Indian J Pediatr DOI 10.1007/s12098-016-2060-z
REVIEW ARTICLE
Systemic Juvenile Idiopathic Arthritis: Diagnosis and Management Sathish Kumar 1
Received: 28 May 2015 / Accepted: 2 February 2016 # Dr. K C Chaudhuri Foundation 2016
Abstract Systemic juvenile idiopathic arthritis (sJIA) is an inflammatory condition characterized by fever, lymphadenopathy, arthritis, rash and serositis. In sJIA, systemic inflammation has been associated with dysregulation of the innate immune system, suggesting that it is an autoinflammatory disorder. IL-1 and IL-6 play a major role in the pathogenesis of sJIA and treatment with IL-1 and IL-6 inhibitors has shown to be highly effective. Recent data suggests that early cytokine blockage might abrogate chronic, destructive, therapy resistant arthritis phase, reflecting a potential “window of opportunity” in the care of children with sJIA. Keywords Systemic JIA . Interleukin-1 blockade . Treatment
Introduction Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic disease in childhood. Systemic juvenile idiopathic arthritis (sJIA) accounts for approximately 10 % of all types of JIA. But it has the most acute and severe disease and disproportionately high morbidity compared with other subtypes. Historically, sJIA had been referred to as Still’s disease, which was named after George F Still who reported a cohort of 22 children with progressive arthritis,
* Sathish Kumar [email protected]
1
Department of Pediatrics, Christian Medical College, Vellore, Tamil Nadu 632004, India
generalized lymphadenopathy, splenomegaly, fever and anemia [1]. Nowadays, however, the term sJIA is used. In this review, the author will discuss in detail about diagnosis and management of sJIA.
Diagnosis Like some other forms of JIA, the epidemiology of systemic JIA features an early incidence peak between 1 and 5 y of age, although the disease may arise at any time during childhood; both sexes are affected with approximately equal frequency [2, 3]. Systemic JIA is clinically defined by quotidian fever (for at least 3 consecutive days) over 2 wk or more ± arthritis, and at least one of the following symptoms: evanescent rash, generalized lymphadenopathy, hepatomegaly and/or splenomegaly or serositis. As sJIA is a diagnosis of exclusion, exclude infection and malignancy. In systemic JIA, the patient has classical quotidian fever that spikes to greater than 39 °C once or twice daily which typically occurs in the evening. Rash is evanescent in nature and bright salmon pink in color. In sJIA, rash is morbilliform, macular, often with central clearing, and tends to be migratory. Rash initially emerges mostly on the limbs and trunk and less on the face, neck, palms and soles. These diagnostic criteria are based on the 1993 consensus meeting of the International League against Rheumatism (ILAR) which was revised in Edmonton in 2001 [4]. Though a mandatory diagnostic criterion, quotidian fever patterns only occur in two-thirds of sJIA patients. In most children, the disease begins with a severe systemic illness characterized by fever, rash, and arthralgia or frank arthritis along with other characteristic features that include diffuse
Indian J Pediatr
lymphadenopathy, hepatosplenomegaly and serositis, especially pleuritis and pericarditis. Children often require admission to the hospital to facilitate the expeditious investigation of the presenting symptoms, to exclude potential diagnoses such as infections and malignancies.
Other Manifestations Central nervous system manifestations such as seizures, meningismus, irritability and decreased level of consciousness were rarely reported [5]. Ocular manifestations can be seen in sJIA, and uveitis is one of the complications [6]. In addition, Brown’s syndrome (restricted movement of the superior oblique tendon) was seen in 3 children and reported in two case reports [7, 8]. Although nasal septum perforation is a complication of rheumatic illness, it was described in only 3 children with sJIA in a case series [9]. In children with sJIA, laboratory tests reveal anemia (usually hypochromic and microcytic), neutrophilic leukocytosis, thrombocytosis, elevated immunoglobulins, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) and hypoalbuminemia as markers of inflammation.
Macrophage Activation Syndrome Macrophage activation syndrome (MAS) is a severe, potentially life-threatening complication of sJIA. While MAS is clinically apparent in 10 % of sJIA patients, it can occur subclinically in up to 30–40 % [13]. MAS shares clinical and laboratory features with familial/genetic and sporadic/acquired hemophagocytic lymphohistiocytosis (HLH). This observation has led to the hypothesis that sJIA may be pathophysiologically related to HLH or be a “milder” variant [14]. Several analyses of genes related to familial HLH did not provide further evidence. No polymorphisms were detected in the cytotoxicitymediating perforin (PRF1) or granzyme B (GZMB) genes, or the HLH-associated Ras-related protein Rab-27 A (RAB27A) and Munc13–4 (UNC13D) genes that confer cytotoxic granule function [15]. As both MAS and sJIA have similar symptoms, it is very difficult to differentiate. Some of the laboratory findings that are useful in distinguishing the two are the presence of cytopenias, thrombocytopenia, hyperferritinemia, elevated liver enzymes, leukocytosis, normal or decreased ESR, hypofibrinogenemia and hypertriglyceridemia noted in MAS [16]. Growth Failure
Differential Diagnosis Differential diagnosis of sJIA should include infectious, postinfectious etiologies, connective tissue diseases, vasculitis, malignancies and autoinflammatory syndromes [10] because of nonspecific clinical and laboratory findings.
Complications Amyloidosis Amyloidosis is one of the most severe complications of sJIA. Amyloidosis tends to be very rare in North America but affects a larger percentage of individuals in the UK (7.4 %) and Turkey (16 %) [11]. Amyloid deposition on vital organs such as kidney, liver, gastrointestinal tract and heart lead to increased morbidity and mortality. Amyloidosis can be histologically recognized by using Congo red stain, which reveals eosinophilic deposition; when employing polarized light, the characteristic apple-green birefringence surfaces. The first clinical sign of amyloidosis is proteinuria. Rarely nephrotic syndrome is seen [12]. Other symptoms that may suggest amyloidosis are hypertension, hepatosplenomegaly and abdominal pain. Death from progressive renal failure can result in such children with amyloidosis. Hence the inflammatory process of sJIA should be successfully suppressed and then the amyloidosis reverses.
Many children with sJIA require large doses of corticosteroids to control systemic disease, articular disease or both. In fact, in some children, treatment-related morbidity has been worse than disease-related morbidity. Growth delay is due to inflammation of sJIA and corticosteroids. Several studies have reported the use of growth hormone (GH) resulting in improved linear growth [17]. Steroid- and disease-related osteopenia and osteoporosis can have serious consequences. If pathologic fractures involve the vertebral bodies, final height of the child may be impacted. The pain from the fractures also results in immobility, further accelerating the development of osteopenia. Hence corticosteroids dosages should be reduced at earliest or if possible, prevented to avoid these severe complications.
