms/ signs to classify a SARD (termed undifferentiated connective tissue disease (UCTD)) and positive serologic findings, ~ 20–40% of which go on to develop SARD in the 3–5 years [25,26,27]
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