Allison L. Limmer, BA, BS1; Crystal E. Nwannunu, BS1; Radhika Shah, BS, MS2; Kendall Coleman, BSA1; Ravi R. Patel, MD3; Uyen Ngoc Mui, MD3; Stephen K. Tyring, MD, PhD1,3

1Department of Dermatology, McGovern Medical School, The University of Texas Health Sciences Center, Houston, TX, USA
2Texas A&M University College of Medicine, Dallas, TX, USA
3Center for Clinical Studies, Houston, TX, USA

Conflict of interest:
All of the authors have no conflicts to declare for this work.

Epidermolysis bullosa (EB) is a group of rare mucocutaneous fragility disorders often presenting in infancy and early childhood with painful blistering of the skin and mucous membranes. The severity of EB blister burden varies by disease subtype. Studies have shown that patients with generalized severe epidermolysis bullosa simplex (EBS), a variant characterized by extreme fragility, develop blisters in the setting of overproduced, mutated K14 protein, a component of the intermediate filament integral in keratinocyte stability, and constitutive activation of interleukin (IL)-1, a pro-inflammatory cytokine that promotes the hyperproliferation of keratinocytes. Diacerein, a rhein prodrug and anthraquinone, has been shown to reduce expression of K14 and inhibit IL-1 converting enzyme. In clinical trials, topical 1% diacerein was shown to be an effective and safe, non-invasive treatment for patients suffering from EBS. This review examines the clinical trials of topical diacerein and its role in EBS. Diacerein ointment was granted US FDA Rare Pediatric Disease designation in May 2018 and Fast Track development designation in August 2018.

Key Words:
blistering, diacerein, epidermolysis bullosa, treatment


Epidermolysis bullosa (EB) is a group of rare genetic diseases that causes fragile blistering of the skin.1 EB presents most commonly in infancy and early childhood, but in some cases it can present later in adolescence.2 Painful skin blisters often manifest spontaneously or secondary to friction against the skin, minor injury, or even from heat.3 Patients with EB are often called “Butterfly Children,” as their skin is as fragile as the wings of a butterfly.4 This inherited disease not only causes blister formation of the skin, but also can occur within mucosal membranes such as the oral cavity and the respiratory, gastrointestinal, and genitourinary tracts.5,6 The severity of EB varies with the type and inheritance pattern of the disease.4 Milder forms commonly resolve with time, but severe forms are associated with more painful and often disabling blistering, scarring, and deformation that can lead to life-threatening health complications.1

Pathogenesis of Epidermolysis Bullosa

EB often results from either an autosomal dominant (AD) or autosomal recessive (AR) genetic defect.6 Mutations of genes encoding integumentary proteins are the most common causes of poor integrity and skin fragility that lead to blistering in patients with EB.5 EB has been categorized into 4 major types, the most common of which is epidermolysis bullosa simplex (EBS) with an incidence of about 1 in every 25,000-50,000 people.7 EBS is usually inherited in an AD pattern. Defects frequently occur in the keratin filament genes, KRT5 and KRT14, and these mutations lead to destabilization of keratinocyte cytoskeletons within the epidermis. EBS presents with blisters affecting the hands and feet, normally resolving without signs of scarring.5

The major risk factor for this disease is a family history of EB. Prevalence may be found in every racial and ethnic group worldwide and affects both sexes equally.2

Current Treatments

Currently, EBS treatment is limited to caring for blisters through wound care, symptomatic relief, and alleviating secondary complications such as infection.8 Pain management involves the combined use of acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), and opioids depending on the severity of pain, as well as tricyclic antidepressants if the pain is neuropathic in origin. Pruritus can be treated with antihistamines. If the blisters become infected, antibiotic use is indicated but only for short periods of time and in rotation to prevent resistance.9 Corrective gene therapy is currently being researched, as EBS is a monogenic disease.6

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

Patient-Reported Outcomes

Patients who completed both arms of the Wally et al. (2018) study were asked to answer an 8-question quality of life assessment following each 4-week treatment period and follow-up period.8 Interestingly, although the study nurse did not note any significant change in pain and/or pruritis in the study subjects across time or between study groups, the question “Has your skin been itching recently, or have you had pain?” elicited a statistically significant difference between diacerein- and placebo-treated patients.8 Thus, a positive effect of diacerein treatment, according to patients, was reduction in pain and pruritus of treatment areas, though this finding was not confirmed objectively. The other 7 quality of life assessments did not yield significance between diacerein and placebo; still, trends were generally similar and could perhaps become significant with increased power.8


Oral administration of diacerein is associated with gastrointestinal issues; however, topical use is not postulated to induce such effects.15 In the phase 2/3 trial published by Wally et al. (2018), 13 adverse events were recorded, none of which were determined to be severe or treatment-related. Additionally, none of these adverse effects were reported in the treated skin area(s).8 Topical 1% diacerein resulted in blister healing without scarring or other noted side effects. Overall, topical diacerein appears to be a safe and tolerable therapy for patients suffering from EB.8

Future Trials

For EBS, topical 1% diacerein ointment was recently granted Rare Pediatric Disease designation in May 2018 and Fast Track development designation in August 2018. Additional clinical trials are still underway.


Topical diacerein, a rhein prodrug, has made a promising impact as an effective treatment for patients with generalized severe EBS. Its mechanism of blocking key inflammatory pathways, as well as its protective effects against collagen destruction, have been shown in clinical trials to result in improved healing and reduction of blister formation. Although diacerein treatment does not correct the underlying genetic defects associated with EBS, it does target the burdensome symptoms accompanying this chronic disorder and can potentially improve the quality of life in affected patients. Therefore, topical diacerein ointment is poised to be an efficacious treatment of EBS, with clinical trials demonstrating reduction in blister severity and improvement in blister healing, in addition to its low-risk side effect profile.

Updated on May 23, 2019. 


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