Abstract
Objective Systemic sclerosis (SSc) is burdened by Raynaud phenomenon (RP) and digital ulcers (DUs), and sometimes standard vasoactive therapies are ineffective or contraindicated. Selexipag is an oral selective IP prostacyclin receptor agonist approved for the treatment of SSc-related pulmonary arterial hypertension. We aimed to evaluate the clinical and instrumental efficacy of selexipag in SSc digital vasculopathy.
Methods Patients with SSc with severe digital vasculopathy refractory or with contraindication to all other vasoactive therapies were administered selexipag. RP- and DU-related clinical outcomes were evaluated, and digital perfusion was assessed by laser speckle contrast analysis (LASCA), all at baseline and after 3 months.
Results Selexipag was administered to 9 patients with SSc (66.6% female, mean age 52.3 [SD 16.6] yrs). One patient had to stop the drug because of adverse effects. After 3 months of selexipag administration, there was a significant reduction in RP daily episodes (P = 0.01) and RP mean duration (P = 0.04). The number of DUs decreased from 10 to 4 without reaching statistical significance. A significant improvement in mean perfusion of the fingers (P = 0.02) was observed with LASCA.
Conclusion Selexipag showed good potential for the treatment of SSc digital vasculopathy. Our results are certainly preliminary, yet quite encouraging. New trials for the evaluation of selexipag efficacy in SSc digital vasculopathy are needed.
- digital ulcers
- laser speckle contrast analysis
- Raynaud phenomenon
- selexipag
- systemic sclerosis
- vasculopathy
Systemic sclerosis (SSc) is a chronic autoimmune connective tissue disease characterized by a severe vasculopathy that typically exhibits burdensome manifestations such as Raynaud phenomenon (RP) and digital ulcers (DUs) with a negative effect on morbidity and quality of life.1 A group of oral and intravenous vasoactive therapies, namely calcium channel blockers, phosphodiesterase-5 inhibitors (PDE5is), endothelin receptor antagonists (ERAs), and intravenous iloprost, have been approved for the treatment of digital vasculopathy in SSc.2 However, some patients are resistant to these therapies or cannot take them because of contraindications or intolerance.
Selexipag is an oral selective IP prostacyclin receptor agonist approved for the treatment of SSc-related pulmonary arterial hypertension (PAH).3,4 Given its action on the prostacyclin pathway, the aim of this study was to evaluate the clinical and instrumental efficacy of selexipag in SSc digital vasculopathy.
METHODS
Study population. We report the results of an experimental study conducted on patients affected by SSc (according to the 2013 American College of Rheumatology/European Alliance of Associations for Rheumatology criteria5) from October 2020 to March 2021 and from October 2021 to March 2022 at the Rheumatology Unit of the University of Pisa. Patients were considered eligible for selexipag only if they presented with severe digital vasculopathy with RP and/or DUs impairing daily activities and if all the other vasoactive therapies were ineffective or contraindicated. This off-label compassionate use of the drug was approved by hospital officials (Comitato Etico Area Vasta Nord-Ovest) in accordance with the local rules for rare diseases (law 648/96). Each subject gave written informed consent to participate and for the material to be published.
Selexipag was started at a dose of 200 μg bid and was then titrated with weekly increases of 200 μg up to the maximum tolerated dose, with an upper limit dosage of 1200 μg bid. Other ongoing vasoactive therapies were stable in the 6 previous months and were not modified during the study period.
Each patient was evaluated at baseline and after 3 months of therapy with selexipag. Epidemiological and SSc-specific data were collected, especially regarding digital vasculopathy with a self-reported assessment of RP (number of daily episodes, mean duration, and visual analog scale [VAS] for pain of 0-10 during RP attacks) and with evaluation of the number of DUs and their area measured with a ruler.
Laser speckle contrast analysis. After 15 minutes of acclimatization in a temperature-controlled room at 24 ± 1°C, peripheral blood perfusion of the hands was assessed by laser speckle contrast analysis (LASCA; PeriCam PSI, Perimed). Subjects were asked not to smoke or consume caffeine or alcohol for 3 hours prior to the examination. The scanner was placed 20 cm perpendicularly above the dorsal side of the hand. The instrument was calibrated according to the manufacturer’s instructions. A 1-minute recording was obtained for each hand (image acquisition rate: 10 images per second; frames: 11 × 11 cm). Afterward, regions of interest were drawn from the second to fifth finger bilaterally to evaluate the whole digital perfusion (expressed as arbitrary perfusion units) and the proximal–distal gradient (PDG) of perfusion as previously defined.6
Statistical analysis. Categorical data were described by absolute and relative frequency, and continuous data by mean and SD. To compare clinical and LASCA factors between baseline and 3 months, t test for paired data (2-tailed) was applied and a ladder plot was used as graphical representation. Significance was fixed at 0.05 and all analyses were carried out with SPSS version 28 technology.
