Joint Hypermobility, Autonomic Dysfunction, Gastrointestinal Dysfunction, and Autoimmune Markers: Clinical Associations and Response to Intravenous Immunoglobulin Therapy

Abstract

Introduction: We examined autoimmunity markers (AIM) and autonomic dysfunction in patients with chronic neurogastroenterological symptoms and their relationship to joint hypermobility/hypermobility spectrum disorder (JH/HSD).

Methods: AIM positivity was defined as a diagnosis of known autoimmune/autoinflammatory disorder with at least 1 positive seromarker of autoimmunity or at least 2 positive seromarkers by themselves. Three cohorts were studied: (i) retrospective (n = 300), (ii) prospective validation cohort (n = 133), and (iii) treatment cohort (n = 40), administered open-label intravenous immunoglobulin (IVIG).

Results: AIM positivity was found in 40% and 29% of the retrospective and prospective cohorts, the majority of whom (71% and 69%, respectively) had autoinflammatory disorder. Significantly more patients with AIM had elevations of C-reactive protein (31% vs 15%, P < 0.001) along with an increased proportion of cardiovascular autonomic dysfunction (48% vs 29%; P < 0.001), small fiber neuropathy (20% vs 9%; P = 0.002), and HLADQ8 positivity (24% vs 13%, P = 0.01). Patients with JH/HSD were more likely to have AIM (43% vs 15%, P = 0.001) along with more severe autonomic and gastrointestinal (GI) symptom scores. IVIG treatment was associated with robust improvement in pain, GI, and autonomic symptoms, but adverse events were experienced by 62% of patients.

Discussion: Autoimmune markers and autonomic dysfunction are common in patients with unexplained GI symptoms, especially in those with JH/HSD. Many patients seem to respond to IVIG treatment, but this needs to be confirmed by controlled trials. These results highlight the need for vigilance for autoimmune and autonomic factors and JH/HSD in patients with neurogastroenterological disorders. Clinicaltrials.gov , NCT04859829.

Figure 1.

COMPASS-31 scores (means ± Standard Error of Mean), a measure of autonomic dysfunction, of patients with JH/HSD and without^a, as compared with healthy volunteers and patients with other disorders^b. ^aPatients in this study. ^bOther data from a previously published report and provided for comparison (8). *COMPASS scores in all disease categories were significantly higher than healthy controls (P < 0.001, one-way Analysis of Variance). **COMPASS scores in patients with JH/HSD were significantly higher than all other disease categories (P < 0.001). COMPASS scores in all other disease categories, including patients without JH/HSD were not significantly different than each other. COMPASS, composite autonomic symptom score; JH/HSD, joint hypermobility/hypermobility spectrum disorder; SSC, systemic scleroderma. Numbers above the error bars indicate the number of patients in the respective groups.

Figure 2.

Distribution of overall treatment effect (OTE) scores after treatment with IVIG scatter dot plot of individual responses with mean and 95% Confidence Interval (CI) indicated in grey. IVIG, intravenous immunoglobulin.