Approach

The objectives of treatment are:[1][29]​​

  • healing of the blisters, and minimising or resolving associated functional impairment

  • reduction of future exacerbations

  • improved quality of life

  • limit common adverse effects associated with long-term immunosuppressive or corticosteroid treatment.

Initial management of extensive disease often involves hospitalization, and treatment by a dermatologist experienced in managing autoimmune blistering diseases.[1]

Management of paraneoplastic pemphigus (PNP) is complicated; collaboration with an oncologist is essential.

The treatment of moderate-to-severe pemphigus is typically divided into acute and maintenance phases. Unless otherwise indicated, the approach described is appropriate for both pemphigus vulgaris (PV) and pemphigus foliaceus (PF).

Therapeutic agents

First line pharmacotherapies include rituximab and corticosteroids. Azathioprine and mycophenolate are used as corticosteroid-sparing agents. Intravenous immune globulin (IVIG) may be considered in patients with severe/refractory pemphigus.

Rituximab

Rituximab, a murine/human anti-CD20 monoclonal antibody given by intravenous infusion, is effective in the treatment of pemphigus, but serious treatment-related infections have been reported.[34]​​[35][36][37]​​

Among patients with newly diagnosed pemphigus, 41 of 46 patients (89%) assigned to rituximab plus short-term prednisone were in complete remission off-therapy at month 24.[34] The comparable figure for patients assigned to prednisone alone was 34% (15 of 34). The combination of rituximab and prednisone therapy was associated with an absolute risk reduction of 55% compared with prednisone alone (corresponding to a number needed to treat of 2).[34]

In a follow-up study, patients in the rituximab group had a significantly longer 7 year disease-free survival and a significantly lower relapse rate compared with patients in the prednisone alone group (72.1% vs. 35.3% and 42.2% vs. 83.7%, respectively).[36]​  

Some data suggests rituximab may be associated with improved long-term cardiovascular and metabolic health outcomes compared with azathioprine or mycophenolate.[38]​

Corticosteroids

One of the most effective therapies for decreasing autoantibody levels.[1][39] However, long-term use of corticosteroids is associated with significant morbidity (e.g., osteoporosis, mental disturbances, increased susceptibility to infections, avascular necrosis of the hip, diabetes, hypertension, skin atrophy, and poor wound healing). Alternative immunomodulatory treatments reduce risks associated with long-term corticosteroid therapy.

Immunosuppressive agents

Azathioprine and mycophenolate are commonly used immunosuppressants (corticosteroid-sparing agents) for the management of pemphigus.[40][41][42] Cyclophosphamide is associated with potentially severe adverse effects, and is used less frequently.[1] Dapsone may be used in the management of mild PF. Immunomodulatory therapy, alone or in combination with IVIG, has been shown to be effective in prospective studies of patients with PV.[43][44][45]

Azathioprine or mycophenolate may be considered as first line-therapy when rituximab is not available, or in patients with contraindications to rituximab.[1] In some regions, azathioprine and mycophenolate are first line agents for the management of pemphigus, and rituximab is reserved as second line therapy.

An evaluation of thiopurine S-methyltransferase (TPMT) activity is recommended when azathioprine is considered in countries where genetic polymorphisms for decreased TMPT activity are prevalent.[29]

Intravenous immune globulin (IVIG)

IVIG acutely lowers autoantibody titers, and provides a degree of immunoprotection; it may be considered in patients with severe, refractory pemphigus.[1][5]​​ Major adverse effects of IVIG include infusion reaction, anaphylaxis in patients with IgA deficiency, headaches, aseptic meningitis, and blood clots.[45]

Serological monitoring of disease activity

Serum concentrations of IgG autoantibodies against Dsg1 and Dsg3 correlate with the clinical activity of pemphigus and aid therapeutic decision-making.[1][29]​​ Only high titers of anti-Dsg3 antibodies reasonably predict the occurrence of relapse.

Monitoring (ELISA: anti-Dsg1 and/or Dsg3 IgG) is recommended to determine the level of serum autoantibodies at the initiation of treatment, after 3 months, and every 3 to 6 months, on the basis of evolution or relapse.[1][29]​​

Initial management of mild pemphigus vulgaris

Rituximab, with or without an adjunctive corticosteroid, is increasingly the preferred first-line therapy for patients with mild PV, due to its high efficacy and improved long-term health outcomes.[1][36][38]​​ Prednisone, with or without azathioprine or mycophenolate, is an alternative first-line option. 

In patients who do not achieve disease control following initial treatment with corticosteroid therapy alone (i.e., active lesions persist), rituximab is added to corticosteroid therapy.[1]

Rituximab may also be a second line therapy for patients with corticosteroid-related adverse effects, or contraindications to azathioprine or mycophenolate.

The dose of prednisone may be increased in patients with persistent active lesions despite initial therapy with prednisone plus rituximab.[1]

Prednisone should be tapered to a stop within 3 to 4 months in patients receiving concomitant rituximab (as first or second line therapy).

Initial management of mild pemphigus foliaceus

Few treatments have been evaluated in the management of pemphigus foliaceus (PF).

