Ocular cicatricial pemphigoid

INTRODUCTION — Mucous membrane pemphigoid is a heterogeneous group of chronic inflammatory blistering diseases that affect oral, ocular, pharyngeal, laryngeal, genital, or anal mucosa. The characteristic pathologic feature that unites these disorders is the presence of linear deposits of immunoglobulin (Ig)G, IgA, IgM, or C3 in the epithelial basement membrane zone. The term ocular cicatricial pemphigoid (OCP) refers to mucous membrane pemphigoid that clinically presents as a chronic cicatrizing (scarring) conjunctivitis. Involvement of other mucosal sites and nonmucosal skin may also occur in OCP.

Left untreated, OCP eventually results in severe conjunctival scarring and visual loss secondary to keratopathy, with scarring and neovascularization. Thus, early diagnosis and prompt initiation of therapy are essential for optimal management. The treatment of OCP involves the suppression of autoimmune conjunctival inflammation via the use of systemic immunomodulatory drugs. Conscientious ocular care to minimize the secondary consequences of chronic inflammation also is important.

The pathogenesis, clinical manifestations, diagnosis, and treatment of OCP will be reviewed here. Other forms of pemphigoid are discussed separately. (See "Clinical features and diagnosis of bullous pemphigoid and mucous membrane pemphigoid".)

EPIDEMIOLOGY — The incidence of OCP is estimated to be between 1 in 8000 and 1 in 46,000 ophthalmic patients [1-4]. No geographical or racial predilection has been detected.

OCP is primarily a disease of older adults, with an average age of diagnosis between the ages of 60 and 70 years [5-7]. However, due to the nonspecific conjunctival inflammation that characterizes early stage OCP, in some patients the disease may be present for years prior to recognition of the diagnosis.

OCP appears to have a predilection for women. The female to male ratio is estimated to be between 1.5:1 and 3:1 [5]. The occurrence of OCP in children is rare; as of 2011, less than 20 pediatric patients have been reported [8].

PATHOGENESIS — The chronic, cicatrizing conjunctivitis of OCP is a manifestation of a systemic autoimmune disorder characterized by the aberrant production of antibodies that recognize normal components of the mucosal epithelial basement membrane zone. As in other forms of pemphigoid, the interaction of these antibodies with their target antigens is believed to precipitate the clinical manifestations of OCP. (See "Epidemiology and pathogenesis of bullous pemphigoid and mucous membrane pemphigoid".)

Several components of the basement membrane zone have been identified as potential antigenic targets in cicatricial pemphigoid, including:

●Beta-4 peptide of alpha-6 beta-4 integrin (a transmembrane anchoring protein that links basal cell hemidesmosomes to the underlying basement membrane zone) [9-11]

●Laminin 5 [12,13]

●Bullous pemphigoid antigen 2 (BP 180) [14,15]

●Unspecified 168 kilodalton and 45 kilodalton antigens [16,17]

In particular, in OCP, the 205 kilodalton beta-4 peptide of alpha-6 beta-4 integrin appears to be a frequent target antigen [9,10,18]. An epitope in the large cytoplasmic domain of the beta-4 peptide has the strongest binding affinity for autoantibodies in sera from patients with OCP [18]. A study has identified specific epitopes of beta-4 integrin that may be involved in the pathobiology of OCP [19].

In contrast to pemphigoid involving cutaneous surfaces, which typically manifests as disassociation of the epidermis and dermis (eg, blistering skin in bullous pemphigoid), in OCP the immune-mediated process manifests as a chronic, scarring conjunctivitis. The following sequence of events may contribute to the development of the clinical findings in OCP [20-22]:

●Autoantibody binding in the basement membrane zone stimulates an inflammatory cascade that involves the secretion of cytokines and the recruitment of inflammatory cells

●Recruited inflammatory cells sustain inflammation through the secretion of additional proinflammatory cytokines

●The release of profibrotic cytokines by inflammatory cells, such as transforming growth factor (TGF)-beta and interferon (IFN)-gamma contributes to the development of scarring

The inciting factors for OCP are not definitively known. It is suspected that a combination of genetic susceptibility and environmental insults contributes to the production of pathogenic autoantibodies [5]. The HLA DQW7 (HLA DQ-beta*0301) allele has been identified as a potential risk factor for OCP [23,24], and medications or microbial organisms may be relevant environmental contributors.

In a small subset of patients with OCP, a potential contributing factor is detected. Cases in which topical ophthalmic medications or systemic practolol have been linked to the development of OCP (also known as pseudopemphigoid or pseudo-OCP) have been reported [25-32].

