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Wong KO, Bond K, Homik J, et al. Antinuclear Antibody, Rheumatoid Factor, and Cyclic-Citrullinated Peptide Tests for Evaluating Musculoskeletal Complaints in Children [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2012 Mar. (Comparative Effectiveness Reviews, No. 50.)

Cover of Antinuclear Antibody, Rheumatoid Factor, and Cyclic-Citrullinated Peptide Tests for Evaluating Musculoskeletal Complaints in Children

Antinuclear Antibody, Rheumatoid Factor, and Cyclic-Citrullinated Peptide Tests for Evaluating Musculoskeletal Complaints in Children [Internet].

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Introduction

Musculoskeletal Symptoms

Musculoskeletal (MSK) pain is pain that affects muscles, bones, ligaments, tendons, and nerves.57 Childhood MSK pain is common, with estimated prevalence ranging from 2 to 50 percent.1,10,12 Young children especially may have difficulty characterizing their symptoms, which makes accurate assessment based on the patient history difficult. In addition, the presence of MSK pain can cause anxiety among children and their parents. Concerns about the presence of a serious condition such as arthritis or lupus, which could lead to permanent damage, may prompt consultation with a physician.58

MSK pain can be divided into rheumatic and nonrheumatic causes. Nonrheumatic causes account for the majority of childhood MSK pain and are generally attributable to benign conditions including minor physical trauma (i.e., sprains and strains), overuse, and normal body growth.3,5 In contrast, rheumatic causes, such as an inflammatory arthritis, are much less prevalent and are generally chronic and require early diagnosis and treatment to prevent progression and disability. Common rheumatic causes of childhood MSK pain include pediatric systemic lupus erythematosus (pSLE), juvenile idiopathic arthritis (JIA), spondyloarthropathies (including enthesitis, juvenile anklyosing spondylitis, and reactive arthritis), acute rheumatic fever, and Henoch-Schonlein purpura. However, MSK pain is not universally present in children with JIA (16 percent of children with JIA do not report pain59) and pSLE.

A complete history and physical examination is generally considered to be the best way to make a diagnosis of inflammatory arthritis.3,5 However, the complaint of MSK pain is often nonspecific and when combined with a lack of confidence in the MSK physical examination, can make it difficult to arrive at an accurate diagnosis.3,4 Hence, physicians may request additional laboratory tests. Serological tests such as antinuclear antibody (ANA), rheumatoid factor (RF), and cyclic-citrullinated peptide (CCP) may be ordered by physicians when children and adolescents are suspected of having a rheumatic cause for their MSK pain, despite the fact that the diagnostic performance and usefulness of these tests and the proper interpretation of the results for pediatric populations are largely uncertain.

This comparative effectiveness review provides a synthesis of the evidence on the test performance of ANA, RF, and CCP tests in children and adolescents with undiagnosed MSK pain and on the impact of test results on clinical decisionmaking and clinically important outcomes. The report is intended for a broad audience including: primary care physicians who may consider ordering ANA, RF, or CCP tests in a child with MSK pain; health payers who provide coverage for these tests; and parents or caregivers who would like to know whether these tests can determine if their child does or does not have a particular disease.

Pediatric Systemic Lupus Erythematosus and Juvenile Idiopathic Arthritis

Systemic lupus erythematosus (SLE) is an episodic, multisystem, autoimmune disease characterized by widespread inflammation of blood vessels and connective tissues.60 It is estimated that the incidence of pSLE is 0.3 to 0.9 per 100,000 children per year61 and the prevalence is 3.3 to 8.8 per 100,000.62 The onset of pSLE is rare before 5 years of age and uncommon before adolescence, after which the rates of occurrence stabilize.60 The diagnosis of pSLE is generally based on the classification criteria of the American College of Rheumatology (ACR)55,63 which include specific signs, symptoms, and laboratory tests, including a positive ANA (see Appendix A). Left untreated, SLE is often progressive and can be fatal.64 As awareness of the occurrence of pSLE has increased, early diagnosis has become more common60 and rapid introduction of effective immunosuppressive treatment has lead to improved outcomes.64

JIA is the most common chronic inflammatory disease of children affecting approximately 1 in 1,000 children.65,66 Classification criteria developed by the International League of Associations for Rheumatology (ILAR)67 are used worldwide to provide consistency across clinical research studies. The ILAR criteria have supplanted earlier criteria of the ACR68 for the classification of juvenile rheumatoid arthritis (JRA) and the European League Against Rheumatism (EULAR)69 for the classification of juvenile chronic arthritis (JCA). To maintain consistency, the acronym JIA will be used to represent JIA, JRA, and JCA throughout this report.

