Original Article
A Controlled Trial of Azathioprine in Behçet's Syndrome
N Engl J Med 1990; 322:281-285February 1, 1990
- Abstract
- Abstract
Cytotoxic agents have long been used in Behçet's syndrome, especially for eye involvement, but their effectiveness has been uncertain. We conducted a two-year randomized, placebo-controlled, double-blind trial of azathioprine (2.5 mg per kilogram of body weight per day) in Turkish men with Behçet's syndrome without eye disease (group 1; n = 25) or with eye disease (group 2; n = 48). Corticosteroid treatment remained available to all the patients.
All six patients withdrawn from the study because of severe eye disease were receiving placebo (P<0.001). Azathioprine was superior to placebo in the prevention of new eye disease in group 1 (1 vs. 8 patients; P<0.01) and in group 2 among the 14 patients who at entry had disease in only one eye (P<0.001 ). There were fewer episodes of hypopyon uveitis (1 vs. 15; P<0.001) among the group 2 patients who took azathioprine. The patients taking azathioprine also had less frequent oral ulcers, genital ulcers, and arthritis. There were no serious side effects attributable to azathioprine.
We conclude that azathioprine is effective in controlling the progression of Behçet's syndrome, especially its most serious manifestation, eye disease. (N Engl J Med 1990; 322:281–5.)
Media in This Article
Figure 1
Life-Table Analyses for Group 2.Table 1
Characteristics of the Study Groups at Entry.*Article Activity
- Article
BEHçET'S syndrome is a multisystem disorder characterized by recurrent oral and genital ulcers, arthritis, thrombophlebitis, and uveitis. Its cause is presumed to be viral or immunologic,1 , 2 and its basic underlying pathologic process is that of a vasculitis. Eye disease — an indolent anterior and posterior uveitis and retinitis that can lead to blindness — occurs in approximately half the patients with the disorder.1 , 3
Azathioprine, among other immunosuppressive agents, has been reported to be effective in Behçet's syndrome,4 , 5 although controlled studies are lacking. We conducted a two-year randomized, double-blind trial comparing azathioprine (2.5 mg per kilogram of body weight per day) with placebo in patients with Behçet's syndrome. Corticosteroids were available to all patients. This study was undertaken to determine whether azathioprine has a beneficial effect on preexisting eye disease, can prevent the development of new eye disease, and is effective against other manifestations of the disease.
Methods
The trial was conducted at the multidisciplinary Behçet's syndrome outpatient clinic at the hospital of the Cerrahpaşa Medical Faculty, University of Istanbul, between January 1984 and July 1987. When the study began, approximately 400 patients had been registered at this clinic. Two groups of men who fulfilled O'Duffy's criteria for diagnosis6 , 7 were asked to enter the trial. Patient recruitment was limited to 18 months.
Group 1 consisted of consecutive patients under the age of 40 years whose duration of disease was 24 months or less and who had no history or evidence of uveitis. It has been demonstrated that eye involvement usually develops within the first two years.3 Duration of disease was defined as the time since the diagnostic criteria had been fulfilled. Group 2 consisted of consecutive patients of any age and duration of disease who had ophthalmologic evidence of uveitis.
We excluded patients with irreversible bilateral eye disease, those whose fundi were not assessable, those who lived more than a day's journey from the trial center, and those who had received immunosuppressive agents, levamisole, or penicillamine in the previous three months or systemic corticosteroids in the previous month. After the nature of the trial had been explained to them, some patients decided not to participate. Those who gave their consent were randomly assigned, within each group, to azathioprine (2.5 mg per kilogram per day, rounded to the nearest 25 mg) or matching placebo tablets.
Patients returned to the trial center monthly for 24 months for detailed ophthalmologic tests (including slit-lamp examination, trimirror fundus-lens ophthalmoscopy, and measurement with a Snellen chart of the best corrected visual acuity on a scale of 0 to 10/10) and dermatologic, hematologic, and rheumatologic examinations, the results of which were recorded on standardized forms. A complete blood count, platelet count, and determination of the erythrocyte sedimentation rate (by the Westergren method) were performed at each visit. Hematologists monitored the blood counts, and any total white-cell count of less than 4.0X109 per liter was managed initially by reducing the dosage of medication without breaking the code, and repeating the blood count two weeks later. Compliance was assessed by counting the number of pills returned.
