Outcomes of Turkish Ankylosing Spondylitis Patients

Ankylosing spondylitis (AS) is chronic, progressive, systemic inflammatory rheumatic diseases that lead to serious disability. The objective of this study was to determine the demographic, clinic characteristics and CYP2D6*4 gene mutation profiles of the AS patients in Tokat, Turkey. In this retrospective study, we evaluated 103 patients that were diagnosed and followed up as AS in Tokat, Turkey between 2008-2011. Demographical properties (age, sex, education level, age at diagnosis, disease duration), clinical characteristics (HLA27, peripheral/extraarticular involvoment, chest expansion, enthesopathy, modified schouber) and genetic analysis results (CYP2D6*4 gene mutation frequency) of AS patients were assessed. The mean age of AS patients was 36.80±9.25 years. The mean age of female and male 39.10±7.89, 35.40± 9.79 respectively. The female to male ratio was 1:1.6. Major histocompatibility complex, class I, B 27 (HLAB27) was investigated and the rate of positivity was 73.78 %. There was a statistically significant difference between CYP2D6 gene mutation and peripheral /extraarticular involvement (p<0.05). Determining the clinical characteristics and CYP2D6*4 gene mutations of rheumatologic diseases as AS will provide benefits for early diagnosis, treatment, and disease outcome.


INTRODUCTION
Ankylosing spondylitis (AS) is a systemic, chronic, progressive inflammatory disease which mostly affects the musculoskeletal system (1).There are a lot of retrospective studies have been designed to predict the prevalence of AS (1,2).In Turkey, the prevalence of AS and related spondyloarthritis have been determined as 0.49% and 1.05%, respectively, and this results are higher than the observed prevalence in other countries (3).Analysis of disease characteristics will inform us about the disease severity and activity in AS patients and could help in selecting candidate patients for biological treatments (1).

RESULTS
A total of 103 [39 (37.86%) female; 64(61.14%)64 male] AS patients were evaluated in this study and the female to male ratio was 1:1.6.The mean age of the patients was 36.80±9.25 (20-60) years.The ages and characteristics of disease are given in Table 1.Sex-based disease characteristics of patients with AS are shown in Table 2. Male ratio was higher than women but average age mean was higher in women.HLA-B27 positivity was 53.4 % in our study.Of the AS patients 20.38% have positive family history, 84.86% patients have peripheral involvement 26.22% have extraarticular involvement.Enthesopathy was found in 89 (86.4%) of our patients.In radiographic evaluation, 99.03% of patients had sacroiliitis.HLAB27 positivity, Enthesopathy, peripheral/ extrarticular involvement, sacroiliitis ratio was higher in the male group (Table 3).Most of the patients (41.7%) were taking NSAID+ Sulphasalazine theraphy.26.2%s of patient were taking NSAID and 19.4% were taking Anti-tnf + NSAID theraphy respectively (Table 4).Sociodemographic characteristics of AS patients were seen in Table 5. Educational level of patients was low and smoking ratio was high (82.52%).When we examine clinical characteristics according to exercise habit and smoking status of AS patients, there was a statistically significant difference between enthesopathy and exercise habit (p<0.05).CYP2D6*4 gene mutation disribution of AS patients are seen in Table 6.When we examine CYP2D6 gene influence susceptibility to AS (4).The objective of this study was to determine the demographic, clinic characteristics and CYP2D6*4 gene mutation profiles of the AS patients in Tokat, Turkey.

Patients
This study included 103 AS patients from the department of Physical Medicine and Rehabilitation, Gazi Osmanpaşa University in Tokat, Turkey.Informed consent was obtained from all participants.Diagnosis of AS was based on the modified New York criteria (5).Disease characteristics, clinical findings and genetics analysis results (CYP2D6 gene) of the patients were investigated.

Statistical Analysis
Analysis of the data was performed using the computer software SPSS 15.0 (SPSS, Chicago,IL, USA) and OpenEpi Info software package programme (6).Continuous data were given as mean ± SD (standard deviation) and (minmax).The categorical variables were evaluated by chisquare or Fisher's exact test, which where applicable.P value smaller than 0.05 (two-tailed) was regarded as statistically significant.

