Pemphigus Vulgaris

Table I.

Optimal Therapeutic Approach for this Disease

Class I steroids, such as clobetasol, can be applied twice daily to new blisters and erosions on both the face and body. Topical tacrolimus ointment may also be helpful, particularly for lesions on the face where chronic steroid therapy is undesirable. For mucosal disease, dexamethasone elixir, swish and spit 5cc once to twice daily, is easy to use. Clobetasol ointment or gel can also be applied directly to mucosal erosions. Dental trays (fitted by oral medicine) facilitate occlusion of topical steroids to the gingiva at night.

For mild disease, (transient lesions that heal within 1 week), monotherapy with topical corticosteroids may be sufficient. Mild mucosal or mucocutaneous disease may also respond to tetracyclines plus niacinamide (doxycycline 100mg twice daily plus niacinamide 500mg three times daily).

With persistent or widespread disease, oral corticosteroids such as prednisone are indicated. For moderate disease, 0.5mg/kg/day of prednisone or equivalent may be sufficient. Doses generally do not need to exceed 1mg/kg/day of prednisone. If patients flare on 1mg/kg/day of prednisone, the dose can be split to twice daily or three times daily dosing, which increases the therapeutic efficacy without increasing the total daily dose.

Before starting high-dose steroids, tuberculosis screening should be performed (via tuberculin skin testing or Quantiferon-gold blood assay). If patients will be on chronic corticosteroids (at least 5mg daily prednisone equivalent for at least 3 months), osteoporosis counseling and prevention is indicated. Additionally, Pneumocystis prophylaxis should be considered for patients on chronic prednisone, particularly with daily prednisone doses of 15mg or higher. Patients should remain on high-dose steroids until new lesions cease to form, and then the dose can be gradually tapered to the minimum required to control disease. If patients can be managed with 10mg (or ideally 5mg) daily prednisone or less, corticosteroid monotherapy is feasible.

Dapsone (100-200mg daily) can be effective in mucosal disease or to lower the daily corticosteroid dose in patients with stable disease. Dapsone can be used in addition to mycophenolate mofetil or azathioprine. As an advantage, dapsone 100mg daily provides Pneumocystis prophylaxis. Glucose-6-phosphate dehydrogenase (G6PD) activity should ideally be measured before starting therapy, particularly in men of African-American and Middle Eastern descent. Most patients will experience a 1-2 g/dL drop in hemoglobin due to hemolysis, although some patients can experience a severe pancytopenia with or without systemic hypersensitivity reaction. Laboratory monitoring should be performed at least every other week for the first 8 weeks.

In patients requiring greater than 10mg daily prednisone for control of disease activity, or in patients with contraindications to systemic corticosteroid therapy, other immunosuppressants are necessary to reduce or replace systemic corticosteroids. Mycophenolate mofetil and azathioprine have shown approximately equal efficacy and safety in clinical trials for PV, although there is a trend toward both greater efficacy and safety with mycophenolate mofetil.

Mycophenolate mofetil (30-40 mg/kg/day divided twice daily) is generally well tolerated, although side effects of fatigue, gastrointestinal upset, and tremor are not uncommon, particularly at higher doses, and there is a small long-term risk of lymphoma and fatal infection or reactivation from JC virus with progressive multifocal leukencephalopathy. Reduction of corticosteroid dose can be initiated as early as one month after starting mycophenolate mofetil, although maximal effect of mycophenolate mofetil is not achieved until 2-3 months.

Azathioprine can be started at 50mg daily and titrated upward by 50mg every 1-2 weeks until side effect, therapeutic effect, or the target dose of 2.5mg/kg/day occurs. Measurement of the serum thiopurine methyltransferase (TPMT) level prior to the start of azathioprine therapy can be performed, although some studies suggest that TPMT levels do not correlate with the incidence of adverse effects or efficacy of azathioprine therapy. Nevertheless, if serum TPMT levels are very low or very high, azathioprine may not be a good choice for therapy, due to an increased likelihood for adverse effects or lack of effect, respectively. The active metabolites for azathioprine do not significantly accumulate until 6-8 weeks after initiation of therapy, leading to a delayed therapeutic effect.

