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Interferon Alfa-2a in the Treatment of Behçet Disease
A Randomized Placebo-Controlled and Double-blind Study
Erkan Alpsoy, MD;
Cicek Durusoy, MD;
Ertan Yilmaz, MD;
Yilmaz Ozgurel, MD;
Oya Ermis, MD;
Sahin Yazar, MD;
Erdal Basaran, MD
Arch Dermatol. 2002;138:467-471.
ABSTRACT
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Objective To determine the therapeutic efficacy of interferon alfa-2a in the treatment
of Behçet disease.
Design A randomized placebo-controlled and double-blind study.
Setting University referral center.
Patients Fifty patients with Behçet disease were involved in the study.
Intervention The patients were given interferon alfa-2a, 6 x 106
IU, subcutaneously 3 times per week or placebo for 3 months, and examined
clinically at weekly intervals.
Main Outcome Measures For each mucocutaneous lesion and articular symptom, the mean frequency
and duration were evaluated during the 3-month pretreatment, treatment, and
follow-up periods. Pain for oral and genital ulcers was scored on a scale
of 0 to 3. The ocular inflammatory score, the frequency of attacks, and changes
in visual acuities for patients with ocular involvement were assessed before
the study, at the end of treatment, and during the follow-up periods. In addition,
overall responses at the end of the treatment period were graded as follows:
complete remission, disappearance of all clinical signs and symptoms during
treatment; partial remission, greater than a 50% decrease in the frequency,
duration, and severity of pain for oral and genital ulcers and/or a decrease
in the severity and frequency of ocular attacks; stable disease, less than
a 50% change in the clinical signs and symptoms; and no effect or deterioration,
ineffectiveness or worsening of clinical signs and symptoms.
Results Twenty-three interferon alfa-2a– and 21 placebo-treated patients,
ranging in age from 16 to 55 years (mean ± SD age, 32.38 ± 7.94
years), were evaluable for efficacy. Interferon alfa-2a treatment significantly
decreased the duration (P = .02) and pain (P = .01)
of oral ulcers and the frequency of genital ulcers (P = .03) and
papulopustular lesions (P = .01). The mean frequency and duration
of erythema nodosum–like lesions (P = .77 and .27, respectively),
thrombophlebitis (P = .29 and .61, respectively), and articular
symptoms (P = .92 and .74, respectively) also decreased. But there
were no statistically significant differences. An improvement in the severity
and the frequency of ocular attacks occurred in 5 of 6 patients in the interferon
alfa-2a–treated group and in 1 of 3 patients in the placebo-treated
group. Of the 23 patients in the interferon alfa-2a–treated group, 15
responded to treatment (2 complete and 13 partial responses); and of the 21
patients in the placebo group, 3 responded to treatment (3 partial responses)
(P<.005).
Conclusion Interferon alfa-2a is an effective alternative treatment for Behçet
disease, particularly for the management of the mucocutaneous lesions of the
disease.
INTRODUCTION
BEHÇET DISEASE (BD) is a chronic, relapsing, multisystemic inflammatory
process with the clinical features of mucocutaneous lesions and ocular, vascular,
articular, gastrointestinal, urogenital, pulmonary, and neurologic involvement.
The etiopathogenesis of the disease still remains unknown. Although several
immunologic abnormalities have been demonstrated in patients with BD, the
exact mechanism of the inflammatory changes occurring remains to be elucidated.
The most likely hypothesis seems to be that of an autoimmune reaction set
off by infectious agents, such as human herpesvirus 1 or Streptococcus species, in genetically predisposed individuals, and
its basic pathologic process is vasculitis.1-3
No standard therapy has been established for the disease. However, a
wide spectrum of therapeutic agents, including colchicine, levamisole hydrochloride,4 corticosteroids, acyclovir, chlorambucil, cyclophosphamide,5 cyclosporine,6 azathioprine,7 and thalidomide,8 have
been used in the treatment of the disease, with varying success; none of them
result in cure of the disease, and some are associated with significant adverse
effects.
Interferons, a large family of glycoproteins, were first described in
1957 by Isaacs and Lindenmann,9 and are known
to produce a cellular response to the foreign constituents of microbes, tumors,
and antigens. They have been used in the treatment of a wide group of diseases
because of their antiviral, antimicrobial, antitumor, and immunomodulatory
actions. Tsambaos et al10 first introduced
the systemic application of interferon alfa-2a in 3 patients with BD; these
patients showed complete or almost complete remission of the mucocutaneous
lesions and marked improvement of their systemic manifestations after treatment
with 9 to 12 x 106 IU per day for 11 to 16 days. Since then,
several uncontrolled studies11-14
have been published, using interferon alfa-2a or interferon alfa-2b and giving
the agent either daily or 3 times weekly. Promising results have been reported,
especially with interferon alfa-2a. In a review of this literature, Zouboulis
and Orfanos15 concluded that most patients
showed a worthwhile improvement in mucocutaneous lesions, arthritis, and ocular
manifestations. A 2-month treatment, at least, is likely to be necessary to
increase the effectiveness, and the disease generally relapses on discontinuation.
