Rheumatoid Arthritis - RA

  • Diagnosis
  • Monitoring
  • Pharmacogenetics
  • Background
  • Pediatrics
  • Lab Tests
  • References
  • Related Content

Indications for Testing

  • Persistent joint pain with early morning stiffness

Criteria for Diagnosis

Laboratory Testing

  • No single test confirms diagnosis
  • Nonspecific testing
    • CBC with differential – most helpful to rule out infection
    • C-reactive protein (CRP)
  • Specific testing
    • Rheumatoid factor (RF), IgM
      • Prevalence
        • Negative in 30% of early onset RA
        • Present in 5-10% of healthy individuals – prevalence increases with age
        • False positive results in numerous infections (eg, hepatitis C virus [HCV])  or autoimmune disorders (eg, systemic lupus erythematosus [SLE])
        • Sensitivity ranges from 60-90%, specificity ~85% for RA (Ingegnoli, 2014)
      • Presence of abnormal levels of all three RF isotypes has a specificity of 99% for RA
    • Anti-cyclic citrullinated peptide IgG antibody (CCP)
      • Better specificity than RF – 93-95% specific (Sun, 2014)
      • Complements RF, especially in early disease
        • CCP can be detected in up to 38.4% of IgM-RF-negative serum (more specific for early RA)
      • Linked to erosive disease
      • Presence of  CCP and RF isotypes may predict and predate the development of RA (Ingegnoli, 2014; originally described by Rantapää-Dahlqvist, 2003)
      • Elevated titers support the diagnosis of RA
        • Consider using instead of RF when pretest probability for RA is moderate
        • Preferred test for patients with confounding factors that increase frequency of false-positive RF (eg, HCV, SLE, cryoglobulinemia)
    • RF isotypes
      • Combination of RF IgA and CCP may predict radiological damage in RA
      • When screening for RA, IgM-RF and CCP assays are superior to other RF isotypes
    • Synovial fluid analysis from joint aspiration

Imaging Studies

  • Plain x-ray of involved joints may be helpful if erosions are present (defined as cortical break by EULAR, 2013)

Differential Diagnosis

  • C-reactive protein (CRP) may be useful in monitoring disease progression
  • Usefulness of rheumatoid factor (RF) or anti-cyclic citrullinated peptide IgG antibody (CCP) in monitoring therapy is limited
  • For patients taking disease-modifying antirheumatic drugs (DMARDS)
    • Routine laboratory tests including CBC, creatinine, liver transaminases
  • X-ray evaluation for new erosions
  • Compliance monitoring for leflunomide, gold, and other commonly used medications may be appropriate; contact laboratory to discuss available test options​
  • Thiopurine drugs may be used in treatment of RA
    • Thiopurine prodrugs are metabolized via thiopurine methyltransferase (TPMT) enzymatic activity
    • Deficiency of TPMT predicts hematopoietic toxicity after thiopurine treatment
    • Testing to determine activity level may be helpful in dosing thiopurine drugs and help avert bone marrow suppression
      • For deficient activity, dose reduction of 80-90% may be required
      • For intermediate activity, dose reduction of 20-50% may be required
    • Genotype for TPMT cannot be inferred from TPMT activity (phenotype)
    • TPMT phenotype testing does not replace need for clinical monitoring of patients treated with thiopurine drugs
      • Phenotype testing should not be requested for patients currently treated with thiopurine drugs; results will be falsely low
      • Current TPMT phenotype may not reflect future TPMT phenotype, particularly in patients who received blood transfusions within 30-60 days of testing
  • Adalimumab activity and neutralizing antibody testing
    • Adalimumab is a subcutaneous TNF-α inhibitor drug used to treat the symptoms of and prevent the progression of active RA
    • ~1/3 of patients do not respond to induction therapy (primary nonresponse), and among initial responders, response wanes over time in ~20-60% of patients (secondary nonresponse) due to antibody formation
    • Antibody testing may aid in therapy decision-making process
  • Infliximab activity and neutralizing antibody testing
    • Infliximab is a TNF-α inhibitor drug used for the treatment of patients with inflammatory diseases such as RA and psoriasis
    • Up to 30% of patients receiving the recommended dosage of infliximab have primary response failure
      • Necessitates increased infliximab dosage or shortening of the dosage interval
    • Up to 50% of patients treated with infliximab have secondary response failure due to anti-infliximab antibodies
      • Necessitates change to a different TNF-α inhibitor drug
  • Antibody testing may aid in therapy decision-making process

Rheumatoid arthritis (RA) is an autoimmune disorder with progressive and destructive polyarthritis and is the most common adult inflammatory arthritis worldwide.

