Epidermolysis bullosa: The need for novel topical care
May 7, 2018
The advances in epidermolysis bullosa (EB) have been spellbinding. There are now four well-defined forms of EB: EB simplex (EBS), junctional EB (JEB), dystrophic EB (DEB) and Kindler syndrome (KS). There are at least 20 genetic mutations that have been defined via next generation sequencing allowing for precise clinical-pathologic correlation and prognostication. Translational research has demonstrated benefit utilizing protein and mRNA-based approaches, bone marrow transplantation for recessive DEB (RDEB), cell therapy by intradermal injection of allogeneic fibroblasts into RDEB skin, and gene therapy with ex vivo cultures of RDEB keratinocytes (transduced with a retroviral vector containing full-length COL7A1 cDNA) regrafted on patient’s wounds as epidermal sheets. Progress has also been forthcoming for symptomatic relief, an example being losartan, which may alleviate fibrosis in RDEB, by inhibiting TGF-beta. (1)
As exciting as these developments are, dermatologists who see patients with EB today need to address wound care, preferentially with topical therapy that is easy to apply and safe, while basic and translational research continue.
I was enthralled learning of the benefit of CBD oil for EB patients presented last summer at the World Congress of Dermatology. This data, however, has not been formally published (on PubMed). We will have to wait. Maida and Corban reported three patients with pyoderma gangrenosum that were treated with topical medical cannabis compounded in nongenetically modified organic sunflower oil. All patients experienced the onset of analgesia within three to five minutes of application. Clinically significant analgesia (at least a 30% reduction) was associated with reduced opioid utilization in all three cases. The authors concluded that topical medical cannabis has the potential to improve pain management in patients suffering from wounds of all classes (2); presumably including EB.
Birch (Betula species) is a medical plant whose bark has been used as a natural remedy for skin diseases and wound care for centuries. Oleogel-S10 is a semisolid gel, containing 10% triterpene dry extract (TE) from birch bark and refined sunflower oil (SFO) without the need for further excipients. Additionally, in vitro and in vivo studies suggest that it has anticarcinogenic properties, inducing apoptosis in different tumor cells including human squamous cell carcinoma (SCC) cells. Any benefit would be particularly advantageous for EB patients, who are at risk for the development of SCCs. Schwieger-Briel et al conducted an open, blindly evaluated, controlled, prospective trial in patients with dystrophic EB. Healing of wounds treated with and without topical Oleogel-S10 was compared. Twelve wound pairs of 10 patients with DEB (9 with RDEB) were evaluated. In 5 of 12 cases, both blinded reviewers considered epithelialization of the intervention wounds as superior. In 3 cases, only one reviewer considered Oleogel-S10 as superior and the other one as equal to control. Measurements of wound size showed a trend towards accelerated wound healing with the intervention but without reaching statistical significance. (3) I realize that the authors are publishing images of the best result; regardless the photograph of a groin wound healing after only 6 days utilizing Oleogel-S10 in a 50-year-old man was striking. It is difficult to argue with their conclusion: “Our results indicate a potential for faster reepithelialization of wounds in patients with dystrophic EB when treated with Oleogel-S10 but larger studies are needed to confirm significance.”
Wally et al reported that in EBS-DM (Dowling-Meara) keratinocytes, IL-1beta signaling is constitutively activated, resulting in activation of the JNK stress pathway and overexpression of K14 and IL-1beta itself, causing a positive feedback loop. Via this mechanism, expression of the dominantly interfering mutated K14 alleles also increases, potentially aggravating the EBS-DM phenotype. They proposed that therapy interrupting this positive feedback loop by inhibiting IL-1beta, using a neutralizing antibody or diacerein, would seem worthwhile. (4) Diacerin is an anthraquinone that interferes with IL-1; it has been reported that diacerin is a slow-acting disease-modifying drug for osteoarthritis (OA). A Cochrane review of diacerin concluded that the strength of evidence for effectiveness in OA was low to moderate. (5)
Wally et al followed up on their hypothesis by performing a randomized, placebo-controlled trial using a 1% diacerein topical formulation to treat defined skin areas in 17 patients with severe EBS. In a 2-period crossover trial, patients were randomized to either placebo or diacerein for a 4-week treatment and a 3-month follow-up in period 1. After a washout, patients were crossed over during period 2. The prespecified primary end point was the proportion of patients with a reduction of number of blisters by more than 40% from baseline in selected areas over the treatment episode. Of the patients receiving diacerein, 86% in episode 1 and 37.5% in episode 2 met the primary end point (vs 14% and 17% with placebo, respectively). This effect was still significant after the follow-up. Changes in absolute blister numbers were significant for the diacerein group only. No adverse effects were observed. (6)
While the future of EB revolves around gene therapy and gene editing techniques, coupled with the development of renewable patient-specific pluripotential stem cells (7), research in topical care must also continue until such time the molecular revolution fosters a cure for EB.
Point to remember: Topical wound care for patients with EB is essential — novel products such as topical diacerin may be forthcoming.
1. Uitto J, et al. EB2017 – Progress in epidermolysis bullosa research toward treatment and cure. J Invest Dermatol 2018; 138: 1010-6.
2. Maida V, Corban J. Topical medical cannabis: A new treatment for wound pain- three cases of pyoderma gangrenosum. J Pain Symptom Manage 2017; 54: 732-6.
3. Schwieger-Briel A, et al. Betulin-based oleogel to improve wound healing in dystrophic epidermolysis bullosa: A prospective controlled proof-of-concept study. Dermatol Res Pract 2017; 2017:
4. Wally V, et al. The pathogenetic role of IL-1[beta] in sever epidermolysis bullosa simples. J Invest Dermatol 2013; 133: 1901-3.
5. Fidelix TS, et al. Diacerin for osteoarthritis. Cochrane Database Syst Rev 2014; 10; CD005117.
6. Wally V, et al. Diacerin orphan drug development for epidermolysis bullosa simplex: A phase 2/3 randomized placebo-controlled double-blind clinical trial. J Am Acad Dermatol 2018; 78: 892-901.
7. Vanden Oever M, et al. Inside out: Regenerative medicine for recessive dystrophic epidermolysis bullosa. Pediatr Res 2018; 83: 318-24.
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