Disease Course Up to 40 % children with sJIA have a good long-term outcome with a monocyclic course that enters permanent remission after a variable number of months. A small number of patients have a polycyclic course with recurrent episodes of active disease and periods of true remission. Other half of children with sJIA have a more severe, persistent disease course. Spiegel and colleagues identified following as prognostic markers of poor outcome: persistent fever, steroid dependency, thrombocytosis, polyarthritis, hip disease and early joint damage during 3–6 mo of disease onset [18].
Indian J Pediatr
Management Recent studies suggest that targeting these specific cytokines may result in much better outcomes than treating with corticosteroids and traditional Disease-modifying anti-rheumatic drugs (DMARDs) and may avoid the devastating toxicity of high-dose corticosteroid treatment. Advances in the understanding of the disease pathogenesis have resulted in the application of biologic treatments directed at inhibiting cytokines associated with the disease, particularly interleukin (IL) 1 and IL-6. Common drugs used in treatment of sJIA and its doses are tabulated in Table 1. Classical/Traditional Non-targeted sJIA Treatment Regimens During the first days or weeks of clinical symptoms, when the diagnostic workup is still pending or incomplete, patients usually receive Non-steroidal anti-inflammatory drugs (NSAIDs). Most commonly, symptoms of systemic inflammation persist or respond only incompletely. If there is no response to NSAIDs, start oral prednisolone 1–2 mg/kg/d. Divided doses are better than single dose initially. Inj. Methyl prednisolone 30 mg/kg IV (max. 1000 mg) for three to five days can be administered if the child is sick. If joints remain clinically active, intra-articular application of triamcinolone hexacetonide can be effective. Corticosteroids do not significantly affect the disease duration or disease outcome in most sJIA patients and are associated with severe treatmentTable 1
related side-effects. Thus, if long-term administration is necessary, DMARDs or new generation biologics are urgently indicated to reduce or replace corticosteroids. In sJIA, methotrexate has limited efficacy for the joint disease and virtually no impact on the systemic features [19]. In cases refractory to corticosteroid and DMARD treatment, thalidomide has been tried as an option. Thalidomide is reported to control dysregulated pro-inflammatory cytokine expression during immune activation in autoimmune and infectious disorders. However, published evidence for the use of thalidomide in sJIA is sparse and limited to case reports and small series [20]. Little evidence is available in literature for usage of cyclosporine and rituximab in children with recalcitrant sJIA. Given the availability of modern target-directed treatment options, the use of this agent appears obsolete and cannot generally be recommended. As a very last resort in desperate situations, autologous hematopoietic stem-cell transplantation (HSCT) may be considered. This approach takes advantage of massive immune suppression during the conditioning phase and is considered “resetting” the patients’ immune system, thus exerting beneficial effects on the disease course [21]. However nowadays with modern target-directed treatments, HSCT is mostly unnecessary and obsolete or reserved for extraordinarily complicated courses. Anti-IL-1 Treatment Currently, IL-1 inhibition can be achieved by three drugs which act via different mechanisms: IL-1 receptor antagonist,
Common drugs used and their dosages in the treatment of sJIA
Drugs
Dose
Non-Steroidal Anti-inflammatory Drugs Naproxen 15 mg/kg/day PO divided bid (maximum dose 500 mg bid) Ibuprofen 40 mg/kg/day PO divided tid (maximum dose 800 mg tid) Meloxicam 0.125 mg/kg PO once daily (maximum dose 15 mg daily) Indomethacin 1.5–3 mg/kg/day tid Non Biologic Disease-Modifying Anti-rheumatic Drugs Methotrexate 0.5–1 mg/kg PO or SC weekly (maximum dose 25 mg/wk) Biologic Disease-Modifying Anti-rheumatic Drugs Interleukin-1 Inhibitors Anakinra 1–2 mg/kg SC daily (maximum dose 100 mg/day) Canakinumab Rilonacept
15–40 kg: 2 mg/kg/dose SC q8wk >40 kg: 150 mg SC q8wk 2.2 mg/kg/dose SC weekly (maximum dose 160 mg)
Interleukin-6 Receptor Antagonist Tocilizumab 30 kg: 8 mg/kg/dose q2wk (maximum dose 800 mg)
Side effects
Gastritis, renal and hepatic toxicity, pseudoporphyria Gastritis, renal and hepatic toxicity Gastritis, renal and hepatic toxicity Gastritis, renal and hepatic toxicity Nausea, vomiting, oral ulcerations, hepatic toxicity, blood count dyscrasias
Immunosuppressant, GI upset, injection site reaction Immunosuppressant, headache, GI upset, injection site reaction Immunosuppressant, allergic reaction, dyslipidemia, injection site reaction Immunosuppressant, hepatic toxicity, dyslipidemia, cytopenias
Indian J Pediatr
anakinra; IL-1R-IL1RacP-Fc fusion protein, rilonacept; or IL1β antibody, canakinumab. The recombinant IL-1 receptor antagonist, anakinra is the first available drug from this group. The effectiveness of anakinra in sJIA was first reported in two patients resistant to standard treatment protocols in 2004 [22]. In 2011, a multi-center, double-blind, placebo-controlled trial (ANAJIS trial) was performed in 24 patients, 12 of which were treated either with anakinra or with placebo in addition to standard treatment [23]. After one month of treatment, significant differences in both groups were seen with 67 % response rates in the anakinra group vs. 8 % in the placebo group. Also in 2011, Nigrovic et al. retrospectively analysed the effectiveness of anakinra treatment in 46 sJIA patients [24]. However, they could not make a final statement about safety and efficacy of anakinra as “first-line” disease-modifying therapy in sJIA because of varying time to diagnosis, variable treatment regimens and particularly the combination with DMARDs and/or corticosteroids. Still, the study provided evidence of the efficacy of anakinra in sJIA patients with or without additional treatment. In 2014, Vastert et al. documented positive effects of “firstline” anakinra treatment in 24 sJIA patients [25]. Most (22/24) sJIA patients treated with anakinra plus corticosteroids and more than 75 % of those sJIA patients treated with anakinra alone, reached an ACR Pedi90 response or had completely inactive disease. After one year, 85 % (17/20) of all sJIA patients receiving anakinra treatment were clinically inactive. Seven patients, however, required additional treatment to anakinra. In 2012, efficacy of canakinumab, humanized monoclonal inactivating anti-IL-1β antibody was summarized in two phase III clinical trials [26]. In both the trials, patients received canakinumab in active sJIA despite standard treatment with corticosteroids and DMARDs. In the first trial, one third of sJIApatients treated with canakinumab reached clinical remission within 15 d after a single application of the drug. More than 80 % of the patients treated with canakinumab reached an ACRPedi30 response, compared to only 10 % in the placebo group. In the second trial, all patients received canakinumab to taper steroids. In one third of the patients, corticosteroids could be discontinued, about half of the patients tolerated corticosteroid dose reduction. Another anti-IL-1 agent that may prove valuable in the treatment of sJIA is rilonacept. Rilonacept is a fusion protein of the extracellular component of the IL-1 receptor (IL-1RI and IL-1RAcP) and the Fc portion of IgG1, binding both IL1α and IL-1β. Rilonacept yielded ACR Pedi 70 responses in 35–40 % of patients with chronic systemic JIA [27].