Dapsone (combined with a topical corticosteroid), an oral corticosteroid, or rituximab may be considered first line.[1]​ Monotherapy with a potent topical corticosteroid (e.g., betamethasone dipropionate) is also a first-line option, but only in the presence of limited lesions (<5).[1]

The following options are recommended for patients who do not achieve disease control following initial treatment with dapsone and/or topical corticosteroid, and who have persistent active lesions and significant impact upon quality of life:[1]

  • rituximab, with or without a topical corticosteroid

  • a corticosteroid, with or without azathioprine or mycophenolate, if rituximab is contraindicated or not available.

In patients who do not achieve disease control following initial treatment with oral corticosteroid therapy (i.e., active lesions persist), rituximab is added to corticosteroid therapy.

Prednisone should be tapered to a stop within 3 to 4 months in patients receiving concomitant rituximab (as first or second line therapy).

Initial management of moderate to severe disease (PV or PF)

The aim of acute therapy is to halt disease progression.

Rituximab, in association with prednisone prescribed as a tapering dose (to stop after 6 months), is usually given first line for moderate to severe pemphigus.[1][29]​​ Rituximab can be administered as monotherapy if oral corticosteroid therapy is contraindicated.[1] If rituximab is contraindicated or unavailable, prednisone may be prescribed alone, or concomitantly with an immunosuppressant (azathioprine or mycophenolate), as an alternative first line therapy.[1][29]​​

No disease control within 1 month of initial treatment

For patients initially treated with rituximab plus prednisone, an increased dose of prednisone or intravenous corticosteroid pulse therapy is recommended.[1]

Patients treated initially with prednisone alone (and for whom rituximab cannot be prescribed) may benefit from an increased corticosteroid dose (pending upon initial dose of corticosteroid), or the addition of azathioprine or mycophenolate.[1]

Maintenance treatment of moderate to severe disease (PV or PF)

Patients with moderate to severe pemphigus with disease control within 1 month of treatment can continue their existing treatment.[1]

Maintenance therapy 6 months after the initial rituximab cycle

Patients who are in complete remission, on or off therapy, may be candidates for a rituximab infusion if they:[1]

  • initially presented with a severe pemphigus, and/or

  • still have high levels of anti-Dsg at month 3 after initial rituximab therapy.

The optimal dose of rituximab for these patients has not yet been determined.[1]

Those without complete remission after 6 months (on or off therapy) can be considered for two rituximab infusions, administered 2 weeks apart.

Maintenance therapy 12 and 18 months after the initial rituximab cycle

One infusion of rituximab at month 12 is recommended for patients in complete remission (on or off therapy), followed by another rituximab infusion at 18 months.[1] Patients who remain positive for anti-Dsg antibodies should be targeted.

Additional infusions of rituximab after month 18 may be necessary for patients in whom anti-DSG antibodies recur.

Severe/refractory pemphigus

Patients with severe/refractory disease may be recommended IVIG, intravenous corticosteroid pulse therapy, or immunoadsorption (in addition to rituximab, or if there is no response to rituximab treatment, or in addition to an immunosuppressant if there is no possibility to treat the patient with rituximab).[1][46]

Serum IgA deficiency should be ruled out prior to IVIG treatment; complete IgA deficiency is a contraindication for IVIG treatment. Slow IVIG infusion rates, adequate hydration, and lower doses or increased time between cycles, may reduce risk of IVIG-related adverse effects.[1][5]​​

Supportive treatment

Consider the following measures premised on pemphigus variant, individual patient circumstance, and current therapy:[1][29]​​

  • appropriate dental care

  • intralesional injection of corticosteroid

  • adjuvant treatment with super-potent topical corticosteroids

  • antiseptic baths (for patients with extensive skin lesions, especially in cases of bacterial skin infection)

  • covering erosive lesions with low adhesive wound dressings, emollients, and compresses

  • analgesia

  • nutritional management with the help of a dietician.

Paraneoplastic pemphigus: special considerations

Collaboration with an oncologist is a critical component of therapy as PNP patients often have an active malignancy, treatment of which may benefit the PNP.[13]​ However, it should be recognized that PNP can also manifest when patients are in remission.[47][48]

Therapy for PNP also involves close monitoring of lung function via pulmonary function testing as bronchiolitis obliterans and respiratory failure are among the most significant causes of mortality in patients with PNP.[13][31][32]

Bone protection

Patients taking prolonged courses of corticosteroids are at increased risk for osteoporosis and accompanying fractures. Therefore, it is imperative to monitor bone density by routine dual-energy x-ray absorptiometry (DXA) scan and give calcium, vitamin D (as ergocalciferol), and appropriate osteoporosis pharmacotherapy (e.g., a bisphosphonate) for bone supplementation.[1]

See Osteoporosis.

Vaccinations

Immunosuppressants and rituximab contraindicate the use of live vaccines.

Patients receiving oral corticosteroids or immunosuppressive therapy should be vaccinated against seasonal influenza and pneumococcal disease.[1][29]​​​

Standard vaccinations (e.g., tetanus, diphtheria, pertussis, polio) should be updated.

Management in pregnancy

PV rarely occurs during pregnancy. In patients who are pregnant and have active pemphigus, the mainstay of treatment is prednisone. However, azathioprine, dapsone, plasmapheresis, and plasma exchange have all been reported. Perinatal mortality can approach 12%.[49] Consult a specialist for the management of pregnant women.

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