Arthritis & Rheumatism, Volume 62,
November 2010 Abstract Supplement
Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Atlanta, Georgia November 6-11, 2010.
A Pilot Study To Evaluate Digital Perfusion in Scleroderma Patients Treated with Oral Treprostinil.
Shah2, Ami A., Hummers2, Laura K., Rollins4, Kristan D., Walker4, Susan, Wade4, Mike, Anderson3, Cynthia, Wise3, Robert
Raynaud's phenomenon and a small vessel obliterative vasculopathy in scleroderma frequently lead to ischemic digital ulcers (DU). Previous studies have demonstrated a therapeutic effect of intravenous prostacyclin analogs for ischemic DU, but oral prostacyclin analogs have had limited success. During a Phase I pharmacokinetic (PK) trial of an oral treprostinil formulation, we sought to quantify changes in perfusion as assessed by laser Doppler imaging (LDI) and to determine whether improvements in perfusion correlated with drug concentration.
Ten patients with scleroderma and a history of recent or active ischemic DU were enrolled into the study. All subjects received oral treprostinil and titrated the dose up to 4mg twice daily (BID) as tolerated over 68 weeks. Assessments were performed when subjects achieved the 2mg and 4mg (or maximally tolerated) doses. Subjects who did not reach a dose of 2 mg BID during the study had assessments performed only at the end of study visit. Eight serial measures of digital perfusion and drug concentration were obtained at each of the 2 study visits. Repeated measures analyses using random effects models were performed using perfusion and skin temperature as dependent variables of interest and perfusion obtained at drug trough, log-transformed drug concentration, visit number, individual timepoints of Doppler assessment at each PK visit, and left/right hand as potential explanatory variables. Covariates with p-values <0.15 were retained in the statistical model.
Ten subjects with a mean age of 44.3 years and mean scleroderma disease duration of 12.2 years were studied. Seventy percent had limited cutaneous scleroderma. Nine subjects tolerated the 2mg BID dose by the first PK visit, and 6 subjects tolerated the 4mg BID dose by the 2nd PK visit. Two subjects completed the study at 0.5mg BID and 1mg BID, respectively. Subjects experienced transient adverse effects typical of prostacyclin therapy: headache, jaw pain, photosensitivity, fatigue, leg pain, nausea, emesis, diarrhea, abdominal bloating, and flushing.
Perfusion was positively associated with log-transformed plasma concentration at the 4mg visit (but not the 2mg visit), after adjusting for the individual time points of Doppler assessment at each PK visit (p=0.015). Digital skin temperature was positively associated with log-transformed plasma concentration at the 4mg visit (but not the 2mg visit), after adjusting for the individual time points of Doppler assessment at each PK visit (p=0.013).
An increase in digital perfusion was observed with increased treprostinil blood concentrations, suggesting a dose-response relationship. Further investigation with a larger sample size and a control population is needed to confirm this association, to correct for individual subjects' natural perfusion variations, and to evaluate for dose effects.
To cite this abstract, please use the following information:
Shah, Ami A., Hummers, Laura K., Rollins, Kristan D., Walker, Susan, Wade, Mike, Anderson, Cynthia, et al; A Pilot Study To Evaluate Digital Perfusion in Scleroderma Patients Treated with Oral Treprostinil. [abstract]. Arthritis Rheum 2010;62 Suppl 10 :1201