Disease-Modifying Antirheumatic Drugs in Children With Juvenile Idiopathic Arthritis

1
Disease-Modifying Antirheumatic Drugs in Children
With JuvenileIdiopathic Arthritis

• Prepared for
• Agency for Healthcare Research and Quality (AHRQ)
  
• www.ahrq.gov

2
Outline of Material

• Introduction to the health impact and medical
  treatment of juvenile idiopathic arthritis (JIA)
• Systematic review methods used to create the
  comparative effectiveness review
• The clinical questions addressed by the
  comparative effectiveness review
• Results of studies and evidence-based conclusions
  about effectiveness and safety of
  disease-modifying antirheumatic drugs (DMARDs) to
  treat JIA
• Gaps in knowledge and future research needs
• What to discuss with patients and their caregivers

.

• Kemper A, Coeytaux, R, Sanders G, et al.
  Comparative Effectiveness Review No. 28.
• Available at www.effectivehealthcare.ahrq.gov/dmar
  dsjia.cfm

3
Health Impact of Juvenile Idiopathic Arthritis

• JIA is the most common rheumatic disease of
  childhood.
• Prevalence of the disease is estimated to be
  between 7 to 400 per 100,000 children.
• As a chronic, disabling disease, JIA interferes
  with growth and development and causes
  psychological distress.
• Left unchecked, the course of disease results in
  irreversible joint damage and life-long
  disability.
• There is no cure for JIA.

• Helmick CG, Felson DT, Lawrence RC, et al.
  Arthritis Rheum 208858(1)15-25. PMID 18163481.
• Kemper A, Coeytaux, R, Sanders G, et al.
  Comparative Effectiveness Review No. 28.
• Available at www.effectivehealthcare.ahrq.gov/dmar
  dsjia.cfm.
• Manners PJ, Bower C. J Rheumatol
  200229(7)1520-30. PMID 12136914.

4
Characteristics of JIA

• To be considered JIA, onset must occur before 16
  years of age.
• JIA is heterogeneous the presentation of the
  disease and its natural history vary among
  individuals and over time.
• The disease is typically classified into
  categories based on the symptoms displayed and
  their severity.
• Systemic arthritis
• Oligoarthritis
• Rheumatoid-factor positive (RF) polyarthritis
• Rheumatoid-factor negative (RF-) polyarthritis
• Enthesitis-related arthritis
• Psoriatic arthritis
• Undifferentiated

• Goldmuntz EA, Echite PH. Pediatr Rev
  200527(4)324-5. PMID 16581950.
• Kemper A, Coeytaux, R, Sanders G, et al.
  Comparative Effectiveness Review No. 28.
• Available at www.effectivehealthcare.ahrq.gov/dmar
  dsjia.cfm.

5
Treatment of JIA (1 of 2)

• Understanding both the circumstances in which
  DMARDs should be used and which DMARD should be
  selected is challenging because of the
  heterogeneity of the disease and response to
  treatment.
• The approach to treatment is based on the
  severity of symptoms.
• The goal of treatment is to reduce pain,
  swelling, and joint damage. Treatment typically
  includes
• Nonsteroidal anti-inflammatory drugs
• Corticosteroids intra-articular injections or
  rarely, oral
• This approach does not cure the disease but may
  significantly reduce symptoms.

• Kemper A, Coeytaux, R, Sanders G, et al.
  Comparative Effectiveness Review No. 28.
• Available at www.effectivehealthcare.ahrq.gov/dmar
  dsjia.cfm.

6
Treatment of JIA (2 of 2)

• Steroidal and nonsteroidal anti-inflammatory
  drugs alone are often inadequate to relieve
  symptoms and limit progression of disease.
• DMARDs are now in common use for JIA, and several
  have been approved by the U.S. Food and Drug
  Administration for this indication.
• DMARDs inhibit the immune cells and mechanisms
  underlying the symptoms of rheumatic disease.
• There are two classes of DMARDs biologic and
  nonbiologic.

• Kemper A, Coeytaux, R, Sanders G, et al.
  Comparative Effectiveness Review No. 28.
• Available at www.effectivehealthcare.ahrq.gov/dmar
  dsjia.cfm.

7
DMARDs for Treating JIA (1 of 2)

• Nonbiologic, synthetic DMARDs are small-molecule
  chemical drugs.
• The mechanism of action of each of these drugs is
  not well defined and is unknown in some cases.
• Biologic DMARDs block the activity of
  immunostimulatory cytokines and other
  cell-signaling molecules.
• Biologic DMARDs are genetically engineered
  antibodies and proteins.
• Tumor necrosis factor-alpha (TNF-a) blockers are
  the most typical members of this drug class.
• Other targets are interleukins 1 and 6 and the
  transmembrane proteins CD20 and CD28.

• Kemper A, Coeytaux, R, Sanders G, et al.
  Comparative Effectiveness Review No. 28.
• Available at www.effectivehealthcare.ahrq.gov/dmar
  dsjia.cfm.

