Intravenous immunoglobulin therapy for patients with pemphigus foliaceus unresponsive to conventional therapy

Intravenous immunoglobulin therapy for patients with pemphigus foliaceus unresponsive to conventional therapy A. Razzaque Ahmed, MD, and Naveed Sami, MD Boston, Massachusetts Background: Pemphigus foliaceus (PF) is a chronic autoimmune blistering skin disease that is commonly treated with oral corticosteroids and immunosuppressive therapy. In some patients, PF can be refractory to treatment and the resultant side effects of prolonged immune suppression can be potentially fatal. Alternative therapies are needed. Objective: The purpose of this study is to report treatment outcomes with IVIg therapy in 11 patients with severe PF refractory to prednisone and other immunosuppressive therapy. Methods: Selection criteria included documentation of a biopsy and immunopathology in 11 patients who were resistant to treatment or experienced side effects to conventional therapy. IVIg was administered according to a defined protocol. The parameters used to assess clinical response to IVIg included time observed for effective control of disease, duration of IVIg maintenance therapy, total duration of IVIg, number of IVIg cycles, systemic drug therapy, and the frequency of recurrences and relapses. The pre-IVIg and post-IVIg data were statistically analyzed by means of the SAS UNIVARIATE and 2-sided Wilcoxon sign rank and sign tests. Results: All patients had an effective clinical response and remained in clinical remission for a mean period of 18.6 months after discontinuation of IVIg therapy. Serious side effects from IVIg use were not observed. Conclusion: IVIg therapy appears to have potential as a biologic alternative agent in inducing and maintaining clinical remissions in patients with PF who are resistant to more standard conventional treatment. IVIg is effective as monotherapy and may be needed for a period of several months to achieve a long-term clinical remission. (J Am Acad Dermatol 2002;46:42-9.)

P

emphigus foliaceus (PF) is an autoimmune blistering skin disease characterized by in vivo deposits of an autoantibody that binds desmoglein 1 on keratinocyte cell surface and results in the loss of cell adhesion or acantholysis that is characteristic of pemphigus.1 This acantholysis occurs in the upper layers of the stratum malphigii and, therefore, such blisters are subcorneal.1 Most patients with PF are treated with systemic corticosteroids.1-6 Because the disease has a chronic course, patients receiving longterm corticosteroid therapy frequently have serious From the Department of Medicine, New England Baptist Hospital, and the Department of Oral Medicine, Harvard School of Dental Medicine. Accepted for publication April 2, 2001. Reprint requests: A. Razzaque Ahmed, MD, Department of Oral Medicine, Harvard School of Dental Medicine, 188 Longwood Ave, Boston, MA 02115. Copyright © 2002 by the American Academy of Dermatology, Inc. 0190-9622/2002/$35.00 + 0 16/1/116338 doi:10.1067/mjd.2002.116338

42

side effects.6 In such patients, many different drugs, often referred to as “adjuvant therapy,” are used for alleged steroid-sparing effect.1 Some of these adjuvants are azathioprine,7,8 cyclophosphamide,9,10 gold,11-14 methotrexate,15,16 chlorambucil,17 cyclosporine,18 and most recently mycophenolate mofetil,19 dapsone,20-22 antimalarials,23 and different systemic antibiotics.1 Some of these drugs have been used as monotherapy. Several authors describe patients with PF who are resistant to such conventional immunosuppressive agents (ISAs)3,4,24,25 and have been treated with extracorporeal photopheresis,25,26 plasmapheresis,27-31 or pulse intravenous corticosteroids with or without cyclophosphamide.32-34 Even after such approaches, many of these patients do not go into a sustained clinical remission.26,29,34 It is commonly perceived that PF is more benign than pemphigus vulgaris. Although death is uncommon, there are several reports of death occurring in PF.2,4,35-47 The cause of death is linked to myocardial infarction and prolonged drug-induced immune

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suppression such as opportunistic infections35-38 and malignancy.39-41 Therefore, for those patients resistant to conventional therapies, different options are necessary to improve prognosis. In the recent literature, there are 8 patients with severe widespread PF resistant to conventional therapies who were successfully treated with intravenous immunoglobulin (IVIg).48-50 In this report, we describe an additional 11 patients with widespread PF resistant to conventional therapy. A sustained clinical remission was observed when these patients were treated with IVIg.