2005, a small Japanese study documented rapid reduction of disease activity in response to tocilizumab in 10 out of 11 sJIA patients [28]. In 2008, a double-blinded, placebo-controlled phase III trial demonstrated good response (ACR Pedi30) in >90 % of 56 sJIA patients [29], and the long-term open label extension of this trial showed sustained effectiveness for most patients [30]. In 2012, the TENDER trial [31] included 112 patients with sJIA and persistent clinical activity for at least 6 mo regardless of NSAID and corticosteroid treatment. Eighty-five percent of sJIA patients treated with tocilizumab, but only 24 % in the placebo group, reached the primary endpoint of ACR Pedi30 and absence of fever. During the open-label extension phase of the trial, 28 % of the patients had clinically inactive disease one year after initiating tocilizumab. Anti-TNF Agents TNF-α blockade is highly effective in most forms of JIA. In 2009, Russo et al. documented response rates of only 24 % in 45 sJIA patients treated with antiTNF treatments (etanercept, adalimumab, or infliximab). Stable remission was achieved only in 13 % [32]. These response rates are rather disappointing. Limited and inconsistent effects of anti-TNF treatment may reflect a “secondary” role of TNF-α in the molecular pathophysiology of sJIA. While during early-phase of sJIA other cytokines (such as IL-1 and IL-6) drive inflammation, TNF-α may become more important during later stages. Secondary to overall low remission rates in the published reports; TNF-blocking strategies are not commonly used in sJIA and should be reserved for select cases.
Concept of Window of Opportunity We know from other forms of JIA, that adaptive immune mechanisms play a role in the manifestation and maintenance of chronic arthritis. As mentioned before, chronic destructive arthritis is frequently a symptom of “late-stage” sJIA. Thus, advocates of the “window of opportunity” hypothesis claim that, through early induction of stable remission with innate cytokine blocking strategies, such as anti-IL-1 or anti-IL-6 agents, the development of chronic inflammation and subsequent potential priming of adaptive immune-processes may be prevented [33].
Treatment Recommendations Anti-IL-6 Treatment Tocilizumab is a humanized anti-IL-6 receptor antibody, blocking both soluble and transmembrane IL-6 receptors. In
American College of Rheumatology (ACR) recommends that there is a role for a trial of NSAIDs for up to two weeks if disease activity is relatively low and poor prognostic features
Indian J Pediatr
are absent. sJIA children with high disease activity (such as symptomatic pericarditis) are recommended to receive systemic corticosteroids and if they are unresponsive, anakinra is recommended [34]. ACR recommendations do recognize that anakinra could be used as a first-line treatment for active systemic symptoms of sJIA, particularly if there is persistent fever and if poor prognostic features are present. In view of the more recent data, tocilizumab has to considered as an alternative to IL-1 inhibitors. But in children who have active arthritis but no systemic features, include NSAIDS followed by methotrexate. If there is no response to methotrexate, patients should receive either anakinra or a tumor necrosis factor–α inhibitor. The potential role of IL-1 and IL-6 inhibitors for arthritis without systemic features remains to be clarified. In 2013, the American College of Rheumatology updated their treatment recommendations for systemic JIA [35]. Biologic agents that inhibit IL-1 (anakinra or canakinumab) or IL-6 (tocilizumab) are recommended as the first glucocorticoid-sparing therapies for children with active systemic features. Additionally, in some instances, IL-1 or IL-6 inhibitors are considered appropriate to use prior to or in the absence of systemic glucocorticoids. This is a significant departure from the treatment approach that has been used for several decades and may diminish the adverse effects of glucocorticoids commonly associated with the treatment of sJIA.
Compliance with Ethical Standards
Conclusions
10.
Systemic JIA is the most severe and potentially lifethreatening disease in the group of JIA. In contrast to other forms of JIA, sJIA is considered an autoinflammatory disorder. Favourable response to cytokine blocking strategies with IL-1 and IL-6 suggest central involvement of such proinflammatory cytokines in sJIA. Modern treatment options control systemic inflammation and reduce treatmentassociated side-effects of “classical” regimens with corticosteroids. However, multicenter, double-blinded, open-label, placebo-controlled trials in large cohorts are necessary to scientifically prove superiority to standard treatment and long-term safety. Based on our current understanding of the pathophysiology of sJIA and the response to available treatment options, it appears reasonable to apply high-dose corticosteroids in the early stage of disease. If symptoms persist or corticosteroid tapering attempts fail after two to four weeks, modern cytokine-blocking strategies should be introduced to prevent treatment-associated side-effects or disease sequelae. Much remains to be learned about the disease pathogenesis and the optimal treatment of children with sJIA.
11.
Conflict of Interest None. Source of Funding None.
References 1. 2.
3.
4.
5. 6.
7. 8.
9.
12. 13.
14.
15.
16.
17.
18.
19.