8
DMARDs for Treating JIA (2 of 2)

• Methotrexate, a nonbiologic DMARD, is widely used
  and is considered by many to be essential to the
  treatment of JIA.
• Although studies in pediatric populations have
  been performed, the evidence base regarding
  DMARDs for treatment of JIA is more limited
  compared with the wider experience and clinical
  evidence base in adult rheumatoid arthritis.
• Long-term safety of the DMARDs used in children
  with JIA is not well understood.

• Kemper A, Coeytaux, R, Sanders G, et al.
  Comparative Effectiveness Review No. 28.
• Available at www.effectivehealthcare.ahrq.gov/dmar
  dsjia.cfm.

9
DMARDs Included in the Comparative Effectiveness
Review
Nonbiologic DMARDs Nonbiologic DMARDs
Name Target of Activity
Azathioprine Purine synthesis inhibits T-lymphocyte proliferation
D-Penicillamine Unknown
Hydroxychloroquine T-lymphocytes?
Leflunomide Pyridine synthesis
Methotrexate Dihydrofolate reductase folate metabolism
Sulfasalazine Uncertain multifactorial, including impairment of lymphocyte function and cytokine synthesis
Biologic DMARDs Biologic DMARDs
Name Target of Activity
Adalimumab TNF-a
Etanercept TNF-a
Infliximab TNF-a
Abatacept CD28
Anakinra IL-1
Rituximab CD20
Tocilizumab IL-6 receptor
IVIG Fc receptors

• Abbreviations IL interleukin IVIG
  intravenous immunoglobulin TNF-a tumor
  necrosis factor-alpha

• Kemper A, Coeytaux, R, Sanders G, et al.
  Comparative Effectiveness Review No. 28.
  Available at www.effectivehealthcare.ahrq.gov/dmar
  dsjia.cfm

10
Agency for Healthcare Research and Quality (AHRQ)
Comparative Effectiveness Review (CER) Development

• Topics are nominated through a public process,
  which includes submissions from health care
  professionals, professional organizations, the
  private sector, policymakers, members of the
  public, and others.
• A systematic review of all relevant clinical
  studies is conducted by independent researchers,
  funded by AHRQ, to synthesize the evidence in a
  report summarizing what is known and not known
  about the select clinical issue. The research
  questions and the results of the report are
  subject to expert input, peer review, and public
  comment.
• The results of these reviews are summarized into
  Clinician Research Summaries and Consumer
  Research Summaries for use in decisionmaking and
  in discussions with patients. The Summaries and
  the full report, with references for included and
  excluded studies, are available at
  www.effectivehealthcare.ahrq.gov/dmardsjia.cfm.

• Kemper A, Coeytaux, R, Sanders G, et al.
  Comparative Effectiveness Review No. 28.
  Available at www.effectivehealthcare.ahrq.gov/dmar
  dsjia.cfm.

11
Rating the Strength of Evidence From the CER

• The strength of evidence was classified into four
  broad categories

High ??? Further research is very unlikely to change the confidence in the estimate of effect.
Moderate ??? Further research may change the confidence in the estimate of effect and may change the estimate.
Low ??? Further research is likely to change the confidence in the estimate of effect and is likely to change the estimate.
Insufficient ??? Evidence either is unavailable or does not permit estimation of an effect.

• Kemper A, Coeytaux, R, Sanders G, et al.
  Comparative Effectiveness Review No. 28.
• Available at www.effectivehealthcare.ahrq.gov/dmar
  dsjia.cfm.

12
Clinical Questions Addressed by the CER (1 of 2)

• Despite being widely used, there are still
  unanswered questions about the effectiveness and
  safety of DMARDs when used to treat JIA,
  including
• What is the effectiveness of DMARDs when compared
  with conventional anti-inflammatory/anti-immune
  treatments?
• What is the comparative effectiveness of DMARDs,
  both within a drug class and between drug
  classes?
• What is the long-term safety of the DMARDs?
• Drugs in both categories carry safety warnings.
• AntiTNF-a DMARDs are associated with increased
  risk of cancer (lymphoma) and serious infections.

• Kemper A, Coeytaux, R, Sanders G, et al.
  Comparative Effectiveness Review No. 28.
• Available at www.effectivehealthcare.ahrq.gov/dmar
  dsjia.cfm.

13
Clinical Questions Addressed by the CER (2 of 2)

• What is the influence of disease category on
  effectiveness?
• Many assessment instruments are available to
  evaluate treatment effects, disease progression,
  health status, and overall well-being of children
  with JIA.
• What is the reliability, validity, and
  responsiveness of these instruments?

• Kemper A, Coeytaux, R, Sanders G, et al.
  Comparative Effectiveness Review No. 28.
• Available at www.effectivehealthcare.ahrq.gov/dma
  rdsjia.cfm.

14
Clinically Significant Outcomes of Interest (1
of 2)

• For analysis of the clinical study evidence,
  reviewers focused on these outcomes
• Intermediate Outcomes
• Disease activity, symptoms
• Physician global assessment of disease activity
  (PGA)
• Symptom response (e.g., 20, 30, or 50 from
  baseline)
• Parent/patient global assessments of well-being
• Active joint count joints with limited range of
  motion
• Laboratory measures of inflammation
• Erythrocyte sedimentation rate (ESR)
• Radiographic evidence of progression

American College of Rheumatology Pediatric (ACR
Ped) Improvement Score

• Kemper A, Coeytaux, R, Sanders G, et al.
  Comparative Effectiveness Review No. 28.
• Available at www.effectivehealthcare.ahrq.gov/dmar
  dsjia.cfm.

