Impact of low-dose calcipotriol ointment on wound healing, pruritus and pain in patients with dystrophic epidermolysis bullosa: A randomized, double-blind, placebo-controlled trial

Abstract

Background: Wound management is a critical factor when treating patients with the inherited skin fragility disease dystrophic epidermolysis bullosa (DEB). Due to genetic defects in structural proteins, skin and mucous epithelia are prone to blistering and chronic wounding upon minor trauma. Furthermore, these wounds are commonly associated with excessive pruritus and predispose to the development of life-threatening squamous cell carcinomas, underscoring the unmet need for new therapeutic options to improve wound healing in this patient cohort. Vitamin D3 is acknowledged to play an important role in wound healing by modulating different cellular processes that impact epidermal homeostasis and immune responses. In this study, we evaluate the safety and efficacy of low-dose calcipotriol, a vitamin D3 analogue, in promoting wound healing and reducing itch and pain in patients with DEB.

Methods: Eligible DEB patients, aged ≥ 6 years and with a known mutation in the COL7A1 gene, were recruited to a placebo-controlled, randomized, double blind, cross-over phase II monocentric clinical trial. Patients were required to have at least two wounds with a minimum size of 6 cm² per wound. The primary objective was to evaluate efficacy of daily topical application of a 0.05 µg/g calcipotriol ointment in reducing wound size within a 4-week treatment regimen. Secondary objectives were to assess safety, as well as the impact of treatment on pruritus, pain, and bacterial wound colonization in these patients.

Results: Six patients completed the clinical trial and were included into the final analysis. Topical low-dose calcipotriol treatment led to a significant reduction in wound area at day 14 compared to placebo (88.4% vs. 65.5%, P < 0.05). Patients also reported a significant reduction of pruritus with calcipotriol ointment compared to placebo over the entire course of the treatment as shown by itch scores of 3.16 vs 4.83 (P < 0.05) and 1.83 vs 5.52 (P < 0.0001) at days 14 and 28, respectively. Treatment with low-dose calcipotriol did not affect serum calcium levels and improved the species richness of the wound microbiome, albeit with no statistical significance.

Conclusions: Our results show that topical treatment with low-dose calcipotriol can accelerate wound closure and significantly reduces itch, and can be considered a safe and readily-available option to improve local wound care in DEB patients. Trial Registration EudraCT: 2016-001,967-35. Registered 28 June 2016, https://www.clinicaltrialsregister.eu/ctr-search/trial/2016-001967-35/AT.

Keywords: Calcipotriol; Epidermolysis bullosa; Pruritus; Vitamin D3; Wound healing.

Fig. 1

Clinical study design. We performed a two-armed, double blind, randomized, cross-over phase II study. Patients were randomized into two groups receiving either calcipotriol ointment (0.05 µg/g) or the placebo. 1 g of ointment (either verum or placebo) was applied topically on each of two designated target wounds for a period of 4 weeks. After a 2-month wash-out phase the patient crossed over into the second treatment arm. Clinical assessment of patients was performed every two weeks (day 0, 14 and 28) at the study center when wounds were photographed and swabbed for microbiome analysis

Fig. 2

Impact of low-dose calcipotriol treatment on wound healing. a Size of wound area (%) representing mean with 95% confidence intervals (CIs) at baseline (day 0), 14 and 28 days of treatment with low-dose calcipotriol or placebo. Statistical analysis; generalized estimation-equation model based on gamma distribution, * P = 0.006. b Heat plot showing numbers of wounds with 0–10%, 10–20%, 25–50%, 50–100% or > 100% wound area compared to baseline after treatment with low-dose calcipotriol or placebo at 14 and 28 days. c Clinical pictures of wounds of a patient responding well to low-dose calcipotriol (0.05 µg/g) treatment at baseline, 14 and 28 days of treatment with low-dose calcipotriol or placebo

Fig. 3

Influence of low-dose calcipotriol treatment on itch (a) and pain (b). Scores were assessed for each wound at baseline (day 0), 14 and 28 days of treatment with low-dose calcipotriol or placebo using a visual analog scale (VAS) ranging from 0 (no itch/pain) to 10 (maximum itch/pain). Mean with 95% Confidence Intervals (CIs) are shown. Statistical analysis; generalized estimation-equation model based on gamma distribution,*P < 0.05, ***P < 0.0001

Fig. 4

Effects of low-dose calcipotriol treatment on wound microbiome. a Scatter plot showing species richness on intact skin compared to wounds. Each dot represents an individual wound at baseline (day 0). Statistical analysis; Mann Whitney test, ***P = 0.0001. b Relative abundance of staphylococcus species in all wounds and on intact skin at baseline (day 0). c Microbial species richness of wounds at baseline, after 14 and 28 day-treatment with low-dose calcipotriol or placebo. Data are presented as mean of two wounds of individual patients. d Species richness in open vs completely closed wounds after 14 and 28 day- treatment with low-dose calcipotriol or placebo