Cicatricial pemphigoid

Cicatricial pemphigoid is a rare, chronic autoimmune blistering disorder which can produce scarring ¹. Cicatricial pemphigoid can affect the skin only, mucous membranes only or both the skin and mucous membranes. When only mucous membranes are involved, the disease is often referred to as mucous membrane pemphigoid. When only the ocular membranes are involved, it may be referred to as ocular pemphigoid. Risk of scarring depends on the location of disease activity. Initial diagnosis can be a challenge. Due to the risks of serious complications, such as blindness and airway compromise, early and aggressive treatment initiation may be warranted.

Cicatricial pemphigoid is an antibody-mediated blistering disorder. The antibodies target molecules responsible for adhesion within the basement membrane zone of the mucosa and/or skin. This disrupts the normal structure and function of the basement membrane, which allows for the epidermis to separate from the dermis. Clinically, this manifests as blisters and erosions. Several target molecules are associated with the pathogenesis of cicatricial pemphigoid.

Cicatricial pemphigoid is a rare disorder ¹. The exact prevalence and incidence are not known. The incidence of cicatricial pemphigoid estimated in a French study was 1.16 per million per year ². The incidence of cicatricial pemphigoid estimated in German study was 0.87 per million per year ³.

In a study out of Greece, the mean age of onset for cicatricial pemphigoid was found to be 66 years of age, and there was a 1.5:1 female predominance ⁴. Female to male ratio for cicatricial pemphigoid was reported as high as 7:1 in a German population ³.

In a recent retrospective chart review of 162 patients with mucous membrane pemphigoid, 67% percent of patients had ocular involvement at presentation. In those without ocular involvement initially, it was estimated that the risk of developing ocular mucous membrane pemphigoid was 0.014 per person-year ⁵.

HLA-DQB1*0301 is a disease susceptibility marker for cicatricial pemphigoid ⁶.

Cicatricial pemphigoid causes

Autoantibodies targeted to components of the basement membrane zone have been identified as pathogenic in cicatricial pemphigoid ¹. Patients with cicatricial pemphigoid may have antibodies detected to 180-kD bullous pemphigoid antigen (BP180) ⁷, laminin 332 (previously known as epiligrin or laminin-5) ⁸, beta-4-integrin ⁹ and other antigens that are not fully described.

Laminin 332 is a transmembrane protein that connects alpha-6-beta-4 integrin of the hemidesmosome of the keratinocyte to the non-collagenous 1 (NC1) domain of collagen VII. Collagen VII is the attachment for the anchoring fibrils that secure the basement membrane to the dermis. Laminin 332 assists in strengthening the attachment of the epidermis to the dermis from shearing forces.

BP180 is a transmembrane collagen, also referred to as collagen XVII. It is a component of the hemidesmosome of the epithelial cell. The dense plaque of the hemidesmosome binds keratin 5 and keratin 14 within the keratinocyte. BP180 spans the lamina lucida. The non-collagenous portion of the domain (N-terminus) is located near the cellular membrane and the collagenous portion of the domain (C-terminus) spans the lamina lucida and projects into the lamina densa. Sera from patients with bullous pemphigoid mainly target the N-terminus of BP180 whereas sera from cicatricial pemphigoid patients target the C-terminus. The variability in the target may explain the clinical differences seen among bullous pemphigoid and cicatricial pemphigoid patients ¹⁰. The target of the N-terminus would result in a more superficial blister, unlikely to scar, as seen in bullous pemphigoid. The target of the C-terminus would a result in a deeper separation, which would be more likely to scar, as seen in cicatricial pemphigoid ¹¹.

Alpha-6-beta-4 integrin is a component of the hemidesmosome that binds the transmembrane laminin 332 which attaches to collagen VII. Sera and IgG fractions from patients with cicatricial pemphigoid have been shown to target the intracellular portion of alpha-6-beta-4 integrin suggesting that this may have a pathogenic role in cicatricial pemphigoid ¹². A recent study demonstrated that sera from patients with ocular mucous membrane pemphigoid reacted to beta-4 integrin ¹³.

