Pemphigus in the Southeastern United States.

ABSTRACT

Background. Our purpose was to review the course and management of pemphigus treated at a tertiary care center in the southeastern United States.

Methods. We describe 30 patients seen at the Emory Clinic from January 1992 to July 1999.

Results. Equal numbers of men and women from different ethnic backgrounds were affected. Pemphigus vulgaris was more common than pemphigus foliaceous. Pain, sore throat, and pruritus were the most common presenting symptoms. The mean diagnostic delay was 6 months in patients with pemphigus foliaceous and 4.5 months in patients with pemphigus vulgaris. Hospitalization was required in 47% of patients. Adjuvant therapy in addition to systemic orticosteroids was required in 93%. Herpes gingivostomatitis occurred in 33%. Clinical or total remission was obtained in 33%.

Conclusions. Pemphigus occurs in multiple ethnic groups in the southeastern United States. Appropriate treatment is frequently delayed by lack of prompt diagnosis. The complications of pemphigus and its therapy were significant.

PEMPHIGUS includes a group of autoimmune diseases characterized by blisters and erosions of the skin and mucous membranes. [1,2] Pemphigus is one of the best-characterized autoimmune diseases in man. [3] Clinical findings are a consequence of pathogenic autoantibodies that recognize adhesion proteins limited to skin and mucous membrane. Autoantibodies found in patients with pemphigus foliaceous are directed against desmoglein (Dsg) 1. Autoantibodies found in patients with pemphigus vulgaris bind Dsgl or both Dsg3 and Dsgl. Binding of the antibodies to adhesion proteins in epidermis and/or mucosal surfaces results in flaccid blisters and erosions.

We reviewed our experience of 30 patients assessed and treated for either pemphigus vulgaris (PV) or pemphigus foliaceous (PF) in the Dermatology Section of Emory Clinic over a 7-year period. We found the evaluation and treatment of this set of patients to be characterized by significant diagnostic delay and morbidity.

MATERIALS AND METHODS

After approval of the research protocol by the Institutional Review Board of Emory University, the Emory Clinic patient database was queried for the ICD-9 code 694.4, corresponding to the diagnosis of pemphigus. Patients seen in the Dermatology Section of the Emory Clinic during the period January 1992 to July 1999 and diagnosed with pemphigus were identified. Charts were reviewed, and pertinent information was entered into a relational database. Histopathology, direct immunofluorescence (DIF), indirect immunofluorescence (IIF), or a combination of the three confirmed the diagnosis of PV or PF. We reviewed patient charts with respect to sex, race, age at diagnosis, diagnostic delay, diagnostic methods (histology and direct and indirect immunofluorescent assay), remission, hospitalizations, distribution of skin lesions during onset and course of disease, symptoms during onset and course, objective findings, complications of the disease and/or therapy, and the amount, duration, and maximum dose of each therapy .

RESULTS

Clinical Variants

Adequate information for review was found on 30 patients with PV and PF seen in the Dermatology Clinic at Emory University between January 1992 and July 1999. There were 21 cases of PV (70%) and 9 cases of PF (30%). One case of pemphigus vegetans was diagnosed and was included in the PV group. Four cases of paraneoplastic pemphigus were not included in this study. No patients were identified with a diagnosis or pemphigus herpetiformis, IgA pemphigus, or drug-induced pemphigus.

Patient Demographics

Most of the patients came from Georgia (n = 28). The remaining 2 were from Florida and Alabama. There were 15 women (50%) and 15 men (50%). Pemphigus vulgaris was diagnosed in 12 women and 9 men, and pemphigus foliaceous in 3 women and 6 men. Thirteen patients were white, 2 were Hispanic, 6 were Jewish, 1 was of Palestinian descent, and 1 was of Indian descent; the other 7 were black. The mean age at onset of the disease was 54 years among men (range, 41 to 73 years) and 46 years among women (range, 28 to 70) for all pemphigus. In the PV group, the mean age at onset was 50 (range, 30 to 72). The mean age at onset for PF was 52 (range, 28 to 73).

