Differences & Similarities  

By the Department of Dermatology, Johns Hopkins University, School of Medicine.
Baltimore, Maryland
Daniel Mimouni, MD,* Carlos H. Nousari,MD, Deborah L. Cummins, BS, David J. Kouba, MD, PhD, Michael David, MD,** and Grant J. Anhalt, MD *Currently affiliated with the Department of Dermatology, Rabin Medical Center, Petah-Tiqva. **Currently affiliated with Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel

Introduction

The lack of well-designed studies of the treatment of pemphigus has left both physicians and patients with no clear standard of care. This study is the first to assess expert opinions regarding the diagnosis and treatment of PV.

RESULTS

Referral Patterns

All experts reported that they receive pemphigus referrals from general dermatologists. Other referral sources were general and family practitioners and internists, dentists and oral medicine specialists, and direct referrals from the emergency department. Additionally 4 physicians have been contacted by self-referred patients who had researched their symptoms on the Internet. Of those surveyed, 50% receive referrals within 6 months after onset of symptoms, 17% within 1 year, and 8% within 3 years.

Diagnostic Process

Diagnosis is secured by 96% using skin biopsy specimen with direct immunofluorescence, and by indirect immunofluorescence alone for 4%. None of the participating physicians make the diagnosis of PV solely on clinical and histologic evidence.

Treatment

Of the physicians, 75% initially treat with prednisone, used either alone or in conjunction with adjuvant steroid-sparing agents. The remaining 25% initially use nonsteroidal agents, e.g. such as gold, tetracycline, or attempt to eliminate potential triggers such as drugs, concurrent infection, and emotional stress. The physicians who initially used noncorticosteroid drugs did so with no relation to the nature or extent of the disease.

Corticosteroid Treatment

Initial steroid dose ranged from 1mg/kg/d 3mg/kg/d. Long-term dosing approaches varied as follows: 37% of physicians polled stated that their goal is to eliminate corticosteroids completely; 11% had a goal of an alternate daily prednisone dose of 5 mg; 26% were comfortable with a dose of 5 mg/d; and 26% were satisfied with 10 mg/d. All participating physicians stated that their therapeutic approach was influenced by the following parameters: disease extent; rate of disease progression; and clinical response. Immunosuppressants

Azathioprine (Imuran®) was the most frequently used adjuvant immunosuppressant (44% of physicians). Mycophenolate mofetil (CellCept®), cyclophosphamide, and cyclosporine are used by 20%, 16%, and 4% of physicians, respectively. Forty-six percent reported they maintain steroid-sparing immunosuppressants in their patients for 6 months to 1 year, whereas 36% continue the immunosuppressants for 1 to 2 years, and 18% maintain this regimen indefinitely.

Definition of disease control

Of the physicians polled, 53% defined “control” as an absence of new blisters, whereas simply a reduction in the number of blisters was adequate for 32%, and 15% said “control” implied blister-free without any active lesions. Only 5 physicians (21%) use serologic antibody titers routinely to monitor their patients.

Discussion

Despite the high morbidity and potential mortality in PV, we have found distinct differences in the approach to both diagnosis and treatment of PV. As expected, most referrals came from general dermatologists. However, the long delay from onset of symptoms to expert evaluation is quite striking. In PV, similarly to other autoimmune diseases, if the process is not promptly and appropriately controlled, the disease hardens. This generates the opportunity for epitope spreading, making the pemphigus more difficult to treat. While the vast majority of the experts surveyed confirm their clinical diagnosis by tissue biopsy specimen for histopathologic and direct immunofluorescence examination, a wide variety of therapeutic approaches, from initiation to end point, were observed. While the most common therapy was prednisone, 26% add adjuvant immunosuppressants immediately. The most frequently used adjuvant is azathioprine.However, mycophenolate mofetil, which has only recently been introduced, is also frequently prescribed. The vast majority (82%) of experts use adjuvant immunosuppressants for 2 years or less. Eighteen percent use these agents indefinitely. An additional, unresolved issue is the final goal for prednisone maintenance and the possibility of complete cure. There is a lack of standardized criteria for discontinuation of prednisone. This poses a major obstacle in the objective comparison of different studies. This survey also demonstrated that the grading of disease activity in pemphigus is also quite variable. Fifty-three percent of the experts define “disease control” as no newly forming blisters, whereas 15% of the experts defined “control” as blister-free, and nearly one third were satisfied with simply a reduction in the number of blisters.

In summary, there is wide variation in the assessment, diagnostic techniques, and treatment regimens of PV, even among the most experienced authorities in the field. The lag time from symptom onset to referral emphasizes the need for heightened awareness of this potentially fatal disease among primary care physicians, oral specialists, and general dermatologists. Although tremendous strides have been made in the care of patients with pemphigus, there is clearly a need for improved standardization. Large-scale, randomized, controlled trials and consensus standards with regard to patient stratification would facilitate the objective assessment of drug efficacies and help to establish an optimal standard of care for all patients with pemphigus.