Effects of Smoking and HLA-B51 on Clinical Manifestations in Behçet’s Disease: Retrospective Analysis of 209 Patients in a Turkish Population

Abstract

Objectives: This study aims to investigate the separate and cumulative effects of smoking and human leukocyte antigen (HLA)-B51 on the severity and clinical manifestations of Behçet’s disease (BD).
Patients and methods: A total of 209 patients (119 males, 90 females; mean age 42.97±10.44 years; range 23 to 75 years) with BD were included in this retrospective study. The severity and clinical manifestations of BD, smoking habits, and presence of HLA-B51 of patients were obtained from medical records. The severity of BD was evaluated with Behçet’s Syndrome Activity Scale (BSAS). Relationship between smoking habits and presence of HLA-B51 with disease severity and clinical manifestations was investigated.
Results: Presence of HLA-B51 was effective on BSAS, erythema nodosum (EN), articular, ocular and neurological involvements (p=0.001, p=0.011, p=0.013, p=0.001, p=0.038, respectively). Smoking was also effective on BSAS, EN, articular, ocular and neurological involvements (p=0.001, p=0.001, p=0.013, p=0.042, p=0.027, respectively). There was a strong association between positive HLA-B51 with smoking (p=0.004). Smoking and HLA- B51 were effective on articular involvement, smoking was effective on EN, and HLA-B51 and smoking were effective on ocular and neurological involvements (p=0.039, p=0.040, p=0.001, p=0.028, p=0.037, respectively).
Conclusion: Our findings indicate that smoking and HLA-B51 influence severity and systemic involvements of BD with a positive relationship in between. We recommend that smoking and HLA-B51 should be considered simultaneously in BD since this relationship may lead to incorrect inferences.

Introduction

Behçet’s disease (BD) is an autoimmune inflammatory disorder characterized by recurrent oral aphthous ulcers, genital ulcers, and the involvement of musculoskeletal and other systems. Clinical features of BD are affected by both genetic and environmental factors and may vary between individuals and societies.(1,2)

Human leukocyte antigen (HLA)-B51 has been recognized as the strongest genetic predisposing factor for BD. In the literature, a relationship has been reported between HLA-B51 and different manifestations of BD which varies according to regions and ethnic backgrounds.(1,3,4)

Smoking which is the most widespread addiction in the world is an environmental factor associated with many diseases. Toxic components in the cigarette which stimulate vasospasm and platelet aggregation while decreasing the antioxidants in blood damage the vascular and immune systems.(2) There are different speculations about the relationship between BD and smoking. While some authors claim that smoking can activate, others claim that smoking cessation can activate several manifestations of BD. However; the general consensus is that smoking alleviates oral aphthous lesions but aggravates other manifestations of BD.(5-8)

In the literature, there are studies which investigated the effect of HLA-B51 or smoking on the manifestations of BD. However, to our knowledge, there is no other study that investigated the cumulative effects of both on the clinical manifestations of BD. Therefore, in this study, we aimed to investigate the separate and cumulative effects of smoking and HLA-B51 on the severity and clinical manifestations of BD.

Patients and Methods

We retrospectively reviewed the medical records of 209 patients with BD (119 males, 90 females; mean age 42.97±10.44 years; range 23 to 75 years) who were examined in Physical Medicine and Rehabilitation, Dermatology and Ophthalmology Department of Medical Faculty of Akdeniz University between January 2010 and October 2014. Patients older than 18 years of age and who met the 1990 International Study Group classification criteria for BD were included.(9) Patients who had other inflammatory diseases such as rheumatic diseases, infectious diseases (hepatitis B virus, hepatitis C virus, human immunodeficiency virus), and malignancy were excluded. Informed consents were obtained from patients in accordance with the Declaration of Helsinki.

All patients were evaluated for their smoking status and separated into a smoking group (smoking or smoking cessation patients, n=103) and non-smoking group (never smoking patients, n=106). Patients were also classified as HLA-B51 positive (n=62) or negative (n=147). In the last stage, patients were divided into four groups: Group 0 (HLA-B51 negative and non-smoking), Group 1 (HLA-B51 positive and non-smoking), Group 2 (HLA-B51 negative and smoking), and Group 3 (HLA-B51 positive and smoking).

Behçet’s Syndrome Activity Scale (BSAS10) scores were noted for all patients. The manifestations of BD and articular- extra-articular involvements were noted. Patients with articular involvement were classified as monoarticular, oligoarticular, and polyarticular.

Statistical analysis
The IBM SPSS version 20.0 software program (IBM Corporation, Armonk, NY, USA) was used for statistical analysis. Chi-square tests were used for comparing nominal variables. Shapiro-Wilk test was used for testing normality. Multivariate analysis was performed using binary logistic regression with forward conditional method. Four groups were compared using Kruskal- Wallis test, later the groups were compared with each other using Mann-Whitney U test and Bonferroni correction. Alpha significance level less than 0.05 was considered as statistically significant.

