This retrospective study was conducted in the Pediatric Rheumatology Division at Queen Rania Children’s Hospital, Amman, Jordan, which is the only center in the country dedicated to pediatric rheumatology disorders. To the best of our knowledge, this was the first single center comprehensive study describing JIA in Jordan.
According to published international reports, oligoarticular JIA is the most common JIA subtype, as reported in Spain (51%), Sweden (44.7%), and Turkey (41%) (4,5,6). Similarly, oligoarticular JIA was the most common subtype in our cohort with a frequency of 115 (57.7%) patients. With regard to published data from some countries in the Middle East and North Africa (MENA), such as Lebanon (31%), Iraq (48%), Saudi Arabia (40.5%), and Egypt (41.3%), oligoarticular JIA was the most common subtype (7,8,9,10). Whereas other reports from MENA found polyarticular JIA to be the most common subtype in Oman (46.7%) (11) and Tunisia (66%) (12).
We compared our data in this study with those from countries in MENA and other regions, as shown in Table 8.
The current study reported that the mean age at disease onset was 5.08 ± 3.40 years (range: 7 months to 14 years), which was much lower than that reported by Abou El-Soud et al. (14) (mean: 10.5 ± 3.60 years; range: 4–15 years), but similar to that published by Bahabri et al. (15) (mean: six years). It was also lower than the mean age of European origin patients as published by Saurenmann et al. (16) (mean: 6.5 years; range: 6.1 – 6.8 years). This observation might be explained by the younger age range of the pediatric population of our cohort, as patients older than 14 years are seen by adult rheumatology. The current study showed female predominance (116 female patients; male to female ratio: 1:1.2); a higher ratio (1:1.7) was reported by Solau-Gervais et al. (17).
According to table 5, elevated acute phase reactant levels (CRP and ESR) were the most common findings, unlike the report by Al-Hemairi et al. (13), where anaemia was the most common finding at diagnosis (59.7%). Compared to our study, anaemia was observed in only 10%. Whereas in systemic arthritis, anaemia, leukocytosis, and thrombocytosis had much higher percentages than those observed in our study.
ANA was positive in 33.6% of cases, although others, such as Khuffash et al. (18) and Ozdogan et al. (19) recorded fewer numbers (12% and 5%, respectively). This observation reflected on the higher incidence of uveitis. ANA positivity was highest among patients with oligoarticular JIA (61 (53%) patients), which is similar to findings (50%) by Al Wahadneh et al. (20).
Oligoarthritis is an overwhelming disease of the lower limbs, with the knee joint being the most part affected, followed by the ankle joint (21). Similar to data recorded globally, the pattern of joint involvement in oligoarticular JIA in our study had a lower limb predominance, with the knee and ankle joints involved in 80% and 21% of all cases, respectively. Similar joint involvement was found in polyarticular JIA, with the knee and ankle joints involved in 100% and 30% of all cases, respectively.
Extra-articular manifestations in systemic-onset JIA were fever (reported in all patients), followed by skin rash (66.6%). The pattern of joint involvement showed upper and lowered joint involvement, with knee and ankle arthritis reported in 100% and 50%, respectively, whereas elbow and wrist involvement were 28% and 55.5% of all cases, respectively. Our study reported a higher prevalence of both articular and extra-articular manifestations in systemic arthritis than the study from Egypt (22).
Uveitis was reported in 30 (14.2%) patients, which was comparable to results (11.6%) published by Angeles-Han et al. (23). Oligoarticular JIA was the most common subtype associated with uveitis (25 (21.7%) patients). ANA positivity was found in 16 (64%) patients. According to a study from Saudi Arabia, uveitis was observed in 8.1% of patients with oligoarticular JIA (24). Another large population based study in Germany on patients with JIA reported that uveitis occurred in 12% of all JIA subtypes (extended oligoarticular (25%) and persistent Oligoarticular (16%)) (25). However, whether if this complication is due to the high prevalence of oligoarticular JIA is unclear.
MAS is a life-threatening complication of systemic JIA (26). In this study, it was observed in only two (0.9%) patients, whereas Çakan et al. (27) reported a higher incidence (33.9%) of this serious complication. Çakan et al. (27) explained that this high rate of MAS was because the study was conducted in a referral center for pediatric rheumatology and the high percentage of Mediterranean fever (MEFV) gene mutation carriers, which may increase the possibility of developing more auto-inflammatory disorders than in other healthy populations. JIA treatment aims to reduce pain, gain joint function, preserve muscle strength, and avoid systemic complications (28). Although no consensus on JIA treatment has been reached, many guidelines have been established by different rheumatology societies or colleges. In our pediatric rheumatology division, we follow the American College of Rheumatology (ACR) recommendations for the JIA treatment (30). Based on ACR recommendations, we followed the plan to start treatment with NSAIDs, and in case of inadequate response, conventional DMARDs were started. In case of failure, no response, or intolerance, we switched to another DMARD or added a biological agent.