MATERIAL AND METHODS Patients Between January 1993 and July 2000, 11 patients with severe PF involving 50% or more of the total body surface area were studied. Three patients were male and 8 were female. All patients were Caucasian. The age at onset ranged from 27 to 79 years (mean, 55 years). None of the patients experienced mucosal lesions during the entire course of the disease or follow-up.

Ahmed and Sami 43

These side effects affected the quality of life and daily routine activities of each patient. Indications for IVIg therapy In all 11 patients the following 3 criteria were essential to initiate IVIg therapy: a. Fulfillment of diagnostic criteria (biopsy and immunofluorescence) b. Presence of active disease c. Unsatisfactory response or significant side effects from previous therapies Local treatment of active disease Local care consisted of soaking involved sites with topical antiseptic solutions, and nonhealing lesions were injected sublesionally with triamcinolone acetonide (15-20 mg/mL).

Diagnostic criteria In all 11 patients, histologic and immunopathologic studies were performed at the time of the initial diagnosis. In each patient, a biopsy for routine histology was performed on a new vesicle on the skin. A subcorneal vesicle with acantholysis was observed.1 Direct immunofluorescence studies were done on perilesional skin. In all 11 patients, deposits of IgG in the intercellular spaces or the keratinocyte cell surface of the upper epidermis were observed.1 Indirect immunofluorescence with monkey esophagus used as substrate detected anti-intercellular space antibody titers of 160 or higher in the sera of all 11 patients. Using normal human epidermis as substrate, the sera of these 11 patients bound to a 160-kd protein identified as desmoglein 1.51

Determination of IVIg dose and frequency In preliminary studies, 7 additional patients with PF were treated with IVIg at 500 mg/kg, 1 g/kg, 1.5 g/kg, or 2 g/kg per cycle to determine optimal dose and frequency of infusion and duration of therapy. A cycle consisted of the total dose of IVIg divided into 3 equal doses and given on 3 consecutive days by a slow infusion. Clinical response indicated that the initial dose and frequency, 2 g/kg per cycle at 4-week intervals, was optimal to obtain sustained clinical recovery. No significant response or only a temporary clinical response was observed in patients who received doses lower than 2 g/kg per cycle or at a frequency greater than 4 weeks. In patients treated with only 6 to 12 cycles, the disease relapsed within a few weeks after the last infusion. The clinical remission persisted and relapses did not occur when the infusions were continued past the initial control of disease and subsequently gradually reduced. Information of these 7 additional patients has not been included in this study and is on file with the authors.

Previous therapies The details of previous therapies before beginning IVIg therapy are presented in Table I. Recurrence was defined as the appearance of new lesions that did not require change in systemic therapy. Relapses were defined as the appearance of new lesions that necessitated change in systemic therapy for control of disease. The side effects routinely accompanying the prolonged use of oral prednisone are not listed in Table I. These included moon face, buffalo hump, redistribution of body adipose tissues, waist enlargement, and thinning of legs, among others.6 The side effects recorded in Table I are those that required medical intervention or treatment.

IVIg treatment protocol Infusions were given every 4 weeks until all lesions healed. Thereafter, the interval between the infusion cycles was increased to 6, 8, 10, 12, 14, and 16 weeks. The end point of therapy was when the patient remained disease free for a 16-week interval between the last infusion cycles. Although the interval between cycles was gradually increased, the dose remained constant. Vital signs were monitored every 30 minutes during the infusion. Patients were premedicated with 50 mg of diphenhydramine and 2 tablets of acetaminophen (325 mg) 30 minutes before each infusion. Patients were observed for at least 45 minutes after completing each infusion. A

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Table I. Clinical data, pre-IVIg and post-IVIg treatment, side effects, clinical outcomes, and follow-up in 11 patients with pemphigus foliaceus Pre-IVIg treatment

Patient No.

