California Privacy Statement, Through this personalized approach, he discovered his genetic weaknesses and was able to optimize his health 10X better than he ever thought was possible. Systemic lupus erythematosus (SLE): when active, usually a homogenous pattern on ANA or less commonly speckled, rim, or nucleolar when present in high enough titer to be . Association between SARSCoV2 and SLE is not clear. Cite this article. Anti-CCP antibody testing is not used to monitor RA because changes in antibody levels are not linked to changes in disease activity and patients tend to remain positive even with the reduction or disappearance of the symptoms of RA [11, 12, 13]. Most of the time, a positive test result for antinuclear antibodies (ANA) indicates the presence of an autoimmune disorder. Normal Reports | Joe Cohen flipped the script on conventional and alternative medicineand it worked. (2) RF is an autoantibody directed against the Fc portion of immunoglobulin while ACPA are directed against peptides and proteins containing citrulline, a modified form of the amino acid arginine. Rheumatol Int. X-rays of the hands and feet were taken in January 2020 to establish whether anti-CCP-positive non-RA CTD patients had developed bone erosions. Anti-Sm antibody binds to a protein that is attached to DNA. Iwasaki, T., Nakabo, S., Terao, C. et al. X-rays of the hands and feet were taken for all patients in groups 1 and 2, and in 25 out of 31 patients in group 3. However, the presence of immunoglobulins causing pan-agglutination can cause false-positive results. Ann Rheum Dis. Duration of preclinical rheumatoid arthritis-related autoantibody positivity increases in subjects with older age at time of disease diagnosis. 2017;19(1):190. The follow-up length of each patient was defined as the period from the day when serum was collected or the anti-CCP antibody test was ordered in the clinic to the last visit before January 2020 (see Supplementary Figure 1, Additionalfile1). Anti-citrullinated peptide (anti-CCP): antibodies against proteins with post-translational modification of arginine, which may have a role in pathogenesis of RA Newer generation of tests with similar sensitivity (80%) and improved specificity (95%) for RA compared to RF (should be ordered simultaneously in the appropriate clinical setting) Citrullination dependency was evaluated using an in-house ELISA at the Leiden University Medical Center, as described previously [27]. Joe Cohen flipped the script on conventional and alternative medicine and it worked. What it is: A genetic, autoimmune disease where ingested gluten damages the small intestine. Today, anti-histone antibodies are still used as a marker for systemic lupus . In these cases, your doctor will need to factor in the severity of your symptoms, CRP and ESR, and imaging tests [27]. Use. If you also test positive for RF, you likely have the disease [25]. Previous studies detected the anti-CCP antibody in patients with autoimmune hepatitis [34] and tuberculosis [35]; however, the epitope of this antibody was not the citrulline residue and sera reacted with the arginine version of CCP, namely, CAP [14, 15]. Anti-cyclic citrullinated peptides (anti-CCP) are a type of autoantibody: an antibody that works against your body's normal antibodies. Semin Immunopathol. This can lead to a disorder known as autoimmune vasculitis. 2010;62(9):256981. 2015;74(2):37580. Anti-citrullinated protein antibodies (ACPAs) are autoantibodies (antibodies to an individual's own proteins) that are directed against peptides and proteins that are citrullinated.They are present in the majority of patients with rheumatoid arthritis.Clinically, cyclic citrullinated peptides (CCP) are frequently used to detect these antibodies in patient serum or plasma (then referred to as . Severe acute respiratory syndrome coronavirus 2 (SARSCoV2) is a novel viral agent that can cause a life-threatening respiratory disorder named coronavirus disease 2019 (COVID19). The test is also not used to screen for RA patients because it can frequently miss individuals who have the disease [14]. In both cases, anti-CCP antibody titers were assessed using a second-generation enzyme-linked immunosorbent assay (ELISA) kit (MESACUP-2 test CCP; MEDICAL & BIOLOGICAL LABORATORIES, Nagoya, Japan). The entire, 55-min procedure for the detection of RF and anti-CCP using a dual-target ELISA assay is shown schematically in Fig. CAS These include [15]: A rheumatoid factor (RF) test is commonly ordered alongside an anti-CCP test to help make a