Antinuclear Antibody, Rheumatoid Factor, and Cyclic-Citrullinated Peptide Testing for the Evaluation of Musculoskeletal Complaints in Children

1
Antinuclear Antibody, Rheumatoid Factor, and
Cyclic-Citrullinated Peptide Testing for the
Evaluation of Musculoskeletal Complaintsin
Children

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

2
Outline of Material

• Background
• Comparative Effectiveness Review (CER)
  Development
• Clinical Questions Addressed by the CER
• Report Findings
• Conclusion Statements
• Gaps in Knowledge
• What To Discuss With Your Patients

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Background Musculoskeletal Pain

• Musculoskeletal (MSK) pain is pain that affects
  muscles, bones, ligaments, tendons, or nerves.
• MSK pain is common in childhood.
• Published prevalence estimates range from 2 up to
  50 percent.
• Assessment is based on patient history and
  physical examination. Assessment may be
  complicated by children having difficulty
  characterizing their symptoms.
• The presence of specific clinical characteristics
  such as morning stiffness, joint swelling, malar
  rash, and cytopenias may lead to a high suspicion
  of a pediatric rheumatic condition.

Wong KO, Bond K, Homik J, et al. Comparative
Effectiveness Review No. 50. Available at
www.effectivehealthcare.ahrq.gov/anatest.cfm.
4
Background Causes of Musculoskeletal Pain

• Nonrheumatic Causes
• Account for nearly all childhood musculoskeletal
  (MSK) pain.
• Generally attributable to sprains, strains,
  overuse, and normal body growth.
• Rheumatic Causes
• Rheumatic MSK pain is much less prevalent than
  nonrheumatic MSK pain.
• Generally chronic and requires early diagnosis
  and treatment to prevent progression and
  long-term disability.
• Rheumatic causes may include juvenile idiopathic
  arthritis (JIA), pediatric systemic lupus
  erythematosus (pSLE), spondyloarthropathies
  (including enthesitis-related arthritis, juvenile
  ankylosing spondylitis, or reactive arthritis),
  acute rheumatic fever, or Henoch-Schönlein
  purpura.

Wong KO, Bond K, Homik J, et al. Comparative
Effectiveness Review No. 50. Available at
www.effectivehealthcare.ahrq.gov/anatest.cfm.
5
Background Juvenile Idiopathic Arthritis

• Most common chronic inflammatory disease of
  children, with a prevalence of 1 per 1,000
  children.
• Musculoskeletal pain is not universally present
  in children with JIA. Sixteen percent of children
  with juvenile idiopathic arthritis (JIA) do not
  report pain.
• Without effective treatment, JIA can progress and
  cause damage to cartilage, bone, and soft tissues
  and may lead to severe disability and functional
  loss and, in rare cases, to organ failure and
  death.
• Early diagnosis and treatment may reduce the
  progression of the disease and induce remission.
• Only a minority of patients will experience
  complete resolution of JIA symptoms before
  adulthood.

Wong KO, Bond K, Homik J, et al. Comparative
Effectiveness Review No. 50. Available at
www.effectivehealthcare.ahrq.gov/anatest.cfm.
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Background Pediatric Systemic Lupus Erythematosus

• An episodic, multisystem, autoimmune disease.
• Widespread inflammation of blood vessels,
  connective tissues, and organs.
• Estimated incidence of 0.30.9 per 100,000
  children per year estimated prevalence of
  3.38.8 per 100,000 children.
• Onset is rare before 5 years of age and uncommon
  before adolescence.
• Left untreated, pediatric systemic lupus
  erythematosis is often progressive and can be
  fatal.
• Early diagnosis and rapid introduction of
  effective immunosuppressive treatment have led to
  improved outcomes.