In patients who have severe or persistent disease that cannot be controlled with corticosteroids and/or other immunosuppressives, other therapies such as rituximab, intravenous immunoglobulin, plasmapheresis, and cyclophosphamide can be considered.

B-cell depletion therapy with rituximab (anti-CD20 monoclonal antibody) is an effective therapy for PV, and some experts have proposed that it should be considered for first-line therapy. Both lymphoma (375 mg/m² IV weekly x 4 weeks) and rheumatoid arthritis (1000 mg IV on days 1 and 15) dosing regimens can be used. In vivo studies from lymphoma patients indicate that peripheral blood B cells disappear from the circulation within days, although antibody production by plasma cells (which are not well targeted by rituximab) can persist for months; therefore maximal results are usually not observed until 3-6 months after infusion. Recent studies indicate that after rituximab therapy approximately 60% of pemphigus patients will achieve complete remission of disease, and approximately 45% of patients will achieve complete remission of disease off all other systemic immunosuppressive therapies. Relapse after a single cycle of rituximab is commonly observed (approximately 80% of patients); re-treatment with rituximab again induces complete remission in the vast majority of patients.

Fatal infection has occurred with rituximab therapy, including bacterial sepsis, hepatitis B reactivation, and progressive multifocal leukencephalopathy from JC virus, although fatal infection is also a potential side effect of first-line PV therapies, including prednisone and mycophenolate mofetil.

Intravenous immunoglobulin (IVIG, 2 mg/kg, divided over 3-5 days) is effective for PV therapy and can be provided by hospital or home infusion. IVIG induces catabolism of endogenous serum antibodies and offers the advantage of being immunoprotective. A disadvantage of IVIG is that the temporary serum viscosity associated with the infusion can cause stroke or other complications from clotting. The serum half life of IVIG has been reported to range from 8-39 days (average 3-4 weeks). Treatment guidelines for autoimmune blistering disease with IVIG suggest an initial frequency of every 4 weeks until disease remits, increasing to 6, 8, 10, 12, 14, then 16 weeks, the latter being the proposed end point for an initial course of therapy.

Plasmapheresis allows for the rapid removal of antibodies from the circulation, but must always be used in conjunction with adjunctive immunosuppressants to prevent new antibody production.

Cyclophosphamide (50-200mg daily) is among the fastest agents for treating PV. However, its risk of blood count and liver test abnormalities, infertility, and hemorrhagic cystitis with bladder carcinoma, together with the advent of other effective therapies such as rituximab, have led to the decreased use of cyclophosphamide in the management of severe PV.

Patient Management

The goal of treatment is to obtain a complete remission off therapy, although many patients may only achieve a partial remission off therapy, or a complete remission on minimal therapy. When starting patients on therapy, risks of medications should be discussed. There is no systemic medication that for PV that is 100% safe. However, the natural history of untreated PV is to progress to life-threatening disease; therefore the risk-benefit ratio favors treatment.

Open erosions can become superinfected with Staphylococcus aureus or herpesviruses; culture of refractory or worsening lesions should be considered.

Remind patients that their skin during active disease is fragile, so crusted blisters should not be scrubbed and use of massage or other high-pressure showerheads should be avoided.

Patients should receive regularly scheduled dental cleaning from a hygienist experienced with oral blistering disease. Patients often avoid cleanings due to painful mucosal disease; however, over time plaque buildup leads to chronic gingival inflammation that aggravates pemphigus. If necessary, patients can take a short (1-2 week) course of prednisone surrounding their cleanings to prevent flares of disease.