Disease Presentation

Of the 21 patients with PV, 20 (95%) had skin or oral pain, and 11 (52%) had a sore throat at the onset of disease. By contrast, patients with PF primarily had pruritus (8/9; 89%) or skin pain (4/9; 44%). Of the 21 patients with PV, 18 (86%) had oral mucosa lesions at onset of disease. Eight patients (38%) initially had only mucous membrane lesions, and 10 (48%) had both mucous membrane and skin lesions. Three patients with PV (14%) initially had only skin lesions; however, during the course of disease, 19 (90%) had skin involvement. The most common extra-oral sites of lesions in patients with PV during the disease course were chest, back, and scalp. In 2 patients with PV, only the mucous membranes (oral and genital) were involved throughout the course of disease, without skin involvement.

All patients with PF had skin lesions at onset and during the disease course, and none had mucous membrane involvement at any point. The distribution of lesions both at onset and throughout the disease course in patients with PF was variable but centered around the head, neck, and upper trunk. The most common sites were the back, face, scalp, and chest.

Diagnostic Methods

The diagnosis of pemphigus was confirmed by one or all of the following studies: histopathology, IIF, and DIF (Table 1). The results of the original studies done in 1 of the patients was not available because the pemphigus was diagnosed well before the patient came to our institution; therefore, 29 of 30 patients are used to study this parameter. In 29 patients (100%), IIF was done; in 28 (97%), results were diagnostic. Twenty-four patients (71%) had a biopsy done for conventional histopathologic examination; in 23 (95%), the results were consistent with pemphigus. Of those patients, 21 had skin biopsies done, and 3 had mucosal biopsies. In 15 patients (54%), DIF studies were done, either of perilesional skin (12) or noninvolved oral mucosa; these were diagnostic in 13 (87%). The majority of patients had more than one study done. Histopathology, IIF, and DIF were done in 15 patients (50%); histopathology and IIF were done in 9 (31%); and IIF and DIF were done in 3 (10%). No patient had histopathology and DIF . Two cases (7%) were diagnosed on clinical pattern and IIF alone.

Diagnostic Delay

Diagnostic delay is the time between the first sign of disease and confirmation by a method such as histopathology, DIF, or IIF. The mean delay between onset and final diagnosis with histology, DIF, and/or IIF was 6 months (range, 2 weeks to 30 months) for all pemphigus. The mean delay was 4 1/2 months (range, 2 to 12 months) for diagnosing PV and 10 months (range, 2 to 30 months) for diagnosing PF.

Therapy

Each of the 30 patients received at least 1 medication. The average number of agents required was 3 (range, 1 to 8). All patients were treated with systemic corticosteroids at some point during the course of the disease. In 28 patients, adjuvant agents were used in addition to corticosteroids, including azathioprine, cyclophosphamide, dapsone, minocycline, plasmapheresis, mycophenolate mofetil, mercaptopurine, and methotrexate. The total amount of each drug, maximum dose, duration of therapy, and total therapy per month was calculated for each patient (Table 2). Fourteen (47%) of the patients have been hospitalized because of complications of pemphigus or for therapy (ie, plasmapheresis, pulse cyclophosphamide, or LV acyclovir). Ten patients with PV (48%) required hospitalization (mean, 2 admissions; range, 1 to 7 admissions). Four patients with PF (44%) required a single hospitalization.

Four patients (13%) (2 with PV and 2 with PF) reached complete remission, taking no medications. Six additional patients (20%) (5 with PV and 1 with PF) had no identifiable clinical activity with low-dose prednisone therapy ([less than]10 mg/day). Of the 10 patients who showed clinical or total remission, 10 (100%) had been treated with prednisone, 7 (70%) with cyclophosphamide, 3 (30%) with azathioprine, 3 (30%) with dapsone, 2 (20%) with minocycline, and 1 (10%) had plasmapheresis. Six patients (60%) were given at least 3 different agents before reaching remission.