Wong KO, Bond K, Homik J, et al. Comparative
Effectiveness Review No. 50. Available at
www.effectivehealthcare.ahrq.gov/anatest.cfm.
7
Background Using Serological Tests To Diagnose
Musculoskeletal Pain

• The diagnosis of inflammatory arthritis is based
  solely on a patient history and physical
  examination.
• An accurate diagnosis of pediatric
  musculoskeletal (MSK) pain may be complicated by
  a nonspecific pain pattern or lack of confidence
  in the MSK physical examination.
• Serological tests such as antinuclear antibody,
  rheumatoid factor, and cyclic-citrullinated
  peptide may be ordered when children and
  adolescents are suspected of having a rheumatic
  cause for their MSK despite uncertainties about
• their diagnostic performance,
• their usefulness, and
• their proper interpretation for pediatric
  populations.

Wong KO, Bond K, Homik J, et al. Comparative
Effectiveness Review No. 50. Available at
www.effectivehealthcare.ahrq.gov/anatest.cfm.
8
Background Antinuclear Antibody Test

• Can be used to screen for specific autoimmune
  conditions, such as systemic lupus erythematosus,
  Sjögrens syndrome, and systemic sclerosis.
• Techniques used for antinuclear antibody (ANA)
  testing include indirect immunofluorescence (IIF)
  and enzyme immunoassay (EIA, ELISA).
• Neither test has been standardized in children
  methods and interpretation vary by manufacturer
  and testing laboratory.
• Results of studies that compare the use of IIF
  and EIA for ANA testing have been inconsistent,
  with some showing poor correlation and others
  demonstrating consistency.

Wong KO, Bond K, Homik J, et al. Comparative
Effectiveness Review No. 50. Available at
www.effectivehealthcare.ahrq.gov/anatest.cfm.
9
Background Rheumatoid Factor Test

• Rheumatoid factors (RFs) are specific
  autoantibodies that react with the Fc fragment of
  the immunoglobulin (Ig)G molecule.
• RFs serve as the basis of sensitive and specific
  tests for adult rheumatoid arthritis.
• 19S IgM-RF is the isotope most frequently used to
  test for rheumatoid arthritis.
• The presence of RF is typically detected by
  agglutination assays, nephelometry, or enzyme
  immunoassay.
• RFs are not prevalent in pediatric juvenile
  idiopathic arthritis (lt10 of children with
  juvenile idiopathic arthritis have a positive RF
  test result).

Wong KO, Bond K, Homik J, et al. Comparative
Effectiveness Review No. 50. Available at
www.effectivehealthcare.ahrq.gov/anatest.cfm.
10
Background Cyclic-Citrullinated Peptide Antibody
Test

• This test detects the presence of autoantibodies
  to citrullinated peptides in serum.
• Formation of antibodies to cyclic-citrullinated
  peptide (CCP) seems to be specific for adult
  patients with rheumatoid arthritis.
• In adults, a CCP antibody test is usually ordered
  along with a rheumatoid factor test when
  evaluating a patient with inflammatory arthritis.
  
• The prevalence and utility of a positive CCP
  antibody test in children with juvenile
  idiopathic arthritis or with associated rheumatic
  conditions is not clear.

Wong KO, Bond K, Homik J, et al. Comparative
Effectiveness Review No. 50. Available at
www.effectivehealthcare.ahrq.gov/anatest.cfm.
11
Agency for Healthcare Research and Quality
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 Clinician
  Research Summary and the full report, with
  references for included and excluded studies, are
  available at www.effectivehealthcare.ahrq.
  gov/anatest.cfm.

Wong KO, Bond K, Homik J, et al. Comparative
Effectiveness Review No. 50. Available at
www.effectivehealthcare.ahrq.gov/anatest.cfm.
12
Clinical Questions Addressed by the CER (1 of 3)

• Key Question 1 Prevalence and incidence
• In children and adolescents aged 18 years or
  younger, what is the incidence and prevalence of
  undiagnosed musculoskeletal (MSK) complaints?
• In healthy children and adolescents aged 18 years
  or younger, what is the incidence of positive
  test results for antinuclear antibody, rheumatoid
  factor, and cyclic-citrullinated peptide?
• Key Question 2 Natural history
• What proportion of children and adolescents aged
  18 years or younger with undiagnosed MSK pain
  have pain due to noninflammatory etiologies?
• What proportion of children and adolescents aged
  18 years or younger with undiagnosed MSK pain
  have pain due to inflammatory etiologies?
• What proportion of children and adolescents aged
  18 years or younger experience symptom resolution
  or recurrence?

