A double-blind trial of depot corticosteroids in Behçet's syndrome

Abstract

Objectives. Corticosteroids are widely used in Behçet's syndrome despite the absence of controlled studies. We assessed the effect of depot corticosteroids primarily for genital ulcers and secondarily for the other mucocutaneous manifestations of Behçet's syndrome.

Methods. We randomized 86 patients who had active disease with genital ulcers to receive either intramuscular corticosteroid injections (40 mg methylprednisolone acetate) or placebo every 3 weeks for 27 weeks.

Results. Seventy-six patients (88%) completed the treatment. There were no significant differences in the mean number of genital and oral ulcers, or folliculitis between groups. The mean number of erythema nodosum lesions was less in the corticosteroid group as a whole (P=0.0046); subgroup analyses revealed that this was significant for females (P=0.0148) but not for males (P=0.1).

Conclusion. Low-dose depot corticosteroids did not have any beneficial effect on genital ulcers. However, it was useful in controlling erythema nodosum lesions, especially among the females.

Behçet, Corticosteroids, Erythema nodosum, Genital ulcer, Therapy

Behçet's syndrome is a systemic vasculitis of unknown aetiology involving small and large vessels. The disease is characterized by variable clinical manifestations, such as recurrent oral and genital ulcerations, folliculitis, erythema nodosum, panuveitis, arthritis, thrombophlebitis, and gastrointestinal and central nervous system involvement [1, 2]. Genital ulcers occur in 80% of patients, on the scrotum in the male and on the labia (major or minor) in the female. They usually heal with scarring in a few weeks. Unlike oral ulcers, genital ulcers are difficult to treat topically because of their anatomical location. Their major impact is decreased quality of life due to pain and discomfort. Cyclosporin A [3], azathioprine [4], thalidomide [5], colchicine [6], interferon α [7] and dapsone [8] have been shown to be beneficial for genital ulcers in controlled trials. Oral corticosteroids may be helpful in the short term but their use in the long term is of major concern because of side-effects, and there are no controlled data on corticosteroid use in Behçet's syndrome.

We assessed the effect of intramuscular depot corticosteroid injections every 3 weeks for 27 weeks primarily on genital ulcers and secondarily on other mucocutaneous manifestations of Behçet's syndrome and on arthritis.

Patients and methods

Patients

Between February 2001 and March 2002 we recruited consecutive patients fulfilling the criteria for the diagnosis of Behçet's syndrome [9] from the multidisciplinary Behçet's Syndrome Outpatient Clinic at the Cerrahpasa Medical Faculty, Istanbul. This unit, operative since 1976, currently has more than 6000 registered patients.

Inclusion criteria

The patients had to (i) be 18–45 yr of age, (ii) have active disease, defined as the presence of at least one genital ulcer occurring within the preceding 6 months, and (iii) live in Istanbul.

Exclusion criteria

We excluded patients who (i) had received immunosuppressive agents and corticosteroids ≥5 mg/day within the preceding 1 month, (ii) had severe organ involvement or eye disease, or (iii) had diabetes mellitus, active infection, peptic ulcer, hypertension or pregnancy.

Patients were withdrawn from the study if they (i) had any organ involvement or eye disease requiring immunosuppressive agents or corticosteroids, (ii) had hypertension or active infection, or (iii) expressed a wish to withdraw from the study.

Patients continued their previous treatment with colchicine, low-dose aspirin, amitriptyline, acetaminophen or non-steroidal anti-inflammatory drugs during the trial. Topical treatment and any additional systemic drugs, such as thalidomide, were also permitted for oral and genital ulcers; only systemic immunosuppressives were withheld.

The study was approved by the Ethics Committee of Cerrahpasa Medical Faculty and informed consent was obtained from the patients.

Randomization

Subjects were randomly assigned to receive either depot corticosteroid intramuscular injections (40 mg methylprednisolone acetate) or placebo (1 ml of isotonic saline solution) every 3 weeks for 27 weeks. Randomization was achieved using random numbers generated by a computer. A study nurse, not involved in data collection, kept the randomization list and injected the drug or placebo intramuscularly. The syringe was covered with a label to conceal the milky appearance of the corticosteroid solution. The study drugs were purchased commercially. The randomization code was not opened until the data had been entered into the computer for analysis.