Patients left the trial after severe drug reactions or on ophthalmologic advice in cases of severe eye disease; treatment with an alternative immunosuppressive agent was started without breaking the trial code. Patients with less severe exacerbations of eye disease remained in the study and were given additional methylprednisolone (usually 1000 mg intravenously on three alternate days) or oral corticosteroids.
Life-table techniques were used for most statistical analyses. The cumulative proportions of patients in each group who "survived" to the end of each trial stage (months 3, 6, 12, 18, and 24) were calculated. The terminating events were hypopyon uveitis (an intense leukocytic infiltrate of the anterior chamber visible to the naked eye), the use of pulsed intravenous corticosteroids, and withdrawal from the trial. In our analyses, we assumed that these events occurred midway between assessments. The development of eye disease in a group 1 patient or in an unaffected eye in a group 2 patient was considered a terminal event. The survival curves of the treatment and placebo groups were compared with use of the log-rank test,8 and crude event rates were determined with Fisher's exact test. For other analyses, t-tests with 95 percent confidence intervals, Fisher's exact test for two-by-two contingency tables, or paired t-tests were used. All tests were two-tailed.
Results
Base-Line Comparisons
The number of patients and their assignments (to group 1 or 2 and to azathioprine or placebo) are shown in Table 1Table 1
Characteristics of the Study Groups at Entry.*, along with their demographic characteristics. In group 1 the patients assigned to receive azathioprine were significantly and unexpectedly heavier than those assigned to receive placebo. There was also a suggestion in group 1 of an earlier onset of the first symptom in patients assigned to placebo, although the year of diagnosis was the same. Otherwise the azathioprine and placebo subgroups of groups 1 and 2 were well balanced for these variables, for the frequency of the syndrome's manifestations, and for drug treatments. No patient had received azathioprine, and only five patients (two in azathioprine groups and three in placebo groups) had received other immunosuppressive agents.Dropouts and Compliance
Ten patients dropped out of the trial. In seven this was unrelated to disease or treatment. Four, one from each group, left for military service, two during the first month, and one each in months 6 and 21. Three patients in the placebo groups left in months 1, 3, and 15, for unknown reasons.
There was one death in the trial; a patient in group 2 who was taking placebo died during the second month, of pulmonary vascular disease due to Behçet's syndrome and secondary pneumonia. Another patient in group 2 who was taking placebo sought medical care elsewhere in month 5, and a patient in group 1 who was taking azathioprine left in month 16 because of concern about possible azoospermia.
Returned pill counts showed that the median rate of compliance never fell below 84 percent in the azathioprine groups and 83 percent in the placebo groups.
Eye Disease
The effects of azathioprine on eye disease, excluding visual acuity, are shown in Table 2Table 2
Effects of Azathioprine on Eye Disease..Withdrawals Due to Eye Disease
Six patients in group 2 were withdrawn because of severe eye disease (Table 2). All had been receiving placebo and were given alternative medication. Life-table analysis showed that placebo was associated with a significantly higher cumulative rate of withdrawal due to eye disease of 34 percent after two years (log-rank χ2 = 7.4, P<0.001) (Fig. 1Figure 1
Life-Table Analyses for Group 2.A). No patients needed to be withdrawn from group 1.Development of New Eye Disease
In group 1 nine patients were given diagnoses of eye disease during the trial, eight receiving placebo and one azathioprine (P = 0.008 by Fisher's exact test). There was a significantly higher cumulative rate of absence of eye disease in the azathioprine groups (91 percent) than in the placebo groups (28 percent) (log-rank χ2 = 9.8, P<0.001).
In group 2, 14 patients had uniocular eye disease at the start of the trial, 7 receiving azathioprine and 7 placebo. In five in the placebo group and none in the azathioprine group, disease developed in the unaffected eye (Fig. 1B). Despite the small numbers, the difference was significant (log-rank χ2 = 8.0, P<0.001).
Hypopyon Uveitis
In group 2 seven patients taking placebo had 15 episodes of hypopyon uveitis as compared with one taking azathioprine, who had a single episode (P = 0.018 by Fisher's exact test). There were no episodes of hypopyon uveitis in the patients in group 1.
