Treatment of pemphigus

C Balachandran

 Department of Skin & STD, Kasturba Medical College, Manipal - 576 119, Karnataka, India

Correspondence Address:
C Balachandran
Department of Skin & STD, Kasturba Medical College, Manipal - 576 119, Karnataka
India

Introduction

Systemic corticosteroids remain the mainstay of therapy for pemphigus. Their use has transformed what was almost invariably a fatal illness into one whose mortality is now below 10%.[1] Before glucocorticosteroids became available in the 1950′s the mortality rate from pemphigus ranged from 60 to 90 %.[2] Treatment regimens are dictated by the age of the patient, the degree of involvement, the rate of disease progression and the subtype of pemphigus. Most patients who die of pemphigus at present die of complications of therapy. This can be prevented to an extend by the use of various adjuvant therapies mostly immunosuppressives which can reduce the need for steroids.[1]

Lever and Schaumburg Lever[3] initially recommended high fixed dose of prednisolone (200-400 mg/day) for 6 to 8 weeks followed by a rapid decrease to a maintenance level of 15mg/ day. They subsequently modified this regimen to a two-tired approach.[4] Patients with mild disease are treated with 40mg of prednisolone every other day together with a daily immunosuppressive agent, usually azathioprine for atleast one year. Patients with extensive disease are treated as formerly with 200 to 400 mg/day of prednisolone for 5 to 10 weeks. The dose is then reduced to 40mg/day for the first week, 30mg/ day for the second week and 25mg/day for the third week and subsequently switched to a combined treatment schedule, for a milder form of the disease. Bystrin[1] recommends a smaller dose of 20mg/day for 2 weeks for milder disease. Patients who do not respond or who initially have extensive and progressive disease are treated with 80 to 90 mg/day of prednisolone. This dose has to be escalated every 4 to 7 days in 50% increments if there is no improvement. Once the disease activity is controlled as evidenced by the absence of new lesion, the dose is maintained until 80 - 90% lesions are cleared, at which point the dose is gradually tapered by 50% every 2 weeks. Bystrin[1] recommends adjuvant therapies only if there are relative contraindications to the use of corticosteroids or if the corticosteroid dose cannot be reduced because of repeated flares in disease activity.

Adjuvant therapy for pemphigus

The rationale to use drugs other than corticosteroids to treat pemphigus is that they may reduce the need for corticosteroids and hence their side effects and may result in better control of the disease. This includes immunosuppressive drugs like cyclophosphamide, azathioprine, cyclosporine, methotrexate and recently mycophenolate mofetil. Anti-inflammatory agents include gold, dapsone, chloroquine, combination of nicotinamide and tetracycline.

Immunosuppressives are usually started after prednisolone has been tapered to 40mg daily. If prednisolone can be discontinued these agents should be tapered over several months as tolerated until a negative direct immunofluorescent study has been obtained.[2] They are generally ineffective when given alone and their effect takes 4-8 weeks to manifest. Cyclophosphamide appears to be more effective than azathioprine, but toxicity is more which includes bone marrow suppression, haemorrahagic cystitis, bladder fibrosis, sterility and increased risk of malignancy.

Major toxicities of azathioprine include bone marrow suppression, hepato toxicity and a possible increased risk of malignancy.[6] The usual dose is 2-3 mg/kg body weight. During therapy total white cell count and platelet count should be done weekly for first 8 weeks, then biweekly for 8 weeks and once monthly thereafter. Urinalysis also has to be performed in the same manner and cyclophosphamide is to be stopped if RBC appears in urine. Pulse cyclophosphamide 500mg intravenously is also being tried alone′ or with a concomitant pulse of intravenous corticosteroids.[8]

Dexamethasone-Cyclophosphamide pulse therapyMega dose corticosteroids with cyclophosphamide have been used recently for pemphigus unresponsive to high doses of oral corticosteroids. Pasricha et alb have used 100mg of dexamethasone in 500ml of 5% dextrose intravenously with 500mg of cyclophosphamide over 3-4 hours on day 1, followed by dexamethasone alone on the next 2 days. Such pulses are repeated every 4 weeks. On the remaining days 50mg of cyclophosphamide is administered orally daily. The treatment is divided into four phases. The first phase lasts till remission is achieved (generally 6 months to 1 year). In the second phase the same treatment is continued for 6 more months. In phase 3 only 50mg of cyclophosphamide orally is continued for a year. In phase 4 if there is no relapse all treatment is stopped and the patient is followed up for as long as possible. The major side effect of this regime is secondary infection leading to septicemia, particularly in the first phase. The chief advantage of DCP is almost all patients could be induced into remission and side effects of steroid therapy like cushingoid changes, weight gain, cataract, osteoporosis, electrolyte imbalance are not usually seen.[8]

Methyl prednisolone 1 g/day intravenously for 5 days has also been tried.[9] Serious complications particularly in patients who are chronically ill can occur. These include seizures, hypertension, severe electrolyte imbalance, myocardial infarction and sudden death caused by cardiac arrhythmia and pancreatitis.[10] Whether corticosteroid pulse therapy can result in an overall reduction in side effects or mortality or incret the incidence of remissions is unknown.

Intralesional corticosteroids, triamcino acetonide 10-20 mg/ml has also been usec localised mucosal lesions.′ Topical cyclospa may be helpful in resistant mucosal lesions.′

Cyclosporine was first used to treat pemphigus by Thivolet et al.[12] Cyclosporine 6 kg per day with prednisolone 1 mg/kg body weight has been found to be more effective t prednisolone 120mg/day alone.[13] Side effects include nephrotoxicity, hypertension, abnor liver enzyme values, neurologic complications paresthesia, seizures hypertrichosis hypertrophic gingivitis.[14]

Mycophenolate mofetil has recently k used 2 g daily with prednisolone 2 mg/kg daily with good success.[15] There is no significant or hepatic toxicity observed with this drug.

Other corticosteroid sparing c inflammatory adjuvant therapy includes gc During the past decade an oral formulation o drug auranofin, which is less toxic than parenteral form has been used.[16] Parenteral sodium thiomalate or aurothio glucose 25 week, later increased to 50mg/week has k used alone or with steroids.[17] Side effects inc bone marrow toxicity, renal toxicity and cutanf allergic reactions.[18]

Chaffins et al[21] used nicotinamide (1.5 g/day) and tetracycline (2g/day) to treat 11 patients with pemphigus, with complete resolution of lesions in 5 patients.

High doses of intravenous immunoglobulin (500mg/kg/day) has shown encouraging results in some cases.[22],[23]

Other adjuvant treatment in pemphigus includes immuno modulatory procedures like plasmapheresis and extracorporeal photopher-esis.[24],[25] These procedures are intended to remove circulating autoantibodies. The effectiveness of the procedure has to be repeated and simultaneous administration of steroids and other immuno-suppressives are required to prevent rebound effects.[24] At present plasmapheresis appears to be worth while in-patients with severe pemphigus unresponsive to conventional therapy.

In extracorporeal photopheresis 2; peripheral blood leukocytes are photo inactivated with methoxsalen and UVA in an extracorporeal system.

The possible etiologic role of dietary factors in the dc 1elopment, maintenance and/ of exacerbation of pemphigus has recently beer documented.[26] Among the enormous variety o′ chemical compounds that are present in the diet, thiols, isothiocyanates, phenols and tannins seem to be responsible for pemphigus induction it genetically predisposed subjects. It is advisable for pemphigus patients to reduce the consumption o′ foods and drinks with a high content of the above chemical compounds.[26] [Table - 1].

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