Abstract
Rheumatoid arthritis is an autoimmune disorder which involves inflammation of the synovial tissue, leading to synovial proliferation, bone erosion and ultimately joint disability. It is a complex disorder, and the proper etiology is still unknown. Both environmental and genetic factors are responsible for the development of Rheumatoid arthritis. Clinically, the disease is generally diagnosed by the presence of auto-antibodies like Rheumatoid factor. But these are not specifically associated with Rheumatoid arthritis. These are also present in patients with other autoimmune disorders and also in healthy persons. Citrullinated epitopes are shown to be more specific for Rheumatoid arthritis. Citrullination normally occurs in cells undergoing apoptosis, and hence, citrullinated proteins are cleared from body and not encountered by immune system. However, in Rheumatoid arthritis patients, these are not cleared. Anti-citrullinated protein antibodies are detectable in patients at risk of Rheumatoid arthritis long before the onset of the disease. The concentration of which normally increases as the disease progress. Hence, these are important for diagnosis of Rheumatoid arthritis. This review is focused on the importance of anti-citrullinated protein antibodies in disease pathogenesis and its importance in the diagnosis of Rheumatoid arthritis.
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Introduction
Rheumatoid arthritis (RA) is a systematic, inflammatory joints disease, occurs as a chronic inflammatory disorder that is characterized by cartilage destruction [4, 24]. It is related to other autoimmune disease families like insulin-dependent diabetes mellitus (IDDM) and thyroid diseases [45]. Worldwide, its prevalence is about 0.5–1 % while 0.55–0.75 % of the Pakistani population is affected by RA. Women are three times more susceptible than men with sex ratio of 2–4. Although people at any age are vulnerable to the disease, it is more frequent at the age of 40–50 years. Rheumatoid arthritis is not a life-threatening disease directly, but a patient’s life quality is severely affected by it [39].
Exact etiology of RA is not so far known, but its development depends upon interaction between genetics elements in individual and non-genetic factors. Considerable amount of data have suggested that autoimmunity markers and genetic factors and are very good indicators [20]. Genetic factors like MHC-II (major histocompatibility complex II) and non-MHC alleles, processes related to autoimmunity and environmental factors are very crucial in RA pathogenesis [14]. Pathogenesis of RA involves in a number of cellular responses. Autoimmune responses mediated T cell and B cells are important in inflammatory cascade initiation. Then T cells, B cells, macrophages and neutrophils migrate into synovial tissues, where they produce immune mediator that break down the extracellular matrix, in particular that of cartilage [30]. As a result synovial hypertrophy and angiogenesis occurs this leads into osteoclasts activation and then bone erosion. T cells and synovial fibroblast also generate inflammatory cytokines that differentiate monocyte-macrophage lineage cells to mature osteoclasts that leads to bone resorption and erosion [44]. So, diagnosis at early stage and instant, valuable therapy is important in order to avoid joint destruction, functional disability and horrific outcome of infection [2, 35].
The availability of sophisticated and efficient therapies [40] and early intervention is important in preventing irreversible damage of joints [7, 23]. It is utmost crucial to identify RA in the early stage. Although the classification criteria for RA described by American College of Rheumatology (1987) are often used as diagnostic tool for RA in clinical practice, they are not well suited for early diagnosis for RA [5, 36, 51]. The above-mentioned criteria rely mainly on the appearance of RA clinical symptoms but most of the time clinical symptoms do not appear in early stages. So, there is a need to develop a sensitive and specific serological marker, which is present in the early stages. So that rheumatologists would be able to use the expensive and toxic drugs to only those patients who are at high risks [19]. Therefore, a marker should be able to identify the erosive and non-erosive aggression of the infection. The anti-CCP antibodies fortunately meet the criteria for an efficient and useful marker for early RA.
