Dermatology Online Journal

Colchicine and benzathine penicillin in the treatment of Behçet disease: A case comparative study
Professor Makram M Al-Waiz, Professor Khalifa E Sharquie, Dr Mohammed H A-Qaissi, and Dr Raafa K Hayani
Dermatology Online Journal 11 (3): 3

Department of Dermatology & Venereology, College of Medicine, University of Baghdad, Medical City Teaching Hospital

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Abstract

Behçet disease is a chronic relapsing disease characterized by multiple signs and symptoms such as recurrent orogenital ulceration, eye involvement, skin manifestations, and other systemic involvement. Multiple therapeutic modalities have been used to treat Behçet disease. These agents act through different mechanisms and are associated with a variety of side effects. We performed a case-comparative study to evaluate efficacy of combined colchicine and benzathine penicillin in the treatment and prophylaxis of Behçet disease. Sixty-six patients who fulfilled the international study group criteria for diagnosis of Behçet disease were included. The patients were divided into three groups: group 1 (20 patients) received 1.2 Mu benzathine penicillin injection monthly; group 2 (21 patients) received two tablets of colchicine daily (each tablet contained 0.5 mg); and group 3 (25 patients) received both 1.2 Mu benzathine penicillin injection monthly and two tablets of colchicine daily. Each patient was followed up monthly for 5 months, 4 months on treatment and 1 additional month followup. The clinical manifestation index (CMI), the numerical sum of the clinical features, was calculated for each patient initially and then monthly. Pathergy test was performed for each patient monthly. The CMI was reduced by colchicine and benzathine penicillin treatment, and the reduction was highly significant. The reduction in the CMI remains satisfactory and good for 1 month after stopping the treatment. When each colchicine and benzathine Penicillin are used alone the index is also reduced significantly, but this reduction is much less than when both drugs are used together and there is also rapid and earlier relapse. Based on our findings, the combination of colchicine and benzathine penicillin appears to be of greater efficacy in the treatment of Behçet disease than the use of either drug alone.

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Introduction

Behçet disease (BD) is a chronic relapsing disease characterized by multiple signs and symptoms such as recurrent orogenital ulceration, eye involvement, skin manifestations, and other system involvement [1]. The pathogenesis of BD is probably mediated by a combination of factors involving immune dysregulation, inflammatory mediators, and infectious agents such as herpes simplex virus and Streptococcus sp. [2]. Patients with BD have a higher incidence of tonsillitis and dental caries associated with Streptococcus sp.; induction of BD symptoms occurs after dental treatment and Streptococcal antigen skin test [3, 4]. The proportion of Streptococcus sanguis in the oral flora of patients with BD is high [5]. Circulating immune-complex mediated damage together with enhanced neutrophil migration may be involved in the pathogenesis of systemic and mucocutaneous effects of BD [6]. Recommended treatment of BD includes tetracycline and cephalexin [7], potent topical corticosteroids, intralesional glucocorticoids [8], dapsone [9], thalidomide [10], low dose oral methotrexate [11]; these act through different mechanisms and are associated with a variety of side effects. Colchicine was previously used to treat a variety of conditions such as psoriasis [12, 13, 14], recurrent aphthous stomatitis [15], leukocytoclastic vasculitis [16], and others. Benzathine penicillin G is used in depot form. Penicillin G is released slowly from the injected area and this release produces relatively low but persistent concentrations of antibiotic in the blood [17]. The average duration of demonstrable antimicrobial activity in the plasma is about 26 days [17]. Penicillin acts on gram-positive and gram-negative cocci, gram-positive bacilli, and spirochetes [18]. The aim of this work was to evaluate the efficacy of colchicine plus benzathine penicillin in the treatment and prophylaxis of BD.

Figure 1	Figure 2
Figure 1. Genital ulceration of Behçet disease
Figure 2. Eye involvement of Behçet disease

Figure 3	Figure 4
Figure 3. Folliculitis-like involvement
Figure 4. Pathergy response

Patients and methods

This was a case comparative study of colchicine plus benzathine penicillin in the treatment of BD.

Patients

Patients with BD who were registered at the multidiscipline BD clinic in Baghdad Teaching Hospital were recruited in this study. Those who fulfilled the International Study Group for diagnosis of BD were included.

The nature of the treatment was explained to the patients and their formal consent was obtained.

Patients with the following manifestations were included in the study:

• Mucocutaneous manifestations
• Eye involvement
• Joint involvement

Patients with the following manifestations were excluded from the study:

• Neurological involvement
• Cardiovascular involvement
• Other systemic problems
• Pregnancy

A full history was obtained from the patients (age, sex, smoking, first presenting feature, duration of symptoms, frequency of occurrence of symptoms, specific drug history). The size, duration, frequency and the number of the oral, genital ulcers, and the aggravating factors were examined. The patients were asked to stop any other treatment for one month before entering the study.

The clinical manifestation index (CMI) which is the numerical sum of the clinical features was calculated for each patient ( Table 1) [19, 20].

The following investigations were done for the patients:

• Complete blood count and ESR
• C-reactive protein
• GUE
• Blood urea and serum creatinine
• Pathergy test
• HLA typing

The pathergy test was performed under sterile condition without injection of saline by insertion of a 20 gauge needle through the flexor skin of the forearm; the test site was read for erythema, papule formation, and pustule formation at 48 hours [21].

The study included 66 patients divided into 3 groups:

• group 1 (n = 20) was allocated to receive 1.2 million units benzathine penicillin by injection monthly
• group 2 (n = 21) was allocated to receive two tablets of colchicine daily (each tablet contains 0.5 mg).
• group 3 (n = 25) was allocated to receive both 1.2 million units benzathine penicillin injected monthly plus two tablets of colchicine daily.

