Mucous Membrane Pemphigoid

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31

Mucous Membrane Pemphigoid

Introduction

Mucous membrane pemphigoid (MMP), previously known as cicatricial pemphigoid, is a systemic cicatrizing autoimmune disease characterized by chronic blistering of mucous membranes, including ocular, oral, genital, nasopharyngeal, anogenital, and laryngeal mucosa, with ocular (60.1–80%) and oral (90.2%) involvement the most common.1 The disease causes subepithelial damage and excessive scar tissue formation, which can be life threatening if the trachea or esophagus is involved, or sight threatening if the eyes are involved. Cutaneous involvement is seen in approximately 20% of the patients and usually affects the head, neck, and upper trunk.2

Ocular MMP, also known as ocular cicatricial pemphigoid (OCP), is seen as a progressive cicatrizing conjunctivitis, which, if left untreated, bears the risk of symblepharon, ocular surface diseases, corneal ulceration and neovascularization, and ankyloblepharon, causing visual impairment or blindness. It generally presents a chronic course, characterized by periods of activity subsequent to quiescent phases. In large series, approximately 80% of the patients with MMP have ocular involvement,3 and blindness has been reported to occur in 27%.4

The diagnosis of this disease is made difficult because of its early presenting symptoms that can be subtle and non-specific. The signs of MMP often go unrecognized until the resulting erosions and scarring are established. As a chronic and progressive disorder with sequelae that are irreversible and often debilitating, early diagnosis is critical.

Epidemiology

The incidence of MMP is approximately one new case per million inhabitants per year. MMP is considered a potentially fatal autoimmune disease with a mortality usually secondary to aero-digestive tract stricture formation, quoted as 0.028 per 100 000 in the United States during 1992–2002.5

OCP is a relatively rare disease with an estimated incidence of 1 in 15 000 to 1 in 60 000 ophthalmic patients.6 However, these studies do not report the true epidemiologic incidence of this disease because the reported cases are usually not in their earliest stages.3 Typical presentation involves a patient in the sixth or seventh decade of life, although it is recognized that OCP can begin at least as early as the third decade of life.7 In a study involving 130 patients, Foster et al. described that the average age was 64 years with a range of 20 years to 87 years. Females are affected two to three times as frequently as males. It has no racial or geographic predilection.3

Pathogenesis

Ocular cicatricial pemphigoid (OCP) is an autoimmune chronic cicatrizing conjunctivitis (CCC) associated with linear deposition of IgG and IgA aoutoantibodies directed against autoantigens at the conjunctival epithelial basement membrane zone (BMZ)3 that sets in motion a complex series of events. Bhol et al. concluded that a 205-kilodalton (KDa) protein molecule is the putative target antigen for OCP.8 Among others, the target antigen identified by the sera of patients with OCP is located in the basal epithelial cell hemidesmosome cytoplasmic domain of β4 subunit of the α6β4 integrin heterodimer.9 Autoantibodies are thought to cause scarring of the conjunctiva via activation of complement, neutrophils and proinflammatory cytokines. In addition, immunohistochemical study of the conjunctiva from patients with active OCP revealed significantly more T-helper-inducer cells (CD4+) and Langerhans cells in the epithelium and active T cells, fibroblasts and macrophages in the substantia propria compared to the control group.10 Staining for transforming growth factor-beta (TGF-β) is also significantly increased.

The subacute phase of the disease is histologically similar to acute disease. The chronic phase is characterized by an infiltration with T lymphocytes, HLA-DR-expressing cells and macrophages which are mildly increased in number. The epithelium may become thickened, metaplastic and may keratinize at any phase.

Fibrosis results from the stimulation of fibroblasts, often by fibrogenic growth factors as TGF-β, PDGF, TNF and IL-1.11 When quiescent fibroblasts are stimulated to proliferate by these modulators, there is transient expression of proto-oncogenes, including c-fos, c-myc and c-myb. These are a series of genes that are transducers of external growth factors and probably trigger the activation of genes that are required for proliferation.

Several human leukocyte antigens (HLAs), including HLA-DR4 and HLA-DQw3 were first reported to be associated with increased susceptibility to the OCP.12 Furthermore, a prevalence of HLA-DQB1*0301 was first described in patients with pure ocular mucous membrane pemphigoid.13 This allele, however, was later found to be associated with all clinical sites of involvement and possibly to be linked to antibasement membrane IgG production. Interestingly, these studies also suggested a role for this allele in disease severity. Environmental triggers, such as microbial infection or drug exposure may stimulate the genetically susceptible individuals and induce the development of the disease.