In RA, auto-antibodies are present in patient’s serum. These are often not that much specific because these antibodies may also be present in patients with other diseases. Rheumatoid factor (RF) is one of the examples of such antibodies. It is a well-known highly non-specific autoantibody which is intended for to the Fc part of IgG molecules (Waaler 2007). It is normally present in 80 % of RA patients, but in many other diseases, it can be detected. It can also be detected in healthy people, especially in old age people (10–30 %) [31], thus lowering its specificity. Other RA-associated antibodies include ANA (antibodies to nuclear antigens), anti-RA33, anti-GPI (glucose-6-phosphate isomerase), anti-calpastatin, ANCA (anti-neutrophil cytoplasmic antibodies), anti-fibronectin and anti-collagen type II. Such type of auto-antibodies can also be detected in many other autoimmune diseases like SLE (systemic lupus erythematosus) and MCTD (mixed connective tissue disease) and in many normal individuals.
In the past decade, it has been shown that the autoantibodies which are highly specific for RA are aimed at citrulline-containing epitopes. Citrulline is a non-standard amino acid. It is named as because it is not incorporated into proteins during protein production, however, during posttranslational modification of arginine residues, it is incorporate which is carried out by peptidylarginine deiminase (PAD) [41]. The process of citrullination usually takes place in those cells that are going under the process of apoptosis. To our knowledge, the presence of citrullinated antigens in inflamed synovial tissue do not always indicate the presence of ACCP antibodies in serum and synovial fluid, whereas the exact structure of HLA molecules facilitates the induction of autoantibodies directed to citrullinated proteins [15]. History of ACPA started when anti-perinuclear antibodies (APF) and anti-keratin antibodies (AKA) were described [29, 56]. These antibodies can be detected with high specificity in about half RA patients. As a new diagnostic tool for RA, first-generation CCP test (anti-CCP1) has 68 % sensitivity with 97–98 % specificity [37]. For the improvement of CCP test sensitivity, several citrulline-containing peptides libraries were screened with RA serum pool and this led second-generation CCP test development (CCP2). CCP2 test is more sensitive as compared to RF (80 %), with superior specificity (98 %) [51].
Role in pathogenesis of RA
Discovery of ACPA provide us a new way to investigate those factors that are involve in RA. Anti-citrullinated protein antibodies are extremely specific for RA [52]. Before the onset of clinical symptoms, these auto-antibodies can be detected with increasing titers as patients approach disease onset [8, 28, 34]. Anti-citrullinated protein antibodies have been shown to be able to initiate and enhance arthritis in murine models of arthritis [22, 47], and they are able to activate both FcR-positive cells and the complement system, arguing that they could play a role in disease pathogenesis [9, 38, 46].
Several human leukocyte antigen (HLA) alleles, particularly those encoding the shared epitope (SE), are known to be associated with RA susceptibility, especially with ACPA-positive RA [13, 49]. These data indicate that antigen presentation and T cell involvement are important in the induction of ACPA. With T cell help, antigen-exposed B cells can undergo class-switching and avidity maturation. This occurs in germinal centers, where B cells compete for a limited source of antigens on follicular dendritic cells under antigen-specific control of follicular helper T cells [12, 33]. It is known that ACPA-producing B cells undergo isotype switching since ACPA of all isotypes can be detected in sera of RA patients [54]. Relatively little is known about the avidity maturation of ACPA before and during disease manifestation. Recently, we have shown that the avidity of the ACPA response is relatively low as compared to antibody responses against recall antigens in patients with established RA [42]. Recently, several studies have shown that during the pre-disease stage of RA, the ACPA response recognizes more epitopes [48], uses more isotypes and increases in levels [6]. In conclusion, the avidity of ACPA is in general low, but when analyzing individual patients, marked differences in the ACPA avidity can be observed. The avidity maturation of ACPA takes place before disease onset and then stabilizes.
