This is the first report examining the tolerability and clinical response of SSc patients with severe GI disease to linaclotide for the treatment of constipation. Our experience suggests that linaclotide is a safe and effective option in SSc patients with significant lower GI disease manifestations who have not responded adequately to other medications. Patients used linaclotide for a mean duration of 22.6 months for treatment. We found that 90% (28/31) of patients had a favorable response to linaclotide. While, diarrhea, bloating, and abdominal pain were common side effects, no major drug-related adverse events were reported in this cohort of SSc patients, which was likely related to the minimal systemic absorption of this medication.
The majority of patients in this study had severe lower GI disease, with 74% having a history of recurrent pseudo-obstruction or malabsorption (n = 20) and/or were dependent on total parenteral nutrition (n = 3). Though pseudo-obstruction in SSc has historically been attributed to small bowel dysmotility, in our Scleroderma Center, we have found that pseudo-obstruction in SSc is instead associated with severe colonic hypomotility (unpublished data). A recent study suggests that severe colonic involvement is under-reported in the SSc population, and that this complication is associated with a high mortality rate of 27% . Table 1 illustrates that the patients in our cohort tried multiple medications without sufficient symptomatic relief prior to linaclotide initiation. Linaclotide now provides physicians another therapeutic option in the management of such patients in the outpatient setting. Prospective randomized-controlled studies will be important in determining whether the early initiation of linaclotide in patients with lower GI disease manifestations, such as colonic dysmotility, can reduce the risk of recurrent pseudo-obstruction, hospitalization, and death in the longer term.
The majority of patients in our study (90%) on linaclotide therapy reported an improvement in their symptoms. Two patients discontinued therapy due to a lack of efficacy of high-dose linaclotide, and these patients had also not responded lubiprostone, pyridostigmine, and prucalopride. Importantly, one of these non-responders was also on opiate medications (124 morphine equivalent dosing/day), suggesting that rheumatologists should consider specifically targeting opioid-induced constipation when appropriate (i.e. methylnaltrexone).
We had objective GI transit data from thirteen patients in the cohort who underwent nuclear medicine-based whole gut scintigraphy, and 76.9% (10/13) of patients had significantly delayed colonic transit at 72 hours. Despite normal transit by scintigraphy in three patients, all had relief with linaclotide, suggesting that SSc patients may benefit from linaclotide whether or not they have dysmotility. This may be related to dual action of linaclotide, as both a pro-secretory and pro-kinetic agent. Though prior trials of linaclotide reported only high dose prescriptions (290 daily dosing) [9, 10], we identified positive results in patients on both high and low doses of medication.
It is interesting that 3 of the patients with significant lower bowel symptoms had normal colonic transit. None of these patients required high-dose linaclotide. This suggests that SSc patients may have other mechanisms for constipation (e.g. dysbiosis, anorectal dysfunction) outside of transit delays [4, 15]. Characterizing important GI subsets and targeting therapy within the SSc population may help optimize GI treatment responses.
Our study has many strengths. We report a large case series of patients with SSc who were treated with linaclotide for refractory constipation. All patients were seen in the Johns Hopkins Scleroderma Center with standardized data collection and medication reconciliation. The patients in our study have a long follow-up time and systematic screening of a spectrum of SSc-specific clinical features and autoantibodies. As a retrospective series, our data collection was limited by the intrinsic heterogeneity related to clinical documentation and the absence of a matched control group, which will be a focus of future work.