diagnosis. Schellekens GA, Visser H, de Jong BA, et al: The diagnostic properties of rheumatoid arthritis antibodies recognizing a cyclic citrullinated peptide. If you test positive for anti-CCP antibodies but not rheumatoid factor (RF) and are experiencing any symptoms of the disease, you may have RA. Normally, the immune system is tolerant of these proteins, but in patients with RA, the body mounts an immune response and creates antibodies to target and destroy these citrullinated proteins [1]. Kakumanu P, Sobel ES, Narain S, Li Y, Akaogi J, Yamasaki Y, et al. (4,6,10) A systemic review and meta-analysis of 33 studies including patients with RA and healthy or disease controls demonstrated the sensitivity of anti-mutated citrullinated vimentin, anticyclic citrullinated peptide, and RF of 71%, 71%, 77%, with the specificity of 89%, 95%, 73%, and the area under the curve of the summary receiver operating characteristic of 89%, 95%, 82%, respectively. What causes false positive anti-CCP antibodies? 2009;61(11):147283. 1988;31(3):31524. However, we found citrullination dependency was not associated with the risk of developing RA. However, the anti-CCP antibody test is the most widely-used ACPA test in clinical practice due to its accuracy [5]. 2008;58(6):157681. A positive result in combination with other signs and symptoms means you have rheumatoid arthritis. (4,6,10) A systemic review and meta-analysis of 33 studies including patients with RA and healthy or disease controls demonstrated the sensitivity of anti-mutated citrullinated vimentin, anticyclic citrullinated peptide, and RF of 71%, 71%, 77%, with the specificity of 89%, 95%, 73%, and the area under the curve of the summary receiver operating characteristic of 89%, 95%, 82%, respectively. Development of the anti-citrullinated protein antibody repertoire prior to the onset of rheumatoid arthritis. This includes a combination of medications called disease-modifying antirheumatic drugs (DMARDs) that includes methotrexate (Trexall) and biologics (drugs made from living organisms) such as infliximab (Remicade) and etanercept (Enbrel) [29, 4]. Anti-CCP antibody titers were measured based on the discretion of physicians or when serum or plasma was stored regardless of joint symptoms. MAMvd and LAT evaluated citrullination dependency by ELISA. Once a patient develops a positive anti-CCP, it will usually remain positive, despite remission. The anti-cyclic citrullinated peptide (CCP) antibody is a widely used diagnostic biomarker of rheumatoid arthritis (RA). Rheumatol Int. The information on this website has not been evaluated by the Food & Drug Administration or any other medical body. Citrullination dependency was evaluated by an in-house ELISA, the HLA-DRB1 allele was typed, and the results obtained were then compared between RA-overlapping and non-RA anti-CCP-positive CTD patients. In addition to improving symptoms and preventing and reducing joint damage, these medications can reduce anti-CCP levels substantially [30, 31, 4]. . Positive results for cyclic citrullinated peptide (CCP) antibodies may occur in some patients with systemic lupus erythematosus or other autoimmune, connective tissue diseases. 2000 Jan;43(1):155-163, 7. Huizinga TW, Amos CI, van der Helm-van Mil AH, Chen W, van Gaalen FA, Jawaheer D, et al. 2011;70(12):21349. Part of Anti-CCP antibody and other autoantibody markers can be helpful in determining which patients with rheumatoid arthritis may have benefit from treatments such as anti-tumor necrosis factor-alfa (TNFa) monoclonal antibodies. Associations between genetic factors, tobacco smoking and autoantibodies in familial and sporadic rheumatoid arthritis. CAS Knowing the symptoms of autoimmune joint disease is of utmost importance as well. Low . 1 Introduction. The present study was performed in accordance with the Helsinki Declaration and was approved by Kyoto University Graduate School and Faculty of Medicine Ethics Committee (approval numbers: E458 and R1540). To investigate whether the anti-CCP antibody became negative over time, we obtained the latest anti-CCP antibody titer in January 2020 from the medical records of 64 anti-CCP-positive CTD patients whose anti-CCP antibody titers had been measured. Sensitivity/specificity of citrullination dependency for predicting RA development in the population of anti-CCP positive patients with arthritis (n=39) was 96%/18%, and PPV/negative predictive value (NPV) of that was 75%/67%. However, most labs do not offer this test yet [1, 18]. Holman, and H.R.G. 2b). However, it isnt a very sensitive marker, which means that a negative result does not necessarily rule out rheumatoid arthritis [10]. To make a conclusive diagnosis, your doctor will take into account both of your antibody results in combination with CRP and ESR tests and any symptoms you have [25]. 