|Year : 2018 | Volume
| Issue : 1 | Page : 26-32
Long-term outcomes and predictors of biologic treatment in systemic juvenile idiopathic arthritis in a single-center experience in Thailand
Sirisucha Soponkanaporn1, Suphaneewan Jaovisidha2, Soamarat Vilaiyuk1
1 Division of Rheumatology, Department of Pediatrics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
2 Department of Radiology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
|Date of Web Publication||26-Feb-2018|
Dr. Soamarat Vilaiyuk
Division of Rheumatology, Department of Pediatrics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, 270 Rama VI Road, Ratchathewi, Bangkok-10400
Source of Support: None, Conflict of Interest: None
Background: The outcomes of systemic juvenile idiopathic arthritis (SJIA) vary from mild disability to mortality. Due to the socioeconomic problems in Thailand, the delay in receiving some medications, especially biologic agents, might affect the outcomes of this disease. This study aimed to determine the long-term outcomes and predictors of biologic treatment in SJIA patients.
Methods: Patients with SJIA were enrolled over the study period between April 1997 and January 2015. The data were collected from medical records at the initial presentation and the most recent clinical visit. Outcomes evaluated included disease status, functional impairment, and joint destruction.
Results: Of the 68 SJIA patients, 64 (94%) were eligible. The median (interquartile range) age at disease onset and duration of follow-up were 4.4 (2.9–7.9) and 4.2 (2.3–5.9) years, respectively. Nine patients (14%) achieved complete remission, while 12 (18.8%) had persistent active disease and 3 patients died; 2 of them had macrophage activation syndrome, while the other had a severe infection. A predictor of moderate-to-severe disability (childhood health assessment questionnaire ≥0.75) was hip involvement (odds ratios [OR] 27, 95% confidence interval [CI] 3.20–228.05). In addition, the predictors of biologic treatment were female gender (OR 6.4, 95% CI 1.74–23.74), younger age of onset (OR 4.7, 95% CI 1.31–16.66), hepatosplenomegaly (OR 5.9, 95% CI 1.29–27.29), and positive antinuclear antibody (ANA) (OR 6.3, 95% CI 1.19–33.75). Bone erosion was found in 34.2% of SJIA patients.
Conclusion: Hip involvement was the important predictor of moderate-to-severe disability in SJIA, whereas female gender, younger age of onset, hepatosplenomegaly, and positive ANA were the predictors of biologic treatment.
Keywords: Biologic treatment, juvenile idiopathic arthritis, outcomes, predictor, systemic juvenile idiopathic arthritis
|How to cite this article:|
Soponkanaporn S, Jaovisidha S, Vilaiyuk S. Long-term outcomes and predictors of biologic treatment in systemic juvenile idiopathic arthritis in a single-center experience in Thailand. Indian J Rheumatol 2018;13:26-32
|How to cite this URL:|
Soponkanaporn S, Jaovisidha S, Vilaiyuk S. Long-term outcomes and predictors of biologic treatment in systemic juvenile idiopathic arthritis in a single-center experience in Thailand. Indian J Rheumatol [serial online] 2018 [cited 2019 Dec 15];13:26-32. Available from: http://www.indianjrheumatol.com/text.asp?2018/13/1/26/222118
| Introduction|| |
Juvenile idiopathic arthritis (JIA) is the most common cause of chronic arthritis in children. The incidence varies between 0.83 and 23.6/100,000 children per year. It is a heterogeneous group of diseases characterized by arthritis of unknown origin with onset before the age of 16 years and persisting for more than 6 weeks. JIA has been classified into seven subtypes based on the International League of Associations for Rheumatology (ILAR) 2001 revised criteria. Systemic JIA (SJIA) is the most common JIA subtype in many Asian countries, at approximately 37%–54% of JIA patients.,, The disease course of SJIA and outcome of treatment vary from mild disability to mortality, depending on multifactors. In previous studies, persistent systemic features, younger age at onset, polyarticular pattern, and hip arthritis were predictors of poor functional outcome in SJIA., Corticosteroid treatment is the mainstay of therapy, followed by disease-modifying antirheumatic drugs (DMARDs). The biologic agents have been in our treatment guidelines for a decade. However, the socioeconomic problems in Thailand make patients suffer delays in receiving biologic agents at the appropriate time. The disease course and the long-term outcomes of SJIA in Thailand might be different from Western countries or other developed countries. Therefore, the aim of this study was to determine the long-term outcomes, predictors of the biologic treatment and functional impairment of SJIA disease in Thai children.
