A Syndrome of Joint Hypermobility, Autonomic Dysfunction, Gastrointestinal Dysfunction and Autoimmune markers (JAG-A): Clinical Associations and Response to Intravenous Immunoglobulin Therapy

Background and aims We examined autoimmunity markers (AIMs) in patients with unexplained gastrointestinal symptoms, their relationship to joint hypermobility/hypermobility spectrum disorder (JH/HSD) and the response to intravenous immunoglobulin (IVIG). Methods The study comprised of three cohorts, consisting of adolescent or adult patients with gastrointestinal symptoms affecting more than one region of the gut who underwent laboratory tests, whole gut transit studies, and autonomic testing. AIM positive patients were defined based on a diagnosis of known rheumatic disease with one positive seromarker of autoimmunity or at least two positive seromarkers. The three cohorts were (a) Retrospective (n = 300); (b) Prospective validation cohort (n =133); and (c) Patients with AIM (n=32) prospectively treated with IVIG and followed with standardized questionnaires. Results AIMs were found in 39% of the retrospective cohort, of which the majority had a known rheumatic disorder. In the prospective cohort AIMs were noted in 35% overall but the rate was much higher in patients with JH/HSD (49% versus 21%, p=0.001). Significantly more patients with AIMs had elevations of C-reactive protein and erythrocyte sedimentation rate along with trends in tilt table test and HLADQ8 positivity. IVIG treatment was associated with a significantly greater overall treatment effect than controls and robust improvement over baseline in pain, gastrointestinal and autonomic symptoms. Conclusions Autoimmune markers and autonomic dysfunction are common in patients with unexplained gastrointestinal dysmotility, especially in those with joint hypermobility. IVIG treatment was associated with symptomatic improvement in both gastrointestinal and autonomic symptoms. These results need to be corroborated by randomized clinical trials of immunomodulators but suggest that an autoimmune etiology may be important to diagnose in such patients. Clinicaltrials.gov, [NCT04859829][1] ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Trial NCT04859829 ### Funding Statement Funded in part by the Amos Food Body and Mind Center, Johns Hopkins University School of Medicine ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The entire study was approved by the Institutional Review Board of the Johns Hopkins University School of Medicine I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present work are contained in the manuscript [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT04859829&atom=%2Fmedrxiv%2Fearly%2F2023%2F10%2F02%2F2023.10.01.23296388.atom