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
  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)
  Negative RF and negative 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 normal 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 anti–cyclic citrullinated peptide (anti-CCP)

Laboratory Testing

• No single test confirms diagnosis
• CBC with differential – may be helpful to rule out infection
• Erythrocyte sedimentation rate (ESR) (often increased >30 mm/hr) or C-reactive protein (CRP)
• Rheumatoid factor (RF) IgM
  • Negative in 30% of early onset RA
  • Present in 5-10% of healthy individuals, prevalence increases with age
  • Presence of abnormal levels of all three RF isotypes has a specificity of 99% for RA; however, RF in any isotype combination may be found in hepatitis C (HCV), Sjögren syndrome and other chronic infections (eg, systemic sclerosis, cryoglobulinemia, systemic lupus erythematosus [SLE])
• Anti-cyclic citrullinated peptide (CCP) IgG antibody
  • 93-95% specific; positivity supports the diagnosis of RA
    • Consider using instead of RF when pretest probability for RA is moderate
  • As a screening method for RA, IgM-RF and CCP assays are superior to other RF isotypes
  • CCP can be detected in up to 38.4% of IgM-RF-negative sera
  • Linked to erosive disease
  • Good test for patients with arthritis and confounding factors that increase false-positive RF – HCV, SLE, cryoglobulinemia
  • Presence of anti-CCP and IgA-RF may predict the development of RA
• Rheumatoid factor isotypes
  • RF IgA in combination with anti-CCP may predict radiological damage in RA
• Rarely, joint aspiration with synovial fluid analysis may be required to rule out crystalline arthritis

Imaging Studies

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

Prognosis

• Adverse prognosis associated with the following
  • Continued active clinical disease
  • Erosion on x-ray
  • Elevated RF and/or anti-CCP antibodies
  • Elevated ESR or CRP

Differential Diagnosis

• Osteoarthritis
• Infectious arthritis – hepatitis B and C, HIV, Borrelia burgdorferi
• Septic arthritis
• Reactive arthritis – bacterial diarrhea (eg, Campylobacter)
• Seronegative spondyloarthropathies – psoriatic, ankylosing spondylitis
• Connective tissue disease – SLE, mixed connective tissue disease, systemic sclerosis, inflammatory myopathies
• Fibromyalgia
• Crystal-related arthritis – gout, pseudogout
• Thyroid disease
• Hemochromatosis
• Sarcoidosis
• Vasculitis – Wegener granulomatosis, polyarteritis nodosa
• Acute rheumatic fever
• Polymyalgia rheumatica
• Malignancy-related arthritis – hypertrophic osteoarthropathy

Monitoring

Pharmacogenetics and Therapeutic Drug Monitoring

• Methotrexate sensitivity
  • Methotrexate – used in treatment of RA
  • Methylene tetrahydrofolate reductase – important enzyme for metabolism of methylene
    • Certain mutations associated with increased toxicity
  • Testing for mutations may aid in identifying patient prone to toxicity
    • Heterozygous C677T or A1298C – decreased enzyme activity but no correlation with methotrexate intolerance
    • Homozygous C677T – associated with increased plasma homocysteine levels and methotrexate intolerance; dosing adjustments/discontinuation may be required
    • Homozygous A1298C – associated with decreased enzyme activity and lower dose requirements for methotrexate
    • Compound heterozygote (C677T/A1298C) – associated with increased plasma homocysteine levels and methotrexate intolerance
• Thiopurine drugs are used in treatment of RA
  • Thiopurine methyltransferase (TPMT) activity – used to detect individuals with low (abnormal) TPMT activity that may be at risk for excessive myelosuppression when exposed to standard doses of thiopurines such as azathioprine (Imuran^®) and 6-mercaptopurine (Purinethol^®)
    • TPMT phenotype testing does not replace need for clinical monitoring of patients treated with thiopurine drugs
    • Genotype for TPMT cannot be inferred from TPMT activity (phenotype)
      • 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 and is the most common adult inflammatory arthritis worldwide.

Epidemiology

• Incidence
  • Men – 25/100,000
  • Women – 54/100,000
• Age – peaks in 30s-40s
• Sex – M<F

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
  • Low-grade fever
• Joints – polyarticular disease
  • Pain and stiffness in multiple joints
    • Wrist and proximal interphalangeal (PIP) and metacarpophalangeal (MCP) joints most commonly affected
    • Joints are puffy and warm
• Extra-articular involvement
  • Hematological – anemia
  • Joint and spine disease
    • Cervical spine disease due to instability of atlas on axis
    • Joint deformity – swan neck, boutonnière
  • Ocular disease – episcleritis
  • Cardiopulmonary disease
    • Interstitial fibrosis
    • Lung nodules that cavitate
    • Pericarditis may occur in 1/3 of patients
  • Rheumatoid nodules – may resolve
  • Vasculitis – small and medium vessel disease
• Complications
  • Cancer
    • Often secondary to therapy – lymphoma, leukemia most common
  • Cervical atlanto-axial dislocation
  • Appearance of early cardiovascular disease – average 10 years earlier than population statistics
  • Serious infections – rate increased compared to general population
  • Pulmonary interstitial disease

Treatment

• In addition to NSAIDs, aggressive use of disease-modifying antirheumatic drugs to prevent damage

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

  Criteria for Diagnosis of Rheumatoid Arthritis  Based on American College of Rheumatology and European League Against Rheumatism Classification Criteria
  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)
  Negative RF and negative 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 normal 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 anti–cyclic citrullinated peptide (anti-CCP)

Laboratory Testing

• No single test confirms diagnosis
• CBC with differential – may be helpful to rule out infection
• ESR (often increased >30 mm/hr) or CRP
• Anti-CCP antibodies are 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 – less likely to be positive than in adults
• ANA – may be positive

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

Click the plus sign to expand the table of additional tests.

Test Name and Number	Comments
Leflunomide Metabolite, Serum or Plasma  2007460 Method: High Performance Liquid Chromatography/Mass Spectrometry	Monitor leflunomide concentration; verify elimination
Leflunomide (Teriflunomide), Urine 0093306 Method: High Performance Liquid Chromatography/Mass Spectrometry	Monitor leflunomide concentration; verify elimination
Gold, Serum or Plasma 0091265 Method: Graphite Furnace Atomic Absorption Spectroscopy	Monitor gold therapy
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	Diagnose RA with pleural involvement
Rheumatoid Factor 0050465 Method: Quantitative Immunoturbidimetry	Diagnose 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