In addition, intense conjunctival inflammation has been proposed as a potential inciting factor for OCP via a process referred to as epitope spreading [33]. The epitope spreading theory describes the immune detection of normal host antigens during tissue inflammation and the subsequent mounting of an aberrant autoimmune response against those antigens. The development of OCP following Stevens-Johnson syndrome has been attributed to this theory [34]. Additional studies are necessary to determine whether this is a legitimate pathway for the induction of OCP. (See "Stevens-Johnson syndrome and toxic epidermal necrolysis: Pathogenesis, clinical manifestations, and diagnosis".)

CLINICAL MANIFESTATIONS — The clinical manifestations of OCP vary according to the stage of the disease. Extraocular involvement may or may not be present.

Ocular findings — At the time of initial symptoms, OCP may present with unilateral eye involvement. However, bilateral disease usually develops within two to four years [5,35].

Early disease may present only with signs of a chronic or relapsing conjunctivitis, with symptoms such as tearing, irritation, burning, or mucus drainage (picture 1A) [36]. Frank vesicles on the conjunctiva are infrequently detected.

As the disease progresses, fibrosis ensues, resulting in conjunctival shrinkage (picture 1B). Symblephara (fibrotic adhesions between the bulbar and palpebral conjunctivae), which typically begin in the inferior fornix, can become so severe that they impair eye movement (picture 1C) [35,36]. As a consequence of scarring, some patients also may develop lagophthalmos (loss of the ability to completely close the eye).

Moreover, involvement of the eyelid margin can lead to ankyloblepharon (fusion of the lid margins of the upper and lower eyelids). Inflammation and scarring in this area may also disrupt the orientation of eyelash follicles, resulting in trichiasis (inward growth of the eyelashes) or distichiasis (a duplicate row of eyelashes in which one or both grow inward against the eye) (picture 2).

Visual impairment eventually occurs if OCP is not adequately controlled. Xerophthalmia leading to corneal keratinization occurs as a consequence of the destruction of the ducts of the lacrimal glands, the elimination of goblet cells, which produce the mucus component of the tear film, or the development of lagophthalmos. Additionally, direct trauma to the corneal surface in the setting of entropion or trichiasis contributes to corneal keratinization, neovascularization, and scarring (picture 3) [5].

Staging — Staging systems have been developed to assist in the assessment of disease severity and treatment response [5,37,38]. In 1986, we proposed the following categories for the classification of OCP [5]:

●Stage I – Chronic conjunctivitis with subepithelial fibrosis (picture 1A)

●Stage II – Shortening of the inferior fornix (picture 1B)

●Stage III – Symblepharon (picture 1C)

●Stage IV – End-stage disease manifesting as ankyloblepharon, severe sicca syndrome, severe ocular surface keratinization (picture 3)

In the modified version of this staging system, stages II and III are further subdivided in to four groups that describe the degree of involvement (a = 0 to 25 percent, b = 25 to 50 percent, c = 50 to 75 percent, and d = 75 to 100 percent) [37]. For stage II, the designation describes the percent loss of the inferior fornix depth, while in stage III this describes the percentage of horizontal involvement by symblephara. The number of symblephara is also noted. For example, a patient with stage IIcIIIb(2) would have an eye with 50 to 75 percent loss of the inferior fornix and 25 to 50 percent involvement by two symblephara.

Extraocular involvement — Concomitant oral disease is common in patients with OCP. Oral lesions are estimated to occur in approximately 40 percent of patients [35]. Erosive gingivitis is the most common oral manifestation, but involvement manifesting as erosions or vesicles may also occur on the buccal mucosa, palate, alveolar ridge, tongue, and lip [36]. Other mucosal sites affected less frequently than the oral cavity include the pharynx, nose, larynx, genitalia, anus, and esophagus [39].

Compared with oral disease, a smaller subset of patients with OCP has involvement of nonmucosal skin [5]. In one study from an ophthalmologic practice, 16 percent of patients had skin disease [35]. Such patients most frequently present with inflammatory bullae and erosions on the head, neck, and upper trunk [33].

ESTABLISHING THE DIAGNOSIS — The systemic immunomodulatory therapies required for the treatment of OCP are associated with a number of potential adverse effects. This, and the fact that the approach to treatment differs significantly from the therapeutic approach for some of the other disorders that clinically resemble OCP, strongly favor confirmation of the diagnosis whenever feasible (see 'Differential diagnosis' below). A conjunctival biopsy with immunohistochemical studies is a valuable tool for confirming the diagnosis in patients with clinical findings suggestive of OCP. However, clinicians must remain cognizant that inconclusive or negative results do not rule out the diagnosis.