Epidemiology

  • Incidence – 40/100,000 worldwide (Kourilovitch, 2014)
  • Age – peaks in 30s-40s
  • Sex – M<F, 1:2-3

Genetics

  • 30% concordance for twins
  • 80% of Caucasians with RA express HLA-DRB1 or HLA-DRB4 subtypes

Risk Factors

  • Family history
  • Smoking
  • Silicate exposure

Pathophysiology

  • Joint damage begins with proliferation of synovial macrophages and fibroblasts
  • Neovascularization follows
  • Inflamed synovial tissue grows irregularly, forming pannus tissue
  • Pannus invades cartilage and bone with joint destruction

Clinical Presentation

  • Constitutional manifestations
    • Weakness
    • Fatigue
    • Anorexia
    • Fever – typically low-grade
  • Joints – polyarticular disease
    • Pain and stiffness in multiple joints
      • Wrist and proximal interphalangeal (PIP) and metacarpophalangeal (MCP) joints most commonly affected
      • Puffy and warm joints
  • Extra-articular involvement
    • Hematological – anemia
    • Joint and spine disease
      • Cervical spine disease with resultant instability of atlas on axis
      • Joint deformities – swan neck, boutonnière
    • Ocular disease – episcleritis, scleritis, keratoconjunctivitis sicca
    • Cardiopulmonary disease
      • Interstitial fibrosis
      • Lung nodules with cavitation
      • Pericarditis – may occur in 1/3 of patients
      • Pleuritis
    • Rheumatoid nodules – may resolve
    • Renal – glomerulonephritis
    • Vasculitis – small- and medium-size vessel disease predominates
      • May have neuropathy associated with vasculitis
  • Complications
    • Cancer
    • Cervical atlantoaxial dislocation
    • Appearance of early cardiovascular disease – average 10 years earlier than population predictions
    • Serious infections – rate is increased compared to general population
    • Pulmonary interstitial disease

Clinical Background

Juvenile idiopathic arthritis (JIA) is the most common type of arthritis in the pediatric population and begins <16 years.

Epidemiology

  • Incidence – 2-20/100,000
  • Age – onset <16 years

Clinical Presentation

  • International League of Associations for Rheumatology (ILAR) classifies JIA into 7 diseases (clinical subtypes) based on symptoms and number of joints affected
  • Clinical subtypes
    • Oligoarthritis
      • Persistent
      • Extended
    • Polyarthritis
      • RF positive
      • RF negative
    • Systemic arthritis (formally called Still disease)
    • Psoriatic arthritis
    • Enthesitis-related arthritis
  • Symptoms
    • Morning stiffness and pain
    • Swelling and tenderness in the joints, limping
    • Fever, rash, weight loss
    • Fatigue or irritability
    • Inflammation of the eyes – redness, pain, blurred vision, uveitis

Diagnosis

Indications for Testing

  • Persistent joint pain with early morning stiffness

Criteria for Diagnosis

  • Criteria for diagnosis of rheumatoid arthritis – see adult criteria

Laboratory Testing

  • No single test confirms diagnosis
  • Nonspecific testing
    • CBC with differential – most helpful to rule out infection
    • C-reactive protein (CRP)
    • Antinuclear antibodies (ANA) – may be positive
  • Specific testing
    • Rheumatoid factor (RF) IgM
      • Less likely to be positive than in adults
    • Anti-cyclic citrullinated peptide IgG antibody (CCP)
      • Associated with RF-positive polyarticular course of JIA
      • Testing of this antibody is frequently negative; serology most likely positive in polyarticular arthritis form
    • Rheumatoid factor isotypes
      • Combination of RF IgA and CCP may predict radiological damage in RA
    • Synovial fluid analysis from joint aspiration

Imaging Studies

  • Plain x-ray of involved joints may be helpful if local destruction is discovered

Differential Diagnosis

Indications for Laboratory Testing

Tests generally appear in the order most useful for common clinical situations.
Click on number for test-specific information in the ARUP Laboratory Test Directory

