Aldehyde dehydrogenase implicated in mucous membrane pemphigoid

Preliminary studies suggest disulfiram could aid in the treatment of mucous membrane pemphigoid (MMP).

Used topically, the drug may inhibit aldehyde deydrogenase (ALDH), which plays a key role in fibrosis, wrote JK Dart, UCL Institute of Ophthalmology, London.

MMP with ocular involvement causes 60% of cicatrising conjunctivitis in the United Kingdom. In one national incidence survey of 50 MMP patients, the median age was 71 years, with a range from 20 to 90 years old.

Twenty-nine of these patients were male and 32 had extraocular MMP as well as ocular MMP. Of these, 8 had another autoimmune disease and 26 were taking immunosuppressive therapy at a 12-month follow up.

In the 1980s, the term benign mucous membrane pemphigoid (BMMP) changed to cicatricial pemphigoid (CP) to reflect the associated scarring.

The terms cicatricial pemphigoid and mucous membrane pemphigoid have since both been used interchangeably.

Studies describing the sites of involvement have attached the names of the sites, most often ocular CP (OCP) and ocular MMP (OMMP).

Cicatricial pemphigoid is now used to describe a rare disease having the same immunopathology as MMP, but which is limited to the head and neck. It is also called localised CP or Brunsting Perry cicatricial pemphigoid.

MMP involves all the orificial mucosal sites: oral, ocular, nasopharyngeal, genital, and anal. Less often it involves the trachea and oesophagus or skin.

The sites become severely inflamed. Scarring rarely occurs in the oral mucosa, but it is a mandatory part of the diagnosis in the conjunctiva. Oral MMP can have a benign course when restricted to the oral mucosa.

However, about 75% of patients with rapidly progressing ocular MMP undergo sight-threatening complications, making early diagnosis and treatment essential.

Ocular MMP presents with a red eye and persistent conjunctivitis that has not responded to topical therapy or with cicatricial entropion, along with trichisasis which may have failed surgical repair.

Some 30% of patients present with acute conjunctivitis and limbitis leading to rapidly progressive scarring and surface failure if uncontrolled.

Persistent epithelial defect, which occurs in about 20% of patients, has a poor prognosis. The remaining patients present with subacute or low grade chronic inflammation and slowly progressive scarring.

Earliest sign

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.