Complications

The list of complications from pemphigus and from its therapy is extensive (Table 3). Weight gain, anemia, and oral candidiasis were the most common complications of pemphigus and its treatment. The average weight gain of patients after the initiation of steroid therapy was 44 lb (range, 10 to 110 lb). Among 9 patients (30%) who had hypertension as a complication of therapy, 4 (44%) required antihypertensive medications to control blood pressure. Among the 7 (23%) who had diabetes mellitus as a complication of therapy, 3 (43%) required medications to control their blood glucose level. Gingivostomatitis due to herpes simplex virus (HSV) developed during the course of the disease in 7 patients with PV (33%). In each case, patients with HSV presented with acute worsening of stomatitis unresponsive to increased doses of corticosteroid. The HSV infection was confirmed by cultures in 5 of the 7 patients. In the remaining 2, each had a previous history of a positive HSV culture elsewhere and a prompt response to an tiviral therapy. In one patient, positive HSV cultures were obtained despite low-dose antiherpes suppressive therapy (valacyclovir, 500 mg daily). Two patients had total hip replacement for avascular necrosis of the femoral head. One patient had a right-sided cerebrovascular accident (believed to be due to hypovolemic shock) before her transfer to our clinic after plasmapheresis.

DISCUSSION

Pemphigus is an uncommon disease with a worldwide distribution. [4-11] Limited epidemiologic studies have been done in the United States. Worldwide incidence has been estimated to be between 0.5 to 4.0 per 100,000. Our study is the first to characterize the patient populations affected in the southeastern United States. The racial and ethnic makeup of our pemphigus population is representative of the population of Georgia. Previous studies in the northeastern United States have not included patients of African American descent. [12,13] Almost a quarter of the patients in our follow-up study were of African American descent. Within the white population, Jews and individuals of Mediterranean descent were overrepresented, consistent with previous reports.

A major concern from our findings was the diagnostic delay associated with pemphigus. The average delay in diagnosis of pemphigus in general was 6 months, with the delay in specific individuals ranging up to 30 months. Although we were unable to collect exact figures, a number of our patients required evaluation by three or more clinicians before the condition was accurately diagnosed. A greater awareness of pemphigus and its manifestations clearly would benefit patients affected with the disease. In addition, immunofluorescence studies are ideally suited to making a specific diagnosis of pemphigus. Conventional histology, particularly of chronically ulcerated lesions of the skin and mucosa, may yield findings that are nonspecific or, at best, supportive but not diagnostic of pemphigus. In our hands, IIF microscopy provided a diagnosis in more than 95% of our patient population and required only a serum sample.

Pemphigus is associated with significant morbidity and potential mortality. Before the development of systemic corticosteroids, the mortality from pemphigus approached 100%. [14,15] With the introduction of corticosteroid therapy, the mortality rates decreased markedly. However, the complications of pemphigus and its therapy are still extensive, and because of the life-threatening potential of these complications, we emphasize the tapering of aggressive treatment as soon as possible. High-dose oral prednisone was consistently associated with significant weight gain, hypertension, and glucose intolerance. Avascular necrosis of the hip requiring total hip replacement occurred in two patients. They were both 42 years old and had no predisposing factors other than prednisone therapy. The first patient had taken a total of 19,800 mg of prednisone over a 29-month period, and the second patient had taken 1,100 mg over 7 months before avascular necrosis developed.

The use of corticosteroid-sparing cytotoxic agents such as azathioprine or cyclophosphamide is not supported by controlled trials. [16] Retrospective analysis of previous series is complicated by the bias to treat patients with more severe disease or coexisting conditions that make treatment with corticosteroids difficult. Despite this controversy, we believe early treatment with steroid-sparing agents is frequentiy justified because of the consistent morbidity associated with the prolonged high doses of corticosteroids that are required to control severe disease if used alone.

