- Iloprost infusion during more than 5 days improves the healing rate and the time to healing, as well as the proportion of healed DUs at 3 months in SSc-related DUs.

- The value of endothelin receptor antagonists or a combination of PDE-5 inhibitors and of hemodilution during the iloprost infusion remains to be determined.

- Pursuing calcium channel blockers during the iloprost infusion is associated with increased infusion-related side effects.

Systemic sclerosis (SSc) is a severe connective tissue disease in which vasculopathy, autoimmunity and fibrosis are the key events. Despite the progress that has been made in early diagnosis and management of organ-based complications, many challenges still remain in the management of SSc. Therefore, DUs are still common in the course of SSc (from 24 to 58%), and are a major source of disability (1, 2). The presence of DUs has been identified as an independent risk factor of mortality (3). Management of DUs includes a local treatment, such as non-invasive debridement and occlusive dressings, and a systemic administration of calcium-channel inhibitors. A combination of iloprost infusions and phosphodiesterase 5 inhibitors are used in severe cases.

Several clinical trials evaluated the efficacy of iloprost for SSc-related DUs (4–8). In two multicenter double-blinded randomized trials, infusion of iloprost (0.5–2.0 ng/kg/min over 6 h, during 5 consecutive days) was associated with significantly greater proportion of DU healings in comparison to placebo (7, 8). In a meta-analysis of therapies for DU prevention and healing, oral prostanoids (iloprost, beraprost, cisaprost, and treprostinil) were not associated with less occurrence of new DUs, when compared with placebo (9).

Unlike thromboangiitis obliterans, where the duration of iloprost infusion is well-established, the optimal schedule of iloprost infusion in SSc has not yet been defined. Therefore, the benefit of prolonged iloprost therapy is uncertain for SSc patients (10). In addition, the value of additional drugs, such as endothelin receptor antagonists (ERAs, i.e., bosentan) and phosphodiesterase 5 inhibitors (PDE-5, i.e., sildenafil) concomitant to iloprost infusion remains to be determined.

In this retrospective study, we therefore aimed (1) to compare the time to healing between two regimens of ilosprost administration: duration greater than 5 days, or 5 days or less; (2) to assess the factors associated with the time to healing, particularly the benefit of concomitant use of endothelin receptor antagonists with phosphodiesterase 5 inhibitors.

The determination of the optimal duration of iloprost infusions remains a challenge. We report in this retrospective study that extending iloprost treatment for more than 5 days could be an attractive option for active DUs, especially in patients with severe diffuse SSc. Indeed, prolonged infusions of iloprost shortened the healing time by half, in comparison with patients with shorter treatment duration. The value of endothelin receptor antagonists or the combination of PDE-5 inhibitors remains to be determined, while continuation of calcium-channel blockers was associated with higher proportion of adverse side effects.

Although there is some evidence from clinical trials to use iloprost for SSc-related DUs, administration of iloprost in clinical practice follows various non-validated regimens, often based on the physician’s experience (Tables 3, 4; 2–8, 10–28). In addition, some reports have pointed out that long-term recurrent administration of iloprost was associated with no recurrence of DU (20). Unlike thromboangeitis obliterans or peripheral artery disease, the optimal duration and the frequency of iloprost infusions in SSc patients are uncertain. Therefore, guidelines do not provide any recommendations on iloprost dosage and regimen. Herein, using a clinical endpoint (the healing of DUs), the use of a prolonged regimen of iloprost was associated with a shorter healing time and a trend toward higher proportions of patients with healed DUs.

Systemic sclerosis microvascular structural damage and dysfunction represent the initial morphological and functional markers of the disease. Some authors have reported that patients receiving iloprost had an improvement on Doppler and videocapillaroscopy characteristics, when compared with patients without iloprost (29). Unfortunately, these vascular effects were no longer seen at the next infusion (26). Several cappilarscopic and ultrasonographic tools could help to the clinical evaluation of DU healing, and Ultrasound classification of finger pulp blood flow was correlated with the risk of DU (30, 31). We were unable to obtain the results of the vascular examinations, which could have strengthened our data on the benefit of prolonged use of iloprost. However, the beneficial effects of prolonged infusion of iloprost is supported by the mechanisms of the drug. Prostanoids are potent vasodilators, and inhibit platelet aggregation and vascular smooth muscle cell proliferation. In SSc, DUs involve both microvessels and digital arteries (20). Moreover, an increased prevalence of macrovascular diseases proximal to the digital artery has been reported in SSc (27), in particular affecting the ulnar artery. After iloprost, a significant improvement in endothelial-dependent vasodilation was seen only in SSc patients with an “active” Nailfold videocapillaroscopy pattern. The iloprost effects vanished within 7 days after the last infusion (32). Therefore, our results are consistent with those of thromboangeitis obliterans, where a prolonged duration of infusion is required (10, 29). Patients under iloprost have Doppler and videocapillaroscpy improvement in comparison with those without iloprost, but these vascular effects were no longer observed at the following infusion (26).