Age (y) at onset/ Sex

1

77/M

2

46/F

3 4

60/F 34/F

5

Treatment

Total dose of prednisone (mg)

Prednisone 40 mg/d, dapsone 150 mg/d, azathioprine 100 mg/d Prednisone 50 mg/d, dapsone 175 mg/d, methotrexate 15 mg/wk Prednisone 60 mg/d Prednisone 40 mg/d, dapsone 200 mg/d

12,800

51/F

Prednisone 50 mg/d, dapsone 100 mg/d, azathioprine 100 mg/d

16,500

6

61/M

Prednisone 60 mg/d, azathioprine 150 mg/d, cyclosporine 250 mg/d

27,850

7

68/M

30,400

8

37/F

Prednisone 60 mg/d, dapsone 200 mg/d, methotrexate 25 mg/d, tetracycline 2 g/da Prednisone 50 mg/d, dapsone 100 mg/d, gold (oral) 6 g/d

9

66/F

24,600

10

27/F

11

79/F

Prednisone 60 mg/d, azathioprine 150 mg/d, cyclophosphamide 200 mg/d Tetracycline 2 g/d, niacinamide 200 mg/d, dapsone 225 mg/d, prednisone 80 mg/d Prednisone 60 mg/d, dapsone 200 mg/d, azathioprine 150 mg/d, cyclophosphamide 200 mg/d

22,700 22,700 13,800 10,600

18,650

17,900

26,500

Side effects of tx

Duration of systemic tx before No. of IVIg (mo) recurrences

DM, myopathy, insomnia, mood swings, anemia Multiple infections cataract, obesity, psychologic Multiple infections Insomnia, mood swings, weakness, anemia Osteoporosis, psychologic, hypertension, leukopenia, thrombocytopenia DM, hypertension, hepatitis, anemia, leukopenia, multiple infections DM, myopathy, cataract, peptic ulcer, insomnia, anemia Menstrual irregularities, GI distress, rash, oral ulcers, depression, severe weakness Hypertension, psychologic, muscle weakness, anemia, leukopenia GI distress, anemia, weakness

Myopathy, DM, repeated multiple infections, anemia, hepatitis, alopecia

No. of Total No. No. of hospitaliof days Clinical relapses zations hospitalized response*

38

4

5

1

8

5.0

29

5

3

1

6

4.5

16 18

3 4

2 1

0 0

0 0

3.2 5.0

22

4

2

2

18

7.5

40

6

5

4

47

4.5

45

7

5

3

27

6.5

23

4

3

2

15

4.0

26

3

4

5

67

6.7

36

4

5

0

0

5.5

32

7

6

8

121

7.5

DM, Diabetes mellitus; GI, gastrointestinal. *All time periods are in months.

complete blood cell count, serum chemistry test, and routine urinalysis were done before the initiation of each cycle. Criteria to evaluate clinical response to IVIg therapy Time for effective clinical response was the number of months observed to achieve complete healing

and the absence of new lesions. The total number of IVIg cycles infused was recorded. Once IVIg therapy was begun in all patients, the dose of oral prednisone and immunosuppressive agents was tapered, and all systemic therapies were eventually discontinued. The total cumulative dose of prednisone and the duration of its use after initiation of IVIg therapy were recorded. The last adjuvant used varied between patients.

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Post-IVIg treatment Prednisone tx after IVIg

Quality of life

Period of Total observation length after IVIg of followtherapy* up*

Duration of maintenance tx with IVIg*

Duration of IVIg tx*

No. of cycles

Duration*

Dose (mg)

Duration of ISA after IVIg*

20.0

25

15

5

1150

4.0

None

2

1

2

5

18

81

18.5

23

18

3.2

1460

2.0

None

3

0

1

4

15

67

18.8 22.0

22 27

13 16

3.0 3.5

1800 1060

NA 2.0

Nausea None

2 2

0 1

2 2

5 5

24 16

62 60

28.5

36

24

5.6

1680

2.5

None

3

2

1

4

20

78

27.5

32

17

3.0

1250

2.0

None

4

1

1

4

21

93

29.5

36

20

5.5

1480

3.5

None

1

2

1

5

14

91

21.0

25

18

3.8

1375

2.5

Headache

1

0

3

0

22

70

24.3

31

22

4.5

1560

3.0

None

1

5

4

1

26

83

30.5

34.5

19

2.5

950

1.5

Headache

3

5

5

0

15.5

86

29.5

37

26

5.0

1850

2.5

None

1

4

3

2

13

82

Side effects of IVIg

Therefore only the time to discontinue the ISA was recorded. The interval between effective clinical response and end of IVIg therapy was the duration of maintenance therapy. The duration of IVIg therapy was the interval, in months, from the beginning to the end of therapy. The number of recurrences and relapses during the treatment period was recorded. Period of observation since discontinuation of IVIg

