Ross E Petty, Taunton R Southwood, Prudence Manners, John Baum, David N Glass, Jose Goldenberg, Xiaohu He, Jose Maldonado-Cocco, Javier Orozco-Alcala, Anne-Marie Prieur, Maria E Suarez-Almazor, Patricia Woo, International League of Associations for Rheumatology
International League of Associations for Rheumatology classification of juvenile idiopathic arthritis: second revision, Edmonton, 2001.
J Rheumatol. 2004 Feb;31(2):390-2.
Abstract/Text
森雅亮, 成戸卓也, 今川智之, 村田卓士, 武井修治, 冨板美奈子, 伊藤保彦, 藤川敏, 横田俊平: 若年性特発性関節炎におけるメトトレキサート適応拡大の取得.日本小児科学会雑誌, 2008;112(6):1038-1047.
R E Petty, T R Southwood, J Baum, E Bhettay, D N Glass, P Manners, J Maldonado-Cocco, M Suarez-Almazor, J Orozco-Alcala, A M Prieur
Revision of the proposed classification criteria for juvenile idiopathic arthritis: Durban, 1997.
J Rheumatol. 1998 Oct;25(10):1991-4.
Abstract/Text
Maria Beatrice Damasio, Clara Malattia, Alberto Martini, Paolo Tomà
Synovial and inflammatory diseases in childhood: role of new imaging modalities in the assessment of patients with juvenile idiopathic arthritis.
Pediatr Radiol. 2010 Jun;40(6):985-98. doi: 10.1007/s00247-010-1612-z. Epub 2010 Apr 30.
Abstract/Text
Juvenile idiopathic arthritis (JIA) represents a group of heterogeneous diseases characterized by a chronic inflammatory process primarily targeting the synovial membrane. A persistent synovitis is associated with an increased risk of osteocartilaginous damage.With the advent of effective structure-modifying treatment for JIA, it may be possible to significantly reduce or even completely prevent structural damage and associated functional disability. The trend towards early suppression of inflammation, in order to prevent erosive disease, shifts the emphasis away from conventional radiographic detectable structural damage to the slightest traces of early joint damage, and drives the need for alternative imaging techniques more sensitive in detecting early signs of disease activity and damage. In this regard MRI and US are playing an increasing role in the evaluation of arthritic joints.This article will review the key aspects of the current status and recent important advances of imaging techniques available to investigate the child with rheumatic disease, briefly discussing conventional radiography, and particularly focusing on MRI and US. In this era of advancing imaging technology, knowledge of the relative values of available imaging techniques is necessary to optimize the management of children with JIA.
K Martin, E G Davies, J S Axford
Fever of unknown origin in childhood: difficulties in diagnosis.
Ann Rheum Dis. 1994 Jul;53(7):429-33.
Abstract/Text
We have described a child with systemic onset juvenile chronic arthritis who presented initially with fever of unknown origin. Treatment of a presumed infection led to a severe allergic response with Stevens-Johnson syndrome, renal failure and DIC. This reaction obscured the features of the underlying disease and delayed the diagnosis.
R Mouy, J L Stephan, P Pillet, E Haddad, P Hubert, A M Prieur
Efficacy of cyclosporine A in the treatment of macrophage activation syndrome in juvenile arthritis: report of five cases.
J Pediatr. 1996 Nov;129(5):750-4.
Abstract/Text
OBJECTIVES: To evaluate the efficacy of cyclosporine A in the treatment of macrophage activation syndrome (MAS) occurring in children with juvenile arthritis.
STUDY DESIGN: MAS developed in two boys and three girls with systemic juvenile arthritis (four) and polyarticular juvenile arthritis (one). In three children whose condition was life-threatening, increased parenteral administration of corticosteroids failed to improve their condition; therefore cyclosporine A (2 to 5 mg/kg per day) was added. In two other patients with less severe clinical manifestations, cyclosporine A alone (2 to 8 mg/kg per day) was given.