Biopsy — In patients who have extraocular lesions, such as skin or other mucosal lesions, the tissue biopsy for diagnosis should first be attempted in these more easily accessible sites [33,35]. Conjunctival biopsies are generally performed in patients with active disease limited to the ocular mucosa or in patients in whom the disease is strongly suspected despite negative or inconclusive results from extraocular biopsies.

Conjunctival biopsies should always be performed on inflamed conjunctival tissue [33]. Conjunctival biopsies may be obtained from a variety of sites; we typically biopsy the bulbar conjunctiva. The approach to cutaneous biopsies in patients with concomitant skin involvement is reviewed separately. (See "Clinical features and diagnosis of bullous pemphigoid and mucous membrane pemphigoid", section on 'Tissue biopsy'.)

Negative or inconclusive results can occur due to poor biopsy technique or poor handling of the specimen. Conjunctival biopsies should only be performed by ophthalmologists, and only experienced laboratory technicians should process conjunctival tissue. Disease exacerbation and the induction of scarring are potential risks of conjunctival biopsies [33].

Hematoxylin and eosin — The findings in specimens stained with hematoxylin and eosin (H&E) are nonspecific. Examination typically demonstrates an inflammatory infiltrate of variable intensity composed of neutrophils, macrophages, plasma cells, lymphocytes, and Langerhans cells (picture 4) [35]. Squamous metaplasia may also be present (picture 5). The performance of additional histopathologic stains facilitates the identification of other common features, such as decreased goblet cells (PAS stain) (picture 6) and increased mast cells (Giemsa stain) [5].

Immunohistochemistry — Direct immunofluorescence should be performed on all conjunctival biopsy specimens. Linear deposition of immunoglobulin (Ig)G, IgA, IgM, and/or C3 is the characteristic finding (picture 7). However, because the diagnostic sensitivity of direct immunofluorescence in most laboratories may be only around 50 percent, a negative test does not rule out the diagnosis [40].

The utilization of an immunoperoxidase assay may improve the likelihood of diagnosis, and the technique should be performed if immunofluorescence is negative in a patient with clinical features strongly suggestive of OCP (picture 8) [35]. In a retrospective study of 166 patients with suspected OCP, performance of an immunoperoxidase avidin-biotin-complex assay on specimens that yielded negative or inconclusive immunofluorescence results was associated with the detection of additional diagnoses of OCP [40]. The addition of the immunoperoxidase assay increased the sensitivity of testing from 52 to 83 percent.

Of note, immunohistochemical findings consistent with OCP do not definitively rule out all other possible diagnoses. Epidermolysis bullosa acquisita and linear IgA bullous dermatosis, both of which may involve skin and ocular tissue, present with similar findings [33]. Thus, other diagnostic clues are utilized to distinguish OCP from these disorders. The presence of prominent milia formation in skin lesions and the detection of antibodies against type VII collagen via enzyme-linked immunosorbent assay, immunoblotting, or immunoprecipitation support a diagnosis of epidermolysis bullosa acquisita. Predominant linear IgA binding at the basement membrane zone in combination with classic skin lesions resembling a "cluster of jewels" suggests the possibility of linear IgA bullous dermatosis.

Indirect immunofluorescence — Circulating antibodies against the basement membrane zone are less consistently detected in patients with cicatricial pemphigoid than in patients with bullous pemphigoid, and are of little value for diagnosis. Reported rates of antibody detection vary widely, and the probability of a positive result may be affected by the type of technique performed and by individual patient characteristics such as the level of disease activity and sites of involvement [41-43].

Other laboratory studies — No specific laboratory assays are useful for monitoring the activity of OCP. Although one study found increased levels of tumor necrosis factor (TNF)-alpha and decreased levels of interleukin (IL)-6 in sera from patients with active OCP [44] and another study found elevated IL-6, IL-12, and IL-17 levels in conjunctival tissue of patients with OCP [45], additional studies are necessary to determine whether these assays are clinically useful [45].

DIFFERENTIAL DIAGNOSIS — In addition to OCP, a wide variety of other ocular disorders can present with conjunctival inflammation or scarring. Examples include:

●Conjunctivitis and conjunctival scarring:

•Toxic epidermal necrolysis or Stevens-Johnson syndrome sequelae (see "Stevens-Johnson syndrome and toxic epidermal necrolysis: Pathogenesis, clinical manifestations, and diagnosis")

•Epidermolysis bullosa acquisita

•Linear IgA bullous disease with cicatrizing conjunctivitis

•Bullous systemic lupus erythematosus (see "Overview of cutaneous lupus erythematosus", section on 'Bullous cutaneous lupus erythematosus')

•Adenoviral conjunctivitis sequelae (see "Conjunctivitis", section on 'Viral conjunctivitis')

