Diagnosis and Treatment of Pemphigus

Daisuke Tsuruta; Norito Ishii; Takashi Hashimoto

Disclosures

Immunotherapy. 2012;4(7):735-745. 

In This Article

Treatment

As pemphigus is an autoimmune disease, the primary treatment modality has been oral corticosteroids.[9] In addition, several immunosuppressants, including azathioprine, cyclosporine, mizoribine, mycophenolate mofetil and cyclophosphamide, are used.[9] Anti-inflammatory agents, plasmapheresis and intravenous immunoglobulin therapy are applied in severely affected patients.[9] In mild pemphigus cases, particularly pemphigus erythematosus cases, topical corticosteroids are occasionally sufficient. The initial treatment is the most important for the treatment of pemphigus (Box 1).

Oral Corticosteroid

Corticosteroids are steroid hormones produced in the adrenal cortex.[44] Corticosteroids are used as an anti-inflammatory agent because of their suppressive effects on the inflammatory and allergic responses.[45] Currently, most pemphigus patients are treated successfully with systemic corticosteroids.[9,46] Treatment is usually initiated with 0.75–1.25 mg/kg/day prednisolone in combination with immunosuppressants, including azathioprine, mizoribine, mycophenolate mofetil, dapsone, acitretin or cyclophosphamide.[9,46–49] In mild cases of pemphigus, the starting dose can be less than this dose.[9] Approximately 1 week after new blister formation diminished, the daily dosage is tapered rapidly.[9] If the dose of prednisolone becomes less than 25 mg/day, tapering should be more gradual.[9] Patients who do not respond to prednisolone can be treated with betamethasone, the addition of other immunosuppressants, intravenous immunoglobulin, plasmapheresis or steroid pulse therapy.[9,50–53] When newly formed bullae appear, the steroid dose is increased 1.5–2-fold.[9]

Well-known adverse effects of systemic steroids include osteoporosis, gastric ulcer, diabetes mellitus, hyperlipidemia, hypertension and infection.[9] Psychiatric effects including psychosis, mood change or anxiety disorders also occur with steroid use. Among these side effects, severe infection can sometimes cause death with the development of disseminated intravascular coagulation.[54] Therefore, informed consent should be obtained from patients, and counseling should be given for the patient to recognize signs of adverse events. Collecting information on comorbidities and past medical history is also necessary.

Low doses of steroids can be used to minimize adverse effects but, in the USA, European and Asian countries, including Japan, the aforementioned high-dose corticosteroid regimen is commonly used in the treatment of pemphigus. In our practice, the initial treatment for pemphigus is a lower dose of prednisolone (0.3–0.5 mg/day) combined with mizoribine.[55] We have found this combination to be as effective as high-dose prednisolone therapy. In the case of severe disease, intravenous pulsed steroid therapy at a dose of 500–1000 mg of methyl prednisolone is beneficial.[9,56]

Anti-inflammatory Agents

Anti-inflammatory agents used in pemphigus include dapsone (diaminodiphenyl sulfone), gold agents and tetracycline.[9] While the inflammatory cascade is thought to play a significant role in pemphigoid, in pemphigus it has yet to be proven as an etiologic factor. Moreover, the efficacy of anti-inflammatory agents is proven in IgA pemphigus.[9,46]

Immunosuppressants

In patients refractory to steroid therapy or those who cannot tolerate high steroid doses, other immunosuppressants are used. Recently, these alternative immunosuppressants have been applied as initial treatment in combination with steroids in order to decrease the initial dose of steroid. Azathioprine, cyclosporine, mizolibine, mycophenolate mofetil and cyclophosphamide have been used.[9] The adverse effects of each drug are different, but myelosuppression, abnormal data in liver function tests, jaundice, kidney dysfunction, malignancies and infection are common. When the disease improves, steroid dosage should be tapered prior to that of the immunosuppressant.