No. of recurrences

No. of relapses Pre-IVIg

Post-IVIg

therapy was documented. The interval between the date of the biopsy diagnosis and the last office visit was defined as the total duration of follow-up. Quality of life scoring Before the initiation of IVIg therapy, patients were questioned about the quality of life and asked to provide a score, including the effects of the disease and

46 Ahmed and Sami

the influence of the side effects upon their quality of life. The rough scoring system was as follows: 1 = poor, 2 = unsatisfactory, 3 = livable, 4 = reasonably good, and 5 = high quality of life. Tests for statistical analysis The pre-IVIg and post-IVIg data were statistically analyzed with respect to the following variables: number of side effects, relapses, recurrences, duration and dose of prednisone therapy, number of hospitalizations, number of days in hospital, duration of treatment, and patients’ quality of life. The differences between these variables pre-IVIg and post-IVIg were statistically analyzed by means of SAS UNIVARIATE software and the 2-sided Wilcoxon signed rank and sign tests, both of which are nonparametric, and thus do not require the assumption of normality.52 The Wilcoxon sign rank test is the more powerful of the 2 tests and does require the assumption of symmetry, whereas the sign test is unaffected by the skewed data.52 Because the quality of life variable was based on a l to 5 ordinal scale of each patient’s assessment, only the sign test could be used to analyze these data. The relationships between the total amount of prednisone administered before IVIg therapy and the number of hospitalized days, hospital admissions, recurrences, relapses, and side effects were tested by means of SAS CORR with the Pearson and nonparametric Spearman rank correlation coefficient options.

RESULTS Details of clinical profiles, previous therapies with their dose duration and side effects, and details of IVIg therapy on 11 patients are presented in Table I. Pre-IVIg treatment with oral prednisone and adjuvant or immunosuppressive agent Prednisone was used in all patients, in doses ranging from 40 to 80 mg/d (mean, 55.5 mg/d). The total dose of prednisone administered before initiating IVIg therapy was 10,600 to 30,400 mg (mean, 20,209 mg). Ten of 11 patients were treated with adjuvants; 1 patient received 1 adjuvant drug, 6 patients received 2 additional drugs, and 3 patients needed 3 additional agents. Side effects resulting from use of these adjuvants are presented in Table I. Duration of disease and treatment before IVIg therapy varied from 16 to 45 months (mean, 29.5 months). Before IVIg therapy, the number of recurrences ranged from 3 to 7 (mean, 4.6). The number of relapses ranged from 1 to 6 (mean, 3.7). None of the patients had achieved a prolonged or sustained clinical remission, and the clinical course was characterized by relapses and recurrences. The number of hospital admissions ranged from 0 to 8 (mean,

