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ORIGINAL ARTICLE
Ahead of print publication  

Musculoskeletal Ultrasonography in Detecting Disease Activity in Patients of Juvenile Idiopathic Arthritis: A Cross-Sectional Study


1 Department of Gastroenterology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh, India
2 Department of Radio Diagnosis and Imaging, Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh, India
3 Department of Geriatric Medicine, Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh, India

Correspondence Address:
Anup Singh,
Department of Geriatric Medicine, Institute of Medical Sciences, Banaras Hindu University, Varanasi - 221 005, Uttar Pradesh
India
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/injr.injr_38_19

  Abstract 


Background: Musculoskeletal ultrasonography (MSUS) is a powerful tool to detect subclinical disease in juvenile idiopathic arthritis (JIA). The study was done to compare the results of clinical examination and ultrasonography (US) in identifying disease activity in joints of patients of JIA.
Methods: Patients of JIA attending rheumatology clinic of a tertiary care referral center in northern India over a span of 1 year from June 2015 to June 2016 were enrolled in the study. The diagnosis of JIA was established using International League of Associations for Rheumatology 2001 criteria. Clinically determination of synovitis was compared to MSUS parameters of active disease such as synovial hypertrophy, effusion, and increased vascularity in large joints only (bilateral knee, ankle, wrist, and elbow).
Results: A total of 108 patients were enrolled in a study period and 864 joints were examined. Synovitis was detected in 305 joints by clinical examination. However, US demonstrated synovitis in 502 joints (additional 209 joints). Twenty patients who were initially thought to be oligoarticular by clinical examination were later classified to polyarticular subtype on the basis of MSUS findings. A significant correlation between erosions and rheumatoid factor and anti-cyclic citrullinated peptide values was found.
Conclusion: Our study found that MSUS has a definite role in assessing the disease activity in JIA patients and this modality may be considered as an adjunct in this context, as well as considered for future inclusion in classification criteria for JIA.

Keywords: Arthritis, juvenile idiopathic arthritis, musculoskeletal ultrasound



How to cite this URL:
Dev S, Verma A, Singh A. Musculoskeletal Ultrasonography in Detecting Disease Activity in Patients of Juvenile Idiopathic Arthritis: A Cross-Sectional Study. Indian J Rheumatol [Epub ahead of print] [cited 2019 May 25]. Available from: http://www.indianjrheumatol.com/preprintarticle.asp?id=257844




  Introduction Top


Musculoskeletal ultrasound (MSUS) has emerged as an indispensable tool for physicians involved in musculoskeletal disorders. MSUS has gained popularity because of its ease of use and no contraindications.[1],[2] Its popularity has increased in recent past in pediatrics because it does not involve radiation. Further, nonossified cartilaginous can be visualized along with vascular structures. It also allows a rapid contralateral comparison. The complexity of pediatric joints includes the nonossified epiphysis of the joint. US can clearly image these nonossified cartilages with comparable specificity and sensitivity to that of magnetic resonance imaging.[3] In clinical practice, the disease activity primarily depends on clinical evaluation in juvenile idiopathic arthritis (JIA). However, it is often difficult to clinically determine whether a perceived joint swelling is secondary to synovitis with joint effusion or is due to soft-tissue edema and/or tenosynovitis. Similarly, pain and limitation of mobility in a joint may not always indicate active arthritis.[4]

In the current International League of Associations for Rheumatology (ILAR) 2001 classification, the patients are classified as oligoarthritis or polyarthritis based on a number of joints affected in children with JIA.[5] Thus, by relying solely on clinical findings, a substantial number of children may be wrongly classified as having extended oligoarticular, when they, in fact, might be having polyarticular disease.[6],[7],[8]

Ultrasonographic evaluation of joints should be performed with high frequency (12–15-MHz) linear transducers that provide sufficient resolution for the evaluation of articular cartilage and intraarticular diseases such as erosions. Incorporation of color or power Doppler (PD) imaging provides diagnostic information regarding synovial vascularity and hyperemia.

