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Kemper AR, Coeytaux R, Sanders GD, et al. Disease-Modifying Antirheumatic Drugs (DMARDs) in Children With Juvenile Idiopathic Arthritis (JIA) [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2011 Sep. (Comparative Effectiveness Reviews, No. 28.)
This publication is provided for historical reference only and the information may be out of date.
Disease-Modifying Antirheumatic Drugs (DMARDs) in Children With Juvenile Idiopathic Arthritis (JIA) [Internet].
Show detailsJIA—Abstract Screening Instructions
An abstract will be included if all of the following criteria apply for RCTs:
- The sample population has JIA according to the current ACR definition (KQ1-KQ5).
- Random allocation to the intervention or placebo/control groups (KQ1-KQ3).
- One or more DMARDs are evaluated (KQ1-KQ4).
- Outcome is change in one of the pre-specified intermediate or final outcomes and is assessed using an acceptable standard (KQ1, KQ2).
- Study duration is at least 3 months (KQ1-KQ4).
- Population may be from primary or specialty care settings (KQ1-KQ5).
- Sample consists of children 18 years or younger. If the study includes adults, at least 80% of the sample will be children or the outcomes must be reported separately for the child subgroup (KQ1-KQ5).
- Original data.
An abstract will be excluded if any of the following criteria apply for RCTs:
- Non-English language publication (KQ1-KQ5)
An abstract will be included if all of the following criteria apply for Observational Studies:
- The sample population has JIA according to the current ACR definition (KQ1-KQ5).
- One or more DMARDs are evaluated (KQ1-KQ4).
- Outcome is change in one of the pre-specified intermediate or long-term outcomes and is assessed using an acceptable standard (KQ1, KQ2).
- Study duration is at least 3 months (KQ1-KQ4).
- Population may be from primary or specialty care settings (KQ1-KQ5).
- Sample consists of children 18 years or younger. If the study includes adults, at least 80% of the sample will be children or the outcomes must be reported separately for the child subgroup (KQ1-KQ5)
- Outcomes are determined prospectively and are assessed using an acceptable standard (KQ1-KQ4).
- For studies of effectiveness, there must be a treatment comparator (KQ1-KQ4).
- Case-control studies, case series, and case reports are acceptable to assess for adverse events of DMARD treatment (KQ3).
- Cross-sectional studies are acceptable to evaluate clinical outcome measure tools (KQ5).
An abstract will be excluded if any of the following criteria apply for Observational Studies:
- Non-English language publication (KQ1-KQ5).
- Cross-sectional studies for the evaluation of the impact of treatment (KQ1-KQ4).
An abstract will be identified as a review if it is a relevant review article, meta-analysis, methods article, or cost-effectiveness analysis.
For each abstract, please mark either “EX” for Exclude, “IN” for Include or “R” for Review.
JIA—Full-Text Screening Instructions/Exclusion Reasons
Key Questions 1-4
Key Questions 1-4 are as follows:
- Key Question 1.
In children with juvenile idiopathic arthritis (JIA), does treatment with disease-modifying anti-rheumatic drugs (DMARDs), compared to conventional treatment (defined as non-steroidal anti-inflammatory drugs [NSAIDs] or intra-articular corticosteroids, with or without methotrexate), improve laboratory measures of inflammation or radiological progression, symptoms (e.g., pain, symptom scores) or health status (e.g., functional ability, mortality)?
- Key Question 2.
In children with JIA, what are the comparative effects of various DMARDs on laboratory markers of inflammation or radiological progression, symptoms (e.g., pain, symptom scores), or health status (e.g., functional ability, mortality)?
- Key Question 3.
In children with JIA, does the rate and type of adverse events differ between the various DMARDs or between DMARDs and conventional treatment?
- Key Question 4.
How do the efficacy, effectiveness, safety, and adverse effects of treatment with DMARDs differ among the various categories of JIA?
General/Introductory Notes
- Key Question (KQ) 4 will draw on the entire body of evidence included for KQs 1-3; therefore, it does not have a separate set of inclusion/exclusion criteria.
- A wider range of study designs are acceptable for KQ 3 than for KQs 1-2, including case reports, non-comparative prospective studies, and retrospective studies. However, study duration must be ≥ 3 months (as for KQs 1-2).
- KQ 5 is very different from KQs 1-4 and has some distinctly different inclusion/exclusion criteria. A separate cheat sheet has been prepared for it.
- For all KQs, the study population may be drawn from primary or specialty care settings.
