Importance of early diagnosis. The early symptomatic phase of rheumatoid arthritis (RA) represents a unique window of opportunity for intervention. Inflammation predominates in this phase of the disease, making immune mechanisms involved in the pathogenesis more responsive to treatment (Figure 1).1 Earlier diagnosis enables early treatment, which is important in the preservation of function for the long term.
Diagnosis of RA relies on patient history, physical examination, laboratory testing, and radiographic evidence of joint damage. RA is a chronic autoimmune disease that causes pain, stiffness, swelling, and limited motion and function of many joints. While RA can affect any joint, the small joints in the hands and feet tend to be involved most often. Chronic inflammation sometimes can affect several other organs as well, leading to comorbidities. The most common comorbidities of RA (in order of prevalence) are:
- Cardiovascular disease, in particular ischemic heart disease.2
- Infections, most commonly tuberculosis.3,4
- Mental health conditions, mainly anxiety and depression.5–8
Classification of RA. The American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) 2010 rheumatoid arthritis classification criteria are based on clinical presentation (synovitis and joint swelling), serology, acute-phase reactants, and duration of symptoms (Figure 2).9 The criteria are designed to identify early-stage patients who are at high risk of persistent and/or erosive disease.9
Figure 1: Cytokinetic Mechanisms in RA1
Figure 2: 2010 ACR/EULAR RA Classification Criteria
Measures of disease activities (Tables 1 and 2)10–14
- The Disease Activity Score (DAS) and its derivatives, DAS28 (a 28-joint count) and DAS-CRP (using CRP [C-reactive protein] in place of ESR [erythrocyte sedimentation rate]), are widely used in randomized controlled trials.10,12
- The advantage of providing a score for current disease activity rather than as a change score (as in ACR20, 50, and 70) makes the various DAS scores a “truer” reflection of the patient’s current disease status.12
- The Simplified Disease Activity Index (SDAI) and an even further simplified version (no acute-phase reactant needed), the Clinical Disease Activity Index (CDAI), are strongly correlated with DAS.12
- The RAPID3 (Routine Assessment of Patient Index Data) instrument was developed for the monitoring of patients in clinical care, given the ease of its use for both patients and rheumatologists.12,14
Table 1: Instruments for Measuring RA Disease Activity10,11
Table 2: Outcome Measures in RA by Disease Activity Instrument
- Laboratory testing can help in the differential diagnosis of RA versus other conditions that manifest with polyarthritis, such as osteoarthritis, and in the identification of subtypes of RA with different prognosis and response to treatment.
- Rheumatoid factor (RF) and anti-citrullinated protein/peptides antibodies (ACPAs) are established biomarkers that are integrated into ACR/EULAR criteria for RA classification.9 The 14-3-3η protein is a newer marker for RA that has higher sensitivity in early RA than either RF or ACPAs and therefore can identify RA in some cases that are not identified using RF or ACPAs.15,16 CRP and ESR are serological acute-phase markers of inflammation that are also integrated into the ACR/EULAR criteria for RA classification.9
RF and citrullinated cyclic peptide (CCP) tests
- The reported sensitivity of RF test is 57% for early RA17 and ranges from 60–86% for established RA.17,18 Specificity is relatively low (70–85%) for early and established RA.16,18–20 RF titer is most often assessed using latex agglutination or immunoturbidimetry, which primarily detects immunoglobulin (Ig) M RF. IgM RF, IgA RF, and IgG RF can also be measured individually with specific immunoassays.16,19 The presence of IgA RF, IgG RF, or both in patients with IgM RF and joint disease markedly increases the likelihood that the patient has RA.20
- ACPAs appear long before signs of inflammation and immunity in the joints of some RA patients and are assessed by immunoassay with a filaggrin-derived CCP. The sensitivity of the CCP test is comparable to that of RF in early (59%)17 and established RA (64–88%).17,20 CCP is also highly specific (90–98%) for early and established RA.16,18,21,22
- The 14-3-3η protein is elevated in serum and synovial fluid during joint inflammation.23 14-3-3η provides higher sensitivity for early RA than RF or CCP antibody testing. The addition of serum 14-3-3η measurement to RF and CCP antibody testing provides greater sensitivity for early RA. This increased sensitivity may translate into treatment earlier in the course of disease, which can minimize irreversible joint damage.15,16
CRP and ESR
- CRP and ESR measurement can be used in combination with other laboratory and clinical results to identify patients with RA. CRP is produced by the liver in response to tissue injury, infection, and inflammation. Levels increase during periods of heightened RA disease activity, but elevations may also reflect inflammation due to other causes, such as infection or injury. The ESR typically rises 24 to 48 hours after an inflammatory stimulus and gradually returns to normal levels. ESR measurement may help assess disease activity when other clinical and laboratory studies yield equivocal results.
