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Anti CCP Antibodies Anti-Cyclic Citrullinated Peptide (anti-CCP) Antibodies Anti-CCP antibodies are potentially important surrogate markers for diagnosis and prognosis in rheumatoid arthritis (RA), because they: • • • • are as sensitive as, and more specific than, IgM rheumatoid factors (RF) in early and fully established disease may predict the eventual development into RA when found in undifferentiated arthritis are a marker of erosive disease in RA may be detected in healthy individuals years before onset of clinical RA First described as a marker for RA in 1964, anti-perinuclear factor (APF) was directed to constituents of the keratohyaline granules near senescent buccal mucosal cell nuclei, later found to contain the “filament aggregating protein” filaggrin. Despite its specificity for RA, because of exacting technical requirements, APF never became widely used. Anti-keratin antibodies (AKA), first described in 1979, bound filaggrin tightly bound to keratin in senescent esophageal cells. As was APF, AKA had greater specificity for RA than RF. Antibodies to the so-called Sa antigen, described first in 1994, bound post-translationally modified vimentin, a cytoskeletal intermediate filament protein found in mesenchymal cells. Since 1998 it has become increasingly evident that all of the above antibodies likely target citrullinated proteins. Citrulline is a non-standard amino acid, created by de-imination of arginine residues in several proteins by the action of peptidylarginine deiminase (PAD). There are several isotypes of this enzyme; in the inflammatory RA synovium, PAD 2 and PAD 4 are abundant. These enzymes cause the local citrullination of synovial proteins, such as fibrin. Interestingly, citrullinated peptides fit better in the HLA DR4 (DRB1*0401 or *0404) antigen binding grooves than the corresponding arginine containing peptides, findings that link this www.healthoracle.org 1 immune response to the shared epitope hypothesis of RA pathophysiology. Citrullinated extracellular fibrin in the RA synovium may be one of the major autoantigens driving the local immune response, suggested by the discovery of local production of anti-CCP and anti-citrullinated filaggrin antibodies in the joint. Also, functional haplotypes of PADI4 may be associated with RA. The citrulline moiety is the true determinant on proteins recognized by APF, AKA, and possibly anti-Sa. Detailed studies of citrullinated filaggrin peptides showed that different patients with RA recognized different linear citrullinated peptides, indicating a polyclonal response. Flanking regions around the citrulline residue are important for the reactivity, so not all sera are reactive with every peptide. The first generation of ELISa for anti-CCP (CCP1), using several filaggrin epitopes, had high specificity for RA and a sensitivity of 65-70% (1). Various cyclic epitopes that mimic true conformational epitopes were selected from libraries of citrullinated peptides for the widely available 2nd generation anti-CCP assay (CCP2). Diagnostic use of autoimmune serology in RA RF has been used as a marker of RA for more than half a century. IgM RF, the isotype most typically detected, is seen not only in RA but also in various other conditions. IgA RF, more easily detected than IgG RF, may be a better indicator of T-cell dependent affinity matured antibodies directed to particular Fc-gamma epitopes relevant to RA than IgM RF, but it has never gained wide interest. The combined detection of IgM and IgA RFs in a serum is a strong indicator of RA. Most studies published to date comparing the sensitivity and specificity of RFs and anti-CCP antibodies for the diagnosis of RA have used the CCP1 assay. In general, the sensitivity of anti-CCP has been comparable to RF (50-75%) with a higher specificity (90-95%). More recent studies using the CCP2 assay show higher sensitivity for RA than CCP1, with equally high specificity. www.healthoracle.org 2 Clinical use of anti-CCP In many early cases of RA, clinical symptoms are milder and nonspecific, and patients will not fulfill ACR classification criteria for RA. Therefore, the detection of a disease-specific autoantibody like anti-CCP could be of great diagnostic and therapeutic importance. Anti-CCP antibodies may be detected in roughly 50-60% of patients with early RA at ‘baseline’(e.g., at their initial encounter with a specialist, usually after 3-6 months of symptoms). The specificity of anti-CCP is around 95-98% as regards undifferentiated forms of arthritis that do not develop into RA. IgM RF is often found in the same patients, but with much lower specificity for RA. One study using a CCP1 assay showed a sensitivity of 55% and a specificity of 97% specificity for RA, when both anti-CCP and IgM RF were positive in the early stage of arthritis. More