- For all KQs, the language of publication must be English.
1. Publication Not Peer-Reviewed
For KQs 1–2
- Publication must be peer-reviewed (excludes editorials, letters to the editor, etc.).
For KQ 3
- Case reports published in non-peer-reviewed form (e.g., as letters) in academic journals are acceptable.
- Other types of studies must be peer-reviewed.
2. Population not JIA/JRA/JCA
For All KQs
- The sample population must have juvenile idiopathic arthritis (JIA) according to the International League of Associations for Rheumatology (ILAR) criteria, or juvenile rheumatoid arthritis (JRA) according to the American College of Rheumatology (ACR) definition, or juvenile chronic arthritis (JCA) according to the European League Against Rheumatism (EULAR) criteria.
- Any subtype of JIA/JRA/JCA of any severity is acceptable.
Notes/Further Guidance
Criteria for Classification of JIA (ILAR = International League of Associations of for Rheumatology) From 1998
Note: All categories require age of onset prior to 16 yrs
| JIA category | Definition | Exclusions |
|---|---|---|
| Systemic arthritis | Arthritis and fever plus one or more: 1. rash, 2. lymph node enlargement, 3. hepato or splenomegaly, 4. serositis | |
| Oligoarthritis | Arthritis of 1-4 joints in the first 6 mo, | Family history of psoriasis or HLA-B27 assoc. disease, RF+, HLA-B27+ males > 8 years, systemic arthritis |
| Persistent | < 5 joints during course, | |
| Extended | > 4 joints after 6 mo | |
| RF- polyarthritis | Arthritis of > 4 joints in the first 6 mo, RF- | RF+, systemic arthritis |
| RF+ polyarthritis | Arthritis of > 4 joints in the first 6 mo, RF + | RF-, systemic arthritis |
| Psoriatic arthritis | Arthritis and psoriasis or arthritis and at least 2 of: (a) dactylitis, (b) nail abnormalities, (c) family history of psoriasis | RF+, systemic arthritis |
| Enthesitis related arthritis | Arthritis and enthesitis OR arthritis or enthesitis with at least 2 of: (a) sacroiliac tenderness and/or spinal pain, (b) HLA-B27, (c) family history of HLA-B27associated disease | Family history of psoriasis, systemic arthritis |
| Other arthritis | Children with JIA who do not fulfill criteria for any category or fulfill criteria for >1 category |
(Reference: Evaluation of the ILAR criteria for juvenile idiopathic arthritis. Krumrey-Langkammerer M, Häfner R.J Rheumatol. 2001 Nov;28(11):2544-7.)
Criteria for Classification of JRA (ACR = American College of Rheumatology) From 1976
Age of onset prior to 16 yrs
Arthritis (swelling, effusion, or presence of 2 or more of the following in one or more joints:
- Limitation of range of motion
- Tenderness or pain on range of motion
- Increased heat
Duration of disease 6 weeks or longer
Onset type defined by type of disease in first 6 months:
- Polyarticular: ≥ 5 inflamed joints
- Oligoarticular (aka: pauciarticular): < 5 joints
- Systemic onset: arthritis with characteristic fever
Exclusion of other forms of juvenile arthritis (psoriatic, spondyloarthopathy = juvenile ankylosing spondylitis, inflammatory bowel disease associated arthritis)
Criteria for Classification of JCA (EULAR = European League Against Rheumatism) From 1977
Age of onset prior to 16 yrs
Arthritis (swelling, effusion, or presence of 2 or more of the following in one or more joints):
- Limitation of range of motion
- Tenderness or pain on range of motion
- Increased heat
Duration of disease 3 months or longer
Onset type defined by characteristics at presentation:
- Polyarticular: ≥ 5 inflamed joints, Rheumatoid factor negative
- Pauciarticular: < 5 joints
- Systemic onset: arthritis with characteristic fever
- Juvenile rheumatoid arthritis: ≥ 5 joints, rheumatoid factor positive
- Juvenile ankylosing spondylitis
- Juvenile psoriatic arthritis
3. Population Not < 18 years
For All KQs
- Study sample must consist of children 18 years or younger. If the study includes adults, at least 80% of the sample must be children, or outcomes must be reported separately for the 18 years or younger subgroup.