Still GF. On a form of chronic joint disease in children. Med Chir Trans. 1897;80:47–60.9. Behrens EM, Beukelman T, Gallo L, et al. Evaluation of the presentation of systemic onset juvenile rheumatoid arthritis: data from the Pennsylvania Systemic Onset Juvenile Arthritis Registry (PASOJAR). J Rheumatol. 2008;35:343–8. 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. Petty RE, Southwood TR, Manners P, et al. International League of Associations for Rheumatology classification of juvenile idiopathic arthritis: Second revision, Edmonton 2001. J Rheumatol. 2004;31:390–2. Calabro JJ. Other extraarticular manifestations of juvenile rheumatoid arthritis. Arthritis Rheum. 1977;20:237–40. Ishihara M, Nakamura S, Okada K, Yokota S, Ohno S. A case of juvenile rheumatoid arthritis with panuveitis. Nihon Ganka Gakkai Zasshi. 1992;96:109–13. Moore AT, Morin JD. Bilateral acquired inflammatory Brown’s syndrome. J Pediatr Ophthalmol Strabismus. 1985;22:26–30. Wang FM, Wertenbaker C, Behrens MM, Jacobs JC. Acquired Brown’s syndrome in children with juvenile rheumatoid arthritis. Ophthalmology. 1984;91:23–6. Avcin T, Silverman ED, Forte V, Schneider R. Nasal septal perforation: a novel clinical manifestation of systemic juvenile idiopathic arthritis/adult onset Still’s disease. J Rheumatol. 2005;32:2429–31. Woo P. Systemic juvenile idiopathic arthritis: diagnosis, management, and outcome. Nat Clin Pract Rheumatol. 2006;2:28–34. Schnitzer TJ, Ansell BM. Amyloidosis in juvenile chronic polyarthritis. Arthritis Rheum. 1977;20:245–52. Schneider R, Laxer RM. Systemic onset juvenile rheumatoid arthritis. Baillieres Clin Rheumatol. 1998;12:245–71. Correll CK, Binstadt BA. Advances in the pathogenesis and treatment of systemic juvenile idiopathic arthritis. Pediatr Res. 2014;75:176–83. Mellins ED, Macaubas C, Grom AA. Pathogenesis of systemic juvenile idiopathic arthritis: some answers, more questions. Nat Rev Rheumatol. 2011;7:416–26. Donn R, Ellison S, Lamb R, Day T, Baildam E, Ramanan AV. Genetic loci contributing to hemophagocytic lymphohistiocytosis do not confer susceptibility to systemic-onset juvenile idiopathic arthritis. Arthritis Rheum. 2008;58:869–74. Sawhney S, Woo P, Murray KJ. Macrophage activation syndrome: a potentially fatal complication of rheumatic disorders. Arch Dis Child. 2001;85:421–6. Bechtold S, Ripperger P, Dalla Pozza R, et al. Growth hormone increases final height in patients with juvenile idiopathic arthritis: data from a randomized controlled study. J Clin Endocrinol Metab. 2007;92:3013–8. Spiegel LR, Schneider R, Lang BA, et al. Early predictors of poor functional outcome in systemic-onset juvenile rheumatoid arthritis: a multicenter cohort study. Arthritis Rheum. 2000;43:2402–9. Martini A Systemic juvenile idiopathic arthritis. Autoimmun Rev. 2012;12:56–9.
Indian J Pediatr 20.
Garcia-Carrasco M, Fuentes-Alexandro S, Escarcega RO, RojasRodriguez J, Escobar LE. Efficacy of thalidomide in systemic onset juvenile rheumatoid arthritis. Joint Bone Spine. 2007;74:500–3. 21. Brinkman DM, de Kleer IM, ten Cate R, et al. Autologous stem cell transplantation in children with severe progressive systemic or polyarticular juvenile idiopathic arthritis: long-term follow-up of a prospective clinical trial. Arthritis Rheum. 2007;56:2410–21. 22. Verbsky JW, White AJ. Effective use of the recombinant interleukin 1 receptor antagonist anakinra in therapy resistant systemic onset juvenile rheumatoid arthritis. J Rheumatol. 2004;31:2071–5. 23. Quartier P, Allantaz F, Cimaz R, et al. A multicentre, randomised, double-blind, placebo-controlled trial with the interleukin-1 receptor antagonist anakinra in patients with systemic-onset juvenile idiopathic arthritis (ANAJIS trial). Ann Rheum Dis. 2011;70:747–54. 24. Nigrovic PA, Mannion M, Prince FH, et al. Anakinra as first-line disease-modifying therapy in systemic juvenile idiopathic arthritis: report of forty-six patients from an international multicenter series. Arthritis Rheum. 2011;63:545–55. 25. Vastert SJ, de Jager W, Noordman BJ, et al. Effectiveness of firstline treatment with recombinant interleukin-1 receptor antagonist in steroid-naive patients with new-onset systemic juvenile idiopathic arthritis: results of a prospective cohort study. Arthritis Rheum. 2014;66:1034–43. 26. Ruperto N, Brunner HI, Quartier P, et al. Two randomized trials of canakinumab in systemic juvenile idiopathic arthritis. N Engl J Med. 2012;367:2396–406. 27. Lovell DJ, Giannini EH, Reiff AO, et al. Long-term safety and efficacy of rilonacept in patients with systemic juvenile idiopathic arthritis. Arthritis Rheum. 2013;65:2486–96. 28. Yokota S, Miyamae T, Imagawa T, et al. Therapeutic efficacy of humanized recombinant anti-interleukin-6 receptor antibody in
29.
30.
31.
32.
33.
34.
35.
children with systemic-onset juvenile idiopathic arthritis. Arthritis Rheum. 2005;52:818–25. Yokota S, Imagawa T, Mori M, et al. Efficacy and safety of tocilizumab in patients with systemic-onset juvenile idiopathic arthritis: a randomised, double- blind, placebo-controlled, withdrawal phase III trial. Lancet. 2008;371:998–1006. Yokota S, Imagawa T, Mori M, et al. Long-term treatment of systemic juvenile idiopathic arthritis with tocilizumab: results of an open label extension study in Japan. Ann Rheum Dis. 2013;72:627–8. De Benedetti F, Brunner HI, Ruperto N, et al. Randomized trial of tocilizumab in systemic juvenileidiopathic arthritis. N Engl J Med 2012;367:2385–95. Russo RA, Katsicas MM. Clinical remission in patients with systemic juvenile idiopathic arthritis treated with anti-tumor necrosis factor agents. J Rheumatol. 2009;36:1078–82. Nigrovic PA. Review: is there a window of opportunity for treatment of systemic juvenile idiopathic arthritis? Arthritis Rheum. 2014;66:1405–13. Beukelman T, Patkar NM, Saag KG, 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. Ringold S, Weiss PF, Beukelman T, et al. 2013 update of the 2011 American College of Rheumatology recommendations for the treatment of juvenile idiopathic arthritis: recommendations for the medical therapy of children with systemic juvenile idiopathic arthritis and tuberculosis screening among children receiving biologic medications. Arthritis Care Res (Hoboken). 2013;65:1551–63.
