Spondyloarthritis; clinical manifestations and evaluation of response to treatment in Iran

Introduction: Spondyloarthropathies (SpAs) are inflammatory diseases with symptoms such as spinal pain, sacroiliac, and peripheral involvement. The prevalence of SpAs is reported from 0.2% to 1.6%. SpAs can cause significant disabilities for patients. Its medical treatment is mainly with non-steroidal anti-inflammatory (NSAIDs) and anti-TNF drugs. Objectives: The primary purpose of this study is to carefully detect the clinical manifestations of patients, demographic characteristics, and the effectiveness of common medications in this disease. Patients and Methods: The present study is a retrospective descriptive study. The statistical population is 101 patients with SpA who have demographic information and items related to clinical conditions, radiographic findings and response to treatment. Results: One hundred one patients with SpA [46 (45.5%) female] with the age of 36.83± 10.45 years were studied. Around 66 patients (64.7%) had ankylosing spondylitis (AS), with the highest prevalence of AS. The most common clinical symptoms in patients were axial and peripheral/ extra-articular symptoms. The response to patients’ treatment were 61 patients (60.4%) had responded to the first stage of treatment, since only one patient needed to change the treatment steps in five times. Conclusion: We found, most patients with SpA were young patients. The most common radiological finding was Sacroiliitis. The most common clinical finding was extra-articular manifestations. Peripheral manifestations of the disease in women and axial images in men were common. The highest response to treatment was observed with the combination of indomethacin, sulfasalazine (SSZ) and indomethacin (alone).


Introduction
Spondyloarthritis (SpA) represents a group of HLAB 27 related diseases with inflammation of the spine, sacroiliac, and less frequently peripheral joints. This group includes ankylosing spondylitis (AS) and peripheral SpAs, psoriatic arthritis (PsA), reactive arthritis (ReA), SpA related to inflammatory bowel disease (IBD) and juvenile SpA. inflammatory back pain, articular (arthritis, enthesitis, dactylitis), and extra-articular (IBD, psoriasis and HLA related uveitis) are common symptoms (1).
There is enormous variation in reported prevalence, but it is estimated that Spa is ranged from 0.20% in South-East Asia to 1.61% in Northern Arctic communities. Each sub-group of Spa has a different prevalence (2). There is not a detailed study about the prevalence of Spa in different Asian races like Iranian people. The different prevalence of HLA B27 is one of the causes of the different prevalence of Spa between nations (3). Some studies said that SpA is a more common disease in men than women (male to female ratio is 2-3:1), but this ratio in the radiologic disease of Spa is equal between genders (4). Most patients with ankylosing spondylitis can experience normal life, while most patients with this disease may suffer from severe dryness in the spine and limited mobility, thereby, the disease intensifies and

Key point
The strength of our study is that we examined the prevalence of spondyloarthropathies and its subtypes for the first time in Iran. In addition, this study helps to understand the clinical manifestations and thus the faster diagnosis. Due to the economic issues, physicians need to pay attention to regular treatments such as indomethacin and sulfasalazine because of their excellent response and low price, which could help increasing medication adherence. According to our results, it is not essential to treat most patients with biological agents.
10.34172/jpe.2022.xx doi makes them disabled (5). Medical treatment of Spa is based on non-steroidal anti-inflammatory drugs (NSAIDs), and the use of tumor necrosis factor inhibitors (TNFi) despite NSAID treatment is not efficient (6).

Objectives
In this study, we try to detect clear manifestations of Spa, the prevalence of each subtype, reveal demographic features and probable relations to better diagnosis and management. We also evaluate response to treatment with common drugs to help therapists choose the best medicine in patients.

Study design
This study was a descriptive-analytical cross-sectional study to determine clinical presentation, the prevalence of each sub-type of SpAs, and the efficiency of indomethacin in the treatment of SpA patients. This study is retrospective and all patients received the standard treatments according to their clinical conditions, and no clinical intervention and invasive testing were performed in their treatment process. In our study, data were provided from patients' medical records, including responses to treatment and results of tests and examinations.

Data source
One hundred-one cases who were diagnosed with SpA from 2016 to 2019 were included. All participants were enrolled in the study through a census. All patients underwent complete physical examination and detailed para-clinical evaluations such as laboratory tests and imaging to diagnose SpA. All subjects had entry criteria; ESSG (European Spondyloarthropathy Study Group) criteria for diagnosis of SpA, New York Modified Criteria for the Diagnosis of Ankylosing Spondylitis, CASPAR (Classification Criteria for Psoriatic Arthritis (CASPAR)) criteria for diagnosis of psoriatic arthritis, patients with IBD and arthritis considered IBD-SpA, patients who got arthritis after urinary tract infection (UTI) or gastrointestinal infections considered as reactive arthritis, and patients with positive ESSG criteria without other criteria considered as undifferentiated SpA.

