Paraneoplastic Pemphigus - Causes, Clinical Features, Complications, Diagnosis, and Treatment

Introduction:

Paraneoplastic pemphigus is a rare, autoimmune-mediated mucocutaneous disease almost always associated with neoplasms. Paraneoplastic pemphigus typically presents with painful mucosal erosions and dusky patches on the skin. A variety of lesions with painful mucosal erosions and different morphologies, ranging from flaccid blisters to widespread lichenoid eruptions, are seen in paraneoplastic pemphigus. Mucosal lesions may be the earliest presenting symptom of the disease. Extensive epidermal loss can result in extreme dehydration, protein depletion, and an increased evaluation risk. Patients often require intensive care and should be managed, similar to burn patients. Adults aged 45 to 70 years are most commonly affected.

What Is Paraneoplastic Pemphigus?

Paraneoplastic is a mucocutaneous, blistering disease almost always associated with confirmed neoplasms. Paraneoplastic autoimmune multiorgan syndrome (PAMS) is another name due to potential autoimmune reactions, which also appear in internal organs, such as bronchiolitis obliterans in the lungs.

Who Gets Paraneoplastic Pemphigus?

Paraneoplastic pemphigus is a rare form of autoimmune bullous disease variant; It is the tiniest but most serious form of pemphigus, about three to five percent of all cases. Most commonly, it develops in adults between 45 to 70 years of age with equal male and female sex prediction, seen in children.

Almost all the cases are associated with the underlying cancerous process.

• Approximately five percent of patients with internal malignancy may develop paraneoplastic pemphigus.

• Paraneoplastic pemphigus is often a presenting feature of Castleman's disease (giant cell or angiofollicular lymph node hyperplasia) seen in children and adolescents.

• Lymphoproliferative neoplasms are the most common underlying disease: precisely, non-Hodgkin lymphoma is the most common type of underlying cancer in adults, followed by chronic lymphocytic leukemia.

What Causes Paraneoplastic Pemphigus?

Paraneoplastic pemphigus is caused by underlying malignancy (most commonly lymphoproliferative neoplasm), which stimulates an autoimmune response.

• Autoreactive T-cells by neoplasm can include both humoral and cell-mediated immunity.

• Components of desmosomes (which interconnect the keratinocytes in the epidermis), such as bullous pemphigoid.

• Humoral immunity through IgG1 autoantibodies against desmosome and hemidesmosome components can cause acantholysis, resulting in intraepidermal blistering and bronchitis obliterans.

• Genetic factors also play a role in the autoimmune response.

What Are the Clinical Features?

There are five major clinical subtypes of paraneoplastic pemphigus available, which are likely linked to the range of autoantibodies:

• Pemphigus like.

• Bullous pemphigoid-like.

Erythema multiforme paraneoplastic pemphigus clinical features may include:

• Painful mucous membrane erosions and extensive refractory mucostomatitis.

• Blisters, hemorrhagic crusting, and genitals.

• Diffuse polymorphic skin lesions, usually seen after mucous membrane involvement, are often very itchy.

• Involvement of other epithelia and internal organs like lungs, gastrointestinal tract, thyroid gland, and kidneys.

• Muscle weakness and high titers of anti-acetylcholine receptor antibodies are evidence of myasthenia gravis.

• Evidence of underlying malignancy.

What Are the Complications of Paraneoplastic Pemphigus?

• Fluid protein and loss from epidermal erosions and blisters can cause dehydration and imbalances.

• Loss of skin barrier function predisposing to sepsis and infections.

• Treatment-resistant for mucosal lesions.

• Malnutrition and dehydration due to painful oropharyngeal lesions.

Potential Eye (Ocular) Complications:

• Pseudomembranous conjunctivitis.

• Conjunctival and corneal erosions or ulcerations.

• Progressive scarring.

• Eyelid thickening.

• Pterygium.

Potential Lung Complications:

• Bronchiolitis obliterans.

• Repeated infections.

• Respiratory failure.

How Is Paraneoplastic Pemphigus Diagnosed?

Paraneoplastic pemphigus diagnosis is based on clinical and histologic findings, direct and indirect immunofluorescence, and immune serology. Once paraneoplastic pemphigus is diagnosed, a thorough search for any underlying malignancy is essential.