Cicatricial pemphigoid symptoms

The mouth is the most common location for involvement with cicatricial pemphigoid. It may be the only site affected. All areas of the oral cavity may be involved including the buccal mucosa, gingiva, tongue, vermillion lips, and palate ¹⁴. The disease may extend to posterior pharynx. Clinical appearance includes desquamative gingivitis, blisters, erosions, and ulcers. Patients with desquamative gingivitis may experience pain or bleeding when brushing teeth. Long-term inflammation and difficulty in maintaining oral hygiene may lead to caries and loss of teeth and alveolar bone ¹⁵. Scarring is uncommon but may present as white reticulated patches or adhesions ¹⁵.

Cicatricial pemphigoid of the ocular mucosa is often progressive. Scar formation can result in blindness. Inflammation may be slowly progressive. The patient may experience non-specific symptoms of eye irritation, such as burning or excessive tearing ⁸. The disease may present in one eye only; however, over the course of a couple of years, the disease typically affects both eyes ¹⁰. Rarely, patients present with frank blisters. Early scarring is first noted in the inferior fornices. Symblepharons are fibrous strands connecting the conjunctiva of the lid to the globe. These are best visualized when pulling down on the lower eyelid and having the patient look up ¹⁰. The endstage of this process results in scarring of the entire conjunctival sack, known as ankyloblepharon ¹⁰. This results in the inability for the lid to close completely ¹⁰. The chronic inflammation of the conjunctiva also leads to fibrosis of the lacrimal glands and goblet cells, resulting in decreased tear and mucin production. Scarring of the lid results in entropion (inward turning of the lid) and trichiasis (in-turning of the eyelashes) ¹⁰. The combination of abrasion of the cornea by entropion and trichiasis, decreased tear production and mucin production, and loss of lid closure function results in keratinization of the corneal epithelium ¹⁰. This ultimately results in decreased visual acuity ¹⁰.

Nasopharyngeal involvement is less common. It may present as crusted nasal lesions, epistasis, or chronic sinusitis ¹⁶. Adhesions and scarring can occur between structures, leading to airway obstruction.[17]. This has been reported to result in sleep apnea ¹⁶. Laryngeal involvement may present as a sore throat or hoarseness.[17] If scarring occurs, then the loss of phonation becomes permanent ¹⁶. Tracheostomy has been reported as a necessary life-saving intervention in patients with the severe disease resulting in airway compromise ¹².

Esophageal involvement may present as pain, dysphagia, odynophagia, and stenosis ¹⁶.

Cicatricial pemphigoid of the genital and anal mucosa is rare. Erosions and ulcerations can lead to considerable discomfort of the genital skin. Scarring can lead to narrowing of the urethra and vaginal opening. Stenosis of these structures may require surgical intervention to restore function ¹³. The most common symptoms of anal involvement are pain and spasm ¹³.

Cutaneous lesions of cicatricial pemphigoid occur in two clinical presentations. The first subtype presents as a more generalized eruption of tense bullae without scarring. The second subtype presents as blisters on an erythematous base occurring in localized areas, resulting in atrophic scarring. This most commonly affects the head and neck area. Activity in the scalp often leads to alopecia ¹¹. Brunsting-Perry pemphigoid, which was once thought to be a form of cicatricial pemphigoid, presents as a scarring bullous eruption of the head and neck skin without mucous membrane involvement. This is now believed to be a phenotype of epidermolysis bullosa acquisita.

Cicatricial pemphigoid complications

Oral mucosal complications include painful scarring lesions and adhesion formation causing limitation in movement.

Gingival complications include caries, loss of gingival tissue, and alveolar bone and tooth loss.

Ocular complications include irritation, decreased tear and mucin production, secondary infection, symblepharons, ankyloblepharons, corneal irritation, corneal neovascularization, corneal ulcers, and blindness.

Nasal complications include discharge, epistaxis, crust formation, chronic sinusitis, scarring, and impaired air flow.

Pharyngeal complications include hoarseness, loss of voice, supraglottic stenosis, and airway compromise.

Esophageal complications include dysphagia, odynophagia, aspiration, and stricture formation.

Anogenital complications include painful ulcerations, stenosis, and stricture formation.

Cicatricial pemphigoid diagnosis

Biopsy of lesional skin for histopathology is recommended.

Biopsy of perilesional skin for direct immunofluorescence is recommended. Direct immunofluorescence typically demonstrates IgG and C3 as a linear band at the basement membrane zone ¹⁷. Linear deposition of IgA at the basement membrane zone is occasionally seen ¹⁸. To increase sensitivity, multiple and repeated sampling may be warranted ¹⁹.