recent studies using the CCP2 assay have shown even higher prevalence at the first visit to clinics; in one study anti-CCP antibodies were found in 70% of such patients. Interestingly, using stored samples, anti-CCP could be detected 1.5 to 9 years before the onset of arthritis. A study using the CCP2 assay found progression from undifferentiated polyarthritis to RA in 93% of anti-CCP positive patients but only in 25% of antiCCP negative patients after 3 years of follow-up. In a study of patients with RA or palindromic rheumatism, anti-CCP (CCP1) were found in 55% of both conditions, indicating that palindromic rheumatism is closely related to and often progresses to RA. Several observations have indicated that anti-CCP positive early RA patients may develop a more erosive disease than those without antiCCP. Other investigators have confirmed this, and suggested the superiority of anti-CCP over IgM RF in predicting an erosive disease course. The use of anti-CCP results in the decision whether a patient should be treated aggressively at an early stage or not is an important area for research. In addition, the relationship of levels of anti-CCP antibodies and various therapeutic interventions is under investigation. www.healthoracle.org 3 Conclusions The use of anti-CCP antibodies may allow the clinical rheumatologist to better predict the diagnosis and prognosis of individual patients with RA. Whether this or other serologic tests will allow more rational therapeutic decision-making and hence influence the longterm outcome of the disease will be determined by further study. Testing Rheumatoid arthritis is both common and chronic, with significant consequences for multiple organ systems. Better understanding of its pathophysiology has led to the development of targeted therapies that have dramatically improved outcomes. The key to therapeutic success lies in identifying individuals who will have severe destructive disease as early as possible, so that effective treatment can be initiated before irreversible damage occurs. Anti-cyclic citrullinated peptide (anti-CCP) antibody testing is particularly useful in the diagnosis of rheumatoid arthritis, with high specificity, presence early in the disease process, and ability to identify patients who are likely to have severe disease and irreversible damage. However, its sensitivity is low, and a negative result does not exclude disease. Anti-CCP antibodies have not been found at a significant frequency in other diseases to date, and are more specific than rheumatoid factor for detecting rheumatoid arthritis. We discuss antiCCP antibody testing in rheumatoid arthritis, with an emphasis on diagnostic performance, prognostic capability, and relevance to pathogenesis and new treatment paradigms in rheumatoid arthritis. Rheumatoid arthritis (RA) is a common systemic autoimmune disease with a prevalence of about 1% worldwide. The American College of Rheumatology (ACR) criteria for the classification of RA are not very well suited to diagnose RA at an early stage of the disease, because these criteria rely heavily on the expression of clinical symptoms of RA. In early RA these clinical parameters are often not (yet) manifest. Therefore, a specific and sensitive (serological) marker, which is www.healthoracle.org 4 present very early in the disease, is needed. A good marker should ideally not only indicate the development of the disease, but also be able to predict its erosive or non-erosive progression. The serological parameter that meets these requirements for a good and useful marker for early RA is the anti-citrullinated protein antibody. The sensitivity of this antibody is comparable to that of the rheumatoid factor (RF) (approximately 80%), but its specificity is much higher, about 98%. Several assays have been developed to detect this class of auto-antibodies, which are termed anti-CCP because the most sensitive test is based upon cyclic citrullinated peptides. Most patients with rheumatoid arthritis (RA) have some marker of the disease in the blood. This might include: • • • • • positive rheumatoid factor (RF) cyclic citrullinated peptide (CCP) antibody elevated measures of inflammation an increase erythrocyte sedimentation rate (ESR) C-reactive protein (CRP). On the other hand, occasionally a patient with RA may have active disease and all these tests are normal. In general, those patients without these abnormalities in the blood are less likely to develop joint damage. Almost all patients with lupus have the presence of the antinuclear antibodies (ANA) or if negative, an SSA antibody or antiphospholipid antibodies (associated with an increased risk of thrombosis such as a blood clot or stroke or miscarriage). Once again, there are patients, although rare, who have lupus despite these negative tests. Most Sjögren’s syndrome patients will typically exhibit