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Christos C. Zouboulis, MD; Constantin E. Orfanos, MD

Arch Dermatol. 1998;134:1010-1016.

ABSTRACT
Objective  To evaluate the efficacy and safety of systemic interferon alfa treatment in patients with Adamantiades-Behçet disease.

Data Sources  Reports and abstracts published in 1986 through 1997 in all languages were identified by the MEDLINE database, the Reference Index Related to Behçet's Disease, the Behçet disease conference proceedings, and abstract booklets. The indexing terms used were Behçet and interferon.

Study Selection  Twenty-two reports identified were included to estimate the efficacy of interferon alfa on mucocutaneous, ocular, and joint manifestations. Responses of individual mucocutaneous signs were evaluated in 8 reports. Adverse effects were sufficiently documented in 12 reports. All patients met the criteria of the Behçet Syndrome Research Committee of Japan or those of the International Study Group for Behçet's Disease.

Data Extraction  Data were extracted and evaluated according to the following criteria: complete remission, disappearance of all manifestations during treatment; partial remission, greater than 50% decrease in the number, severity, duration, and/or frequency of recurrence of the lesions; stable disease, less than 50% change in the manifestations; and progressive disease, greater than 50% deterioration of existing manifestations or/and the development of new ones.

Data Synthesis  Systemic interferon alfa has been administered in 144 patients with Adamantiades-Behçet disease by subcutaneous or intramuscular injections of 3 to 18x10⁶ units of interferon alfa-2a (70 patients) or 3 to 5x10⁶ units of interferon alfa-2b (74 patients) daily or 3 times per week for 1 to 60 months. Seventy-four percent (92/124) of patients with mucocutaneous manifestations, 95% (37/39) of patients with uveitis, and 93% (51/55) of patients with arthropathy/arthritis exhibited a partial or complete response. Interferon alfa-2a regimens were more effective than interferon alfa-2b ones on mucocutaneous (47% vs 7% complete response) and ocular (67% vs 8% complete response; P <.001) manifestations. Mucocutaneous and ocular manifestations responded within 1 to 4 months after initiation of therapy. Thirty-eight percent (20/52) of patients with mucocutaneous lesions, 73% (8/11) of patients with uveitis, and 88% (21/24) of patients with arthropathy/arthritis experienced recurrences immediately or up to 7 months after discontinuation of treatment. Mild adverse effects were generally recorded; transient influenzalike symptoms (87% vs 63%; P <.05) and reversible leukopenia (24% vs 4%; P <.05) occurred more often under interferon alfa-2a regimens, while reversible mild alopecia was more common in patients receiving interferon alfa-2b (2% vs 28%; P<.01).

Conclusions  Systemic interferon alfa treatment is reasonable for Adamantiades-Behçet disease. A 3-month high-dose regimen (9x10⁶ units 3 times per week) followed by a low maintenance dose (3x10⁶ units 3 times per week) is recommended.

INTRODUCTION

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ADAMANTIADES-BEHÇET disease is a systemic inflammatory disorder with a chronic progressive course that is clinically characterized by recurrent oral ulcers, genital ulcers, and iritis with hypopyon.^1-2 Its diverse clinical manifestations were originally attributed to a unique nosological entity by Adamantiades in 1931³ and Behçet in 1937.⁴ The initial pathological process is a systemic neutrophilic reaction of the small vessels.^5-6

Although the pathogenesis of the disease remains unknown, its cause is presumed to be multifactorial, implicating a genetic predisposition,⁷ involvement of infectious agents (bacterial or viral),^8-9 immunological processes,¹⁰ and endothelial cell dysfunction.¹¹ A pathogenetic viral candidate seems to be herpes simplex virus 1 in view of the detection of IgG antibodies against herpes simplex virus 1 in patients' serum,¹² the inappropriate response of patients' lymphocytes to herpes simplex virus 1,^13-14 and the identification of herpes simplex virus 1 DNA sequences in patients' blood^15-16 and saliva.¹⁷ On the other hand, several reports have described a number of abnormalities in the immune system, including defects of both cellular and humoral immunity. Despite a marked increase in the number of natural killer cells in the peripheral blood of patients with active-stage Adamantiades-Behçet disease, the natural killer cell activity was found to be significantly lower^18-21 than that of patients in the inactive stage and normal controls. Impaired prostacyclin synthesis²² and endothelial cell swelling and proliferation²³ have also been identified.