4. No Acceptable DMARD Intervention
For KQs 1 -4
- Study must include one of the DMARDs on our list (see table below) either:
- ◦
Alone;
- ◦
In combination with another DMARD on our list; or
- ◦
In combination with conventional treatment.
| Generic Name | US Trade Name | Mechanism of Action | FDA-approved for JIA | Warnings—Increased Risk |
|---|---|---|---|---|
| Abatacept | Orencia | Anti-CD28, T-cell costimulator antibodies; biologic | Yes | Infections |
| Adalimumab | Humira | TNF inhibitor; biologic | Yes | Infections; cancer |
| Anakinra | Kineret | IL-1 receptor antagonist; biologic | No | Infections |
| Canakinumab | Ilaris | IL-1 blocker; biologic | No | Vertigo |
| Etanercept | Enbrel | TNF inhibitor; biologic | Yes | Infections; cancer |
| Infliximab | Remicade | TNF inhibitor; biologic | No | Infections; cancer |
| IVIG | Baygam, Carimune NF, Flebogamma 5% DIF, Gammar P, Gamunex 10%, Gammagard S/D, Gammagard Liquid 10%, Gammar P, Iveegam EN, Octagam 5%, Panglobulin, Polygam S/D, Privigen 10% Vivaglobin | Interaction with activating Fc receptors; biologic | No | Hepatitis; acute renal failure; venous thrombosis; aseptic meningitis |
| Rilonacept | Arcalyst | IL-1 blocker; biologic | No | Infection |
| Rituximab | Rituxan | Binds to CD20 antigen; biologic | No | Progressive multifocal leukoencephalopathy; severe skin reactions; infusion reactions |
| Tocilizumab | Actemra | IL-6 receptor antagonist; biologic | No | Infections; elevated lipid levels |
| Azathioprine | Azasan; Imuran | Purine Synthesis Inhibitor; non-biologic | No | Cancer; bone marrow suppression |
| Cyclosporine A | Neoral Gengraf | Inhibits calcineurin; non-biologic | No | Infections; nephrotoxicity; hepatotoxicity |
| D-Penicillamine | Depen; Cuprimine | Unknown (May lower IgM rheumatoid factor, depresses T-cell activity); non-biologic | No | Allergic reactions; Goodpasture's syndrome; hematologic toxicities; hepatotoxicity; myasthenia gravis |
| Hydroxy-chloroquine | Plaquenil | Not well understood, may reduce T-lymphocyte transformation and chemotaxis; non-biologic | No | Kidney damage; retinopathy |
| Leflunomide | Arava | Isoxazole immunomodulatory agent; non-biologic | No | Hepatotoxicity |
| Methotrexate | Methotrexate LPF | Unknown (anti-metabolite, inhibits dihydrofolic acid reductase); non-biologic | Yes | Hepatotoxicity; cancer |
| Mycophenolate mofetil | CellCept | Guanosine synthesis inhibitor; non-biologic | No | Cancer; bone marrow suppression |
| Sulfasalazine | Azulfidine Sulfazine | Unknown; non-biologic | Yes | Bone marrow suppression; hepatotoxicity; Stevens Johnson Syndrome |
| Tacrolimus (FK506) | Prograf | Reduces T-cell and IL-2 activity; non-biologic | No | Cancer; infection |
| Thalidomide | Thalomid | Unknown; non-biologic | No | Birth defects; neuropathy |
Included DMARDs (Table 2 from project protocol). List of DMARDs, their mechanism of action, FDA approval status for JIA, and examples of significant warnings from the drug product label.
5. No Acceptable Comparator
For KQ 1, Acceptable Comparators Are
- Conventional treatment, defined as “NSAIDs or intra-articular corticosteroids, with or without methotrexate” (see table below for acceptable NSAIDs and corticosteroids)
| Generic Name | US Trade Name | Drug Type | FDA-Approved for JIA | Warnings— Increased Risk |
|---|---|---|---|---|
| Betamethasone | Celestone | Intra-articular corticosteroid | Yes | Subcutaneous atrophy ; Cushing syndrome |
| Triamcinolone Acetonide | Kenolog | Intra-articular corticosteroid | Yes | Subcutaneous atrophy; Cushing syndrome |
| Triamcinolone Hexacetonide | Aristospan | Intra-articular corticosteroid | No | Subcutaneous atrophy; Cushing syndrome |
| Celecoxib | Celebrex | NSAID | Yes | Hepatotoxicity; nephrotoxicity; gastritis |
| Etodolac | Lodine | NSAID | No | Cardiovascular thrombotic events; gastritis |
| Ibuprofen | Motrin Advil | NSAID | Yes | Gastritis; hepatotoxicity; nephrotoxicity |
| Indomethacin | Indocin Indocin SR | NSAID | Yes | Headaches: gastritis; hepatotoxicity; nephrotoxicity |
| Meloxicam | Mobic | NSAID | Yes | Gastritis; hepatotoxicity; nephrotoxicity |
| Naproxen | Naprosyn Aleve | NSAID | Yes | Gastritis; hepatotoxicity; nephrotoxicity |
| Oxaprozin | Daypro | NSAID | Yes | Cardiovascular thrombotic events; gastritis |
| Tolmetin | Tolectin | NSAID | Yes | Gastritis; hepatotoxicity; nephrotoxicity |
For KQ 2, Acceptable Comparators Are
- Any other DMARD on our list (see table above) either:
- ◦
Alone;
- ◦
In combination with another DMARD on our list; or
- ◦
In combination with conventional treatment (defined as above).