15
Clinically Significant Outcomes of Interest (2
of 2)

• Long-term outcomes
• Pain control
• Clinical remission
• Quality of life (QoL)
• Growth and development
• Health Status
• Child Health Assessment Questionnaire (CHAQ), for
  example
• Joint function
• Functional ability
• Mortality

• Kemper A, Coeytaux, R, Sanders G, et al.
  Comparative Effectiveness Review No. 28.
• Available at www.effectivehealthcare.ahrq.gov/dmar
  dsjia.cfm.

16
Adverse Effects

• Known risks associated with DMARDs
• Lymphoma
• Infections
• Other adverse effects of interest
• Mortality
• Hepatitis
• Bone marrow suppression
• Nausea or vomiting
• Risks to the fetus or pregnant mother

• Kemper A, Coeytaux, R, Sanders G, et al.
  Comparative Effectiveness Review No. 28.
• Available at www.effectivehealthcare.ahrq.gov/dmar
  dsjia.cfm.

17
Summary of Study Characteristics Evaluated in the
Effectiveness Review PICOTS

• Population Individuals 18 years of age or
  younger with a diagnosis of juvenile idiopathic
  (JIA), rheumatoid (JRA), or chronic (JCA)
  arthritis, as defined by these organizations
• JIA International League of Associations for
  Rheumatology (ILAR)
• JRA American College of Rheumatology (ACR)
• JCA European League Against Rheumatism (EULAR)
• Interventions Biologic and nonbiologic DMARDs
  added to conventional anti-inflammatory treatment
  (NSAIDs and intra-articular or oral
  corticosteroids)
• Comparators (1) Baseline treatment (NSAIDs and
  intra-articular corticosteroids) with or without
  methotrexate or (2) another DMARD
• Outcomes Intermediate and long-term disease
  status, health status, inflammation markers, and
  radiographic progression
• Timing Intervention period of at least 3 months
• Setting Any setting for treatment of JIA

• Kemper A, Coeytaux, R, Sanders G, et al.
  Comparative Effectiveness Review No. 28.
• Available at www.effectivehealthcare.ahrq.gov/dmar
  dsjia.cfm.

18
Controlled Studies in This CER Combining
Nonbiologic DMARDs and Conventional
Anti-inflammatory Drugs (1 of 2)
DMARD (No. of studies) Comparators and Other Interventions Allowed Study Population (n) Categories at Onset
D-Penicillamine or Hydroxychloroquine (2) Placebo, with NSAIDs, acetaminophen Polyarticular (142) Pauciarticular (11) Systemic (9)
D-Penicillamine or Hydroxychloroquine (2) Gold, with NSAIDs, acetaminophen Polyarticular (49) Pauciarticular (23)
D-Penicillamine (1) Placebo, with pyridoxine hydrochloride Polyarticular (35) Pauciarticular (14) Systemic (25)
Sulfasalazine (1) NSAIDs Polyarticular (32) Oligoarticular (37)
Azathioprine (1) Placebo, with NSAIDs, prednisolone Polyarticular (16) Pauciarticular (9) Systemic onset (7)
Abbreviations DMARD disease-modifying antirheumatic drug NSAIDs nonsteroidal anti-inflammatory drugs Abbreviations DMARD disease-modifying antirheumatic drug NSAIDs nonsteroidal anti-inflammatory drugs Abbreviations DMARD disease-modifying antirheumatic drug NSAIDs nonsteroidal anti-inflammatory drugs

• Kemper A, Coeytaux, R, Sanders G, et al.
  Comparative Effectiveness Review No. 28.
• Available at www.effectivehealthcare.ahrq.gov/dmar
  dsjia.cfm.

19
Controlled Studies in This CER Combining
Nonbiologic DMARDs and non-DMARD
Anti-inflammatory Drugs (2 of 2)
DMARD (No. of studies) Comparators and Other Interventions Allowed Study Population (n) Categories at Onset
Methotrexate (3) NSAIDs, methylprednisolone JIA (63)
Methotrexate (3) Placebo, with NSAIDS, prednisolone JIA (127)
Methotrexate (3) Placebo, with NSAIDs, prednisolone, intra-articular corticosteroids Extended oligoarticular (43) Systemic (45)
Abbreviations JIA juvenile idiopathic arthritis NSAIDs nonsteroidal anti-inflammatory drugs Abbreviations JIA juvenile idiopathic arthritis NSAIDs nonsteroidal anti-inflammatory drugs Abbreviations JIA juvenile idiopathic arthritis NSAIDs nonsteroidal anti-inflammatory drugs

• Kemper A, Coeytaux, R, Sanders G, et al.
  Comparative Effectiveness Review No. 28.
• Available at www.effectivehealthcare.ahrq.gov/dmar
  dsjia.cfm.

