Juvenile idiopathic arthritis: Rethinking remission


Juvenile idiopathic arthritis (JIA) refers to a heterogenous group of all forms of chronic arthritis in childhood with no apparent cause that begins prior to age 16 years and lasts for more than 6 weeks.


Juvenile idiopathic arthritis (JIA) refers to a heterogenous group of all forms of chronic arthritis in childhood with no apparent cause that begins prior to age 16 years and lasts for more than 6 weeks.1,2 It is the most common form of rheumatic disease in children, with an estimated incidence of 2 to 20 cases per 100,000 children and prevalence of 16 to 150 cases per 100,000 children worldwide.1,3 In the United States, it is estimated that more than 300,000 children currently have JIA.

Diagnosis and treatment of JIA has improved over the years with an increased understanding of the different subtypes and clinical presentations of JIA and the availability and efficacy of newer antirheumatic medications to treat these subtypes.4 The efficacy of methotrexate as first-line treatment for most patients with JIA, combined with other conventional disease-modifying antirheumatic drugs (DMARDs) and/or the more recent biologic agents as needed, has resulted in an increasing number of patients who attain longer periods of disease control and clinical remission. Despite these improvements, the response to therapy is as heterogeneous as the subtypes themselves and many children who achieve clinical remission experience recurrence and disease flares even while on continuous medication.5

What is emerging is recognition of the need to better understand the biology underlying the differences among the subtypes of JIA in terms of response to therapy and outcomes6 and the need to understand this biology to develop better individualized treatment. New data from a study that used gene expression profiling in a cohort of JIA patients suggest that current definitions of clinical remission thought to indicate a return to normal patterns of gene expression in children who attain control of disease activity do not accurately describe the underlying biology of clinical remission. Rather, the underlying biology of clinical remission seems to involve the counterbalancing of proinflammatory responses by anti-inflammatory responses.6

“Although children in remission on medication appear to be completely normal, our medications do not result in normal immune homeostasis,” according to James Jarvis, MD, clinical professor and chief, Allergy/Immunology and Rheumatology, University of Buffalo, New York, a lead investigator of the study.

The implications, he emphasized, are that although children can now achieve long-term disease-free periods when they stay on their medications, their vulnerability to disease persists. “While our findings explain why children who appear to be doing well experience disease recurrences, they don’t explain how to prevent them,” he said.

For pediatricians who see children with JIA, these new data and understanding of remission emphasize the need to continually treat children with JIA with appropriate medications for years and not just months, even when they are doing well, according to Jarvis.

To help pediatricians manage JIA in their patients, this article provides a brief primer on the subtypes of JIA and their clinical presentation; an update on the most current treatments and outcomes; and a look at the emerging issue and evidence on the biology of remission and therapeutic response that is promising to help better tailor treatment and optimize outcomes for children with JIA.


Subtypes of JIA and clinical presentation

Distinct phenotypes of the disease have been recognized based on disease presentation, clinical course, and specific biomarkers.6 Currently the disease is classified into specific disease subtypes with distinct clinical presentations (Table 1).1,7

Despite these subtypes, the disease remains heterogeneous in terms of response to therapy and overall outcome.5,6

Current treatment goals and options

The goal of treatment of all subtypes of JIA is control of active inflammation and symptoms of the disease, as well as prevention of morbidities such as joint damage, functional limitations, and growth disturbances.8 Current definitions of disease control and remission include recognition that patients treated for JIA are on a spectrum of active disease and inactive disease while on medication as well as off medication.5 Criteria for inactive disease are shown in Table 2.