Wong KO, Bond K, Homik J, et al. Comparative
Effectiveness Review No. 50. Available at
www.effectivehealthcare.ahrq.gov/anatest.cfm.
13
Clinical Questions Addressed by the CER (2 of 3)

• Key Question 3 Diagnostic Performance
• In children and adolescents aged 18 years or
  younger with undiagnosed musculoskeletal pain,
  what is the test performance (sensitivity,
  specificity, and positive and negative predictive
  values) of
• ANA for JIA when compared with a clinical
  diagnosis?
• ANA for pSLE when compared with a clinical
  diagnosis?
• RF for pSLE when compared with a clinical
  diagnosis?
• RF for JIA when compared with a clinical
  diagnosis?
• CCP for pSLE when compared with a clinical
  diagnosis?
• CCP for JIA when compared with a clinical
  diagnosis?

Wong KO, Bond K, Homik J, et al. Comparative
Effectiveness Review No. 50. Available at
www.effectivehealthcare.ahrq.gov/anatest.cfm.
14
Clinical Questions Addressed by the CER (3 of 3)

• Key Question 4. Accuracy Modifiers
• In children and adolescents aged 18 years or
  younger with undiagnosed MSK pain, do age, sex,
  race/ethnicity, comorbidities, and recent
  infections modify the diagnostic performance
  (sensitivity, specificity, and positive and
  negative predictive values) of ANA, RF, and CCP
  for pSLE or JIA when compared with a clinical
  diagnosis?
• Key Question 5. Clinical Impacts of Test Results
• In children and adolescents aged 18 years or
  younger with undiagnosed MSK pain, do ANA, RF,
  and CCP test results affect referral decisions,
  additional tests ordered, clinical management,
  and patient and parent anxiety due to the
  clinical uncertainty and additional tests?

Wong KO, Bond K, Homik J, et al. Comparative
Effectiveness Review No. 50. Available at
www.effectivehealthcare.ahrq.gov/anatest.cfm.
15
Rating the Strength of Evidence From the
Comparative Effectiveness Review

• 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.
Wong KO, Bond K, Homik J, et al. Comparative
Effectiveness Review No. 50. Available at
www.effectivehealthcare.ahrq.gov/anatest.cfm.
16
Report Findings Prevalence of Musculoskeletal
Pain Among Healthy Children

• Prevalence estimates of musculoskeletal (MSK)
  pain ranged from 2 to 52 percent, varying with
  age and sex.
• Up to 30 percent of children and adolescents
  report episodes of pain lasting more than 6
  months.
• In childhood, the prevalence of JIA was 1 per
  1,000, and the prevalence of pSLE was 8.8 per
  100,000.
• In children with MSK pain, 97 percent of cases
  result from noninflammatory causes.
• Of the 3.3 percent of pediatric cases of MSK pain
  that result from inflammatory causes 2.5 percent
  result from toxic synovitis and 0.8 percent
  result from inflammatory arthritides.
• Recurrence rates of pediatric MSK pain are high
  and vary by body site. Age, sex, headache,
  abdominal pain, and combined pain are predictors
  of recurrence for nontraumatic MSK pain.

Wong KO, Bond K, Homik J, et al. Comparative
Effectiveness Review No. 50. Available at
www.effectivehealthcare.ahrq.gov/anatest.cfm.
17
Report Findings Etiology of Musculoskeletal Pain
Among Healthy Children
Cause Prevalence ()a
Physical trauma 44
Overuse 24
Osteochondroses 10
Hypermobility 3
Growing pain 4
Viral infection 4
a Prevalence of these etiologies vary with age.
Wong KO, Bond K, Homik J, et al. Comparative
Effectiveness Review No. 50. Available at
www.effectivehealthcare.ahrq.gov/anatest.cfm.
18
Report Findings Prevalence of Positive
Serological Test Results Among Healthy Children

• The prevalence of positive tests results in
  healthy children was as follows
• Antinuclear antibody 018 percent (median 3)
• Rheumatoid factor approximately 3 percent
  (median 0)
• Cyclic-citrullinated peptide antibody 00.6
  percent (median lt1)