NSAIDs have traditionally been the mainstay treatment for all kinds of JIA during the first four to six weeks of initial treatment, either alone or with combination with intra-articular steroid injection (31). NSAIDs were used in 174 (82.8%) patients—oligoarticular JIA (103 (89.2%) patients) and systemic JIA (35 (96.7%) patients—at diagnosis or during their disease course. A higher percentage of 99% of patients with oligoarticular JIA in central Italy received NSAIDs (29).
Systemic steroids are used in the treatment of JIA at diagnosis or during disease flare (36). In our cohort, systemic steroids were used in 91% of patients. A short course of low dose systemic steroids was used as bridging therapy in 127 patients with oligoarticular and polyarticular JIA at the time of diagnosis or during disease flare and in all patients with systemic arthritis to control systemic manifestation.
Methotrexate (MTX) is the cornerstone treatment in oligoarticular, polyarticular, and systemic JIA with articular inflammation predominance (32). In our cohort, MTX was used in 81.4% of the cases 76.7%, 100%, and 90% of cases in oligoarticular, polyarticular, and systemic JIA, whereas MTX was used in 66% of cases in the Omani study (11). Other DMARDs were used in cases of MTX toxicity or intolerance; leflunomide, sulfasalazine, myfortic (MMF), and hydroxychloroquine were administered in 6 (2.8%), 2 (0.95%), 1, and 4 (1.9%) cases, respectively.
Biological treatment has been found to be safe and effective in severe JIA or refractory cases to synthetic DMARDs (33). In our cohort, biological agents were used in 105 (50%) patients. These agents include anti -TNF (tumour necrosis factor), which is a cytokine that plays a role in the pathogenesis of JIA and found in higher levels in the synovial fluid. Tocilizumab, a monoclonal antibody directed against IL-6 receptor, increased serum levels in systemic arthritis. Anakinra is a human recombinant IL-1 receptor antagonist, plays a role in the pathogenesis of JIA, and is a preferred treatment option for systemic arthritis. Rituximab is a human monoclonal antibody directed against CD20 lymphocytes, which results in increased B-cell apoptosis and decreased levels of mature B cells expressing CD20 (34). In our cohort, anti-TNF drugs were used in 74 (35.2%) patients. Infliximab (30 (14.2%) patients) was the most common anti-TNF used, followed by etanercept (25 (12%) patients). Whereas adalimumab and golimumab were used in 15 (7.1%) and 4 (1.9%) patients, respectively. In comparison, biological DMARDs were used in 28.4% of patients from Saudi Arabia, with adalimumab being the most common biological treatment (9). This difference could be due to the larger size of our cohort and a more severe disease at the time of diagnosis in our cohort. Thirty eight (18%) patients in our cohort used more than one biological agent, and this group of patients reflects the more severe course in our cohort. Most of them switched to another biological agent due to the inefficiency of the previous agents.
Tocilizumab was used in 17 (8%) patients—13 patients with systemic arthritis. Anakinra (IL-1 antagonist) was used in one (0.5%) patient with systemic arthritis (Anakinra is not yet registered in Jordan, and it was offered to the patient from outside the country). Rituximab was used in 8 (3.8%) patients—five patients were with systemic arthritis refractory to DMARDs, steroids, and other biological treatments. Alexeeva et al. (35) showed that rituximab may be effective in severe systemic arthritis resistant to immunosuppressive treatment, glucocorticoid therapy, and other biological treatments.
In our cohort, 31% of all patients showed active disease during the last follow-up. Remission on medication was observed in 56%, and off medication in 13%; whereas Shen et al. (38) reported patients with active disease, remission on medication, and off medication during the last follow-up (40%, 14.9%, and 45.1%, respectively). A similar outcome was reported by Chhabra et al. (39), where inactive disease was reported in 73% (remission on medication (25%) and remission off medication (47%). The low percentage of remission off medication can be explained by difficulty in achieving remission off medication in both psoriatic and enthesitis related arthritis.
Our study limitations included the design (being a retrospective study), setting (single center rather than population based, which may give more details about JIA characteristics), and limited severity spectrum (that it did not include ‘mild cases’, which are not referred to our hospital or misdiagnosed). In addition, we did not include patients with JIA who were older than 14 years at disease onset due to governmental policy of pediatric age cut-off, contrary to ILAR’s definition.