Patients with inactive disease are considered in 1 of 2 categories of clinical remission: clinical remission on medication (CRM), defined as 6 continuous months of inactive disease on medication; and clinical remission off medication (CR), defined as 12 continuous months of inactive disease off all antiarthritis and antiuveitis drugs.8 With the current treatment approaches, many patients are now able to attain CRM but CR remains challenging.5

To achieve clinical remission, early and aggressive treatment that combines new and older therapies is recommended.4,5 For most children with JIA, methotrexate has become the first-line therapy. For specific types of JIA, the addition of other agents to methotrexate have shown improved efficacy (Table 3).4

Treating patients early and aggressively has been found to provide optimal efficacy.4,5,9 Data from the Trial of Early Aggressive Therapy in JIA (TREAT JIA) study, which compared methotrexate alone or with etanercept in children with newly-diagnosed JIA, showed a higher likelihood and longer duration of clinical remission in patients treated with more aggressive therapy.10 In addition, some have suggested there may be a window of opportunity to provide the best treatment for chronic arthritis, and that window may vary widely depending on the underlying disease and individual patient characteristics. Regardless of what that window may be, early and aggressive treatment to control potentially debilitating and painful symptoms of JIA that may also affect growth in children is needed.4


Understanding biological remission and clinical implications

Although many children with JIA now achieve CRM and attain sustained periods of disease control with these new medications, emerging data are showing that the biological state of CRM in these children does not point to a restoration of immunological normalcy as postulated. Instead, new data suggest that the biological state of CRM indicates attainment of a homeostatic state in which proinflammatory disease networks are counterbalanced by the emergence of anti-inflammatory networks.6,11

In a study published in 2013 to determine whether CRM achieved in a typical clinical setting resulted in a return to normal immune homeostatis, Jiang and colleagues used gene expression profiling to examine medication-specific effects on gene transcriptional profiles in 2 cohorts of children with polyarticular onset rheumatoid factor-negative JIA and a cohort of healthy controls.6 The study found numerous differences in gene expression in peripheral blood mononuclear cells and granulocytes between the JIA cohorts who achieved remission induced by either methotrexate alone or with etanercept and the cohort of healthy controls.

The study also found that treatment with combined methotrexate and etancercept produced distinct gene expression responses more biologically focused at the gene expression level than the responses detected among the patients treated by methotrexate alone that were more heterogeneous.6

The study concluded that CRM in children with polyarticular JIA is a distinct biological state that does not reflect a return to normalization of immune homeostasis.6 Rather, gene expression in peripheral blood mononuclear cells and granulocytes remains abnormal in children who achieve CRM compared with healthy children. “Computational analysis shows that remission is a lot closer to the active disease state than it is to normal,” said Jarvis.

In addition, the study showed that CRM achieved by methotrexate alone differs from CRM achieved by combined methotrexate and etancercept.6 In particular, the study found significant differences in the CRM state in JIA neutrophils depending on whether CRM was achieved with methotrexate alone or methotrexate plus etancercept.

These findings, conclude the investigators, “provide a framework from which to understand therapeutic response in JIA and, furthermore, may be used to develop strategies to increase the frequency with which remission is achieved in adult forms of rheumatoid arthritis.”6

More recent data on the possibility of using biomarkers developed from gene expression profiles to predict disease status in children treated for JIA was recently presented in an abstract at the European League Against Rheumatism annual congress in June 2014. Yao and colleagues showed that long-term disease status at 12 months could be accurately predicted in newly diagnosed patients only after treatment was initiated.12 The study included children with polyarticular JIA enrolled in the TREAT study who were treated either with methotrexate alone or methotrexate with etanercept.

Main message to pediatricians

Ongoing investigation is needed to identify biomarkers to better predict which children with JIA will respond to which particular therapies. Until then, Jarvis emphasizes the need for pediatricians to recognize the need for continuous medication treatment in children with JIA, even those who achieve clinical remission.

“Overall the lives of children with JIA are far more normal than they were 30 years ago when I started,” said Jarvis. However, he emphasized the need for pediatricians to be on the lookout for signs and symptoms of recurring active disease in children who have achieved clinical remission while continuously taken their medications. “Pediatricians need to be aware that, even in children who have been doing well, morning stiffness, gait disturbance, and joint swelling can recur and referral to a pediatric rheumatologist is highly desirable,” he said.