Follow-up and data collection

Fasting blood sugar levels of the patients were determined at entry into the trial. The patients were examined every 3 weeks by a dermatologist (C.M.) and a rheumatologist (S.Y.) for 27 weeks. Post-treatment follow-up continued for an additional two visits, 4 and 8 weeks after the trial ended. The numbers of mucocutaneous lesions and of joints with arthritis were recorded at each visit. The number of follicular lesions was graded as 0 = no lesion, 1 = 1–5 lesions, 2 = 6–15 lesions and 3 = more than 15 lesions. Eye examination was done at study entry and at the last visit or at any time when necessary. The physicians involved in patient assessment were blinded to the treatment allocation.

Side-effects were recorded by questioning the patients at each visit for fatigue, increased appetite, weight gain, swelling of the face, hypertrichosis, abdominal pain or any other symptom volunteered by the patient.

Outcome measures

The difference in the mean number of genital ulcers between the two arms of the study was the primary outcome during the treatment period, and the differences in the mean numbers of other mucocutaneous lesions and attacks of arthritis were the secondary outcome measures.

Statistical analysis

Aiming at a power of 80% and a significance level of 0.05, a target sample of 84 patients in total (42 in each arm) was calculated, assuming a 30% response in the placebo and a 60% response in the steroid group (two-tailed). The analyses were performed on the basis of intention-to-treat. All of the clinical parameters were based on the data obtained by the physicians at clinical visits. The baseline demographic data were compared by Student's t-tests and χ² tests (both two-tailed). The differences between the mean number of lesions among the drug and placebo groups were analysed by the Mann–Whitney U-test (two-tailed). Data are given as the mean and s.d.

Role of sponsor

The sponsor had no say in the study design, data interpretation or publication decisions.

Results

Patients

Eighty-six patients (43 female, 43 male) entered the trial. Seventy-six patients (88%; 36 male, 40 female) completed the treatment and 72 patients (84%; 34 male, 38 female) completed the post-treatment observation periods (Fig. 1). Clinical characteristics at baseline were similar in the corticosteroid and placebo arms (Table 1) except that the corticosteroid arm had significantly fewer patients with a history of erythema nodosum than the placebo arm [13/42 (31%) vs 27/44 (61%), P = 0.004].

Fig. 1.

Outcome of randomization and follow-up of the patients.

Table 1.

Patients’ characteristics at baseline

	Steroid (n = 42)	Placebo (n = 44)
Female/male	21/21	22/22
Age (yr), mean ± s.d.	31.7 ± 7	29.4 ± 6
Body weight (kg), mean ± s.d.	65.6 ± 11	65.7 ± 10
Disease duration (yr), mean ± s.d.a	3.9 ± 4.7	2.8 ± 3.3
Clinical manifestations: no. of patients (%)
Genital ulcers	42 (100)	44 (100)
Oral ulceration	42 (100)	44 (100)
Folliculitis	37 (88)	36 (82)
Erythema nodosum	13 (31)b	27 (61)b
Arthritis	11 (26)	9 (21)
Positive pathergy result	25 (60)	32/43 (73)
Receiving colchicine at baseline, no. of patients (%)	18 (43)	24 (55)
Receiving other drugs at baseline, no. of patients
NSAIDsb	1	4
Low-dose aspirin	3	3
Amitriptyline	2	4
Fasting blood glucose (mg/dl), mean ± s.d.	81 ± 13	83 ± 14
New patients, no. (%)	25 (60)	20 (46)

^aTime elapsed since diagnostic criteria had been fulfilled; ^bP = 0.004.

In subgroup analysis, a significant difference between the corticosteroid and placebo arms persisted among the males [3/21 (14%) vs 11/22 (50%), P = 0.012], and there was a trend in the same direction among the females [10/21 (48%) vs 16/22 (73%), P = 0.092].

The numbers of withdrawals and drop-outs and the reasons for them are given in Fig. 1. One man in the corticosteroid group was excluded from the outcome analyses as he did not return to the clinic after the randomization of treatment. Two men, one in each treatment arm, developed eye involvement and were withdrawn from the trial because they required immunosuppressives (Fig. 1).