| Methods|| |
SJIA patients in the pediatric rheumatology clinic, Ramathibodi Hospital, between April 1998 and January 2015 were enrolled in this study. The diagnosis of SJIA was diagnosed based on ILAR criteria.
Data were collected from medical records at the time of diagnosis and the most recent clinical visit. Extracted parameters included sex, age at onset, duration from diagnosis to treatment initiation, joint involvement, rash, serositis, hepatosplenomegaly, medications, mortality rate, and cause of death. The complications were also recorded, including macrophage activation syndrome (MAS) according to the Histiocyte Society criteria in 2004, uveitis, avascular necrosis, interstitial lung disease (ILD), amyloidosis, and joint deformities. Laboratory data included complete blood count, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), liver function test, rheumatoid factor, and antinuclear antibody (ANA) with a titer of >1:80 considered positive.
Treatment guidelines for SJIA at Ramathibodi Hospital depend on phenotypes of disease. In patients with active systemic diseases and varying degrees of synovitis, nonsteroidal anti-inflammatory drug and corticosteroids are the mainstay of treatment. DMARDs are introduced in patients with active systemic synovitis. Moreover, biologic treatment such as tocilizumab, etanercept, and infliximab are initiated when SJIA patients fail two DMARDs or cannot discontinue corticosteroid within 6 months. However, in some patients, biologic treatment is unable to be initiated on time due to socioeconomic limitations.
Outcomes of SJIA were assessed in three categories, namely, disease status, functional impairment, and joint destruction. Disease status can be classified into four groups according to the European League Against Rheumatism disease activity criteria: (1) active, increasing number of active joints irrespective of drug therapy; (2) stable, stable number of active joints but requiring drug therapy; (3) inactive, no evidence of active joint and/or extraarticular features without drug therapy for <2 years; (4) remission, no evidence of active joint and/or extraarticular features without drug therapy for ≥2 years.
Functional impairment was assessed using childhood health assessment questionnaire (CHAQ) score. CHAQ was completed by children aged ≥8 years or by their parents if the children were aged <8 years. Patients with CHAQ score ≥0.75 were classified as moderate-to-severe disability, as in previous studies.,,
Joint destruction was evaluated by performing plain radiographs of all symptomatic joints and contralateral joints on the recent date of follow-up. Plain radiographs were scored by an expert musculoskeletal radiologist according to the Dale radiographic classification system: grade 0, normal joints; Grade 1, juxtaarticular osteoporosis and/or periarticular soft tissue swelling; Grade 2, growth abnormality, bony erosion not present; Grade 3, growth abnormality and marginal bony erosions; Grade 4, deformation and severe erosions; and Grade 5, gross destruction and deformity., Therefore, the Dale radiographic classification Grades 3–5 represents bone erosion.
Pattern of disease course was classified into 3 groups after >2-year follow-up; (1) monophasic, one episode of active disease lasting <2 years and no recurrence of active disease during the follow-up period; (2) polycyclic, active disease followed by inactive disease for any period of time and recurrence of active disease during the follow-up period; and (3) persistent, active disease including patients with persistent systemic symptoms and/or persistent arthritis symptoms ≥2 years.
STATA version 13.0 (StataCorp, College Station, TX, USA) was used for statistical analysis. Categorical variables were expressed as frequencies and percentages and continuous data were shown as median and interquartile range (IQR). A stepwise multiple logistic regression model was used to determine predictors of the biologic treatment and functional impairment. The significant level was set at 0.05. The results were presented as the odds ratios (ORs) with corresponding 95% confidence interval (CI).
