Background/Purpose

Ischemic digital ulcers (DU) occur in over 40% of systemic sclerosis (SSc) patients. Treprostinil diolamine, a newer prostacyclin analog that has been developed for oral delivery, improves cutaneous perfusion and temperature in SSc. A large randomized, double-blind, placebo-controlled clinical trial of treprostinil was conducted in SSc patients with DU. While this trial did not meet the desired endpoint (change in net ulcer burden at 20 wks), there was a significant improvement in several secondary endpoints that measured Raynaud’s severity. Subjects enrolled into an open label extension study (DISTOL-EXT) after the clinical trial; after termination of DISTOL-EXT, all participants were withdrawn from oral treprostinil. We investigated whether active, indeterminate, and total DU burden increased in DISTOL-EXT participants after they discontinued treprostinil.


Methods

In this multi-center, retrospective study, medical records for the year after discontinuation of treprostinil were reviewed. Data from these routine clinical visits were abstracted into a template designed a priori to capture information on the number of active and indeterminate DU at the end of the extension study and at subsequent visits. Participants who did not have a subsequent visit with documentation of DU status were excluded. We examined the number of new DU that developed from the end of the extension study (baseline) through the first year after discontinuation of treprostinil. The number of active, indeterminate and total DU 3-6 months (time A) and >6-12 months (time B) after discontinuation of treprostinil were compared to baseline by the paired t-test.


Results

Fifty-one subjects from 9 SSc Centers were included for analysis. At the conclusion of the treprostinil extension study, the mean number of active, indeterminate and total DU was 0.25 (SD 0.63), 0.22 (SD 0.54) and 0.47 (SD 0.78), respectively. The number of active DU increased from baseline to time A (mean 1.62, p=0.004, N=23) and time B (mean 1.03, p=0.076, N=30). The number of indeterminate DU increased from baseline to time B (mean 0.42, p=0.03, N=30) but not time A. The total DU burden increased significantly from baseline to time A (mean 2.1, p=0.002, N=23) and time B (mean 1.45, p=0.01, N=30) as shown in the Figure. The majority of patients required intensive vasodilator therapy and pain medication: calcium channel blockers (60.8%), PDE 5 inhibitors (21.6%), any pain medication (58.8%), opioids (33.3%). Three patients were hospitalized for complications from digital ulcers, and 4 patients required surgical intervention. Five patients were subsequently diagnosed with pulmonary hypertension.

Conclusion

Total DU burden increased significantly after discontinuation of oral treprostinil diolamine. These data provide supportive evidence of a beneficial effect of oral treprostinil diolamine for the vascular complications of SSc.