Patients should ideally be maintained in complete remission for at least 1 year before all immunosuppressive therapy is discontinued. Often patients want to taper off their medications quickly, but then flare and have to go back on high doses of medications for disease control, which may reduce the chance for disease remission. Typically, corticosteroids are tapered off first, then adjunctive immunosuppressants are slowly tapered over the course of one year. However, the tapering regimen should be tailored for each patient depending on side effects and response to therapy. It is common for patients to have a small flare with each dose taper; as long as lesions heal within one week and no further lesions form, the taper can be continued.

The Centers for Disease Control recommends that all patients on immunosuppressive therapy receive influenza and other regularly scheduled vaccinations. While on immunosuppressive therapy, patients should be reminded that they should not receive live vaccines (e.g. nasal influenza or zoster.)

Unusual Clinical Scenarios to Consider in Patient Management

Pregnant patients with PV should be referred for high-risk obstetrical care. Maternal PV is associated with low birthweight and rarely stillbirths in newborns. Additionally, neonatal PV can result from placental transfer of disease-causing IgG from the maternal circulation. Pregnant patients are usually treated with prednisone monotherapy, as most other immunosuppressive agents are pregnancy category D, including mycophenolate mofetil, azathioprine, tetracyclines, and cyclophosphamide. Dapsone is pregnancy category C.

There are sparse data regarding the safety of immunosuppressives in men whose pregnant wives can be exposed to drugs in seminal fluid. Rare cases of birth defects with azathioprine use by fathers has been reported. An ongoing registry of male transplant patients receiving mycophenolate mofetil has shown no significant increase in birth defects.

In hospitalized patients with severe disease, blood should be cultured so that bacteremia can be identified and treated. A thin layer of triamcinolone 0.1% ointment can be spread on sterile linens and wrapped around patients twice daily. Unfortunately, there is no single consensus regimen among experts about how to treat severe pemphigus, owing to the sparsity of randomized controlled trials in this rare disease. Historically, these patients were treated with corticosteroids, cyclophosphamide, and plasmapheresis due to their rapid therapeutic effect. Several other regimens can be considered for the hospitalized patient, including:

• intravenous corticosteroids (as high as 60 mg methylprednisolone four times daily), adjunctive immunosuppressant such as mycophenolate mofetil, and IVIG (which is immunoprotective)

• intravenous corticosteroids (+/- adjunctive immunosuppressant) and rituximab for long term control

• intravenous corticosteroids (+/- adjunctive immunosuppressant), plasmapheresis to immediately remove serum antibodies, followed by rituximab for long term control

The timing of certain combinations of medications should be considered. For example, rituximab infusion should not be administered immediately before plasmapheresis or IVIG, as the former would clear the rituximab and the latter may induce its catabolism. However, rituximab is thought to rapidly bind and deplete circulating B cells (within days), and peripheral B cell counts begin to recover 8 days after infusion.

Theoretically therefore, plasmapheresis and IVIG could be considered as early as 1-4 weeks after completion of rituximab infusion, although studies indicate that rituximab half-life progressively increases with subsequent weekly infusions (suggesting saturation of in vivo binding sites), and that a higher serum concentration is associated with better treatment outcome in B cell lymphomas. Conversely, plasmapheresis can be performed immediately prior to rituximab, but the ideal timing of rituximab infusion after a course of IVIG is unknown, with recommendations ranging from 1-6 weeks based on the serum half life of IVIG.

IgA pemphigus is characterized by tissue-bound and circulating IgA antibodies targeting keratinocyte cell surface antigens. Two histologic types have been identified: (1) subcorneal pustular dermatosis (SPD), and (2) intraepidermal neutrophilic dermatosis (IEND). The antigen in the SPD type is desmocollin 1. The antigen in IEND remains to be defined, although a subset of these patients produce IgA autoantibodies to Dsg3 or Dsg1.

Strictly speaking, patients with IgA pemphigus will demonstrate only IgA autoantibodies on serologic studies. Some pemphigus vulgaris patients may demonstrate a mixed IgG/IgA autoantibody profile on DIF or IIF; these cases are best classified as pemphigus vulgaris. Clinically, IEND may present with a herpetiform appearance of the vesicles, while SPD clinically resembles Sneddon-Wilkinson disease, with superficial annular or circinate vesicopustules and erosions with central crust.