Written informed consent and age-appropriate assent were received from patients and parents before the study was performed. This study was approved by the Ethics Committee for Research of Ramathibodi Hospital.
| Results|| |
Of the 68 SJIA patients, 64 SJIA patients were eligible for the study and the remaining four patients were lost follow-up. There were 30 boys and 34 girls, whose median (IQR) age at disease onset was 4.4 (2.5) years and duration of follow-up period was 4.2 (1.8) years. All patients presented with high-grade fever, 98.4% presented with arthritis, around half of whom had polyarthritis, 79.7% had salmon rash, 26.6% had hepatosplenomegaly, and 10.9% had serositis at initial presentation. The most common joint involvements were wrists (43%), knees (43%), and ankles (37%). Hip joint involvement at disease onset was about 9%. The white blood cell counts, platelet counts, ESR, CRP, and interleukin-6 levels were elevated at disease onset and returned to normal levels during the follow-up period, as shown in [Table 1].
|Table 1: Laboratory data at initial presentation and 4-year follow-up period in 64 systemic juvenile idiopathic arthritis patients|
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Systemic corticosteroid was a mainstay of treatment (87.5%) and most SJIA who had chronic arthritis required DMARDs, with 82.8% of the patients receiving methotrexate and 42.2% receiving both methotrexate and sulfasalazine. Due to socioeconomic problems in Thailand, patients who failed two DMARDs were indicated for biologic agents. Therefore, sulfasalazine was added after patients failed methotrexate. Around 20% had intraarticular steroid injections. Almost half of the patients failed conventional therapy, corticosteroids and DMARDs, so biologic treatment was indicated. As tocilizumab was launched in Thailand in 2010 and antitumor necrosis factor (anti-TNF) agents in 2005, there was a period of unavailability for tocilizumab. From the 34 patients (53.1%) given biologic treatment, 29 (85.3%) received one biologic agent (26 patients [89.7%] with tocilizumab and 3 patients [10.3%] with etanercept). Five patients (14.7%) received two biologic agents, 4 initially receiving etanercept while the other receiving infliximab. They all failed to respond to anti-TNF agents, so they were switched to tocilizumab treatment thereafter. For patients receiving anti-TNF agents, only 37.5% responded to treatment. Around 66.7% of tocilizumab-treated patients had complete response and 33.3% had partial response. The dose and frequency of tocilizumab treatment was 8 mg/kg every 2 weeks and the median duration of tocilizumab treatment was 3.1 years (IQR 2.8). During biologic treatment, there was no immunosuppressive medication in patients with clinical remission. However, nonremission patients still had received immunosuppressive medications, including corticosteroids (14.6%), methotrexate (4.7%), corticosteroids and methotrexate (35.9%), methotrexate and sulfasalazine (4.7%), corticosteroids, methotrexate, and sulfasalazine (40.1%).
Regarding disease activity, nine patients (14.1%) achieved complete remission, eight (12.5%) were clinically inactive, 35 (54.7%) attained stable disease, and 12 (18.8%) had persistent active disease. Two patients died from MAS and severe infection and one patient died from a severe infection. Therefore, the most severe complication that led to high mortality rate in SJIA patients in this study was MAS and severe infection. Eleven patients (17.2%) had MAS, most of whom developed it during active disease. Three out of eleven patients had partial response to intravenous immunoglobulin and were subsequently treated with systemic corticosteroids. Only 27% responded to systemic corticosteroids alone, while the remaining patients needed cyclosporine A as additional treatment. One patient, who had persistent and refractory disease, developed amyloidosis around 10 years after the onset of SJIA. Another SJIA patient in this study was diagnosed with ILD. The overall complications of SJIA patients during 4-year follow-up period are shown in [Figure 1].
|Figure 1: Complications of systemic juvenile idiopathic arthritis patients during 4-year follow-up. *MAS: Macrophage activation syndrome|
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After using logistic regression analysis, the predictors of biologic treatment were female sex, younger age of onset, hepatosplenomegaly, and positive ANA, as shown in [Table 2]. Around 8% of SJIA patients had moderate-to-severe disability, defined by CHAQ ≥0.75. In those patients, hip involvement was the only predictor of moderate-to-severe disability, with an OR of 27.0 and 95% CI 3.2–228.1. Regarding joint destruction assessment in 35 patients, the median duration from disease onset to time of radiographic assessment was 2.7 (IQR 1.7) years. Dale radiographic classification grade 1 was found the most and grade 5 was found the least, as shown in [Figure 2]. Bone erosion, which included Dale radiographic classification Grades 3–5, was found around 34.2%.