Rheumatoid Arthritis Panel 2003277
Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay/Immunoturbidimetry

Rheumatoid Arthritis Panel with Reflex to Rheumatoid Factors, IgA, IgG, and IgM by ELISA 2003278
Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay/Quantitative Immunoturbidimetry/Quantitative Enzyme-Linked Immunosorbent Assay

Thiopurine Methyltransferase, RBC 0092066
Method: Enzymatic/Quantitative Liquid Chromatography-Tandem Mass Spectrometry

Limitations

Does not replace clinical monitoring

Genotype cannot be inferred from TPMT activity (phenotype)

TPMT inhibitors may contribute to false-low results

TPMT activity should be assessed prior to treatment with thiopurine drugs

Blood transfusion within 30 days will reflect donor status

Thiopurine Drug Metabolites 2011134
Method: Quantitative Liquid Chromatography/Tandem Mass Spectrometry

Limitations

Limit of quantification (LOQ)

  • LOQ – 12.5 pmol/8 x 108 RBC (6-TGN)
  • LOQ – 325 pmol/ 8 x 108 RBC (6-methyl mercaptopurine nucleotide [6-MMPN])

Thiopurine Methyltransferase (TPMT) Genotyping, 4 Variants 2012233
Method: Polymerase Chain Reaction/Fluorescence Monitoring

Limitations

Only targeted TPMT allele variants will be detected by this panel

Diagnostic errors can occur due to rare sequence variations

Genotyping in patients who have received allogenic stem cell/bone marrow transplant will reflect donor status

Genotyping cannot distinguish the *1/*3A genotype from the *3B/*3C genotype

Thiopurine drug metabolism and risk for toxicity may be affected by genetic and nongenetic factors that are not evaluated by this test

Test does not assess for TPMT allele variants associated with ultra-high enzyme activity

Genotyping does not replace the need for therapeutic drug monitoring or clinical observation

Infliximab Activity and Neutralizing Antibody 2008320
Method: Cell Culture/Quantitative Chemiluminescent Immunoassay/ Semi-Quantitative Chemiluminescent Immunoassay

Adalimumab Activity and Neutralizing Antibody 2011248
Method: Cell Culture/Quantitative Chemiluminescent Immunoassay/ Semi-Quantitative Chemiluminescent Immunoassay

Additional Tests Available

CBC with Platelet Count and Automated Differential 0040003
Method: Automated Cell Count/Differential

Comments

Initial evaluation to rule out infection

C-Reactive Protein 0050180
Method: Quantitative Immunoturbidimetry

Comments

Preferred test to assess and monitor inflammation

Sedimentation Rate, Westergren (ESR) 0040325
Method: Visual Identification

Comments

Assess and monitor inflammation

Leflunomide Metabolite, Serum or Plasma  2007460
Method: High Performance Liquid Chromatography/Mass Spectrometry

Comments

Therapeutic monitoring and evaluating full elimination of the drug (eg, toxicity, pregnancy)

Methotrexate, Sensitive 2005405
Method: Quantitative Immunoassay

Comments

Monitor methotrexate concentration

Cyclic Citrullinated Peptide (CCP) Antibody, IgG 0055256
Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay

Comments

Diagnose and prognosticate RA

Rheumatoid Factor, Body Fluid 2003347
Method: Quantitative Immunoturbidimetry

Comments

Aids in diagnosis of pleural involvement in RA

For information on body fluid reference ranges and/or interpretive guidance visit http://aruplab.com/bodyfluids/

Rheumatoid Factor 0050465
Method: Quantitative Immunoturbidimetry

Comments

Aids in diagnosis of RA

Rheumatoid Factors, IgA, IgG, and IgM by ELISA 0051298
Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay/Quantitative Enzyme-Linked Immunosorbent Assay.