RESULTS: After the introduction of cyclosporine A, rapid improvement was obtained in all patients and apyrexia occurred within 24 to 48 hours. The biologic abnormalities disappeared more slowly (up to 5 weeks for liver enzymes).
CONCLUSIONS: These observations underline the usefulness of cyclosporine A in this complication. The use of this drug may circumvent the need for increased doses of corticosteroids in some patients. The mechanism of action of cyclosporine A remains speculative, but these results indicate indirectly that T-helper lymphocytes may play a role in the pathogenesis of MAS.
E H Giannini, G D Cawkwell
Drug treatment in children with juvenile rheumatoid arthritis. Past, present, and future.
Pediatr Clin North Am. 1995 Oct;42(5):1099-125.
Abstract/Text
Rheumatology made its debut as a legitimate subspecialty of pediatrics sometime in the 1940s in Europe, and in the 1970s in North America. Therapy of juvenile rheumatoid arthritis has evolved from salicylates and gold injections to newer, less toxic nonsteroidal anti-inflammatory drugs and methotrexate. Corticosteroids remain as important drugs when life-threatening complications or blinding iridocyclitis develop. Immune response modifiers and gene therapies offer considerable potential for eventually halting or curing the disease but have yet to make a substantial impact on therapy. Methods for the correct conduct and interpretation of data from clinical trials are discussed.
Philip J Hashkes, Ronald M Laxer
Medical treatment of juvenile idiopathic arthritis.
JAMA. 2005 Oct 5;294(13):1671-84. doi: 10.1001/jama.294.13.1671.
Abstract/Text
CONTEXT: The treatment of juvenile idiopathic arthritis (JIA) has changed markedly in the last 15 years. Many children with JIA are not treated by pediatric rheumatologists.
OBJECTIVE: To review the best evidence for the treatment of JIA.
DATA SOURCES: English-language trials of JIA between 1966 and 2005 were searched using MEDLINE, EMBASE, the Cochrane database, and abstracts from recent rheumatology and pediatric scientific meetings.
STUDY SELECTION: Randomized controlled trials and open studies including at least 10 patients for medications without controlled trials.
DATA EXTRACTION: For studies after 1997, the American College of Rheumatology Pediatric 30 outcome measure was used to define patients as responders. For older studies, the primary response outcome measure defined by the authors was used.
DATA SYNTHESIS: Thirty-four controlled studies were identified. Nonsteroidal anti-inflammatory drugs are effective only for a minority of patients, mainly those with oligoarthritis. Intra-articular corticosteroid injections are very effective for oligoarthritis. Methotrexate is effective for the treatment of extended oligoarthritis and polyarthritis and less effective for systemic arthritis. Sulfasalazine and leflunomide may be alternatives to methotrexate. Antitumor necrosis factor medications are highly effective for polyarticular course JIA not responsive to methotrexate but are less effective in systemic arthritis. There is a lack of evidence for the optimal treatment of systemic and enthesitis-related arthritis.
CONCLUSIONS: Despite many advances in the treatment of JIA, there is still a lack of evidence for treatment of several disease subtypes. The treatment plan needs to be individualized based on the JIA subtype.
A O Adebajo, M A Hall
The use of intravenous pulsed methylprednisolone in the treatment of systemic-onset juvenile chronic arthritis.
Br J Rheumatol. 1998 Nov;37(11):1240-2.
Abstract/Text
An open prospective study using i.v. methylprednisolone in children with juvenile chronic arthritis (JCA) who had had a systemic exacerbation of disease is described. Eighteen children aged from 3 to 14 yr and 9 months (mean 9.7 yr) were treated. Ten patients (55%) had a loss of all systemic features 1 month after the pulse, and eight (45%) had a reduction in the active joint count. At this time, five of the patients on oral prednisolone had achieved a reduction in dosage. Also at 1 month, a reduction in erythrocyte sedimentation rate was observed in 11 patients (61%) and of C-reactive protein in 11 of 16 (72%). Altogether, 13 patients (72%) had a good response, while a further three (16%) went into remission. Our conclusions are that pulse methylprednisolone provides good short-term benefit in patients with systemic-onset JCA; no serious side-effects were noted. Further long-term studies are warranted.
