|Ahead of print publication
Clinical profile of juvenile idiopathic arthritis from a tertiary care hospital in Northern India
Arun Hegde1, Suchi Acharya2, Kavita Singh3, Uday Bhanu Kovilapu4
1 Department of Rheumatology, Command Hospital (Southern Command), Pune, Maharashtra, India
2 Department of Pediatrics, AFMC, Pune, 3Department of Radiodiagnosis, AFMC, Pune, Maharashtra, India
3 Centre for chronic conditions and injuries, Public Health Foundation of India (PHFI), Gurugram, Haryana, India and Visiting scholar, Stanford University, Stanford, California, USA
4 Department of Radiodiagnosis, AFMC, Pune, Maharashtra, India
|Date of Submission||28-May-2020|
|Date of Acceptance||07-Sep-2020|
Department of Pediatrics, AFMC, Wanowrie, Pune - 411 040, Maharashtra
Source of Support: None, Conflict of Interest: None
Background: Juvenile idiopathic arthritis (JIA) is the most common rheumatological disorder in children with wide variation in its clinical profile.
Objective: The aim is to study the clinical, laboratory, radiological, and treatment profile of children with JIA attending the rheumatology clinic of a tertiary care hospital in Northern India.
Methods: In this prospective observational study, we analyzed the clinical, serological, radiological, and treatment profile of 56 consecutive JIA patients attending our hospital between January 2013 to December 2016.
Results: Out of 56 children, 38 (67.8%) were boys and 18 (32.2%) were girls. Five (8.9%), 15 (26.8%), 16 (28.5%), and 20 (35.7%) children had oligoarticular, systemic-onset JIA (SOJIA), polyarticular JIA, and enthesitis-related arthritis (ERA), respectively, with male: female ratios being 0.67:1. 6.5:1, 0.45:1 and 9:1, respectively. Mean age at disease onset was 6.7 ± 4.3 (mean ± standard deviation), 6.6 ± 4.5, 6.0 ± 2.6, and 10.4 ± 3.2 years in SOJIA, polyarticular, oligoarticular and ERA, respectively. Arthritis was present in all patients. Fever, lymphadenopathy, hepatosplenomegaly, and rash were exclusive to patients with SOJIA. Uveitis and anti-nuclear antibody (ANA) positivity (3.5% each) were rare findings. Knee was the most common joint involved in all subtypes except SOJIA, where the wrist was most commonly involved. All children with SOJIA and polyarticular JIA required conventional synthetic disease-modifying anti-rheumatic drugs. Seven children with SOJIA, six children with polyarticular JIA and six children with ERA received biological disease-modifying anti-rheumatic drugs, in view of refractory disease.
Conclusion: JIA-ERA, followed by polyarticular JIA, were most common subtypes of JIA in our study. The knee is the most common joint to be involved. Uveitis and ANA positivity are rare findings in our subsets of children.
Keywords: Enthesitis related arthritis, juvenile idiopathic arthritis, oligoarticular juvenile idiopathic arthritis, polyarticular Juvenile idiopathic arthritis, rheumatoid factor, systemic-onset juvenile idiopathic arthritis
| Introduction|| |
Juvenile idiopathic arthritis (JIA) is defined as arthritis of unknown etiology, which begins before the age of 16 years and persists for at least 6 weeks. It is the most common rheumatological disorder in children, which may persist into adulthood and result in significant morbidity. The worldwide incidence of JIA ranges from 0.8 to 22.6/100,000 children/year, while prevalence ranges from 7 to 401/100,000. Studies on its prevalence in the Indian population are rare. Chopra et al, in a Community-oriented program for control of rheumatic diseases study conducted in Pune district, reported a prevalence of 0.26 for JIA. The latest (2001) international league of associations for rheumatology (ILAR) criteria classifies JIA into 6 subtypes-systemic-onset JIA (SOJIA), oligoarticular JIA (persistent and extended), polyarticular JIA (rheumatoid factor (RF) positive and RF negative), psoriatic, enthesitis-related arthritis (ERA) and undifferentiated arthritis. This differentiation into various subsets is based on the predominant clinical and laboratory manifestations. JIA remains a diagnosis of exclusion, with clinical and laboratory findings helping to exclude secondary causes of arthritis. Treatment in JIA is aimed at preventing complications such as growth retardation and improving the quality of life. The introduction of the biological disease-modifying anti-rheumatic drugs (bDMARDs) for patients who are inadequate responders to conventional synthetic disease modifying anti-rheumatic drugs (csDMARDs) have dramatically improved the disease outcome.
Studies on JIA from different parts of the world have shown variations in disease patterns.,,,, Numerous Indian studies too have demonstrated heterogeneity in their observations, which also differ from the west.,,,, For instance, ANA positivity and uveitis have been reported commonly in children with oligoarticular JIA in the west, but are rare in Indian children.,, Most Indian studies on the profiling of the various JIA subtypes have been carried out before 2010.,,,, We, in our study, attempted to investigate the clinical profile of JIA amongst children presenting to our tertiary care hospital.