It is important to note that in all three of the published criteria patients are classified based on characteristic symptoms and signs, including the presence of objective arthritis for a minimum of 6 to 12 weeks. In spite of significant overlap, the classification criteria vary in terms of how the presence of RF is addressed. In the ILAR criteria, the presence of a positive RF on two occasions excludes five of the seven subtypes of JIA. In the EULAR criteria, a positive RF changes the classification from JCA to JRA. In the ACR criteria, RF is not considered at all in the classification. Therefore, depending on the criteria being used, the reported prevalence of RF will be different.

In adults with suspected rheumatoid arthritis, tests for RF70 and, more recently, CCP antibodies are frequently requested as part of the diagnostic work-up.70,71 Although there is less evidence supporting the usefulness of these tests in children, they are often ordered as part of the diagnostic evaluation of a child suspected to have JIA.

Without effective treatment, JIA can progress and cause damage to cartilage, bone, and soft tissues, and may lead to severe disability, functional loss, and, in rare cases, organ failure and death.66,71 Although early diagnosis and treatment may reduce the progression of the disease and induce remission, only a minority of patients experience complete resolution of JIA prior to adulthood.66

Antinuclear Antibody, Rheumatoid Factor, and Cyclic-Citrullinated Peptide Tests

The immune system is a defense system that fends off foreign invaders including bacteria and viruses. However, the immune system may malfunction and mislabel one’s own body cells as foreign particles, and this may elicit an attack response. When the immune system attacks one’s own body cells, it produces autoantibodies that target specific antigens naturally found in the body. ANA, RF, and CCP are examples of the autoantibodies specifically targeting the nuclear particles, the fragment crystallizable (Fc) portion of the immunoglobulin (Ig) G, and CCPs, respectively. An ANA test is often used to screen for autoimmune conditions,74 especially when a diagnosis of SLE is suspected.

The gold standard for ANA testing is the indirect immunofluorescence (IIF) ANA test, which involves incubation of serial dilutions of the patient’s sera with substrate cells, usually human epithelial tumor line (HEp-2).72 If antibody to nuclear elements is present, binding to the substrate will be detected by fluorescein-conjugated anti-human Ig, which attaches to the antibody and is visually inspected using a fluorescence microscope. The assessment of fluorescence is based on the interpretation of this inspection and, as a result, may be somewhat subjective and vary from one laboratory to another. Each laboratory determines the cutoff used for a positive test, and as a result, titers from one laboratory cannot be compared with another. Research has shown that using a high titer ANA does not increase the positive predictive value for connective tissue disease.73

The detection of antibodies may also be assessed using enzyme immunoassay (EIA). In EIA, an antigen is affixed to a surface, and then the patient serum sample is applied over the surface so ANA, if present, can bind to the antigen. EIA methods and expected results vary among manufacturers because there is no agreed standard for the antigen preparations that should be included or for the concentration(s) of the relevant antigen preparations.74 Results of studies that compare IIF and EIA for ANA have been inconsistent, with some showing poor correlation,26 and others demonstrating consistency.74

RFs are Ig that react specifically with the Fc fragment of the IgG molecule. RFs are found in all Ig isotypes (i.e., IgA, IgG, IgD, IgM, and IgE), but the 19S IgM-RF is the most frequently used isotype for rheumatic disease testing, including arthritis.75 The presence of RFs is typically determined by agglutination assays, nephelometry, or EIA. The agglutination assay method mainly employs latex beads as a substrate to which human or rabbit IgG is bound. Nephelometry is a photometric test in which complexes formed between the IgG and RF are detected by light scattering, which is dependent upon the concentration of those immune complexes. Latex agglutination and nephelometry only measure 19S IgM-RF, whereas EIAs have been designed to measure the various RF isotypes.75

The CCP test detects the presence of autoantibodies to citrullinated peptides in serum.76 Abnormal citrullination of various peptides is present in a variety of human diseases, including rheumatoid arthritis, psoriasis, and multiple sclerosis. However, the formation of antibodies to citrullinated peptides seems to be specific for adult patients with rheumatoid arthritis.71 Anti-CCP2 (a second-generation assay) is currently the most widely used anti-CCP assay.71 Anti-CCP antibodies and anti-citrullinated filaggrin antibodies are locally produced in inflamed joints, and citrullinated fibrin is found in the synovia of patients with rheumatoid arthritis.77 In adults, a CCP test is usually ordered along with a RF test when evaluating a patient with inflammatory arthritis and when rheumatoid arthritis is considered on the differential diagnosis. The utility of the CCP test in pediatric rheumatic conditions is not clear.

Objectives of This Evidence Report

In order to better understand how the ANA, RF, and CCP tests perform in the clinical setting in which a child with MSK pain will be seen, it is important to know the prevalence of MSK complaints (including MSK pain and joint swelling) in children who do not have JIA and pSLE. It is also important to be aware of the rate of false positives for these tests (i.e., the proportion of otherwise healthy children who have a positive ANA, RF, or CCP). The appropriate interpretation of test performance also requires an understanding of the disease progression and changes in signs and symptoms in children with MSK pain who may or may not also have JIA or pSLE.

