Rheumatoid Arthritis - RA

Rheumatoid arthritis (RA) is an autoimmune disorder with progressive and destructive polyarthritis and is the most common adult inflammatory arthritis worldwide. No single laboratory test confirms the diagnosis. Infliximab and adalimumab, TNF-α inhibitor drugs used to treat the symptoms of RA, may require monitoring for primary or secondary response failure.

Diagnosis

Indications for Testing

Persistent joint pain with early morning stiffness

Criteria for Diagnosis

Laboratory Testing

  • No single test confirms diagnosis
  • Nonspecific testing
  • 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
    • Anticyclic citrullinated peptide (anti-CCP) IgG antibody 
      • 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
  • HLA-B27 – limited clinical utility; may assist in diagnosis if other clinical signs and symptoms are present

Imaging Studies

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

Differential Diagnosis

Monitoring

  • Routine laboratory tests
    • CBC, creatinine, liver transaminases – for patients taking disease-modifying antirheumatic drugs (DMARDS)
    • CRP – may be useful in monitoring disease progression
  • RF or anticyclic citrullinated peptide (anti-CCP) IgG antibody
    • Limited use
  • X-ray evaluation
    • For new erosions
  • Infliximab and adalimumab activity and neutralizing antidrug antibody (ADA)
    Clinical Interpretation of Adalimumab/Infliximab and Antibody Testing Results
    Adalimumab/Infliximab Activity Neutralizing Antibody Titer Clinical Interpretation

    Not detected

    Not detected

    Subtherapeutic dose (nonimmune-mediated failure)

    Consider higher dosage of adalimumab or shortening the dosing interval

    Not detected

    Detected

    Neutralizing antibodies may be responsible for failure (immune-mediated failure)

    Consider alternate anti-TNF-α drug

    Detected

    Not detected

    Adalimumab/infliximab activity detected and no neutralizing antibodies present – likely a mechanistic failure

    Consider alternate therapy (non-anti-TNF-α drug)

     

    Detected

    Detected

    Future retesting suggested to rule out decreasing activity and/or increasing neutralizing antibodies

    • Infliximab and adalimumab are tumor necrosis factor (TNF)-α inhibitor drugs used for the treatment of patients with chronic inflammatory and autoimmune diseases, including RA
    • In general, patients with inadequate effects either do not respond at all (primary response failure) or they respond initially but have later relapses (secondary response failure) despite increased dosage and/or more frequent administration of the drug (Bendtzen, 2013)
    • Immunogenicity of TNF antagonist drugs and development of ADAs are major causes of secondary treatment failure (defined as loss of clinical response after initial improvement of clinical signs and symptoms)
    • Circulating adalimumab levels have been shown to vary considerably between patients
      • These differences are related to route and frequency of administration and patient-related features such as age, sex, weight, drug metabolism, and concomitant medications such as methotrexate and other immunosuppressants
  • Compliance monitoring for leflunomide, gold, and other commonly used medications
    • May be appropriate; contact laboratory to discuss available test options​

Pharmacogenetics

  • Thiopurine drugs may be used in treatment of RA
    • Thiopurine prodrugs are metabolized via thiopurine methyltransferase (TPMT) and nudix hydrolase 15 (NUDT15) enzymatic activity
    • Deficiency of TPMT ​and/or NUDT15 predicts hematopoietic toxicity after thiopurine treatment
    • Testing to determine activity level may be helpful in dosing thiopurine drugs and help avert bone marrow suppression
      • A significant dose reduction may be needed in patients with TPMT and/or NUDT15 variants or patients with demonstrated TPMT enzyme activity deficiency
      • Guidelines for thiopurine dosing are published
    • Genotype for TPMT ​and/or NUDT15 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​

Background

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

Pediatrics

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

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
    • CRP
    • Antinuclear antibodies (ANA) – may be positive
  • Specific testing
    • RF IgM
      • Less likely to be positive than in adults
    • Anti-CCP IgG antibody
      • Associated with RF-positive polyarticular course of JIA
      • Testing of this antibody is frequently negative; serology most likely positive in polyarticular arthritis form
    • RF 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

ARUP Lab Tests

Aid in diagnosis and prognostication of RA

Includes CCP antibody, IgG and RF

Includes CCP, IgG; RF; and RF, IgA/IgG/IgM

Reflex pattern: if CCP IgG ≥20 units and/or RF ≥15 IU/mL, then RF, IgG/IgM/IgA by EIA will be performed

Phenotype test to assess risk for severe myelosuppression with standard dosing of thiopurine drugs

Testing should be performed prior to initiation of thiopurine therapy

For therapy optimization or toxicity evaluation, order thiopurine metabolites by LC-MS/MS

Does not replace clinical monitoring

Genotype cannot be inferred from TPMT activity (phenotype)

TPMT inhibitors may contribute to falsely low results

TPMT activity should be assessed prior to treatment with thiopurine drugs

Blood transfusion within 30 days will reflect donor status

Phenotype test used to optimize therapy for patients who are taking thiopurine drugs

Thiopurine metabolite concentrations are identified to assess therapeutic and toxic concentrations

If thiopurine therapy has not been initiated, order thiopurine methyltransferase, red blood cell

Genotype test to assess risk, due to genetics, for severe myelosuppression with standard dosing of thiopurine drugs

Use for individuals being considered for thiopurine therapy or who have had an adverse reaction to thiopurine therapy

Preferred test for patients with recent heterologous blood transfusion

Can be performed irrespective of thiopurine therapy

Evaluate response failure to infliximab or biosimilar therapy

Determine and adjust dosage or identify the need for change to another anti-TNF-α inhibitor

Evaluate response failure to infliximab or biosimilar therapy

Determine and adjust dosage or identify the need for change to another anti-TNF-α inhibitor

Reflex pattern: if Infliximab drug level is not detected, then Infliximab neutralizing antibody titer will be added

Evaluate response failure to adalimumab therapy

Determine and adjust dosage or identify the need for change to another anti-TNF-α inhibitor

Evaluate response failure to adalimumab therapy

Determine and adjust dosage or identify the need for change to another anti-TNF-α inhibitor

Reflex pattern: if adalimumab drug level is not detected, then adalimumab neutralizing antibody titer will be added

Related Tests

May aid in prognostication for rheumatoid arthritis

Rheumatoid arthritis panel is preferred for the workup of suspected rheumatoid arthritis or undifferentiated inflammatory arthritides

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

Initial evaluation to rule out infection

Preferred test to assess and monitor inflammation

Assess and monitor inflammation

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

Monitor methotrexate concentration

Highly specific serologic test that aids in the workup of suspected rheumatoid arthritis or undifferentiated inflammatory arthritides

Rheumatoid arthritis panel is the preferred test

Aid in diagnosis of pleural involvement in RA

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

Aid in diagnosis of RA

Medical Experts

Contributor

Delgado

Julio Delgado, MD, MS
Professor of Clinical Pathology, University of Utah
Chief, Division of Clinical Pathology, University of Utah and ARUP Laboratories
Chief Medical Officer and Director of Laboratories at ARUP Laboratories
Contributor

Genzen

Jonathan R. Genzen, MD, PhD

Associate Professor of Clinical Pathology, University of Utah

Chief Operations Officer, Medical Director of Automated Core Laboratory and Farmington Health Center Clinical Laboratory, at ARUP Laboratories

Contributor
Contributor
Contributor
Contributor

References

Additional Resources
Resources from the ARUP Institute for Clinical and Experimental Pathology®