The sonographic signs include synovial hypertrophy, joint effusion, tenosynovitis, enthesitis, and bone erosion.[9],[10] PD-ultrasonography (PD-US) assessment of synovial vascularization has been shown to be more sensitive than serum markers of inflammation in the identification of active disease in JIA.[11],[12] Furthermore, it demonstrated that the Doppler signal is correlated with clinical activity and with serum levels of interleukin-6.[13] Various systems using quantitative or semi-quantitative methods have been proposed to evaluate synovial Doppler flow in adults, but none of those techniques have been validated in JIA.[11],[14]

Very few studies so far have investigated ultrasonographic assessments of children with JIA.[2],[14],[15],[16] Hence, this study was done to find the utility of PD-US in diagnosing JIA.


  Methods Top


A study was done in a rheumatology clinic of tertiary care hospital in eastern Uttar Pradesh, India. JIA patients attending rheumatology clinic between June 2015 and June 2016 were enrolled in the study after taking patient assent and written parent/guardian consent. The diagnosis of JIA was established by an experienced rheumatologist using ILAR 2001 criteria. Ethical approval was taken from Ethical Committee of Institute of Medical Science, Banaras Hindu University (Dean/2014-15/EC/1364).

Patients were investigated for complete blood count, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), renal function test, liver function test, rheumatoid factor (RF), anti-cyclic citrullinated peptide (anti-CCP) antibodies, anti-nuclear antibodies (ANA, by ELISA, >60 U/ml considered positive), urine – routine and microscopic examination. Human leukocyte antigen (HLA) B27 was done in all patients by using polymerase chain reaction technique with sequence-specific primers. Every patient was evaluated clinically for joint involvement of bilateral knee, elbow, wrist, and ankle along with small joints of hands and feet. Each joint was evaluated clinically for signs of activity such as pain, tenderness, swelling, and restriction of movement. Musculoskeletal US (MSUS) was performed by experienced radiologist using Xario, Toshiba corporation Inc. equipment. Multi-frequency linear array transducer of frequency range 7–11 MHz was used. Low frequency (3–5 MHz) curved transducer was used only to visualize certain deep structures, but all objective data were tabulated by linear array transducer only. Four large joints of the body (viz., wrist, elbow, knee, and ankle) were assessed bilaterally, plus the joints in which complaints were made, were also assessed using both gray-scale B mode Doppler and PD studies. If there were findings in one joint and no complaints were made in the symmetrically joint in other limbs then that joint was also assessed. Radiological features such as synovial hypertrophy, increased vascularity, erosions, effusions, tenosynovitis, reduced joint space, and enthesitis were studied. Each of the findings was defined as in the Outcome Measures in Rheumatology Clinical Trials (OMERACT).[10]

The statistical analysis was done using statistical software SPSS for Windows (SPSS Inc., Version 16, Chicago, USA). Fisher's exact test was used for the categorical variable because the sample size was small. The normality of the data was checked by the Kolmogorov–Smirnov test, and it was normal. Since there was no any outliers, so we preferred Pearson correlation. P < 0.05 is considered as statistically significant.


  Results Top


A total of 108 patients were diagnosed with JIA in the study period. The median age of patients was 14 years (range 11–15) with male to female ratio of 1.8:1. Enthesitis-related arthritis (ERA) was the largest group comprising 50.9% of the total study population. The polyarticular RF-positive children were the second largest group (18.5%). The median duration of illness before presentation was 24 months (range 12–48). HLA-B27 was positive in 49 cases (45.3%) and out of these 44 patients were in ERA group (80%), and ANA was positive in only 7 cases (6.4%). RF was positive in a total of 32 patients including 20 patients of polyarticular RF-positive subtype. Three patients of systemic onset JIA were positive for RF and rest of nine cases were positive in other subtypes of JIA. Different forms of JIA are shown in [Table 1].
Table 1: Frequency of different forms of juvenile idiopathic arthritis