Philip Kahn
Juvenile idiopathic arthritis - an update on pharmacotherapy.
Bull NYU Hosp Jt Dis. 2011;69(3):264-76.
Abstract/Text
Juvenile idiopathic arthritis (JIA) consists of a collection of all forms of chronic arthritis in childhood with no apparent cause. JIA is the most common rheumatic disease in children and may result in significant pain, joint deformity, and growth impairment, with persistence of active arthritis into adulthood. The extra-articular features of JIA, such as anterior uveitis or macrophage activation syndrome, are often the greater focus of therapy. Prior to the mid 1990s, the therapeutic armamentarium for JIA was more limited, utilizing non-specific agents, many with significant adverse effects. In the current era of target-specific biologic therapy, it is possible to better tailor therapy for patients. Through continued translational research and clinical trials, the biology mediating disease is better understood, and there is the hope of safer, more effective medicine and potential cure. This review will outline the clinical features of JIA as well as provide the latest updates in current and future pharmacotherapy.
E H Giannini, J T Cassidy, E J Brewer, A Shaikov, A Maximov, N Kuzmina
Comparative efficacy and safety of advanced drug therapy in children with juvenile rheumatoid arthritis.
Semin Arthritis Rheum. 1993 Aug;23(1):34-46.
Abstract/Text
Results from three randomized placebo-controlled trials were combined in a meta-analysis to compare the clinical utility of four advanced drug therapy agents used to treat juvenile rheumatoid arthritis (JRA): D-penicillamine (10 mg/kg/d), hydroxychloroquine (6 mg/kg/d), auranofin (oral gold, 0.15 to 0.20 mg/kg/d), and two low dose levels of methotrexate [5MTX, 5 mg/M2/wk; 10MTX, 10 mg/M2/wk]. A total of 520 children with JRA were enrolled into these trials. Only 10MTX resulted in significantly greater improvement than placebo in variables that assess effectiveness: physician's global assessment, a composite index, and erythrocyte sedimentation rate. Treatment effect sizes were the largest in the 10MTX group for all articular disease indices. The short-term safety profiles were similar across all treatment groups. It is concluded that the current trend among pediatric rheumatologists to use oral methotrexate as the first advanced drug therapy in JRA is appropriate and that the minimum effective dose is 10 mg/M2/wk.
E H Giannini, E J Brewer, N Kuzmina, A Shaikov, A Maximov, I Vorontsov, C W Fink, A J Newman, J T Cassidy, L S Zemel
Methotrexate in resistant juvenile rheumatoid arthritis. Results of the U.S.A.-U.S.S.R. double-blind, placebo-controlled trial. The Pediatric Rheumatology Collaborative Study Group and The Cooperative Children's Study Group.
N Engl J Med. 1992 Apr 16;326(16):1043-9. doi: 10.1056/NEJM199204163261602.
Abstract/Text
BACKGROUND: The antimetabolite methotrexate has been shown in placebo-controlled trials to be effective in adults with rheumatoid arthritis. Methotrexate may also be effective in children with resistant juvenile rheumatoid arthritis, but the supporting data are from uncontrolled trials.
METHODS: Centers in the United States and the Soviet Union participated in this randomized, controlled, double-blind trial designed to evaluate the effectiveness and safety of orally administered methotrexate. Patients received one of the following treatments each week for six months: 10 mg of methotrexate per square meter of body-surface area (low dose), 5 mg of methotrexate per square meter (very low dose), or placebo. The use of prednisone (less than or equal to 10 mg per day) and two nonsteroidal antiinflammatory drugs was also allowed.