The other major result is the benefit of concomitant vasoactive drugs. Two extensive, multicenter placebo-controlled studies have proved bosentan to be an effective treatment option in preventing new DUs and in the treatment of current DUs in relatively small series (22, 23). However, the beneficial effect of combining bosentan with iloprost has not yet been reported. Here, we found no improvement with this dual therapy, particularly among patients with the longer iloprost regimen, as they received more frequently an endothelin receptor antagonist. This result is consistent with the results of RAPIDS-2 (for the Randomized, double-blind, Placebo-controlled study with bosentan on the healing and prevention of Ischemic Digital ulcers in patients with systemic Sclerosis), where treatment with bosentan reduced the occurrence of new DU in patients with SSc, but had no effect on healing of DU compared to placebo (23). To date, it is unclear why a drug that presumably promotes vasodilation as an antagonist of ET-1 would not also promote ulcer healing. One hypothesis is that the expression of endothelin receptors on keratinocytes suggests that ET-1 could be a modulator of function and, therefore, receptor blockade might impair epithelialization despite beneficial effects on other aspects of healing. Likewise, PDE-5 inhibitors have also been studied for curing DU in SSc. In a French randomized study, even though the healing time was not improved under sildenafil, there was a significant decrease in the number of DUs in favor of sildenafil at the 8th and 12th week (33). To our knowledge, data is scarce on this aspect, and we have not found data suggesting that these various drug combinations could improve healing time in patients with SSc. However, the present study could not allow us to draw a definitive conclusion, due to the small number of patients treated with each drug and combination of drugs.

Prolonged duration of iloprost can be a source of morbidity and disability, due to increased frequency and duration of hospitalizations and venous access. In addition, no criteria has yet been determined to stop the treatment. It is questionable to prescribe a drug that can possibly be responsible for side effects, without clear guidelines based on robust studies. Another important problem relates to strategies for preventing the recurrence of DUs, and in particular the preventive use of endothelin receptor antagonists or PDE-5 inhibitors. Only a small proportion of our cohort was treated by endothelin receptor inhibitor, though this drug is known as an effective preventive drug for DU recurrence (22, 23), even though 90% of the infusions were performed for recurrent DUs. However, these data are similar to a recent analysis from the observational real-life DESScipher study, showing that the proportion of patients with a combination therapy is still low with 32.6% patients under 2 drugs and 11.5% under three or more therapies (16).

Several limitations should be addressed, in particular the retrospective nature of the study and the limited number of iloprost infusions. In addition, the classification criteria for defining healing are heterogeneous. Finally, the duration of iloprost infusion has been based on the physician’s experience and may therefore differ between two medical centers. Despite these limitations, a prolonged use of iloprost in patients with severe diffuse SSc with dominant microcirculatory involvement is coherent and seem to improve the healing rates.

To conclude, a prolonged administration of iloprost may improve the healing rate and the time to healing of DUs related to SSc. Prospective randomized studies are guaranteed to confirm these data and define the optimal duration of iloprost.

The original contributions presented in this study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.

CJ, HL, OF, SR, YB, and AM: conception and design of the study and analyzing and interpretation of data. CJ and AM: acquisition of data. CJ, HL, ST, OF, SR, YB, and AM: drafting and final approval of the manuscript. All authors contributed to the article and approved the submitted version.

AM was investigator of CELGENE, ROCHE, CHUGAI founded trials with APHP and Hôpital 15-20 promotion; AM received several fees for congress travels and experts’ use from LFB, SANOFI, SHIRE, and CELGENE. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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