Rheumatoid Arthritis - RA

Diagnosis

Indications for Testing

  • Persistent joint pain with early morning stiffness

Criteria for Diagnosis

  • Criteria for diagnosis of rheumatoid arthritis

    Criteria for Diagnosis of Rheumatoid Arthritis 

    Based on American College of Rheumatology and European League Against Rheumatism Classification Criteria (Aletaha, 2010)

    Any joint involvement

    Score

    • Large joint

    0

    • 2-10 large joints

    1

    • 1-3 small joints

    2

    • 4-10 small joints

    3

    • >10 joints (≥1 small joint)

    5

    Serology (≥1 test result required)

     
    • Normal RF and normal ACPA*

    0

    • Low-positive RF or low-positive ACPA

    2

    • High-positive RF or high-positive ACPA

    3

    Acute phase reactants (≥1 test result required)

     
    • Normal CRP and ESR

    0

    • Abnormal CRP or ESR

    1

    Duration of symptoms

     
    • <6 weeks

    0

    • >6 weeks

    1

    Rheumatoid arthritis diagnosed when score ≥6

    *Anti–citrullinated protein antibody (ACPA) – tested as anticyclic citrullinated peptide (anti-CCP)

Laboratory Testing

  • No single test confirms diagnosis
  • Nonspecific testing
    • CBC with differential – most helpful to rule out infection
    • Erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP) – often increased, particularly if active disease is present
  • 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)
    • Pooled sensitivities and specificities for RF and CCP
      Pooled Sensitivities and Specificities with Confidence Intervals (CI) for RF and CCP
       SensitivitySpecificity
      Anti-CCP67% (CI= 65-68%)94% (CI= 93-94%)
      RF71% (CI= 69-72%)83% (CI= 82-84%)
      Anti-CCP and RF57% (CI= 33-80%)96% (CI= 89-100%)
      Anti-CCP or RF78% (CI= 52-90%)82% (CI= 79-96%)
      Source: Sun, et al, 2014
    • 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 local destruction is present

Differential Diagnosis

Monitoring

  • Erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP) may be useful in monitoring disease progression
  • Usefulness of RF or 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
  • 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

Pharmacogenetics and Therapeutic Drug Monitoring

  • 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

Clinical Background

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

Pediatrics

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
    • Persistent oligoarthritis
    • Extended oligoarthritis
    • Rheumatoid factor (RF)-positive polyarthritis
    • RF-negative polyarthritis
    • Systemic arthritis
    • 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

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
    • Erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP) – often increased, particularly if active disease is present
    • 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

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
Test Name and Number Recommended Use Limitations Follow Up
Rheumatoid Arthritis Panel 2003277
Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay/Immunoturbidimetry

Aids in diagnosis and prognostication of RA

Includes cyclic citrullinated peptide  antibody, IgG (CCP) and rheumatoid factor (RF)

   
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

Aids in diagnosis and prognostication of RA

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

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

Detect risk for severe myelosuppression with standard dosing of thiopurine drugs

Individualize dosing of thiopurine drugs

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

Optimize therapy for thiopurine drugs

Identify thiopurine metabolite concentrations that may lead to toxicity

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

Evaluate response failure to infliximab therapy

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

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

Evaluate response failure to adalimumab therapy

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

   
Additional Tests Available
 
Click the plus sign to expand the table of additional tests.
Test Name and NumberComments
CBC with Platelet Count and Automated Differential 0040003
Method: Automated Cell Count/Differential

Initial evaluation to rule out infection

C-Reactive Protein 0050180
Method: Quantitative Immunoturbidimetry

Assess and monitor inflammation

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

Assess and monitor inflammation

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

Use for therapeutic monitoring

Other trade names – A77 1726, teriflunomide

Therapeutic and toxic ranges are not well established – proposed range is 50-100 μg/mL

Analytical sensitivity – 0.005 μg/mL (5 ng/mL)

Adverse drug reactions (eg, diarrhea, hypertension, liver toxicity) do not correlate well with serum concentrations

Gold Quantitative, Serum or Plasma 0091265
Method: Quantitative Graphite Furnace Atomic Absorption Spectroscopy

Monitor gold concentration

Methotrexate, Sensitive 2005405
Method: Quantitative Immunoassay

Monitor methotrexate concentration

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

Diagnose and prognosticate RA

Rheumatoid Factor, Body Fluid 2003347
Method: Quantitative Immunoturbidimetry

Aids in diagnosis of pleural involvement in RA

Rheumatoid Factor 0050465
Method: Quantitative Immunoturbidimetry

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.

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