1). The false-positive rate of anti-CCP is difficult to come by. The 1987 revised ACR criteria were used to diagnose RA; therefore, the potential effect of anti-CCP positivity on the RA or non-RA classification was excluded. Springer Nature. Anti-cyclic citrullinated peptide antibodies in type 1 autoimmune hepatitis. Arthritis Rheum. Ryu YS, Park SH, Lee J, Kwok SK, Ju JH, Kim HY, et al. 2014 Jul;73(7):1316-1322, 2. Terao C, Ohmura K, Kochi Y, Ikari K, Maruya E, Katayama M, et al. The anti-CCP-positive sera of patients may also react with cyclic arginine peptides (CAP), in which the citrulline residues of CCP peptides are substituted with arginine residues. In the most common scenario, Lyme triggers false positive tests for rheumatoid arthritis, usually rheumatoid factor, but occasionally anti-CCP antibodies; and, these antibodies disappear when Lyme is successfully treated. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. 1). They are heterogenous and usually composed of immunoglobulin M (IgM). The dependency on citrullination was evaluated by subtracting absorbance values of anti-CAP from that of anti-CCP. Anti-RNP (anti-U1 ribonucleoprotein) is a non-specific antibody that occurs in many patients with lupus and other rheumatic diseases. The anti-cyclic citrullinated peptide (CCP) antibody is a widely used diagnostic biomarker of rheumatoid arthritis (RA). Therefore, the clinical significance of the presence of the anti-CCP antibody in non-RA CTD patients remains unclear. Derivation and validation of the Systemic Lupus International Collaborating Clinics classification criteria for systemic lupus erythematosus. TI, SN, and KO wrote the main manuscript. (3-5) To facilitate early diagnosis, the American College of Rheumatology/European League Against Rheumatism 2010 RA classification criteria recommend testing for rheumatoid factor (RF) and anticitrullinated protein antibodies (ACPA). contrary to popular belief anti ccp is not 100% specific for RA. Thirty-three anti-CCP-positive non-RA CTD patients were retrospectively followed up for the development of RA. These patients may develop RA in the future because the emergence of anti-citrullinated protein antibodies (ACPA), including the anti-CCP antibody, precedes the onset of RA [3,4,5,6]. Ann Rheum Dis. We also investigated the citrullination dependency of anti-CCP test results because anti-CCP antibodies may react with the non-citrullinated part of CCP peptides, which have been reported in several diseases, such as SLE [16], autoimmune hepatitis [14], and tuberculosis [15]. Arthritis Res Ther. Terms and Conditions, The Dangers of a Misdiagnosis. In most cases, a positive ANA test indicates that your immune system has launched a . After further incubation and washing to remove unbound conjugate, substrate (3,3',5,5' tetramethylbenzidine) is added and allowed to incubate. A flow chart of the present study is shown in Fig. The frequency of antibodies against cyclic citrullinated peptides and rheumatoid factor in healthy population: a field study of rheumatoid arthritis from northern Turkey. Majka DS, Deane KD, Parrish LA, Lazar AA, Baron AE, Walker CW, et al. We thank all the attending physicians who substantially contributed to the acquisition of data. Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease characterized by interactions between the environment, specific genetic risk factors, and the human immune system. CTD onset times were available for 64 out of 72 patients (groups 1,2, and 3 in Fig. However anti-CCP is not associated with extraarticular features (unlike RF) variation of . Anti-CCP antibody, a marker for the early detection of rheumatoid arthritis. A large-scale association study identified multiple HLA-DRB1 alleles associated with ACPA-negative rheumatoid arthritis in Japanese subjects. Ding B, Padyukov L, Lundstrom E, Seielstad M, Plenge RM, Oksenberg JR, et al. If CCP antibodies are found in your blood, it can be a . Arthritis Rheum. Objective: To determine the frequency of anti-CCP antibodies in psoriatic arthritis and to describe the clinical characteristics of such patients. 