Outcome measures

There were no significant differences in the mean numbers of genital ulcers or in the mean numbers of oral ulcerations and cases of folliculitis and arthritis during the treatment and post-treatment periods (Tables 2–4). Erythema nodosum occurred significantly less in the treatment arm (0.1 ± 0.3 vs 0.3 ± 0.5, P = 0.0046) compared with the placebo group. When the women and men were analysed separately, this significant difference remained robust among the women (0.2 ± 0.4 vs 0.4 ± 0.5, P = 0.0148) but not among the men (0.1 ± 0.1 vs 0.2 ± 0.4, P = 0.1). The effect of corticosteroids observed among the female patients disappeared during the post-treatment period (Table 2).

Table 2.

Mean number of lesions during treatment and post-treatment periods among males and females

	Treatment period					Post-treatment period
	Steroid (n = 41)	Placebo (n = 44)	Pa	Steroid (n = 34)	Placebo (n = 40)	Pa
Genital ulcers	0.3 ± 0.4	0.3 ± 0.4	0.7	0.1 ± 0.2	0.1 ± 0.4	0.9
Oral ulceration	1.8 ± 1.0	1.8 ± 1.2	0.7	1.9 ± 1.6	2.0 ± 2.3	0.6
Erythema nodosum	0.1 ± 0.3	0.3 ± 0.5	0.0046	0.2 ± 0.4	0.6 ± 1.9	0.7
Folliculitis	1.1 ± 0.7	1.0 ± 0.6	0.5	1.0 ± 0.8	0.9 ± 0.7	0.7
Joints with arthritis	0.1 ± 0.4	0.1 ± 0.3	0.9	0.1 ± 0.4	0.1 ± 0.3	0.5

Values are mean ± s.d. for the unadjusted total number of lesions in patients during the whole trial. All outcome measures were based on the data observed by the physician at three weekly clinic visits during the treatment period and monthly clinic visits during the post-treatment period.

^aMann–Whitney U-test (two-tailed).

Additional treatment

Additional treatment was given in both the corticosteroid and the placebo arm; four patients in each arm received colchicine, three patients in each arm received amitriptyline, nine patients in each arm received non-steroidal anti-inflammatory drugs and one patient in the placebo arm received low-dose aspirin. One female patient with severe oral ulcerations from the corticosteroid arm and one female patient with severe genital ulcers from the placebo arm were treated with short courses of thalidomide.

Side-effects

The side-effects described as a response in the questionnaire at each visit were similar in the corticosteroid and placebo arms and these events were mild (Table 5). The mean body weights of corticosteroid- and placebo-treated patients were 65.1 ± 10 and 65.6 ± 10 kg, respectively, at the last visit, which were not different from the baseline in both groups (Table 1).

Discussion

In this first double-blind, placebo-controlled study of the use of corticosteroid in Behçet's syndrome, we have shown that low-dose depot corticosteroids were not beneficial for genital ulcers, oral ulcerations, folliculitis or arthritis in Behçet's syndrome. However, it was significantly useful in controlling erythema nodosum lesions, especially among the females. In general, female patients with Behçet's syndrome have a more favourable course [10] and are more responsive to colchicine treatment compared with males [6]; this is similar to what was observed in the present trial. This suggests less severe disease expression among the females. On the other hand, when the data were analysed for each gender separately, although with smaller samples, the mean numbers of mucocutaneous lesions were similar between the two genders (Tables 3 and 4). Other explanations for the lack of a corticosteroid effect among the males are a beta error or the use of less sensitive outcome measures.

Table 3.

Mean number of the lesions during treatment and post-treatment periods among females only

	Treatment period					Post-treatment period
	Steroid (n = 21)	Placebo (n = 22)	Pa	Steroid (n = 18)	Placebo (n = 22)	Pa
Genital ulcers	0.2 ± 0.3	0.4 ± 0.4	0.4	0.0 ± 0.1	0.2 ± 0.6	0.2
Oral ulceration	1.8 ± 1.1	1.8 ± 1.3	0.9	1.9 ± 1.7	2.1 ± 2.2	0.9
Erythema nodosum	0.2 ± 0.4	0.4 ± 0.5	0.0148	0.2 ± 0.5	0.8 ± 2.5	0.9
Folliculitis	0.7 ± 0.6	0.8 ± 0.4	0.6	0.6 ± 0.7	0.8 ± 0.7	0.3
Joints with arthritis	0.2 ± 0.6	0.1 ± 0.4	0.8	0.2 ± 0.6	0.1 ± 0.3	0.2

Values are mean ± s.d. for the unadjusted total number of lesions in patients during the whole trial. All outcome measures were based on the data observed by the physician at 3-weekly clinic visits during the treatment period and monthly clinic visits during the post-treatment period.