Aims and objectives
To study the clinical, laboratory, radiological, and treatment profile of children with JIA attending the rheumatology clinic of a tertiary care hospital in Northern India.
| Methods|| |
This was a prospective observational study.
The study was conducted among children attending the rheumatology out patient department (OPD) and among those admitted in the pediatric ward of our tertiary care hospital in Northern India.
Children diagnosed with JIA as per “ILAR classification criteria were recruited into the study.
Children diagnosed with arthritis due to secondary causes like neoplastic diseases, hemophilia, and rheumatic fever were excluded. Children with septic arthritis and arthritis secondary to systemic lupus erythematosus and juvenile dermatomyositis were also excluded from the study.
Period of study
The study was carried out between January 01, 2013 and December 31, 2016.
The details regarding clinical symptoms, laboratory investigations at the onset, radiologic findings, clinical progression of the disease, and the patterns of csDMARD)/bDMARD drug use were recorded. All children underwent baseline complete blood count, liver, and renal function tests. Hematological parameters were measured using Siemens Advia® 2120i Autoanalyzer, and biochemical parameters were measured using Siemens Dimension® RxL Max® Autoanalyzer. Erythrocyte sedimentation rate (ESR) was done by the Westergren method. C reactive protein (CRP) and RF were done by nephelometry (Beckmann Coulter system). All patients with SOJIA underwent analysis for serum ferritin. Anti-nuclear antibody (ANA) was done by immunofluorescence using Aesku Hep 2 cell line kit. HLA B27 was done by polymerase chain reaction (Bag diagnostics, Germany). Children with JIA-ERA underwent plain radiographs of the pelvis (short-axis posteroanterior view) to look for sacroiliitis. Children who were negative for sacroiliitis on radiograph underwent magnetic resonance imaging (MRI) of the sacroiliac (SI) joint. All children who were exhibited bDMARDs were screened for the presence of latent tuberculosis by means of a TB QuantiFERON gold test and a plain chest radiograph to rule out active tuberculosis, along with serology for hepatitis B surface antigen and anti hepatitis C virus. Children with polyarticular, oligoarticular, and JIA-ERA underwent screening for uveitis by an ophthalmologist.
We reported summary statistics for the continuous measures (age, ESR, CRP) as mean (standard deviation) for the variables, which were normally distributed, and median (interquartile range [IQR]) for the variables with skewed distribution (not normally distributed) and for categorical variables (sex and sub-types of JIA) as n (%). Data were also plotted on the pie chart for sub-types of JIA. We used STATA version 12.0 SE; Stata Corp, TX, the USA, for all descriptive statistical analysis.
Written informed consent was taken from the parents of all enrolled children. In addition, all children > 7 years of age provided assent.
The ethics committee, Army Hospital (Research and Referral), New Delhi, approved this study.
| Results|| |
A total of 56 children were recruited in the study. Thirty-eight (67.85%) were boys and 18 (32.15%) were girls with a male: female ratio (M: F) of 2.1:1. The distribution of various subtypes of JIA is depicted in [Figure 1], and distribution as per se x and age at onset is depicted in [Table 1].
|Figure 1: Subtypes of Juvenile Idiopathic Arthritis (n = 56) SOJIA: Systemic onset juvenile idiopathic arthritis, ERA: Enthesitis related arthritis|
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Polyarticular juvenile idiopathic arthritis
The wrist and knee each were involved in 12/16 children. The pattern of joint involvement in different JIA subtypes is depicted in [Figure 2]. Nine children were RF positive, and seven were RF negative. One child tested ANA positive. None of the children had uveitis or rheumatoid nodules during the period of the study. The median and IQR of ESR and CRP are summarized in [Table 2]. All patients required csDMARDs in form of methotrexate (MTX), two children required sulfasalazine (SSZ) in addition. Six children required bDMARDs, in view of high disease activity. Four children received tumor necrosis factor-alpha inhibitors (TNFi) in form of etanercept at doses of 0.8 mg/kg subcutaneous (SC) weekly (15, 12, 24, and 40 doses, respectively). One each received anti interleukin-6 therapy with tocilizumab at doses of 8 mg/kg once every 4 weeks (six doses) and selective co-stimulation modifier abatacept at doses of 10 mg/kg monthly (12 doses).
|Figure 2: Joint involvement in juvenile idiopathic arthritis SOJIA: Systemic onset juvenile idiopathic arthritis, ERA: Enthesitis related arthritis|
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Systemic onset juvenile idiopathic arthritis
Arthritis and fever were the most common presentations and were seen in all 15 children, followed by lymphadenopathy in ten, hepatosplenomegaly in eight and rash in seven children, respectively. The Wrist joint was the most common joint involved in 14/15 children, followed by knee and small joints of hands in 12/15 children [Figure 2]. The acute phase reactants are summarized in [Table 2]. All children required csDMARDs (MTX), whereas one child required cyclosporine in view of being refractory to MTX. Seven children required bDMARDs in form of tocilizumab, 12 mg/kg every 2 weeks in view of high disease activity. The numbers of doses required were 1, 4, 29, 23, 3, 6 and 12, respectively, in these children. One child developed macrophage activation syndrome (MAS) during the disease course.