•Paraneoplastic pemphigus (see "Paraneoplastic pemphigus")

•Sebaceous cell carcinoma of the conjunctiva (see "Sebaceous carcinoma")

•Intraepithelial epithelioma (squamous cell carcinoma of the conjunctiva)

•Corynebacterium diphtheriae conjunctivitis

●Conjunctival scarring:

•Damage from ionizing radiation

•Trauma

•Porphyria cutanea tarda (see "Porphyria cutanea tarda and hepatoerythropoietic porphyria: Pathogenesis, clinical manifestations, and diagnosis")

•Progressive systemic sclerosis (scleroderma) (see "Clinical manifestations and diagnosis of systemic sclerosis (scleroderma) in adults")

•Congenital ichthyosiform erythroderma (see "Overview and classification of the inherited ichthyoses", section on 'Lamellar ichthyosis and congenital ichthyosiform erythroderma')

The clinical history and assessment of other signs and symptoms are often useful for narrowing the differential diagnosis. If OCP remains in the differential, a biopsy of involved skin or mucosal tissues can be of value. (See 'Establishing the diagnosis' above.)

INDICATIONS FOR REFERRAL — All patients with known or suspected OCP require referral to an ophthalmologist, preferably one with significant experience in this disease. Additionally, treatment should be managed by a clinician with expertise in immunosuppressive therapy, such as an ophthalmologist, dermatologist, rheumatologist, hematologist, or other clinician who is comfortable with this role.

Continued ophthalmology follow-up is essential for evaluating the response to therapy. Moreover, the presence of extraocular involvement warrants assessment and follow-up by specific clinical specialists based upon the sites of disease (eg, dermatologist, dentist, otolaryngologist, or gastroenterologist). (See 'Extraocular involvement' above.)

TREATMENT — The primary goal of treatment in OCP is the prevention of scarring and vision loss. Whenever possible, patients should be managed by clinicians who have experience in treating this disease.

The most important therapeutic interventions are the initiation of systemic immunomodulatory drugs to suppress conjunctival inflammation and the implementation of practices that minimize secondary ocular damage. While patients with mild to moderate conjunctival inflammation and slowly progressing disease can often be managed with ocular care and conventional immunomodulatory therapies such as dapsone, methotrexate, mycophenolate mofetil, or azathioprine, patients with more aggressive or refractory disease typically require treatment with cyclophosphamide. In addition, several studies suggest that intravenous immune globulin (IVIG) and rituximab may have benefits for severe cases.

Ocular care — A variety of nonpharmacologic measures are beneficial in the management of OCP:

●Ocular lubrication – Xerophthalmia (dry eye) can lead to corneal damage, and the liberal use of ocular lubricants may help to prevent vision loss. Punctual plugs and punctual cautery, which prevent drainage of liquid from the eye, also can be helpful in the treatment of xerophthalmia [35].

●Prevention and treatment of infection – Patients with OCP are at increased risk for ocular infections due to the presence of a compromised ocular surface [46]. The use of lid hygiene techniques on a daily basis may minimize the occurrence of ocular infections [35]. We instruct patients to apply warm compresses for two minutes followed by vertical lid massage (10 strokes downward on the upper lid and 10 strokes upward on the lower lid) twice daily. This procedure expresses the lipid contents of the meibomian glands. Prompt identification and treatment of infections also is important.

●Eyelash removal – Injury to the cornea as a result of trichiasis (inward turning of the eyelashes) can lead to visual impairment or blindness if left untreated. Eyelashes can be removed temporarily with manual epilation or permanently with cryoepilation or electrolysis. Cryoepilation should be performed when the disease is well controlled to reduce the risk for procedure-related exacerbations of OCP [35,46]. Other potential adverse effects of cryoepilation include ocular edema and depigmentation.

Mild to moderate disease — In 2004, an international consensus panel of experts released recommendations for the medical management of patients with mucous membrane pemphigoid, which included patients with OCP. Based upon a review of the published literature and clinical experience, the consensus panel concluded that dapsone (50 to 200 mg/day for 12 weeks) was an appropriate initial therapy for patients with mild ocular disease [33]. A systematic review of randomized trials and uncontrolled studies also found evidence to support the use of dapsone in cicatricial pemphigoid [47].