an elevated ESR or have a positive ANA, RF, SSA or SSB antibody in their blood. It is important to remember that while blood tests are helpful in confirming a diagnosis and assessment of disease activity, it is more important to diagnose and treat based on the patient’s clinical presentation. www.healthoracle.org 5 According to the Arthritis Foundation, if you have signs or symptoms of arthritis for more than two weeks, it is time to see a doctor. These warning signs include: • • • • joint pain stiffness swelling difficulty moving a joint Self treating is not recommended for patients with new symptoms until the cause can be confirmed. The reason for this caution is that arthritis may be a symptom of a more serious condition such as lupus, rheumatoid arthritis, infection or malignancy. An accurate diagnosis leads the way to proper treatment. Some patients may have more than one problem causing their arthritis such as: • rheumatoid arthritis and fibromyalgia • psoriatic arthritis and gout The presence of a positive RF or CCP in this patient would help confirm a diagnosis of rheumatoid arthritis (RA). On the other hand, up to 30 % of patients with RA may not have these antibodies, especially early in their disease. In addition, the presence of a RF, especially at a low level is not uncommon in patients who do not have, and never will develop RA. The anti-CCP antibody is more likely to be associated with RA, so if elevated at a high level, the patient without typical manifestations of RA may be more likely to develop the disease. The other two blood tests mentioned are the ESR and CRP. These blood tests measure inflammation and are typically elevated in patients with active RA. Normal levels do not rule out RA, but those www.healthoracle.org 6 patients may be less likely to develop damage in their joints than patients with high levels of inflammation, especially an elevated CRP. An anti-nuclear antibody (ANA) is an important test in our example patient to evaluate for systemic lupus erythematosus or SLE. While low levels of ANA are common in RA, high levels of ANA in this example patient may indicate possible lupus, especially if the CCP and RF are negative. Finally, on subsequent visits, the RF and CCP are not typically reordered if positive. On the other hand, the ESR and CRP are frequently ordered as they can help confirm (in addition to the patients history and exam) whether the arthritis is active or in remission. Anti-Cyclic Citrullinated Peptide (Anti-CCP) antibodies are very suggestive of a diagnosis of Rheumatoid Arthritis (RA) although their absence does not exclude this diagnosis. Anti-CCP antibodies carry a higher predictive value than Rheumatoid Factor for: • • • Diagnosis of RA Disease activity Radiologic damage Rheumatoid Factor (RF) is an antibody (classically IgM) to selfimmunoglobulin. Presence of RF in serum from a patient with suspected RA increases the likelihood of the diagnosis of RA. Of patients with RA, those with RF positivity tend to have more aggressive arthritis than those without RF. Rheumatoid Factor or anti-CCP antibodies may be present prior to the onset of arthritis (particularly anti-CCP antibodies). With established RA more patients will become positive over time. This leads to a higher prevalence of anti-CCP and/or RF in patients who have established RA, and in patients that have been referred to specialist clinics. This leads to “sensitivity” of such assays being higher in these patient groups when compared with most general www.healthoracle.org 7 practice settings. The sensitivity of anti-CCP antibodies for RA (3766%) is only marginally better than of RF (17-71%). Therefore CCP should not be used as a screening test in patients unlikely to have RA. Some RA patients who are RF negative are positive for anti-CCP (up to one third in one series). Anti-CCP antibodies are associated with a higher likelihood of radiologically evident joint damage, especially when RF is also present. The additional value of anti-CCP testing to other disease markers (radiology, RF) is relatively less in established RA than early RA. In some cases, a diagnosis may not be readily apparent on an initial evaluation. Symptoms may resolve in time, or new symptoms may develop that provide information and lead to a diagnosis. Once a diagnosis is established and other associated conditions excluded, self treatment may be an option. Nonetheless, it is always best to discuss your therapy with a physician as patients may experience adverse effects from self treatment. For example, NSAIDS are available over-the-counter (OTC). We know that these medications may increase the risk of bleeding ulcers, cardiovascular, kidney and liver disease. Taking these medications without physician supervision may put a patient at increased risk of developing a life threatening adverse event. In addition, while over