Background & Aims Celiac disease (CeD) is a prevalent autoimmune condition. Recurrent signs and symptoms are common despite treatment with a gluten free diet (GFD), yet no approved or proven non-dietary treatment is available. Methods In this multicenter randomized, double-blind, placebo-controlled study, we assessed larazotide acetate 0.5, 1, or 2 mg three times daily to relieve ongoing symptoms in 342 adults with CeD who had been on a GFD for ≥12 months and maintained their current GFD during the study. The study included a 4-week placebo run-in, 12-week treatment, and 4-week placebo run-out phase. The primary endpoint was the difference in average on-treatment Celiac Disease Gastrointestinal Symptom Rating Scale score (CeD-GSRS). Results The primary endpoint was met at the 0.5 mg dose of larazotide acetate with fewer symptoms compared with placebo by Modified Intention to Treat (n=340) (ANCOVA p=0.022, MMRM p=0.005). The 0.5mg dose showed effect on exploratory endpoints including, 26% decrease in Celiac Disease Patient Reported Outcome Symptomatic Days (p=0.017); 31% increase in Improved Symptom Days (p=0.034); ≥50% reduction from baseline of weekly average Abdominal Pain Score for ≥6 out of 12 weeks of treatment (p=0.022); and a decrease in Non-GI symptoms of headache and tiredness (p=0.010). The 1 and 2 mg doses were no different than placebo for any endpoint. Safety was comparable to placebo. Conclusions Larazotide acetate 0.5 mg reduced signs and symptoms in CeD patients on a GFD better than a GFD alone. While results were mixed, this study represents the first successful trial of a novel therapeutic agent targeting Tight Junction regulation in patients with CeD who are symptomatic despite a GFD. Clinicaltrials.gov, NCT01396213

SUMMARY Background

SUMMARY Background Gastrointestinal tract involvement is a common cause of debilitating symptoms in patients with systemic sclerosis. There are no disease modifying therapies for this condition and the treatment remains symptomatic, largely owing to the lack of a clear understanding of its pathogenesis. Aim To investigate novel aspects of the pathogenesis of gastrointestinal involvement in systemic sclerosis To summarize existing knowledge regarding the cardinal clinical gastrointestinal manifestations of systemic sclerosis and its pathogenesis, emphasizing recent investigations that may be valuable in identifying potentially novel therapeutic targets. Methods Electronic (Pubmed/Medline) and manual Google search Results The gastrointestinal tract is the most common internal organ involved in systemic sclerosis. Any part of the gastrointestinal tract from the mouth to the anus can be affected. There is substantial variability in clinical manifestations and disease course and symptoms are non-specific and overlapping for a particular anatomical site. Gastrointestinal involvement can occur in the in the absence of cutaneous disease. Up to 8% of systemic sclerosis patients develop severe gastrointestinal tract symptoms. This subset of patients display increased mortality with only 15% survival at 9 years. Dysmotiity of the gastrointestinal tract causes the majority of symptoms. Recent investigations have identified a novel mechanism in the pathogenesis of gastrointestinal tract dysmotility mediated by functional anti-muscarinic receptor autoantibodies. Conclusion Despite extensive investigation the pathogenesis of gastrointestinal involvement in systemic sclerosis remains elusive. Although treatment currently remains symptomatic, an improved understanding of novel pathogenic mechanisms may allow the development of potentially highly effective approaches including intravenous immunoglobulin and microRNA based therapeutic interventions.

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IBD disease severity is the most important predictor of both physical and mental health-related quality of life in patients with this condition despite the presence of other chronic conditions.