Oligoarticular juvenile idiopathic arthritis
Out of five, three children had persistent oligoarticular JIA, while two had extended oligoarticular JIA. The wrist and knee were involved in three children each [Figure 2]. The acute phase reactants are summarized in [Table 2]. One child was ANA positive. None had uveitis. Four children required MTX, while one recovered on intra-articular and oral steroids given along with non-steroidal anti-inflammatory drugs (NSAIDS). One patient required SSZ, in addition to MTX. One patient required tocilizumab for high disease activity at doses of 8 mg/kg, every 4 weeks. A total of 21 doses were required to achieve remission in this child.
Juvenile idiopathic arthritis-enthesitis related arthritis
The knee (14/20 children) and ankle (13/20 children) were the most commonly involved joints [Figure 2]. Two children had anterior uveitis. Fourteen (70%) children were HLA B27 positive. Both children with uveitis were HLA B27 positive. Two children had a positive family history for axial spondyloarthritis in their fathers. Four children (20%) had bilateral sacroiliitis on the radiograph of the pelvis. Ten children underwent additional imaging in form of MRI of SI joint among which five showed evidence of active sacroiliitis. Thus, a total of 9/20 (45%) had sacroiliitis. Sixteen children required csDMARDs in form of SSZ, while six children required bDMARDs in form of TNFi. Three children received etanercept at doses of 0.8 mg/kg SC (12, 20, and 25 doses, respectively), and three received Infliximab at doses of 5 mg/kg (9, 5, and 3 doses, respectively) to achieve disease remission.
| Discussion|| |
JIA-ERA (35.7%) was the commonest subtype of JIA observed in our study, the prevalence of which was similar to a large community-oriented study done from India (35.7%) as well as international studies from Taiwan (37.4%) and Singapore (32.8%). Interestingly, the spectrum of JIA in our study was different from the west, where-in, oligoarticular JIA has been reported as the most common subtype and even from certain Indian studies,,,,,,, where-in, polyarticular JIA was reported as the commonest subtype. It is very difficult to provide an explanation for these differences, as it could have resulted from different ethnicities of the population, changing patterns of disease presentation itself, referral bias, or the small sample size of our study. Moreover, the majority of these studies, excepting two, were conducted before 2010. A comparison of the prevalence of JIA subtypes across various studies is summarized in [Table 3]. We did not encounter any child with psoriatic JIA in our series. The probable reason could be that children usually do not manifest certain classical manifestations such as distal interphalangeal joint arthritis, nail pits, and arthritis mutilans. Furthermore, subtle findings like a skin rash in a hidden area could be easily overlooked in a busy OPD setting. Nevertheless, none of the children in our study had a family history of psoriasis. Maybe a longer period of observation would be required to elicit a switch in the clinical subtype of JIA from an ERA subtype to a psoriatic subtype.
