Diagnostic Test Accuracy of Histological Muscle and Skin Biopsies of Rheumatoid Arthritis Patients Revealing Objective Chronic Widespread Pain Phenomena Related to Fibromyalgia

To determine the diagnostic test accuracy (the sensitivity and specificity) of both muscle- and skin-biopsies for fibromyalgia phenotyping and detection by clinical referral (RA with concomitant CWP) as the reference standard (i.e. fulfilment of 2016 FM criteria).

Background Pain poses a huge challenge in the management of Rheumatoid arthritis (RA) patients, affecting approximately half of this patient population, even in patients with low disease activity. 1/3 report significant pain. As the composite DAS-28 score has become the standard tool for monitoring RA patients in daily routine, the patient's history of joint pain is of great importance as it influences the VAS applied for patient global assessment and the tender joint count (TJC), which is the single factor with the highest impact on the final DAS-28 score. However, the TJC score is not always associated with clinically quantified inflammation but can be associated with central pain mechanisms, as seen in Fibromyalgia (FM). FM is characterized by widespread pain and tenderness, often accompanied by disturbed sleep, fatigue, cognitive impairment, emotional distress, and multiple symptoms from various organ systems. The prevalence of FM varies between 1-3 percent in the general population. However, among patients with RA, the prevalence is reported to be 12-17%.

The sensation of pain is a product of the interaction of multiple processes. Nociceptors transduce mechanical, chemical, or thermal stimuli into electric signals, which are transmitted through the dorsal horn of the spinal cord to the brainstem and higher cortical areas. The Periaqueductal grey substance (PAG) and the rostral ventromedial medulla (RVM) modulate the pain signal through descending pathways to the dorsal horn of the medulla. In chronic pain states, changes in nociceptive signaling may involve sensitization of nociceptive neurons and ascending spinal tracts accompanied by dysfunction of descending pain modulatory pathways. Changes in nociceptive signaling with lowering of pain thresholds could be an explanation of a high TJC in RA patients if inflammation is not present. As RA patients with FM have similar complaints to patients with primary FM, including former histopathology studies in FM is relevant. Several muscle biopsy studies have been performed on FM patients with conflicting results. Four studies found no differences, three studies report changes associated with ischemia, and few studies report differences between muscle biopsies obtained from FM and healthy controls; however, no pathognomonic pathology in the FM muscles has been detected. Today, consensus exists regarding pathology in muscle biopsies with inflammatory myopathy, which was not the case when all earlier studies were performed. In our study, we apply this method to muscle biopsies from patients with RA and fibromyalgia.

Polyneuropathy is associated with autoimmune diseases. Evidence suggests that small fiber neuropathy (SFN) is likely to contribute to the pain in FM. In skin biopsies, SFN is associated with intra-epidermal nerve fiber density (IENFD). It can be evaluated histologically and quantified. The technique has recently been validated. No muscle or skin biopsy study has been performed on RA patients with or without concomitant FM.

Research question and aim. To determine the sensitivity and specificity of both muscle- and skin biopsies for fibromyalgia phenotyping and detection by clinical referral (RA with concomitant CWP) as the reference standard (i.e., fulfillment of 2016 FM criteria).