New drugs are continuously being evaluated for Adamantiades-Behçet disease, since there is still no standard therapeutic regimen. Interferon alfa therapy was introduced more than 10 years ago^24-26 because of its antiviral activity against herpes simplex virus 1,²⁷ its ability to augment in vitro the decreased activity of patients' natural killer cells,^{19, 28} and its capacity to inhibit neovascular proliferation.^29-31

This study summarizes existing data on the efficacy and safety of systemic interferon alfa regimens in patients with Adamantiades-Behçet disease.

PATIENTS AND METHODS

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DATA SOURCES

Twenty-two original studies, case reports, and abstracts published from 1986 through December 1997 in all languages were identified by the MEDLINE database, the Reference Index Related to Behçet's Disease,³² the Behçet disease conference proceedings, and abstract booklets. The indexing terms used were Behçet and interferon.

STUDY SELECTION

All 22 studies and case reports identified were included to estimate the efficacy of interferon alfa on mucocutaneous, ocular, and joint manifestations. Eight studies were designed to evaluate the responses of the individual mucocutaneous signs. Adverse effects were sufficiently documented in 12 studies and case reports. All patients documented met the criteria of the Behçet Syndrome Research Committee of Japan³³ or those of the International Study Group for Behçet's Disease.¹

DATA EXTRACTION

Data were extracted by one of us (C.C.Z.) and evaluated according to the following criteria: complete remission (CR) was defined as the disappearance of all manifestations during treatment; partial remission (PR), a greater than 50% decrease in the number, severity, duration, and/or frequency of recurrence of the lesions; stable disease, a less than 50% change in the manifestations; and progressive disease, greater than 50% deterioration of existing manifestations or/and the development of new ones.

STATISTICAL ANALYSIS

Efficacy and toxic effects of interferon alfa-2a and interferon alfa-2b were compared by ² test (where applicable). Differences were considered significant at P<.05.

RESULTS

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One hundred forty-four patients (44% male and 56% female; mean age, 34.6 years; age range, 12-60 years) with Adamantiades-Behçet disease were treated with systemic interferon alfa (Table 1).^{24-26,28, 34-50} The majority of patients were treated particularly for mucocutaneous manifestations (86 patients), while 34 patients received the compound for ocular lesions; 22 patients, for joint involvement; 1 patient, for ocular and gastrointestinal tract manifestations; and 1 patient, for neurological signs and symptoms.

View this table: [in this window] [in a new window] Table 1. Interferon Alfa Treatment in Adamantiades-Behçet Disease*

Different therapeutic schedules of subcutaneous or intramuscular interferon alfa injections were applied for periods ranging between 1 and 60 months. Seventy patients received 3 to 18x10⁶ units of interferon alfa-2a (Roferon A; Hoffmann-La Roche, Basel, Switzerland) and 74 patients, 3 to 5x10⁶ units of interferon alfa-2b (Intron A; Schering Plough, Bloomfield, NJ) daily to 3 times per week.

Ninety-two (74%) of 124 patients with mucocutaneous manifestations experienced a PR or CR under interferon alfa treatment, while 29 (23%) did not respond and 3 (2%) showed disease progression (Table 1. In addition, 37 (95%) of 39 patients with uveitis and 51 (93%) of 55 patients examined for arthropathy and/or arthritis exhibited a PR or CR. Interferon alfa-2a regimens were found more effective than interferon alfa-2b ones on mucocutaneous (47% vs 7% CR; P <.001) and ocular (67% vs 8% CR; P <.001) manifestations.