REVIEW ARTICLE
Systemic Juvenile Idiopathic Arthritis: Diagnosis and Management Sathish Kumar 1
Received: 28 May 2015 / Accepted: 2 February 2016 # Dr. K C Chaudhuri Foundation 2016
Abstract Systemic juvenile idiopathic arthritis (sJIA) is an inflammatory condition characterized by fever, lymphadenopathy, arthritis, rash and serositis. In sJIA, systemic inflammation has been associated with dysregulation of the innate immune system, suggesting that it is an autoinflammatory disorder. IL-1 and IL-6 play a major role in the pathogenesis of sJIA and treatment with IL-1 and IL-6 inhibitors has shown to be highly effective. Recent data suggests that early cytokine blockage might abrogate chronic, destructive, therapy resistant arthritis phase, reflecting a potential “window of opportunity” in the care of children with sJIA. Keywords Systemic JIA . Interleukin-1 blockade . Treatment
Introduction Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic disease in childhood. Systemic juvenile idiopathic arthritis (sJIA) accounts for approximately 10 % of all types of JIA. But it has the most acute and severe disease and disproportionately high morbidity compared with other subtypes. Historically, sJIA had been referred to as Still’s disease, which was named after George F Still who reported a cohort of 22 children with progressive arthritis,
* Sathish Kumar [email protected]
1
Department of Pediatrics, Christian Medical College, Vellore, Tamil Nadu 632004, India
generalized lymphadenopathy, splenomegaly, fever and anemia [1]. Nowadays, however, the term sJIA is used. In this review, the author will discuss in detail about diagnosis and management of sJIA.
Diagnosis Like some other forms of JIA, the epidemiology of systemic JIA features an early incidence peak between 1 and 5 y of age, although the disease may arise at any time during childhood; both sexes are affected with approximately equal frequency [2, 3]. Systemic JIA is clinically defined by quotidian fever (for at least 3 consecutive days) over 2 wk or more ± arthritis, and at least one of the following symptoms: evanescent rash, generalized lymphadenopathy, hepatomegaly and/or splenomegaly or serositis. As sJIA is a diagnosis of exclusion, exclude infection and malignancy. In systemic JIA, the patient has classical quotidian fever that spikes to greater than 39 °C once or twice daily which typically occurs in the evening. Rash is evanescent in nature and bright salmon pink in color. In sJIA, rash is morbilliform, macular, often with central clearing, and tends to be migratory. Rash initially emerges mostly on the limbs and trunk and less on the face, neck, palms and soles. These diagnostic criteria are based on the 1993 consensus meeting of the International League against Rheumatism (ILAR) which was revised in Edmonton in 2001 [4]. Though a mandatory diagnostic criterion, quotidian fever patterns only occur in two-thirds of sJIA patients. In most children, the disease begins with a severe systemic illness characterized by fever, rash, and arthralgia or frank arthritis along with other characteristic features that include diffuse
Indian J Pediatr
lymphadenopathy, hepatosplenomegaly and serositis, especially pleuritis and pericarditis. Children often require admission to the hospital to facilitate the expeditious investigation of the presenting symptoms, to exclude potential diagnoses such as infections and malignancies.
Other Manifestations Central nervous system manifestations such as seizures, meningismus, irritability and decreased level of consciousness were rarely reported [5]. Ocular manifestations can be seen in sJIA, and uveitis is one of the complications [6]. In addition, Brown’s syndrome (restricted movement of the superior oblique tendon) was seen in 3 children and reported in two case reports [7, 8]. Although nasal septum perforation is a complication of rheumatic illness, it was described in only 3 children with sJIA in a case series [9]. In children with sJIA, laboratory tests reveal anemia (usually hypochromic and microcytic), neutrophilic leukocytosis, thrombocytosis, elevated immunoglobulins, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) and hypoalbuminemia as markers of inflammation.
Macrophage Activation Syndrome Macrophage activation syndrome (MAS) is a severe, potentially life-threatening complication of sJIA. While MAS is clinically apparent in 10 % of sJIA patients, it can occur subclinically in up to 30–40 % [13]. MAS shares clinical and laboratory features with familial/genetic and sporadic/acquired hemophagocytic lymphohistiocytosis (HLH). This observation has led to the hypothesis that sJIA may be pathophysiologically related to HLH or be a “milder” variant [14]. Several analyses of genes related to familial HLH did not provide further evidence. No polymorphisms were detected in the cytotoxicitymediating perforin (PRF1) or granzyme B (GZMB) genes, or the HLH-associated Ras-related protein Rab-27 A (RAB27A) and Munc13–4 (UNC13D) genes that confer cytotoxic granule function [15]. As both MAS and sJIA have similar symptoms, it is very difficult to differentiate. Some of the laboratory findings that are useful in distinguishing the two are the presence of cytopenias, thrombocytopenia, hyperferritinemia, elevated liver enzymes, leukocytosis, normal or decreased ESR, hypofibrinogenemia and hypertriglyceridemia noted in MAS [16]. Growth Failure
Differential Diagnosis Differential diagnosis of sJIA should include infectious, postinfectious etiologies, connective tissue diseases, vasculitis, malignancies and autoinflammatory syndromes [10] because of nonspecific clinical and laboratory findings.
Complications Amyloidosis Amyloidosis is one of the most severe complications of sJIA. Amyloidosis tends to be very rare in North America but affects a larger percentage of individuals in the UK (7.4 %) and Turkey (16 %) [11]. Amyloid deposition on vital organs such as kidney, liver, gastrointestinal tract and heart lead to increased morbidity and mortality. Amyloidosis can be histologically recognized by using Congo red stain, which reveals eosinophilic deposition; when employing polarized light, the characteristic apple-green birefringence surfaces. The first clinical sign of amyloidosis is proteinuria. Rarely nephrotic syndrome is seen [12]. Other symptoms that may suggest amyloidosis are hypertension, hepatosplenomegaly and abdominal pain. Death from progressive renal failure can result in such children with amyloidosis. Hence the inflammatory process of sJIA should be successfully suppressed and then the amyloidosis reverses.
Many children with sJIA require large doses of corticosteroids to control systemic disease, articular disease or both. In fact, in some children, treatment-related morbidity has been worse than disease-related morbidity. Growth delay is due to inflammation of sJIA and corticosteroids. Several studies have reported the use of growth hormone (GH) resulting in improved linear growth [17]. Steroid- and disease-related osteopenia and osteoporosis can have serious consequences. If pathologic fractures involve the vertebral bodies, final height of the child may be impacted. The pain from the fractures also results in immobility, further accelerating the development of osteopenia. Hence corticosteroids dosages should be reduced at earliest or if possible, prevented to avoid these severe complications.
