Discussion by Michael B. Raizman, MD

Donnenfeld et al 䡠 MMC for Ocular Cicatricial Pemphigoid Discussion by Michael B. Raizman, MD Dr. Donnenfeld and associates report on a novel approach to the treatment of a relatively uncommon, but often devastating, disease. Until now, ocular cicatricial pemphigoid (OCP) was treated with systemic therapy directed at the suppression of the immune response. Ocular cicatricial pemphigoid is thought to begin with deposition of antibody and complement in the conjunctiva and other mucous membranes, as well as the skin. Subsequent inflammation and fibroplasia result in the characteristic scar formation. In the eye, this can lead to pain and loss of vision. Abrogation of inflammation with systemic therapy often leads to disease quiescence. How can mitomycin C effectively halt an autoimmune disease? Mitomycin C inhibits DNA synthesis in fibroblasts and other cells. It seems reasonable to credit this drug with halting progression of symblepharon in OCP, but how can it reduce inflammation and control an autoimmune process? If Dr. Donnenfeld and associates are correct in their findings, we must rethink the pathogenesis of OCP or the mechanism of action of mitomycin. We know from the use of mitomycin C in glaucoma surgery that the conjunctiva often is left thin and relatively avascular. Perhaps mitomycin has a direct effect on blood vessels that limits inflammation in OCP. Perhaps the fibroblasts play an active role in inducing inflammation through the release of cytokines, and this production is reduced by mitomycin C. The authors addressed the limitations of the study. Ocular cicatricial pemphigoid is a systemic disease, and patients can have severe involvement outside the eye. Nonetheless, in the majority of patients, ocular disease is the most difficult to control and other

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sites are not actively involved. A local ocular therapy would benefit the majority of our patients. They did not try alternative oral therapies before mitomycin C therapy. Some of these patients may have done well with dapsone, methotrexate, or azathioprine, but this does not detract from the validity of their findings. Spontaneous remissions are hard to exclude in such a small study. Supporting the efficacy of the drug was the finding of contralateral progression, but the opposite eye may not be a good control: what if eyes with less-advanced disease progress more rapidly? This could lead to bias. The long-term risk of mitomycin C cannot be determined in this study. Topical mitomycin C led to severe ischemic necrosis and infection many years after pterygium surgery in some cases. We cannot be certain that subconjunctival injection will be safer than topical. Grading of disease progression can be most difficult. Measuring hyperemia is subjective, and hyperemia can arise from mechanical factors unrelated to disease activity, such as trichiasis. Symblepharon progression can be even harder to determine because it can happen so slowly. What if eyes with OCP have slowly progressive symblepharon develop over many years after mitomycin C therapy, despite the absence of hyperemia? There are surprising but promising findings in this study. The rapid reduction in conjunctival hyperemia is impressive. The relatively long-term effect of a single injection is remarkable. The short-term safety is encouraging, especially in comparison to the potential toxicity of systemic therapy. The ability of two patients to undergo ocular surface surgery without disease exacerbation is impressive. I remain skeptical, but believe that this pilot study justifies a subsequent large controlled trial. This could be an important advance in the treatment of OCP.

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