For KQ 3, Acceptable Comparators Are
- None or any
Included NSAIDs and intra-articular corticosteroids (Table 1 from project protocol). List of intra-articular corticosteroids and NSAIDs FDA approval status for JIA, and examples of significant warnings from the drug product label.
6. Study Not Prospective
Relevant Only to KQs 1-2
- Any prospective comparative study is acceptable. Studies evaluating a prospective treatment group vs. a historical control group are also acceptable.
For KQ 3
- Studies are not required to be prospective. For KQ3, any study design is acceptable (comparative or non-comparative, prospective or retrospective, any size [including case studies with n = 1]).
7. No Outcome of Interest
For KQs 1-2
- Study must include at least one of the following intermediate or long-term outcomes:
- ◦
Intermediate outcomes include:
- ▪
Laboratory measures of inflammation
- ▪
Active joint count
- ▪
Number of joints with limited range of motion
- ▪
Radiographic evidence of progression of disease
- ▪
Global assessment of current status
- ◦
Long-term outcomes include:
- ▪
Pain control
- ▪
Clinical remission
- ▪
Quality of life
- ▪
Growth
- ▪
Development
- ▪
Joint function
- ▪
Functional Ability
- ▪
Mortality
For KQ 3
- Study must report adverse events
- We are especially (but not exclusively) interested in:
- ◦
Mortality
- ◦
Malignancy
- ◦
Serious infection
- ◦
Hepatitis
- ◦
Bone marrow suppression
- ◦
Nausea or vomiting
- ◦
Risks to fetus or pregnant mother
8. Outcomes Not Measured Using an Objective Standard
Relevant Only to KQs 1-2
- Outcomes must be measured using an objective standard
9. Study Duration < 3 Months
Relevant Only to KQs 1-2
- Study duration must be ≥ 3 months.
For KQ 3
- Any study duration is acceptable.
JIA—Full-Text Screening Instructions/Exclusion Reasons
Key Question 5
Key Question 5. What is the validity, reliability, responsiveness, and feasibility of the clinical outcomes measures for childhood JIA that are commonly used in clinical trials or within the clinical practice setting?
General/Introductory Notes
- For this and all other Key Questions (KQs), the study population may be drawn from primary or specialty care settings.
- For this and all other KQs, the language of publication must be English.
- For KQ 5 specifically:
- ◦
Any treatment intervention/comparator is acceptable (including none).
- ◦
Any study design is acceptable (including RCTs, non-randomized controlled trials, and observational studies [controlled or uncontrolled, cross-sectional or longitudinal]).
- ◦
Any study duration is acceptable (study does not need to be ≥ 3 months).
1. Publication Not Peer-Reviewed
- Publication must be peer-reviewed (excludes editorials, letters to the editor, etc.).
2. Population Not JIA/JRA/JCA
For All KQs
- The sample population must have juvenile idiopathic arthritis (JIA) according to the International League of Associations for Rheumatology (ILAR) criteria, or juvenile rheumatoid arthritis (JRA) according to the American College of Rheumatology (ACR) definition, or juvenile chronic arthritis (JCA) according to the European League Against Rheumatism (EULAR) criteria.
- Any subtype of JIA/JRA/JCA of any severity is acceptable.