DISCUSSION
Ankylosing spondylitis (AS) is a chronic inflammatory disease of the spine with unknown etiology (7).In the western world the prevalence and incidence of AS are 0.2% and 6/10.000,respectively.In Germany the prevalence is 0.55% and similarly in Turkey the prevelance of AS is 0.49% (7).The strongest known contributing factor for AS, the major histocompatibility complex (MHC) class I molecule human leukocyte antigen (HLA)-B27, is known since 1973 [8] (2).In Asian countries male to female ratio has been reported (7.2:1 and 9.2:1) which is higher than other countries (9,10).In this study 84.46% patients have peripheral involvement, 126.22% patients have extraarticular involvement.The most common was spinal involvement with 53.4%.The rate of peripheral arthritis was reported as 47% for Middle East Arab 50% for South Asian, and 60% for Korean patients (8,9).In radiographic evaluation, 99.03% of patients had sacroiliitis and en-    (13).NSAIDs are also widely used to ameliorate spinal pain in AS and TNF blockers seem to have no influence on new bone formation in AS (9,11,12).Sulfasalazine has shown mild to moderate effects on disease-related peripheral symptoms in AS (14).While methotrexate (MTX) is useful in RA, its role in AS is unclear at best.There is little data supporting the use of MTX in patients with AS.The quality of life of patients with AS is decreased in comparison to the normal population (15).Physiotherapy and group exercises are recommended to AS patients.Several studies in AS showed that supervised individual exercises and physical therapy in groups led to significantly better outcomes compared to patients who performed only home exercises without supervision or no physiotherapy at all (8).When we examine clinical characteristics according to exercise habit and smoking status of AS patients, there was a statistically significant difference between enthesopathy and exercise habit (p<0.05).According to our result exercise increased enthesopathy risk, so that in the presence of enthesopathy resting should be offered.Based on large family and genome-wide association studies, the susceptibility to AS has been estimated to be 80-90% genetically determined (16).In this study 20.38% of the patients have positive family history.The average risk of developing AS in a first-degree relative of AS patients is about 8%, but only <1% in second-degree relatives.The risk in HLA-B27 positive first-degree relatives is about 12%, but <1% in HLA-B27-negative relatives (8,17).CYP2D6 gene influence susceptibility to AS (4).
Brown et al reported that weak linkage demonstrated between CYP2D6 and AS (17).In this study in 53 patients CYP2D6*4 gene mutation frequency of AS patients were assessed.And when we examine CYP2D6*4 genotype frequencies according to the clinical characteristics in AS patients we found that peripheral /extraarticular involvement was higher in the CYP2D6*4 gene mutation carrier group than non-carrier group (p<0.05).Based on this finding we may say that CYP2D6*4 gene mutation may influence peripheral /extraarticular involvement in Turkish AS patients.However a study conducted in a different Turkish population showed no significant association between CYP2D6*4 allele and AS (4).Most recently, two new genetic loci have been shown to be associated with AS besides HLA-B27.2: the IL23 R(eceptor), which is involved in the Th(elper cell) 17-pathway of immune responses, and the ARTS-1 or ERAP-1, an enzyme which is relevant for the processing of peptides in the cytoplasm (8,18).
AS related epidemiologic studies have been designed to predict the prevalence.In this study we described the prevalence and clinical characteristics of AS patients in a Turkish population who live in Tokat province.
Outcomes of the investigations will probably result in more accurate information for AS.

Table 1 .
Characteristics of the patients with AS

Table 2 .
Sex-based disease characteristics of patients with AS

Table 3 .
Clinical findings and peripheral involvement of the patients with AS

Table 4 .
Drug use of patients with AS

Table 6 .
Clinical characteristics distribution according to exercise habit and smoking.

Table 7 .
Distribution of CYP2D6 gene mutation

Table 8 .
CYP2D6 genotype frequencies according to the clinical characteristics in AS patients