Indirect immunofluorescence is recommended; however, it is only positive in a small percentage of patients. The titer is usually low ¹⁷. Indirect immunofluorescence on the salt-split skin may show an epidermal or dermal pattern. Indirect immunofluorescence shows the presence of IgG or IgA autoantibodies. To increase the diagnostic utility of the indirect immunofluorescence, it has been recommended to perform with a concentrated assay, using salt-split skin study, and evaluate for both the presence of IgG and IgA ¹¹.

Enzyme-linked immunosorbent assay (ELISA) testing for the presence of anti-BP180 C terminal domain and anti-laminin 332 may be helpful in diagnosis; however, this may not be readily available through all laboratories ²⁰.

Cicatricial pemphigoid treatment

For the mild disease of the oral mucosa and skin, topical therapies can be effective. Moderate to high potency topical steroids, in gel or ointment form, can be used initially 2 to 3 times per day. The frequency of topical steroid application can be slowly tapered based on patient response. To improve the effectiveness of topical therapies, blotting the area with a disposable tissue to remove moisture before the application of medication may be helpful. Patients may apply the medication with a finger or cotton-swab and rub into the affected areas gently for 30 seconds. Patients should be advised to abstain from eating or drinking for 30 minutes after application to increase absorption ²¹. Customized prosthetic devices, such as dental trays, can occlude the topical steroid over the affected sites in the mouth ²². Calcineurin inhibitors, such as tacrolimus, have also been reported as a topical therapeutic option ²³. Complications of long-term use of topical steroids are uncommon. A cutaneous application may lead to hypopigmentation and atrophy. Although these adverse effects are not commonly seen in the mucous membranes, the risk for oral candidiasis and herpes simplex reactivation is a concern  ²¹. In addition to topical therapies, the importance of oral care has been emphasized as a critical part in the treatment of mucous membrane pemphigoid. This consists of brushing teeth with a soft bristle toothbrush twice daily, flossing daily, and visiting the dentist every 3-6 months  ²¹. If topical therapies are not effective for mild to moderate disease, then dapsone may be effective ²⁴. Typical dose ranges from 50 to 200 mg daily. Systemic corticosteroids can be used in addition to the dapsone.

For mild to moderate ocular involvement, systemic corticosteroids (prednisone 1 to 2 mg/kg/day) alone or in combination with dapsone can be considered. Proper ocular care is important. Since dry eyes are common with ocular pemphigoid, frequent use of lubricants is recommended in the form of artificial tear drops or petrolatum-based ointments. Cleansing away excess exudates from the eyes helps to prevent secondary bacterial infections ²¹.

For severe or rapidly progressive disease involving the ocular, nasopharyngeal, or anogenital mucosa, a combination of systemic corticosteroids (prednisone 1 to 2 mg/kg/day) plus an additional immunosuppressive agent has been recommended. Immunosuppressive agents that have shown efficacy include azathioprine (1 to 2 mg/kg/day), mycophenolate mofetil (2 to 2.5 g/day) or cyclophosphamide (1 to 2 mg/kg/day) ²¹. The goal of adjuvant immunosuppressive therapy is to allow taper of prednisone over 6 to 12 months. Intravenous immunoglobulin has been used with success to treat cicatricial pemphigoid ²⁵. Tumor necrosis factor-alpha inhibitors have been used in the treatment of cicatricial pemphigoid ²⁶. Rituximab has been used alone or as adjuvant therapy for the treatment of mucous membrane pemphigoid ²⁷.

Cicatricial pemphigoid prognosis

Cicatricial pemphigoid is a chronic, progressive disease that results in scarring. Patients require long-term follow-up to monitor for complications as a result of scarring and possible relapse. Due to the potentially serious complications that can arise with cicatricial pemphigoid, it is recommended that therapy is initiated early and aggressively. Patients benefit from a multidisciplinary approach to treatment. Although some patients benefit from immunosuppressive treatment and even have long-term remission, some patients have a refractory disease without a response of disease activity or only temporary control of disease activity with a given treatment ¹¹.