Disease Course Up to 40 % children with sJIA have a good long-term outcome with a monocyclic course that enters permanent remission after a variable number of months. A small number of patients have a polycyclic course with recurrent episodes of active disease and periods of true remission. Other half of children with sJIA have a more severe, persistent disease course. Spiegel and colleagues identified following as prognostic markers of poor outcome: persistent fever, steroid dependency, thrombocytosis, polyarthritis, hip disease and early joint damage during 3–6 mo of disease onset [18].
Indian J Pediatr
Management Recent studies suggest that targeting these specific cytokines may result in much better outcomes than treating with corticosteroids and traditional Disease-modifying anti-rheumatic drugs (DMARDs) and may avoid the devastating toxicity of high-dose corticosteroid treatment. Advances in the understanding of the disease pathogenesis have resulted in the application of biologic treatments directed at inhibiting cytokines associated with the disease, particularly interleukin (IL) 1 and IL-6. Common drugs used in treatment of sJIA and its doses are tabulated in Table 1. Classical/Traditional Non-targeted sJIA Treatment Regimens During the first days or weeks of clinical symptoms, when the diagnostic workup is still pending or incomplete, patients usually receive Non-steroidal anti-inflammatory drugs (NSAIDs). Most commonly, symptoms of systemic inflammation persist or respond only incompletely. If there is no response to NSAIDs, start oral prednisolone 1–2 mg/kg/d. Divided doses are better than single dose initially. Inj. Methyl prednisolone 30 mg/kg IV (max. 1000 mg) for three to five days can be administered if the child is sick. If joints remain clinically active, intra-articular application of triamcinolone hexacetonide can be effective. Corticosteroids do not significantly affect the disease duration or disease outcome in most sJIA patients and are associated with severe treatmentTable 1
related side-effects. Thus, if long-term administration is necessary, DMARDs or new generation biologics are urgently indicated to reduce or replace corticosteroids. In sJIA, methotrexate has limited efficacy for the joint disease and virtually no impact on the systemic features [19]. In cases refractory to corticosteroid and DMARD treatment, thalidomide has been tried as an option. Thalidomide is reported to control dysregulated pro-inflammatory cytokine expression during immune activation in autoimmune and infectious disorders. However, published evidence for the use of thalidomide in sJIA is sparse and limited to case reports and small series [20]. Little evidence is available in literature for usage of cyclosporine and rituximab in children with recalcitrant sJIA. Given the availability of modern target-directed treatment options, the use of this agent appears obsolete and cannot generally be recommended. As a very last resort in desperate situations, autologous hematopoietic stem-cell transplantation (HSCT) may be considered. This approach takes advantage of massive immune suppression during the conditioning phase and is considered “resetting” the patients’ immune system, thus exerting beneficial effects on the disease course [21]. However nowadays with modern target-directed treatments, HSCT is mostly unnecessary and obsolete or reserved for extraordinarily complicated courses. Anti-IL-1 Treatment Currently, IL-1 inhibition can be achieved by three drugs which act via different mechanisms: IL-1 receptor antagonist,
Common drugs used and their dosages in the treatment of sJIA
Drugs
Dose
Non-Steroidal Anti-inflammatory Drugs Naproxen 15 mg/kg/day PO divided bid (maximum dose 500 mg bid) Ibuprofen 40 mg/kg/day PO divided tid (maximum dose 800 mg tid) Meloxicam 0.125 mg/kg PO once daily (maximum dose 15 mg daily) Indomethacin 1.5–3 mg/kg/day tid Non Biologic Disease-Modifying Anti-rheumatic Drugs Methotrexate 0.5–1 mg/kg PO or SC weekly (maximum dose 25 mg/wk) Biologic Disease-Modifying Anti-rheumatic Drugs Interleukin-1 Inhibitors Anakinra 1–2 mg/kg SC daily (maximum dose 100 mg/day) Canakinumab Rilonacept
15–40 kg: 2 mg/kg/dose SC q8wk >40 kg: 150 mg SC q8wk 2.2 mg/kg/dose SC weekly (maximum dose 160 mg)
Interleukin-6 Receptor Antagonist Tocilizumab 30 kg: 8 mg/kg/dose q2wk (maximum dose 800 mg)
Side effects
Gastritis, renal and hepatic toxicity, pseudoporphyria Gastritis, renal and hepatic toxicity Gastritis, renal and hepatic toxicity Gastritis, renal and hepatic toxicity Nausea, vomiting, oral ulcerations, hepatic toxicity, blood count dyscrasias
Immunosuppressant, GI upset, injection site reaction Immunosuppressant, headache, GI upset, injection site reaction Immunosuppressant, allergic reaction, dyslipidemia, injection site reaction Immunosuppressant, hepatic toxicity, dyslipidemia, cytopenias
Indian J Pediatr
anakinra; IL-1R-IL1RacP-Fc fusion protein, rilonacept; or IL1β antibody, canakinumab. The recombinant IL-1 receptor antagonist, anakinra is the first available drug from this group. The effectiveness of anakinra in sJIA was first reported in two patients resistant to standard treatment protocols in 2004 [22]. In 2011, a multi-center, double-blind, placebo-controlled trial (ANAJIS trial) was performed in 24 patients, 12 of which were treated either with anakinra or with placebo in addition to standard treatment [23]. After one month of treatment, significant differences in both groups were seen with 67 % response rates in the anakinra group vs. 8 % in the placebo group. Also in 2011, Nigrovic et al. retrospectively analysed the effectiveness of anakinra treatment in 46 sJIA patients [24]. However, they could not make a final statement about safety and efficacy of anakinra as “first-line” disease-modifying therapy in sJIA because of varying time to diagnosis, variable treatment regimens and particularly the combination with DMARDs and/or corticosteroids. Still, the study provided evidence of the efficacy of anakinra in sJIA patients with or without additional treatment. In 2014, Vastert et al. documented positive effects of “firstline” anakinra treatment in 24 sJIA patients [25]. Most (22/24) sJIA patients treated with anakinra plus corticosteroids and more than 75 % of those sJIA patients treated with anakinra alone, reached an ACR Pedi90 response or had completely inactive disease. After one year, 85 % (17/20) of all sJIA patients receiving anakinra treatment were clinically inactive. Seven patients, however, required additional treatment to anakinra. In 2012, efficacy of canakinumab, humanized monoclonal inactivating anti-IL-1β antibody was summarized in two phase III clinical trials [26]. In both the trials, patients received canakinumab in active sJIA despite standard treatment with corticosteroids and DMARDs. In the first trial, one third of sJIApatients treated with canakinumab reached clinical remission within 15 d after a single application of the drug. More than 80 % of the patients treated with canakinumab reached an ACRPedi30 response, compared to only 10 % in the placebo group. In the second trial, all patients received canakinumab to taper steroids. In one third of the patients, corticosteroids could be discontinued, about half of the patients tolerated corticosteroid dose reduction. Another anti-IL-1 agent that may prove valuable in the treatment of sJIA is rilonacept. Rilonacept is a fusion protein of the extracellular component of the IL-1 receptor (IL-1RI and IL-1RAcP) and the Fc portion of IgG1, binding both IL1α and IL-1β. Rilonacept yielded ACR Pedi 70 responses in 35–40 % of patients with chronic systemic JIA [27].
