Anti-gephyrin autoantibodies have been tied to lower gastrointestinal (GI) dysfunction, such as severe constipation and distention, in patients with systemic sclerosis (SSc), new research suggests. Researchers also found that gephyrin is expressed in the patient’s enteric nervous system (ENS), which regulates gut motility.

Dr Zsuzsanna McMahan

“While there are many antibodies that are helpful in identifying patients at risk for extraintestinal complications of this disease, markers that identify patients at higher risk for gastrointestinal complications are limited. Furthermore, the biological mechanisms that cause and perpetuate the progression of gastrointestinal disease in scleroderma are not well-understood, making it challenging to distinguish between patients whose gastrointestinal disease will progress from those whose GI disease will remain stable/mild,” Zsuzsanna H. McMahan, MD, MHS, told Medscape Medical News in an email. McMahan is co-first author on the study along with Subhash Kulkarni, PhD. They conducted the research with colleagues when they both worked at Johns Hopkins University in Baltimore, Maryland.

When asked for comment, Kimberly Lakin, MD, MS, assistant professor of medicine at Weill Cornell Medical College and a rheumatologist at Hospital for Special Surgery, New York City, called the study “interesting and novel.”

Dr Kimberly Lakin

“Not only did [anti-gephyrin antibodies] correlate with the presence of lower GI symptoms, but also higher levels of antibodies correlated with worse lower GI symptoms. This suggests that not only could this antibody be used to predict who may have constipation and potentially need more aggressive GI interventions, but it may also be useful in quantifying GI severity in systemic sclerosis, although more research is still needed,” said Lakin, who was not involved with the research.

The study was published online August 2 in Arthritis & Rheumatology.

In the cross-sectional study, researchers identified gephyrin as an autoantigen in sera from a single patient with SSc by isolating it from immunoprecipitations performed with murine myenteric plexus neuron lysates, and then characterizing it by mass spectrometry and validating it in further assays. That patient had GI dysfunction but no defined SSc-associated autoantibodies.

McMahan and colleagues then investigated the prevalence of the autoantibody by screening the sera of 188 patients with SSc who presented consecutively to the Johns Hopkins Scleroderma Center between April 2016 and August 2017, as well as 40 controls, and compared GI symptom severity between antibody-positive and antibody-negative patients with SSc.

A total of 16 (8.5%) of the 188 patients with SSc had anti-gephyrin antibodies, compared with none of the controls. Of these 16 patients, 4 had no other defined SSc antibodies. In the SSc cohort, severe constipation was more common in anti-gephyrin antibody-positive patients, compared with antibody-negative patients (46% vs 15%). Antibody-positive patients also had higher constipation scores, and severe distension and bloating occurred in the antibody-positive group more than twice as often (54% vs. 25%).

Patients with severe constipation, distention, and bloating had higher anti-gephyrin antibody levels. After adjusting for confounders such as disease duration, patients with severe constipation were nearly five times as likely (odds ratio [OR], 4.74; P = .010) to be anti-gephyrin antibody-positive, and patients with severe distention and bloating were nearly four times as likely (OR, 3.71; P = .027) to be antibody-positive.

Last, the authors showed via immunohistochemistry that gephyrin is expressed in the myenteric ganglia of human GI tissue.

“Gastrointestinal function is highly regulated by the ENS, so it is interesting that antibodies that target a protein expressed by ENS cells (gephyrin) were identified in patients with scleroderma who have severe lower bowel dysfunction,” said McMahan, who is associate professor in the division of rheumatology and co-director of the scleroderma program at the University of Texas Health Science Center at Houston. “Gephyrin is a key mediator of normal communications between nerves in the gut, so it is tantalizing to speculate that autoimmune-mediated disruption (eg, an inhibitory or blocking antibody) in neural (ENS) communications in the gut might lead to impaired bowel transit and prominent constipation.”

The study was supported by grants from the National Institute of Arthritis and Musculoskeletal and Skin Diseases and other NIH grants, as well as the Scleroderma Research Foundation, Rheumatology Research Foundation, Jerome L. Greene Foundation, Martha McCrory Professorship, and Chresanthe Stauraluakis Memorial Discovery Fund. The study authors and Lakin report no relevant financial relationships.

Arthritis Rheumatol.  Published online August 2, 2023. Abstract

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