2009;60(1):308. Re-testing later on may be required in . Causes of MSK pain are divided into nonrheumatic and rheumatic categories. What Are Anti-cyclic Citrullinated Peptide Antibodies and why are they elevated in RA? Information is shared for educational purposes only. (3,4,8,9), Compared to early serologic tests for RA including RF, several studies have demonstrated that ACPA have much improved specificity for RA. (Package insert: Quanta Lite CCP3 IgG ELISA. Therefore, we retrospectively investigated whether anti-CCP antibody-positive non-RA CTD patients developed RA and clarified whether HLA-DRB1 SE and the citrullination dependency of the anti-CCP antibody are predictive factors for RA. Anti-CCP antibodies are commonly found in rheumatoid arthritis patients and are thought to play a key role in the disease process. If you test positive for anti-CCP antibodies, yet youre healthy and arent showing symptoms of RA, you have a much greater risk of developing the disease [19]. An antinuclear antibody test is a blood test that looks for certain kinds of antibodies in your body. Therefore, we excluded anti-CCP-negative samples and examined citrullination dependency. 1992;19(3):42430. Antibodies and autoantibodies are proteins made by the immune system. Testing is performed on the Agility instrument by Dynex. Petri M, Orbai AM, Alarcn GS, Gordon C, Merrill JT, Fortin PR, et al. This ANA testing method led to an increase in rheumatology referrals for RNP . Frustrated by the lack of good information and tools, Joe decided to embark on a learning journey to decode his DNA and track his biomarkers in search of better health. The detection of anti-CCP is useful for the diagnosis of RA because of its similar sensitivity but higher specificity compared with RF. 2007;66(4):5116. A positive anti-CCP and negative RF blood test show that you may be in the early stages of the disease or may have it in the future. Your email address will not be published. Antibodies normally target harmful substances, such as . (6,7) In addition to the use of RA and ACPA IgG to diagnose RA, RF and ACPA isotype antibodies and other serologic biomarkers have been used to predict if, and when, an individual who has inflammatory arthritis (IA) may develop future clinically apparent IA and access genetic and/or environmental risks. (sensitivity) versus the false positive rate (1 - specificity) for various possible cutpoints of a diagnostic test. However, in 2010, the American College of Rheumatology changed their criteria for diagnosing RA to include the presence of anti-CCP antibodies [9]. Arthritis Rheumatol. . SelfDecode has the strictest sourcing guidelines in the health industry and we almost exclusively link to medically peer-reviewed studies, usually on PubMed. Long-term follow-up of patients with anti-cyclic citrullinated peptide antibody-positive connective tissue disease: a retrospective observational study including information on the HLA-DRB1 allele and citrullination dependency. Although we considered an anti-CCP titer 100 to be 100, the relationship between the anti-CCP antibody titer and the risk of developing RA is supported by patients with a high ACPA level having a high score in the 2010 ACR/EULAR classification criteria of RA [26] as well as a high anti-CCP antibody titer being more strongly associated with RA in the general population [32]. Furthermore, the 100% positive predictive value of anti-CCP Abs confers a remarkable advantage on this serum marker in comparison with RF. 2a). Furthermore, our observation period, 8.9years, was sufficiently long to assess the outcomes of the anti-CCP-positive population because the median period during which an anti-CCP-positive population developed RA was previously reported to be 4.5years [4]. Arthritis Rheum. Testing for anti-CCP antibodies helps doctors to diagnose RA patients and determine how severe the disease is, as well as predict the likely outcome of the disease. Even patients with Rheumatoid arthritis can have a positive ANA. A positive result for cyclic citrullinated peptide (CCP) antibodies indicates a high likelihood of rheumatoid arthritis (RA). Joe is a thriving entrepreneur, with a mission to empower people to take advantage of the precision health revolution and uncover insights from their DNA and biomarkers so that we can all feel great all of the time. 3.2.2. Though Lyme disease is treatable, it can become disastrous if left untreated. Rheumatoid arthritis affects about 1% of the total population, but as few as 1 in 2 people who have RA will actually have a positive CCP IgG blood test result. These antibodies react with CAP, which is the arginine version of CCP (the citrulline residues of CCP were replaced by arginine). Testing positive for anti-CCP antibodies increases the risk of developing a more aggressive form of rheumatoid arthritis. Ann N Y Acad Sci. (10) Based on these studies, there exist a subset of patients with RA who are negative for RF and ACPA IgG (seronegative) who must be diagnosed clinically or with use of emerging diagnostic tests.