Background/Purpose:  Fatigue is a common symptom of Systemic Autoimmune Rheumatic Disease (SARD) and has been proposed to result from the elaboration of pro-inflammatory factors in these conditions. Patients with SARD have a protracted pre-clinical phase during which progressive immunologic derangements occur culminating in disease, however it is unknown at what point during this progression that fatigue develops and whether it is associated with any specific immunologic changes. The objective of the current study was to determine whether ANA⁺ individuals who lack sufficient symptoms for a SARD diagnosis suffer from fatigue and assess the correlation between fatigue, autoantibody profile, and the presence of an interferon signature.

Methods:  Healthy ANA^– controls and ANA⁺ (≥1:160 by immunofluorescence) participants with no (ANA No Symptoms, ANS), at least one symptom (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 the modified 2010 ACR criteria questionnaire (score ≥ 13). Peripheral blood IFN-induced gene expression was quantified by NanoString and the normalized levels of 5 ubiquitously expressed IFN-induced genes summed to produce an IFN5 score. ANAs and levels of specific autoantibodies were measured by the hospital laboratory.

Results:  Fatigue and fibromyalgia were assessed in 117 individuals (22 healthy controls (HC), 30 ANS, 25 UCTD, 40 SARD). All ANA⁺ subjects were significantly more fatigued than HC (FACIT-F score (mean ± SD): HC = 49.45 ± 5.54, ANA⁺ subjects = 28.78 ± 14.52, p < 0.0001) and this was true for each of the subsets examined independently. None of the HC and 35.8% of the ANA⁺ subjects had fibromyalgia (p = 0.0004), with similar proportions in all ANA⁺ subsets. As many of the ANA⁺ subjects with low fatigue scores also had fibromyalgia, we assessed whether fatigue was present in ANA⁺ subjects without fibromyalgia. Even in the absence of fibromyalgia, all ANA⁺ subsets were significantly more fatigued than HC (HC = 49.45 ± 5.54, ANS = 40.61 ± 11.31, UCTD = 34.62 ± 12.62, SARD = 33.24 ± 11.66, all p < 0.05), with no significant differences between subsets. There was no association between the FACIT-F score in ANA⁺ subjects (as a group or the individual subsets) and the titre of ANA, number of different autoantibody specificities, or IFN5 score, either in the presence or absence of fibromyalgia.

Conclusion: Fatigue is common in ANA⁺ individuals who lack sufficient criteria for a SARD diagnosis and cannot be solely attributed to fibromylagia or the extent of the immunologic derangement.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/fatigue-in-anti-nuclear-antibody-positive-individuals-with-insufficient-criteria-to-diagnose-a-systemic-autoimmune-rheumatic-disease/