Clinical Reference / Therapeutic Strategies / Pemphigus Vulgaris & Paraneoplastic Pemphigus

Pemphigus Vulgaris & Paraneoplastic Pemphigus


Key Points

  • Pemphigus vulgaris is a severe, potentially life-threatening autoimmune blistering disorder. Treatment is always indicated, and all patients should be under the care of a dermatologist.
  • Systemic steroids are typically used for treatment initiation, however due to the need for prolonged treatment and high morbidity of long steroid courses, the early introduction of steroid-sparing agents is a key principle of treatment.
  • New developments in treatment, particularly the availability of effective and well- tolerated steroid-sparing agents, have greatly improved the outlook for patients with this disease.

Introduction

Pemphigus vulgaris (PV) is an autoimmune-mediated intraepidermal blistering disorder caused by the production of IgG autoantibodies to epidermal cell-cell adhesion molecules (desmogleins 1 and 3, 160 and 130 kD respectively), resulting in separation and rounding up of epithelial cells (acantholysis) and intraepidermal clefting leading to blister formation. The typical age of onset of PV is 40-60 years. Incidence is roughly equal in men and women. PV is a rare disease, with an incidence 1-10 people per million worldwide. Regional and ethnic variation in incidence is significant, with increased incidence in Ashkenazi Jews and in persons of Mediterranean and Asian descent.

The disease clinically manifests with superficial blisters that rapidly rupture leaving moist open erosions that are susceptible to superinfection. Affected areas include the cutaneous surface (often including the face) and mucosal surfaces of the mouth (palate, gingiva, buccal mucosa) and less commonly the pharynx and vocal folds and anogenital mucosa. The disease often begins in the oral mucosa, with only subsequent involvement of other skin areas that may appear weeks to months later. Disease may remain mucosal-only (correlating with circulating anti-desmoglein 3 autoantibodies), cutaneous-only (anti-desmoglein 1 antibody predominant), or manifest with mucocutaneous involvement (anti-desmogleins 1 and 3 antibodies). Mucosal lesions of PV tend to present as slow-healing, painful erosions that may make oral intake difficult. Given the rarity of this condition, the correct diagnosis may not be reached for a prolonged period despite the patient presenting to multiple healthcare professionals.

PV used to be almost uniformly fatal within several years prior to the availability of systemic corticosteroids, with patients typically dying from infection and other complications of epidermal barrier failure. The life-threatening nature of PV mandates aggressive therapy, however, in the era of corticosteroids, more morbidity has resulted from the treatment than from the disease itself.

While systemic steroids were previously the sole mainstay of treatment, availability of effective steroid-sparing agents and more recently rituximab infusions have greatly improved outcomes in this disease.

Paraneoplastic Pemphigus

Paraneoplastic pemphigus is associated with an underlying malignancy (most commonly non-Hodgkin lymphoma) or with Castleman’s disease (especially in children). Less common underlying neoplasms include Hodgkin lymphoma, chronic lymphocytic leukemia, thymoma, lung carcinoma, and sarcoma.

The pathogenic autoantibodies include those of PV (desmogleins 1 and 3) as well as several other autoantibodies, including those to plakin family components periplakin (190 kD), envoplakin (210 kD), desmoplakin II (210 kD), bullous pemphigoid antigen 1 (230 kD), desmoplakin 1 (250 kD), and plectin (500 kD), among others.

The clinical presentation of paraneoplastic pemphigus may resemble that of PV, however, a severe refractory stomatitis is more typically seen with paraneoplastic pemphigus. This may involve any portion of the oral mucosa, however, it classically involves the vermillion and may resemble erythema multiforme. In fact, a subset of paraneoplastic pemphigus patients with erythema multiforme-like clinical lesions and keratinocyte necrosis on histology has been shown to have worse prognosis. Additionally, severe GI and respiratory involvement (the latter in the form of bronchiolitis obliterans) may be seen, which may be a source of considerable morbidity and mortality.

The diagnosis of paraneoplastic pemphigus is made similarly to that for pemphigus vulgaris; however, on direct immunofluorescence, in addition to the intercellular deposition of IgG, there may be deposition of IgG along the dermoepidermal junction (linear or granular pattern) not seen with PV. Additionally, indirect immunofluorescence demonstrates autoantibodies that bind to rat bladder epithelium in vitro.