Future directions

Distinct phenotypes of JIA have been recognized based on disease presentation, clinical course, and specific biomarkers,6 which has led to classifying the disease into 6 subtypes. However, the disease remains heterogeneous in terms of response to therapy and overall outcome regardless of the subtypes.5,6

Newer treatment options over the past decades have offered significant improvements in clinical outcomes, with increasing numbers of children with specific subtypes treated with specific agents attaining remission of disease and sustained disease control. However, disease recurrence and flares persist for many of these children who attain clinical remission.

Emerging evidence that CRM is a distinct biological state that differs from normal, as well as the differences in gene expression in children who achieve CRM on different treatment regimens, is helping to identify future biomarkers that may help predict therapeutic response and make possible tailored treatment to optimize outcomes.



1. Kahn P. Juvenile idiopathic arthritis: an update for the clinician. Bull NYU Hosp Jt Dis. 2012;70(3):152-166.

2. Foeldvari I, Bidde M. Validation of the proposed ILAR classification criteria for juvenile idiopathic arthritis. International League of Associations for Rheumatology. J Rheumatol. 2000;27(4):1069-1072.

3. Ravelli A, Martini A. Juvenile idiopathic arthritis. Lancet. 2007;369(9563):767-778.

4. Stoll ML, Cron RQ. Treatment of juvenile idiopathic arthritis: a revolution of care. Pediatr Rheumatol Online J. 2014;12:13. eCollection 2014.

5. Shenoi S, Wallace CA. Remission in juvenile idiopathic arthritis: current facts. Curr Rheumatol Rep. 2010:12(2):80-86.

6. Jiang K, Frank MB, Chen Y, Osban J, Jarvis JN. Genomic characterization of remission in juvenile idiopathic arthritis. Arthritis Res Ther. 2013;15(4):R100.

7. National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS). Juvenile arthritis. NIH publication no. 13-4942. Available at: http://www.niams.nih.gov/Health_Info/Juv_Arthritis/. Published August 2013, Accessed June 23, 2014.

8. Ringold S, Wallace CA. Measuring clinical response and remission in juvenile idiopathic arthritis. Curr Opin Rheumatol. 2007;19(5):471-476.

9. Bartoli M, Tarò M, Magni-Manzoni S, et al. The magnitude of early response to methotrexate therapy predicts long-term outcome of patients with juvenile idiopathic arthritis. Ann Rheum Dis. 2008;67(3):370-374.

10. Wallace CA, Giannini EH, Spalding SJ, et al; Childhood Arthritis and Rheumatology Research Alliance (CARRA). Clinically inactive disease in a cohort of children with new-onset polyarticular juvenile idiopathic arthritis treated with early aggressive therapy: time to achievement, total duration, and predictors. J Rheumatol. 2014;41(6):1163-1170.

11. Knowlton N, Jiang K, Frank MB, et al. The meaning of clinical remission In polyarticular juvenile idiopathic arthritis: gene expression profiling in peripheral blood mononuclear cells identifies distinct disease states. Arthritis Rheum. 2009;60(3):892-900.

12. Yao J, Jiang K, Franks MB, et al. Developing prognostic biomarkers from whole blood expression profiling in juvenile idiopathic arthritis: influence of early therapy on treatment outcome. Abstract OP0187. Ann Rheum Dis. 2014; 73(suppl 2).



Ms Nierengarten, a medical writer in St. Paul, Minnesota, has over 25 years of medical writing experience, coauthoring articles for Lancet Oncology, Lancet Neurology, Lancet Infectious Diseases, and Medscape. Dr Oski, Department of Pediatrics, Tuba City Regional Health Care Corporation, Arizona, is an editorial advisory board member for Contemporary Pediatrics. The author and the reviewer have nothing to disclose in regard to affiliations with or financial interests in any organizations that may have an interest in any part of this article.


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