Mucous Membrane Pemphigoid

Tais Hitomi Wakamatsu and Jose Alvaro Pereira Gomes

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.