In addition to providing this background information, the objectives of this report were to assess the test performance of ANA, RF, and CCP tests in children and adolescents with undiagnosed MSK pain and/or joint swelling compared with clinical diagnoses of pSLE and JIA; to explore the difference in test performance for accuracy modifiers including age, sex, race or ethnicity, comorbidities, and recent infections; and, to evaluate the impact of test results on clinical decisionmaking and clinically important outcomes such as referrals, ordering of additional tests, clinical management, and anxiety experienced by children and parents. We addressed the following Key Questions (KQs):

Key Questions

KQ 1. Prevalence and Incidence

KQ 1.1. In children and adolescents aged 18 years or less, what is the incidence and prevalence of undiagnosed MSK complaints?

KQ 1.2. In healthy children and adolescents aged 18 years or less, what is the incidence of positive test results in ANA, RF, and CCP?

KQ 2. Natural History

KQ 2.1. What proportion of children and adolescents aged 18 years or less with undiagnosed MSK pain is due to non-inflammatory etiologies?

KQ 2.2. What proportion of children and adolescents aged 18 years or less with undiagnosed MSK pain is due to inflammatory etiologies?

KQ 2.3. What proportion of children and adolescents aged 18 years or less experiences symptom resolution or recurrence?

KQ 3. Diagnostic Performance

KQ 3.1. In children and adolescents aged 18 years or less with undiagnosed MSK pain and/or joint swelling, what is the test performance (sensitivity, specificity, and positive and negative predictive values) of ANA for pSLE compared with a clinical diagnosis?

KQ 3.2. In children and adolescents aged 18 years or less with undiagnosed MSK pain and/or joint swelling, what is the test performance (sensitivity, specificity, and positive and negative predictive values) of ANA for JIA compared with a clinical diagnosis?

KQ 3.3. In children and adolescents aged 18 years or less with undiagnosed MSK pain and/or joint swelling, what is the test performance (sensitivity, specificity, and positive and negative predictive values) of RF for pSLE compared with a clinical diagnosis?

KQ 3.4. In children and adolescents aged 18 years or less with undiagnosed MSK pain and/or joint swelling, what is the test performance (sensitivity, specificity, and positive and negative predictive values) of RF for JIA compared with a clinical diagnosis?

KQ 3.5. In children and adolescents aged 18 years or less with undiagnosed MSK pain and/or joint swelling, what is the test performance (sensitivity, specificity, and positive and negative predictive values) of CCP for pSLE compared with a clinical diagnosis?

KQ 3.6. In children and adolescents aged 18 years or less with undiagnosed MSK pain and/or joint swelling, what is the test performance (sensitivity, specificity, and positive and negative predictive values) of CCP for JIA compared with a clinical diagnosis?

KQ 4. Accuracy Modifiers

KQ 4.1. In children and adolescents aged 18 years or less with undiagnosed MSK pain and/or joint swelling, 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 compared with a clinical diagnosis?

KQ 4.2. In children and adolescents aged 18 years or less with undiagnosed MSK pain and/or joint swelling, 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 JIA compared with a clinical diagnosis?

KQ 5. Clinical Impacts of Test Results

KQ 5. In children and adolescents aged 18 years or less with undiagnosed MSK pain and/or joint swelling, 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?

Analytic Framework

The analytic framework (Figure 1) depicts the five KQs within the context of the pediatric population (≤18 years) with MSK complaints. In general, the figure illustrates how diagnostic accuracy may be modified by demographic and clinical factors. It also indicates how test results may influence four important areas including referral to specialists, additional tests, decisions regarding clinical management, and parents’ and patients’ level of anxiety. The epidemiology and natural history of the targeted rheumatic conditions are described independently of the test results.

Figure 1 depicts the five key questions of this report which aimed to answer questions on the use of antibody testing for musculoskeletal conditions in pediatric populations (≤ 18 years). The flow diagram begins on the left hand side of the page and identifies how children with undiagnosed MSK pain related to the epidemiology and natural history of disease. It then links how test results may be influenced by four areas including referral to specialists, additional tests, decisions regarding clinical management, and parents’ and patient’s level of anxiety. Finally, it demonstrates how diagnostic accuracy may be modified by demographic and clinical factors.

Figure 1

Analytic framework for antibody testing for MSK complaints in pediatric populations (≤18 years). ANA = antinuclear antibody; CCP = cyclic-citrullinated peptide; JIA = juvenile idiopathic arthritis; MSK = musculoskeletal; SLE = systemic lupus erythematosus; (more...)

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