Mizoribine & Mycophenolate Mofetil Both mycophenolate mofetil and mizoribine are inhibitors of inosine monophosphate dehydrogenase in purine synthesis, required for T- and B-cell growth.[57] Mizoribine is a newly developed immunosuppressive agent with low toxicity. Some case reports show that mizoribine is effective for the treatment of autoimmune bullous diseases. We recently reported that mizoribine is effective for pemphigus vulgaris based on 11 patients treated at our institution.[55] An oral dose of 150 mg once daily is the current regimen for the treatment of pemphigus.[9]

Azathioprine Azathioprine is a purine analog immunosuppressive prodrug, and is metabolized into the active form, 6-mercaptopurine, which inhibits purine synthesis.[58]

This inhibits proliferation of rapidly dividing cells, particularly lymphocytes.[59] Azathioprine combined with oral corticosteroid is studied for the treatment of pemphigus, in which azathioprine was considered to have a steroid-sparing effect.[9] Bone marrow suppression is the major side effect of azathioprine, particularly in patients carrying homozygous mutations of thiopurine methyltransferase.[60] A dose of 50–100 mg daily is the current regimen for the treatment of pemphigus.[9]

Methotrexate Methotrexate inhibits the metabolism of folic acid,[61] and is used as a chemotherapeutic and immunosuppressive agent.[61,62] Methotrexate allosterically inhibits dihydrofolate reductase, which plays a role in tetrahydrofolate synthesis.[61] As folic acid is essential for normal cell growth and replication,[63] methotrexate is effective against malignant cell growth and has anti-inflammatory effects. Methotrexate was also reported to have a steroid-sparing effect.[64] Methotrexate is used for the treatment of pemphigus at a dose of 10–50 mg/week.[9] The major side effect is infection and liver dysfunction.[9]

Cyclophosphamide Cyclophosphamide is also an antitumor and immunosuppressive agent.[65] It is converted in the liver to the active metabolite, phosphoramide mustard.[65] The phosphoramide mustard form of cyclophosphamide irreversibly cross-links DNA, resulting in cell death.[66] The corporative effect of cyclophosphamide combined with systemic steroids was reported by several authors, although its use is complicated by the occurrence of side effects.[67] Therefore, cyclophosphamide is usually applied as a second-line drug if patients are resistant to combination therapy using other immunosuppressants.[9] Daily oral cyclophosphamide or cyclophosphamide pulse therapy is used for the treatment of pemphigus.[9] Major side effects are bone marrow suppression, interstitial pneumonia, infertility, hemorrhagic cystitis and bladder carcinoma.[68,69]

Cyclosporine Cyclosporine binds to the T-cell-specific cytosolic protein, cyclophilin.[70] The cyclosporine–cyclophilin complex inhibits calcineurin, responsible for the transcription of IL-2, leading to reduced function of effector T cells.[71] Cyclosporine is also used for the treatment of pemphigus.[9] A dose of 3–5 mg/kg/day is used as adjuvant therapy for pemphigus combined with systemic steroids.[9] However, some authors report that the effect of cyclosporine in the treatment of pemphigus is limited, compared with azathioprine or mycophenolate mofetil.[72] The major side effects of cyclosporine are hypertension and renal dysfunction.[73]

Plasmapheresis Plasmapheresis is employed to rapidly lower circulating autoantibodies.[74] In addition, plasmapheresis is known to remove components other than immunoglobulins, including thrombotic factors, toxic mediators or inflammatory mediators.[75] Plasmapheresis is often applied in steroid-refractory pemphigus cases. In order to avoid rebound, consecutive plasmapheresis is required. Both simple plasmapheresis and double-filtration plasmapheresis are used.[9] Double-filtration plasmapheresis is usually performed three-times per week and repeated six- to eight-times.[9] Plasmapheresis is a relatively safe treatment with mild adverse effects, including thrombocytopenia, hypocalcemia, urticaria, fever, hypotension, nausea and dizziness.[9] Recently, a new apheresis approach, IgG-specific immunoadsorption, was introduced for the treatment of pemphigus.[76,77] Unlike plasmapheresis, immunoadsorption does not need substitution of freshly frozen plasma or human albumin. Immunoadsorption can be performed either with disposable absorbers or with reusable systems, and immunoglobulins are selectively removed from the blood. Several reports showed that immunoadsorption treatment leads to rapid disease control by significant decrease of autoantibodies in pemphigus.[78–81]