|Table 2: Predictors of biologic treatment in systemic juvenile idiopathic arthritis patients|
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|Figure 2: Radiographic abnormalities according to dale radiographic classification system in 35 systemic juvenile idiopathic arthritis patients. *Grade 0, normal joints; Grade 1, juxtaarticular osteoporosis and/or periarticular soft tissue swelling; Grade 2, growth abnormality and bony erosion not present; Grade 3, growth abnormality and marginal bony erosions; Grade 4, deformation and severe erosions; Grade 5, gross destruction and deformity|
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For the disease course, most patients (62.5%) had persistent disease, while 34.4% had monophasic and only 3.1% had polycyclic disease. Monophasic and polycyclic disease course were classified as a nonpersistent disease course. Laboratory data and medications between nonpersistent and persistent disease course are shown in [Table 3]. Patients with nonpersistent disease courses tended to use less corticosteroids and were able to discontinue corticosteroids faster than those with persistent disease courses. Although 60% of patients with persistent disease course received biologic treatment, persistent disease course was not a predictor of biologic treatment in this study.
|Table 3: Laboratory data and medications in systemic juvenile idiopathic arthritis patients between nonpersistent and persistent disease course patterns|
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| Discussion|| |
SJIA has heterogeneous in disease course and severity. Outcomes of the disease also vary due to nationality and treatment strategy. Therefore, this study focused on clinical characteristics, outcomes, complications, predictors of biologic treatment and functional impairment in SJIA patients. Patients in this study had a range of disease severity. Patients' demographic data in the present study was different to previous studies. For example, median age of onset in this study was 4.4 years, which was younger than studies in Japan, Taiwan, Northern Norway and Southwestern Sweden, which varied from 7.5–10 years.,,, Furthermore, there was one patient who did not have arthritis at disease onset. This can be explained by arthritis being absent in one-third of SJIA patients at initial presentation, and a previous study has reported that mean duration of the presence of arthritis was 75 days. Among the patients with arthritis, polyarthritis was as common a pattern as oligoarthritis, which was different to a previous report in which polyarthritis was more common. These findings can be explained by the different phenotypes of SJIA among different ethnic groups. For disease outcomes, we found that only 14.0% of the individuals were in clinical remission, which was lower than others. Tsai et al. reported that 28.6% of patients had complete remission, while 37.0% of patients in study of Russo and Katsicas achieved remission. The difference in ethnicity, severity of the disease, remission criteria, and the treatment strategies between studies might lead to the variation in remission rates. Most patients in this study were treated with a step-up approach. Biologic treatment is indicated when patients fail two DMARDs or patients are corticosteroid dependent. Nevertheless, some patients were unable to afford biologic treatment, leading to delays in treatment. This could result in poor disease outcomes and more complications. From the 60% of patients indicated for biologic agents but who could not afford it on time, none of them was in remission, 27.8% developed deformities, and 22.2% had spine fractures due to prolonged use of corticosteroids. Furthermore, as this study was done in a single tertiary care center, patients tended to have poorer disease course.