20
Results Combining Nonbiologic DMARDs and
Conventional Anti-inflammatory Drugs
DMARD (No. of studies) Treated, Control Disease Activity (Symptoms) Health Status Inflammation (ESR) Radiographic Progression
D-Penicillamine (3) 116, 110 /- /- NR NSD NR
Hydroxychloroquine (2) 82, 74 NSD NR NSD NR
Sulfasalazine (1) 35, 34 NR NSD
Azathioprine (1) 17, 15 NSD NSD NR
Methotrexate (3) 119, 114 AJC NSD PGA (2 studies) (2/3 studies) Mixed results in 1 study NR in 2 studies NR
Abbreviations AJC affected joint count ESR erythrocyte sedimentation rate NR not reported NSD no statistically significant difference PGA physician global assessment of disease activity Abbreviations AJC affected joint count ESR erythrocyte sedimentation rate NR not reported NSD no statistically significant difference PGA physician global assessment of disease activity Abbreviations AJC affected joint count ESR erythrocyte sedimentation rate NR not reported NSD no statistically significant difference PGA physician global assessment of disease activity Abbreviations AJC affected joint count ESR erythrocyte sedimentation rate NR not reported NSD no statistically significant difference PGA physician global assessment of disease activity Abbreviations AJC affected joint count ESR erythrocyte sedimentation rate NR not reported NSD no statistically significant difference PGA physician global assessment of disease activity

• Kemper A, Coeytaux, R, Sanders G, et al.
  Comparative Effectiveness Review No. 28.
• Available at www.effectivehealthcare.ahrq.gov/dmar
  dsjia.cfm.

21
Summary of Results Adding Nonbiologic DMARDs to
JIA Treatment

• Adding methotrexate to anti-inflammatory
  treatments improves disease activity, as scored
  by physicians.
• Strength of Evidence Moderate
• The results for other nonbiologic DMARDs are
  inconsistent and often statistically
  nonsignificant. For many outcomes, no
  observations are available. The evidence is
  insufficient to permit conclusions about benefits
  of nonbiologic DMARDs other than methotrexate.
• Strength of Evidence Insufficient

• Kemper A, Coeytaux, R, Sanders G, et al.
  Comparative Effectiveness Review No. 28.
• Available at www.effectivehealthcare.ahrq.gov/dmar
  dsjia.cfm.

22
Controlled Studies in This CER Adding Biologic
DMARDs to JIA Treatment (1 of 2)
DMARD (No. of studies) Comparators and Other Interventions Allowed Study Population (n)
Abatacept (1) Placebo, with MTX, NSAIDs, oral corticosteroids, analgesics Persistent oligoarticular (5) Extended oligoarticular (43) Polyarticular (205) Systemic (60)
Adalimumab (1) Placebo, with MTX, NSAIDs, oral corticosteroids Polyarticular (171)
Anakinra (1) Placebo, with MTX, NSAIDs, oral corticosteroids Polyarticular (33) Pauciarticular (6) Systemic (11)
Tocilizumab (1) Placebo, with oral corticosteroids JIA (43)
Abbreviations JIA juvenile idiopathic arthritis MTX methotrexate NSAIDs nonsteroidal anti-inflammatory drugs Abbreviations JIA juvenile idiopathic arthritis MTX methotrexate NSAIDs nonsteroidal anti-inflammatory drugs Abbreviations JIA juvenile idiopathic arthritis MTX methotrexate NSAIDs nonsteroidal anti-inflammatory drugs

• Kemper A, Coeytaux, R, Sanders G, et al.
  Comparative Effectiveness Review No. 28.
• Available at www.effectivehealthcare.ahrq.gov/dmar
  dsjia.cfm.

23
Controlled Studies in This CER Adding Biologic
DMARDs to JIA Treatment (2 of 2)
DMARD (No. of studies) Comparators and Other Interventions Allowed Study Population (n)
Etanercept (2) Placebo, with NSAIDs, oral corticosteroids Polyarticular (62) Pauciarticular (6) Systemic (34)
Etanercept (2) Placebo, with MTX, prednisone, analgesics JRA with uveitis (12)
IVIG (3) Placebo , with NSAIDs, MTX, SSZ, hydroxychloroquine Polyarticular (19)
IVIG (3) Methylprednisolone, with NSAIDs, MTX, oral corticosteroids JCA (20)
IVIG (3) Placebo, with NSAIDs and up to 2 nonbiologic DMARDs JRA Systemic (31)
Etanercept (1), conventional care and MTX and/or SSZ Infliximab, conventional care ,and MTX and/or SSZ JIA Polyarticular (24)
Infliximab or Infliximab MTX (1) Placebo, with NSAIDs, opioids, oral corticosteroids Polyarticular (74) Pauciarticular (28) Systemic onset (19)

• Kemper A, Coeytaux, R, Sanders G, et al.
  Comparative Effectiveness Review No. 28.
• Available at www.effectivehealthcare.ahrq.gov/dma
  rdsjia.cfm.