Patients with pure IgA pemphigus will typically respond to dapsone or sulfapyridine monotherapy. If dapsone is not effective, not sufficient, or contraindicated due to allergy, a trial of corticosteroid monotherapy is worthwhile, as many patients can be controlled on 10mg prednisone daily or lower. In refractory cases, other standard combination treatments for pemphigus (typically also including dapsone) are used.

Paraneoplastic pemphigus is a life-threatening autoimmune bullous disorder with an appoximately 90% mortality rate. Because of the expanding clinical spectrum of the condition, the term paraneoplastic autoimmune multiorgan syndrome has been utilized. Clinically, patients have severe mucosal erosions classically including the lips, while the cutaneous features may resemble pemphigus vulgaris, erythema multiforme, or lichen planus, individually or in combination. The disease is characterized by autoantibodies targeting the plakin family (desmoplakin, envoplakin, and periplakin), although antibodies against desmogleins, hemidesmosomal proteins, and alpha 2-macroglobulin can also be observed.

Histologically the picture may be variable, characteristically combining suprabasal acantholysis typical of pemphigus vulgaris with vacuolar alteration of the epidermal-dermal junction and lichenoid inflammation. Direct immunofluoresence (DIF) classically demonstrates cell surface IgG staining, although this can be weak to undetectable in patients with a more lichenoid rather than bullous presentation. DIF also demonstrates IgG +/- complement and/or fibrinogen at the epidermal-dermal junction. Indirect immunofluorescence utilizing rat bladder epithelium is confirmatory.

Associated malignancies are most characteristically non-Hodgkins lymphoma, chronic lymphocytic leukemia, Castleman’s disease (particularly in children), and less often, thymoma, sarcoma, and Waldenstrom’s macroglobulinemia. Mortality is usually due to overwhelming sepsis, complications of therapy, or bronchiolitis obliterans (especially in children or those cases associated with Castleman’s disease). Treatment is difficult, but parallels that used in pemphigus vulgaris. Any associated malignancy must be treated aggressively with the appropriate oncologic protocol.

What is the Evidence?

Payne, AS, Stanley, JR, Wolff, K, Goldsmith, LA, Katz, SI, Gilchrest, B, Paller, AS, Leffell, DJ. “Pemphigus”. Dermatology in general medicine. 2011. (A more complete review of the clinical presentation and management of pemphigus.)

Murrell, DF, Dick, S, Ahmed, AR, Amagai, M, Barnadas, MA, Borradori, L. “Consensus statement on definitions of disease endpoints and therapeutic response for pemphigus”. J Amer Acad Dermatol. vol. 58. 2008. pp. 1043-6. (An international consensus of definitions for disease endpoints [such as remission, relapse, and treatment failure].)

Onuma, K, Kanbour-Shakir, A, Modery, J, Kanbour, A. “Pemphigus vulgaris of the vagina–its cytomorphologic features on liquid-based cytology and pitfalls: case report and cytological differential diagnosis”. Diagn Cytopathol. vol. 37. 2009. pp. 832-5. (Case report of pemphigus vulgaris of the vagina.)

Amagai, M, Komai, A, Hashimoto, T, Shirakata, Y, Hashimoto, K, Yamada, T. “Usefulness of enzyme-linked immunosorbent assay using recombinant desmogleins 1 and 3 for serodiagnosis of pemphigus”. Br J Dermatol. vol. 130. 1999. pp. 351-7. (Describes the development of the desmoglein ELISA, including sensitivity and specificity.)