Since the course of mucocutaneous manifestations was precisely documented in 44 patients who received interferon alfa-2a, the evaluation criteria were applied separately for each type of mucocutaneous lesion (Table 2). In general, interferon alfa-2a was equally effective on all types of mucocutaneous lesions (Figure 1 and Figure 2). About 68% to 80% of the lesions exhibited a PR or CR.

View this table: [in this window] [in a new window] Table 2. Efficacy of Interferon Alfa-2a on Mucocutaneous Manifestations of Adamantiades-Behçet Disease*

View larger version (72K): [in this window] [in a new window] Figure 1. Large genital ulcer in a 28-year-old patient before (left) and 1 week after (right) the initiation of treatment with interferon alfa-2a, 9x106 units 3 times per week.

View larger version (52K): [in this window] [in a new window] Figure 2. Disseminated erythema nodosum in a 27-year-old male patient that persisted for 4 months before (left) and 1 week after (right) the initiation of treatment with interferon alfa-2a, 9x106 units 3 times per week.

When reported, the mucocutaneous and ocular manifestations progressively responded to interferon alfa within 1 to 4 months after the initiation of treatment. The maximum response was achieved at about 2 to 4 months and persisted during the further treatment period. Of 52 patients with mucocutaneous lesions who had a PR or CR, 20 (38%) relapsed immediately or up to 7 months after the discontinuation of treatment, while 32 (62%) showed no recurrences in a follow-up period longer than 8 months. Discontinuation of treatment in 11 patients with uveitis resulted in immediate relapses in 7 patients and in 1 patient 6 months later. Twenty-one (88%) of 24 patients with arthritis evidenced a posttherapeutic increase in the frequency of arthropathy/arthritis attacks to pretreatment levels. Reintroduction of the drug in 9 patients with mucocutaneous lesions and 5 patients with uveitis led to a new response of the manifestations. However, relapses were also reported during therapy with interferon alfa. A patient with an initial PR followed by a relapse 15 months after the initiation of treatment (9x10⁶ units of interferon alfa-2a 3 times per week) developed interferon alfa antibodies and responded again when the dose was increased to 15x10⁶ units of interferon alfa-2a 3 times per week.

Mild and tolerable adverse effects were recorded with transient influenzalike symptoms and increased body temperature less than 38.5°C in 82 (73%) of 113 patients, reversible mild alopecia in 20 (18%), and reversible leukopenia (2.0-4.0x10⁹/L because of an absolute reduction of neutrophils) in 14 (12%) (Table 3). The 2 interferon alfa isotypes used for systemic treatment caused overall similar adverse effects. However, influenzalike symptoms (P<.05) and mild leukopenia (P<.01) were more commonly reported in patients treated with interferon alfa-2a regimens and reversible mild alopecia (P<.01) in patients receiving interferon alfa-2b. Leukopenia leading to discontinuation of treatment (3 patients [4]) was detected in patients receiving interferon alfa-2b. The therapy was also discontinued in 1 patient who suffered from depression and developed an acute psychotic syndrome and severe myopathy under long-term interferon alfa treatment (about 4 years). Another patient previously given long-term immunosup-pressive therapy displayed an acute exacerbation of the disease with mucocutaneous, joint, and ocular manifestations as well as myopathy, fatigue, hypotension, and diarrhea during the first weeks of treatment with interferon alfa-2a.

View this table: [in this window] [in a new window] Table 3. Adverse Effects During Interferon Alfa Treatment of Adamantiades-Behçet Disease*

COMMENT

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The data of the present review clearly support the effectiveness of systemic interferon alfa in the treatment of Adamantiades-Behçet disease. Patients with both the mucocutaneous and the ocular manifestations of the disease are likely to benefit from the treatment. In addition, arthralgia/arthritis seems to improve with systemic interferon alfa treatment.