Results

The demographic and clinical characteristics of patients are summarized in Table 1. Smoking rate was significantly higher in male sex than female sex. Demographic and clinical characteristics of patients with BD according to sex are summarized in Table 2.

Table 1. Demographic and clinical characteristics of 209 patients with Behçet’s disease

Table 2. Demographic and clinical characteristics of patients with Behçet’s disease according to sex

Table 3. Demographic and clinical characteristics of human leukocyte antigen-B51-positive and -negative patients with Behçet’s disease (n=209)

Table 4. Demographic and clinical characteristics of smoking and non-smoking patients with Behçet’s disease (n=209)

Three binary logistic regression models were performed to analyze factors affecting articular, ocular involvements, and EN. Both smoking and HLA-B51 were effective on articular involvement. Smoking was effective on EN. While smoking or HLA alone was not effective, HLA-B51 with smoking was effective on ocular and neurological involvements (Table 5).

Table 5. Three different binary logistic regression models for analyzing factors affecting articular, ocular involvements, and erythema nodosum

Table 6. Effects of positive human leukocyte antigen-B51 and/or smoking on Behçet’s Syndrome Activity Scale scores (n=209)

Discussion

In this study, both smoking and positive HLA- B51 were found to be effective on BSAS, EN, articular, ocular and neurological involvements. Surprisingly, smoking rate was higher in the patients with positive HLA-B51 than in patients with negative HLA-B51.

In the literature, many studies have shown that HLA-B51 and smoking are factors associated with clinical manifestations of BD.(2,5,7,11) Gür et al.(12) have reported that HLA-B51 rate in Behçet's patients with articular involvement was significantly higher than patients without articular involvement, but smoking rates were not significantly different among them. In our study, both HLA-B51 and smoking were shown to be effective, but both of them when they are together were not more influential on articular involvement.

In the literature, an association between HLA-B51 with clinical involvement and prognosis of BD has been reported.(13-16) Results of these studies partially support our findings, but they have not examined whether patients smoke or not. Bilgin et al.(2) have also reported that cystoid macular edema among current smoking patients with BD was significantly higher than non- smoking patients, but smoking was inefficient on other ocular involvement. They have not examined HLA-B51. Their finding might seem to be partially different at first glance from our finding; however, they have accepted their patients who quit smoking in the not smoking category. Hirohata(17) reported that positive HLA- B51 rate was higher in patients with neurological involvement than patients without neurological involvement in BD.

According to our results, smoking is a risk factor for ocular and neurological involvements in patients with positive HLA-B51. Therefore, we may recommend that both HLA and smoking habits should be evaluated in patients with BD as well as studies on clinical findings of BD.

Another relationship referred to in the literature is between poor prognosis and severe complications of BD with male sex.(18) The results of some studies have shown that systemic involvements, disease severity and poor prognosis of BD were associated with male sex.(19,20) Moreover, Hirohata(17) has affirmed that HLA-B51, smoking, and male sex is strongly associated with chronic progressive BD with neurological involvement.

Male sex was not associated with BD manifestation in our study. Also, there was no significant difference between males and females in terms of HLA-B51. In studies associating systemic involvements and disease severity of BD with male sex, HLA-B51 frequency was generally higher in males than females. Besides, when taking into account that males generally smoke more than females, as in our study, this relationship may be due to direct smoking and/or indirect positive HLA-B51.

In their meta-analysis, Maldini et al.(21) have reported that HLA-B51 was significantly associated with male sex, and ocular and skin involvements including EN. In our study, EN seems to be associated with both HLA-B51 and smoking, but the influence factor was smoking on EN. The increased EN in patients with positive HLA-B51 may be due to the association of positive HLA-B51 with smoking. Also, the relationship between male sex with positive HLA-B51 and smoking may indicate that males smoke more because they have higher HLA-B51 frequency than females.

A relationship between smoking and severity of BD has been shown in the literature.(22) However, there are conflicting results about the relationship between HLA-B51 and smoking with severity of BD.(23-25) In our study, both smoking and HLA-B51 were found to be effective on BD. In addition, their concurrent presence was demonstrated to be more effective on BD activity scores.

The limitation of this study is that there was no control group. There is need for further studies in this regard.

In conclusion, we may say that smoking and HLA-B51 are influential factors on severity and systemic involvements of BD and there is a positive relationship between them. This relationship affects severity and same clinical manifestations of BD, sometimes leading to incorrect inferences. Therefore, we recommend that smoking and HLA-B51 should be considered simultaneously in BD with clarifications by further studies.

The authors declared no conflicts of interest with respect to the authorship and/or publication of this article.

The authors received no financial support for the research and/or authorship of this article.

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