In addition to their immunomodulatory effects, ability to augment the
decreased activity of a patient's natural killer cells, and capacity to inhibit
neovascular proliferation, the antiviral activities of interferons, together
with the putative association between BD and viral infection, particularly
human herpesvirus 1, provide a rationale for testing their therapeutic potential.
Therefore, the present randomized double-blind and placebo-controlled study
was undertaken to investigate whether interferon alfa-2a is effective in the
treatment of BD.
PATIENTS AND METHODS
Fifty patients with BD (19 females and 31 males; mean ± SD age,
32.92 ± 8.62 years; age range, 16-55 years), diagnosed as having BD
according to the criteria of the International Study Group for Behçet's
Disease,16 were involved in the study between
June 3, 1996, and March 31, 2000. Exclusion criteria consisted of patients
who had hepatic, renal, cardiovascular, infectious, or other autoimmune disease;
those with a coagulopathy; and those who had received recent systemic therapy
for at least 12 weeks and topical therapy for at least 4 weeks before enrolling
in the study. Pregnant or lactating women were not included in the study.
We excluded patients who at the initiation of the treatment period had active
cerebral or retinal vasculitis. Patients with irreversible bilateral eye disease
and those who had cataract or posterior synechia that interfered with visual
acuity or the fundus examination were also excluded.
The patients were observed for 3 months before the study. All attacks
were recorded during this period. The research protocol was approved by the
ethics committees, and all patients or their guardians gave signed informed
consent. Administration of either placebo or interferon alfa-2a was commenced
depending on the sequence randomly allocated to the subject. The dissolvent
of interferon alfa-2a was used as placebo, which was identical in appearance
to the interferon alfa-2a injection. Patients were given interferon alfa-2a,
6 x 106 IU, or placebo subcutaneously 3 times a week. Patients
were informed about the study design and the possible adverse effects of the
interferon alfa-2a therapy before study enrollment. Because the influenzalike
symptoms that occur after injections are a well-known adverse effect of the
interferon alfa-2a treatment and could hamper the performance of such a controlled
study, subjects were given oral acetaminophen, 1000 mg before injections and
500 mg after 6 hours, during the first month of the therapy.
All signs and symptoms were recorded during the 3-month treatment period.
The patients were examined clinically at weekly intervals and were followed
up for another 3 months after the treatment. During all of these procedures,
the subject was observed and assessed by an investigator (E.A.) who was blinded
to the test medication being used. The results were based on a combination
of the data obtained by the physician at clinic visits and the data reported
by the patients on the occurrence of lesions between the visits. For each
mucocutaneous lesion and articular symptom, the mean frequency and duration
were evaluated during the pretreatment, treatment, and follow-up periods.
The mean frequency and duration of lesions were calculated per patient. Pain
for oral ulcers (OUs) and genital ulcers (GUs) was scored on a scale of 0
to 3 (0 indicates absent; 1, mild; 2, moderate; and 3, severe). The following
pain scores, which were based on a system developed by Alpsoy et al17 for patients with BD, were used. For OUs, 0 indicates
no symptoms; 1, mild pain with eating/drinking and/or speaking; 2, moderate
pain and partial difficulty in eating/drinking and/or speaking; and 3, severe
pain and marked difficulty in eating/drinking and/or speaking. For GUs, 0
indicates no symptoms; 1, mild pain with physical activity; 2, moderate pain
and partial difficulty in physical activity; and 3, severe pain and marked
difficulty in physical activity. In addition, overall responses at the end
of the treatment period were graded as follows: complete remission (CR), the
disappearance of all clinical signs and symptoms during the treatment; partial
remission (PR), greater than a 50% decrease in the frequency, duration, and
severity of pain for OUs and GUs and/or a decrease in the severity and frequency
of attacks for ocular involvement; stable disease, less than a 50% change
in the clinical signs and symptoms; and no effect or deterioration, ineffectiveness
or worsening of clinical signs and symptoms.