Data collection and study design
In this study, patients' medical records were observed, and required variables including demographic, clinical, paraclinical, and imaging data were recorded. Demographic data includes gender, age, age of onset of clinical presentation, age of diagnosis of disease, and delayed time of diagnosis. Clinical presentations were categorized as anterior uveitis (AU), extra-articular, root, and peripheral involvement. Plasma hemoglobin, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) were laboratory data. Each type of treatment and its response were recorded too. Response to treatment assessed with Assessment of SpondyloArthritis international Society (ASAS) -ESR criteria. Back pain, peripheral pain/swelling, duration of morning stiffness, patient global (patients assessment in measuring disease activity), and ESR are items of ASDAS-ESR criteria (7). Its spectrum is from inactive disease to very high disease activity, since <1.3 is categorized as inactive disease, <2.1 is defined as low disease activity, <3.5 is described as high disease activity, and >3.5 represents very high disease activity (8). According to results we got from ASDAS-ESR differences, the current situation's response to treatment was evaluated. In response to treatment, less than 1.1 (<1.1) was defined as clinically important improvement, and response to treatment more than 2 (>2) represents major improvement.

Statistical analysis
Data entered to statistical software SPSS 22 and analyzed using descriptive and analytical statistics. The quantitative data is described with mean and standard deviation. The qualitative data were expressed as frequency and frequency percentage. Chi-square and Fisher exact test were used to determine the relationship between qualitative variables, and for quantitative data, the independent-T test was used. The significance level in this study was considered less than 0.05.

Results
In the present study, 101 patients with SpA were studied, of which 46 (45.5%) were female, and 55 (54.5%) were male. The mean and age deviation of patients was 36.83± 10.45, and the highest number of patients was in the age range of 21-35 years (Table 1). In this study,35 (34.6%) of the patients had symptoms of the disease in the age range of 21 to 30 years,1 (0.9%) was less than 10 years, and 2 patients (1.9%) were more than 50 years in the first clinical symptoms of the disease (Table 2).
Among the 101 study patients, 66 (64.7%) of the patients were diagnosed with AS, with the highest prevalence being related to AS, since one (1%) of the patients were diagnosed with HLA-related uveitis ( Table 3).
The prevalence of the disease among women and men 3 Volume 7, Issue 1, 2022 According to the results, the most radiological findings were related to sacroiliac. Around 61% of the total population have sacroiliac manifestations on radiography (Table 4). According to the results, most of the clinical signs were related to axial and peripheral-extra-articular involvement. About 22 patients (21.8%) had axial involvement, and 12 patients (11.9%) had peripheral joint involvement ( Table 5). The presence of concurrent peripheral involvement in women was four times more than men and simultaneous axial and root involvement in men was five times more than women (Table 6).
Patients' disease status was assessed at the time of referral using ASDAS-ESR scoring system, 57 (56.4%) of patients in very high condition, 40 (39.6%) of patients in high condition, 3 (3%) were in low-condition. Only one patient (1%) could not be evaluated with ASDAS-ESR due to having AU without joint involvement and was reported as an inactive condition (Table 7).
In this study, the ASDAS-ESR test was used to evaluate the outcome of patients' response to treatment; based on the results of the ASDAS-ESR difference, the response phase of patients' treatment was measured and compared  to the current situation. After treatment was divided based on the numbers obtained, greater than equal to 1/1, the clinical condition of patients was considered as clinically important improvement, and greater than equal to two was considered a major improvement. In this study, 85 cases in the group of major improvement and 15 cases were included in the clinically important improvement group. Only one case of AU was observed that due to lack of joint involvement, and it was not possible to assess his clinical condition based on the ASDAS-ESR test, thus estimating the patient based on clinical condition and diagnosis and was considered as wholly (Table 8).
According to the results of treatment response of the patients and their need to change the drug, 61 (60.4%) of the patients had responded to the first stage of treatment, and only one patient needed to change the treatment steps five times. The highest response to treatment in the first stage was the response to indomethacin and sulfasalazine (SSZ) drugs in combination or indomethacin (alone), while the response to treatment of other drugs in the first stage such as adalimumab, celecoxib and etanercept was not the same as others. Based on the study results, the drug combination of SSZ, Enbrel, and indomethacin was also an effective drug used in treating the fifth stage only in the present study (Tables 9 to 13).