24
Results Adding Biologic DMARDs to JIA Treatment
(Methotrexate Permitted)
DMARD (No. of Studies), n Treated, n Control MTX Permitted? Improvement with biologic DMARD when compared with non-DMARD anti-inflammatory treatment Improvement with biologic DMARD when compared with non-DMARD anti-inflammatory treatment Improvement with biologic DMARD when compared with non-DMARD anti-inflammatory treatment
DMARD (No. of Studies), n Treated, n Control MTX Permitted? Symptoms/ Disease Activity Health Status Inflammation (ESR)
Abatacept (1) 60, 62 Yes NSD in Parent/Patient global assessment NSD
Adalimumab (1) 68, 65 Yes NR NR
Anakinra (1) 25, 25 Yes NSD
Infliximab or Infliximab MTX (1) 60, 62 In one comparison NSD NR NR
Tocilizumab (1) 20, 23 No No statistics Similar results No statistics Greater decrease with tocilizumab
Etanercept (2) 32, 31 In one study compared with no MTX NSD compared with MTX
IVIG (3) 32, 38 Yes NSD in 1 study in 1 study NR in 1 study NR NSD in one study NR in two studies

• Kemper A, Coeytaux, R, Sanders G, et al.
  Comparative Effectiveness Review No. 28.
• Available at www.effectivehealthcare.ahrq.gov/dmar
  dsjia.cfm.

25
Summary of Results Adding Biologic DMARDs to JIA
Treatment (Methotrexate Permitted)

• Health status improved when biologic DMARDs were
  added to treatment.
• Strength of Evidence Low
• Improvements in a measure of inflammation, ESR,
  were inconsistent across studies.
• Strength of Evidence Insufficient
• Radiographic evidence of progression was not
  reported.
• Strength of Evidence Insufficient

• Kemper A, Coeytaux, R, Sanders G, et al.
  Comparative Effectiveness Review No. 28.
• Available at www.effectivehealthcare.ahrq.gov/dmar
  dsjia.cfm.

26
Meta-analysis of Discontinuation Trials
ofBiologic DMARDs

• Randomized discontinuation trials include only
  patients who respond to a treatment during a
  run-in phase. These studies evaluate the
  sustainability of treatment effects.
• Data from four discontinuation trials were
  combined in a meta-analysis to determine the risk
  of a disease flare for patients receiving
  biologic DMARDs when compared to those who
  discontinued treatment.
• The trials included only patients who failed to
  improve with methotrexate therapy. Study
  durations were 2 months to 4 years.
• Result The risk of a flare in patients who
  continued treatment was half that of those who
  discontinued treatment (relative risk 0.46, 95
  confidence interval 0.36, 0.63).
• NNT 3 (the number needed to treat NNT to see
  this effect in one patient more than in untreated
  patients is three)
• Strength of Evidence Moderate

• Kemper A, Coeytaux, R, Sanders G, et al.
  Comparative Effectiveness Review No. 28.
• Available at www.effectivehealthcare.ahrq.gov/dmar
  dsjia.cfm.

27
Summary Nonbiologic and Biologic DMARDs Compared
With Conventional Anti-inflammatory Treatments (1
of 2)

• Improved ESR is inconsistently associated with
  treatment, and the evidence is insufficient to
  estimate treatment effects.
• ESR is influenced by factors that may be
  unrelated to treatment.
• Strength of Evidence Insufficient
• The evidence about how both biologic and
  nonbiologic DMARDs affect radiographic evidence
  of disease progression is insufficient to permit
  a conclusion about treatment effects.
• Strength of Evidence Insufficient

• Kemper A, Coeytaux, R, Sanders G, et al.
  Comparative Effectiveness Review No. 28.
• Available at www.effectivehealthcare.ahrq.gov/dmar
  dsjia.cfm.

28
Summary Nonbiologic and Biologic DMARDs Compared
With Conventional Anti-inflammatory Treatments (2
of 2)

• Health status improves with treatment by both
  classes of DMARDs, but statistically significant
  differences from controls are not consistent.
• Strength of Evidence Low
• Overall, the evidence indicates that when
  compared with conventional anti-inflammatory
  treatment alone, adding methotrexate provides
  more consistent improvement in disease activity
  as assessed by physicians.
• Strength of Evidence Moderate
• For patients whose disease responds to a biologic
  DMARD after inadequate response to methotrexate,
  the risk of a flare is reduced by 54 while
  treatment with the biologic DMARD continues.
• Strength of Evidence Moderate

• Kemper A, Coeytaux, R, Sanders G, et al.
  Comparative Effectiveness Review No. 28.
• Available at www.effectivehealthcare.ahrq.gov/dmar
  dsjia.cfm.