(4,7,9). Methods . Objective: We sought to characterize a novel cohort of patients with lung disease, anti-cyclic citrullinated peptide (CCP) antibody positivity, without rheumatoid arthritis (RA) or other connective tissue disease (CTD). 2005;52(11):34338. Low levels of anti-CCP can be found in the test results of certain patients but may not enough to produce a positive result. antibodies are routinely tested for by ELISA at Clinipath. However, limited information is currently available on the long-term outcomes of anti-CCP-positive non-RA CTD patients. However, a large proportion of systemic sclerosis patients with the anti-CCP antibody developed erosive arthritis. Although all 60 samples tested positive for the anti-CCP antibody using a commercial ELISA kit, 5 out of 33 RA-overlapping CTD and 6 out of 27 non-RA CTD serum samples tested negative using our in-house CCP ELISA. About 20% of RA patients are seronegative, meaning that their RF and anti-CCP lab results both continue to come back . (2) We evaluated only anti-CCP-positive patients and did not re-evaluate the serology of anti-CCP negative CTD patients, some of whom may have newly developed anti-CCP antibody. ESR and CRP Tasliyurt T, Kisacik B, Kaya SU, Yildirim B, Pehlivan Y, Kutluturk F, et al. 1987:417. The Mann-Whitney U test was used to analyze absorbance difference between anti-CCP and anti-CAP patients. Elsevier, Amsterdam. Ann Rheum Dis. 2014;66(12):181827. Antibodies are . 26460649). The present study was supported in part by JSPS KAKENHI (grant no. Significant threshold was set to p=0.05. Arthritis Rheum. A positive result by itself does not automatically lead to a diagnosis. A positive result for cyclic citrullinated peptide (CCP) antibodies may be suggestive of rheumatoid arthritis (RA) if compatible clinical features of disease are present. Align your health hacks with your genes for optimal health & cognitive function. (2-4) Patients with RA may be categorized based on the phase of disease (early versus established), presence or absence of antibodies (seropositive versus seronegative), clinical manifestations (joint erosion, interstitial lung disease, or cardiovascular), or specific risks (genes, gender, or smoking). The isotype and IgG subclass distribution of anti-carbamylated protein antibodies in rheumatoid arthritis patients. Despite this limitation, PPV for developing RA in non-RA CTD patients (2/33, 6.1%) was markedly lower than that in healthy individuals (8296%) [3, 4] and similar to the incidence of RA complications in CTD patients in the present study ((group 1 and group 2)/group 0 in Fig. Anti-CCP antibodies can be detected in RA patients years before they show any symptoms [19, 20]. (PPTX 45 kb), Prevalence of arthritis in anti-CCP-positive non-RA CTD patients. Anti-histone antibodies are autoantibodies that are a subset of the anti-nuclear antibody family, which specifically target histone protein subunits or histone complexes. 2008;1143:26885. Further studies on auto-antigens of the anti-CCP antibodies in non-RA CTD patients are warranted. a Comparison of citrullination dependency between rheumatoid arthritis (RA)-overlapping connective tissue diseases (CTD) and non-RA CTD patients. Two out of 33 anti-CCP-positive CTD patients (6.1%) developed RA during a mean follow-up period of 8.9years. To assess whether anti-CCP-positive CTD patients had suffered from arthritis during this time frame, the attending physicians of patients completed a questionnaire survey in September 2020. 2010 Rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Citrullinated proteins increase their levels substantially when an inflammatory cascade is activated such as in RA [1, 2]. RFs are used as a marker in individuals with suspected rheumatoid arthritis (RA) or other autoimmune conditions. Zhu JN, Nie LY, Lu XY, Wu HX: Meta-analysis: compared with anti-CCP and rheumatoid factor, could anti-MCV be the next biomarker in the rheumatoid arthritis classification criteria? 