With an estimated incidence of only 1 per 10,000 to 50,000,1 ocular cicatricial pemphigoid (OCP) is a rare disease that affects the conjunctiva, cornea, and eyelids. Thought to be caused by a type II hypersensitivity reaction, the etiology of and risk factors for developing this disease remain largely unknown.1,2
The production of an autoantibody against a subunit of hemidesmosomes within the conjunctival basement membrane may play a role in the condition’s development.2 Another name for ocular cicatricial pemphigoid, ocular mucous membrane pemphigoid (MMP), may be a component of systemic MMP.2,3
Signs of ocular cicatricial pemphigoid
The earliest signs of ocular cicatricial pemphigoid in the conjunctiva are hyperemia, papillary reaction, and dry eye syndrome.1 In the eyelids, the first signs include blepharitis, trichiasis, and entropion.1
Early corneal signs include punctate epithelial erosions, exposure keratitis, epithelial defects, ulcers, and vascularization.1 At the time of diagnosis, the disease has typically already progressed to include subconjunctival fibrosis and shortening of the inferior fornix.1
As the disease worsens, it may further include symblephara and keratinization of the cornea as limbal stem cell function fails.1 Ankyloblepharon, or fusion of the upper and lower eyelids, may develop in those with end-stage disease.1
Diagnosis of OCP
Diagnosing ocular cicatricial pemphigoid is typically made based on clinical picture and histology.2,3 Direct immunofluorescence testing of a conjunctival biopsy from an active area may also confirm the diagnosis by displaying linear staining of the epithelial basement membrane.2 Further, histopathology may show a subepithelial blister with inflammatory infiltrates.3
However, immunofluorescence may be less effective in diagnosing severe disease due to basement membrane destruction.2 With the clinical picture of MMP having great variability, immunofluorescence testing of lesions is key to diagnosis.3
Traditional treatments for ocular cicatricial pemphigoid
Traditionally, the first-line treatment for mild to moderate disease, whether ocular or systemic, is dapsone.1,3 Moderate to severe disease may be treated with systemic corticosteroid pulses for 6 to 8 weeks with immunosuppressive therapy.1-3 Due to the slow onset of action of immunomodulatory drugs, these are commonly started at the same time as corticosteroids to allow for a longer period of time to therapeutic levels.2
In those with severe or rapidly progressive disease, cyclophosphamide is the drug of choice, as eye involvement constitutes a high-risk disease.2,3 When systemic steroids and cyclophosphamide fail to treat the disease, intravenous immunoglobulin (IVIg) is a treatment option that may be administered every 3 to 4 weeks.2
Systemic treatment is mainly based on anti-inflammatory and immunomodulatory therapies to target an assumed autoimmune component of disease development and progression.2 While systemic treatment is needed to stop the progression of ocular cicatricial pemphigoid, other therapies can be used for symptomatic treatment.
Topical therapies are occasionally used adjunctively, specifically corticosteroids.3 Their use does not affect the disease process; however, it may provide some symptomatic relief.3 Additional topical treatments have been occasionally shown to be beneficial in slowing disease progression.
The effects of topical calcineurin inhibitors (cyclosporin A and tacrolimus) have been assessed, with more success reported with the use of tacrolimus than cyclosporin A. In the treatment of advanced disease, mitomycin C has been trialed, with studies showing inconsistent effects on disease progression.3
Novel treatments for OCP
Mycophenolate
Mycophenolate is one drug that has been attempted in the treatment regimen for moderate to severe ocular cicatricial pemphigoid or refractory disease, usually in combination with corticosteroids or other immunosuppressant therapy.1 In a study by Çiftçi et al., four out of six patients with OCP treated with mycophenolate and steroids gained partial or complete remission.5
However, systemic therapy often comes with adverse effects. These effects of mycophenolate include nausea, diarrhea, abdominal pain, fever, and anemia.6 Across multiple studies, mycophenolate treatment is beneficial in diseases of higher severity or insensitivity to traditional treatments.7 While it reduces inflammation, it will not affect cicatrization.7
Adrenocorticotropic hormone (ACTH): Intramuscular Corticotropin Injections
Corticotropin gel is used to treat some autoimmune conditions and may be administered intramuscularly or subcutaneously.4 Monotherapy with intramuscular corticotropin injections may present an avenue for treating ocular cicatricial pemphigoid that fails steroid-sparing immunosuppressants.
A report by Chen et al. describes the first published case of corticotropin injections treating ocular cicatricial pemphigoid. An 80-year-old woman with a longstanding disease was treated with intramuscular injections of corticotropin after subcutaneous injections of the same were discontinued due to skin effects.4
The patient had failed therapy with dapsone, mycophenolic acid, methotrexate, prednisone taper, azathioprine, and IVIg due to adverse effects or lack of disease improvement.4
Subcutaneous/Repository corticotropin injections
Subcutaneous (or repository) adrenocorticotropic hormone (ACTH) injections have been trialed as a treatment for ocular cicatricial pemphigoid with some success. In the case of a 75-year-old woman with OCP who failed other treatments or discontinued due to side effects, twice-weekly subcutaneous ACTH injections were effective in controlling conjunctival inflammation.6
While existing conjunctival scarring remained, the repository corticotropin injections (RCI) allowed for disease control until it worsened again following treatment discontinuation for 3 months.6 This patient did not have any significant adverse effects from treatment.6
Treatment with RCI is reported to be successful and relatively safe in managing MMP, with all patients in a study by Sharon et al. showing good disease control and no significant side effects.8 This treatment modality presents an option for those with severe or refractory disease; however, there is little literature on which it has been reported and commented on.
Conclusion
OCP is a progressive disease that may require complex treatment plans for its management. With a high degree of variation between patients and between the stages of disease progression, individualized treatment plans are of utmost importance.
Treatment options range from the conventional treatment options of dapsone, systemic steroids, cyclophosphamide, IVIg, and calcineurin inhibitors to the new, rising treatment options of mycophenolate and intramuscular and subcutaneous ACTH injections.
While there is little reported experience with ACTH injections in the literature, it has been proven to be largely safe and effective in the reported cases.
