Epidermolysis Bullosa Simplex Clinical Trial
Official title:
Diacerin for the Treatment of Epidermolysis Bullosa Simplex
Epidermolysis bullosa simplex type Dowling-Meara (EBS-DM) is one of the most severe subtypes
of EBS. Blisters and erosions of the skin and mucous membranes upon minor trauma are the
consequence of dominantly inherited mutations in either the keratin 5 (K5) or keratin 14
(K14) gene, which encode proteins constituting the intermediate filament (IF) network in
basal keratinocytes . Autosomal dominant mutations lead to a conformational change and an
increased self-aggregation of the protein. Upon stress, aggregates present in the periphery
of the cytoplasm, subsequently leading to the disintegration and collapse of the IF network.
Clinically, patients suffer from blistering of the skin and mucous membranes upon minor
trauma, resulting in an impaired life quality due to pain and pruritus . In vitro studies on
Dowling-Meara keratinocytes revealed a significant upregulation of the pro-inflammatory
cytokine interleukin-1beta (IL-1ß). Apart from paracrine effects of IL-1ß upon wounding
(e.g. attraction of lymphocytes, activation of dermal fibroblasts), IL-1ß also activates
keratinocytes via the cjun N-terminal kinase (JNK) stress pathway. The activation of this
pathway leads to the activation of a number of transcription factors and the enhanced
transcription of a number of genes, like matrix metalloproteinases, kallikreins, but also
IL-1ß itself and K14 . Interestingly, this state of activation is constitutive and was also
found in keratinocytes from non-lesional sites. It seems that the upregulation of IL-1ß and
K14 in the presence of dominant Dowling-Meara mutations, results in a positive feedback
loop, potentially aggravating the EBS-DM phenotype. This was strongly corroborated by the
fact that when impairing IL1ß signaling, using IL-1ß neutralizing antibody (IL-1Ab) or the
small molecule diacerein, expression levels of IL-1ß and K14 decreased and keratinocytes
were much less susceptible to heat shock in vitro . Furthermore, activation levels of JNK
widely correlated with expression levels of K14 and IL-1ß. (Wally V et al, 2013). These
findings led to the hypothesis that blocking IL-1ß will also lead to an amelioration of the
EBSDM phenotype in effected patients. Based on previous in vitro findings diacerein was
chosen to be topically applied in a pilot study with five patients suffering from EBS-DM. In
that study , each participant received 1% diacerein-cream for one armpit, and placebo for
the other (randomized withdrawal). The number of blisters was reduced significantly (left:
-78%; right: -66% of baseline) within two weeks and remained significantly below the initial
level even during withdrawal in four patients. These findings pointed to a relevant effect
of diacerein and provide important information for our confirmative study.
Diacerein is a component of the rhubarb root, which is reported to block the release of
active IL-1b by inhibiting plasma membrane-bound IL-1 converting enzyme . Diacerien is
already approved for systemic application in osteoarthritis . In general, small molecules
(SM) are low molecular weight compounds with biological functions that can influence
molecular processes. They allow a symptomatic treatment, offering a short-term benefit for
patients in terms of an amelioration of the phenotype. Although this kind of treatment does
not correct genetic alterations, it can still be highly beneficial by damping down disease
symptoms, thereby increasing life quality and minimizing secondary manifestations.
It is important to emphasize that besides dressings, there are currently no other
treatments, therefore, investigators do not prevent an accepted treatment for the patient
and there is no risk for the participant. The treatment will be given only to the armpits
although the disease can involve other areas, so stopping dressings in the armpits during
the study does not risk the patient. Should there be any deterioration of the patient,
whether it is related to the treatment with diacerein or not, investigators will stop the
use of diacerein.
n/a
Allocation: Randomized, Intervention Model: Crossover Assignment, Masking: Double Blind (Subject, Caregiver, Investigator), Primary Purpose: Treatment
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