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Of 864 joints examined in 108 patients, clinical examination detected active synovitis in 305 joints whereas US detected synovitis in 502 joints. Hence, an additional 199 joints, synovitis was diagnosed by US. There was a moderate agreement with Cohen's kappa value of 0.54 between clinical examination and US. Overall findings on physical examination are described in [Table 2]. [Table 3] shows the comparison of number of joints in which synovitis was detected by clinical examination and US. [Table 4] shows the overall ultrasonographic findings of various joints. In US, minimal joint effusion was the most common finding in 328 cases (most common in knee), while synovial hyperplasia was present in 292 (most common in ankle) joints. Activity on PD was present only in 80 joints. In PD setting, the gain was medium with a medium wall filter as well and a pulse repetition frequency of approximately 9.2k with dynamic range-55.
Table 2: Findings of physical examination

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Table 3: Joint involvement detected by physical examination and by ultrasonography

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Table 4: Ultrasonographic findings in joints

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Overall sensitivity and specificity of detecting synovitis by clinical examination is summarized as in [Table 5]. It was found that the presence of only swelling has a sensitivity of 43% while tenderness and restriction of movement have a sensitivity of 27% and 8.8%. On combining all findings, the sensitivity increased to 60.7% with specificity was 99.48%.
Table 5: Comparison of sensitivity of clinical findings with ultrasonography

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[Table 6] shows the significant discordance in detecting synovitis in more than four joints between US findings and clinical examination.
Table 6: Comparing number of joints involved clinically and by ultrasonography

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Significant correlation between erosions and RF (r = 0.548; P = 0.00) and Anti-CC P values (r = 0.30; P = 0.021) was found in the polyarticular group. The highest discrepancy between clinical synovitis and US synovitis was found for oligoarticular group. Twenty patients who were initially thought to be oligoarticular by clinical examination were later classified into polyarticular subtype on the basis of MSUS finding.


  Discussion Top


Ultrasound has many advantages in children and is widely being used in JIA to confirm suspected clinical findings of synovitis. Furthermore, it is used widely in performing arthrocentesis and giving intra-articular injections.[17] Ultrasound is well accepted, without radiation, portable, accessible and fast, and lacks needs of sedation or general anesthesia and is an ideal modality to use in pediatric rheumatology. It can be used to compare symptomatic with the asymptomatic sites and can be repeatedly used to confirm the diagnosis. MSUS has been shown to be a sensitive tool for the diagnosis of subclinical synovitis in rheumatoid arthritis (RA), but its validity has not been established in JIA. Unlike in adults, US definitions of components of synovitis have not been proposed in children. OMERACT has provided standardized definitions for synovitis by US in adults; there is a lack of such standardized definitions in childhood.[10]

The advantage of our study over others is that all subtypes of JIA were included in the study.

Our primary objective was to assess the sensitivity of physical examination in comparison to US. Various studies have described US features of JIA in comparison to physical examination. A study by Magni-Manzoni et al., with 32 JIA patients found the utility of detecting subclinical synovitis by US. The finding of US variables correlated well with clinical measures of joint swelling, but there was poor correlation with joint tenderness and restricted range of motion. Five patients of oligoarticular variety were later classified as having polyarticular.[18]

Similarly, Breton et al. compared physical and US findings at 558 peripheral joints in JIA patients, in which 69 (12.5%) had ultrasonographic synovitis and 83 (15%) had abnormal physical findings.[19] Another study by Haslam et al. studied 17 patients of oligoarticular arthritis in which 15 joints were found to have synovitis on US which was absent on clinical examination. Subclinical synovitis was detected in six patients, and one patient was classified as having polyarticular disease on the basis of US.[4]

A study by Janow et al., 2011 compared the sensitivity and specificity of physical examination to US. In a cohort of 19 patients, ankle and knee were examined and found physical examination to be only 64% sensitive and 86% specific. There was agreement between physical examination and US in 75% of cases. They suggested that US augmented findings in patients with at least one active joint count.[20] In contrast, our study showed sensitivity and specificity of physical examination to be 60.7% and 99.48%, respectively.

