Early arthritis is a group of rheumatic and nonrheumatic disorders characterized by unclassified arthritis beginning with mono-, oligo-, or polyarthritis, lasting up to 3 months. Rheumatoid factor (RF-IgM) is negative in many patients, and the patients have so other symptoms corresponding to the classification criteria for other diseases. The course of the disease is impossible to predict, as well as the time needed to diagnose the disease in individual patients. There are no laboratory tests that clearly differentiate early rheumatoid arthritis from other types of early arthritis, such as arthritis in infectious (viral or bacterial), reactive arthritis, arthritis accompanying cancer and systemic connective tissue diseases (1, 2).

Early arthritis represents an essential diagnostic, prognostic and therapeutic issue, all the more that the majority of patients with early unclassified arthritis develop RA at different time points (3).

There are many reasons why it is difficult to diagnose RA at an early stage of its development. Early unclassified arthritis needs to be differentiated from a number of inflammatory joint diseases, such as: systemic lupus erythematosus and other systemic connective tissue diseases, reactive arthritis, psoriatic arthritis, osteoarthritis (mainly hand osteoarthritis), as well as arthritis associated with infections and cancer.

Other factors that make early RA diagnosis difficult can be as follows: low discriminative power of the conventional ACR 1987 classification criteria for early forms of the disease, inability to detect moderate synovitis in a physical examination, absence of diagnostically reliable laboratory tests, late detecting joint erosions in conventional radiography, and difficulty in obtaining early rheumatological consultation (tab. 1).

According to the European League Against Rheumatism recommendations for the diagnosis of early arthritis, patients presenting with arthritis of more than one joint should be referred to and seen by a rheumatologist, ideally within six weeks after the onset of symptoms. Another step in the diagnostic procedure should be also to try to determine the patients at risk of developing persistent erosive arthritis in order to introduce an optimum therapeutic strategy as early as possible (4).

RA is associated with two antibody systems: rheumatoid factor (RF) and ACPA-antibody to citrullinated peptide (5). Rheumatoid factor is an antibody to the Fc portion of immunoglobulin G (IgG) and has been the core factor used in the diagnostics and prognosis of RA. High rheumatoid factor levels are associated with severe erosive disease, rheumatoid nodules, vasculitis and extra-articular symptoms. The role of rheumatoid factor in pathogenesis and maintenance of RA is yet to be clearly understood. Rheumatoid factor was found not only in patients with RA, but also in patients with other diseases and in some healthy individuals, especially in the elderly, which reduces the factor’s specificity and diagnostic reliability.

Anti-citrullinated protein antibodies (ACPA), i.e.: vimentin, filaggrin, collagen type II, fibrinogen and α-enolase, represent another powerful biomarker in RA diagnostics and prognosis.

The presence of citrulline generated posttranslationally by peptidilarginine diminaze (PAD2) is essential in citrullinated peptides (6). Anti-citrulline antibodies are detected in patients with RA and have been for many years used in RA diagnostics. Anti-citrulline antibodies include in particular: anti-keratin antibodies (AKA), anti-filaggrin antibodies (AFA) and antiperinuclear factor (APF). AKA, AFA and APF have a number of variables but they react with native filaggrin, and are therefore referred to as anti-filaggrin antibodies (AFA) (9, 10). They represent relatively high specificity for RA (> 90%), but have low sensitivity (> 30%) and do not meet the diagnostic test criteria. Anti-RA33 and anti-Sa antibodies were also thought to be useful in early RA diagnostics (11, 12). Anti-RA33 antibodies are antibodies against a specific heterogeneous nuclear ribonucleoprotein complex (A2-RNP). Anti-Sa antibodies were confirmed to be directed to vimentin found in human spleen and placenta extract. Anti-filaggrin antibodies like, anti-RA33 and anti-Sa antibodies show high specificity, but low sensitivity in RA diagnostics.

The ELISA method with the use of synthetic filaggrin-derived citrullinated peptides marked a significant progress in RA diagnostics. Anti-CCP1 (1st generation) test was based on incorporating cyclic peptide into a filaggrin molecule, representing 69% sensitivity and 81% specificity in RA diagnostics. In order to achieve higher sensitivity, citrullinated peptides were used instead of filaggrin to develop an anti-CCP2 (2^nd generation) test representing 82% sensitivity and 95% specificity (13, 14).

Two new tests that detect citrullinated peptides autoantibodies have been introduced recently: anti-CCP3 (3rd generation) test and anti-MCV test for modified citrullinated vimentin. Anti-CCP3 test is based on a modified cyclic peptide used in anti-CCP1 and anti-CCP2 tests. Mutated citrullinated vimentin is used in the anti-MCV test (15-17). Anti-CCP3 test has comparable sensitivity and specificity to the anti-CCP2 test, which is similar to the anti-MCV test, which offers a clinically significant benefit – identification of anti-CCP2 negative patients.

Anti-CCP2 and anti-MCV positive test combination shows 69% sensitivity and 89% specificity in the diagnostics of early rheumatoid arthritis; anti-MCV and RF-IgM positive test combination shows 71% sensitivity and 88% specificity. The highest sensitivity and specificity was shown for anti-CCP2+RF-IgM test combination (74% and 96%, respectively), which was used in the development of the new classification criteria for RA (tab. 2) (15).

The diagnostic parameters of anti-CCP2 test for early RA were confirmed in a number of studies. Anti-CCP2 test was found to offer 82% sensitivity and 95% specificity in the diagnostics of early RA lasting up to 3 years (19). In steady long-term RA, the test sensitivity equalled 77%. Goldbach-Mansky R et al. (20) have demonstrated 41% sensitivity and 91% specificity of the anti-CCP2 test in a group of 238 patients with very early arthritis lasting up to 3 months, while the rheumatoid factor (RF-IgM) was demonstrated to offer 66% sensitivity and 87% specificity. The differences in the assessment of anti-CCP2 test sensitivity may depend on the selection of study subjects (very early RA vs. early RA vs. advanced RA, etc.). It is commonly claimed that the anti-CCP2 test has the highest specificity for RA (97%). Rheumatoid factor (RF-IgM) shows a slightly higher sensitivity than the anti-CCP2 test (68.4%), but has a lower specificity (84%). Anti-CCP2 test is positive in 40% RA patients who remain negative for the rheumatoid-factor, which reflects the test’s additional diagnostic value. The high predictive value of anti-CCP2 and rheumatoid factor for RA development and progress was demonstrated in a number of studies (22). The presence of anti-CCP2 antibodies and the rheumatoid factor may be the predictive factor of RA, as shown on a group of blood donors and patients with unclassified arthritis (23).

Based on two years of observation of a group of patients with early synovitis, Visser H et al. used a logistic regression model to develop prediction criteria for the course of early arthritis to differentiate patients with self-limiting, non-erosive, progressive and progressive erosive type of the disease. Anti-CCP2 antibodies, the rheumatoid factor and early joint erosions were once again proved to be powerful predictors of erosive RA.

Kastbom A et al. demonstrated that anti-CCP2 positive patients typically exhibit high inflammatory activity and are more likely to develop joint erosions at an early stage of the disease as compared to anti-CCP2 negative patients.