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.

Initial Evaluation

After an initial negative workup for herpetic stomatitis (viral DFA or culture or course of empiric acyclovir), non-healing oral ulcerations lasting longer than a month should generally be evaluated by biopsy for both hematoxylin and eosin (H&E) and direct immunofluorescence (DIF); this may be performed by a dermatologist, otolaryngologist, or oral medicine specialist. Patients with skin lesions suspicious for PV should be referred to a dermatologist for a skin biopsy.

The diagnosis of PV is made via biopsy of lesional skin or epithelium for H&E, and perilesional epithelium for DIF. The latter demonstrates IgG in an intercellular “chicken wire” pattern. Indirect immunofluorescence demonstrates circulating immunoreactants that bind to monkey esophagus in vitro. Disease is also correlated to positive circulating titers of anti-epithelial cell surface IgG (via IIF) or anti-desmoglein 1 and 3 antibodies (via ELISA), however, these tests are not typically ordered until a positive biopsy result is obtained.

Pemphigus vulgaris

Differential diagnosis

IgA pemphigus

Pemphigus foliaceus

Paraneoplastic pemphigus

Bullous pemphigoid

Hailey-Hailey disease

Oral aphthae

Herpes simplex gingivostomatitis or Oral herpes zoster

Erosive lichen planus

Erythema multiforme / Stevens-Johnson syndrome / Toxic epidermal necrolysis

Also includes:
Cicatricial pemphigoid
Linear IgA bullous dermatosis
Oral manifestations of Crohn’s disease
Pyostomatitis vegetans

Treatment

Because overwhelming evidence suggests a cause-and-effect relationship between pemphigus autoantibody and the disease activity, therapy is aimed at both resolution of cutaneous lesions and elimination of circulating antibody. The titers of the circulating anti-epithelial cell surface IgG (via IIF) or anti-desmoglein 1 and 3 antibodies (via ELISA) should be determined at baseline (after the diagnosis is confirmed by biopsy) and at approximately 6-month intervals while on treatment as a marker of disease activity and likelihood of future relapse.

Treatment is aimed at achieving a rapid and sustained remission with the eventual goal of maintenance with low-dose therapy, or ideally tapering off all treatment. Initial remission is typically achieved through the use of high-dose corticosteroids. This should be accompanied by early initiation of a steroid-sparing agent, given the need for long-term treatment in most cases of PV and the desire to avoid the undesirable side effects of prolonged high-dose corticosteroids (including but not limited to hypertension, diabetes, osteoporosis, and cataracts).

The recent availability of rituximab for PV has changed the face of treatment for PV by allowing the potential for early and sustained remissions off treatment with a relatively favorable side effect profile. Rituximab is a chimeric monoclonal antibody against the B-cell surface marker CD20 that targets B cells for destruction (plasma cells are spared). This drug was initially approved for use in non-Hodgkin’s lymphoma and then in rheumatoid arthritis and is now being employed experimentally for a variety of autoimmune conditions. The most common reported side effects have included infusion reactions and bacterial infections, with several reports of fatal sepsis reported. Other rare side effects include progressive multifocal leukoencephalopathy.

Due to cost and side effect concerns, rituximab therapy is typically reserved as a second-line treatment for refractory PV, however, increasing numbers of patients with either contraindications to other treatments or access to the medication are now undergoing first-line treatment for PV with rituximab, usually in combination with systemic corticosteroids, with promising results.

First steps

  1. Treat with prednisone 60-80 mg/day (1.0-1.5 mg/kg/day is typical).
  2. Mycophenolate mofetil 2.0 g daily along with the prednisone.

Ancillary steps

  1. In the case of persistent oral lesions, treat for candidiasis with oral fluconazole 150 mg once weekly.
  2. Evaluate for herpetic gingivostomatitis, which may be a complicating factor, and treat if positive.
  3. Dental trays filled with superpotent topical steroids and worn for 4-8 hours daily may be effective for refractory gingival disease.

Subsequent steps

  1. In patients responding to the above treatment, gradually taper the systemic steroids and immunosuppressives over many months.
  2. The titer of the circulating autoantibody (via IIF or ELISA, as described above) may be useful in determining response to treatment and the rate at which immunosuppressive therapy can be tapered. It should be monitored about every 6 months and should decrease with each measurement.
  3. In refractory pemphigus vulgaris, consider the following options:
  • Increasing the dose of mycophenolate mofetil to 3 g/day.
  • Monthly pulse steroids of 1 g of methylprednisolone daily for one to several days intravenously; or dexamethasone 100 mg oral daily for 3-5 days.
  • Rituximab IV[1]—either using the rheumatoid arthritis protocol (1 g IV on days 1 and 14) or the lymphoma protocol 375 mg/m2) weekly for 4 weeks—studies have shown roughly equal efficacy in terms of initial and sustained remissions with both protocols.
  • High-dose intravenous immunoglobulin 2 g/kg/month given over several days.
  • Daily cyclophosphamide 1-3 mg/kg/day; or cyclophosphamide 50 mg per day in combination with monthly pulses of 0.5-1 mg/m2.
  • Cyclophosphamide treatment (1-3 mg/kg/day) is combined with systemic steroid therapy and often pulse systemic steroid treatment in refractory cases.