RESULTS: The 127 children (mean age, 10.1 years) had a mean duration of disease of 5.1 years; 114 qualified for the analysis of efficacy. According to a composite index of several response variables, 63 percent of the children who received low-dose methotrexate improved, as compared with 32 percent of those in the very-low-dose group and 36 percent of those in the placebo group (P = 0.013). As compared with the placebo group, the low-dose group also had significantly larger mean reductions from base line in the number of joints with pain on motion (-11.0 vs. -7.1), the pain-severity score (-19 vs. -11.5), the number of joints with limited motion (-5.4 vs. -0.7), and the erythrocyte sedimentation rate (-19.0 vs. -6 mm per hour). In the methotrexate groups only three children had the drug discontinued because of mild-to-moderate side effects; none had severe toxicity.
CONCLUSIONS: Methotrexate given weekly in low doses is an effective treatment for children with resistant juvenile rheumatoid arthritis, and at least in the short term this regimen is safe.
Masaaki Mori, Takuya Naruto, Tomoyuki Imagawa, Takuji Murata, Syuji Takei, Minako Tomiita, Yasuhiko Itoh, Satoshi Fujikawa, Shumpei Yokota
Methotrexate for the treatment of juvenile idiopathic arthritis: process to approval for JIA indication in Japan.
Mod Rheumatol. 2009;19(1):1-11. doi: 10.1007/s10165-008-0123-3. Epub 2008 Sep 25.
Abstract/Text
Methotrexate (MTX), the primary treatment for the articular-type juvenile idiopathic arthritis (JIA), is effective and brings about radiological improvement. Patient compliance is good, and it is recognized that its known side effects, namely, disruption of liver function and induction of pulmonary lesions, are unlikely to be severe at the low MTX doses that are administered. In Japan, MTX was granted approval in 1999 by the then Ministry of Health and Welfare specifically for treating rheumatoid arthritis in adult patients, allowing it be generally used in medical institutions for patients having National Health Insurance. However, in the pediatric field, its use outside the indications has so far been unavoidable, and has been left to the discretion of the physician. Finally, at the present conference, expansion of the indications of MTX for JIA was approved in Japan. It is noteworthy that this expansion of indications was achieved without requiring clinical trials on children sponsored by the pharmaceutical company: it was achieved rather by collecting necessary information through ongoing efforts (including collection and analysis of information about approval status in foreign countries, adequate evidence from the literature, implementation of a clinical use survey in Japan, etc.). It also merits attention that the maximum dose (10 mg/m2) was set on the basis of pharmacokinetic data from children, rather than relying on the dosing method and dose for adults.
F Halle, A M Prieur
Evaluation of methotrexate in the treatment of juvenile chronic arthritis according to the subtype.
Clin Exp Rheumatol. 1991 May-Jun;9(3):297-302.
Abstract/Text
Methotrexate therapy was evaluated in 30 children with juvenile chronic arthritis according to the type of onset. The systemic form seemed less responsive than the ANA positive form with a polyarticular course or polyarticular onset. The clinical improvement, particularly in the ANA positive polyarticular course was confirmed by a significant decrease in the values of the ESR. Side effects occurred in 12 patients and consisted of gastrointestinal upset, mouth ulcers, slight leucopenia and elevated transaminases. They led to discontinuation of the treatment in only one child. Concomitant therapy could be stopped in 50% of the patients with an ANA positive polyarticular course, but remained necessary in the two other groups. These results indicate a differential effect of MTX therapy according to the type of JCA.
Timothy Beukelman, Nivedita M Patkar, Kenneth G Saag, Sue Tolleson-Rinehart, Randy Q Cron, Esi Morgan DeWitt, Norman T Ilowite, Yukiko Kimura, Ronald M Laxer, Daniel J Lovell, Alberto Martini, C Egla Rabinovich, Nicolino Ruperto
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 Apr;63(4):465-82. doi: 10.1002/acr.20460.
Abstract/Text
D J Lovell, E H Giannini, A Reiff, G D Cawkwell, E D Silverman, J J Nocton, L D Stein, A Gedalia, N T Ilowite, C A Wallace, J Whitmore, B K Finck
Etanercept in children with polyarticular juvenile rheumatoid arthritis. Pediatric Rheumatology Collaborative Study Group.