Patients with active eye disease were examined by an ophthalmologist
(Y.O.) at weekly intervals (or daily when necessary); and patients without
eye symptoms, at monthly intervals. The ophthalmologic examination included
a Snellen visual acuity measurement, a slitlamp examination of the anterior
segment, and direct and indirect ophthalmoscopy of the vitreous and fundus.
Intraocular pressures were measured by applanation tonometry. Cells and flare
in the anterior chamber and vitreous were graded from 0 to 4+. Ocular inflammatory
scores,18 frequency of attacks, and changes
in visual acuities (a change of 2 lines in Snellen acuity is regarded as significant)
for each patient were assessed before the study, at the end of treatment,
and during the follow-up periods.
Adverse events were also documented during the treatment period. No
patients were given any concurrent disease-specific or immunosuppressive systemic
drugs during the 9-month study period. Topical corticosteroid drops and mydriatic
agents remained available for patients with ocular involvement whenever necessary.
A full blood cell count, including hemoglobin level, leukocyte count and differential,
platelet count, and erythrocyte sedimentation rate, and routine biochemical
tests were performed before treatment and repeated monthly. Abnormal test
results and adverse reactions became new exclusion criteria.
The mean frequency and duration of each mucocutaneous lesion and articular
symptom, and the pain of OUs and GUs in the pretreatment period, were compared
with those of the treatment and posttreatment periods in the group of patients
treated with interferon alfa-2a and placebo, and a repeated-measure analysis
of variance was used to test the changes in groups. Differences in improvement
ratings (overall responses) between groups were tested using the  2 test. P .05 was accepted as significant.
RESULTS
Of the 50 patients involved in the study, 23 in the interferon alfa-2a–treated
group and 21 in the placebo group were evaluable for efficacy. The duration
of the disease ranged from 6 months to 22 years. Treatment groups were not
significantly different with respect to age (P =
.71), duration (P = .90), and male-female ratio (2 = 1.36; P = .24) at the beginning of the
study (Table 1).
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Demographic Data of the Patients With Behçet Disease*
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Six patients (2 in the interferon alfa-2a–treated group and 4
in the placebo group) failed to complete the study. The reasons for their
withdrawal were severe eye disease in 3 patients (1 in the interferon alfa-2a–treated
group and 2 in the placebo group), progressive mucocutaneous symptoms in 1
(in the interferon alfa-2a–treated group), new eye disease and mucocutaneous
symptoms in 1 (in the placebo group), and progressive mucocutaneous and articular
symptoms in 1 (in the placebo group). In all patients, medication was well
tolerated, and no patients were withdrawn from the study because of adverse
events.
MUCOCUTANEOUS LESIONS
Interferon alfa-2a treatment significantly decreased the duration (interaction
of group by treatment effect: F1.6,67.7 = 4.24, P = .02) and pain (F1.8,76.8 = 4.94, P = .01) of OUs and the frequency of GUs (F1.8,77.9 = 3.93, P = .03) and papulopustular lesions (F1.5,64.8
= 5.18, P = .01). In most patients receiving interferon
alfa-2a, OUs improved rapidly after the initiation of treatment. Some patients
had mild, short-term (3-5 days), multiple, minor ulceration attacks. The mean
frequency and duration of erythema nodosum–like lesions (P = .77 and .27, respectively) and of thrombophlebitis (P = .29 and .61, respectively) also decreased. But there were no statistically
significant differences. Generally, all symptoms tended to return to pretreatment
levels in the posttreatment follow-up period. In the placebo group, no significant
difference was found in measured mucocutaneous lesion variables.
OCULAR MANIFESTATIONS
There was a general improvement in ocular manifestations of patients
receiving interferon alfa-2a therapy compared with their own pretreatment
periods. Of 6 patients, 5 experienced a decrease in the severity and the frequency
of attacks (3 CRs and 2 PRs). The therapy resulted in ineffectiveness in 1
patient. In the placebo group, only 1 patient experienced a decrease in the
severity and the frequency of attacks, while 2 showed no effect or a deterioration
of the ocular symptoms. In the interferon alfa-2a–treated group, 9 of
11 eyes maintained or improved their visual acuity. Five eyes had an improved
acuity at the end of the treatment, and only 3 improved at the end of the
follow-up period. In the placebo group, 2 of 6 eyes had an improved acuity,
and 2 of 6 eyes maintained the same acuity. At the end of these 2 patients'
follow-up period, 3 of the 4 eyes maintained their acuity and 1 still had
an improved acuity. In the interferon alfa-2a–treated group, the inflammatory
score decreased in 7 eyes. In 4 eyes, the score was unchanged. In the placebo
group, the inflammatory score decreased in 3 eyes and remained unchanged at
the end of the treatment in 3 eyes.