Discussion
This study aimed to identify SpAs manifestations accurately, identify the most common findings, and evaluate the effectiveness of existing therapies in treating patients, especially among Iranians. Therefore, physicians can identify and treat patients more easily and quickly.
We found that the most common disease among SpAs is ankylosing spondylitis.
According to our study, most of the clinical signs were related to axial and peripheral or extra-articular involvement. Peripheral manifestations of the disease are more common among women, but axial manifestations are more common among men. Likewise, the prevalence of the disease among women and men by age has a similar pattern. In a study done in London (9), female/male ratio was 2:1, which women were twice more than men, and peripheral manifestation of SpAs was more common in men. Another study (10) showed that men experience more peripheral symptoms compared to women. They reported that 63% (2/3) peripheral arthritis in men and 20% in women.
We found that the most common disease among SpAs is ankylosing spondylitis. SpAs prevalence is different in every region; it was from 0.01% (11) in Japan to 2.5% in Northern Arctic natives (12,13). Saraux et al found a 0.30% prevalence of SpAs in France with almost equal prevalence in men (0.31%) and women (0.29%). They showed, ankylosing spondylitis and psoriatic arthritis were the most common sub-types in this study (14). Collantes et al (15) discovered that the prevalence of SpAs in Spain is 68% in men and 32% in women. Moreover, ankylosing spondylitis was the most common type of SpAs, as same to our study. The prevalence of the disease among women and men by age has a similar pattern.
According to our research, simple and accessible drugs such as indomethacin can still be good choices with a significant impact on the treatment of patients. NSAIDs and non-pharmacological therapy are the first line of SpAs    therapy (16,17). A study showed that all NSAIDs have similar efficacy for controlling axial SpAs, and they are not associated with more adverse effects than placebos (18). Wang et al (19) reviewed 26 trials of 20 NSAIDs to compare their efficacy in ankylosing spondylitis. All 20 NSAIDs were more effective than placebos for reducing pain, and 15 of them were significantly better than placebo, and they did not have a significant difference in decreasing morning stiffness and side effects. Overall, they revealed that etoricoxib and oxaprozin were better than other NSAIDs in controlling pain and were safer than naproxen.
Poddubnyy et al (20) followed SpA patients for two years on NSAIDs intake. They found that high-dose NSAIDs were associated with lessen radiographic spinal progression in AS patients. They discovered that diclofenac, ibuprofen, indomethacin, and piroxicam were most frequently NSAIDs used in SpAs. There is not enough studies that examined the efficacy of Indomethacin on SpAs patients.
Van der Horst-Bruinsma et al (21) suggested that SSZ with typical therapy of axial spondyloarthropathies (NASID+ physical exercise) could be a proper regime for peripheral SpAs. In contrast, Braun et al, (22)  Sieper et al (23) identified that combination therapy with infliximab+naproxen is more efficient than Naproxen alone. They figured outpatients with early active axial SpA who had infliximab + naproxen had more significant clinical remission than patients who used naproxen alone. In our study, patients how used SSZ+ indomethacin had better disease control. The strengths of our study were to identify the most common manifestations of SpA by comparing gender, radiologically and clinically among Iranians and evaluating the effect of common treatments. Our study's limitations are as follows: a retrospective study, lack of attention and study of the impact of factors such as patients' occupation and profession, underlying diseases such as diabetes and autoimmune diseases, smoking, family history, nutritional status and limited statistical population of patients. Further longitudinal studies with more detailed laboratory and clinical examinations among a larger number of patients, especially of different races, can be helpful in generalization the results of our study.

Conclusion
According to the present study results, the largest group of patients with SpA were young, and the most common radiological finding was related to sacroiliitis, although the most common manifestations of the disease were extraarticular. Peripheral manifestations are more common among women than men and axial types among men. After referral and receiving the first stage of treatment, which was often a combination of indomethacin and SSZ or indomethacin alone, they had the highest response to treatment, and their clinical status has significantly improved compared to the time of referral.

Limitations of the study
This study is retrospective. Lack of comparison groups to more accurately assess the effectiveness of different types of drugs, limited statistical population of patients, nonconsideration of racial differences. We hope that these limitations will be addressed through future longitudinal studies.