By Jean-Claude Bystryn, M.D.
Professor of Dermatology
Director of Immunofluorescence Laboratory
The Ronald O. Perelman
Department of Dermatology
New York University Medical Center
Pemphigus vulgaris (PV) can enter into remissions in which all manifestations of the disease disappear and all therapy can be discontinued. How often, and when this occurs is unclear. Review of all major studies of PV conducted during the past four decades describes remissions as occurring in less than one-third of patients.1 However, a problem with these studies is that the incidence of remissions is usually provided at only a single time point. Thus, it is unclear how long it takes for remissions to appear, how long they last and what happens when therapy is discontinued. Further complicating interpretations of the results is that the meaning of remission is often unclear. The criteria used by different investigators to define this event differ and/or are not provided. The practical outcome of this incomplete information is uncertainty about the management of pemphigus. It is unclear whether treatment simply suppresses the manifestations of the disease and must be continued permanently, or whether complete and durable remissions can be induced that permit therapy to be safely discontinued.
To answer these questions we examined the induction of remissions in 40 patients with pemphigus vulgaris who were followed for a prolonged period (on the average of 7.7 years) by the same investigator. The results of the study have recently been published in the Journal of the American Academy of Dermatology.2
A strict set of entry criteria was used to include patients in the study, to minimize the effects of patient selection bias on the results. These included: a) diagnosis of PV confirmed by clinical, histologic and immunofluorescence criteria; b) first seen shortly (<3 months) after the diagnosis of pemphigus, to exclude bias from early death; c) seen continuously by the same investigator during the course of their illness; and d) a minimum of two years of follow-up information from onset of disease. All patients were treated conventionally with steroids, with or without adjuvants, using guidelines that have previously been published.3 All patients were followed and evaluated using defined criteria for disease activity and remissions, to ensure a consistent evaluation of clinical outcome. Scores were recorded for the most severe phase of the disease during the first year of treatment, yearly on the anniversary of diagnosis, and at last follow-up. Complete remission was defined as a period greater than one month during which the patient was on no systemic therapy and lesion-free. Partial remission was defined as a period greater than one month during which the patient was lesion-free and on no more than 15 mg./day of prednisone or its equivalent; or on only 100 mg./day or less of cyclophosphamide or azathioprine; or only on gold or dapsone. Duration of remission was classified as short if at least one month but less than 6 months, and as long if 6 months or longer. Time to partial or complete remission was calculated from date of diagnosis to onset of partial or complete remission. The results show that pemphigus improved with time in almost all patients. Improvement was particularly rapid during the first two years of therapy, with the severity score declining 64% from an average of 5.3 during the most severe phase of the illness to 1.9 two years after diagnosis (see Figure 1). Severity continued to decline, albeit more slowly, during the ensuing years. Five years after diagnosis the average severity score was only 1.4, indicating the disease was inactive or treated with <15 mg./day of Prednisone in most patients.
Remissions were found to be much more common than previously reported. This is probably because the incidence of remissions increases with time, and we studied patients for prolonged periods. Remissions that were complete and long-lasting (no evidence of disease and no systemic therapy for at least 6 months) occurred in 25%, 50% and 75% of patients 2, 5 and 10 years after diagnosis. These remissions were durable, lasting on the average over 4 years. Actual duration is probably longer, since most patients in remission were still in remission at last follow-up. The bulk of the remaining patients were in partial remissions or had mild disease controlled on 15 mg./day or less of Prednisone or with only an adjuvant (see Fig 1).3
The course of pemphigus in different patients as evidenced by induction of remissions and flare in disease activity was variable, but followed one of 4 patterns. In pattern 1, the disease responded rapidly to treatment and went into a remission that was complete and long lasting. This occurred in 17% of the patients. There was no flare in disease activity when treatment was stopped. The average time to complete remission was 15 months and the remissions were maintained to last follow-up for an average of over 4 years. In pattern 2, seen in 37% of patients, response to therapy was slower and intermittent but complete and long-lasting remissions were also eventually induced in all patients. Pemphigus in these patients fluctuated between periods of partial or complete remissions of various length, which were punctuated by flares in disease activity as the intensity of therapy was decreased. Relapses were usually less severe than initial disease activity. With continued therapy, all patients eventually had long-lasting, complete remissions that persisted for longer than 6 months following termination of all systemic therapy. The average time to the first complete long-lasting remission was 35 months. In the third pattern, seen in 35% of patients, disease activity also fluctuated but no long-lasting complete remissions were induced during the course of this study. This may be because these patients were on the average followed for a shorter period of time.
However, disease activity in most of these patients eventually became mild and could be controlled by low doses of Prednisone (15mg/day or less), or with only an adjuvant. There was no mortality in patients whose disease followed these three patterns. In pattern 4, seen in 10% of patients, the disease was resistant to therapy and never went into a remission of any type. Mortality in this small group was high, occurring in two of four patients.
Two factors were identified as predictive of the course of pemphigus. One was initial severity and extent of disease. Patients with mild or moderate disease at diagnosis were twice as likely to enter a long-lasting complete remission as those with severe disease. The other was early response to treatment. Patients who responded rapidly to treatment were over twice as likely to enter a long and complete remission as those with a slower response.
These results indicate that the outlook of pemphigus is more favorable than currently believed. The disease can be converted into an inactive state in the majority of patients. Most patients will eventually enter a complete and durable remission that permits systemic therapy to be safely discontinued without an exacerbation in disease severity. The remaining patients will usually have only mild disease controllable with low doses of Prednisone or an adjuvant. The practical implication of these observations is that the ultimate goal of treatment in pemphigus vulgaris is to discontinue all treatment.
1. Bystryn J-C, Steinman NM. The adjuvant therapy of pemphigus – an update. Arch Dermatol 1996; 1 32:203-212.
2. Herbst A, Bystryn JC. Patterns of remission in pemphigus vulgarism. J Am Acad Dermatol 2000; 42:422-7.
3. Bystryn J-C. Therapy of pemphigus. Semin Dermatol 1988;7:186-194.