Secondary infection is a common complication of immunosupressive therapy in patients with pemphigus. The development of oral candidiasis in patients receiving long-term corticosteroid therapy is well recognized and was the most common infection observed in our patient population. However, the development of herpetic gingivostomatitis was almost as common a complication in our patient population. In 5 patients, viral cultures confirmed HSV infection, and in 2 the clinical appearance and response to antiviral therapy strongly suggested HSV stomatitis. The clinical presentation was generally abrupt worsening of stomatitis associated with severe pain that failed to respond to increased doses of corticosteroids. All these patients were successfully treated with oral famciclovir or valacyclovir, but some required doses generally necessary for varicella-zoster virus infection. Although in some case reports, HSV has been noted to complicate pemphigus, [17-22] the frequency of the complication appears to be more comm on than suggested by these sporadic reports. It is important to have high clinical suspicion in patients who are taking systemic corticosteroids and immunosuppressive drugs and who have lesions that do not clear with the standard therapy for pemphigus.

In summary, pemphigus affects patients from a variety of ethnic backgrounds living in the southeastern United States. Prompt and aggressive therapy is associated with good outcome, though the treatment is associated with significant morbidity. A greater awareness of this disorder by the general medical community will benefit this patient population by decreasing the significant diagnostic delay. Practitioners should consider the diagnosis of pemphigus in patients who have persistent stomatitis and/or a generalized erosive or crusted skin eruption and should refer such patients for evaluation by a dermatologist or an oral surgeon.

References

(1.) Nousari HG, Anhalt GJ: Pemphigus and bullous pemphigoid. Lancet 1999; 354:667-672

(2.) Ahmed AR: Clinical features of pemphigus. Clin Dermatol 1983; 1:13-21

(3.) Amagai M: Autoimmunity against desmosomal cadherins in pemphigus. J Dermatol Sci 1999; 20:92-102

(4.) Alsaleh QA, Nanda A, A1-Baghli NM, et al: Pemphigus in Kuwait. Int J Dermatol 1999; 38:351-356

(5.) Bastuji-Garin 5, Souissi R, Blum L, et al: Comparative epidemiology of pemphigus in Tunisia and France: unusual incidence of pemphigus foliaceous in young Tunisian women. J Invest Dermatol 1995; 104:302-305

(6.) Hafeez ZH: Pemphigus in Pakistan, a study of 108 cases [corrected] [published erratum appears in JPMA J Pak Med Assoc 1998; 48:60]. JPMA J Pak Med Assoc 1998; 48:9-10

(7.) Hietanen J, Salo OP: Pemphigus: an epidemiological study of patients treated in Finnish hospitals between 1969 and 1978. Acta Derm Venereal 1982; 62:491496

(8.) Krain LS: Pemphigus. epidemiologic and survival characteristics of 59 patients, 1955-1973. Arch Dermatol 1974; 110:862-865

(9.) Kyriaki KP, Tosca AD: Epidemiologic observations on the natural course of pemphigus vulgaris. Int J Dermatol 1998; 37:215-219

(10.) Mascarenhas MF, Hede RV, Shukla P, et al: Pemphigus in Goa. J Indian Med Assoc 1994; 92:342-343

(11.) Micali G, Musumeci ML, Nasca MR: Epidemiologic analysis and clinical course of 84 consecutive cases of pemphigus in eastern Sicily. Int J Dermatol 1998; 37:197-200

(12.) Ryan JG: Pemphigus. a 20-year survey of experience with 70 cases. Arch Dermatol 1971; 104:14-20

(13.) Lever WF, Schaumburg-Lever G: Immunosuppressants and prednisone in pemphigus vulgaris: therapeutic results obtained in 63 patients between 1961 and 1975. Arch Dermatol 1977; 113:1236-1241