Ocular cicatricial pemphigoid

Ocular cicatricial pemphigoid is considered a subtype of mucous membrane pemphigoid and these terms are sometimes used interchangeably ²⁸. Ocular cicatricial pemphigoid is a type of autoimmune conjunctivitis that leads to cicatrization (i.e. scarring) of the conjunctiva ²⁹. If ocular cicatricial pemphigoid is left untreated, it can lead to blindness.

Ocular cicatricial pemphigoid incidence rates are vary between 1 in 12,000 to 60,000 ³⁰. A study in the UK found that ocular cicatricial pemphigoid represents 61% of cicatricial conjunctivitis and is estimated to occur with an incidence of 1 in 1 million ³¹.

Women are affected more than men by a ratio of 2:1 ³⁰. Age on onset is usually age 60 to 80 and rarely younger than 30 ³¹. There is no racial predilection ³².

Progression of ocular cicatricial pemphigoid is measured in months and years and, without therapy, results in keratinization of the ocular surface and cicatricial ankyloblepharon (fusion of palpebral and bulbar conjunctiva, not to be confused with congenital palpebral ankyloblepharon, which describes a localized adhesion of the upper and lower eyelids). Though there are reports of spontaneous remission of ocular cicatricial pemphigoid, these cases are the exception.

In terms of medical therapy, chronic steroid-sparing immunomodulators are the mainstay. Dapsone is a common initial agent, but requires initial testing to rule out hemolytic anemia, agranulocytosis, hepatitis, and G6PD deficiency. Agents such as methotrexate, azathioprine and mycophenolate mofetil have also been used. Recent evidence suggests that monotherapy with mycophenolate mofetil controls ocular cicatricial pemphigoid in up to 70% of patients within one year of presentation with fewer side effects than other agents. This evidence was corroborated by the outcome of the present case. Oral corticosteroids are effective at controlling inflammation, but symptoms usually recur once they are tapered. Ahmed and colleagues recommend reserving them only for the most severe inflammation and tapering down within the first 3 months ³³. Targeted therapy with monoclonal antibodies (daclizumab and rituximab) has also shown some promise and was recently shown to arrest recalcitrant ocular cicatricial pemphigoid when used in combination with intravenous immunoglobulin (IVIG) ³⁴. When initiating steroid-sparing immunomodulatory therapy, it is reasonable to enlist the help of an internist or rheumatologist to ensure appropriate monitoring. Aggressive lubrication is of utmost importance to optimize the ocular surface—preferably with preservative-free artificial tears and ointment or autologous serum tears if needed. Doxycycline, topical corticosteroids, and cyclosporine can help to reduce inflammation and increase tear production.

Surgical therapy may be indicated when scarring becomes advanced and/or ocular surface decompensation threatens permanent visual decline. Mucous membrane grafting from sites such as the nose and hard palate can slow or relieve cicatrization and treat symblepharon. Medroxyprogesterone can be added to reduce the stimulus for neovascularization.

In stage 4 ocular cicatricial pemphigoid, the type 2 Boston keratoprosthesis may be the only means of preserving or restoring visual function. This device creates a clear aperture through the upper eyelid. The lids are permanently sutured closed resulting in total coverage of the ocular surface.

Figure 1. Ocular cicatricial pemphigoid

Footnote: This is a patient with typical ocular cicatricial pemphigoid showing symblepharon characteristic of stage 3 disease. Note the rolled edges of the lids with extensive madurosis.

[Source ³⁵ ]

Ocular cicatricial pemphigoid causes

The exact cause of ocular cicatricial pemphigoid remains to be elucidated but the existing evidence supports a type 2 hypersensitivity (antibody dependent) response caused by an autoantibody to a cell surface antigen in the basement membrane of the conjunctival epithelium and other similar squamous epithelia ³⁶.

Investigations into the underlying target antigen have led to several possible suspects. The autoantigens responsible for bullous pemphigoid [BP230 (i.e. Bullous pemphigoid antigen 1, a desmoplakin) and BP180 (i.e. Bullous pemphigoid antigen 2, a transmembrane hemidesmosome)] were studied, and the sera of patients with ocular cicatricial pemphigoid was shown to bind these antigens ³⁶. However, further investigation supports that the more likely autoantigen is actually the beta-4 subunit of the alpha-6 beta-4 integrin of hemidesmosomes ³⁷.