|Table 3: Comparison of juvenile idiopathic arthritis subtypes across various studies from India and Asia|
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Overall, a male (67%) preponderance was noticed in our study, which was similar to several Indian studies,,, but was in contrast to Western studies,, where in a female preponderance was noticed. This could have resulted out of a gender bias in our country, where-in male children are cared far more as compared to the girl child, and are brought to health care facilities more readily by their parents in case of disease. Our findings of male preponderance in SOJIA and ERA, and female preponderance in polyarticular and oligoarticular JIA were in consonance with the studies by Sircar et al. and Suni et al. The average ages of disease onset in oligoarticular JIA in our study were 6 years. Oligoarticular JIA usually presents in the 0–6 years age group. We observed a later onset of age (six years), which was in consonance with the observations of Seth et al. and Shen et al. but less than that observed by Suni et al. and Kunjir et al. (9.75 years). The probable reason could be that the earlier onset subsets could have been mild and not reported. The mean age at onset of the other subtypes of JIA was comparable with other studies, as depicted in [Table 4].,,,,,
|Table 4: Comparison of mean age at onset and immunological parameters in juvenile idiopathic arthritis|
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The pattern of joint involvement in our study revealed the knee joint to be the most frequently involved joint, followed by wrist, ankle, small joints of hands, and elbows, in that order. This finding of ours is similar to that of several Indian studies.,, Hip joint arthritis was exclusively seen in ERA and oligoarticular subtypes only. This aspect has also been highlighted by Mistry et al. in their review on JIA-ERA where-in, they observed that SI and hip joint involvements were characteristic of ERA, and up to one-third of ERA eventually developed hip arthritis. None of our cases had temporomandibular joint involvement, which was in consonance with several Indian,, and Asian studies.,
Fever, rash, lymphadenopathy, hepatosplenomegaly was exclusively seen in SOJIA. None of the other JIA subtypes showed any extraarticular manifestations, except for uveitis in JIA-ERA. These findings of ours are in consonance with a series of studies.,, One child with SOJIA developed MAS during the disease course. MAS is now being increasingly diagnosed in SOJIA, and its incidence has been reported to be in the range of 1.5%–6.8%.,
The acute phase reactants like ESR, CRP, and Ferritin were higher in SOJIA than any other subtypes, similar to the findings of other studies.,, Contrary to Western studies, that report a higher frequency of ANA positivity (70%–80%) and uveitis (20%–30%) in their children, our study showed a lower frequency for these (3.5% each). This finding is in consonance with several Indian,,,,, and Asian studies., Low rates of ANA positivity and uveitis seem to be unique features of JIA in Indian children. The reason for this is not fully understood but could have arisen out of geographic and genetic variations. RF positivity was seen in 16% of our JIA patients, more often in the polyarticular JIA subset, which is in consonance with Indian,, and Western studies. RF positive status is closely linked to the occurrence of rheumatoid nodules. However, none of our patients had rheumatoid nodules, similar to the findings of Suni et al., and Viswanathakumar andKumar. Contrastingly, few Indian workers have reported a higher incidence of rheumatoid nodules ranging from 3% to 8%., 70% of children with ERA were positive for HLA-B27, similar to the studies by Aggarwal and Misra, (82%), Kunjir et al., (88%), and Shen et al. (82%). Comparison of immunological parameters in JIA across various studies is illustrated in [Table 4].
Among children with ERA, 45% showed evidence of active sacroiliitis (including radiographs and MRI, taken together) in our study, which was similar to a study from Taiwan (47%), while Kunjir et al. in their community-based Indian study observed sacroiliitis in 19% of their ERA patients. The positivity on the radiograph of the pelvis in our study was also 20% but improved on using MRI. The probable reason for this could be that MRI as an imaging modality, can pick up subtle bone marrow edema, an entity now being referred to as nonradiographic spondyloarthritis in adults. Mistry et al. in their review have highlighted a number of studies that have used MRI to image the SI joint in children, although more studies would be required before it can be considered for inclusion in guidelines.
Management of JIA has evolved over the last two decades with the introduction of bDMARDs, which are now being increasingly used and have resulted in improved disease outcomes. All children in our study were initiated on therapy with NSAIDs. Naproxen was the most common NSAID used, either alone or in combination with other csDMARDs (MTX or SSZ), similar to study by Viswanathakumar and Kumar. MTX was the most common prescribed csDMARD. All children with SOJIA and polyarticular JIA required csDMARDs for disease control, which was in consonance with other studies., bDMARDs were most frequently required in SOJIA, followed by polyarticular JIA and ERA, as has been brought out by Saini et al. Tocilizumab was the most frequently used bDMARD in SOJIA and polyarticular JIA, whereas it was TNFi (etanercept/infliximab) in ERA. Contemporary literature also suggests this pattern of use.,,
Our study had few strengths being one of the few Indian studies to have utilized MRI as an imaging modality in nonradiographic ERA as well as attempting to profile the bDMARD use in various subtypes of JIA, although there were limitations too, arising out of the small sample size, lack of use of objective joint disease activity measures such as JADAS, lack of assessment of disease damage parameters and documentation of drug-related side effects, due to which it might not be possible to generalize the results to a larger population. Furthermore, the authors would like to submit that one child who was enrolled as oligoarticular JIA at presentation could have subsequently evolved into a polyarticular subtype during the course of the study, considering the involvement of the wrist joint during disease evolution, which is rare in the oligoarticular subtype, and the subsequent requirement of multiple doses of tocilizumab in the child to achieve clinical remission.
| Conclusion|| |
The current study suggests that JIA-ERA may be the commonest subtype of JIA in Indian children. Low incidences of ANA positivity, uveitis, and rheumatoid nodules are unique features exclusive to the Indian children. MRI of the SI joint is emerging as an important tool for diagnosing sacroiliitis in JIA. bDMARDs in the form of TNFi and tocilizumab are now being increasingly used for disease control and are efficacious in reducing morbidity arising out of disease.
Financial support and sponsorship
The bDMARDs used in the study were provided free to the patients by the Government of India, and all laboratory and radiological investigations were carried out in the hospital free of cost.
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4]