There are many complications in SJIA that need to be considered. The most severe, potentially life-threatening complication of SJIA is MAS, which is classified as secondary hemophagocytic lymphohistiocytosis (HLH). We found that MAS occurred in around 17% of SJIA patients, while previous studies reported 7%–15%.,,, When HLH 2004 criteria were used to diagnose MAS, the prevalence of MAS in SJIA may be lower than it should be due to low sensitivity of these criteria for MAS diagnosis. Since SJIA is the disease of systemic inflammation with relatively high levels of white blood cell counts and platelet counts, the cutoff levels should be different from other etiologies of HLH. The criteria for MAS diagnosis should be used separately from HLH 2004 criteria. Ravelli et al. developed preliminary diagnostic guidelines for MAS complicating SJIA and Davi et al. showed that the preliminary guidelines had stronger ability to diagnose MAS in SJIA than the HLH-2004 criteria. Recently, Ravelli et al. have launched the 2016 classification criteria for MAS in SJIA. Behrens et al. reported that occult MAS occurred in around 50% of SJIA patients and MAS can develop without any known trigger factors. In this study, most SJIA patients developed MAS when they had active disease, but some had MAS after infection. Even though respiratory complications are uncommon in JIA, ILD, one of the fatal complications of SJIA, is still underdiagnosed. Methotrexate induced pneumonitis can occur anytime during therapy but it occurs mostly within the 1st year of treatment. The true incidence of methotrexate-induced pneumonitis in SJIA is difficult to assess due to limited data. However, in adult patients, pulmonary toxicity associated with methotrexate has been reported with an incidence of about 0.3%–8.0% of patients receiving methotrexate for rheumatic diseases.
Another complication that can be commonly found in SJIA is destructive arthritis (34.2% with bone erosion). Since disease onset to time of radiographic assessment was median 2.7 (IQR 1.7) years, some patients had disease duration of more than 2 years at radiographic follow-up. Therefore, this might explain the high prevalence of radiological changes in these patients. Previous studies have also reported that approximately 20%–40% of SJIA patients developed joint destruction,,, which is quite similar to this study.
As for predictors of disease severity, this study revealed that age <5.5 years was a predictor of biologic treatment which reflected disease severity and refractory disease in SJIA patients. This finding is quite similar to the study by Russo et al., which showed patients with early-onset SJIA exhibited a more aggressive disease course than patients with later-onset. Similarly, several studies have reported that younger age at onset is a risk factor for nonremission., Altogether, these confirm that patients with disease onset at a younger age have greater disease severity than older patients. This also emphasizes the importance for clinicians to be concerned about younger patients. In addition, the presence of hip involvement at the initial manifestation was a predictor for moderate-to-severe disability. This finding is similar to a previous study, which showed that hip arthritis is one of the poor prognoses in SJIA with active arthritis. However, the number of patients in the group with moderate-to-severe disability was relatively low. Further studies with a larger sample size should be commenced.
There are some limitations to this study. First, this study was conducted at a tertiary care center. This could lead to selection bias, with patients tending to have greater disease severity. Second, some data were missing due to retrospective chart reviews. This resulted in the number of patients being relatively low to conduct robust statistical analysis. Third, the treatment strategies were inhomogeneous in this cohort since biologic agents were launched in Thailand around 10 years ago, while this study involved patients from 1998 to 2015. However, after subgroup analysis between patients in pre- and post-biologic era, no statistical difference between the two groups in clinical manifestations and outcomes was found because only 7.8% of patients in this study were from the prebiologic era. Therefore, most patients in this study (92.2%) were under a unified treatment strategy during the biologic era. Further studies should be investigated as prospective studies in multiple centers with the same research protocol.
In conclusion, our study suggests that female sex, younger age at disease onset, hepatosplenomegaly, and positive ANA could be important factors that predict poor outcome and refractory disease in SJIA patients, whereas hip arthritis was the predictor of moderate-to-severe disability. These data may be useful in identifying patients at high risk and provide early therapeutic intervention to ameliorate outcome.
The authors would like to thank Dittapol Muntham, Section for Clinical Epidemiology and Biostatistics, Faculty of Medicine Ramathibodi Hospital, Mahidol University for statistical analysis. We also thank Adam Dale, a native English and an English language Instructor at IGenius Language Institute, for proofreading the English. We are greatly thankful to Prof. Pat Mahachoklertwattana for his valuable comments and suggestions.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Symmons DP, Jones M, Osborne J, Sills J, Southwood TR, Woo P, et al.
Pediatric rheumatology in the United Kingdom: Data from the British pediatric Rheumatology Group National Diagnostic Register. J Rheumatol 1996;23:1975-80.
