Risk factors of persistent synovitis development in early undifferentiated arthritis patients

Introduction Patients with early arthritis are meant to be those with the potential for development of persistent synovitis (PS) but in whom a recognized clinical pattern does not exist [1]. Most patients with early arthritis cannot be diagnosed as a defined disease entity. Early arthritis may evolve into rheumatoid arthritis (RA) or other well-defined diseases and may resolve on its own or may remain undifferentiated [2]. It has been suggested that very early inflammatory disease may differ immunologically from disease of longer duration, and intervention at this stage, before the development of PS, offering a unique opportunity for a qualitative improvement in outcome [3,4]. Management of inflammatory arthritis on the basis of suppression of synovitis to minimize damage would seem to be an appropriate aim of therapy in this patient group [5]. As distinct clinical or laboratory risk factors have not yet been well declared, the diagnosis of PS currently relies on clinical features [6]. Ultrasonography (US) is a relatively cheap and noninvasive imaging modality; multiple joints in a short period of time and bone structure as well as soft tissue can be examined. Moreover, it has a better sensitivity than physical examination in the detection of synovitis in early arthritis [7].


Introduction
Patients with early arthritis are meant to be those with the potential for development of persistent synovitis (PS) but in whom a recognized clinical pattern does not exist [1]. Most patients with early arthritis cannot be diagnosed as a defined disease entity. Early arthritis may evolve into rheumatoid arthritis (RA) or other well-defined diseases and may resolve on its own or may remain undifferentiated [2]. It has been suggested that very early inflammatory disease may differ immunologically from disease of longer duration, and intervention at this stage, before the development of PS, offering a unique opportunity for a qualitative improvement in outcome [3,4]. Management of inflammatory arthritis on the basis of suppression of synovitis to minimize damage would seem to be an appropriate aim of therapy in this patient group [5]. As distinct clinical or laboratory risk factors have not yet been well declared, the diagnosis of PS currently relies on clinical features [6]. Ultrasonography (US) is a relatively cheap and noninvasive imaging modality; multiple joints in a short period of time and bone structure as well as soft tissue can be examined. Moreover, it has a better sensitivity than physical examination in the detection of synovitis in early arthritis [7].
The aim of this study was to the identify risk factors for PS development in early undifferentiated arthritis (EUA) patients attending Al Sharqia Governorate hospitals, Egypt.

Laboratory assessment
Each patient underwent the following: (1) Complete blood count.

Radiological assessment
Conventional plain radiograph of the hands and feet were available for all patients. Osteopenia, joint space narrowing, and erosions, if present, were evaluated. An erosive joint is defined as the joint having, at least, one erosion (erosion means a lesion with an interrupted cortex) [13]. Radiographs of other joints were also obtained as clinically indicated.
Ultrasonography: US assessment was performed for all participants using a Toshiba Nemu 20 (Toshiba Corporation Medical System Company, Model: SSA-550A, Japan) using linear transducer with a frequency of 5-10 MHz. US assessment was performed both longitudinally and transversely by high-frequency US and PD with constant B-mode setting. Each patient underwent an US assessment by two expert radiographers who were blinded to the clinical and laboratory findings, on the day of entry into the study and 12 months later for all of the patients. A systematic multiplanar gray scale and PD ultrasound examination of 38 joints (both metacarpophalangeal joints 1-5; metatarsophalangeal joints 2-5; proximal interphalangeal joints 1-5, both wrists, elbows, shoulders, knees, and ankles) was performed on the basis of standard EULAR reference scans [14]. PD parameters were adjusted at the lowest permissible pulse repetition frequency to maximize the sensitivity (50-1000 Hz). Low wall filters were used. The dynamic range was 20-40 dB. Color gain was set just below the level at which color noise appeared (no flow should be visualized at bony surface). This setting resulted in gain from 18-30 dB Doppler spectrum to exclude artifacts. Joints were scored on a four-grade semiquantitative scale for joint effusion, synovitis, bone erosions, and PD signal [15].
Sharqia Governorate, Egypt) during the period from December 2011 to December 2012. EUA patients were defined as those with clinical profile, examination, or laboratory data suggesting the presence of an inflammatory arthritic disorder but in whom a specific rheumatic disease has not been diagnosed [8]. Disease duration ranged from 6 weeks to 6 months. At the end of recruitment period, 100 patients were recruited; 20 patients were lost/did not wish to continue the follow-up or participate in the study. The remaining 80 (56 women/24 men) patients completed the study. All patients signed informed consent to be included in the study, and the ethics committee approved the study protocol.

Exclusion criteria
Patients satisfying the American College of Rheumatology classification criteria for RA [9] and the European Spondyloarthropathy Study Group criteria for spondyloarthropathry [10] were excluded. Patients who were found to have a specific rheumatic diagnosis were also excluded.

Assessment and outcome measures
Assessment was performed twice (baseline and after 1 year). At each assessment, different clinical and laboratory parameters were assessed in addition to radiographic assessment, including conventional Plain radiograph and Ultrasonography (High Resolution Ultrasonography (HRUS) and power Doppler (PD)].
Outcome of PS was detected by clinical, laboratory, and radiological (HRUS or PD) assessments.
Control group: Forty apparently healthy volunteers (28 women/12 men) proved by clinical and laboratory investigations and having age-matched and sexmatched with the patients were recruited from persons attending the dental clinic.

Clinical assessment
Complete history taking, complete general and local examinations, and functional assessment by health assessment questionnaire-20 [11] were performed.
The health assessment questionnaire (HAQ-20) [11]: The HAQ-20 assesses a patient's level of functional ability. There are 20 questions in eight categories of functioning. The stem of each item asks over the past week. For each item, there is a four-level difficulty scale that is scored from 0 to 3. The highest component score in each category determines the score for the category.