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2.4). The total number of days of hospital stay ranged from 0 to 121 days (mean, 28.1). IVIg therapy outcome data An effective clinical response was achieved in 3.2 to 7.5 months (mean, 5.3 months). The duration of IVIg therapy ranged from 22 to 37 months (mean, 29.8 months). Maintenance therapy with IVIg was continued for a period ranging from 18.5 to 30.5 months (mean, 24.6 months). The total number of cycles of IVIg ranged from 13 to 26 (mean, 18.9). All 11 patients went into remission. Once IVIg therapy was started, the dose of prednisone, which ranged from 40 to 85 mg/d (mean, 66.8 mg/d), was rapidly tapered over 3.0 to 5.6 months (mean, 4.05 months). The total cumulative dose of prednisone ranged from 950 to 1850 mg (mean, 1419.5 mg), and the duration of ISA varied from 1.5 to 4 months (mean, 2.6 months). All systemic therapies were tapered and eventually discontinued, and IVIg was used as monotherapy. During IVIg therapy, the frequency of relapses ranged from 0 to 2 (mean, 0.9) and the frequency of recurrences, from 1 to 4 (mean, 2.2). The period of observation since discontinuation of IVIg therapy ranged from 13 to 26 months (mean, 18.6 months). The total follow-up period was 61 to 95 months (mean, 78.0 months). During IVIg therapy and the follow-up period, none of the patients were hospitalized for reasons related to PF or to IVIg therapy. Statistical analysis of clinical outcome parameters The comparison of the variables used to assess responses before and after IVIg therapy are presented in Table II. Both the Wilcoxon and sign tests demonstrated a highly statistically significant difference in the dose and duration of prednisone therapy, side effects, recurrences, relapses, hospital admissions, and days of hospital stay compared with other treatments. The data also indicate that before IVIg therapy, the total cumulative dose of prednisone demonstrates a direct correlation with the number of hospitalizations, days of hospital stay, frequency of side effects, and recurrences and relapses as calculated by means of the Pearson correlation coefficients (range, 0.620.78; 2-sided P < .05). These results were corroborated as statistically significant by the Spearman correlation coefficient. By means of the sign test, IVIg therapy resulted in a statistically significant (P < .0001) improvement in the patients’ quality of life.

DISCUSSION We have described 11 patients with extensive PF. These patients were initially treated with conven-

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Table II. Pemphigus foliaceus: Comparison of treatment outcomes before and after IVIg therapy

Clinical variable

Total dose of prednisone (mg) Duration (mo) of prednisone tx Side effects (No.) No. of hospital admissions Total No. of days hospitalized Duration (mo) of tx No. of relapses No. of recurrences No. of remissions Quality of life

No.

Avg before IVIg

Minimum

11 11 11 11 11 11 11 11 11 11

20,209 29.5 4.7 2.4 28.1 29.5 3.7 4.6 0 1.5

10,600 16 1 0 0 16 1 3 0 1

tional therapy consisting of long-term, high-dose oral corticosteroid therapy in combination with ISAs. Despite prolonged use (mean, 36.4 months) of such combination therapies, a sustained and effective clinical remission could not be achieved. Several reports describe multiple patients with severe PF who are refractory to prednisone and adjuvant conventional ISAs or who are unable to tolerate such therapy because of the onset of debilitating and sometimes potentially fatal side effects as a result of prolonged immune suppression.35-47 The use of IVIg was considered reasonable and medically necessary because (1) other therapeutic options were relatively contraindicated or had failed to provide satisfactory control, (2) IVIg has proven to be effective in other chronic inflammatory and autoimmune diseases, (3) IVIg has no known drug interactions, and (4) IVIg is relatively safe because the incidence of serious side effects is low compared with other therapies such as systemic corticosteroids and ISAs.53 In all 11 PF patients, an effective clinical response was observed after the initial use of IVIg (mean, 5.3 months). Its continued use resulted in a sustained clinical remission. The mean duration of IVIg as maintenance therapy was 24.6 months. During this period a gradual prolongation of intervals between infusion cycles was achieved, and eventually IVIg was discontinued in all patients. After cessation of IVIg, the patients were followed up for a mean period of 18.6 months. Recurrence or long-term side effects were not observed. Hence this study suggests that IVIg therapy is effective in inducing and maintaining a sustained remission and that it is a safe therapeutic agent. During periods of national shortage of IVIg, recurrences and relapses were observed because patients did not receive their infusions at optimal doses or frequencies. An effective clinical response was