RESULTS
Of 300 patients with SSc routinely followed up during the study period, 9 presented with a severe digital vasculopathy refractory or intolerant to other vasoactive drugs and therefore started selexipag. Most of them were female (66.6%) with a mean age of 52.3 (SD 16.6) years and a mean disease duration of 13.2 (SD 9.7) years. Most patients had a limited cutaneous subset (77.7%) and positivity for anticentromere autoantibodies (55.5%). Notably, all patients presented with a previous history of DUs and 7 (77.7%) had active ulcerations at baseline. Two subjects were smokers and 2 had concomitant PAH. PDE5i and ERA therapies were ongoing in 22.3% and 44.5% of the cohort, respectively (combined in PAH cases); no patients were taking concomitant calcium channel blockers.
All patients completed the 3 months of therapy except for 1 patient who had to stop the drug after 3 weeks for headache, arthromyalgias, and hypotension, which were the same adverse effects previously experienced with iloprost; these data were not analyzed further. Another patient complained of jaw pain, which was also, in this case, already present with iloprost, but this adverse effect was made bearable with paracetamol. The final dosage ranged from 800 to 1200 μg bid.
Regarding the 8 patients with SSc evaluated, as reported in the Table and Figure 1, from a clinical point of view, selexipag administration resulted in a significant reduction of RP daily episodes (P = 0.01) and RP mean duration (P = 0.04). Although not significant, VAS pain showed decreasing values (5.00 vs 3.29). The same was found with the number of DUs, which in 3 months decreased from 10 to 4 with no new DUs but without reaching statistical significance. Notably, 3 out of 6 patients with baseline DUs completely healed, and the other half showed a reduction in all DU areas. Evaluating LASCA results (Figure 2), we observed a significant improvement in the mean perfusion of the fingers (P = 0.02), whereas the PDG showed a small increase that was not statistically significant.
Clinical and LASCA comparison between baseline and 3 months of selexipag therapy.
Individual and mean trend of clinical and LASCA variables during selexipag therapy. LASCA: laser speckle contrast analysis; PU: perfusion unit.
Visual chromatic difference of perfusion obtained with LASCA before and after 3 months of selexipag. LASCA: laser speckle contrast analysis.
DISCUSSION
Since digital vasculopathy represents a major cause of worsening morbidity and quality of life in SSc and some patients experience no benefit with or cannot take current vasoactive therapies, we sought to investigate the efficacy of selexipag administered off-label for compassionate use. Selexipag is approved for the treatment of SSc PAH but, given its action on the same prostacyclin pathway as iloprost, it is reasonable to also expect a peripheral vasodilating effect. Unlike iloprost, selexipag offers some additional benefits. First, oral administration solves the problem of difficulty in finding venous access in patients with SSc. The titration of the dosage ensures that each patient can take the maximum tolerated dose of the drug. Finally, the daily intake guarantees a constant presence of the drug in the body, thus overcoming the debate regarding the short half-life of iloprost which affects an administration scheme that is not yet completely standardized.7
Our results showed that selexipag administration can result in an improvement both in clinical manifestations, reducing and mitigating the severity of RP with an overall healing trend of DUs, and in digital perfusion, as revealed by LASCA. The safety profile was consistent with that observed in previous PAH studies.3 So far, 2 case reports reported the efficacy of selexipag in the treatment of RP and DUs.8,9 The only randomized placebo-controlled trial was published in 2017 but failed in its primary aim to demonstrate a reduction in RP frequency.10 However, as also stated by the authors, there were several issues that may have influenced the trial. Among them, the study was designed with a fast titration and a treatment period of only 8 weeks, with 83.3% of patients taking a final selexipag dosage ≤ 800 μg bid. It is conceivable that a longer observation period with a higher drug dosage could have led to more significant results. Moreover, the trial was not designed to assess the effect of selexipag on DUs.
Our study has several limitations, mainly owing to its open-label nature with few patients and without a control group. The small number of the cohort and the short period of observation may have negatively affected some outcomes such as DU healing. The observation period was limited to cold months, and seasonal variability could have been a potential biasing factor. Moreover, an upper limit dosage of 1600 μg bid as in PAH could have led to even better results. Finally, we could have had RP variables self-assessed continuously during the follow-up period.
In conclusion, the results obtained so far are certainly preliminary but quite encouraging, thus laying the foundation for the design of a new trial that could evaluate, with a standardized titration and an adequate observation time, the efficacy of selexipag in SSc digital vasculopathy. In this context, the use of LASCA as a tool to quantify the perfusion benefit of a vasoactive therapy should be promoted.
Footnotes
The authors declare no conflicts of interest relevant to this article.
- Accepted for publication March 8, 2023.
- Copyright © 2023 by the Journal of Rheumatology