- Arend WP, Dayer JM. Cytokines and cytokine inhibitors or antagonists in rheumatoid arthritis. Arthritis Rheum. 1990;33:305-315.
- Symmons DP, Gabriel SE. Epidemiology of CVD in rheumatic disease, with a focus on RA and SLE. Nat Rev Rheumatol. 2011;7:399-408.
- Wasko MC. Comorbid conditions in patients with rheumatic diseases: an update. Curr Opin Rheumatol. 2004;16:109-113.
- Mikuls TR, Saag KG. Comorbidity in rheumatoid arthritis. Rheum Dis Clin North Am. 2001;27:283-303.
- Dickens C, McGowan L, Clark-Carter D, Creed F. Depression in rheumatoid arthritis: a systematic review of the literature with meta-analysis. Psychosom Med. 2002;64:52-60.
- Minor MA, Brown JD. Exercise maintenance of persons with arthritis after participation in a class experience. Health Educ Q. 1993;20:83-95.
- Odegård S, Finset A, Mowinckel P, et al. Pain and psychological health status over a 10-year period in patients with recent onset rheumatoid arthritis. Ann Rheum Dis. 2007;66:1195-1201.
- Soderlin MK, Hakala M, Nieminen P. Anxiety and depression in a community-based rheumatoid arthritis population. Scand J Rheumatol. 2000;29:177-183.
- Aletaha D, Neogi T, Silman AJ, et al. 2010 Rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheum. 2010;62:2569-2581.
- Anderson J, Caplan L, Yazdany J, et al. Rheumatoid arthritis disease activity measures: American College of Rheumatology recommendations for use in clinical practice. Arthritis Care Res (Hoboken). 2012;64:640-647.
- Singh JA, Saag KC, Bridges SL Jr, et al. 2015 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis. Arthritis Rheumatol. 2016;68(1):1-26.
- Yazici Y. Monitoring response to treatment in rheumatoid arthritis—which tool is best suited for routing “real world” care? Bull NYU Hosp Jt Dis. 2007;65(suppl 1):S25-28.
- Zatarain E, Strand V. Monitoring disease activity of rheumatoid arthritis in clinical practice: contributions from clinical trials. Nat Clin Pract Rheumatol. 2006;2:611-618.
- Pincus T, Yazici Y, Bergman MJ. RAPID3, an index to assess and monitor patients with rheumatoid arthritis, without formal joint counts: similar results to DAS28 and CDAI in clinical trials and clinical care. Rheum Dis Clin North Am. 2009;35:773-778.
- Maksymowych WP, van der Heijde D, Allaart CF, et al. 14-3-3η is a novel mediator associated with the pathogenesis of rheumatoid arthritis and joint damage. Arthritis Res Ther. 2014;16:R99.
- Maksymowych WP, Naides SJ, Bykerk V, et al. Serum 14-3-3η is a novel marker that complements current serological measurements to enhance detection of patients with rheumatoid arthritis. J Rheumatol. 2014;41:2104-2113.
- Dubucquoi S, Solau-Gervais E, Lefranc D, et al. Evaluation of anti-citrullinated filaggrin antibodies as hallmarks for the diagnosis of rheumatic diseases. Ann Rheum Dis. 2004;63:415-419.
- Greiner A, Plischke H, Kellner H, Gruber R. Association of anti-cyclic citrullinated peptide antibodies, anti-citrullin antibodies, and IgM and IgA rheumatoid factors with serological parameters of disease activity in rheumatoid arthritis. Ann N Y Acad Sci. 2005;1050:295-303.
- 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.
- Suzuki K, Sawada T, Murakami A, et al. High diagnostic performance of ELISA detection of antibodies to citrullinated antigens in rheumatoid arthritis. Scand J Rheumatol. 2003;32:197-204.
- Bizzaro N, Mazzanti G, Tonutti E, et al. Diagnostic accuracy of the anti-citrulline antibody assay for rheumatoid arthritis. Clin Chem. 2001;47:1089-1093.
- Lee DM, Schur PH. Clinical utility of the anti-CCP assay in patients with rheumatic diseases. Ann Rheum Dis. 2003;62:870-874.
- Kilani RT, Maksymowych WP, Aitken A, et al. Detection of high levels of 2 specific isoforms of 14-3-3 proteins in synovial fluid from patients with joint inflammation. J Rheumatol. 2007;34:1650-1657.