Diagnostic Services Immunology/Rheumatology Clinical Focus Osteoarthritis and Rheumatoid Arthritis Laboratory Markers for Diagnosis and Prognosis Clinical Background This Clinical Focus discusses laboratory tests available to Osteoarthritis (OA) is the most common form of arthritis assist in differentiating RA from OA and other conditions that in the United States, affecting 13.9% of adults over 25 years manifest with polyarthritis. The associations between test of age.1 It is characterized by loss of hyaline cartilage in the results and disease progression are also discussed. joints and radiographic changes, such as decreased joint space and osteophytes. Rheumatoid arthritis (RA) is much Disease Classification Criteria less common and affects different joint tissues. It occurs in The American College of Rheumatology has published 7,8,9 0.5% to 1% of people in the United States, with prevalence guidelines for the classification of OA in different joints. being 2 to 3 times higher in women than men.2,3 RA is an Depending on the joint, classification criteria may include autoimmune disease characterized by chronic, systemic joint symptoms (pain, stiffness, swelling, enlargement, inflammation, which predominantly affects the synovial deformation), age, erythrocyte sedimentation rate, membranes and articular structures in joints but may radiological criteria (presence of osteophytes or narrowing damage organs such as the heart and lungs.4 Both diseases of joint space), synovial fluid tests (color, appearance, appear to have a genetic component, but the exact causes white blood cell count), or the sensation of crackling in the are unknown. joint called crepitus (Table 1). Sensitivity and specificity for diagnosis vary based on 1) the joint (knee, hand, hip); 2) Differentiating OA and RA is important because treatments the classification method (traditional vs classification tree); differ. OA is often treated with drugs that alleviate and 3) the criteria (clinical vs clinical and radiographic vs symptoms but do not change the disease course, such as clinical and laboratory). acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs). NSAIDs may also be used to treat the symptoms Diagnosis of RA relies on patient history, physical of RA, but other options are available that can change the examination, laboratory testing, and radiographic evidence disease course. Disease-modifying anti-rheumatic drugs of joint damage. The American College of Rheumatology (DMARDs) (eg, methotrexate, leflunomide) or biological (ACR)/European League Against Rheumatism (EULAR) therapies (eg, adalimumab, etanercept, infliximab) can 2010 Rheumatoid Arthritis Classification Criteria are based often ameliorate RA, improve the clinical outcome, and in on clinical presentation (synovitis, joint swelling), serology, some cases achieve remission. Treatment of RA early in the acute-phase reactants, and duration of symptoms. The course of the disease can prevent or minimize irreversible criteria are designed to identify early-stage patients who 5 joint damage.5 are at high risk of persistent and/or erosive disease. Once other conditions such as OA, systemic lupus Many symptoms of OA and RA overlap, including pain, erythematosus, psoriatic arthritis, gout, and arthritis swelling, and stiffness in the joints. These similarities caused by viral infection (eg, parvovirus B19, rubella, can cause difficultly when differentiating the diseases. hepatitis C virus) have been ruled out, a patient is classified However, some symptoms and laboratory markers can as having RA if a score of ≥6 out of a possible 10 is reached. assist with differentiation. For example, joint stiffness is Details of the scoring system and classification criteria can less common in OA patients, and joint swelling is hard and be found in the Figure and reference 5. bony in OA but soft and tender in RA.6 In addition, some Osteoarthritis and Rheumatoid ArthritisOsteoarthritis and Rheumatoid laboratory markers are elevated in RA patients but normal in OA patients. Clinical Focus Clinical Diagnostic Services Immunology/Rheumatology Table 1. Criteria for Diagnosis of Osteoarthritis in Different Joints Hip (Clinical and Knee (Clinical and Laboratory)a,7 Handa,8 Radiographic)a,9 • Knee pain • Hand pain, aching, or stiffness • Hip pain Plus ≥5 of the following Plus ≥3 of the following Plus ≥2 of the following • Age >50 years • Hard tissue enlargement of ≥2 • ESR <20 mm/hour b • Joint stiffness <30 minutes of 10 selected joints • Osteophytes (femoral or • Crepitus • Hard tissue enlargement of ≥2 acetabular) distal interphalangeal joints • Bony tenderness • Joint space narrowing • <3 swollen (superior, axial, and/or medial) • Bony enlargement metacarophalangeal joints • No palpable warmth • Deformity of ≥1 of 10 selected b • ESR <40 mm/hour joints • RF <1:40 • Synovial fluid clear, viscous, or white blood cell count <2,000/mm3 Sensitivity: 92% Sensitivity: 94% Sensitivity: 89% Specificity: 75% Specificity: 87% Specificity: 91% a Schema presented are in traditional format. Depending on the joint, schema may also be available in traditional or classification tree format for clinical criteria alone or in combination with radiographic criteria.7-9 Other schema have different sensitivities (86% to 95%) and specificities (69% to 98%). b Selected joints include 1st carpometacarpal and 2nd and 3rd distal and proximal interphalangeal joints of each hand. This table is provided for informational purposes only and is not intended as medical advice. A physician’s test selection and interpretation, diagnosis, and patient management decisions should be based on his/her education, clinical expertise, and assessment of the patient. Individuals Suitable for Testing can be especially useful early in the disease course for • Individuals with symptoms of arthritis not attributed to establishing diagnosis. diagnosed conditions Rheumatoid factor (RF) and cyclic citrullinated peptide • Individuals with arthritis requiring differential diagnosis (CCP) antibody are established biomarkers that are of OA from RA integrated into ACR/EULAR criteria for RA classification.5 • Individuals with established RA 14-3-3η protein is a newer marker for RA that has higher sensitivity in early RA than either RF or CCP and can thus Test Availability identify RA in some cases that are not identified using RF A list of tests that may be useful in RA diagnosis, or CCP. Together, these 3 markers can help differentiate RA assessment of prognosis, and follow-up is provided in from conditions that present with arthritis because they are Table 2. Diagnosis of RA can help differentiate OA from RA. positive less often in many non-RA conditions, such as OA. These markers may also alert clinicians to the coexistence Test Selection of RA in a patient with OA. Diagnosis Laboratory testing can help differentiate RA from other C-reactive protein (CRP) and erythrocyte sedimentation rate conditions that manifest with polyarthritis, such as OA, (ESR) are serological acute-phase markers of inflammation mainly by assisting with the diagnosis of RA. These tests that are also integrated into the ACR/EULAR criteria for RA classification.5 ESR can also help classify OA (Table 1).7,9 Figure. ACR/EULAR Classification Criteria for Rheumatoid Arthritis Patient with swollen joint(s) not explained by another condition 1 large joint 0 points 2-10 large joints 1 point Joint Involvement 1-3 small joints, w/ or w/o a large joint 2 points 4-10 small joints, w/ or w/o a large joint 3 points >10 joints w/ at least 1 small joint 5 points <6 weeks 0 points Symptom Duration ≥6 weeks 1 point Normal RF and CCP Ab 0 points RF and CCP Aba Low-positive RF or CCP Ab 2 points High-positive RF or CCP Ab 3 points Normal CRP and ESR 0 points CRP and/or ESR Elevated CRP or ESR 1 point Add points. Patient with ≥6 points (out of 10 possible) is classified as having RA. ACR/EULAR indicates American College of Rheumatology/European League Against Rheumatism; RF, rheumatoid factor; CCP Ab, cyclic citrullinated peptide antibody; CRP, C-reactive protein; and ESR, erythrocyte sedimentation rate. a These classification criteria are weighted for RF and CCP. However, 14-3-3η adds diagnostic sensitivity to the traditional markers of RF and CCP.10 This figure was developed by Quest Diagnostics based on reference 5. It is provided for informational purposes only and is not intended as medical advice. A physician’s test selection and interpretation, diagnosis, and patient management decisions should be based on his/her education, clinical expertise, and assessment of the patient. Criteria are designed to identify early-stage patients who are at high risk of persistent and/or erosive disease. Criteria have been designed to facilitate study of people with early-stage disease; they are not intended as diagnostic criteria.5 Diagnostic Services Immunology/Rheumatology Table 2. Tests Available to Support Diagnosis, Prognosis, and Follow-up of Rheumatoid Arthritis Test Code Assay Method Clinical Use 91472 Rheumatoid Arthritis Immunoturbidimetry (RF) Provides additional Diagnostic Panel IdentRA™ ELISA (CCP antibody and diagnostic and prognostic with 14-3-3 etaa 14-3-3 eta protein) value relative to each Includes RF IgM, CCP IgG, and assay alone 14-3-3 eta protein 19878 Rheumatoid Arthritis ELISA (RF IgG/A/M, CCP) Assist in diagnosis and Diagnostic Panel, Immunobead based enzyme determining prognosis of Comprehensive immunoassay (SS-A, SS-B) RA; may help differentiate Includes RF (IgG), RF (IgA), RF RA from primary