• Clinic: Refractory mucosal erosions, painful with or without skin rash in the setting of an underlying neoplasm.

How Is the Lesion Seen Under a Microscope?

Two types of lesions, which may overlap based on clinical phenotypes:

Blisters: Suprabasal acantholysis with sparse inflammatory infiltrate is seen.

Erythematous Maculopapular Lesions: Lichenoid interface changes with dense mononuclear immune cell infiltrate are seen.

Direct Immunofluorescence:

• A net-like pattern of intercellular Ig3 and C3 within the epidermis.

• Granular or linear IgG and C3 deposits are seen along the basement membrane zone at a dermo-epidermal junction (unique to paraneoplastic pemphigus compared to other forms of pemphigus.

Indirect Immunofluorescence:

• Circulating antibodies targeting intracellular proteins of cells within stratified squamous or transitional epithelium are characteristic of paraneoplastic pemphigus.

• Indirect immunofluorescence testing of patient serum is performed to detect antibodies.

• Anti-plakin is a specific screening test helpful to differentiate paraneoplastic pemphigus from other forms of pemphigus.

Immunoprecipitation and Immunology: Detecting autoantibodies against the 210- KD band of envoplakin and the 190- KD band of periplakin is both sensitive and specific for diagnosis.

What Is the Differential Diagnosis of Paraneoplastic Pemphigus?

• Drug-induced pemphigus.

• Bullous pemphigoid.

• Stevens-johnson syndrome.

• Erythema multiforme.

• Lichen planners.

• Graft-versus-host disease.

• Herpes simplex virus.

• Major apthous ulcer.

• Chemotherapy-induced stomatitis.

• Staphylococcal scalded skin syndrome.

• Mucous membrane pemphigoid.

• Pemphigus vulgaris.

What Is the Treatment for Paraneoplastic Pemphigus?

General Measures:

• Paraneoplastic pemphigus may require treatment in a specialist burns unit.

• Multi-disciplinary, interprofessional approach with input from ophthalmology, oral medicine, urology or gynecology, oncology, respiratory, dermatology.

• Gastroenterology, wound care specialists, dietitians, and physiotherapists.

• Early diagnosis and treatment did for the underlying malignancy.

• Treatment for dehydration, infection, and also electrolyte imbalance.

• Meticulous wound care with emollients, appropriate dressings, and antiseptic baths.

• Bioengineered dressings for several cases.

• Prevention of bedsores/pressure injuries.

Oral Care:

• Analgesic mouthwashes and orally applied topical corticosteroids.

• Nasogastric tubes for feeding as needed.

• Eye and bladder cases.

• Analgesia.

Specific Measures: The optimal treatment for paraneoplastic pemphigus whose response to treatment therapy is variable; treatment options may include:

• Topical corticosteroids or topical calcineurin inhibitors.

• Systemic immunosuppression:

First Line:

• High-dose corticosteroids.

• Additional immunosuppression options: Azathioprine, Cyclosporine, Cyclopamine, or Mycophenolate mofetil.

• Rituximab (monoclonal antibody).

• Alemtuzumab (monoclonal antibody).

• Plasmapheresis.

• Intravenous immunoglobulin.

• Biosynthetic dressings.

Paraneoplastic pemphigus management is done by treating underlying malignancy by surgical excision or following appropriate chemotherapy, radiotherapy, or immunotherapy.

How to Prevent Paraneoplastic Pemphigus?

Paraneoplastic pemphigus is most commonly associated with underlying cancer, particularly hematological cancers, such as lymphoma and leukemia, and prevention is not straightforward.

Surgical resection of solid tumors with both the pre and post-surgical usage of high-dose intravenous immunoglobulin therapy can lower the risk of bronchiolitis (producing obstruction due to inflammation and fibrosis) in patients with paraneoplastic pemphigus.

Conclusion:

Paraneoplastic has a poor prognosis, with a mortality rate ranging from 70 to 90 %. The leading cause of death in these patients is respiratory failure. However, prompt diagnosis and early treatment initiation with various therapies may improve prognosis.