2005, a small Japanese study documented rapid reduction of disease activity in response to tocilizumab in 10 out of 11 sJIA patients [28]. In 2008, a double-blinded, placebo-controlled phase III trial demonstrated good response (ACR Pedi30) in >90 % of 56 sJIA patients [29], and the long-term open label extension of this trial showed sustained effectiveness for most patients [30]. In 2012, the TENDER trial [31] included 112 patients with sJIA and persistent clinical activity for at least 6 mo regardless of NSAID and corticosteroid treatment. Eighty-five percent of sJIA patients treated with tocilizumab, but only 24 % in the placebo group, reached the primary endpoint of ACR Pedi30 and absence of fever. During the open-label extension phase of the trial, 28 % of the patients had clinically inactive disease one year after initiating tocilizumab. Anti-TNF Agents TNF-α blockade is highly effective in most forms of JIA. In 2009, Russo et al. documented response rates of only 24 % in 45 sJIA patients treated with antiTNF treatments (etanercept, adalimumab, or infliximab). Stable remission was achieved only in 13 % [32]. These response rates are rather disappointing. Limited and inconsistent effects of anti-TNF treatment may reflect a “secondary” role of TNF-α in the molecular pathophysiology of sJIA. While during early-phase of sJIA other cytokines (such as IL-1 and IL-6) drive inflammation, TNF-α may become more important during later stages. Secondary to overall low remission rates in the published reports; TNF-blocking strategies are not commonly used in sJIA and should be reserved for select cases.
Concept of Window of Opportunity We know from other forms of JIA, that adaptive immune mechanisms play a role in the manifestation and maintenance of chronic arthritis. As mentioned before, chronic destructive arthritis is frequently a symptom of “late-stage” sJIA. Thus, advocates of the “window of opportunity” hypothesis claim that, through early induction of stable remission with innate cytokine blocking strategies, such as anti-IL-1 or anti-IL-6 agents, the development of chronic inflammation and subsequent potential priming of adaptive immune-processes may be prevented [33].
Treatment Recommendations Anti-IL-6 Treatment Tocilizumab is a humanized anti-IL-6 receptor antibody, blocking both soluble and transmembrane IL-6 receptors. In
American College of Rheumatology (ACR) recommends that there is a role for a trial of NSAIDs for up to two weeks if disease activity is relatively low and poor prognostic features
Indian J Pediatr
are absent. sJIA children with high disease activity (such as symptomatic pericarditis) are recommended to receive systemic corticosteroids and if they are unresponsive, anakinra is recommended [34]. ACR recommendations do recognize that anakinra could be used as a first-line treatment for active systemic symptoms of sJIA, particularly if there is persistent fever and if poor prognostic features are present. In view of the more recent data, tocilizumab has to considered as an alternative to IL-1 inhibitors. But in children who have active arthritis but no systemic features, include NSAIDS followed by methotrexate. If there is no response to methotrexate, patients should receive either anakinra or a tumor necrosis factor–α inhibitor. The potential role of IL-1 and IL-6 inhibitors for arthritis without systemic features remains to be clarified. In 2013, the American College of Rheumatology updated their treatment recommendations for systemic JIA [35]. Biologic agents that inhibit IL-1 (anakinra or canakinumab) or IL-6 (tocilizumab) are recommended as the first glucocorticoid-sparing therapies for children with active systemic features. Additionally, in some instances, IL-1 or IL-6 inhibitors are considered appropriate to use prior to or in the absence of systemic glucocorticoids. This is a significant departure from the treatment approach that has been used for several decades and may diminish the adverse effects of glucocorticoids commonly associated with the treatment of sJIA.
Compliance with Ethical Standards
Conclusions
10.
Systemic JIA is the most severe and potentially lifethreatening disease in the group of JIA. In contrast to other forms of JIA, sJIA is considered an autoinflammatory disorder. Favourable response to cytokine blocking strategies with IL-1 and IL-6 suggest central involvement of such proinflammatory cytokines in sJIA. Modern treatment options control systemic inflammation and reduce treatmentassociated side-effects of “classical” regimens with corticosteroids. However, multicenter, double-blinded, open-label, placebo-controlled trials in large cohorts are necessary to scientifically prove superiority to standard treatment and long-term safety. Based on our current understanding of the pathophysiology of sJIA and the response to available treatment options, it appears reasonable to apply high-dose corticosteroids in the early stage of disease. If symptoms persist or corticosteroid tapering attempts fail after two to four weeks, modern cytokine-blocking strategies should be introduced to prevent treatment-associated side-effects or disease sequelae. Much remains to be learned about the disease pathogenesis and the optimal treatment of children with sJIA.
11.
Conflict of Interest None. Source of Funding None.
References 1. 2.
3.
4.
5. 6.
7. 8.
9.
12. 13.
14.
15.
16.
17.
18.
19.