29
Head-to-Head Studies of DMARDs in This Review
DMARD 1 DMARD 2 Other Treatments Allowed Study Populations Category at Onset
D-Penicillamine Hydroxychloroquine NSAIDs, prednisone Study 1 JRA Pauciarticular onset (41) Polyarticular onset (31)
D-Penicillamine Hydroxychloroquine NSAIDs, prednisone Study 2 JRA Polyarticular (142) Pauciarticular (11) Systemic (9)
Sulfasalazine Hydroxychloroquine NSAIDs, prednisone JCA Oligoarticular onset (13) Polyarticular onset (23) Systemic onset (3)
Leflunomide Methotrexate NSAIDs, prednisone, intra-articular corticosteroids JRA Polyarticular (94)
Etanercept Infliximab MTX, prednisolone, sulfasalazine, intra-articular corticosteroids, NSAIDs JIA Polyarticular (24)

• Kemper A, Coeytaux, R, Sanders G, et al.
  Comparative Effectiveness Review No. 28.
• Available at www.effectivehealthcare.ahrq.gov/dmar
  dsjia.cfm

30
Results Head-to-Head Comparisons of DMARDs
DMARD ( studies) (together with non-DMARD care) MTX Permitted? Disease Activity (Measurement Tools Used) Health Status Inflammation (ESR) Radiographic Progression
D-Penicillamine vs. Hydroxychloroquine (2) No NSD (AJC, PGA) NR NSD NR
Sulfasalazine vs. Hydroxychloroquine (1) No Similar (PGA, PrGA no statistical analysis) NR Similar (no statistical analysis) NR
Leflunomide vs. Methotrexate (1) No MTX is a comparator NSD (AJC, PGA,PGW ACR Ped30, 50, 70) NSD NSD NR
Etanercept vs. Infliximab (1) Yes NSD (AJC, PGA, PGW, ACR Ped 50, 75) NSD (CHAQ) NSD NR
Abbreviations AJC affected joint count CHAQ Child Health Assessment Questionnaire MTX methotrexate NR not reported NSD no statistically significant difference measured PGA physician global assessment of disease activity PGW physician assessment of general well-being PrGA parent global assessment of well-being Abbreviations AJC affected joint count CHAQ Child Health Assessment Questionnaire MTX methotrexate NR not reported NSD no statistically significant difference measured PGA physician global assessment of disease activity PGW physician assessment of general well-being PrGA parent global assessment of well-being Abbreviations AJC affected joint count CHAQ Child Health Assessment Questionnaire MTX methotrexate NR not reported NSD no statistically significant difference measured PGA physician global assessment of disease activity PGW physician assessment of general well-being PrGA parent global assessment of well-being Abbreviations AJC affected joint count CHAQ Child Health Assessment Questionnaire MTX methotrexate NR not reported NSD no statistically significant difference measured PGA physician global assessment of disease activity PGW physician assessment of general well-being PrGA parent global assessment of well-being Abbreviations AJC affected joint count CHAQ Child Health Assessment Questionnaire MTX methotrexate NR not reported NSD no statistically significant difference measured PGA physician global assessment of disease activity PGW physician assessment of general well-being PrGA parent global assessment of well-being Abbreviations AJC affected joint count CHAQ Child Health Assessment Questionnaire MTX methotrexate NR not reported NSD no statistically significant difference measured PGA physician global assessment of disease activity PGW physician assessment of general well-being PrGA parent global assessment of well-being

• Kemper A, Coeytaux, R, Sanders G, et al.
  Comparative Effectiveness Review No. 28.
• Available at www.effectivehealthcare.ahrq.gov/dmar
  dsjia.cfm.

31
Summary of Results Head-to-Head Comparisons of
DMARDs

• In the few head-to-head comparisons to date,
  disease activity and health status improve to a
  similar degree in both treatment arms.
• Nonbiologics D-penicillamine or sulfasalazine
  versus hydroxychloroquine leflunomide versus
  methotrexate
• Biologics Etanercept versus infliximab
• Strength of Evidence Low
• Larger studies and more precise outcome
  assessments are needed to reveal any
  statistically significant differences that may
  exist.

• Kemper A, Coeytaux, R, Sanders G, et al.
  Comparative Effectiveness Review No. 28.
• Available at www.effectivehealthcare.ahrq.gov/dmar
  dsjia.cfm.

32
Studies Reporting Adverse Effects Associated With
DMARDs

• 13 randomized controlled trials describing 14
  DMARD interventions included a placebo comparison
  and reported adverse effects.
• 914 unique patients were included.
• 151 other publications reported adverse effects
  in patients with JIA treated with DMARDs.
• 4,344 patients were included.
• Patient populations in the reports may overlap
  with randomized controlled trials and with each
  other.
• 2 studies reported cases of malignancies in
  children undergoing DMARD treatment for JIA.
• Patient populations were not identified.

• Kemper A, Coeytaux, R, Sanders G, et al.
  Comparative Effectiveness Review No. 28.
• Available at www.effectivehealthcare.ahrq.gov/dmar
  dsjia.cfm.

33
Adverse Effects Associated With DMARDs

• Both nonbiologic and biologic DMARDs are
  associated with increased risks for adverse
  effects, for example
• Nonbiologic DMARDs
• Nausea, other gastrointestinal upset
• Skin rashes
• Kidney, liver, and other organ toxicity
• Serious infections
• Biologic DMARDs
• Serious infections
• Allergic and hypersensitivity reactions
• TNF-alpha blockers may increase the risk of
  lymphoma and other malignancies

• Kemper A, Coeytaux, R, Sanders G, et al.
  Comparative Effectiveness Review No. 28.
  Available at www.effectivehealthcare.ahrq.gov/dmar
  dsjia.cfm.