Petty RE, Southwood TR, Manners P, Baum J, Glass DN, Goldenberg J, et al.
International league of associations for rheumatology classification of juvenile idiopathic arthritis: Second revision, edmonton, 2001. J Rheumatol 2004;31:390-2.
Fujikawa S, Okuni M. Clinical analysis of 570 cases with juvenile rheumatoid arthritis: Results of a nationwide retrospective survey in Japan. Acta Paediatr Jpn 1997;39:245-9.
Huang H, Qian X, Yu H, Li J, Zhang Y. Clinical analysis in 202 children with juvenile idiopathic arthritis. Clin Rheumatol 2013;32:1021-7.
Vilaiyuk S, Soponkanaporn S, Jaovisidha S, Benjaponpitak S, Manuyakorn W. A retrospective study on 158 Thai patients with juvenile idiopathic arthritis followed in a single center over a 15-year period. Int J Rheum Dis 2016;19:1342-50.
Russo RA, Katsicas MM. Patients with very early-onset systemic juvenile idiopathic arthritis exhibit more inflammatory features and a worse outcome. J Rheumatol 2013;40:329-34.
Modesto C, Woo P, García-Consuegra J, Merino R, García-Granero M, Arnal C, et al.
Systemic onset juvenile chronic arthritis, polyarticular pattern and hip involvement as markers for a bad prognosis. Clin Exp Rheumatol 2001;19:211-7.
Henter JI, Horne A, Aricó M, Egeler RM, Filipovich AH, Imashuku S, et al.
HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer 2007;48:124-31.
Wood PH. Nomenclature and classification of arthritis in children. In: Munthe E, editor. The Care of Rheumatic Children. Basel: EULAR publisher; 1978. p. 47-50.
Singh G, Athreya BH, Fries JF, Goldsmith DP. Measurement of health status in children with juvenile rheumatoid arthritis. Arthritis Rheum 1994;37:1761-9.
Dempster H, Porepa M, Young N, Feldman BM. The clinical meaning of functional outcome scores in children with juvenile arthritis. Arthritis Rheum 2001;44:1768-74.
Spiegel LR, Schneider R, Lang BA, Birdi N, Silverman ED, Laxer RM, et al.
Early predictors of poor functional outcome in systemic-onset juvenile rheumatoid arthritis: A multicenter cohort study. Arthritis Rheum 2000;43:2402-9.
Hyrich KL, Lal SD, Foster HE, Thornton J, Adib N, Baildam E, et al.
Disease activity and disability in children with juvenile idiopathic arthritis one year following presentation to paediatric rheumatology. Results from the childhood arthritis prospective study. Rheumatology (Oxford) 2010;49:116-22.
Dale K, Paus AC, Laires K. A radiographic classification system in juvenile rheumatoid arthritis applied to the knee. Eur Radiol 1994;4:27-32.
Larsen A, Dale K, Eek M. Radiographic evaluation of rheumatoid arthritis and related conditions by standard reference films. Acta Radiol Diagn (Stockh) 1977;18:481-91.
Singh-Grewal D, Schneider R, Bayer N, Feldman BM. Predictors of disease course and remission in systemic juvenile idiopathic arthritis: Significance of early clinical and laboratory features. Arthritis Rheum 2006;54:1595-601.
Tsai HY, Lee JH, Yu HH, Wang LC, Yang YH, Chiang BL, et al.
Initial manifestations and clinical course of systemic onset juvenile idiopathic arthritis: A ten-year retrospective study. J Formos Med Assoc 2012;111:542-9.
Moe N, Rygg M. Epidemiology of juvenile chronic arthritis in northern Norway: A ten-year retrospective study. Clin Exp Rheumatol 1998;16:99-101.
Svantesson H, Akesson A, Eberhardt K, Elborgh R. Prognosis in juvenile rheumatoid arthritis with systemic onset. A follow-up study. Scand J Rheumatol 1983;12:139-44.
Sawhney S, Woo P, Murray KJ. Macrophage activation syndrome: A potentially fatal complication of rheumatic disorders. Arch Dis Child 2001;85:421-6.