Pitfalls

  1. Before beginning immunosuppressive therapy, examine patients for contraindications to such therapy, including the presence of a positive tuberculin test (PPD or Quantiferon®-Gold), as well as hepatitis B and C serologies. Prior to beginning immune suppressive therapy, consider the following vaccinations: hepatitis B, herpes zoster, and strep pneumoniae (pneumococcus). Annual flu vaccines are also recommended.
  2. In the presence of a history of tuberculosis, treat concomitantly with oral isoniazid 300 mg/day throughout steroid or immunosuppressive therapy.
  3. Closely follow patients for clinical complications of immunosuppression and high-dose steroid therapy. Patients on long term steroids need appropriate osteoporosis prophylaxis with calcium/vitamin D supplementation, as well as bisphosphonates in some cases.

Paraneoplastic Pemphigus

Paraneoplastic pemphigus is very refractory to treatment, with high mortality rates that may be in excess of 90%. Treatment of the underlying neoplasm is the cornerstone of therapy, though is not always beneficial. This includes removal of any underlying carcinoma or thymoma, chemotherapy for underlying lymphoma, and rituximab or alemtuzumab for persistent chronic lymphoma.

Treatment algorithms are similar to the treatment of pemphigus vulgaris, with the following exceptions:

  1. Cyclosporine A 7 mg/kg/day may be used if mycophenolate mofetil is ineffective as a steroid-sparing agent.
  2. Tacrolimus ointment 0.1% may be used for persistent oral disease.
  3. Pulse systemic steroids with cyclophosphamide may be used in refractory cases.
  4. Rituximab has also been used successfully to treat paraneoplastic pemphigus.

[1] Increasingly, rituximab is being considered as a first- or second-line treatment for early disease, given promising evidence of durable remissions and ability to maintain remission off medication.

Clinical Case

  • A 59-year-old man with no prior medical history presented reporting a 6-week history of non-healing painful sores in the mouth. There was no improvement despite empiric courses of azithromycin and acyclovir

Initial evaluation

  • On exam, the patient had erythematous irregular erosions on the soft palate and gingiva
  • The initial workup for herpetic stomatitis (viral DFA or culture or empiric acyclovir) was negative
  • As non-healing oral ulcerations lasting longer than a month should generally be evaluated, a biopsy for both H&E and DIF was carried out
  • The patient’s medications were carefully reviewed to evaluate for any agents as causes of drug-induced pemphigus (including, but not limited to, thiol-containing drugs, penicillamine, enalapril, and captopril) so that any suspected culprits could be discontinued if possible

Follow-up evaluation

  • A positive H&E and DIF for pemphigus vulgaris were obtained and the baseline titers of the circulating anti-epithelial cell surface IgG (via IIF) or anti-desmoglein 1 and 3 antibodies (via ELISA) were determined; all were elevated.
  • Hepatitis serologies and Quantiferon Gold were checked and negative
  • Patient received vaccinations for zoster and influenza
  • Treatment was initiated with 60 mg prednisone daily and 2 g mycophenolate mofetil daily

Two-month follow-up evaluation

  • After 2 months, patient was in clinical remission and able to gradually taper prednisone down to a dose of 5 mg per day. If remission is sustained, mycophenolate mofetil will be weaned at 6 months or later
  • The titers of the circulating anti-epithelial cell surface IgG (via IIF) or anti-desmoglein 1 and 3 antibodies (via ELISA) will be rechecked at approximately 6-month intervals while on treatment, as a marker of disease activity and likelihood of future relapse

References

Ahmed AR, Shetty S. (2015). A comprehensive analysis of treatment outcomes in patients with pemphigus vulgaris treated with rituximab. Autoimmun Rev, 14(4): 323–31. doi: 10.1016/j.autrev.2014.12.002

Currimbhoy S, Zhu V, Dominguez AR, Pandya AG. (2015) Rituximab in the treatment of 38 patients with pemphigus with long-term follow-up. J Eur Acad Dermatol Venereol, March 19, 2015 [epub ahead of print]. doi: 10.1111/jdv.13103.

Gregoriou S, Efthymiou O, Stefanaki C, Rigopoulos D. (2015) Management of pemphigus vulgaris: challenges and solutions. Clin Cosmet Investig Dermatol, 8: 521-527. doi: 10.2147/CCID.S75908

Leger S, Picard D, Ingen-Housz-Oro S, et al. (2012) Prognostic factors of paraneoplastic pemphigus. Arch Dermatol, 148(10): 1165-1172. doi: 10.1001/archdermatol.2012.1830

Olszewska M, Kolacinska-Strasz Z, Sulej J, et al. (2007) Efficacy and safety of cyclophosphamide, azathioprine, and cyclosporine (ciclosporin) as adjuvant drugs in pemphigus vulgaris. Am J Clin Dermatol, 8(2): 85-92.

Sinistro A, Calabresi V, Lupi F, et al. (2015) The pathogenic activity of anti-desmoglein autoantibodies parallels disease severity in rituximab-treated patients with pemphigus vulgaris. Eur J Dermatol, November 6, 2015. [epub ahead of print] doi: 10.1684/ejd.2015.2652

Wang HH, Liu CW, Li YC, Huang YC. (2015) Efficacy of rituximab for pemphigus: a systematic review and meta-analysis of different regimens. Acta Derm Venereol, 95(8): 928–932. doi: 10.2340/00015555-2116

Zhu X, Zhang B. (2007) Paraneoplastic pemphigus. J Dermatol, 34(8): 503-511. doi: 10.1111/j.1346-8138.2007.00322.x