Although there are relatively fewer data on other systemic therapies such as methotrexate, mycophenolate mofetil, and azathioprine, these agents have also been used successfully by clinicians (including ourselves) for patients with OCP. No randomized trials have been performed that compare the efficacy of these therapies in OCP. Thus, factors such as concern for drug adverse effects, patient tolerance, drug availability, and drug cost heavily influence the choice of therapy:

●Dapsone – Dapsone is a sulfonamide antibiotic with antiinflammatory properties and proven efficacy in OCP [5,6,33,47]. The benefit of dapsone for ocular involvement was documented in a 12-week randomized trial in which 40 patients with stage III (see 'Staging' above), biopsy-proven OCP were treated with either dapsone (2 mg/kg per day) or cyclophosphamide (2 mg/kg per day) [5]. Among the 20 patients treated with dapsone, 14 (70 percent) had complete suppression of conjunctival inflammation and scar formation. All of the patients treated with cyclophosphamide responded, but we reserve the use of cyclophosphamide for patients with severe or refractory disease. (See 'Severe or refractory disease' below.)

Dapsone was also effective in a retrospective study in which the majority of patients had stage III, biopsy-proven OCP [6]. Dapsone (2 mg/kg per day for at least three months) inhibited cicatrization in 31 of 69 patients (45 percent), including 26 of 28 patients with milder conjunctival inflammation defined as <2+ severity on a 0 to 4+ scale (93 percent).

Dapsone is typically administered in doses of 50 to 200 mg per day [33]. A 12-week period is a reasonable trial of therapy; alternative therapy should be considered if no response is observed after this time [33]. Hemolytic anemia is a common adverse effect of dapsone that occurs to some degree in most patients who take dapsone but can be catastrophic in individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency [48,49]. In addition, idiosyncratic leukopenia and aplastic anemia may occur in the first three months of treatment; thus, patients must receive frequent hematologic monitoring early in the course of therapy. Methemoglobinemia, another potential adverse effect of dapsone, is a dose-dependent event unrelated to G6PD status.

Sulfasalazine and sulfapyridine are additional sulfonamide agents that have been used in the management of patients with OCP [50,51]. These agents may be less effective than dapsone [50].

●Methotrexate – Methotrexate is a folic acid antagonist that may improve OCP [52,53]. Methotrexate (5 to 25 mg given once weekly) was effective in a retrospective study of 17 patients with non-drug-induced OCP (12 patients) or drug-induced OCP (5 patients). Fifteen patients (88 percent, including all patients with drug-induced disease) achieved or maintained complete control of inflammation and 12 out of 17 patients (71 percent, including all but one patient with drug-induced disease) had no progression of cicatrization [52]. A potential limitation of this study is that only four patients had biopsy-proven OCP.

Gastrointestinal distress, oral ulcers, myelosuppression, hepatotoxicity, pulmonary fibrosis, and renal toxicity are potential adverse effects of methotrexate. The coadministration of folic acid may lessen the gastrointestinal symptoms and oral ulcers. Dose adjustments are necessary if methotrexate must be administered in patients with renal insufficiency. The drug also is teratogenic and is relatively contraindicated in patients who abuse alcohol or who have preexisting liver disease. (See "Major side effects of low-dose methotrexate".)

●Mycophenolate mofetil – Mycophenolate mofetil is an immunosuppressive agent that reversibly inhibits de novo purine synthesis via inhibition of the enzyme inosine monophosphate dehydrogenase. In a retrospective study in which mycophenolate mofetil (500 to 1000 mg twice daily) was given to 34 patients who had failed azathioprine and a sulfonamide or who received mycophenolate mofetil as a step-down therapy after cyclophosphamide, the drug was beneficial [50]. Out of 46 treatment episodes in which mycophenolate mofetil was the principal treatment agent, 59 percent were associated with complete clinical resolution of conjunctival inflammation. When only treatment episodes in patients with biopsy-proven disease were considered (11 episodes), the response rate rose to 73 percent.

Additional support for the efficacy of mycophenolate mofetil stems from a separate retrospective study in which 19 of 23 OCP patients treated with mycophenolate mofetil (500 mg twice daily, then adjusted according to response) achieved control of inflammation within one year, including 16 of 19 who received mycophenolate mofetil as monotherapy [54]. In another retrospective study of 38 patients who received mycophenolate mofetil (with or without initial concomitant prednisone) for OCP, complete or partial responses occurred in 11 and 14 of the 34 patients available for follow-up at 12 months (32 and 41 percent, respectively) [55].

Mycophenolate mofetil is generally a well-tolerated drug, with gastrointestinal distress (eg, nausea, vomiting, diarrhea) as its most common associated adverse effect. Additionally, mycophenolate mofetil may induce cytopenia and the drug has teratogenic effects. (See "Mycophenolate: Overview of use and adverse effects in the treatment of rheumatic diseases", section on 'Adverse effects'.)

