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

NCT06305026 | Completed

• 1 other identifier: S-20190160
• Study Type: observational
• Target: 48
• Locations: 1 country
• Sites: 1

Brief Summary

Background: Chronic widespread pain is challenging in the management of the patient with rheumatoid arthritis (RA), affecting approximately one third of this patient population. However, pain is not always caused by disease activity (inflammation) but can be associated to 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. Among patients with RA the prevalence of concomitant FM is reported to be 12-17% compared to 1-3% in the general population. In general the pain, felt by the fibromyalgia patients is considered to be due to lower pain thresholds because of abnormal central pain processing. Pain reported by RA patients with concomitant FM could potentially be explained by this phenomenon. Little is known about RA patients fulfilling criteria for FM. Muscles-studies of FM patients have not found any histopathological explanation of the pain felt, however an old study of muscle changes in RA patients found changes that could explain muscle pain. Small fiber neuropathy (SFN) is a condition associated with autoimmune diseases, and evidence suggests that SFN is likely to contribute to the pain observed in FM. Objectives: To determine the diagnostic test accuracy (sensitivity and specificity) of both muscle- and skin-biopsies for fibromyalgia phenotyping and detection by clinical referral (RA with concomitant FM) as the reference standard (i.e. fulfilment of 2016 FM criteria). Data collection: Will be done as study subjects are included and stored in REDCAP. Eligibility criteria for participants and settings where the data will be collected: RA patients will be assessed in the daily clinic in Esbjerg and Odense and examined for concomitant FM (I.e. satisfying the 2016 criteria for FM). Patients will afterwards be invited to participate in the study. Inclusion will continue until 25 RA patients fulfilling FM criteria and thus based on the expected prevalence at least 25 (- and maximum 50) RA patients not fulfilling FM critieria has undergone the index tests. Whether participants form a consecutive, random, or convenience series: Participants form a consecutive series. Description of the index test and reference standard: Twenty-five RA patients with concomitant FM and more than 25 (- maximum 50 patients) RA patients not fulfilling FM criteria will undergo the index tests. Muscle and skin biopsies will be performed in each group using standardized techniques. The reference standard will be fulfillment of the 2016 criteria for fibromyalgia. Estimates of diagnostic accuracy and their precision: Regarding muscle- and skin biopsies sensitivity, specificity and positive predictive value will be calculated using two times two table. Regarding skin biopsies, median values in the two groups (RA +/- FM) will be compared using a two-sample t-test.

Conditions

Rheumatoid Arthritis; Fibromyalgia, Secondary; Widespread Chronic Pain; Muscle Disorder

Outcome Measures

Primary Outcomes (2)

• Muscle pathology

  Two muscle biopsies from every patient will be necessary. The proportion of patients in each group (RA with and without FM) will be compared regarding muscle fibers, the vascular domain, connective tissue, and inflammation (non-parametric tests). International consensus exists regarding clear histological signs of disease; therefore, dichotomization is feasible and relevant. Definition of and rationale for test #1 (Muscle biopsy) positivity cut-offs: The muscle pathologists evaluate the muscle biopsies, and the test result will be reported as dichotomous, that is, pathological or non-pathological according to international consensus.

  The biopsies will be performed the day the patients give written consent coresponding to day/time of inclusion. Estimated period of time over which the event is assessed is 40 weeks.

• Skin biopsies

  3 mm punch skin biopsies 10 cm proximal from the right ankle will be evaluated regarding IENFD density. The proportion of patients in each group (RA with and without FM) will be compared (non-parametric test). Definition of and rationale for test #2 (Skin biopsy) positivity cut-offs: Skin biopsies regarding intra epidermal nerve fiber density (IENFD) will be evaluated. IENFD will be considered abnormal according to values outside the 95% percentile of the normal range according to age. The proportion of patients with abnormal values will be compared in the two groups.

  The biopsies will be performed the day the patients give written consent coresponding to day/time of inclusion. Estimated period of time over which the event is assessed is 40 weeks.

Secondary Outcomes (3)

• Cold pressure test

  The Test will be performed the day the patients give written consent coresponding to day/time of inclusion. Estimated period of time over which the event is assessed is 40 weeks.

• Pain pressure threshold (PPT)

  The Test will be performed the day the patients give written consent coresponding to day/time of inclusion. Estimated period of time over which the event is assessed is 40 weeks.

• Computerized Cuff pressure algometry (CPA)

  The Test will be performed the day the patients give written consent coresponding to day/time of inclusion. Estimated period of time over which the event is assessed is 40 weeks.

Study Arms (2)

RA patients with concomitant fibromyalgia

Diagnostic Test: Muscle- and skin biopsies

RA patients without concomitant fibromyalgia

Diagnostic Test: Muscle- and skin biopsies

Interventions

Muscle- and skin biopsies DIAGNOSTIC_TEST

RA patients with and without concomitant fibromyalgia will be examined with muscle and skin biopsies.

RA patients with concomitant fibromyalgia; RA patients without concomitant fibromyalgia

Eligibility Criteria

• Age: 18 Years - 100 Years
• Sex: all
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

RA patients with or without concomitant fibromyalgia

You may qualify if:

• Age equal to or over 18
• RA patient

You may not qualify if:

• Alcohol abuse
• Wheelchair users, and patients who require personal assistance with daily activities.
• Medication with glucocorticoids within the last 6 weeks.
• A diagnosis of a systemic autoimmune disease other than RA
• Peripheral vascular disease manifested by claudication or ischemic rest pain
• Neuropathy
• Diabetes
• Patients with abnormal TSH levels.

Sponsors & Collaborators

• Esbjerg Hospital - University Hospital of Southern Denmark: lead
• Odense University Hospital: collaborator

Study Sites (1)

Esbjerg Hospital

Esbjerg, 6700, Denmark

Location

Biospecimen

Retention: SAMPLES WITH DNA

Muscle Biopsies and skin biopsies

MeSH Terms

Conditions

Arthritis, Rheumatoid; Fibromyalgia; Chronic Pain; Muscular Diseases

Condition Hierarchy (Ancestors)

Arthritis; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Skin and Connective Tissue Diseases; Autoimmune Diseases; Immune System Diseases; Neuromuscular Diseases; Nervous System Diseases; Pain; Neurologic Manifestations; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Study Design

• Study Type: observational
• Observational Model: CASE CONTROL
• Time Perspective: CROSS SECTIONAL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: MD

Study Record Dates

• First Submitted: February 22, 2024
• First Posted: March 12, 2024
• Study Start: February 7, 2024
• Primary Completion: November 22, 2024
• Study Completion: June 1, 2025
• Last Updated: August 12, 2025

Record last verified: 2025-08

Data Sharing

• IPD Sharing: Will not share

Locations

DK (1)