Each patient was followed up monthly for 5 months, 4 months on treatment and a subsequent month without treatment. CMI was calculated for each patient initially and then monthly. The patients were examined clinically and then by ophthalmologist, rheumatologist or other specialist as indicated. The laboratory investigations mentioned above were performed for each patient monthly. Also the pathergy test was done monthly. The patients were instructed to report any side effect of the drug.

Statistical analysis

Collected information was coded and analyzed using SPSS 0.7 (Statistical Package for Social Science). Data were arranged and distributed in number, percent, mean, and standard deviation. Association between different variables measured by using Paired t-test and One Way ANOVA test (analysis of variance). Significance was considered with p < 0.05. (Table 1 [19, 20])

Results

The study comprised 71 patients; 32 females (45 %) and 39 males (55 %). Five patients defaulted from the study. Three patients were receiving BP injection while the other two were receiving oral colchicine. Sixty-six patients completed the study, 28 females (42.4 %) and 38 males (57.5 %). Their ages ranged between 19 and 62 years with a mean ± SD of 35.5 ± 10.44 years. The duration of the disease was 2-22 years with a mean ± SD of 8.01 ± 6.23 years. Pathergy test was positive in 63.6 percent of patients. Family history was positive in 18.1 percent of patients.

The effect of BP injection treatments on clinical manifestation index (CMI) (group A):

The CMI before therapy ranged between 5 and 13 with a mean ±SD of 8.95±1.85. The mean of CMI started to decline after the first month of therapy with BP injection to significantly lower levels (5.70, 3.85, 3.60 and 3.35) for the first, second, third, and fourth months respectively (p = 0.05). After stopping the treatment in the fifth month, the mean of CMI returned to a value significantly different from the baseline value (the mean was 8.05) (Table 2, Fig. 1). The peak reduction in the mean of CMI was in the second month and there was no further reduction in the third and fourth months of therapy.

The effect of oral colchicine treatments on clinical manifestation index (CMI) (group B)

The CMI before therapy ranged between 5 and 15 with a mean ± SD of 9.48± 2.80. The mean of CMI started to decline after the first month of therapy with oral colchicine to a significant lower levels (4.52, 3.10, 2.24, and 2.10) for the first, second, third, and fourth months respectively (p = 0.05). After stopping the treatment in the fifth month, the mean of CMI returned to a value significantly different from the baseline value (the mean was 7.23) (Table 3, Fig. 1). The peak reduction in the mean of CMI was in the third month, there was no further reduction in the fourth month of therapy.

The effect of a combination of oral colchicine and injected BP on clinical manifestation index (CMI) (group C)

The CMI before therapy ranged between 5 and 15 with a mean ±SD of 9.16±2.56. The mean of CMI started to decline directly after the first month of therapy with a combination treatment to a significant lower levels (2.64, 1.84, 1.32, 1.32) for the first, second, third, and fourth months respectively (p = 0.05). After stopping treatment in the fifth month, the mean of CMI started to rise again gradually but remained significantly lower than the level before therapy (p = 0.00000001) (Table 4, Fig. 1). The peak reduction in the mean of CMI was in the third month, there was on further reduction in fourth month of therapy.

When the three groups compared to each other, group C was more effective (p = 0.00000001) than groups A and B (p = 0.0005337 and 0.00000034 respectively).

Side effects

No side effects were seen in group A throughout the study period. There was hair loss in one patient and mild gastrointestinal disturbances in three patients in group B. Also there were mild gastrointestinal disturbances in two patients in group C.

Discussion

The etiology of BD is still obscure but probably multifactorial; exacerbations occur in genetically predisposed individuals in association with infection or other immunologic stimulation [8]. Treatment of BD is still not well established although many drugs have been used to control the signs and symptoms of the disease; these drugs include cortisone, dapsone, colchicine, azathioprine [8] More recently zinc sulfate has been used successfully as an immune modulator and antioxidant in a double blinded cross over study.

Multiple drug regimes are often used in medicine to enhance action and decrease side effects. The aim of this work is mainly to evaluate the efficacy of combination oral colchicine and injected BP in the management of BD.

The clinical manifestation index was reduced by colchicine and BP treatment, and the reduction was highly significant. The reduction in the CMI remains satisfactory and good 1 month after stopping the treatment. This means that the combination of colchicine and BP has therapeutic and prophylactic roles in BD.

When colchicine or BP was used alone, the index was also reduced and the reduction was statistically significant, but the reduction was more marked with the combination of BP and colchicine.

In this study, the BP treatment was found to be completely devoid of significant side effects. The previously reported serious side effects seen with colchicine, such as polyneuropathy [23], pancytopenia [24, 25], and renal failure [25] were not observed in this study. There was hair loss in one patient and mild gastrointestinal disturbances in five patients. The small dose of colchicine (0.5mg twice daily) used might explain the low incidence of side effects.

The mechanism of action of colchicine in BD may be attributed to inhibition of PMN chemotaxis and lysosomal degranulation [26]. BP acts mainly on Streptococcus sanguis, which is present in the oral flora of a high proportion patients with BD [27]. Decreasing this flora may prevent abnormal immune reaction and response to the heat-shock protein normally present in tissue and microbial agents; this in turn prevents tissue injury.

Colchicine and BP are effective as single agents in the treatment of BD. A combination of both colchicine and BP proved to have more efficacy in the treatment of BD compared to either drug alone. The relapse rate was higher when colchicine or BP were given individually in comparison with the combined therapy. The side effects with this mode of therapy were negligible. A long term follow up is recommended to evaluate the prophylactic effect of a combination treatment. This multiple drug regimen is highly recommended in the treatment of patients with BD.

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