Grant J. Anhalt, MD
Head, Dermatoimmunology Department
Johns Hopkins University
Vice President in charge of Scientific Affairs, The International Pemphigus Foundation
Prior to the introduction of an effective therapy with oral corticosteroids in the 1950s, the disease had a dismal natural course with a 50% mortality rate at 2 years and 100% mortality rate by five years after the onset of the disease.
The mortality rate now is estimated at about five percent and death is almost invariably due to the complications of immunosuppressive therapy. This disease is rare enough so as to render large scale controlled treatment trials impractical.
Therefore, treatment recommendations are based on information gleaned from uncontrolled small series, case reports and the personal experience and biases of the author.
Long-term therapy for pemphigus vulgaris must be directed toward reducing autoantibody synthesis, because as long as significant levels of antiepithelial antibodies are present, the disease will persist. Therefore, topical treatments are of secondary importance, and sustained improvement occurs only with treatment of the hematipoietic system. Those that have resistant disease or are intolerant of corticosteroids should receive a second, steroid-sparing agent. In decreasing order of efficacy, these agents are cyclophosphamide, azathioprine, chlorambucil, methotrexate and gold.
Oral corticosteroids remain the first line of treatment for all cases of PV. Some individuals with PV respond rapidly and completely to treatment with moderate doses of oral corticosteroids, others are rather refractory. About one-half of patients respond to oral corticosteroids alone (prednisone 1.0 mg per kg per day, tapered slowly over 6 to 9 months).
Almost all individual treated with prednisone require every-other-day maintenance indefinitely to control their disease. It had been standard practice to use very large doses of corticosteroids in refractory cases. Typically, an individual would be treated initially with 60 or 80 mg of prednisone per day. It there was not a rapid response to therapy, the dose of corticosteroids would be doubled and often doubled again. Under this regimen, patients would be treated with several hundred milligrams of prednisone per day, often with devastating or fatal complications. With the advent of effective immunosuppressive agents, it is generally not necessary to use such massive doses of costico-steroids.
Cyclophosphamide (Cytoxan), is an extremely effective agent in the treatment of PV, but it is also very toxic. It is very effective in reducing autoantibody synthesis, and has a preferential cytotoxic affect on proliferative plasma cells. It is generally reserved for patients who have the most therapy-resistant forms of PV in a dose of 1 or 2 mg per kg per day of by intermittent intravenous pulse. Major side effects include a predictable leukopenia, toxic effects of urinary metabolites causing hemorrhagic cystitis, and an increased lifetime risk of malignancy. The precise risk of lymphoma, leukemia, or bladder carcinoma secondary to treatment with cyclophophamide has not been established for patients with PV, but in patients treated with similar dosed for Wegener's granulomatosis, the lifetime risk may approach 5% to 10%. In addition, treatment may produce sterility in patients with childbearing potential. Chlorambucil (Leukeran) is a useful alternative to cyclophosphamide if a patient has developed hemorrhagic cystitis due to cyclophoshamide therapy but still requires an alkylating agent to reduce anitbody synthesis. Major potential problems of chlorambucil include its carcinogenic potential, and prolonged and unpredictable neutropenia.
Azathioprine (Imuran) is more widely used for the control of corticosteroid-resistant pemphigus. It is preferentially used under several circumstances: 10 In young individuals, it is more desirable to use a less toxic agent to reduce the lifetime risk of malignancy and potential for sterility. 20 If a patient cannot be monitored closely by complete blood counts and urinalysis or is not compliant. 3) If the patient is intolerant of cyclophosphamide due to profound leukopenia, thrombocytopenia or hemorrahagic cystitis. Azathioprine, however must be used in adequate doses for proper effect. Initial doses of 2 to 3 mg per kg per day are usually required to produce reduction of anitbody synthesis. Again, it should be used in conjunction with a low dose of oral corticosteroids.
Methotrexate was used for the treatment of pemphigus before other agents were available. It is a less effective but generally well-tolerated therapy for patients who cannot use alkylating agents or azathioprine.
Intramuscular gold has also been reported widely to be effective in management of both PV and pemphigus foliaceus. Response to this therapy has not been generally recognized, and the drug is not uniformly beneficial in everyone's experience. The incidence of allergic phenomena, such as nephritis and cutaneous or pulmonary hypersensitivity reactions, is very high and approaches 25%. Therefore gold is being used with much less enthusiasm now than it has been in the past.
The side effects appear to be the same whether one administers gold by mouth or intramuscularly.
Plasmapheresis has been used with mixed results in the therapy of pemphigus. If plasmapheresis alone is used, it can produce a short-term decrease in circulating autoantibody levels with subsequent clinical improvement. However, it must be recognized that the levels with subsequent clinical improvement. However, it must be recognized that the autoantibodies are under feedback inhibition control. If one simply removes the end-product, the B cells that produce the antibody are actually stimulated to produce more and a rebound flare with worsening of the disease will occur several weeks after plasmapheresis has been discontinued. Therefore, it is best to reserve plasmapheresis as an adjunct to therapy and to use it in conjunction with an alkylating agent. After the plasmapheresis has been discontinued, the loss of circulating anitbody from the serum causes a preferential stimulation of the B cells producing the autoantibody. As they proliferate, they are preferentially destroyed by the cyclophosphamide. The patients who are treated with this combination of plasmapheresis and an alkylating agent sometimes go into prolonged disease-free remissions after 1 or 2 years of therapy.
Cyclosporin (Sandimmune) has been used with benefit in some cases of PV, but it is not generally accepted to be particularly effective. The high incidence of pephrotoxicity also limit its usefulness.
Finally, treatment should always be adjusted according to the disease activity that is clinically apparent, without being unduly influenced by autoantibody titers as estimated by indirect immunofluorescence. The anitbody titers generally are high when the disease is active and are low or undetectable when the disease is in remission. If a patient is in apparent clinical remission but has persistent low titers, that should not prevent planned reduction of drug dosages. The indirect immunofluorescent titer is most useful during maintenance if a patient develops a flare of disease activity. In this circumstance, a low or negative anitbody titer would be reassuring that the flare may be self-limited and may not require increased drug dosages. On the contrary, a high titer raises more concern and prompts earlier intervention.
Most cases of pemphigus foliaceus can be controlled by oral corticosteroids alone. A starting dose of 0.5 to 1.0 mg per kg per day, with a slow taper over a period of six months and the use of an alternative-day steroid regimen, is usually effective. Topical or intralesional steroids are somewhat effective in limited cases of pemphigus foliaceus. The list of drugs that are useful as a second or steroid sparing agents is identical to that in PV, with ;the possible addition of anitmalarials such as hydroxychloroquine (Plaquenil), 200 mg twice daily. The necessity of using an immunosuppressive agent, such as cyclophosphamide, azathioprine, or other agents such as gold or methotrexate in management of this disease is less frequent than in PV. Efficacy and toxicities of these therapies have already been outlined