ARTICULAR SYMPTOMS
The mean frequency and duration of articular symptoms decreased during
the 3-month treatment period in the interferon alfa-2a–treated group,
but the difference was not statistically different. Articular symptoms also
tended to return to pretreatment levels in the posttreatment follow-up period.
ADVERSE EFFECTS
The primary adverse effects of interferon alfa-2a therapy were mild
flulike symptoms (fever, chills, headache, fatigue, and myalgia) that started
a few hours after the injection and continued less than a day, especially
within the first 2 weeks of treatment. Of 23 patients treated with interferon
alfa-2a, 18 had flulike symptoms. Three patients in the placebo group also
complained from similar symptoms after the injections without respect to the
time of the treatment. Other adverse effects, including reversible alopecia
(n = 1), leukopenia (n = 1), and diarrhea (n = 1), were observed only in patients
with BD treated with interferon alfa-2a.
OVERALL RESPONSE
Of the 23 patients in the interferon alfa-2a–treated group, 15
responded to treatment (2 CRs and 13 PRs); and of the 21 patients in the placebo
group, 3 responded to treatment (3 PRs) (23 = 14.7, P<.005). Four patients in the interferon alfa-2a–treated
group and 3 in the placebo group showed less than a 50% change, while 4 in
the interferon alfa-2a–treated group and 15 in the placebo group experienced
ineffectiveness or worsening of clinical signs and symptoms.
COMMENT
Oral ulcers and GUs, the most common of mucocutaneous lesions in patients
with BD, are characterized by recurrent and painful ulcerations of the oral
and genital mucosa, respectively. They are identical to aphthae (or aphthous
stomatitis) in appearance, but they tend to be more frequent and multiple.
Patients may have single or multiple ulcers that often present during a 1-
to 4-week period. Oral ulcers and GUs are a required feature for the diagnosis
of BD and often are the initial presenting sign. In our study, interferon
alfa-2a treatment significantly decreased the duration and pain of OUs and
the frequency of GUs. In most patients, OUs improved rapidly after the initiation
of interferon alfa-2a treatment. Some patients had mild, short-term (3-5 days),
multiple, minor ulceration attacks that have been reported previously.11, 19-20 Genital ulcers also
improved rapidly, although some patients had mild short-term attacks within
the 3-month treatment period. These results show that interferon alfa-2a treatment
is effective on OUs and GUs, and this effect decreases gradually after the
cessation of treatment. Other researchers13-15,21
have noted similar results.
Cutaneous lesions of the disease are varied and include mainly papulopustular
lesions, erythema nodosum–like lesions, and superficial thrombophlebitis.
Papulopustular lesions, the most common type of skin lesions in patients with
BD, are cutaneous sterile, follicular, or acnelike lesions on a erythematous
base that appear as a papule and in 24 to 48 hours become a pustule.22 Erythema nodosum–like lesions occur mainly
on the lower extremities, but can also be seen on the face, neck, and buttocks.
The lesions generally resolve within 2 to 3 weeks with residual pigmentation,
but recurrences are common. Superficial thrombophlebitis is frequently confused
with erythema nodosum. The subcutaneous venules of the extremities, especially
in male patients, tend to develop thrombosis, leading to sclerosis. The small
vein can be palpated as a stringlike hardening of the subcutaneous tissue
with reddening of the overlying skin.5 In our
study, the mean frequency of papulopustular lesions statistically significantly
decreased with interferon alfa-2a treatment. The mean frequency and duration
of erythema nodosum–like lesions and thrombophlebitis also decreased.
But there were no statistically significant differences because of, most likely,
few patients with erythema nodosum–like lesions and thrombophlebitis.
Previous studies12-13,20-21,23
have also reported marked improvements in the respected cutaneous symptoms
with treatment with interferon alfa-2a.
Ocular involvement is a serious complication of BD. It is characterized
by repeated, explosive, ocular inflammatory attacks that may lead to blindness
in up to 25% of the eyes.24 Symptoms are bilateral
in most of the patients. Young male patients are at an increased risk for
the severe complications of ocular involvement, and they usually require aggressive
treatment with immunosuppressive agents. Previous studies23, 25-31
have reported encouraging results from the use of interferon alfa-2a in patients
with BD. The treatment of ocular symptoms of the disease with interferon alfa-2a
alone or in combination with low-dose corticosteroids led to CR or PR in 21
of 23 patients with BD (18 CRs and 3 PRs). We have also observed an improvement
in ocular manifestations of patients receiving interferon alfa-2a therapy.