Corticosteroid Treatment of Deteriorating Eye Disease
To treat deteriorating eye disease, injections of methylprednisolone ( 1 g on three alternate days) were required once by a single patient in group 1 who was taking placebo. In group 2 high-dose methylprednisolone was required by 6 patients (9 episodes) taking azathioprine and 10 patients (16 episodes) taking placebo (Table 2). According to survival-curve analysis, intravenous steroid treatment was not required in 78 percent of those in the azathioprine groups, as compared with 47 percent of those in the placebo groups (log-rank χ2 = 3.4, 0.10>P>0.05). In addition, there were four patients in group 2 taking placebo and one taking azathioprine who required oral corticosteroids; this number was too small to allow statistical analysis (Table 2).
Visual Acuity
Visual acuity was analyzed in group 2 alone by comparing the mean of the numerators of visual acuity for each eye at the beginning and end of the trial by paired t-test (mean [±SD] delta visual acuity [dva] equaled mean visual acuity at the first visit minus mean visual acuity at the last visit). Patients who dropped out were excluded.
With data on the six patients withdrawn from the trial because of severe eye disease included, the mean visual acuity was unchanged between the first and last visits in the azathioprine group (dva = 0.17±1.39; P not significant). There was a small but significant deterioration in visual acuity in the placebo group (dva =1.08±2.59; P<0.025) that was also evident when data on the six patients who were withdrawn were excluded from the analysis (dva = 1.19±1.67; P<0.01). As expected, the mean decrease in visual acuity between the first and last trial visits was largest in the six patients who were withdrawn (dva = 3.06±2.40; P<0.025).
Eye Changes in Group 1
Of the eight group 1 patients taking placebo in whom eye disease developed, two had transient vitreal cells at more than one visit, and one had cells in the anterior chamber on one occasion. In three patients, retinal vasculitis developed. Visual acuity decreased significantly in only one patient. Transient cells in the vitreous were noted in one patient (azathioprine group) on one occasion only.
Effect of Azathioprine on Extraocular Manifestations of Behçet's Syndrome
The effects of azathioprine on extraocular manifestations of Behçet's syndrome were analyzed by combining data on groups 1 and 2. The results are summarized in Table 3Table 3
Extraocular Manifestations.. No patient was withdrawn because of severe extraocular manifestations.There were few patients (never more than one at each visit) with major or herpetiform mouth ulcers9 in either group. Thus, formal analysis was confined to minor ulcers. Azathioprine did not prevent the development of new oral ulcers (Table 3). For those in the azathioprine groups who completed the trial, the prevalence of mouth ulcers decreased significantly, from 43 to 11 percent (P<0.005 for the difference in proportions). The reduction among patients taking placebo was not significant.
The frequency of genital ulceration was low, ranging from 0 to 16 percent in the azathioprine groups and from 3 to 19 percent in the placebo groups. Among those initially free of genital ulcers, 3 in the azathioprine groups (cumulative percentage, 9.8) eventually had ulcers, as compared with 12 in the placebo groups (cumulative percentage, 44.2) (log-rank χ2 = 7.62, P<0.001).
Azathioprine was also beneficial in preventing attacks of arthritis among those who were initially free of this symptom. Seven patients in the placebo groups had arthritis for the first time during the study, as did one in the azathioprine groups (χ2 = 6.60, P<0.02). There was also more deep-vein thrombosis in the placebo groups than the azathioprine groups (χ2 = 2.90, 0.10>P>0.05). Superficial thrombophlebitis was too rare to be analyzed. Papulopustular lesions were not affected by azathioprine.
Neurologic involvement was present in only six patients, all in group 2 — three taking azathioprine and three taking placebo. One group 2 patient taking azathioprine and one taking placebo had pyramidocerebellar involvement. The one taking azathioprine had a variable course and required oral corticosteroids to control increases in intracranial pressure; the other dropped out of the study in the first month. One patient had each of the following: a long-standing brain-stem disorder (Wallenberg's syndrome) that remained unchanged (group 2, azathioprine); brief episodes of numbness of the right side, paresthesias, and upper-motor-neuron signs (group 2, placebo); a mild peripheral neuropathy with an uncertain relation to Behçet's syndrome (group 2, placebo); and hesitancy in micturition plus an episode of severe headache that gradually and spontaneously resolved (group 2, azathioprine).