Studies of HLA (human leukocyte antigen) typing have found an increased susceptibility to the disease in patients with HLA-DR4 ³⁶. The HLA-DQB1*0301 allele in particular shows a strong association with ocular cicatricial pemphigoid and other forms of pemphigoid disease ³⁸. HLA-DQB1*0301 is thought to bind to the beta-4 subunit of the alpha-6 beta-4 integrin (the suspected autoantigen in ocular cicatricial pemphigoid) ³⁹.

Although the exact mechanism remains to be elucidated, the existing evidence supports the production of an autoantibody in susceptible individuals to the beta-4 subunit of the alpha-6 beta-4 integrin of hemidesmosomes in the lamina lucida of the conjunctival basement membrane ³⁷.

Binding of the autoantibody to the autoantigen activates complement, resulting in the cytotoxic destruction of the conjunctival membrane ³⁶. Disruption of the conjunctival basement membrane subsequently leads to bullae formation ⁴⁰.

The associated cellular inflammatory infiltrate of the epithelium and substantia propria manifests as the chronic conjunctivitis that is the hallmark of this disease ⁴⁰. Eosinophils and neutrophils mediate inflammation in the early and acute phases of the disease, similar to what is observed in the skin ²⁸. Chronic disease has largely lymphocytic infiltration ²⁸. Fibroblast activation leads to subepithelial fibrosis, which in early disease appears as fine white striae most easily seen in the inferior fornix ⁴¹. A scar in the upper palpebral conjunctiva may also be seen. Over time, the fibrotic striae contract, leading to conjunctival shrinkage, symblepharon formation, and forniceal shortening ²⁸. In severe cases of conjunctival fibrosis, entropion, trichiasis and symblepharon may develop, leading to associated keratopathy and corneal vascularization, scarring, ulceration, and epidermalization ⁴¹.

The clinical course and severity is variable. Recurrent inflammation causes loss of Goblet cells and obstruction of lacrimal gland ductules, leading to aqueous and mucous tear deficiency ⁴². The resulting xerosis is severe, and along with progressive subepithelial fibrosis and destruction of limbal stem cells leads to limbal stem cell deficiency and ocular keratinization ³⁷.

Several pro-inflammatory cytokines are found to be elevated in the conjunctival tissues of patients with ocular cicatricial pemphigoid. Levels of Interleukin (IL) 1, Tumor Necrosis Factor (TNF) Alpha, migration inhibition factor, and macrophage colony-stimulating factor, and IL-13 have been found to be elevated ⁴⁰. IL-13 has been found to have a pro-fibrotic and pro-inflammatory effect on conjunctival fibroblasts, and may be implicated in the progressive conjunctival fibrosis that can occur despite clinical quiescence ⁴⁰.

Additionally, testing of the tears of patients with ocular cicatricial pemphigoid found elevated levels of IL-8, Matrix Metalloproteinase (MMP) 8, MMP-9, and myeloperoxidase (MPO), which are thought to result from neutrophilic infiltrate in patients with ocular cicatricial pemphigoid ⁴³.

Ocular cicatricial pemphigoid symptoms

The commonest symptoms of ocular cicatricial pemphigoid are:

• Inturned eyelashes (trichiasis) rubbing the eye
• Red, gritty sore or dry eyes with sensitivity to light
• Conjunctivitis (red sticky eye) that keeps returning despite courses of antibiotic eyedrops
• Droopiness and closing of the eyelid

If you have inturned eyelashes that often need to be pulled out, it is essential to have a careful assessment by an eye consultant who is expert in diagnosing ocular cicatricial pemphigoid, to evaluate the underlying cause of the inturned eyelashes.

In patients with mucous cicatricial pemphigoid, oral involvement is most common (in 90% of cases), followed by ocular involvement (in 61% of cases) ⁴⁴. Ocular involvement of mucous cicatricial pemphigoid is considered high risk and carries a poorer prognosis (despite treatment) than when oral mucosa and/or skin alone are affected ³¹. Up to one third of patients with oral disease progress to ocular involvement ⁴⁴.

Additional sites of involvement include the oropharynx, nasopharynx, esophagus, larynx, genitalia, and anus ³⁶. The skin is involved in approximately 15% of cases ³⁶. Dysphagia may be a presenting symptom ³⁶.