A treatment period of 2 to 4 months seems to be essential to obtain a maximum response.^{28, 34, 47} Long-term treatment may be indicated for some patients who tend to have a relapse immediately after discontinuation^{24, 28, 46} and intermittent treatment cycles for others with recurrences within the first few posttreatment months.^{25-26,28, 34, 37, 45}

However, long-term interferon alfa therapy (>6 months) induces binding (15%) and/or neutralizing interferon antibodies (5% to 7%)^{47, 51-52} and/or autoantibodies against the epidermis (32%).⁵³ Three patients treated with interferon alfa for chronic myelogenous leukemia developed several characteristic features of Adamantiades-Behçet disease 6 to 36 months after the initiation of treatment, and 2 additional patients with chronic myelogenous leukemia exhibited a positive pathergy test result after interferon alfa treatment.^54-55 Recent in vivo studies have reported cases of autoimmune diseases associated with long-term administration of interferon alfa or interferon beta.^53-54 Two of our patients who received interferon alfa treatment developed myopathy and an acute psychotic syndrome.⁵⁶ On the other hand, no difference was detected among 3- and 9-month interferon alfa regimens with regard to efficacy scores and remission periods.^{37, 42} These facts emphasize the need for a 6-month limit of continuous interferon alfa therapy in the majority of patients and for a close clinical follow-up of patients treated with interferon alfa for a long period.

The following observations demonstrate the optimal interferon alfa dose for Adamantiades-Behçet disease. The high-dose interferon alfa-2a regimens were more effective than the low-dose interferon alfa-2b ones on mucocutaneous and ocular manifestations during treatment. Better posttreatment remission results have been observed with higher interferon alfa doses (9x10⁶ units 3 times per week) than with lower doses of the drug (4.5x10⁶ units 3 times per week) in the first 3 months of treatment.^{37, 42} On the other hand, low doses of interferon alfa (3x10⁶ units per week) have been shown to result in more effective clinical natural killer cell activation than higher doses.⁵⁷ Therefore, for treatment of Adamantiades-Behçet disease with interferon alfa, we initially recommend a high-dose regimen (9x10⁶ units 3 times per week) for 3 months followed by a low maintenance dose (3x10⁶ units 3 times per week).

Interestingly, topical interferon alfa and systemic interferon beta and interferon gamma are probably not able to provide similar results. The promising results of a pilot study with topical interferon alfa-2c treatment on oral ulcers of patients with Adamantiades-Behçet disease⁵⁸ could not be confirmed by a randomized, double-blind trial.⁵⁹ Despite initial therapeutic studies suggesting that interferon gamma could lead to improvement of the mucocutaneous lesions,⁶⁰ the regimen did not improve ocular manifestations,⁶¹ and neither our unpublished data nor those of others were able to confirm a beneficial effect of the substance on patients with Adamantiades-Behçet disease.⁶² On the other hand, the description of a patient whose mucocutaneous and ocular manifestations were improved by systemic interferon beta needs further confirmation.⁶³

Justified criticism concerning the documentation of "improvement" in therapeutic studies of Adamantiades-Behçet disease because of the recurrent character of the lesions^{24, 45, 64} led the investigators of most reports reviewed here to carry out long-term recording of the frequency and duration of the manifestations before and after the treatment period or to define criteria for evaluating the course of the lesions. However, a controlled study is now essential to confirm the efficacy of interferon alfa in Adamantiades-Behçet disease.

AUTHOR INFORMATION

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Accepted for publication April 16, 1998.

Presented in part at the Seventh International Conference on Behçet's Disease, Tunis, Tunisia, October 11, 1996.

Reprints: Christos C. Zouboulis, MD, Department of Dermatology, University Medical Center Benjamin Franklin, The Free University of Berlin, Hindenburgdamm 30, D-12200 Berlin, Germany (e-mail: zoubbere{at}zedat.fu-berlin.de).

From the Department of Dermatology, University Medical Center Benjamin Franklin, The Free University of Berlin, Berlin, Germany.

REFERENCES

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