Results
Baseline clinical, laboratory, and radiological features of participants included in the study are depicted in Table 1.
Baseline data of the SLA group and PS patients showed that family history of any specific rheumatic disease, TJC, SJC, and anti-CCP2 titer were significantly Joint effusion was scored as follows: A score of 0 = no effusion, 1 = minimal amount of joint effusion, 2 = moderate amount of joint effusion (without distension of the joint capsule), and 3 = extensive amount of joint effusion (with distension of the joint capsule).
Synovitis was defined as the presence of abnormal hypoechoic material within joint recesses, tendon sheaths, or bursae. Intra-articular synovitis, tenosynovitis, and bursitis were graded semiquantitatively from 0 to 3 and it was scored as follows: A score of 0 = no synovial thickening, 1 = minimal synovial thickening (filling the angle between the periarticular bones, without bulging over the line linking tops of the bones), 2 = synovial thickening bulging over the line linking tops of the periarticular bones but without extension along the bone diaphysis, and 3 = synovial thickening bulging over the line linking tops of the periarticular bones with extension to at least one of the bone diaphyses.
Bone erosions were defined as changes in the bone surface of the area adjacent to the joint and scored as follows: A score of 0 = regular bone surface, 1 = irregularity of the bone surface without formation of a defect seen in two planes, 2 = formation of a defect in the surface of the bone seen in two planes, and 3 = bone defect creating extensive bone destruction.
PD signal was used to display flow signal in the synovium and scored as follows: A score of 0 = no flow in the synovium, 1 = single vessel signals, 2 = confluent vessel signals in less than half of the area of the synovium, and 3 = vessel signals in more than half of the area of the synovium.

Statistical analysis
Statistical analysis was performed using SPSS statistical software, version 11.0 (SPSS Inc., Chicago, Illinois, USA). Quantitative variables were given as mean ± SD and categorical variables as frequencies and percentages. The t-test or the Wilcoxon ranksum test were used according to the distribution of the variable, and the c 2 -test was used for categorical variables. P value less than 0.05 was considered statistically significant. Exact test was used if less than 20% of cells demonstrated less than 5 expected observations. Variables that show a significance level were subjected to Logistic regression analysis to identify the risk factors of PS. Intraobserver and interobserver agreement was assessed using the κ coefficient. κ value for intraobserver reproducibility was 0.73, indicating high reproducibility.    [19]. In the present study, family history of any specific rheumatic disease, SJC, anti-CCP2 titer, HRUS total synovitis score, and PD total score were the baseline significant risk factors for more evident in the PS group. Synovitis was estimated significantly in the PS group according to HRUS total score of synovitis and PD total score (Table 2).
According to logistic regression analysis, the most significant risk factor for PS development in EUA patients was the baseline PD total score [odds ratio and 95% confidence interval was 0.376 (0.215-0.613)] (Table 4 and Figs. 2 and 3).

Discussion
The aim of this study was to identify the risk factors for PS development in EUA patients attending Al Sharqia Governorate hospitals, Egypt. After 1 year, 25% of 80 EUA patients showed evidence of spontaneous remission (SLA). SLA was defined as the absence of arthritis and synovitis on the examination of a patient who has not taken DMARDs or glucocorticoids in the last 3 months [16]. Seventy-five (75%) had PS: 27% had RA, 23% had spondyloarthropathy, and 30% remained undifferentiated (UA). Thabet et al. [17] agreed with our finding that UA has a variable disease course, as 40% of their patients had spontaneous remission, 30% had RA, and 30% remained UA.
In the present study, family history, TJC, SJC, and anti-CCP2 titer were significantly evident in the PS group. This is in agreement with the finding of El Miedany et al. [1], as they found that arthritis of the small joints of the hands and anti-CCP were significantly detected in persistent inflammatory arthritis patients.
Furthermore, results of the present study did not support the findings reported by Jansen et al. [18] who found that sex and rheumatoid factor are significantly related to the development of PS. The patients included in their study were clinically suspected to have RA, which is one of the exclusion criteria of patients of the present study, and this could be considered an explanation for this finding.
Synovitis was significantly more detected in the PS group according to HRUS total score of synovitis and PD total score. This is in accordance with the findings Continuous data are expressed as mean ± SD; categorical data are expressed as number and percentage, anti-CCP2, anticyclic citrullinated peptide2; DD, disease duration before baseline evaluation; FH, family history of any specific rheumatic disease; HAQ-20, health assessment questionnaire; HRUS, high resolution ultrasonography; PD, power Doppler; PS, persistent synovitis; RF, rheumatoid factor; SJC, swollen joint counts; SLA, self-limiting arthritis; TJC, tender joint counts. a Significant difference. scoring in all patients with artheralgia or subclinical disease [24,25].

Conclusion
Baseline PD total score is a significant risk factor for PS development in EUA patients.

Recommendation
PD examination of all patients presenting with EUA should be performed.
PS development after 1 year of follow-up. This is in agreement with other previous studies [18,20,21].
In addition, CRP and radiograph were not the significant baseline risk factors for PS development in patients of the present study. These data confirmed the findings of two earlier reports [5,22].
The authors of this study found that baseline CRP and radiograph were not the significant risk factors of PS detection after 1 year of follow-up. This may be explained by the notion that EUA may differ immunologically and radiologically from disease of longer duration UA as stated by two previous studies [5,23].
Moreover, in the present study, baseline HRUS total synovitis score and PD total score were the significant risk factors for development of PS. The most significant risk factor was the baseline PD total score (P < 0.001). This is in agreement with two other previous studies, which stated that US is a promising diagnostic tool in predicting arthritis and recommended extensive US