There are several clinical scoring systems for ocular cicatricial pemphigoid, including schema from Foster, Mondino, and Tauber ³¹. Clinicians vary in which system they utilize for grading disease clinically and although there are proponents for each system, no consensus exists regarding which system is best to use ⁴⁵. The existing classification schema are limited by the lack of direct correlation with disease progression and therefore no system can be used to predict need for immunosuppression ⁴⁵.

Mondino’s Classification System is based on inferior forniceal depth ³⁶. A normal inferior forniceal depth is approximately 11 mm ³⁶.

• Stage 1: up to 25% inferior forniceal depth loss ⁴⁵
• Stage 2: 25-50% inferior forniceal depth loss ⁴⁵
• Stage 3: 50-75% inferior forniceal depth loss ⁴⁵
• Stage 4: greater than 75% inferior forniceal depth loss ⁴⁵

Foster’s Classification System has four stages as well and is based on specific clinical signs ³⁶:

• Stage 1 Early stage: May include nonspecific symptoms and minimal findings which lead to under-recognition of the disease. Commonly presents as chronic conjunctivitis, tear dysfunction, and subepithelial fibrosis ³⁶ Subepithelial fibrosis manifests as fine gray-white striae in the inferior fornix. Signs and symptoms are usually bilateral, and may be asymmetric.
• Stage 2 Shortening of the fornices. A normal inferior forniceal depth is approximately 11 mm. A reduced inferior forniceal depth is abnormal and should prompt further investigation ³⁶
• Stage 3 Symblepharon formation. Can be detected by pulling the lower eyelid down while the patient looks up and vice versa ³⁶
• Stage 4 Ankyloblepharon. Represents end-stage disease, with surface keratinization, and extensive adhesions between the eyelid and the globe, resulting in restricted motility ³⁶

Ocular cicatricial pemphigoid diagnosis

Ocular cicatricial pemphigoid diagnosis is based on clinical signs and positive direct immunofluorescence testing of the conjunctiva ²⁹. The gold standard for diagnosis is conjunctival biopsy with direct immunofluorescence testing for IgG, IgA, IgM, and C3. Positive staining reveals a linear pattern in the basement membrane zone of the conjunctival epithelium similar to that seen in other anti-basement-membrane-antibody conditions such as Goodpasture disease of the kidney. Conjunctival biopsy of an actively involved area is needed and the conjunctival tissue must be submitted unfixed for analysis ²⁹. If involvement is diffuse, biopsy of the inferior conjunctival fornix is recommended ³⁶. Judicious biopsy is advisable as ocular cicatricial pemphigoid is an obliterating disease of the conjunctiva and only the minimal amount of tissue necessary should be removed. Alternatively, biopsy of an active oral mucosa lesion can be diagnostic as well ³⁶.

Immunofluorescence reveals linear staining of the epithelial basement membrane zone ³¹. The sensitivity of immunofluorescence may be as low as 50%, especially for longstanding/severe cicatrization because of the loss of immunoreactants and the destruction of basement membrane in longstanding disease ²⁹.

Serological testing is not routinely used in diagnosis. Sequential photographs are useful to monitor clinical progression ³⁰.

Ocular cicatricial pemphigoid treatment

Without treatment, ocular cicatricial pemphigoid progresses in up to 75% of patients ⁴⁶. While systemic treatment stops progression of cicatrization in most patients, it fails in approximately 10% of them ⁴⁶. Systemic therapy is necessary in ocular cicatricial pemphigoid as ocular involvement comprises a high risk subset of mucous membrane pemphigoid and is insufficiently treated with topical therapy alone. Systemic treatment is best managed by a physician trained in the management of anti-inflammatory and immunomodulatory treatment given the significant risk of systemic complications necessitating frequent blood test monitoring ³¹. Several drugs are effective in treating ocular cicatricial pemphigoid and a step-wise approach of escalation of therapy when there is insufficient response is recommended ⁴⁷.

Topical therapy can be used as an adjunct for surface disease but should not be used in place of systemic therapy. Topical therapy includes optimizing lubrication of the ocular surface with artificial tears and punctual plugging ⁴⁷. Topical and subconjunctival steroids can relieve symptoms but are ineffective for treatment of the underlying disease ⁴⁷. Topical cyclosporine has been found to be ineffective while topical tacrolimus has been shown to be successful in small case series ³⁰. Subconjunctival mitomycin-c has also been investigated in small case series with variable effect ⁴⁷.