Diagnosis

Clinical Features

The natural history of OCP begins with unilateral chronic conjunctivitis that becomes bilateral after a variable period. In relapsing-remitting OCP, symptoms and signs typically evolve over a period of several weeks, stabilize, and then often extend over many years with periods of activity followed by quiescent phases every few months. Diagnosis of this disease in its early stages is difficult and most cases are not recognized as OCP until they reach the advanced stage.

Early in the disease, signs of subepithelial fibrosis appear in the inferior and superior tarsal conjunctiva and consist of fine white lines that are often perivascular. Ocular symptoms are variable and consist of foreign body sensation, burning sensation, discharge, and hyperemia. They are not always correlated to disease severity, and progressive fibrosis can occur even in asymptomatic patients. Subsequently, the fibrosis progresses and leads to fornix foreshortening, symblepharon formation, entropion, trichiasis, and, in the terminal stage, ankyloblepharon. Conjunctival fibrosis also can cause severe dry eye syndrome because of the destruction of goblet cells and obliteration of lacrimal gland ductules. Corneal lesions are frequent in this setting and may be complicated by bacterial and fungal superinfection and lead to corneal perforation and xerosis.

To assess the progression of the fibrotic process and treatment efficacy, it is important to quantify fibrosis and conjunctival inflammation. The classification of Foster et al. (Fig. 31.1) uses as an index the degree of inferior fornix foreshortening and the number and extension of symblephara.14 Subepithelial fibrosis is characteristic of stage I of OCP, with stage II showing fornix foreshortening. Symblepharon formation is the hallmark of stage III. Stage IV, end-stage disease, is characterized by ankyloblepharon and surface keratinization. Mondino’s classification quantifies inferior fornix depth loss.15 Stage II is a reduction of 25–50%; stage III, 50–75%; stage IV, more than 75%. Normal depth is approximately 11 mm.

Laboratorial Features

Immunopathological techniques may be helpful in characterizing the underlying pathogenetic processes in mucous membrane pemphigoid. Conjunctival biopsies using the immunofluorescent or immunoperoxidase technique provide the only definitive evidence of OCP. Direct and indirect immunofluorescence are sensitive but non-specific indicators for OCP, because findings are often indistinguishable from those seen in patients with other subepithelial blistering diseases.

Immunochemical techniques, including immunoblotting, immunoprecipitation and enzyme-linked immunosorbent assay (ELISA), have simplified the diagnostic process and have identified novel protein targets recognized by autoantibodies in different subgroups of mucous membrane pemphigoid.

Direct Immunopathology

Direct methods of immunofluorescence microscopy or immunohistochemistry examinations on perilesional mucosa biopsies detect continuous deposits of any one or combination of the following in the epithelial BMZ: IgG, IgA, and/or C3 (Fig. 31.2). Direct immunofluorescence (DIF) evidence has been recommended as a mandatory requirement for the diagnosis of MMP.16 However, conjunctival DIF is positive in only 20–83% of cases of ocular MMP,17 and the results can be initially positive then subsequently negative, and vice versa, during the course of the disease, apparently unrelated to disease activity or treatment.

Differential Diagnosis

The differential diagnosis of MMP includes other immunobullous diseases, erythema multiforme, lupus erythematosus, lichen planus, and lichenoid drug eruptions. Similar to OCP, many disorders may cause subepithelial fibrosis with or without inflammation (Box 31.1).20 OCP may represent the sequela of a prior bout of Stevens–Johnson syndrome, occurring a few months to as much as 30 years previously. Drug-induced cicatrizing or inflammatory conjunctivitis, also known as ocular pseudopemphigoid, can arise from long-term use of certain ophthalmologic preparations (antiviral and glaucoma medications) or biologic drugs (epidermal growth factor receptor tyrosine kinase inhibitors).

Box 31.1

Differential Diagnosis of Cicatrizing Conjunctivitis

1A Static or Very Slowly Progressive Conjunctival Scarring

1. Trauma

2. Infection

3. Allergic eye disease

4. Drug-induced conjunctival cicatrization†

5. Mucocutaneous disorders

6. Immunobullous disorders

7. Systemic disease

†A subset of patients with these diseases may develop autoantibody-positive progressive conjunctival scarring similar to MMP.

