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    Aldehyde dehydrogenase implicated in mucous membrane pemphigoid

     

    Often, the earliest sign of in patients with subacute disease is medial canthal scarring and the loss of the plica and caruncle.

    Medial canthal scarring is usually an early sign of MMP and is not as frequent in conjunctival scarring due to other causes.

    Sometimes linear scarring in the sulcus subtarsalis of the upper tarsus is present early in the disease.

    Other signs progress in the following order: subepithelial reticular fibrosis, infiltration of the tarsal and bulbar conjunctiva, shortening of the fornices, symblepharon and cicatricial entropion, and ankyloblepharon. A total dry “skin like” effect usually occurs late in the disease subsequent to scarring of the lacrimal ductules.

    Some patients have a genetic predisposition to MMP. It is possible a subset undergo damage to the conjunctival basement membrane that exposes the basement membrane epitopes triggering an autoimmune response.

    In most cases, Dart believes, the disease develops as a loss of tolerance to epethelial basement membrane proteins. He hypothesises the inflammatory response is both the result of a variable balance between epithelial basement membrane autoreactive T-cell-mediated inflammation in the lesional tissues and the result of circulating autoantibodies to basement membrane proteins.

    He further hypothesises the scarring results from the inflammatory response in MMP rather than directly from the autoimmune pathogenesis.

    Dart and colleagues have recently shown that the ALDH/retinoic acid metabolic pathway regulates profibrotic activity in ocular MMP conjunctival fibroblasts in vitro.

    ALDH is overexpressed in ocular MMP conjunctiva at the gene and protein level, compared with controls, he wrote. These controls adopt a profibrotic phenotype when treated with retinoic acid the metabolic product of ALDH. On the other hand, inhibiting ALDH with disulfiram abolishes the profibrotic phenotype in MMP conjunctiva, resulting in the adoption of a normal control phenotype.

    Disulfiram also prevented scarring in a mouse model of ovalbumin induced severe conjunctival inflammation in vivo. In vitro, it restored these mouse conjunctival firbroblasts to a normal phenotype.

    Since disulfiram is already licensed for alcohol abuse control, it could be repurposed for topical treatment of conjuncival scarring in ocular MMP, he wrote, arguing that a randomized controlled trial is in order.

    Similar treatments might work for Stevens-Johnson syndrome, atopic keratoconjunctivitis, and trachoma.

    Current treatments start with control of surfaces diseases such as blepharitis, dry eye, corneal punctuate epitheliopathy, keratinisation, trichiasis, entropion and lagophthalmos, persistent epithelial defects, corneal perforation, and iatrogenic toxicity.

    The next step is control of immune mediated inflammation with systemic immunomodulation. (Topical immunomodulation has not been successful, Dart wrote.)

    Following that come treatments aimed at control of fibrosis, prophylaxis of corneal ulceration and exposure, and improving vision in patients with corneal blindness.

    The addition of disulfiram could add significantly to the armamentarium if supported by clinical trials, Dart concludes.

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