Intravenous Immunoglobulin

Intravenous immunoglobulin is used for antibody deficiency syndrome, acute infections and autoimmune diseases.[82] The mechanism of action of intravenous immunoglobulin therapy for autoimmune diseases is not well established, but it is speculated to be based on interactions with activating Fc receptors on macrophages[83] and direct binding to autoantibodies, suppressing the binding of autoantibodies to the target autoantigen.[83] In addition, idiotype–anti-idiotype interactions may occur and reduce autoantibody activity.[84] Intravenous immunoglobulin at a dose of 400 mg/kg/day for 5 consecutive days is the standard protocol.[9] Intravenous immunoglobulin is the only treatment for pemphigus that does not have any immunosuppressive effects.[9]

Rituximab

Rituximab is a chimeric monoclonal antibody against CD20, primarily expressed on B cells.[9] It is used in the treatment of lymphoma, leukemia, organ transplantation and autoimmune diseases. Rituximab acts by destroying normal and malignant B cells through binding to CD20. The standard dose is 375 mg/m2/week for four cycles.[9] This approach is extremely effective for refractory pemphigus cases. There are many successful clinical trials for rituximab all over the world.[84–90] In addition, successful treatment by the combination of immunoadsorption and rituximab was also reported.[78] However, this treatment carries the risk of life-threatening adverse effects, including sepsis.[85,86] Therefore, strict management is required when applying this treatment. The major side effects of rituximab, other than infection, are nausea, vomiting, facial edema, chills and cough.[9]

Topical Therapy

Topical steroid can be used for the treatment of pemphigus. In mild cases, a single application of potent topical steroid can control the lesion.[91] Regarding oral erosion, steroid mouthwash, paste, ointment or aerosol is used.[92] Topical cyclosporine can also be used for the treatment of oral pemphigus lesions.[93] Furthermore, we began treating intractable oral lesions with oral cyclosporine A syrup [Tsuruta D et al. Effect of topical cyclosporine on six cases of pemphigus vulgaris assessed by pemphigus disease area index (PDAI) (2012), Submitted]. In total, six patients with pemphigus vulgaris were effectively treated with this technique.

Treatment Regimen

We divided the treatment into two phases: initiation and maintenance. The initiation phase lasts 2–4 weeks and ends when steroids can adequately control lesions and inhibit new bulla formation, as assessed by the PDAI. The ELISA index is also useful to assess treatment efficacy. However, worsening clinical appearance occurs prior to changes in the ELISA index.

Informed consent before systemic therapy is required. The treating physician should explain the adverse reactions of each treatment option to the pemphigus patient. Wearing a face mask is required when patients go outside. The increased risk of erosion with solid and rigid food intake and newly formed bullae with mild friction should be explained to patients.

The starting dosages of systemic steroid use are as follows. Prednisolone 30 mg daily, combined with a proton pump inhibitor, bisphosphonate and a strong topical corticosteroid are used for mild cases of pemphigus. By contrast, severe cases are treated with 60-mg daily prednisolone alone or combined with azathioprine or mizoribine, plus proton pump inhibitor, bisphosphonate and strong topical corticosteroid are also used.

If the initial systemic steroids cannot control lesions after approximately 2 weeks, diaminodiphenyl sulfone or mizoribine is added. If this also fails, immunosuppressants, intravenous immunoglobulin, plasmapheresis or steroid pulse therapy should be initiated. Intravenous immunoglobulin or plasmapheresis is used if the patient can be hospitalized. If the patient cannot be hospitalized, various immunosuppressants are selected, including azathioprine, cyclophosphamide, cyclosporine or mycophenolate mofetil. Usually, an immunosuppressant should be used for more than 1 month. Change of the systemic steroid to another type, such as betamethasone, dexamethasone or methylprednisolone, is another option. In the maintenance phase of treatment of pemphigus, symptoms and lesions are controlled with minimal steroids and immunosuppressants. Treatment efficacy is assessed by clinical examination, PDAI and ELISA index for Dsg. Prednisolone is tapered at a rate of 5–10 mg/day until a dose of 0.4 mg/kg/day or 20 mg daily of prednisolone is reached. In patients on a daily prednisolone dose of less than 0.4 mg/kg/day or 20 mg, a 1–3-mg/day decrease weekly is selected. The final target dosage of systemic prednisolone is ≤0.2 mg/kg/day or 10 mg daily. The prednisolone dose should be decreased prior to immunosuppressants. If new bulla formation rapidly increases after prednisolone tapering, the dose is increased by 1.5–2-fold.

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