*Rare cases can develop progressive scarring.

(In: Ocul Surf 2008;6:128–42. Ocular mucous membrane pemphigoid: diagnosis and management strategies. Saw VP, Dart JK.)

Treatment

Inflammation

Inflammation resulting from systemic immune imbalance requires treatment with systemic immunosuppressive agents. Previous studies showed that almost 75% of the patients require systemic immunosuppression21 and 46% require continuing systemic treatment to avoid disease reactivation. There is no evidence that topical therapy alters the natural history of the disease.3

The immunosuppressive therapeutic approach should take into consideration the severity and the progression of the disease, the patient’s age, health and anticipated tolerance of treatment-related side effects, and the response to treatment (Fig. 31.3). For patients with severe disease or rapid progression of disease, the initial treatment should be with cyclophosphamide (1–2 mg/kg/day) and prednisone (1–1.5 mg/kg/day)22 for 6–8 weeks, and sometimes in conjunction with intravenous pulses of methylprednisolone (500 mg–1 g, up to three doses over 3 days). Because cyclophosphamide is associated with an increased risk of bladder carcinoma, the safe duration of treatment with this agent is limited to 12–18 months. Cyclophosphamide can also be administered intravenously if patients cannot tolerate the oral form. When the disease is controlled, prednisone administration should be slowly tapered while maintaining the immunosuppressive regimen for a longer period. In a preliminary study, intravenous immunoglobulin has been reported to be a safe and effective therapy for recalcitrant ocular disease23 or as an alternative to conventional immunosuppression. Monoclonal antibody therapies are potential treatments for severe refractory MMP.

For moderate disease, patients should be treated with azathioprine (1–2 mg/kg/day) or mycophenolate mofetil (500 mg–1 g/day). Nicotinamide and tetracycline have also been reported as an effective therapy in mild to moderate case, with 50% of patients responding to the treatment. For patients with mild disease, initial treatment with dapsone (diaminodiphenylsulfone; 50–200 mg/day) for 12 weeks or sulphapyridine (500 mg one or two times/day, given as sulfasalazine 500 mg one or two times/day when sulphapyridine is unavailable) should be initiated.

Topical ocular immunomodulation treatment can be used for improving symptoms and for adding additional control of the conjunctival inflammation. This local treatment can be done with topical corticosteroids (e.g. fluoromethalone or prednisolone 0.5%), 0.05–2% cyclosporine, tacrolimus or pimecrolimus.

Dry Eye

Dry eyes in OCP patients may be caused by lacrimal gland duct obstruction, cicatricial meibomian gland dysfunction and/or poor lid apposition. Tear deficiency is a major cause of symptoms, although loss of vision is usually due to surface failure before the onset of aqueous tear deficiency. Surface failure and stem cell deficiency occur late in the progression of the disease. Management of the dry eye must be integrated with the management of the other components of both the ocular surface disease and inflammation.

Treatment of dry eye starts with the use of lubricants. The use of lubricants without preservatives avoids toxicity. Autologous serum drops improve the ocular surface due to their effect as a physiological tear replacement as serum contains many of the components of tears, including growth factors, vitamins, and albumin.

The lacrimal puncta are often occluded spontaneously as part of the disease. In case they are not closed, occlusion is helpful and its use has been associated with objective and subjective improvement. The wearing of moisture chamber spectacles helps to alleviate ocular discomfort associated with dry eye, increasing the periocular humidity in patients wearing such spectacles. Contact lenses, either large limbal-diameter rigid gas-permeable or gas-permeable scleral lenses, are useful for treating dry eye and improving vision in some patients.