Ramanan AV, Schneider R. Macrophage activation syndrome following initiation of etanercept in a child with systemic onset juvenile rheumatoid arthritis. J Rheumatol 2003;30:401-3.
Demirkaya E, Ozen S, Bilginer Y, Ayaz NA, Makay BB, Unsal E, et al.
The distribution of juvenile idiopathic arthritis in the eastern Mediterranean: Results from the registry of the turkish paediatric rheumatology association. Clin Exp Rheumatol 2011;29:111-6.
Ravelli A, Magni-Manzoni S, Pistorio A, Besana C, Foti T, Ruperto N, et al.
Preliminary diagnostic guidelines for macrophage activation syndrome complicating systemic juvenile idiopathic arthritis. J Pediatr 2005;146:598-604.
Davi S, Minoia F, Pistorio A, Horne A, Consolaro A, Rosina S, et al.
Performance of current guidelines for diagnosis of macrophage activation syndrome complicating systemic juvenile idiopathic arthritis. Arthritis Rheumatol 2014;66:2871-80.
Ravelli A, Minoia F, Davì S, Horne A, Bovis F, Pistorio A, et al.
2016 Classification criteria for macrophage activation syndrome complicating Systemic juvenile idiopathic arthritis a European league against rheumatism/American college of rheumatology/paediatric rheumatology international trials organisation collaborative initiative. Ann Rheum Dis 2016;75:481-9.
Behrens EM, Beukelman T, Paessler M, Cron RQ. Occult macrophage activation syndrome in patients with systemic juvenile idiopathic arthritis. J Rheumatol 2007;34:1133-8.
Minoia F, Davì S, Horne A, Demirkaya E, Bovis F, Li C, et al.
Clinical features, treatment, and outcome of macrophage activation syndrome complicating systemic juvenile idiopathic arthritis: A multinational, multicenter study of 362 patients. Arthritis Rheumatol 2014;66:3160-9.
Kimura Y, Weiss JE, Haroldson KL, Lee T, Punaro M, Oliveira S, et al.
Pulmonary hypertension and other potentially fatal pulmonary complications in systemic juvenile idiopathic arthritis. Arthritis Care Res (Hoboken) 2013;65:745-52.
Imokawa S, Colby TV, Leslie KO, Helmers RA. Methotrexate pneumonitis: Review of the literature and histopathological findings in nine patients. Eur Respir J 2000;15:373-81.
Kremer JM, Alarcón GS, Weinblatt ME, Kaymakcian MV, Macaluso M, Cannon GW, et al.
Clinical, laboratory, radiographic, and histopathologic features of methotrexate-associated lung injury in patients with rheumatoid arthritis: A multicenter study with literature review. Arthritis Rheum 1997;40:1829-37.
Lin SJ, Huang JL, Chao HC, Lee WY, Yang MH. A follow-up study of systemic-onset juvenile rheumatoid arthritis in children. Acta Paediatr Taiwan 1999;40:176-81.
Schneider R, Lang BA, Reilly BJ, Laxer RM, Silverman ED, Ibanez D, et al.
Prognostic indicators of joint destruction in systemic-onset juvenile rheumatoid arthritis. J Pediatr 1992;120:200-5.
Lomater C, Gerloni V, Gattinara M, Mazzotti J, Cimaz R, Fantini F, et al.
Systemic onset juvenile idiopathic arthritis: A retrospective study of 80 consecutive patients followed for 10 years. J Rheumatol 2000;27:491-6.
Flatø B, Lien G, Smerdel A, Vinje O, Dale K, Johnston V, et al.
Prognostic factors in juvenile rheumatoid arthritis: A case-control study revealing early predictors and outcome after 14.9 years. J Rheumatol 2003;30:386-93.
Beukelman T, Patkar NM, Saag KG, Tolleson-Rinehart S, Cron RQ, DeWitt EM, et al.
2011 American college of rheumatology recommendations for the treatment of juvenile idiopathic arthritis: Initiation and safety monitoring of therapeutic agents for the treatment of arthritis and systemic features. Arthritis Care Res (Hoboken) 2011;63:465-82.
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3]