Comments

May be useful when combined with anti-CCP to predict radiological damage in RA

Guidelines

Aletaha D, Neogi T, Silman A, Funovits J, Felson D, Bingham C, Birnbaum N, Burmester G, Bykerk V, Cohen M, Combe B, Costenbader K, Dougados M, Emery P, Ferraccioli G, Hazes J, Hobbs K, Huizinga T, Kavanaugh A, Kay J, Kvien T, Laing T, Mease P, Ménard H, Moreland L, Naden R, Pincus T, Smolen J, Stanislawska-Biernat E, Symmons D, Tak P, Upchurch K, Vencovský J, Wolfe F, Hawker G. 2010 Rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheum. 2010; 62(9): 2569-81. PubMed

American Society for Clinical Pathology. Choosing Wisely - Five Things Physicians and Patients Should Question. An initiative of the ABIM Foundation. [Last revision Feb 2015; Accessed: Jan 2016]

van der Heijde D, van Mil A, Aletaha D, Bingham C, Burmester G, Dougados M, Emery P, Felson D, Knevel R, Kvien T, Landewé R, Lukas C, McInnes I, Silman A, Smolen J, Stanislawska-Biernat E, Zink A, Combe B. EULAR definition of erosive disease in light of the 2010 ACR/EULAR rheumatoid arthritis classification criteria Ann Rheum Dis. 2013; 72(4): 479-81. PubMed

General References

Bizzaro N. Antibodies to citrullinated peptides: a significant step forward in the early diagnosis of rheumatoid arthritis. Clin Chem Lab Med. 2007; 45(2): 150-7. PubMed

Brunner J, Sitzmann F. The diagnostic value of anti-cyclic citrullinated peptide (CCP) antibodies in children with Juvenile Idiopathic Arthritis. Clin Exp Rheumatol. 2006; 24(4): 449-51. PubMed

Corrao S, Calvo L, Licata G. The new criteria for classification of rheumatoid arthritis: what we need to know for clinical practice. Eur J Intern Med. 2011; 22(3): 217-9. PubMed

Huizinga T, Pincus T. In the clinic. Rheumatoid arthritis. Ann Intern Med. 2010; 153(1): ITC1-1-ITC1-15; quiz ITC1-16. PubMed

Ingegnoli F, Castelli R, Gualtierotti R. Rheumatoid factors: clinical applications. Dis Markers. 2013; 35(6): 727-34. PubMed

Kourilovitch M, Galarza-Maldonado C, Ortiz-Prado E. Diagnosis and classification of rheumatoid arthritis. J Autoimmun. 2014; 48-49: 26-30. PubMed

Mahroum N, Mahagna H, Amital H. Diagnosis and classification of adult Still's disease. J Autoimmun. 2014; 48-49: 34-7. PubMed

Prince F, Otten M, van Suijlekom-Smit L. Diagnosis and management of juvenile idiopathic arthritis. BMJ. 2010; 341: c6434. PubMed

Rantapää-Dahlqvist S, de Jong B, Berglin E, Hallmans G, Wadell G, Stenlund H, Sundin U, van Venrooij W. Antibodies against cyclic citrullinated peptide and IgA rheumatoid factor predict the development of rheumatoid arthritis. Arthritis Rheum. 2003; 48(10): 2741-9. PubMed

Scott D, Wolfe F, Huizinga T. Rheumatoid arthritis. Lancet. 2010; 376(9746): 1094-108. PubMed

Sun J, Zhang Y, Liu L, Liu G. Diagnostic accuracy of combined tests of anti cyclic citrullinated peptide antibody and rheumatoid factor for rheumatoid arthritis: a meta-analysis. Clin Exp Rheumatol. 2014; 32(1): 11-21. PubMed

Waits J. Rational use of laboratory testing in the initial evaluation of soft tissue and joint complaints. Prim Care. 2010; 37(4): 673-89, v. PubMed

Wasserman A. Diagnosis and management of rheumatoid arthritis. Am Fam Physician. 2011; 84(11): 1245-52. PubMed

References from the ARUP Institute for Clinical and Experimental Pathology®

Copple S, Giles R, Jaskowski T, Gardiner A, Wilson A, Hill H. Screening for IgG antinuclear autoantibodies by HEp-2 indirect fluorescent antibody assays and the need for standardization. Am J Clin Pathol. 2012; 137(5): 825-30. PubMed

Tebo A, Jaskowski T, Davis W, Whiting A, Clifford B, Zeft A, McNally B, Hill H, Bohnsack J, Prahalad S. Profiling anti-cyclic citrullinated peptide antibodies in patients with juvenile idiopathic arthritis. Pediatr Rheumatol Online J. 2012; 10(1): 29. PubMed

Medical Reviewers

Last Update: February 2016