Five of 6 patients in the interferon alfa-2a–treated group and 1 of
3 in the placebo group experienced improvement. Although patients treated
with interferon alfa-2a had better results regarding the severity and the
frequency of attacks, visual acuity, and the inflammatory score, they all
tended to return to pretreatment levels during the follow-up period. Because
of the limitations at study enrollment, the number of the patients did not
lead us to apply a statistical evaluation. In addition, the durations of the
treatment and follow-up periods, compared with those of previous studies,
were not sufficient to draw a final conclusion. But, it seems likely that
interferon alfa-2a therapy may be a therapeutic alternative in the treatment
of ocular symptoms. However, because some patients experienced recurrences
under the treatment, we cannot recommend interferon alfa-2a treatment alone
as a first-line treatment choice.
The beneficial effects of interferon alfa-2a therapy for articular symptoms
have been previously reported.10-11,21, 25, 28-30
We also observed a decrease in the mean frequency and duration of articular
symptoms during the treatment period in the interferon alfa-2a–treated
group, but the difference was not statistically different. In addition, the
decrease in the mean frequency and duration of articular symptoms did not
persist during the follow-up period.
The primary adverse effects of interferon alfa-2a therapy are flulike
symptoms that start a few hours after the initiation of the therapy and continue
less than a day. Nausea, vomiting, anorexia, diarrhea, weight loss, hematologic
changes, and a transient increase of hepatic transaminase levels are seen
less frequently.15 In our study, almost every
patient given interferon alfa-2a manifest a flulike syndrome, especially within
the first 2 weeks of the treatment. Because the patients were given oral acetaminophen
before and after the interferon alfa-2a injections during the first month
of the therapy, flulike symptoms were mild and tolerable. Interestingly, 3
patients in the placebo group also complained from similar symptoms after
the injections without respect to the time of the treatment. Other adverse
effects, including reversible alopecia, leukopenia, and diarrhea, were observed
only in patients with BD receiving interferon alfa-2a treatment.
In our study, interferon alfa-2a significantly decreased the duration
and pain of OUs and the frequency of GUs and papulopustular lesions. The mean
frequency and duration of erythema nodosum–like lesions, thrombophlebitis,
and articular symptoms also decreased. We have also observed an improvement
in ocular manifestations. However, all symptoms tended to return to pretreatment
levels during the follow-up period. This suggests a possible need for maintenance
therapy. Although several effective treatments for BD exist, none of them
result in cure of the disease and some are associated with significant adverse
effects compared with interferon alfa-2a treatment. Therefore, our results
indicate that interferon alfa-2a treatment may be an effective alternative,
particularly for the mucocutaneous lesions of BD.
AUTHOR INFORMATION
Accepted for publication August 30, 2001.
Corresponding author: Erkan Alpsoy, MD, Department of Dermatology,
Akdeniz University School of Medicine, 07070 Antalya, Turkey (e-mail: alpsoy{at}med.akdeniz.edu.tr).
From the Department of Dermatology, Akdeniz University School of Medicine
(Drs Alpsoy, Durusoy, Yilmaz, Ermis, Yazar, and Basaran), and the Department
of Ophthalmology, Antalya State Hospital (Dr Ozgurel), Antalya, Turkey.
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Efficacy of interferon alpha in the treatment of refractory and sight threatening uveitis: a retrospective monocentric study of 45 patients
Bodaghi et al.
Br J Ophthalmol 2007;91:335-339.
ABSTRACT
| FULL TEXT
Treatment of Behcet's syndrome
Barnes
Rheumatology (Oxford) 2006;45:245-247.
FULL TEXT
A double-blind trial of depot corticosteroids in Behcet's syndrome
Mat et al.
Rheumatology (Oxford) 2006;45:348-352.
ABSTRACT
| FULL TEXT
Behcet's Disease: A Review
Al-Otaibi et al.
JDR 2005;84:209-222.
ABSTRACT
| FULL TEXT
Infliximab for Recurrent, Sight-Threatening Ocular Inflammation in Adamantiades-Behcet Disease
Sfikakis et al.
ANN INTERN MED 2004;140:404-406.
FULL TEXT
Behcet's syndrome
Stanford
Br J Ophthalmol 2003;87:381-382.
FULL TEXT
Behcet's disease: a new target for anti-tumour necrosis factor treatment
Sfikakis
Ann Rheum Dis 2002;61:ii51-53.
ABSTRACT
| FULL TEXT
From the Library
Br J Ophthalmol 2002;86:1195-1195.
FULL TEXT
Interferon Alfa-2a Is Effective for Mucosal Manifestations of Behcet's Disease
Journal Watch Dermatology 2002;2002:4-4.
FULL TEXT
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