Rheumatoid Arthritis Diagnostic Panel

Understanding Rheumatoid Arthritis
Rheumatoid Arthritis (RA) is a chronic and progressive inflammatory disorder resulting in destructive polyarthritis. It is characterized by proliferation of the synovial membrane leading to damage of the articular structures.¹

Demographics and Epidemiology
RA affects one percent of the population with greater prevalence in highly developed countries. In the U.S. there are 2.1 million RA patients.¹ Onset generally occurs between ages 30 and 50, but the younger the patient, typically, the poorer the prognosis.¹ Women are affected three times more often than men. It is estimated that 10–20 percent of those with early inflammatory arthritis go on to have persistent polyarthritis and ultimately RA.¹

Early Diagnosis: the Challenges and the Importance
Early RA symptoms are quite non-specific. These may include malaise, fatigue, weakness, muscle soreness, low-grade fever, weight loss, and monoarticular or oligoarticular pain and stiffness in the morning1. American College of Rheumatology's (ACR) Classification Criteria are rarely recognized in the early stages of the disease.⁴

Later symptoms are more specific and can lead to a definitive diagnosis via clinical evaluation. But typically this is 2-5 years after disease onset.¹ One problem with waiting to diagnose based on clinical evaluation is that radiographic evidence of bone destruction is evident in 2/3 of patients within the first two years of disease.¹

However, recent studies have shown that the early use of disease-modifying, anti-rheumatic drugs (DMARDs) can slow and vary the disease course.¹ New treatments specific to RA have greater impact when prescribed early.² These treatments suppress the immune system to reduce inflammation and slow joint destruction.³ These facts underscore how fundamentally important early diagnosis can be in terms of improving the prognosis of an RA patient. The problem again is that it may take several years before a definitive diagnosis of RA may be made on the basis of ACR’s Classification Criteria.

The New RA Panel: Earlier Diagnosis
Highly specific and sensitive tests are necessary to diagnose and initiate aggressive treatment regimens early on in the disease course.⁵ No one test exists that can accurately and definitively diagnose all RA.

Testing for Rheumatoid Factor (RF) alone is not enough. It can be found in only 70-80% of RA patients.⁵ Additionally, RF is present in numerous other rheumatic disorders.

Recent results show anti-cyclic citrullinated peptide (anti-CCP) is highly specific for early diagnosis and prognosis of RA (97%).⁵ Unlike RF, anti-CCP is found in only a small number of people without RA.⁵ Anti-CCP has shown strong association for erosive arthritis.³

*The specificity of anti-CCP and the sensitivity of RF together provide clinicians with a 95–99 percent positive predictive value for RA.⁵

The Combined Panel
Sensitivity and specificity of anti-CCP and RF for presence of RA.⁶

	CCP	RF
Sensitivity%	66.0	71.6
Specificity%	90.4	80.3

Further evidence for a combined panel.

% Positivity	Anti-CCP	RF
RA7	74	70
Sjogren's Syndrome8	8	59
Hepatitis C9	0	44
Osteoarthritis7	8	13
Psoriatic Arthritis10	7	11
Healthy Donors5	1	7

Test Results
Anti-CCP + / RF + ³
In early RA, these positive test results for both RF and anti-CCP are predictive of disease progression and joint destruction.

Anti-CCP + / RF – ^8-11
This result is consistent with rheumatoid arthritis in a patient with polyarthritis. A positive anti-CCP result is often found in patients with early RA and may be associated with progression of joint destruction.

Anti-CCP – / RF + ³
This result is possibly consistent with rheumatoid arthritis in a patient with polyarthritis. However, positive RF and negative anti-CCP are found in patients with other rheumatic diseases such as systemic lupus erythematosus, scleroderma, primary Sjögren's syndrome, mixed connective tissue disease, polymyositis/dermatomyositis and cryoglobulinemia. These test results may also be found in 5-6% of healthy older individuals.

Anti-CCP – / RF – ³
These serologic results may be found in 10–20 percent of patients with polyarthritis that is clinically and radiologically indistinguishable from RA.

Diagnose Earlier
Use of the RA panel can help diagnose RA earlier than using RF alone or diagnosing via clinical evaluation. Earlier diagnosis means earlier treatment and the potential to reduce the long-term affects of RA.¹

Key Assays for diagnosis and monitoring of RA

Assay	Clinical Use
Rheumatoid Factor (RF)	Widely used test to assist in diagnosis and determine prognosis; primarily detects IgM RF
Anti-Cyclic Citrullinated Peptide (Anti-CCP)	Assists in diagnosis and determining prognosis of RA – more specific than RF
Rheumatoid Arthritis Diagnostic Panel -RF-Anti-CCP	Provides additional diagnostic and prognostic value relative to either assay alone
Erythrocyte Sedimentation Rate (ESR)	Assesses disease activity, however, limited by sample stability, influenced by anemiaand protein concentration
C-Reactive Protein (CRP)	Assesses disease activity. More rapid change than ESR. Not influenced by anemia or protein concentration

References
¹ Cush, JJ and Kavanaugh, A. Rheumatoid Arthritis: Early Diagnosis and Treatment, First Edition. Caddo, OK: Professional Communications, Inc., 2005.
² Visser, H, le Cessie S, Vos K et al. How to diagnose rheumatoid arthritis early: a prediction model for persistent (erosive) arthritis. Arthritis Rheum. 2002; 46:357-365.
³ Vencovsky J. Machacek S, Sedova L, et al. Autoantibodies can be prognostic markers of an erosive disease in early rheumatoid arthritis. Ann Rheum Dis. 2003; 62:427-430.
⁴ Harrison BJ, Symmons DP, Barrett EM, Silman AJ. The performance of the 1987 ARA classification criteria for rheumatoid arthritis in a population based cohort of patients with early inflammatory polyarthritis. American Rheumatism Association. J Rheumatol. 1998;25:2324-2330.
⁵ Vallbracht I, Rieber J, Oppermann M, et al. Diagnostic and clinical value of anti-cyclic citrullinated peptide antibodiescompared with rheumatoid factor isotypes in rheumatoid arthritis. Ann Rheum Dis. 2004; 63:1079-1084.
⁶ Lee DM, Schur PH. Clinical utility of the anto-CCP assay in patients with rheumatic diseases. Ann Rheum Dis. 2003; 62:870-874.
⁷ Sauerland U, Becker H, Seidel M, et al. Clinical utility of the anti-CCP assay: experiences with 700 patients. Ann N Y Acad Sci. 2005; 1050:314-318.
⁸ Gottenberg Je, Mignot S, Nicaise-Rolland P, et al. Prevalence of anti-cyclic citrullinated peptide and anti-keratin antibodies in patients with primary Sjögren’s syndrome. Ann Rheum Dis. 2005; 64:114-117.
⁹ Wener MH, Hutchinson K, Morishima C, et al. Absence of antibodies to cyclic citrullinated peptide in sera of patients with hepatitis C virus infection and cryoglobulinemia. Arthritis Rheum. 2004; 50:2305-2308.
¹⁰ Alenius GM, Berglin E, Rantapaa-Dahlqvist S. Antibodies against cyclic citrullinated peptide (CCP) in psoriatic arthritis with or without manifestations of joint inflammation. Ann Rheum Dis. 2005; [Epub ahead of print].

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