Maximum

Avg after IVIg

Minimum

Maximum

30,400 45 6 8 121 45 6 7 0 3

1420 4.1 0.3 0 0 29.8 0.9 2.2 1 4.5

950 2.5 0 0 0 22 0 1 1 4

1850 5.6 1 0 0 37 2 4 1 5

Difference

Sign test P value

Sign rank test P value

18,789 25.4 4.4 2.4 28.1 –0.3 2.6 2.4 –1 –3.0

.0010 .0010 .0020 .0078 .0078 .9999 .0039 .0010 .0010 .0010

.0010 .0010 .0020 .0078 .0078 .9805 .0039 .0010 .0010 —

observed promptly after reinstitution of IVIg as monotherapy. These observations suggest that abrupt cessation is inadvisable and that a gradual withdrawal of IVIg most likely facilitates maintaining a sustained remission. There is evidence to indicate that IVIg is useful in treating several chronic inflammatory and autoimmune diseases such as Kawasaki’s disease, chronic inflammatory neuropathies, myasthenia gravis, dermatomyositis, and idiopathic thrombocytopenic purpura.53-55 There are 5 proposed mechanisms of action of IVIg.56 Conventional therapy with prednisone and immunosuppressive agents may decrease autoantibody production by directly affecting autoreactive B cells. In this study, when patients were treated with such agents, a satisfactory or successful outcome was not observed, which suggests that immune suppression may not be the optimal treatment strategy. Instead, these patients responded to IVIg and have maintained in sustained remission. Hence such patients may benefit from immunomodulatory therapies such as IVIg. Continuous infusions of IVIg probably reconstitute the breakdown of immunoregulatory circuits.53 It appears IVIg is a safe therapeutic agent. No significant immediate or long-term side effects were observed while the patients were receiving IVIg (mean, 29.8 months) and during the period of observation after discontinuation (mean, 18.6 months). Premedication with diphenhydramine and acetaminophen is recommended to prevent allergic reactions and headaches53,54 in patients receiving IVIg therapy. Hypersensitivity reactions frequently occur in patients with IgA deficiency.53-55,57 Serious side effects such as acute renal failure and aseptic meningitis have also been reported.53-55,57 There is evidence in the literature that long-term use of high-dose systemic corticosteroids and ISAs

48 Ahmed and Sami

can result in several side effects that have grave consequences.35-41 Eight of 11 patients in this study were hospitalized while they were being treated with conventional ISAs. Patients experienced significant side effects to such therapies and required hospitalizations. A direct correlation between the total cumulative dose of prednisone administered and the number of side effects and days of hospital stay was observed. Therefore this correlation shows that physicians treating PF need to be aware of the total cumulative dose along with the highest dose of prednisone used. However, while receiving IVIg therapy, none of the patients needed hospitalization for similar reasons. Initiation of IVIg therapy also facilitated the lowering and eventual discontinuation of corticosteroids, whereas earlier such attempts had failed. Hence IVIg is an alternate therapy for such patients and has a steroid-sparing effect. In patients in whom conventional therapies have failed, other alternative therapies have been attempted. Some of these are pulse cyclophosphamide, with or without intravenous corticosteroid therapy,32-34 extracorporeal photopheresis,25,26 or plasmapheresis.27-31 However, long-term follow-up after cessation of such therapies is not always available to critically determine their influence on the clinical course of disease. In addition, such therapies are frequently accompanied by side effects that carry a high rate of morbidity and mortality. IVIg provided a higher quality of life as determined by using a simple scoring system in which each patient served as his/her own control. This report of our experience in treating 11 patients provides evidence that IVIg could be significantly useful in the overall treatment strategies used in PF. A randomized multicenter control trial that carefully defines the inclusion criteria, criteria to determine efficacy, long-term follow-up, and the end points could address some of these vital issues. We are grateful to the medical directors of the insurance companies that provided approval for IVIg therapy for the patients in this study. REFERENCES 1. Scott JE, Ahmed AR.The blistering diseases. Med Clin North Am 1998;82:1239-83. 2. Ryan JG. Pemphigus: a 20 year experience with 70 cases. Arch Dermatol 1971;104:14-20. 3. Rosenberg FR, Sanders S, Nelson CT. Pemphigus: a 20-year review of 107 patients treated with corticosteroids. Arch Dermatol 1976;112:962-70. 4. Krain LS. Pemphigus: epidemiologic and survival characteristics of 59 patients, 1955-1973. Arch Dermatol 1974;110:862-5. 5. Alsaleh QA, Nanda A, Al-Baghli NM, Dvorak R. Pemphigus in Kuwait. Int J Dermatol 1999;38:351-6.