Several potential topical or systemic pharmacologic agents may stimulate aqueous secretion, mucous secretion, or both. The topical agents currently under investigation are diquafosol, rebamipide, gefarnate, ecabet sodium and 15(S)-HETE. Two orally administrated cholinergic agonists, pilocarpine and cevilemine, have been evaluated in clinical trials and were found to significantly improve symptoms of dryness and aqueous tear production. Salivary gland transplantation may also constitute an option for the treatment of severe dry eye secondary to OCP. This may be considered a step prior to limbal stem cell and corneal transplantation.24

Eyelid Abnormalities

Trichiasis is a common and potentially sight-threatening complication of ocular cicatricial pemphigoid (OCP) and is the major risk factor for microbial keratitis. It may also cause punctate epitheliopathy, corneal abrasions, conjunctival metaplasia, provoke additional conjunctival inflammation, and increase ocular surface symptoms. It is usually secondary to cicatricial entropion and may involve either the upper or lower lid. Trichiasis can be treated with several methods: laser thermoablation, lid split through the gray line and anterior lamellar reposition, excision with oral mucous membrane or amniotic membrane transplantation or cryotherapy. Another option of protection against the trauma provoked by the eyelashes in contact to the conjunctiva and cornea is a scleral contact lens.25

Basenment Membrane Abnormalities

The complex autoimmune disorder with multiple components of the immune system participating in the OCP results in an inflamed conjunctiva at the BZM level with formation of bullae and scarring. Chronic conjunctivitis is the common cause of many complications of this disease. In order to establish control of the inflammation and maintain a stable conjunctiva, decreasing the symblepharon formation in patients with OCP, several studies have been performed using amniotic membrane transplantation (Fig. 31.4). It has unique properties that improve the pain, confer anti-inflammatory, antiadhesive and antiangiogenic effects, has the ability to stimulate re-epithelialization and lacks immunogenicity. Previous studies demonstrated that amniotic membrane can be used as an initial step in attempting to reconstruct the ocular surface in patients with advanced OCP.26

Limbal Stem Cell Deficiency

Progressive conjunctival scarring results in loss of goblet cells and keratinization of the ocular surface epithelia with complete corneal opacification. Prolonged inflammation, which is associated with conjunctivalization of the cornea, destroys corneal stem cells and is the main reason for the failure of penetrating keratoplasty in these cases. Furthermore, the long-term success of a limbal allograft is at risk because of ongoing inflammation.

Tsubota et al. reported successful visual improvement in 9/9 eyes with use of limbal allografts and amniotic membrane transplantation in conjunction with systemic immunosuppression with dapsone and cyclosporine. Penetrating keratoplasty was also performed in 5 of the 9 eyes.26 Other reports of the outcomes of surface reconstructive surgery that used living-related limbal allografts27 or cultivated epithelial stem cells28 describe results for only two or three OCP eyes. Once ocular surface inflammation and progression have been controlled, attention can be turned to other means of improving vision (Fig. 31.5).

When ocular surface reconstruction and penetrating keratoplasty fail, keratoprosthesis (KPro) surgery may provide the only potential means of restoring vision in patients with progressive OCP (Fig. 31.6). However, transcorneal KPros, such as the Boston type I device have shown limited results in the long-term follow-up of advanced OCP patients with severe dry eye. This device carries a guarded prognosis in OCP due to the high risk of corneal melting and device extrusion. Boston type II KPros or the osteo-odonto-keratoprosthesis (OOKP) devices appear to be better options for these cases of OCP in comparison to the Boston type 1 device.29

References

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24. Sant’ Anna, AE, Hazarbassanov, RM, de Freitas, D, et al. Minor salivary glands and labial mucous membrane graft in the treatment of severe symblepharon and dry eye in patients with Stevens–Johnson syndrome. Br J Ophthalmol. 2011;96:234–239.

25. Siqueira, AC, Santos, MS, Farias, CC, et al. [Scleral contact lens for ocular rehabilitation in patients with Stevens-Johnson syndrome]. Arq Bras Oftalmol. 2010;73:428–432.

26. Tsubota, K, Satake, Y, Ohyama, M, et al. Surgical reconstruction of the ocular surface in advanced ocular cicatricial pemphigoid and Stevens–Johnson syndrome. Am J Ophthalmol. 1996;122:38–52.

27. Santos, MS, Gomes, JA, Hofling-Lima, AL, et al. Survival analysis of conjunctival limbal grafts and amniotic membrane transplantation in eyes with total limbal stem cell deficiency. Am J Ophthalmol. 2005;140:223–230.

28. Nishida, K, Yamato, M, Hayashida, Y, et al. Corneal reconstruction with tissue-engineered cell sheets composed of autologous oral mucosal epithelium. N Engl J Med. 2004;351:1187–1196.

29. Dohlman, CH, Terada, H. Keratoprosthesis in pemphigoid and Stevens–Johnson syndrome. Adv Exp Med Biol. 1998;438:1021–1025.

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