Indications for Testing

• Persistent joint pain with early morning stiffness

Criteria for Diagnosis

• American College of Rheumatology criteria – at least 4 required for diagnosis
  • Morning stiffness – for at least 1 hour over a period of at least 6 months
  • Arthritis of 3 or more joints – from wrist, PIP, MCP, elbow, knee, ankle, metatarsophalangeal
  • Hand joint involvement – wrist, MCP, PIP
  • Symmetric arthritis – same joints as arthritis
  • Rheumatoid nodules – subcutaneous nodules around joints
  • Positive rheumatoid factor
  • Radiographic changes – erosions or loss of density of joints

Laboratory Testing

• No single test confirms the 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, the IgM-RF and the 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 cofounding 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; please contact the 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
  • 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 infection rate increased
  • 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 – 10-50/100,000
• 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

• American College of Rheumatology criteria, 1986
  • Age onset <16 years
  • Arthritis duration ≥6 weeks
  • Exclusion of other forms of juvenile arthritis

Laboratory Testing

• No single test confirms the 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

Guidelines

• Saag KG, Teng GG, Patkar NM, Anuntiyo J, Finney C, Curtis JR, Paulus HE, Mudano A, Pisu M, Elkins-Melton M, Outman R, Allison JJ, Suarez Almazor M, Bridges SL Jr, Chatham WW, Hochberg M, MacLean C, Mikuls T, Moreland LW, O'Dell J, Turkiewicz AM, Furst DE. American College of Rheumatology 2008 recommendations for the use of nonbiologic and biologic disease-modifying antirheumatic drugs in rheumatoid arthritis. Arthritis Rheum. 2008; 59 (6) :762-784.PubMed

General

• Bizzaro N. Antibodies to citrullinated peptides: a significant step forward in the early diagnosis of rheumatoid arthritis. Clin Chem Lab Med. 2007; 45 (2) :150-157.PubMed
• Brunner J, Sitzmann FC. The diagnostic value of anti-cyclic citrullinated peptide (CCP) antibodies in children with Juvenile Idiopathic Arthritis. Clin Exp Rheumatol. 2006; 24 (4) :449-451.PubMed
• Dannecker GE, Quartier P. Juvenile idiopathic arthritis: classification, clinical presentation and current treatments. Horm Res. 2009; 72 Suppl 1 :4-12.PubMed
• Daul P, Grisanti J. Monitoring response to therapy in rheumatoid arthritis - perspectives from the clinic. Bull NYU Hosp Jt Dis. 2009; 67 (2) :236-242.PubMed
• Huizinga TW, Pincus T. In the clinic. Rheumatoid arthritis. Ann Intern Med. 2010; 153 (1) :ITC1-ITC1.PubMed
• Petty RE, Southwood TR, Baum J, Bhettay E, Glass DN, Manners P, Maldonado-Cocco J, Suarez-Almazor M, Orozco-Alcala J, Prieur AM. Revision of the proposed classification criteria for juvenile idiopathic arthritis: Durban, 1997. J Rheumatol. 1998; 25 (10) :1991-1994.PubMed
• Pincus T, Sokka T. Laboratory tests to assess patients with rheumatoid arthritis: advantages and limitations. Rheum Dis Clin North Am. 2009; 35 (4) :731-vii.PubMed
• Plenge RM. Rheumatoid arthritis genetics: 2009 update. Curr Rheumatol Rep. 2009; 11 (5) :351-356.PubMed
• Prahalad S, Martins TB, Tebo AE, Whiting A, Clifford B, Zeft AS, McNally B, Bohnsack JF, Hill HR. Elevated serum levels of soluble CD154 in children with juvenile idiopathic arthritis. Pediatr Rheumatol Online J. 2008; 6 :8-.PubMed
• Scott DL, Wolfe F, Huizinga TW. Rheumatoid arthritis. Lancet. 2010; 376 (9746) :1094-1108.PubMed
• Shmerling RH. Testing for anti-cyclic citrullinated peptide antibodies: is it time to set this genie free?. Arch Intern Med. 2009; 169 (1) :9-14.PubMed
• Smolen JS, Aletaha D. The assessment of disease activity in rheumatoid arthritis. Clin Exp Rheumatol. 2010; 28 (3 Suppl 59) :S18-S27.PubMed
• Song YW, Kang EH. Autoantibodies in rheumatoid arthritis: rheumatoid factors and anticitrullinated protein antibodies. QJM. 2010; 103 (3) :139-146.PubMed
• Suresh E. Recent advances in rheumatoid arthritis. Postgrad Med J. 2010; 86 (1014) :243-250.PubMed
• Woo P. Systemic juvenile idiopathic arthritis: diagnosis, management, and outcome. Nat Clin Pract Rheumatol. 2006; 2 (1) :28-34.PubMed

Acute Phase Proteins
Connective Tissue Diseases
Hyperuricemia
Mixed Connective Tissue Disease
Osteomyelitis
Septic Arthritis