the counter supplements and herbs may have benefit in helping arthritic symptoms, many of these treatments have not been extensively studied and pose a potential risk also. Anti-CCP antibodies cannot be used to exclude a diagnosis of RA. In patients in whom inflammatory arthritis is likely, the presence of antiCCP antibodies is highly specific (90-98%) for a diagnosis of RA, and consideration for DMARD therapy is important. There is increasing evidence that patients with RA benefit from early introduction of effective disease modifying anti-rheumatic drug (DMARD) therapy. Patient selection is important to provide treatment to patients who have the most to gain from therapy, especially if commenced early in www.healthoracle.org 8 the course of the disease before bony erosions develop. However, when a patient presents with arthritis of recent onset, a definite diagnosis of the underlying pathology is very difficult. Other Conditions Some Juvenile Inflammatory Arthritis (JIA) patients are anti-CCP positive, but at a lower prevalence than in adult RA, and the role of anti-CCP for JIA is not as well defined. One series of Sjögren’s syndrome (SS) patients were positive for anti-CCP in 8% (>60% of SS cases have RF), but 90% of these fulfilled ACR criteria for RA (and so were likely to have RA with secondary SS). Anti-CCP passivity has been noted in other conditions (gout, osteoarthritis, sarcoid, psoriatic arthritis) in some series, but at low prevalence (<10% of cases). Some of these patients may develop clinically evident RA in the future. Patients with Polymyalgia Rheumatica (PMR) are usually anti-CCP negative. Combination Approach A combination of markers has been shown to provide more clinical information than single tests. Markers that have been shown to have some predictive power include: Erythrocyte Sedimentation Rate (ESR), anti-CCP, C Reactive Protein (CRP), and RF. Testing for anti-CCP antibodies. The assay will provide a quantitative value in arbitrary ELISA units (EU). Reference range: < 20 EU Weak positive: 20-39 EU Moderate positive: 40-59 EU Strong positive: >60 EU Specimen required: Serum www.healthoracle.org 9 The Role of Anti-CCP in the Laboratory Diagnosis of Rheumatoid Arthritis Rheumatoid Arthritis (RA) is one of the most common systemic autoimmune diseases, affecting approximately 0.5–1.0% of the world population.1 The American Rheumatism Association criteria for the classification of RA includes: 1. 2. 3. 4. 5. 6. 7. morning stiffness, arthritis of three or more joint areas, arthritis of hand joints, symmetric arthritis, rheumatoid nodules, serum rheumatoid factor (RF), and Radiographic changes. A patient should have four of the seven criteria to be diagnosed with RA and the first four criteria should be present for at least six weeks. Until recently, the only serological test routinely performed for the detection of RA was for the presence of IgM RF. RF is found in approximately 50%–90% of these patients, but it is also found in patients with infections, other autoimmune diseases, and some healthy individuals with increasing frequency in older age groups, thus limiting its specificity for RA. Several studies have shown that anti-perinuclear auto-antibodies, otherwise known as anti-keratin auto-antibodies, are found in patients with RA. It has been discovered that these antibodies recognize an epitope that contains the deamidated form of arginine called citrulline. Enzyme-Linked Immunosorbent Assay (ELISA) testing for these auto-antibodies directed against anti-cyclic citrullinated peptide (anti-CCP) is reasonably sensitive (68%) and highly specific (98%) in patients with RA. The pathogenesis of antiCCP antibodies in rheumatoid arthritis has been shown to be attributable to the body’s humoral response to citrulline. Citrullination is the post-translational conversion of arginine to www.healthoracle.org 10 citrulline by an enzyme called peptidylarginine deiminase (PAD). See figure 1. PAD activation is assisted by calcium ions. PAD is normally present as inactive intracellular enzymes. During programmed cell death (apoptosis) in the synovial joints of patients with rheumatoid arthritis, PAD may leak out of the dying cells. Once activated, PAD will cause citrullination of extracellular arginine. In the synovium, the citrulline acts as an antigenic stimulant to induce anticitrullinated protein antibodies (ACPA) locally produced by plasma cells.7 The ELISA that detects these autoantibodies uses synthetic cyclical citrulline peptides. Figure 1 The original ELISA for the anti-CCP sequence was not broadly marketed due to low sensitivity and technical complexity. However, the second generation anti-CCP test (often referred to in the literature as CCP-2/CCP2) shows superior performance compared to the original peptide.8 The vast majority of the laboratories that offer this test utilize the