Notes/Further Guidance
Criteria for Classification of JIA (ILAR = International League of Associations of for Rheumatology) from 1998
Note: All categories require age of onset prior to 16 yrs
| JIA category | Definition | Exclusions |
|---|---|---|
| Systemic arthritis | Arthritis and fever plus one or more: 1. rash, 2. lymph node enlargement, 3. hepato or splenomegaly, 4. serositis | |
| Oligoarthritis | Arthritis of 1-4 joints in the first 6 mo, | Family history of psoriasis or HLA-B27 assoc. disease, RF+, HLA-B27+ males > 8 years, systemic arthritis |
| Persistent | < 5 joints during course, | |
| Extended | > 4 joints after 6 mo | |
| RF- polyarthritis | Arthritis of > 4 joints in the first 6 mo, RF- | RF+, systemic arthritis |
| RF+ polyarthritis | Arthritis of > 4 joints in the first 6 mo, RF + | RF-, systemic arthritis |
| Psoriatic arthritis | Arthritis and psoriasis or arthritis and at least 2 of: (a) dactylitis, (b) nail abnormalities, (c) family history of psoriasis | RF+, systemic arthritis |
| Enthesitis related arthritis | Arthritis and enthesitis OR arthritis or enthesitis with at least 2 of: (a) sacroiliac tenderness and/or spinal pain, (b) HLA-B27, (c) family history of HLA-B27associated disease | Family history of psoriasis, systemic arthritis |
| Other arthritis | Children with JIA who do not fulfill criteria for any category or fulfill criteria for >1 category |
(Reference: Evaluation of the ILAR criteria for juvenile idiopathic arthritis. Krumrey-Langkammerer M, Häfner R.J Rheumatol. 2001 Nov;28(11):2544-7.)
Criteria for Classification of JRA (ACR = American College of Rheumatology) from 1976
Age of onset prior to 16 yrs
Arthritis (swelling, effusion, or presence of 2 or more of the following in one or more joints:
- Limitation of range of motion
- Tenderness or pain on range of motion
- Increased heat
Duration of disease 6 weeks or longer
Onset type defined by type of disease in first 6 months:
- Polyarticular: ≥ 5 inflamed joints
- Oligoarticular (aka: pauciarticular): < 5 joints
- Systemic onset: arthritis with characteristic fever
Exclusion of other forms of juvenile arthritis (psoriatic, spondyloarthopathy = juvenile ankylosing spondylitis, inflammatory bowel disease associated arthritis)
Criteria for Classification of JCA (EULAR = European League Against Rheumatism) from 1977
Age of onset prior to 16 yrs
Arthritis (swelling, effusion, or presence of 2 or more of the following in one or more joints):
- Limitation of range of motion
- Tenderness or pain on range of motion
- Increased heat
Duration of disease 3 months or longer
Onset type defined by characteristics at presentation:
- Polyarticular: ≥ 5 inflamed joints, Rheumatoid factor negative
- Pauciarticular: < 5 joints
- Systemic onset: arthritis with characteristic fever
- Juvenile rheumatoid arthritis: ≥ 5 joints, rheumatoid factor positive
- Juvenile ankylosing spondylitis
- Juvenile psoriatic arthritis
3. Population Not < 18 Years
For All KQs
- The study sample must consist of children 18 years or younger. If the study includes adults, at least 80% of the sample must be children, or outcomes must be reported separately for the 18 years or younger subgroup.
4. No Clinical Outcome Measure (Test) of Interest
- Study must report at least one clinical outcome measure for childhood JIA that is commonly used in clinical trials or within the clinical practice setting.
Notes/Further Guidance
The following list of specific measures/instruments was agreed on after discussions with the project's technical expert panel (TEP).
- Measures of disease activity:
- ◦
Active joint count (AJC)
- ◦
Physician global assessment of disease activity (PGA)
- ◦
Parent/patient global assessment of well-being (PGW)
- Measure of functional status/disability:
- ◦
Childhood Health Assessment Questionnaire (CHAQ)
- Measures of health-related quality of life:
- ◦
Child Health Questionnaire (CHQ)
- ◦
Pediatric Quality of Life Inventory (PedsQL) 4.0
- ◦
Pediatric Quality of Life Inventory Rheumatology Module (PedsQL-RM)
- Composite measures of response to therapy and developing definitions of disease status:
- ◦
American College of Rheumatology Pediatric Response Criteria (ACR Pediatric 30)
- ◦
A consensus-based definition of remission
- ◦
Flare
- ◦
Minimal disease activity (MDA)
5. No Data Reported on Test Performance
- Outcomes to be evaluated here are:
- ◦
Validity of clinical outcomes measures
- ◦
Reliability of clinical outcomes measures (inter- and intra-rater reliability, test-retest reliability)
- ◦
Responsiveness of clinical outcomes measures (standardized response mean and responsiveness index).
- ◦
Feasibility of clinical outcomes measures (specifically, time to administer).
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