(14.) Lever WF, Schaumburg-Lever G: Treatment of pemphigus vulgaris. results obtained in 84 patients between 1961 and 1982. Arch Dermatol 1984; 120:44-47

(15.) Lever WF: Pemphigus and pemphigoid. a review of the advances made since 1964. J Am Acad Dermatol 1979; 1:2-31

(16.) Bystryn JC, Steinman NM: The adjuvant therapy of pemphigus. an update. Arch Dermatol 1996; 132:203-212

(17.) Zouhair K, el Ouazzani T, Azzouzi S, et al: Herpetic super-infection of pemphigus: 6 cases. [in French]. Ann Dermatol Venerol 1999; 126:699-702

(18.) Takahashi I, Kobayashi TK, Suzuki H, et al: Coexistence of pemphigus vulgaris and herpes simplex virus infection in oral mucosa diagnosed by cytology, immunohistochemistry, and polymerase chain reaction. Diagn Cytapathal 1998; 19:446-450

(19.) Palleschi GM, Falcos D, Giacomelli A, et al: Kaposi's varicelliform eruption in pemphigus foliaceous. Int J Dermatal 1996; 35:809-810

(20.) Asvesti C, Papadogeorgakis H: Pemphigus erythematosus and herpetic infection due to HSV type II (Letter). Clin Exp Dermatol 1991; 16:311

(21.) Ladurelle AS, Escallier F, Meyer P, et al: Pemphigus vulgaris superinfected by herpes simplex virus II in the absence of corticosteroid therapy (Letter). [in French]. Presse Med 1991; 20:312

(22.) Grunwald MH, Katz I, Friedman-Birnbaum R: Association of pemphigus vulgaris and herpes simplex virus infection. Int J Dermatol 1986; 25:392-393

TABLE 1.
Results of Studies Used to Diagnose Pemphigus
                       Pemphigus Vulgaris  Pemphigus Foliaceus
                           (21 cases)           (7 cases)
IIF (No.)
  Diagnostic                   19                   9
  Nondiagnostic                 1                   0
   Total                       20                   9
Histopathologic (No.)
  Diagnostic                   17                   4
  Nondiagnostic                 1                   0
   Total                       18                   4
DIR (No.)
  Diagnostic                   11                   5
  Nondiagnostic                 2                   0
  Total                        13                   5
IIF = Indirect immunofluorescence,
DIR = direct immunofluorescence.
TABLE 2.
Summary of Most CommonMedications Used to Treat Pemphigus
                              Mean     Mean Total    Mean
                    No.      Maximum   Dose/Month  Duration
Medication        Patients  Dose (mg)     (mg)     (months)
Prednisone           30         70       1,100        26
Azathioprine         15        120       3,000         7
Cyclophosphamide     13        150       3,100        23
Dapsone              12        130       3,400        11
Minocycline           6        160       3,700         6
TABLE 3.
Complications of Pemphigus and Therapy in 30 Patients
                              No.
Complications               Patients
Cushingoid features            16
Weight gain                    15
Oral candidiasis               10
Anemia                         10
Fatigue                        10
Hypertension                    9
Insomnia                        8
Leukopenia                      8
Herpetic gingivostomatitis      7
Joint pain                      7
Diabetes mellitus               7
Muscle pain                     6
Lower extremity edema           5
Gastrointestinal bleeding       5
Shortness of breath             4
Depression                      4
Headache                        3
Osteopenia                      3
Tremor                          3
Avascular necrosis of hip       2
Anxiety                         2
Hepatits                        1
Alopecia                        1
Pneumonia                       1

KEY POINTS

* Pemphigus occurs equally in men and women, and it affects multiple ethnic groups.

* Diagnosis was delayed an average of 4.5 months to 6 months, depending on the variant. Diagnostic delay results in a delay in adminstration of appropriate treatment.

* Hospitalization was necessary in 47% of our patients.

* Thirty-three percent of our patients had a clinical or total remission.