^aMann–Whitney U-test (two-tailed).

Table 4.

The mean number of the lesions during treatment and post-treatment periods among males only

	Treatment period					Post-treatment period
	Steroid (n = 20)	Placebo (n = 22)	Pa	Steroid (n = 16)	Placebo (n = 18)	Pa
Genital ulcers	0.3 ± 0.5	0.3 ± 0.5	0.8	0.1 ± 0.2	0.0 ± 0.1	0.1
Oral ulceration	1.8 ± 1.1	1.8 ± 1.1	0.7	1.8 ± 1.5	1.8 ± 2.4	0.5
Erythema nodosum	0.1 ± 0.1	0.2 ± 0.4	0.1	0.2 ± 0.3	0.4 ± 0.8	0.7
Folliculitis	1.6 ± 0.7	1.3 ± 0.7	0.1	1.4 ± 0.7	1.0 ± 0.7	0.1
Joints with arthritis	0.0 ± 0.1	0.1 ± 0.1	0.7	0.0 ± 0.1	0.1 ± 0.3	0.6

Values are mean ± s.d. for the unadjusted total number of lesions in patients during the whole trial. All outcome measures were based on the data observed by the physician at 3-weekly clinic visits during the treatment period and monthly clinic visits during the post-treatment period.

^aMann–Whitney U-test (two-tailed).

Table 5.

Adverse effects

	Steroid (n = 36)			Placebo (n = 39)
Adverse effect	≤2 visits	≥3 visits	≤2 visits	≥3 visits
Fatigue	15 (17)	15	8 (14)	26
Increased appetite	6 (5)	2	18 (3)	2
Weight gain	17 (11)	9	20 (14)	10
Swelling of face	4 (1)	–	4 (1)	1
Abdominal pain	8	–	7 (2)	6
Hypertrichosis	2 (1)	1	2	–

The table is based on positive answers to a predefined list of questions. Data are numbers of patients who had any adverse effects during the treatment period. The numbers in parentheses are the numbers of patients who had adverse affects in the post-treatment period in parentheses.

Erythema nodosum occurred significantly less often in the corticosteroid treatment group (Table 2). It is to be noted that the patients in the treatment arm historically had had less frequent erythema nodosum lesions when compared with the placebo arm. When the genders were analysed separately, a positive history of erythema nodosum remained significant among the males and there was a trend for more erythema nodosum among the females. This casts doubt on the importance of the lessening of erythema nodosum lesions in the active treatment group in the trial, in that the females had fewer erythema nodosum lesions to start with. On the other hand, the disappearance of a significance difference between treatment and placebo groups with cessation of therapy suggests that the effect of corticosteroids on erythema nodosum that we noted among the females was real. As our trial was designed primarily for patients with genital ulcers, a properly controlled study is warranted in male patients with erythema nodosum. Moreover, the number of patients studied was not high enough to show a difference with respect to arthritis.

Another limitation of our trial, in addition to a beta error, is that the half-life of intramuscular injection of 40 mg methylprednisolone acetate is approximately 139 h (range 58–886 h). A more frequent dosing interval and/or a higher dosage could have been more effective in the lesions of Behçet's syndrome. However, the reason we chose this dose and frequency was to avoid the well-known side-effects of corticosteroids. In our trial, adverse effects were similar and mild among both groups during both the treatment and post-treatment periods.

There were further limitations of our trial. Our patients had limited disease as they had mainly mucocutaneous lesions, and Behçet's syndrome shows geographical variability [11]. Therefore, our conclusions may not be generalizable to all patients with Behçet's syndrome.

In conclusion, in this, the first double-blind placebo-controlled study of depot corticosteroids in Behçet's syndrome, low-dose depot steroids were not effective in treating genital ulcers, or oral ulceration or folliculitis. Corticosteroids can be used in controlling erythema nodosum lesions, especially among females.

^†These authors contributed equally to this work.

This study was supported by the Association for the Advancement of the Rheumatology Section at Cerrahpasa Medical Faculty.

The authors do not have any conflict of interest.

Author notes

Department of Dermatology, 1Division of Rheumatology, Department of Medicine, 2Department of Ophthalmology and 3Department of Biostatistics, Behçet's Syndrome Research Centre, Cerrahpasa Medical Faculty, University of Istanbul, Turkey.