●Azathioprine – Azathioprine, a purine derivative that exerts immunosuppressive effects through the inhibition of RNA and DNA synthesis and repair, has been effective for OCP in case reports and retrospective studies [6,50,56,57]. In a retrospective study in which 60 patients received azathioprine as principal therapy after failure to respond sufficiently to a sulfonamide or as a step-down therapy after cyclophosphamide, azathioprine controlled ocular inflammation in 47 percent of 80 treatment episodes in all patients and 48 percent of 37 treatment episodes in patients with biopsy-proven OCP [50].

Bone marrow suppression is a potential severe adverse effect of azathioprine, which may be related to the activity of thiopurine methyltransferase (TPMT), an enzyme involved in the metabolism of the drug. The assessment of TPMT activity should be performed prior to the administration of azathioprine. Dose adjustments may be necessary based upon the result. (See "Pharmacology and side effects of azathioprine when used in rheumatic diseases", section on 'Adverse effects' and "Thiopurines: Pretreatment testing and approach to therapeutic drug monitoring for adults with inflammatory bowel disease".)

Severe or refractory disease — Aggressive treatment is warranted for patients with severe or rapidly progressive OCP to minimize scarring and visual loss. Based upon the limited available data, combination therapy with cyclophosphamide and prednisone is highly effective and is the treatment of choice for severe OCP [6,7,33]. Newer evidence indicates that intravenous immune globulin (IVIG) and rituximab used independently or together may also be effective.

Although systemic glucocorticoids are sometimes utilized to suppress acute inflammation in patients with OCP, they are not recommended as primary therapy due to the multiple adverse effects of long-term treatment and the high likelihood for disease relapse following tapering or discontinuation [5]. The preferred role of systemic glucocorticoids is as adjunctive therapy while awaiting the onset of action of other agents in patients with severe or rapidly progressive disease. (See "Major adverse effects of systemic glucocorticoids".)

Cyclophosphamide plus prednisone — Cyclophosphamide is an alkylating agent commonly used as an antineoplastic agent in oncology. The immunosuppressive properties of cyclophosphamide account for its beneficial effects in autoimmune blistering disease.

The efficacy of cyclophosphamide is supported by two randomized trials:

●In a six-month, randomized trial, 24 patients with bilateral stage III, biopsy-proven OCP were treated with either cyclophosphamide (2 mg/kg per day) plus prednisone or prednisone plus a placebo pill [5]. Prednisone was administered as 1 mg/kg per day for one week followed by a taper over 12 weeks to 0.25 mg/kg every other day. Prednisone was subsequently discontinued in the cyclophosphamide group.

By eight weeks, all 12 patients treated with cyclophosphamide and prednisone achieved complete resolution of conjunctival inflammation. In addition, progression of scarring did not occur in the cyclophosphamide group during the course of the study. In contrast, only 5 out of 12 patients in the prednisone group had complete resolution of conjunctival inflammation, and, among those who responded, disease recurred when the dose fell below 0.25 mg/kg every other day.

●In a 12-week, randomized trial in which 40 patients with stage III, biopsy-proven OCP were treated with cyclophosphamide (2 mg/kg per day) plus prednisone or dapsone (2 mg/kg per day), all 20 patients treated with cyclophosphamide exhibited resolution of clinically evident inflammation and no patients had progression of conjunctival scarring [5]. In contrast, similar results were observed in only 14 out of 20 patients treated with dapsone.

Efficacy of cyclophosphamide is also documented in prospective and retrospective case series [58,59].

Cyclophosphamide can be administered orally or intravenously. A response to therapy takes approximately six to eight weeks, which provides the rationale for the use of prednisone at the initiation of therapy [5]. We typically begin intravenous cyclophosphamide therapy with 1 g/m² given every two weeks, and adjust the dose according to the degree of resultant leukopenia. We aim to maintain the white blood cell count above 3000/mm³, the absolute neutrophil count above 1000/mm³, and the platelet count above 70,000/microL. When utilizing oral cyclophosphamide therapy we prescribe initial doses of 1 to 2 mg/kg per day [33]. Prednisone (1 to 1.5 mg/kg/day) is initiated at the same time as cyclophosphamide therapy. Once improvement is achieved, we taper the prednisone over the course of approximately three months.

As noted above, leukopenia is expected during treatment with cyclophosphamide, and a complete blood count should be monitored weekly for the first two to three months of therapy and at least monthly thereafter [60]. Gastrointestinal distress, hemorrhagic cystitis, bladder cancer, infections, hair loss, and reproductive problems such as amenorrhea, premature ovarian failure, and azoospermia also can occur with cyclophosphamide. The drug is teratogenic and, thus, is contraindicated in pregnancy. (See "General toxicity of cyclophosphamide in rheumatic diseases".)