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6. Ratnam KV, Phay KL, Tan CK. Pemphigus therapy with oral prednisone regimens: a 5-year study. Int J Dermatol 1990;29:363-7. 7. Van Dijk TJA, Van Velde JL. Treatment of pemphigus and pemphigoid with azathioprine. Dermatologica 1973;147:179-85. 8. Burton JL, Greaves MW. Azathioprine for pemphigus and pemphigoid–a 4 year follow-up. Br J Dermatol 1974;91:103-9. 9. Piamphongsant T, Ophaswongse S. Treatment of pemphigus. Int J Dermatol 1991;30:139-46. 10. Pasricha JS, Sood VD, Minocha T. Treatment of pemphigus with cyclophosphamide. Br J Dermatol 1975;93:573-6. 11. Panday AG, Dyke C. Treatment of pemphigus with gold. Arch Dermatol 1998;134:1104-7. 12. Zone J, Ward J, Boyce E, Schupbach C. Penicillamine-induced pemphigus. JAMA 1982;247:2705-7. 13. Penneys NS, Eaglstein WH, Frost P. Management of pemphigus with gold compounds: a long-term follow-up report. Arch Dermatol 1976;112:185-7. 14. Walton S, Keczkes K. Pemphigus foliaceus: successful treatment with adjuvant gold therapy. Clin Exp Dermatol 1987;12:364-5. 15. Piamphongsant T, Sivayathorn A. Pemphigus: combined treatment with methotrexate and prednisone. J Med Assoc Thai 1974;58:174-6. 16. Kahana M, Levy A, Schewach-Millet M, Eisenstein Z, Ronnen M, Feinstein A. Pemphigus foliaceus coexisting with toxic multinodular goiter. Int J Dermatol 1986;25:465-6. 17. Shah N, Green AR, Elgart GW, Kerdel F. The use of chlorambucil with prednisone in the treatment of pemphigus. J Am Acad Dermatol 2000;42:85-8. 18. Gupta AK, Ellis CN, Nickoloff BJ, Goldfarb MT, Ho VC, Rocher LL. Oral cyclosporine in the treatment of inflammatory and noninflammatory dermatoses. Arch Dermatol 1990;126:339-50. 19. Katz KH, Marks JG, Helm KF. Pemphigus foliaceus successfully treated with mycophenolate mofetil as a steroid-sparing agent. J Am Acad Dermatol 2000;42:514-5. 20. Galambrun C, Cambazard F, Clavel C, Versini P, Stephan JL. Pemphigus foliaceus. Arch Dis Child 1997;77:255-7. 21. Mehravaran M, Morvay M, Molnar K, Olah J, Korom I, Husz S, et al. Juvenile pemphigus foliaceus. Br J Dermatol 1998;139:496-9. 22. Piamphongsant T. Pemphigus controlled by dapsone. Br J Dermatol 1976;94:681-5. 23. Hymes SR, Jordan RE. Pemphigus foliaceus: use of antimalarial agents as adjuvant therapy. Arch Dermatol 1992;128:1462-4. 24. Ioannides D, Chrysomallis F, Bystryn JC. Ineffectiveness of cyclosporine as an adjuvant to corticosteroids in the treatment of pemphigus. Arch Dermatol 2000;136:868-72. 25. Azana JM, de Misa RF, Harto A, Ledo A. Severe pemphigus foliaceus treated with extracorporeal photochemotherapy. Arch Dermatol 1997;133:287-9. 26. Wollina U, Lange D, Looks A. Short-time extracorporeal photochemotherapy in the treatment of drug-resistant autoimmune bullous diseases. Dermatology 1999;198:140-4. 27. Tan-Lim R, Bystryn JC. Effect of plasmapheresis therapy on circulating levels of pemphigus antibodies. J Am Acad Dermatol 1990;22:35-40. 28. Sondegaard K, Carstens J, Jorgensen J, Zachariae H.The steroidsparing effect of long-term plasmapheresis in pemphigus. Acta Derm Venereol (Stockh) 1995;75:150-2. 29. Roujeau JC, Andre C, Fabre MJ, Lauret P, Flechet ML, Kalis B, et al. Plasma exchange in pemphigus. Arch Dermatol 1983;119:21521. 30. Bahmer FA, Bambauer R, Stenger D. Penicillamine-induced pemphigus foliaceus-like dermatosis. Arch Dermatol 1985;121: 665-8. 31. Cintin C, Joffe P. Pemphigus foliaceus treated successfully with plasma exchange. Int J Dermatol 1992;31:871-2.

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