34
General Findings of Adverse Event Reports

• There are few direct comparisons of DMARDs in
  children with JIA, and the evidence is
  insufficient to determine if there are
  differential rates of adverse effects between
  drugs or drug classes.
• Adverse event rates may be underestimated by
  clinical trials that exclude patients because of
  adverse effects in a run-in phase.
• The evidence about adverse effects in patients
  with JIA has not been collected or reported
  systematically in patients with JIA.

• Kemper A, Coeytaux, R, Sanders G, et al.
  Comparative Effectiveness Review No. 28.
• Available at www.effectivehealthcare.ahrq.gov/dmar
  dsjia.cfm.

35
Specific Findings About Adverse Effects

• Methotrexate is associated with more laboratory
  abnormalities than are other DMARDs.
• Combination therapy with infliximab and
  methotrexate is associated with more serious
  adverse effects and infections than are other
  DMARDs.
• Two publications that surveyed the world
  literature identified 66 cases of malignancy in
  children with JIA who were treated with
  TNF-ablocking DMARDs.
• In this effectiveness review, 11 cases of
  malignancy were identified in more than 4,000
  patient reports.

• Kemper A, Coeytaux, R, Sanders G, et al.
  Comparative Effectiveness Review No. 28.
• Available at www.effectivehealthcare.ahrq.gov/dmar
  dsjia.cfm.

36
Evaluating JIA Assessment Instruments (1 of 3)

• For this review, seven individual outcomes
  instruments that are used in composite
  assessments were evaluated. They measure
• Disease activity
• Active joint count (AJC)
• Physician global assessment of disease activity
  (PGA)
• Parent global assessment of well-being (PGW)
• Functional Status and Disability
• CHAQ
• Health-Related Quality of Life (QoL)
• Child Health Questionnaire (CHQ)
• Pediatric Quality of Life Inventory (PedsQL)
• Pediatric Quality of Life InventoryRheumatology
  Module (PedsQL-RM)

• Kemper A, Coeytaux, R, Sanders G, et al.
  Comparative Effectiveness Review No. 28.
• Available at www.effectivehealthcare.ahrq.gov/dmar
  dsjia.cfm.

37
Evaluating JIA Assessment Instruments (2 of 3)

• Composite assessments combine results from
  multiple outcome measures to describe disease
  status.
• These assessments are used in both clinical
  research and patient care settings.
• Examples are
• ACR Pediatric response criteria (Peds 30, 50, 70,
  90, etc.)
• This assessment reports the degree of improvement
  from baseline status as a percentage.
• Flare
• A consensus-based definition of remission
• Minimal disease activity

• Kemper A, Coeytaux, R, Sanders G, et al.
  Comparative Effectiveness Review No. 28.
• Available at www.effectivehealthcare.ahrq.gov/dmar
  dsjia.cfm.

38
Evaluating JIA Assessment Instruments (3 of 3)

• There are three test characteristics that are
  used to describe outcome assessment tools. They
  are
• Validity How well an instrument measures what it
  claims to measure examined in comparison to
  other measurements.
• Reliability The consistency of the instrument in
  measuring the construct of interest.
• Reproducibility is the testretest reliability.
• Responsiveness Determined by two properties (1)
  reproducibility and (2) the ability to register
  changes in scores when a patients symptom status
  shows clinically important improvement or
  deterioration.

• Kemper A, Coeytaux, R, Sanders G, et al.
  Comparative Effectiveness Review No. 28.
• Available at www.effectivehealthcare.ahrq.gov/dmar
  dsjia.cfm.

39
Results From Evaluation of JIA Assessment
Instruments (1 of 2)
Instrument No. of Studies, No. of Subjects Validity Reliability Responsive-ness
Active Joint Count 12 8,064 Moderate for functional status Poor for psychosocial aspects of QoL No Data High
Physician Global Assessment of Disease Activity 12 8,668 Moderate correlation with CHAQ QoL measures Disease Activity Measurements No Data Difficult to measure with this tool
Parent/Patient Assessment of Well-being 8 8,182 Moderate correlation with CHAQ Physical aspects of QoL measures Disease -activity measurements Poor correlation with Psychosocial aspects of QoL Moderate Moderate
Abbreviations CHAQ Childhood Health Assessment Questionnaire QoL quality of life Abbreviations CHAQ Childhood Health Assessment Questionnaire QoL quality of life Abbreviations CHAQ Childhood Health Assessment Questionnaire QoL quality of life Abbreviations CHAQ Childhood Health Assessment Questionnaire QoL quality of life Abbreviations CHAQ Childhood Health Assessment Questionnaire QoL quality of life

• Kemper A, Coeytaux, R, Sanders G, et al.
  Comparative Effectiveness Review No. 28.
• Available at www.effectivehealthcare.ahrq.gov/dmar
  dsjia.cfm.