Laboratory Assessments and Side Effects
Low total white-cell counts (<4.0X109 per liter) were measured on 21 occasions in 11 patients receiving azathioprine and in 3 receiving placebo. All resolved with the temporary reduction or cessation of treatment. The erythrocyte sedimentation rate was the only index of activity measured in this trial. No important or useful trends were identified.
There were no serious side effects attributable to azathioprine that required withdrawal. Gastrointestinal side effects were more frequent in the azathioprine groups (174 episodes in 782 visits; 23 percent) than the placebo groups (105 episodes in 612 visits; 18 percent) (χ2 = 5.25, P<0.05). These episodes included abdominal pain (6 percent in the azathioprine groups vs. 3 percent in the placebo groups), nausea (6 vs. 5 percent), and indigestion (5 vs. 1 percent).
Discussion
We conducted a randomized, controlled, doubleblind trial of azathioprine in the treatment of Behçet's syndrome. Azathioprine was selected because of its reported efficacy in open studies4 , 5 and its relative lack of toxicity10 11 12 as compared with other immunosuppressive agents. Our study was restricted to men, since they have been shown to have more severe disease.13 Including women would have made interpreting the results more difficult, especially with the limited number of patients who present at a single center.
Random assignment resulted in well-balanced azathioprine and placebo subgroups in both group 1 and group 2, although the first symptoms were significantly more recent in the azathioprine subgroup of group 1. However, both groups satisfied the diagnostic criteria at similar times before entry. This would have been a potential source of bias only if (contrary to our previous observations3) the development of eye involvement is more frequent earlier in the disease.
There were relatively few patients in group 1; many patients without eye disease refused to enter the trial. Patients in group 1 had many episodes of transient cells in the vitreous, but visual acuity did not change by more than one point in those who remained asymptomatic (data not shown). We debated whether this represented intraobserver variation in slit-lamp examination, but the changes were usually in patients receiving placebo. Subclinical eye disease has not been adequately studied in Behçet's syndrome.
The effects of azathioprine in patients with established eye disease (group 2) were less subtle (Table 2). All six patients who were withdrawn on ophthalmologic advice because of severe eye disease were from the placebo group; a seventh patient in group 2 who was taking placebo had a marked reduction in vision and left the trial in month 5 to seek medical care elsewhere. There was no evidence that azathioprine was useful in restoring compromised vision, but it was superior to placebo in preserving visual acuity in those with established eye disease.
The effects of azathioprine on extraocular manifestations of the disease were also favorable, as proved by statistically significant reductions in the frequency of oral and genital ulcerations and arthritis. The protocol did not consider the outcome of individual oral ulcers, so we could not assess whether the improvement was due to the healing or prevention of lesions. The similarity in the numbers of new cases of oral ulceration suggests that the benefits may come from improved healing. For genital ulcers, arthritis, and possibly deep-vein thrombosis, the data support a preventive effect.
The rarity of neurologic involvement in our patients did not permit us to draw conclusions. Neurologic involvement is a serious cause of morbidity and occurs in about 5 percent of patients in the prospective studies of Behçet's syndrome.14
Inflammatory bowel disease, which also causes considerable morbidity, especially among the Japanese, is rarely observed in Turkish patients.1 , 3 None of our patients had such involvement.
In summary, our study shows the benefit of azathioprine in controlling the progression of Behçet's syndrome, especially in its most serious manifestation, eye disease. The question of whether patients with asymptomatic eye disease should be treated remains a difficult one. Studies with larger numbers of patients are needed before a firm conclusion can be reached on whether prophylactic azathioprine should be recommended for this group.
We are indebted to the Wellcome Foundation for its support in funding this study and for the supply of matching Imuran (azathioprine) and placebo tablets, and to Mrs. Emine Öztürk for secretarial assistance.
Source Information
From the Departments of Rheumatology, Ophthalmology, Dermatology, and Hematology, Cerrahpaşa Medical Faculty, University of Istanbul, Turkey (H.Y., H.P., Y.T., Y.Ö., S. Serdaroğlu, V.O., S.Y., B.Y., A.M.); the Department of Rheumatology, London Hospital, London (C.G.B., A.S., S. Somani); and the Wellcome Research Laboratories, Beckenham, Kent, United Kingdom (G.E.L.). Address reprint requests to Dr. Yazici at Safa Sok. 17/4, Kadiköy, Istanbul, Turkey.
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