2004;50(2):3806. False positives are more common with RF than anti-CCP. 2009;36(12):268290. The prevalence of HLA-DRB1 SE in RA-overlapping CTD and non-RA CTD patients was similar to that in ACPA-positive RA patients and healthy subjects in a previous study, respectively [11]. Arthritis Care Res. van Venrooij WJ, van Beers JJ, Pruijn GJ. Deane KD, Holers VM: Rheumatoid arthritis pathogenesis, prediction, and prevention: An emerging paradigm shift. Furthermore, no reaction was seen when the structurally similar but antigenically unique control peptide was used in the assay using ChonBlock (Fig. Fusconi M, Vannini A, Dall'Aglio AC, Pappas G, Cassani F, Ballardini G, et al. They are more often found in severe forms of the disease and increase the risk of more rapid destruction of the joints [3, 8, 4]. Your email address will not be published. Elkayam O, Segal R, Lidgi M, Caspi D. Positive anti-cyclic citrullinated proteins and rheumatoid factor during active lung tuberculosis. CAP, the arginine version of CCP (the citrulline residues of CCP were converted to arginine), and CCP were coated on the same plate, and reactivities against CAP and CCP were compared. Your immune system normally makes antibodies to help you fight infection. b A similar analysis was performed by stratifying all samples for which HLA data were available based on positivity for the HLA-DR shared epitope (SE). Despite its high specificity, previous studies reported that 510% of non-RA connective tissue disease (CTD) patients tested positive for the anti-CCP antibody [1, 2]. 2006;65(8):11102. They are found in around 30-40% of patients with SLE. 2017;76(1):11925. 2010 Sep;62(9):2569-2581, 3. An ANA test detects antinuclear antibodies (ANA) in your blood. Hensvold AH, Magnusson PK, Joshua V, Hansson M, Israelsson L, Ferreira R, et al. Ann Rheum Dis. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The possession of HLA-DRB1 SE was also compared between 22 non-RA CTD patients and 32 RA-overlapping CTD patients. Note that each number in parentheses [1, 2, 3, etc.] Until recently, rheumatoid factor (another antibody involved in RA) was the only antibody used to help diagnose the disease. Antinuclear Antibody Panel (ANA Test) Antibodies are proteins made by your immune system. Kasukawa R TT, Miyawaki S, Yoshida H, Tanimoto K, Nobunaga M, Suzuki T, Takasaki Y, Tamura T. Preliminary diagnostic criteria for classification of mixed connective tissue disease: In: Kasukawa R, Sharp GC (Eds) Mixed Connective Tissue Disease and Antinuclear Antibodies. A plus sign next to the number [1+, 2+, etc] means that the information is found within the full scientific study rather than the abstract. Currently, they are not widely used in clinical practice [22]. Doctors use the anti-CCP antibody test in combination with other tests and symptoms to diagnose rheumatoid arthritis and determine the likely course of the disease. Google Scholar. Citrullination dependency was more common in patients with SE, although it was not statistically significant (p=0.11) (Fig. Shiboski SC, Shiboski CH, Criswell L, Baer A, Challacombe S, Lanfranchi H, et al. While RA is a lifelong disease, diagnosing it early and treating it properly will give the best chance at controlling its progression and allowing you to live a healthy and active lifestyle. These antibodies are made as a direct attack of specific proteins found naturally in the body. Patients who test positive for rheumatoid factor aren't necessarily diagnosed with rheumatoid arthritis right away. Antibodies directed against the Fc fragment of immunoglobulin G (IgG) are called rheumatoid factors (RFs). We screened 842 CTD patients whose primary diagnosis was not RA in our database. (3,4,8,9) Compared to early serologic tests for RA including RF, several studies have demonstrated that ACPA have much improved specificity for RA. Ann Rheum Dis. Specific autoantibodies precede the symptoms of rheumatoid arthritis: a study of serial measurements in blood donors. The aim of this study was to evaluate the specificity of SARS-Cov-2 serological assays using . Anti-CCP. TI and SN analyzed the data. Despite its high specificity, previous studies reported that 5-10% of non-RA connective tissue disease (CTD) patients tested positive for the anti-CCP antibody [1, 2].These patients may develop RA in the future because the emergence of anti-citrullinated protein antibodies . Effects of smoking and shared epitope on the production of anti-citrullinated peptide antibody in a Japanese adult population. To assess the reliability of the diagnosis, we evaluated all SLE patients by chart review and found that all patients fulfilled the ACR 1997 or SLICC 2012 criteria.
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