There are a lot of studies that demonstrate the ACPA presence as a prognostic tool for severity of disease, RA development, as well as radiographic erosions in synovitis of recent onset [14, 18, 26, 27]. ACPA higher levels have been found in both, individuals who developed RA or who did not develop it. Several studies marked the predictive value ACPA presence [1, 11, 17]. Though, it is unclear until now, whether ACPA high levels predict poorer outcome or not [10, 25, 43]. In a study of 104 RA patients, ACPA higher baseline levels were linked with erosive disease after 2 years [53]. Ninety-nine RA patients in another study reported a slightly significant correlation between radiographic progression and baseline serum ACPA levels (Meyer et al. 2006). Another study of early 238 RA individuals showed a higher radiographic progression rate of high-positive ACPA versus low-positive ACPA patient groups after 10 years [43]. Two studies marked the levels of ACPA levels in individuals having longstanding RA. One study found a weak association in almost 180 patients between radiographic progression rate and ACPA levels. The other study was cross-sectional, consisting 241 RA patients. In this study, mean of disease duration was about for 8.6 years. In patients, mean of ACPA levels were similar with or without erosions [10, 25]. Several single nucleotide polymorphisms are linked with this disease like PTPN22, and it is specifically correlated with RA-ACPA positive [21, 32]. Whereas DRB1*03 is correlated with RA-ACPA negative disease, but not all of studies have confirmed this correlation [16, 55]. So such differences indicate that there are different disease entities of ACPA-positive and ACPA-negative RA.
Role as a new diagnostic biomarker
The diagnosis and treatment of RA has made tremendous progress in the last few years. Experts are even suggesting that a paradigm shift has occurred in the field of rheumatology. The development of effective diagnostic sero-markers and corresponding test systems, particularly ELISA, APF and AKA test assays, represents enormous progress in RA diagnostics but their problematic and lengthy immunofluorescence test format never let them to become typical tests for diagnosis. The widely used Anti-CCP2 assays that have high diagnostic sensitivity and specificity are widely used nowadays. It also shows significant prognostic and predictive worth in RA. It is a more specific test than RF because other types of arthritis and immunological disorders can be distinguished on the basis of this, and the signs and symptoms of which are mostly similar to RA [1, 11].
Anti-CCP2 test is more appropriate for diagnosis of early RA because these antibodies are present at early stage of the disease, and probably, this is due to this reason that in some advanced stage RA patients, the anti-CCP2 test shows negative results [28, 34]. But this is hard to say that a person showing positive result of anti-CCP2 test will develop RA in coming years or months, and this can also be just simply a false positive test. However, this test is in particular of great advantage to the clinician as these antibodies can be used as early markers for the onset of RA. In some studies, it was reported that a positivity of anti-CCP2 indicates the stage of undifferentiated arthritis, which will progress to RA within 3 years [3, 50]. In conclusion, anti-CCP2 assay has a lot more importance in the diagnosis of RA, and on the basis of these advantages, it has been included in the 2010 classification criteria for RA.
Conclusion
There is no proper assay available for the diagnosis of RA. Current assays like RF are not much specific for RA and are also detected in patients with other autoimmune disorders and in healthy individuals. So there is a need for the development of an assay which may be more specific for RA and which may also help in early diagnosis of RA before the onset of the diseased condition. ACPAs, which are citrullinated antibodies, are more specific for RA. This is second-generation CCP test (CCP2), which has more sensitivity as compared to RF and CCP1 (80 %) and more specificity than ever test available for RA (98 %). The presence of ACPA is prognostic for the disease severity. As shown in different studies, it is concluded that the level of ACPA is low before the onset of the disease and as the disease progress, ACPA level raises. However, ACPA is also detected in persons who are at risk of RA, before the disease onset.
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Moeez, S., John, P. & Bhatti, A. Anti-citrullinated protein antibodies: role in pathogenesis of RA and potential as a diagnostic tool. Rheumatol Int 33, 1669–1673 (2013). https://doi.org/10.1007/s00296-012-2635-6
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DOI: https://doi.org/10.1007/s00296-012-2635-6