Wong KO, Bond K, Homik J, et al. Comparative
Effectiveness Review No. 50. Available at
www.effectivehealthcare.ahrq.gov/anatest.cfm.
19
Report Findings Clinical Bottom Line Regarding
the Utility of Clinical Testing

• The RF test may have a potential application only
  in confirming a suspected clinical diagnosis of
  JIA (i.e., a diagnosis based on a comprehensive
  patient history and physical examination).
• One retrospective cohort study examined records
  of 437 pediatric hospital patients with MSK pain
  who had an RF test. They found very limited
  utility of the RF test for diagnosing JIA with a
  positive predictive value of 45 percent and a
  negative predictive value of 77 percent
  (sensitivity 4.8 specificity 98).
• Strength of Evidence Low
• The evidence is insufficient to evaluate the
  sensitivity and specificity of most test-disease
  combinations.
• Thus, the test performance of the ANA or CCP
  antibody tests in children with undiagnosed MSK
  pain is unknown, as is the performance of the RF
  test for diagnosing pSLE.
• Strength of Evidence Insufficient

Wong KO, Bond K, Homik J, et al. Comparative
Effectiveness Review No. 50. Available at
www.effectivehealthcare.ahrq.gov/anatest.cfm.
20
Conclusions (1 of 2)

• The prevalence of MSK pain varies with age and
  sex.
• Nearly all MSK pain in children (97) results
  from noninflammatory causes.
• A review of the patients history and performance
  of an MSK examination remain the most appropriate
  methods for diagnosing rheumatic etiologies of
  pediatric MSK pain in a timely fashion.
• There is low-strength evidence for the utility of
  RF in diagnosing JIA in children with undiagnosed
  MSK pain (sensitivity 4.8, specificity 98).
  
• The low sensitivity suggests that diagnosis of
  JIA should not rely on serological tests alone,
  but may be combined with thorough clinical
  assessment that suggests the presence of
  inflammatory arthritis.
• The use of laboratory tests as diagnostic
  measures or for broad screening of pediatric
  rheumatic conditions remains unsupported.

Wong KO, Bond K, Homik J, et al. Comparative
Effectiveness Review No. 50. Available at
www.effectivehealthcare.ahrq.gov/anatest.cfm.
21
Conclusions (2 of 2)

• Methodological limitations of existing studies
  prevent further assessment of the sensitivity and
  specificity of the ANA, RF, and CCP serological
  tests.
• These serological tests have potential use only
  as an adjunct to a clinical assessment that
  suggests the presence of an inflammatory
  arthritis or connective tissue disease.

Wong KO, Bond K, Homik J, et al. Comparative
Effectiveness Review No. 50. Available at
www.effectivehealthcare.ahrq.gov/anatest.cfm.
22
Gaps in Knowledge

• No studies examined clinically important outcomes
  that may affect quality of life and psychosocial
  well-being.
• The impact of the ANA, RF, and CCP test results
  on referrals, ordering of additional tests, and
  patient management.
• Increase in family anxiety levels due to positive
  test results, faulty diagnosis of a rheumatic
  condition, and referral to a pediatric
  subspecialist.
• Studies examined children with known disease
  status rather than a spectrum of children with
  undiagnosed MSK symptoms, thus providing evidence
  regarding test performance that likely
  overestimates both sensitivity and specificity
  values.
• No studies addressed the patient or clinical
  characteristics that could modify the accuracy of
  these serological tests including age, sex, race,
  history of recent infections, and presence of
  other characteristics other than MSK pain.

Wong KO, Bond K, Homik J, et al. Comparative
Effectiveness Review No. 50. Available at
www.effectivehealthcare.ahrq.gov/anatest.cfm.
23
What To Discuss With Your Patients

• That musculoskeletal pain is common and may recur
• That inflammatory causes are found in only 3
  percent of children
• The important role of a complete patient history
  and physical examination in diagnosing a
  rheumatic cause of musculoskeletal pain

Wong KO, Bond K, Homik J, et al. Comparative
Effectiveness Review No. 50. Available at
www.effectivehealthcare.ahrq.gov/anatest.cfm.