Beissert, S, Werfel, T, Frieling, U, Bohm, M, Sticherling, M, Stadler, R. ” A comparison of oral methylprednisolone plus azathioprine or mycophenolate mofetil for the treatment of pemphigus”. Arch. Dermatol. vol. 142. 2006. pp. 1447-54. (This prospective randomized trial of 40 pemphigus patients demonstrated equal efficacy and safety between mycophenolate mofetil [2g daily] and azathioprine [2mg/kg/day] as steroid sparing agents in pemphigus, with a trend toward greater efficacy and safety for mycophenolate mofetil.)

Chams-Davatchi, C, Esmaili, N, Daneshpazhooh, M, Valikhani, M, Balighi, K, Hallaji, Z. “Randomized controlled open-label trial of four treatment regimens for pemphigus vulgaris”. J Am Acad Dermatol. vol. 57. 2007. pp. 622-8. (This trial compared prednisolone alone to prednisolone plus azathioprine [2.5mg/kg/day], mycophenolate mofetil, [2g/day] or pulse IV cyclophosphamide among 120 patients with PV. All agents were effective as steroid sparing agents, although azathioprine was associated with a significantly lower mean total prednisolone dose as compared to mycophenolate mofetil.)

Beissert, S, Mimouni, D, Kanwar, A, Solomons, N, Kalia, V, Anhalt, GJ. “Treating pemphigus vulgaris with prednisone and mycophenolate mofetil: a randomized, placebo-controlled trial”. J Invest Dermatol. vol. 130. 2010. pp. 2041-8. (This trial randomized patients to mycophenolate mofetil [MMF] 2 or 3g daily versus oral corticosteroids [1-2mg/kg/day]. Treatment with MMF was not associated with a significantly improved treatment response, although time to relapse and length of sustained response was significantly increased. There were several caveats to this study, including the fact that after randomization, the placebo-treated group had significantly milder disease than the MMF-treated group.)

Joly, P, Mouquet, H, Roujeau, JC. “A single cycle of rituximab for the treatment of severe pemphigus”. New Engl J Med. vol. 357. 2007. pp. 545-52. (Largest published case series of 21 pemphigus patients treated with rituximab. 18 patients achieved complete remission within 3 months, and 20 patients achieved complete remission within 12 months. After treatment with corticosteroids or a second cycle of rituximab, 18 patients remained disease-free at 34 months, with 8 patients completely off corticosteroid therapy. Two patients had severe complications including pyelonephritis and fatal sepsis.)

Ahmed, AR, Spigelman, Z, Cavacini, LA, Posner, MR. “Treatment of pemphigus vulgaris with rituximab and intravenous immune globulin”. New Engl J Med. vol. 355. 2006. pp. 1772-9. (Nine out of eleven pemphigus vulgaris patients had sustained remissions lasting 22-37 months, and the two who relapsed had sustained remissions after a second course of rituximab only. No infections occurred. The authors propose that IVIG replaces the beneficial antibodies otherwise depleted by rituximab. However, the safety and efficacy of the combined regimen compared to rituximab or IVIG alone, as well as the optimal timing of rituximab and IVIG infusions, remains unknown.)

Ahmed, AR, Dahl, MV. “Consensus statment on the use of intravenous immunoglobulin therapy in the treatment of autoimmune mucocutaneous blistering diseases”. Arch Dermatol. vol. 139. 2003. pp. 1051-9. (Provides guidelines for the use of IVIG, including indications, prescreening, premedications, dose, frequency, monitoring, and therapeutic endpoints.)

Tsunda, D, Ishi, N, Ohyama, B, Fukuda, S. “IgA pemphigus”. Clin Dermatol. vol. 29. 2011. pp. 437-42. (A review of all aspects of IgA pemphigus – clinical features, laboratory finding, pathophysiology and treatment.)

Frew, JW, Murrell, DF. “Paraneoplastic pemphigus (paraneoplastic autoimmune multiorgan syndrome: clinical presentations and pathogenesis”. Dermatol Clin. vol. 29. 2011. pp. 419-25. (An excellent review of the clinical spectrum and laboratory assessment of paraneoplastic pemphigus/PAMS.)