If the disease remains quiescent following a few years of systemic therapy, many practitioners are often able to discontinue systemic therapy successfully ⁴⁷. However, it is important to continue to monitor the patient for recurrence of disease as up to 22% of patients relapse ⁴⁷.

Complications

Seemingly trivial surgical intervention and conjunctival trauma can lead to serious exacerbation of disease ³⁶. Surgical intervention, such treatment of trichiasis, entropion and cataract should be deferred if possible until control of active disease is achieved ³⁰. In some situations this may not be possible and a multi-disciplinary approach is best ³⁰.

Inferior eyelid retractor plication for trichiasis avoids surgery on the conjunctiva and has been shown to be safe and effective when undertaken in the setting clinically quiescent ocular cicatricial pemphigoid ⁴⁸. Cryotherapy for the treatment of trichiasis has also been shown to be safe and moderately effective when undertaken in the setting clinically quiescent ocular cicatricial pemphigoid ⁴⁹. In a case series of patients with well controlled ocular cicatricial pemphigoid undergoing entropion repair, successful repair was performed in all patients regardless of type of surgery ⁵⁰.

Safe and successful performance of cataract surgery has been shown in several case series of patients with well-controlled ocular cicatricial pemphigoid.[32] [33] A clear corneal incision is recommended to reduce the risk of exacerbation ⁵¹.

Glaucoma is also a possible complication of ocular cicatricial pemphigoid and is particularly difficult to diagnose and treat. IOP measurements are unreliable, and examination and ancillary testing are limited by ocular surface disease. A case series of 61 patients with severe ocular cicatricial pemphigoid found that 21% of patients also had glaucoma and an additional 9% developed glaucoma over the course of the follow-up ⁵².

Persistent epithelial defect may need amniotic membrane graft or ProkeraⓇ.

ocular cicatricial pemphigoid has been described in patients with other concurrent rheumatologic illnesses including rheumatoid arthritis, lupus, and HLA-B27 spondyloarthropathies ⁵³.

Ocular cicatricial pemphigoid treatment options

Mild Disease

Dapsone is an effective and commonly used anti-inflammatory treatment in ocular cicatricial pemphigoid for mild disease and in the absence of rapid progression ³¹. Dapsone is started at a dose of 50 mg/day and slowly increased as tolerated by up to 25mg every 7 days to an effective dose, which is usually between 100-200mg/day ³¹. If significant improvement is not achieved within 3 months, escalation of therapy is recommended such as to azathioprine or methotrexate ⁴⁷.

Systemic complications of dapsone include hemolysis and methemoglobinemia ³¹. G6PD (glucose-6-phosphate dehydrogenase) deficiency is a contraindication to dapsone therapy as dapsone can precipitate a hemolytic crisis ³¹. All patients should be screened for G6PD deficiency before initiation of therapy with dapsone ³¹.

Sulphapyridine is also an oral antibiotic and is a well-tolerated alternative in patients with mild disease who are unable to take dapsone ⁵⁴. Sulphapyridine’s efficacy (effective in approximately 50% of patients) is lower than dapsone however ⁵⁴.

Moderate to Severe Disease

Corticosteroids have a rapid effect and are useful during the acute phase of severe or rapidly progressive disease ³¹. Adjuvant corticosteroid-sparing immunomodulatory/immunosuppressive therapy should be initiated simultaneously as it may take weeks to become therapeutic ³¹. This will allow a quicker taper from steroids and the shortest course of steroid therapy necessary given the significant systemic side effects of long-term steroid therapy ³¹. Generally, one quiescence is achieved, steroids are tapered slowly.[22] Screening for tuberculosis (TB) is recommended prior to the initiation of steroid therapy ³¹.

Azathioprine has been shown to be an effective steroid sparing therapy ⁴⁷. It takes 8-12 weeks of treatment to achieve maximal effect and thus should be used initially concurrently with steroids ³¹. Screening for thiopurine methyltransferase (TPMT) deficiency is recommended prior to initiation of azathioprine as TPMT-deficient patients are at higher risk of developing mvelosuppression ³¹. Systemic complications include leukopenia, pancytopenia, infection, malignancy, and drug-induced hypersensitivity syndrome ⁴⁷.