Still GF. On a form of chronic joint disease in children. Med Chir Trans. 1897;80:47–60.9. Behrens EM, Beukelman T, Gallo L, et al. Evaluation of the presentation of systemic onset juvenile rheumatoid arthritis: data from the Pennsylvania Systemic Onset Juvenile Arthritis Registry (PASOJAR). J Rheumatol. 2008;35:343–8. 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. Petty RE, Southwood TR, Manners P, et al. International League of Associations for Rheumatology classification of juvenile idiopathic arthritis: Second revision, Edmonton 2001. J Rheumatol. 2004;31:390–2. Calabro JJ. Other extraarticular manifestations of juvenile rheumatoid arthritis. Arthritis Rheum. 1977;20:237–40. Ishihara M, Nakamura S, Okada K, Yokota S, Ohno S. A case of juvenile rheumatoid arthritis with panuveitis. Nihon Ganka Gakkai Zasshi. 1992;96:109–13. Moore AT, Morin JD. Bilateral acquired inflammatory Brown’s syndrome. J Pediatr Ophthalmol Strabismus. 1985;22:26–30. Wang FM, Wertenbaker C, Behrens MM, Jacobs JC. Acquired Brown’s syndrome in children with juvenile rheumatoid arthritis. Ophthalmology. 1984;91:23–6. Avcin T, Silverman ED, Forte V, Schneider R. Nasal septal perforation: a novel clinical manifestation of systemic juvenile idiopathic arthritis/adult onset Still’s disease. J Rheumatol. 2005;32:2429–31. Woo P. Systemic juvenile idiopathic arthritis: diagnosis, management, and outcome. Nat Clin Pract Rheumatol. 2006;2:28–34. Schnitzer TJ, Ansell BM. Amyloidosis in juvenile chronic polyarthritis. Arthritis Rheum. 1977;20:245–52. Schneider R, Laxer RM. Systemic onset juvenile rheumatoid arthritis. Baillieres Clin Rheumatol. 1998;12:245–71. Correll CK, Binstadt BA. Advances in the pathogenesis and treatment of systemic juvenile idiopathic arthritis. Pediatr Res. 2014;75:176–83. Mellins ED, Macaubas C, Grom AA. Pathogenesis of systemic juvenile idiopathic arthritis: some answers, more questions. Nat Rev Rheumatol. 2011;7:416–26. Donn R, Ellison S, Lamb R, Day T, Baildam E, Ramanan AV. Genetic loci contributing to hemophagocytic lymphohistiocytosis do not confer susceptibility to systemic-onset juvenile idiopathic arthritis. Arthritis Rheum. 2008;58:869–74. Sawhney S, Woo P, Murray KJ. Macrophage activation syndrome: a potentially fatal complication of rheumatic disorders. Arch Dis Child. 2001;85:421–6. Bechtold S, Ripperger P, Dalla Pozza R, et al. Growth hormone increases final height in patients with juvenile idiopathic arthritis: data from a randomized controlled study. J Clin Endocrinol Metab. 2007;92:3013–8. Spiegel LR, Schneider R, Lang BA, et al. Early predictors of poor functional outcome in systemic-onset juvenile rheumatoid arthritis: a multicenter cohort study. Arthritis Rheum. 2000;43:2402–9. Martini A Systemic juvenile idiopathic arthritis. Autoimmun Rev. 2012;12:56–9.
Indian J Pediatr 20.
Garcia-Carrasco M, Fuentes-Alexandro S, Escarcega RO, RojasRodriguez J, Escobar LE. Efficacy of thalidomide in systemic onset juvenile rheumatoid arthritis. Joint Bone Spine. 2007;74:500–3. 21. Brinkman DM, de Kleer IM, ten Cate R, et al. Autologous stem cell transplantation in children with severe progressive systemic or polyarticular juvenile idiopathic arthritis: long-term follow-up of a prospective clinical trial. Arthritis Rheum. 2007;56:2410–21. 22. Verbsky JW, White AJ. Effective use of the recombinant interleukin 1 receptor antagonist anakinra in therapy resistant systemic onset juvenile rheumatoid arthritis. J Rheumatol. 2004;31:2071–5. 23. Quartier P, Allantaz F, Cimaz R, et al. A multicentre, randomised, double-blind, placebo-controlled trial with the interleukin-1 receptor antagonist anakinra in patients with systemic-onset juvenile idiopathic arthritis (ANAJIS trial). Ann Rheum Dis. 2011;70:747–54. 24. Nigrovic PA, Mannion M, Prince FH, et al. Anakinra as first-line disease-modifying therapy in systemic juvenile idiopathic arthritis: report of forty-six patients from an international multicenter series. Arthritis Rheum. 2011;63:545–55. 25. Vastert SJ, de Jager W, Noordman BJ, et al. Effectiveness of firstline treatment with recombinant interleukin-1 receptor antagonist in steroid-naive patients with new-onset systemic juvenile idiopathic arthritis: results of a prospective cohort study. Arthritis Rheum. 2014;66:1034–43. 26. Ruperto N, Brunner HI, Quartier P, et al. Two randomized trials of canakinumab in systemic juvenile idiopathic arthritis. N Engl J Med. 2012;367:2396–406. 27. Lovell DJ, Giannini EH, Reiff AO, et al. Long-term safety and efficacy of rilonacept in patients with systemic juvenile idiopathic arthritis. Arthritis Rheum. 2013;65:2486–96. 28. Yokota S, Miyamae T, Imagawa T, et al. Therapeutic efficacy of humanized recombinant anti-interleukin-6 receptor antibody in
29.
30.
31.
32.
33.
34.
35.
children with systemic-onset juvenile idiopathic arthritis. Arthritis Rheum. 2005;52:818–25. Yokota S, Imagawa T, Mori M, et al. Efficacy and safety of tocilizumab in patients with systemic-onset juvenile idiopathic arthritis: a randomised, double- blind, placebo-controlled, withdrawal phase III trial. Lancet. 2008;371:998–1006. Yokota S, Imagawa T, Mori M, et al. Long-term treatment of systemic juvenile idiopathic arthritis with tocilizumab: results of an open label extension study in Japan. Ann Rheum Dis. 2013;72:627–8. De Benedetti F, Brunner HI, Ruperto N, et al. Randomized trial of tocilizumab in systemic juvenileidiopathic arthritis. N Engl J Med 2012;367:2385–95. Russo RA, Katsicas MM. Clinical remission in patients with systemic juvenile idiopathic arthritis treated with anti-tumor necrosis factor agents. J Rheumatol. 2009;36:1078–82. Nigrovic PA. Review: is there a window of opportunity for treatment of systemic juvenile idiopathic arthritis? Arthritis Rheum. 2014;66:1405–13. Beukelman T, Patkar NM, Saag KG, 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. Ringold S, Weiss PF, Beukelman T, et al. 2013 update of the 2011 American College of Rheumatology recommendations for the treatment of juvenile idiopathic arthritis: recommendations for the medical therapy of children with systemic juvenile idiopathic arthritis and tuberculosis screening among children receiving biologic medications. Arthritis Care Res (Hoboken). 2013;65:1551–63.
