© Borgis - Postępy Nauk Medycznych 2/2012, s. 103-108
Wczesne zapalenie stawów – aktualny stan wiedzy
Early arthritis – current state of knowledge**
Professor Eleonora Reicher Institute of Rheumatology, Warsaw
Consultant: prof. Anna Filipowicz-Sosnowska, MD, PhD
Wczesne zapalenie stawów jest często niezróżnicowanym zapaleniem o różnym początku (jedno-, kilku- i wielostawowym) w którym czas trwania choroby nie przekracza 3 miesięcy. U wielu chorych czynnik reumatoidalny (RF-IgM) jest ujemny oraz brak jest innych objawów umożliwiających spełnienie kryteriów klasyfikacyjnych. Większość chorych z wczesnym niezróżnicowanym zapaleniem stawów rozwija w różnie długim okresie czasu reumatoidalne zapalenie stawów (RZS). W doniesieniu przedstawiono znaczenie występowania, miana i typu przeciwciał anty-cytrulinowych w diagnostyce i prognozowaniu we wczesnym zapaleniu stawów, rolę zakażenia Porphyromonas gingivalis jako potencjalnego czynnika etiopatogenetycznego w RZS, trudności w ocenie klinicznej wczesnego zapalenia błony maziowej i niską przydatność konwencjonalnej radiografii we wczesnym wykrywaniu zmian destrukcyjnych w stawach. Przedstawiono różnice w odniesieniu do czułości i specyficzności starych (ACR 1987) i nowych (ACR/EULAR 2010) kryteriów klasyfikacyjnych RZS.
Early arthritis is often undifferentiated with various oncet (mono, oligo or polyarticular) and the duration of the symptoms less than 3 months. Most of the patients have negative rheumatoid factor (RF-IgM) and also there is no present other clinical symptoms satisfied for fulfiling classification criteria. Majority of patients with undifferentiated arthritis, in the various period of time, progress to rheumatoid arthritis (RA). In this review focuses on the importance of occurrence anti-citrullinated peptides (ACPA), they level and nature in making the diagnosis and prognosis of early arthritis, the role of Porphyromonas gingivalis infection as potential etiological factor of inflammation in RA, diffculty in clinical assessment of synovitis and inability of conventional radiography to detect early destructive changes in the joints. The differences in the sensitivity and specyficity the old (ACR 1987) and new (ACR/EULAR 2010 ) classification criteria for RA was discussed.
What is early arthritis?
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).
Table 1. Difficulties in establishing an early diagnosis of rheumatoid arthritis.
|– Differential diagnosis with other types of polyarthritis.|
– Moderate synovitis is not detected in a physical examination.
– There are no reliable diagnostic laboratory tests.
– Conventional radiography does not detect early erosive lesions.
– Difficulties in obtaining early rheumatological consultation.
– The 1987 ACR classification criteria offer poor discriminative ability for early RA.
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).
Antibodies as an early rheumatoid arthritis biomarker
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 (2nd 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).
Table 2. Sensitivity and specificity of anti-CCP, anti-MCV and RF-IgM tests in patients with early rheumatoid arthritis.*
|Anti-CCP2 + anti-MCV||68
|Anti-MCV + RF-IgM||71
|Anti-CCP2 + RF-IgM||74
*Van der Linden MPM et al. Arthritis Rheum 2009; 60: 2232-41 (the summary of results modified by the author).
Anti-citrulline autoantibodies in the diagnostics and prognostics of early rheumatoid arthritis
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).
Anti-CCP2 antibodies and the rheumatoid factor (RF-IgM) are the best predictors of persistent RA in patients with very early synovitis.
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.
In another study, Syversen S et al. demonstrated that RA patients with high levels of anti-CCP2 antibodies are 10 times more likely to develop joint erosions in comparison to anti-CCP2 negative patients and approximately 5 times more likely as compared to patients with low anti-CCP2 antibody levels. The study outcomes contributed to the development of a new classification criteria for early RA, and confirmed the importance of early introduction of biological therapy.
Anti-MCV antibodies detect an antigen that occurs naturally in the body, while anti-CCP3 antibodies detect synthetic citrullinated peptide. Anti-MCV antibodies are less frequently detected in early polyarthritis as compared to anti-CCP2 antibodies, despite being more powerful predicting factors of severe erosive course of the disease. Patients with anti-MCV and anti-CCP2 antibodies represent a similar subtype of RA. The level of antibodies in synovial fluid is substantially higher than in serum, which indicates that they are generated and produced locally, depending on genetic predisposition (27).
Throughout 30 months of observation study by Guziana MC et al. on group of 253 patients with early polyarthritis, changes in the autoantibody levels were confirmed to be induced by intensive therapy with disease-modifying antirheumatic drugs (DMARDs). Treatment-related changes or reversions in RF-IgM levels can occur, especially if the antibody titre is low at the beginning of the disease, which is a favourable prognostic factor for radiographic progression. Anti-MCV antibodies may disappear or re-occur during the treatment. However, the presence of anti-MCV autoantibodies – irrespectively of any possible antibody level fluctuations or reversions – remains an independent predictor of a severe course of the disease and is associated with a low likelihood of remission. Unlike RF-IgM and anti-MCV, the level of anti-CCP2 antibodies is generally stable during the treatment.
Anti-CCP antibodies indicate aggressive course of the disease and correlate positively with the genetic factors predisposing to the development of RA, such as in particular: protein tyrosine phosphatase N22 gene (PTPN22) and shared epitope (SE), mainly HLA-DRB104 (29). Anti-CCP antibodies do not identify any specific antigen initiating or maintaining an inflammatory immune response in the joint, but are directed towards a variety of citrullinated proteins and have limited cross-reactivity.
Porphyromonas gingivalis – a potential etiological factor of rheumatoid arthritis
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