40
Results From Evaluation of JIA Assessment
Instruments (2 of 2)
Instrument No. of Studies, No. of Subjects Validity Reliability Responsiveness
CHAQ 25 13,374 Moderate correlation with Other measures of disease activity Moderate to strong inter-rater reliability Poor Varies depending on baseline severity
CHQ 5 4,687 Moderate correlation with Disease-activity measurements Physical components of CHAQ Poor correlation with Psychosocial domains of CHAQ Moderate to strong inter-rater for physical components Poor in psychosocial domains Poor
Pediatric Quality of Life Inventory (PedsQL and PedsQL- RM) 2 173 Insufficient data Moderate to strong inter-rater for physical components Poor in psychosocial domains Insufficient data

• Kemper A, Coeytaux, R, Sanders G, et al.
  Comparative Effectiveness Review No. 28.
• Available at www.effectivehealthcare.ahrq.gov/dmar
  dsjia.cfm.

41
Evaluating JIA Assessment InstrumentsConclusions
(1 of 2)

• No one instrument or outcomes measure appears to
  be superior in measuring disease activity or
  functional status.
• Reliability and validity are moderate for the
  physical scales of most measures examined but are
  poor in the psychosocial domains.
• The CHAQ is the most frequently studied
  instrument for assessing health/disease status
  for patients with JIA. It shows moderate to high
  validity and reliability.
• CHAQ responsiveness appears to be affected by
  disease subtype and baseline severity.

• Kemper A, Coeytaux, R, Sanders G, et al.
  Comparative Effectiveness Review No. 28.
• Available at www.effectivehealthcare.ahrq.gov/dmar
  dsjia.cfm.

42
Evaluating JIA Assessment InstrumentsConclusions
(2 of 2)

• Current evidence is inadequate to fully
  understand the validity, reliability, and
  responsiveness of the clinical outcomes measures
  that are used in composite assessments of JIA
  (such as the ACR Pediatric).
• An outcome instrument that accurately describes
  all aspects of JIAincluding disease activity,
  functional status, and quality of lifeis needed
  to improve both comparative effectiveness
  research and understanding of the overall impact
  of JIA.

• Kemper A, Coeytaux, R, Sanders G, et al.
  Comparative Effectiveness Review No. 28.
• Available at www.effectivehealthcare.ahrq.gov/dmar
  dsjia.cfm.

43
Conclusions About Benefits and Adverse Effects of
DMARDs (1 of 2)

• Adding methotrexate to treatment with
  anti-inflammatory drugs improves disease
  activity, as scored by physicians.
• Strength of Evidence Moderate
• For children who respond to a biologic DMARD,
  continuing treatment reduces the risk of a flare
  by 56 (NNT 3).
• Strength of Evidence Moderate
• Health status improves with treatment with both
  biologic and nonbiologic DMARDs, but
  statistically significant differences from
  controls are not consistent.
• Strength of Evidence Low
• Evidence is insufficient to state how DMARDs
  affect markers of inflammation and radiographic
  progression of disease.
• Strength of Evidence Insufficient

• Kemper A, Coeytaux, R, Sanders G, et al.
  Comparative Effectiveness Review No. 28.
• Available at www.effectivehealthcare.ahrq.gov/dmar
  dsjia.cfm.

44
Conclusions About Benefits and Adverse Effectsof
DMARDs (2 of 2)

• Few studies of sufficient size make direct
  comparisons of DMARDs in well-characterized
  patient populations thus, it is not clear in
  which circumstances one DMARD will yield better
  outcomes than another.
• No one instrument for measuring disease activity
  or functional status has been identified as
  clearly superior.
• Evidence about the rate, types, and severity of
  adverse effects is too limited to permit
  conclusions about specific risks to patients with
  JIA.

• Kemper A, Coeytaux, R, Sanders G, et al.
  Comparative Effectiveness Review No. 28.
• Available at www.effectivehealthcare.ahrq.gov/dmar
  dsjia.cfm.

45
Knowledge Gaps and Future Research Needs

• The systematic review identified areas where
  evidence about the use of DMARDs to treat JIA is
  limited or absent, including
• The comparative effectiveness of DMARDs for JIA
  has rarely been examined in direct, head-to-head
  studies.
• The effects of DMARDs on measures of inflammation
  and radiographic progression are not established
  in the literature their impact on JIA-associated
  conditions, such as uveitis and macrophage
  activation syndrome, has not been examined.
• The evidence is too limited to understand how
  patient characteristics, disease subtype, and
  variability in the disease process affect
  response to treatment.
• There are few high-quality data about the safety
  of DMARDs. Standardized definitions, measurement,
  and reporting of the adverse effects associated
  with DMARDs are needed, together with long-term
  data collection.

• Kemper A, Coeytaux, R, Sanders G, et al.
  Comparative Effectiveness Review No. 28.
• Available at www.effectivehealthcare.ahrq.gov/dmar
  dsjia.cfm.

46
What To Discuss With Your Patients andTheir
Caregivers

• The role of DMARDs for reducing JIA-related
  symptoms.
• The natural history of JIA and the potential
  benefits and adverse effects of DMARDs.
• The importance of communicating symptoms to you
  and completing any assessment questionnaires you
  use.
• Patient and caregiver preferences and values
  regarding treatment.

• Kemper A, Coeytaux, R, Sanders G, et al.
  Comparative Effectiveness Review No. 28.
• Available at www.effectivehealthcare.ahrq.gov/dmar
  dsjia.cfm.