Topical Diacerein Ointment for Epidermolysis Bullosa Simplex

A Review

Allison L. Limmer, BA, BS; Crystal E. Nwannunu, BS; Radhika Shah, BS, MS; Kendall Coleman, BSA; Ravi R. Patel, MD; Uyen Ngoc Mui, MD; Stephen K. Tyring, MD, PhD


Skin Therapy Letter. 2019;24(3):7-9. 

In This Article

Phase Trials

Studies have demonstrated that patients with generalized severe epidermolysis bullosa simplex (EBS-gen/sev) (formerly EBS Dowling-Meara/EBS-DM), a variant of EBS with extreme intolerance to mechanical stress, heat shock, and osmotic shock, develop painful blisters and injury after even minor disruption to the skin and/or mucous membranes.[10] EBS-gen/sev pathology involves the overproduction of mutated K14 protein, a component of the intermediate filament integral in keratinocyte stability, and the constitutive activation of interleukin (IL)-1β, a proinflammatory cytokine that promotes the hyperproliferation of keratinocytes.[11] Diacerein, a rhein prodrug and anthraquinone, has been shown to reduce expression of K14, inhibit IL-1 converting enzyme, and exert a protective effect on cartilage matrix destruction in patients with osteoarthritis when administered orally.[12,13]

Thus, Wally et al. (2013) developed a topical formulation of diacerein with the aim of providing relief for patients suffering from EBS-gen/sev.[14] This double-blind, randomized, placebo-controlled pilot study employed ultraphil® as the base for a 1% diacerein treatment cream, with ultraphil® alone as placebo. The study recruited 5 patients diagnosed with EBS-gen/sev and mutated K14 protein. Phase 1 (P1) of the study was open label, with all patients receiving 1% diacerein cream to apply on both axillae in the evening for 6 weeks. Blisters were documented every other day by the patient and every other week by a study nurse. Patients also took photos of their axillae with a tape measure in the frame for computerized calculation of blister area. In phase 2 (P2), the second 6-week period, patients applied 1% diacerein to one axilla and placebo to the other in a blinded, randomized fashion. The primary endpoint was designated as time to half the effect of P1 results, namely time to loss of efficacy. This study showed a statistically significant reduction in blistering in the first 2 weeks of P1, which remained stable throughout the phase. The examiners missed their primary endpoint in P2, as no loss of efficacy was noted; researchers proposed this result could be secondary to carryover from the P1 arm of the study. This pilot study suggested that a reasonably sustained reduction in blistering can be noted within 2 weeks of initiating 1% diacerein treatment.[14]

Wally et al. (2018) completed the only phase 2/3 randomized, placebo-controlled, double-blind clinical trial to date.[8] Of the 15 EBS-gen/sev-diagnosed patients initially enrolled, 8 were randomly assigned to the diacerein treatment group and 7 to the placebo group for the first 4 weeks. One patient left the placebo group after the first visit and was replaced; a second placebo patient became ill during the first 4-week period and was replaced for the first 4-week period only, returning for the second treatment period. Both events were considered not treatment-related. After the first 4 weeks, the patients completed a 3-month follow-up phase and mean washout period of 5.6 months. After this time, the groups crossed over, with patients previously in the diacerein group now in the placebo group and vice versa. The 1% diacerein treatment cream was made in ultraphil® as described above. The placebo cream was composed of 0.005% tartrazine in ultraphil® to mimic the yellow hue of the treatment cream. The primary endpoint was designated as the percent of patients with a reduction in blister number from baseline to over 40% within treatment areas in each of the 4-week periods. Researchers also identified and analyzed two secondary endpoints: continued reduction of blister count from baseline to over 40% at the end of the follow-up period and recurrence of baseline blister count plus/minus 10% at the end of each 4-week period. Blisters counts were conducted by 3 independent, blinded raters from photographs taken at each visit; the raters arrived at a consensus count, which was used for statistical analyses.[8]

Among all patients, 39 skin areas were treated, including the arms/axillae, legs, trunk, buttocks, and feet. Throughout both 4-week treatment periods, 102 blisters were counted at baseline in the placebo group, and 97 blisters were counted at baseline in the diacerein group. Researchers noted that blisters healed without scarring or obvious adverse effects. Upon evaluation of the primary endpoint after the first 4-week period, 86% of diacerein-treated and 14% of placebo-treated patients had reduced blister counts of greater than 40%. After the follow-up period, all diacerein-treated patients and only 57% of placebo-treated patients achieved a reduction in blister count of over 40%. In the second 4-week period, 37.5% of diacerein-treated and 17% of placebo-treated patients achieved greater than 40% reduction in blister counts. And at the end of the second follow-up period, 75% of diacerein-treated versus 17% of placebo-treated patients exhibited a greater than 40% decrease in blister number. The mean change in blister counts from start to end in the 4-week treatment periods as well as the mean change from start to end in follow-up periods was significantly different only in diacerein-treated groups, not in placebo-treated groups. Blister counts were also significantly different between diacerein- and placebo-treated groups after both 4-week treatment periods and follow-up periods. Lastly, diacerein-treated groups saw a significant decrease in blister number from the end of treatment periods to the end of follow-up periods.[8]

Upon evaluation of the secondary endpoint, 1 diacerein-treated patient versus 4 placebo-treated patients reached blister numbers greater than or equal to 90% of baseline. There was no significant difference between diacerein and placebo group recurrence in the first 4-week period; however, after follow-up, significantly more patients in the placebo group achieved 90% or more of their original blister counts.[8]