Project Overview

Dr. McMahan: Though up to 90% of patients with scleroderma have GI dysmotility, heterogeneity exists among patients. Some patients have predominantly upper GI symptoms, while others have predominantly lower GI symptoms. The presence of various GI dysmotility patterns in scleroderma can complicate the management of patients and thus supports the need for systematic, quantitative assessment of GI subgroups. Understanding the differences among GI subgroups may also provide insight into disease mechanisms.

The assessment of GI motility in patients with scleroderma has evolved in recent years. The use of a traditional, regionally-targeted motility study to assess one portion of the GI tract at a time (e.g. gastric emptying study) is inadequate in scleroderma, because co-existing dysfunction in other GI regions may be missed. GI symptoms are also not reliable, which increases the likelihood of incomplete assessments. Whole gut transit studies emerged to meet a clinical demand that could not be met by regionally-targeted GI studies. Both the scintigraphy-based whole gut transit and the wireless motility capsule were developed to assess transit from the esophagus to the colon, and are now validated and recommended by the American and European Neurogastroenterology and Motility Societies for this purpose. Scintigraphy is considered to be the most physiologic way to assess GI transit because radiotracer is consumed within a meal. It is, therefore, an optimal approach to distinguish between GI dysmotility patterns among patients.

We hypothesize that distinct enteric neuromuscular pathways are important targets of the autoimmune response in scleroderma GI dysmotility and that disruption of these pathways by immune-mediated damage leads to GI dysmotility. We will use the whole gut transit study to define homogenous SSc patient subsets with distinct motility patterns. We will also collect clinical and demographic information, validated GI patient-reported outcome measures, as well as patient serum along with these studies. These studies will establish a framework to ultimately study disease mechanism among clearly phenotyped SSc patient subsets.

How this work will impact patients

This project will provide critical information to guide patient care. We have identified GI dysmotility patterns using the whole gut transit, which are not fully defined by clinical symptoms. Many of these patterns would have been missed using region-specific GI motility studies. The whole gut transit study provides the opportunity to objectively delineate GI dysmotility patterns from the esophagus to the colon, allowing for more precisely targeted therapies. We will also correlate symptoms of GI dysmotility using a well-developed patient-reported outcome measure with objectively measured GI dysmotility patterns.

The project will establish objectively-defined scleroderma-related GI dysmotility subsets. Interestingly, one scleroderma GI subgroup is characterized by delays in the foregut and hindgut (especially the proximal colon), which are regions where motility is predominantly controlled by the vagus nerve. This is the same pattern that we identified in patients with a form of autonomic dysfunction known as postural orthostatic tachycardia syndrome. This suggests that patterns of GI dysmotility in scleroderma may reflect dysfunction in important neural pathways. The clear delineation of GI neuroanatomical patterns of dysmotility in scleroderma is an essential first step in determining whether GI subgroups are random or mechanistically related.

And finally, this project may also yield biomarkers for risk stratification and outcome prediction. In scleroderma, autoantibodies associate tightly with specific clinical phenotypes. For example, antibodies to topoisomerase-1 associate closely with interstitial lung disease, while antibodies to RNA polymerase 3 associate with renal crisis and rapidly progressive diffuse cutaneous disease. Interestingly, associations between scleroderma GI outcomes (e.g. gastroparesis) and autoantibodies are not well-defined, which is likely due to poorly defined GI subsets. Defining the associations between scleroderma autoantibodies (measured on all patients in the Johns Hopkins Scleroderma Center Database) and GI outcomes (measured by the whole gut transit study) may prove useful biomarkers for diagnosis and provide relevant information on specific GI risk in patients.