Rheumatoid Arthritis

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

Multiple scales are available to assess arthritis disease activity
ESR or CRP may be useful in monitoring disease progression
- No adequate studies demonstrating usefulness of RF or anti-CCP in monitoring therapy
For patients on disease-modifying antirheumatic drugs (DMARDS)
- Routine laboratory tests – CBC, creatinine, liver transaminases
Compliance monitoring for leflunomide, gold, and other commonly used medications may be appropriate; contact laboratory to discuss available test options
X-ray evaluation for new erosions

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

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 – a nemia
- 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

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

Tests generally appear in the order most useful for common clinical situations

Test name: CBC with Platelet Count and Automated Differential

ARUP #: 0040003

Methodology: Automated Cell Count/Differential

Use:

Helpful in initial evaluation to rule out infection

Test name: C-Reactive Protein

ARUP #: 0050180

Methodology: Quantitative Immunoturbidimetry

Use: Monitor inflammation in patient with RA

Test name: Sedimentation Rate, Westergren (ESR)

ARUP #: 0040325

Methodology: Visual Identification

Use:

Monitor inflammation in patient with RA

Test name: Rheumatoid Arthritis Panel

ARUP #: 2003277

Methodology: Semi-Quantitative Enzyme-Linked Immunosorbent Assay/Immunoturbidimetry

Use:

Diagnose and prognosticate RA

Test name: Rheumatoid Arthritis Panel with Reflex to Rheumatoid Factors, IgA, IgG, and IgM by ELISA

ARUP #: 2003278

Methodology: Semi-Quantitative Enzyme-Linked Immunosorbent Assay/Quantitative Immunoturbidimetry/Quantitative Enzyme-Linked Immunosorbent Assay

Use:

Diagnose and prognosticate RA

Test name: Methylenetetrahydrofolate Reductase (MTHFR) 2 Mutations

ARUP #: 0055655

Methodology: Polymerase Chain Reaction/Fluorescence Monitoring

Use:

Help predict methotrexate sensitivity, which may be associated with toxicity

Test name: Thiopurine Methyltransferase, RBC

ARUP #: 0092066

Methodology: Enzymatic/Quantitative Liquid Chromatography-Tandem Mass Spectrometry

Use:

TPMT enzyme activity can be inhibited by several drugs including the following

Naproxen
Ibuprofen
Ketoprofen
Furosemide
Sulfasalazine
Mesalamine
Olsalazine
Mefenamic acid
Thiazide diuretics
Benzoic acid

Patients should abstain from these drugs for at least 48 hours prior to TPMT testing in order to avoid falsely low results

Measures only enzyme activity

Limitations:

TPMT activity for patients who have recently received a blood transfusion may not accurately reflect future TPMT phenotype

Additional Tests Available

Test name: Leflunomide Metabolite, Serum or Plasma

ARUP #: 2007460

Methodology: High Performance Liquid Chromatography/Mass Spectrometry

Comments:

Monitor leflunomide concentration; verify elimination

Test name: Leflunomide (Teriflunomide), Urine

ARUP #: 0093306

Methodology: High Performance Liquid Chromatography/Mass Spectrometry

Comments:

Monitor leflunomide concentration; verify elimination

Test name: Gold, Serum or Plasma

ARUP #: 0091265

Methodology: Graphite Furnace Atomic Absorption Spectroscopy

Comments:

Monitor gold therapy

Test name: Methotrexate, Sensitive

ARUP #: 2005405

Methodology: Quantitative Immunoassay

Comments:

Monitor methotrexate concentration

Test name: Cyclic Citrullinated Peptide (CCP) Antibody, IgG

ARUP #: 0055256

Methodology: Semi-Quantitative Enzyme-Linked Immunosorbent Assay

Comments:

Diagnose and prognosticate RA

Test name: Rheumatoid Factor, Body Fluid

ARUP #: 2003347

Methodology: Quantitative Immunoturbidimetry

Comments:

Diagnose RA with pleural involvement

Test name: Rheumatoid Factor

ARUP #: 0050465

Methodology: Quantitative Immunoturbidimetry

Comments:

Diagnose RA

Test name: Rheumatoid Factors, IgA, IgG, and IgM by ELISA

ARUP #: 0051298

Methodology: 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

General

ARUP Institute for Clinical and Experimental Pathology®

Comprehensive Review: March 2012
Last Update: January 2013

Acute Phase Proteins

Connective Tissue Diseases

Hyperuricemia

Mixed Connective Tissue Disease

Osteomyelitis

Septic Arthritis