Associations between various serological and radiological parameters were also studied. In a study by Gilliam et al., with 68 JIA patients of JIA it was found that patients with joint erosions and joint space narrowing had significantly elevated levels of RFs and anti-CCP antibodies. ESR and CRP were associated with synovitis.[21] In our study also, there was again a significant correlation between erosions and RF and anti-CC P values. It was seen that erosions were significantly present in patients with RF-positive polyarticular group. Furthermore, these patients had a higher value of anti-CCP antibodies.

Further, whether US should be used for guiding treatment in patients who have attained remission is a matter of discussion. A study by Miotto e Silva et al. highlights the importance of using MSUS in follow-up of JIA patients in remission to predict flares.[22] However, another recent study showed the repeated US has no role in predicting flares.[23] ARCTIC randomized controlled strategy trial to determine whether a treatment strategy based on the structured ultrasound assessment would lead to improved outcomes in RA concluded that systematic use of ultrasound in the follow-up of patients with early RA treated according to current recommendations is not justified.[24] Similarly, using US to detect synovitis for follow-up in patients of JIA may lead to overtreatment. Therefore, more randomized clinical trials are required to study role of US in detecting disease flare in JIA.

Limitation of the study includes nonevaluation of small joints such as metacarpophalangeal and metatarsophalangeal joints. In addition, both US and clinical examination are observer-dependent assessment which has its own limitations. We have also not performed grading on PD for synovitis. Furthermore, the age range from 11 to 15 years is very narrow, and we need more studies with wider age groups of JIA patients. Further, we have included the evaluation of only four joints in the study, due to feasibility issues. In addition, we have not separately looked for damaged joints, which could have been evident on a longitudinal follow-up.


  Conclusion Top


From the findings of the study, it can be suggested that seeing the low sensitivity of physical examination for active synovitis, asymptomatic joints should also be screened with US in patients with at least one actively inflamed joint. It can be concluded that use of US in children with JIA may allow earlier diagnosis of joint synovitis or extension of arthritis to clinically normal joints making an impact on diagnosis and choice of therapy

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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Matsos M, Harish S, Zia P, Ho Y, Chow A, Ioannidis G, et al. Ultrasound of the hands and feet for rheumatological disorders: Influence on clinical diagnostic confidence and patient management. Skeletal Radiol 2009;38:1049-54.  Back to cited text no. 2
    
3.
Bhatnagar N. Pediatric musculoskeletal ultrasound. Ind J Rheumatol 2018;13:S57-64.  Back to cited text no. 3
    
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Haslam KE, McCann LJ, Wyatt S, Wakefield RJ. The detection of subclinical synovitis by ultrasound in oligoarticular juvenile idiopathic arthritis: A pilot study. Rheumatology (Oxford) 2010;49:123-7.  Back to cited text no. 4
    
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Petty RE. Growing pains: The ILAR classification of juvenile idiopathic arthritis. J Rheumatol 2001;28:927-8.  Back to cited text no. 5
    
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Shanmugavel C, Sodhi KS, Sandhu MS, Sidhu R, Singh S, Katariya S, et al. Role of power Doppler sonography in evaluation of therapeutic response of the knee in juvenile rheumatoid arthritis. Rheumatol Int 2008;28:573-8.  Back to cited text no. 6
    
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Shahin AA, Shaker OG, Kamal N, Hafez HA, Gaber W, Shahin HA. Circulating interleukin-6, soluble interleukin-2 receptors, tumor necrosis factor alpha, and interleukin-10 levels in juvenile chronic arthritis: Correlations with soft tissue vascularity assessed by power Doppler sonography. Rheumatol Int 2002;22:84-8.  Back to cited text no. 13
    
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22.
Miotto e Silva VB, Mitraud SA, Furtado RN, Natour J, Len CA, Terreri MT. Patients with juvenile idiopathic arthritis in clinical remission with positive power Doppler signal in joint ultrasonography have an increased rate of clinical flare: A prospective study. Pediatr Rheumatol Online J 2017;15:80.  Back to cited text no. 22
    
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    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]



 

 
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