Due to the potential long-term effects of cyclophosphamide, we limit the duration of treatment with cyclophosphamide to 12 months. Patients who reach this duration of therapy are transitioned to other immunomodulatory agents.

Intravenous immune globulin — Intravenous immune globulin (IVIG) may be effective for the treatment of OCP that is refractory to other therapies [61-64]. In a nonrandomized study of 16 patients with OCP, the administration of IVIG with gradual withdrawal of conventional therapy was associated with a shorter time to clinical remission compared with the time required in patients who were maintained on conventional therapy (4 versus 8.5 months). In addition, total control of disease activity was achieved in all patients treated with IVIG compared with only three out of eight patients who continued conventional therapy. Sustained remissions of 24 to 48 months have been reported after completion of IVIG therapy [63].

Although the initial cost of treatment with IVIG can be limiting, a retrospective study in the United States that compared the cost of IVIG and conventional immunosuppressive therapy in patients with severe mucous membrane pemphigoid found that the overall cost of disease management was lower in patients treated with IVIG [65].

Adverse effects of IVIG include hypersensitivity reactions, headache, vasculitis, aseptic meningitis, renal failure, myocardial infarction, and thrombosis. (See "Intravenous immune globulin: Adverse effects".)

Rituximab — Rituximab is a chimeric monoclonal antibody that targets the CD20 antigen on pre-B and mature B lymphocytes. Uncontrolled studies and a case report support its efficacy in OCP [66-70].

In a series of 25 patients with biopsy-proven, severe, refractory mucous membrane pemphigoid that included 10 patients with active stage III or IV OCP, rituximab (375 mg/m² once weekly for four weeks for one or two cycles) was associated with resolution of conjunctival inflammation in 9 of the 10 patients after one treatment cycle and in all patients after two cycles (median time to remission 10 weeks) [68]. Long-lasting improvement after rituximab occurred in 76 percent of the patients with mucous membrane pemphigoid, with maintenance of complete or partial responses during a median follow-up period of 24 months.

Of note, two patients who were simultaneously treated with systemic immunosuppressive therapy developed severe, fatal infections. Additional potential side effects of rituximab include nausea, serum sickness-like reactions, and infusion reactions. A boxed warning on the drug label of rituximab has been mandated by the US Food and Drug administration due to reports of progressive multifocal leukoencephalopathy. (See "Rituximab: Principles of use and adverse effects in rheumatoid arthritis".)

Combination therapy with rituximab and IVIG may be of value for the management of patients with severe OCP. In a retrospective study of 12 patients with OCP that was refractory to conventional therapies, disease progression ceased in the six patients who were treated with rituximab and IVIG and in none of the patients who were given other aggressive therapies (cyclophosphamide, infliximab, and/or IVIG) [67]. Additional studies are necessary to explore the efficacy of rituximab with and without IVIG.

Other — Other systemic therapies that have been used for patients with severe or refractory OCP include subcutaneous cytosine arabinoside and daclizumab [35]. Oral cyclosporine and oral tacrolimus are poorly effective for arresting disease progression in OCP [71,72].

Local therapy — Local therapy with agents such as topical corticosteroids, topical tacrolimus, topical cyclosporine, and topical or subconjunctival mitomycin C has a limited role in the management of OCP, as they have no effect on suppressing the underlying immune dysfunction [5,73-75].

Surgical intervention — Surgical procedures are used to treat ocular damage related to OCP. Examples include the removal of symblephara that inhibit lid function, the repair of entropion, and the use of surgical procedures that address visual impairment due to corneal damage. Corneal procedures that have been used in OCP include amniotic membrane transplantation, limbal stem cell transplantation, lamellar or penetrating keratoplasty (corneal transplants), and the placement of keratoprostheses (artificial corneas) [35].

Prior to the performance of ocular surgery, complete control of inflammation should be obtained with immunomodulatory drugs to improve the likelihood of a good surgical outcome. In addition, the level of immunosuppression is typically increased in the perioperative period to reduce the risk of surgery-induced disease exacerbations [35,36].

PROGNOSIS AND CESSATION OF THERAPY — In most patients, OCP is a slow, progressive disease process. Advancement of the disease from initial conjunctival inflammation to end-stage disease characterized by bilateral blindness may take 10 to 30 or more years [5]. However, some patients progress more quickly, and periods of severe exacerbation and rapid scarring may occur. Early identification of the disease and the prompt implementation of appropriate treatment are key factors in the prevention of adverse disease sequelae.