second-generation CCP assay. In 2005, a third generation of anti-cyclic citrullinated peptide (CCP3) was made available for the laboratory diagnosis of RA. These assays have been reported to recognize additional citrulline epitopes that are not identifiable with the second-generation CCP assays. The CCP3 assays have had reported results of up to 5% increased sensitivity www.healthoracle.org 11 compared to the CCP2 assays.9,10 To the contrary, however, several publications have shown similar diagnostic performance between the CCP3 and CCP2 assays.11,12 Recently, Nishimura et al. performed a meta-analysis of published studies regarding the diagnostic accuracy of anti-CCP and RF for rheumatoid arthritis.13 Their results showed a positive likelihood ratio of 12.46 and a negative likelihood ratio of 0.36 for anti-CCP antibody in patients with RA. The same study showed a positive likelihood ratio of 4.86 and a negative likelihood ratio of 0.38 for RF. These results indicate that anti-CCP positivity alone is more specific than IgM RF for the diagnosis of RA. In addition to diagnostic value, several studies have shown that antiCCP may also add prognostic significance in the determination of development of erosive disease in RA.14,15sp> Kroot, EJ et al showed that anti-CCP positive patients developed significantly more severe radiologic damage than those patients who were anti-CCP negative.14 Although the presence of anti-CCP is not currently required for the diagnosis of RA, future classification criteria will most likely incorporate its use as an adjunct to IgM RF as a laboratory diagnostic tool. Additionally, RA patients with positive CCP status may benefit from its prognostic value by receiving earlier customized treatment regimens that could potentially delay the development of erosive disease. High positivity of anti-CCP antibodies in patients with Down syndrome. The aim of the present study was to evaluate the prevalence of anticyclic citrullinated peptide (CCP) antibodies in patients with Down’s syndrome (DS) previously tested for IgM rheumatoid factor (RF) and to correlate the results with clinical findings. Eighty-eight patients with DS previously tested for IgM-RF were divided into two groups matched for sex and age. Group A consists of 42 RF positive patients and group B of 44 RF negative patients. The presence of anti-CCP www.healthoracle.org 12 antibody was determined using a second-generation enzyme-linked immunosorbent assay. A total of 52.3% (45/86) of DS patients were positive for anti-CCP antibodies. Twenty-four patients (57.1%) of the RF positive group and 21 (47.7%) of the RF negative group presented anti-CCP circulating antibodies. The concordance between both tests was 54.6%. None of the patients had clinical evidence of rheumatoid arthritis or juvenile idiopathic arthritis. Although a high prevalence of anti-CCP antibodies was observed in DS patients, no association has been found presently with clinical disease. Careful follow-up of these patients will be necessary to clarify the real significance of these findings. Usefulness of anti-CCP antibodies in patients with hepatitis C virus infection with or without arthritis, rheumatoid factor, or cryoglobulinemia. The presence of antibodies to cyclic citrullinated peptide (CCP) has high specificity in the diagnosis of rheumatoid arthritis (RA). Hepatitis C virus (HCV) infection may induce extra-hepatic manifestations, such as polyarthritis that mimic RA. The aim of this study was to determine the prevalence of anti-CCP antibodies in HCV-infected patients with or without arthritis, rheumatoid factor (RF), or cryoglobulinemia and to investigate whether anti-CCP antibodies may be helpful in discriminating patients with RA from patients with HCV-associated arthropathy. A total of 44 patients with RA, 34 patients with HCV infections, and 42 control patients with non-RA rheumatic diseases were recruited for the study. Anti-CCP antibody levels were determined by enzyme-linked immunosorbent assay. We found that, consistent with other reports, patients with RA were more likely to have high titers of anti-CCP antibody than HCVinfected or control patients. A significant number of HCV-infected patients with neither RF nor cryoglobulinemia were also positive for anti-CCP antibodies (the three positive values were 36.10, 8.65, and 5.83 U/ml, P < 0.01 compared with the control patients). The presence of cryoglobulinemia and/or RF in HCV-infected patients www.healthoracle.org 13 did not affect the anti-CCP outcomes. Although anti-CCP antibodies remain to be a very useful tool in discriminating RA from non-RA, HCV-infected patients with neither RF nor cryoglobulinemia may have anti-CCP antibodies. Because of limited patient numbers, this tentative conclusion may need further confirmation with inclusion of more patient population. www.healthoracle.org 14