N Engl J Med. 2000 Mar 16;342(11):763-9. doi: 10.1056/NEJM200003163421103.
Abstract/Text
BACKGROUND: We evaluated the safety and efficacy of etanercept, a soluble tumor necrosis factor receptor (p75):Fc fusion protein, in children with polyarticular juvenile rheumatoid arthritis who did not tolerate or had an inadequate response to methotrexate.
METHODS: Patients 4 to 17 years old received 0.4 mg of etanercept per kilogram of body weight subcutaneously twice weekly for up to three months in the initial, open-label part of a multicenter trial. Those who responded to treatment then entered a double-blind study and were randomly assigned to receive either placebo or etanercept for four months or until a flare of the disease occurred. A response was defined as an improvement of 30 percent or more in at least three of six indicators of disease activity, with no more than one indicator worsening by more than 30 percent.
RESULTS: At the end of the open-label study, 51 of the 69 patients (74 percent) had had responses to etanercept treatment. In the double-blind study, 21 of the 26 patients who received placebo (81 percent) withdrew because of disease flare, as compared with 7 of the 25 patients who received etanercept (28 percent) (P=0.003). The median time to disease flare with placebo was 28 days, as compared with more than 116 days with etanercept (P<0.001). In the double-blind study, there were no significant differences between the two treatment groups in the frequency of adverse events.
CONCLUSIONS: Treatment with etanercept leads to significant improvement in patients with active polyarticular juvenile rheumatoid arthritis. Etanercept is well tolerated by pediatric patients.
Masaaki Mori, Syuji Takei, Tomoyuki Imagawa, Hiroyuki Imanaka, Nobuaki Maeno, Rumiko Kurosawa, Yoshifumi Kawano, Shumpei Yokota
Pharmacokinetics, efficacy, and safety of short-term (12 weeks) etanercept for methotrexate-refractory polyarticular juvenile idiopathic arthritis in Japan.
Mod Rheumatol. 2005;15(6):397-404. doi: 10.1007/s10165-005-0431-9.
Abstract/Text
We examined and evaluated the pharmacokinetics, efficacy, and safety of etanercept in patients with methotrexate (MTX)-refractory polyarticular juvenile idiopathic arthritis (JIA) in Japan. All MTX-refractory polyarticular JIA patients 4-17 years old received 0.4 mg of etanercept per kilogram of body weight subcutaneously twice weekly for up to 3 months in the open-label, prospective, and multicenter trial. A response was defined as an improvement of 30%, 50%, 70%, or more from baseline in at least three of six indicators of disease activity, with no more than one indicator worsening by more than 30% from baseline (30%, 50%, or 70% definition of improvement, respectively), and disease activity score (DAS28) by EULAR (European League Against Rheumatism) response criteria. At the end of the 12-week study, 20 of the 22 patients (90.9%) had responses with both 30% and 50% definition of improvement after etanercept treatment. To our surprise, 15 of 22 patients (68.2%) had a response with 70% definition of improvement. Moreover, in DAS28, eight patients were evaluated as having a good response and there were no patients with a poor response to etanercept. Treatment had to be stopped in one patient who developed joint contracture during the study period, but there were no significant adverse events in the other patients. In conclusion, treatment with etanercept leads to significant improvement in patients with active polyarticular JIA in Japan. Etanercept is well tolerated by pediatric patients as well as adults.
Tomoyuki Imagawa, Shumpei Yokota, Masaaki Mori, Takako Miyamae, Syuji Takei, Hiroyuki Imanaka, Yasuhito Nerome, Naomi Iwata, Takuji Murata, Mari Miyoshi, Norihiro Nishimoto, Tadamitsu Kishimoto
Safety and efficacy of tocilizumab, an anti-IL-6-receptor monoclonal antibody, in patients with polyarticular-course juvenile idiopathic arthritis.
Mod Rheumatol. 2012 Feb;22(1):109-15. doi: 10.1007/s10165-011-0481-0. Epub 2011 Jun 12.