Although OCP is a chronic, relapsing disease, long-term remission amounting to cure of the disease is possible in some patients [7,50,76]. In one series of 104 patients followed for an average of four years, prolonged periods of remission off therapy occurred in approximately one-third of patients (average length of remission of 34 months, range 2 to 75 months) [71,76]. Since disease relapse is unpredictable, continued long-term follow-up of patients in remission is essential.

We proceed with attempts to slowly taper therapy in patients in whom disease activity (conjunctival inflammation) has been quiescent for two years. Inflammation related to trichiasis or glandular dysfunction may be confused with active pemphigoid, and interventions to minimize the effects of such findings are important for the accurate assessment of disease status. (See 'Ocular care' above.)

CATARACT SURGERY — Cataracts are a common occurrence in patients with OCP, a finding related to the age at which OCP typically occurs and the chronic use of topical or systemic corticosteroids for treatment. Data on cataract surgery in patients with OCP are limited, and there is concern that surgery may induce exacerbations of conjunctival inflammation and contribute to the progression of OCP. (See "Cataract in adults".)

However, case series document successful cataract surgery in patients with OCP, suggesting that cataract surgery can be safely performed in patients in whom optimal medical control of OCP is achieved prior to cataract surgery [77-79]. The author has successfully performed cataract surgery with posterior lens chamber implantation (small incision surgery without suture or disturbance of the conjunctiva) in many patients with quiescent OCP through perioperative management with oral prednisone (1 mg/kg for two days prior to surgery and for ten or more days postoperatively), continuation of the chemotherapeutic agent that put the OCP into remission until at least six months after surgery, and the use of topical corticosteroids and topical antibiotics as adjunctive therapies.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Mucous membrane pemphigoid".)

SUMMARY AND RECOMMENDATIONS

●Overview – Ocular cicatricial pemphigoid (OCP) is a form of mucous membrane pemphigoid that manifests as a chronic cicatrizing conjunctivitis. Early diagnosis and treatment are essential for the prevention of severe scarring and blindness. (See 'Introduction' above.)

●Epidemiology – OCP is a relatively uncommon disorder that preferentially affects older adults. Women are more likely to be affected than men. OCP rarely occurs in children. (See 'Epidemiology' above.)

●Pathogenesis – The pathogenesis of OCP is likely to involve the stimulation of an inflammatory response by autoantibodies that bind to normal components of the conjunctival basement membrane zone. The beta-4 peptide of alpha-6 beta-4 integrin appears to be a frequent target antigen. (See 'Pathogenesis' above.)

●Clinical manifestations – The clinical findings in OCP vary according to the stage of the disease. Disease initially manifests as a chronic conjunctivitis and progresses to conjunctival fibrosis manifesting and conjunctival contracture or symblepharon (picture 1A-C). Xerophthalmia (dry eye) and trichiasis (inward turning of the eyelashes) are additional common findings (picture 2). Corneal damage resulting in visual impairment may also occur (picture 3). (See 'Clinical manifestations' above.)

●Diagnosis – The treatments used for the management of OCP have multiple potential adverse effects, and confirmation of the diagnosis with immunohistochemical studies on biopsy specimens should be performed whenever feasible. The characteristic immunohistochemical finding is linear deposition of IgG, IgA, or C3 along the basement membrane zone (picture 7). Negative direct immunofluorescence results are common and should not be used to rule out the diagnosis. (See 'Establishing the diagnosis' above.)

In patients with extraocular skin or mucosal lesions, initial biopsies for diagnosis can be performed at those sites. Conjunctival biopsies are necessary in patients with disease limited to the ocular mucosa or in those in whom the diagnosis is highly suspected despite negative extraocular biopsy results. (See 'Biopsy' above.)

●Management:

•Indications for referral – All patients with known or suspected OCP require referral to an ophthalmologist. Whenever possible, patients should be managed by clinicians experienced in the management of this disease. (See 'Indications for referral' above.)

•Treatment – Systemic immunomodulatory therapy and eye care practices aimed at reducing the risk for scarring and visual impairment are the most important components of the management for patients with OCP:

-Mild to moderate disease – For patients with mild to moderate OCP, we recommend treatment with dapsone based upon the evidence in support of its efficacy (Grade 1B). Other effective therapies that have been less studied include mycophenolate mofetil, methotrexate, and azathioprine. Topical therapy alone should not be used for the management of OCP. (See 'Treatment' above and 'Mild to moderate disease' above.)

-Severe or refractory disease – Patients with severe, rapidly progressive, or refractory disease require aggressive treatment. We recommend treatment with cyclophosphamide and prednisone (Grade 1B). IVIG and rituximab are additional treatments that have shown promising results in early studies. Additional studies are necessary to determine whether these interventions should be considered first-line treatment options for severe OCP. (See 'Severe or refractory disease' above.)