Background/Purpose: Gastrointestinal (GI) involvement is the most common internal organ affected in systemic sclerosis (SSc). Constipation is a common GI complication in SSc that affects over 50% of patients. It can be severe and impacts quality of life. We sought to examine the safety, tolerability, and efficacy of linaclotide, a selective agonist of guanylate cyclase C (GC-C) as an intervention for SSc patients with refractory constipation.

Methods: We performed a retrospective analysis of all patients seen at Johns Hopkins Scleroderma Center between August 2012 and January 2019 who were prescribed linaclotide as an outpatient for refractory constipation. All patients had data prospectively collected in our longitudinal database if they met criteria for systemic sclerosis. Patients were defined as linaclotide responders if they were to medication for at least 12 months and had documentation of clinical effectiveness documented by the treating physician. We examined the prescribed dose and frequency of the drug, rates of symptom improvement, duration of treatment, treatment response, and side effect profiles among linaclotide-treated patients.

Results: Thirty-one patients with SSc were treated for refractory constipation with linaclotide. We found that the majority of patients (90.3%; 28/31) had a favorable response to treatment and tolerated it well, while only three patients (9.7%) reported ineffectiveness or had intolerable side effects. Low-dose linaclotide achieved adequate symptom control in approximately 2/3 patients (58.1%; 18/31), though high-dose linaclotide (equivalent to at least 145 mcg daily dosage) was required in a subset (41.9%; 13/31). The most common side effects were diarrhea, cramping, or bloating, which was present in 8 patients (8/31, 25.8%). Ineffectiveness, cost, and abdominal pain were the complaints cited among those who discontinued therapy. We then evaluated the subset of linaclotide-treated SSc patients with objectively measured colonic transit times by whole gut scintigraphy. We found that 11/14 (78.6%) had delayed colonic transit and 3/14 (21.4%) had normal colonic transit. This demonstrated that while severely delayed colonic transit was present among a subset of patients treated with linaclotide, not all significant constipation in SSc is associated with delayed colonic . The presence of responders to linaclotide in both groups (8/11, 72.7%, with delayed transit; 3/3, 100%, with normal transit) suggests that SSc patients with refractory may respond favorably to linaclotide, independent of colonic transit abnormalities.

Conclusion: Linaclotide is a well-tolerated and efficacious prosecretory agent that can be used to manage refractory constipation in who have failed management with over the counter laxatives and/or stool softeners. We find that low-dose treatments with linaclotide are an effective option with a lower side effect profile than high-dose treatment regimens, though high doses are required for optimal symptom control in some patients.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/linaclotide-for-the-treatment-of-gastrointestinal-symptoms-in-systemic-sclerosis/