Abstract/Text
We evaluated the safety and efficacy of tocilizumab in polyarticular-course juvenile idiopathic arthritis (pJIA) with polyarticular or oligoarticular onset. Patients received 8 mg/kg tocilizumab every 4 weeks in the open-label studies: initial study (to week 12) and then an extension study (at least 48 weeks). Nineteen patients intractable to conventional methotrexate therapy were enrolled. Seventeen patients had polyarticular-onset pJIA; two had oligoarticular-onset pJIA. Mean age was 11.6 years; mean disease duration 5.3 years. American College of Rheumatology Pediatric (ACR Pedi) 30, 50, 70, and 90 response rates, respectively, were 94.7%, 94.7%, 57.9%, and 10.5% at week 12, and 100%, 94.1%, 88.2%, and 64.7% at week 48. Mean disease activity score (DAS28) remained below the remission level (2.6) from week 24. Administration was discontinued in two patients during the extension study because the ACR Pedi 50 response was judged insufficient (one patient) and antitocilizumab antibodies developed (one patient). Adverse events were generally mild, and the four serious adverse events resolved spontaneously or with treatment. In conclusion, tocilizumab showed early and sustained efficacy and tolerability for treating intractable pJIA, which suggests that it is a promising new treatment for this disease.
Shumpei Yokota, Tomoyuki Imagawa, Masaaki Mori, Takako Miyamae, Yukoh Aihara, Shuji Takei, Naomi Iwata, Hiroaki Umebayashi, Takuji Murata, Mari Miyoshi, Minako Tomiita, Norihiro Nishimoto, Tadamitsu Kishimoto
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 Mar 22;371(9617):998-1006. doi: 10.1016/S0140-6736(08)60454-7.
Abstract/Text
BACKGROUND: Systemic-onset juvenile idiopathic arthritis does not always respond to available treatments, including antitumour necrosis factor agents. We investigated the efficacy and safety of tocilizumab, an anti-interleukin-6-receptor monoclonal antibody, in children with this disorder.
METHODS: 56 children (aged 2-19 years) with disease refractory to conventional treatment were given three doses of tocilizumab 8 mg/kg every 2 weeks during a 6-week open-label lead-in phase. Patients achieving an American College of Rheumatology Pediatric (ACR Pedi) 30 response and a C-reactive protein concentration (CRP) of less than 5 mg/L were randomly assigned to receive placebo or to continue tocilizumab treatment for 12 weeks or until withdrawal for rescue medication in a double-blind phase. The primary endpoint of the double-blind phase was an ACR Pedi 30 response and CRP concentration of less than 15 mg/L. Patients responding to tocilizumab and needing further treatment were enrolled in an open-label extension phase for at least 48 weeks. The analysis was done by intention to treat. This study is registered with ClinicalTrials.gov, numbers NCT00144599 (for the open-label lead-in and double-blind phases) and NCT00144612 (for the open-label extension phase).
FINDINGS: At the end of the open-label lead-in phase, ACR Pedi 30, 50, and 70 responses were achieved by 51 (91%), 48 (86%), and 38 (68%) patients, respectively. 43 patients continued to the double-blind phase and were included in the efficacy analysis. Four (17%) of 23 patients in the placebo group maintained an ACR Pedi 30 response and a CRP concentration of less than 15 mg/L compared with 16 (80%) of 20 in the tocilizumab group (p<0.0001). By week 48 of the open-label extension phase, ACR Pedi 30, 50, and 70 responses were achieved by 47 (98%), 45 (94%), and 43 (90%) of 48 patients, respectively. Serious adverse events were anaphylactoid reaction, gastrointestinal haemorrhage, bronchitis, and gastroenteritis.
INTERPRETATION: Tocilizumab is effective in children with systemic-onset juvenile idiopathic arthritis. It might therefore be a suitable treatment in the control of this disorder, which has so far been difficult to manage.
武井修治.若年性特発性関節炎に対する抗体療法.治療学,2010;44(2):185-190.
日本リウマチ学会: 若年性特発性関節炎 初期診療の手引き2015. メディカルレビュー社. 2015.