Methotrexate has been shown to be an effective monotherapy for ocular cicatricial pemphigoid with fewer adverse effects when compared to azathioprine, cyclophosphamide, and dapsone ³¹. The Systemic Immunosuppressive Therapy for Eye Diseases (SITE) trial found that cyclophosphamide was effective in controlling inflammation in 70.7% of patients with ocular cicatricial pemphigoid at 1 year, with 66.9% patients on less than or equal to 10mg of prednisone ⁵⁵. Low dose methotrexate is particularly effective in mild to moderate ocular cicatricial pemphigoid ³¹. Systemic complications include hepatotoxicity, nephrotoxicity, pneumonitis, pulmonary fibrosis, pancytopenia, and malignancy ⁴⁷.

Tetracyclines are a well-tolerated anti-inflammatory agent and have been found to be effective for mild to moderate ocular cicatricial pemphigoid, particularly when combined with nicotinamide ³¹.

Mycophenolate mofetil has been shown to be a well tolerated and effective therapy for ocular cicatricial pemphigoid ⁴⁷. Therapeutic dosage is usually 1000-2000mg/day ⁴⁷. Systemic complications include leukopenia ⁴⁷.

Cyclosporine has only been used in small series of patients and has been reported to have variable levels of effectiveness ³¹.

Severe Disease

Cyclophosphamide is first line in patients with severe disease or rapid progression ³¹. It should be started in conjunction with steroids and can be dosed orally or IV ³¹. A short course of pulsed IV therapy (ex. 3 days) can be particularly effective in achieving rapid control if needed, such as prior to surgery ⁴⁷. The SITE trial found that cyclophosphamide was effective in controlling inflammation in 80.8% of patients with ocular cicatricial pemphigoid at 1 year, with 58.5% of patients on less than or equal to 10mg of prednisone ⁵⁶. Systemic complications include myelosuppression, carcinogenesis, and teratogenicity ⁴⁷.

Intravenous Immunoglobulin (IVIG) is reserved for patients with progressive disease that is unresponsive to systemic steroids and cyclophosphamide and has been found to be an effective therapy ⁴⁷. Dosing is every 3-4 weeks until quiescence is achieved, usually requiring 4-12 cycles ⁴⁷. Systemic complications are severe, and include anaphylaxis, disseminated intravascular coagulation (DIC), aseptic meningitis, and acute renal failure ⁴⁷. Therefore, IVIG is which is reserved for refractory disease.

Biologics, including the anti-TNF agents Etanercept and infliximab, the IL-2 antagonist daclizumab, and the anti-CD20 antibody rituximab have been shown to be efficacious in small studies of patients with refractory ocular cicatricial pemphigoid ³¹. The combination of IVIG and rituximab has been shown to be effective as well in refractory ocular cicatricial pemphigoid ³¹.

Ocular cicatricial pemphigoid prognosis

The course of ocular cicatricial pemphigoid is characterized by chronic relapsing and remitting cicatrizing conjunctivitis and progressive conjunctival subepithelial fibrosis causing distorted anatomy, such as trichiasis and entropion, tear film abnormalities (exposure and meibomian gland dysfunction), and limbal stem cell deficiency, results in severe corneal epitheliopathy, persistent epithelial defect, corneal stromal ulceration, secondary infection, corneal neovascularization, and blindness. In the end, the cornea is fully scarred, vascularized, and keratinized. Unfortunately some patients can permanently lose their eyesight due to ocular cicatricial pemphigoid causing permanent scarring of the cornea, the clear front window of the eye, as a consequence of severe dryness, corneal infection or damage to limbal stem cells. It may take 10 to 30 years to reach this endstage. Of 111 patients, 26% had glaucoma, most with advanced, with a long history of medication use, optic nerve damage, and visual field loss ⁵⁷.

In a few patients, the condition can go into remission for 1 year or more and the immunosuppressive medication can be stopped. However the majority of mucous membrane pemphigoid patients continue on oral immunosuppressive medication for life.

The only medication which has been reported to put ocular cicatricial pemphigoid into remission for more than 1 year is cyclophosphamide, which is effective but can cause side effects.

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