Background

This test is a antinuclear antibody, often found in autoimmune disorders. It may provide important information specific to rheumatoid arthritis, particularly with early identification and prognosis.

OUTLINE

Reference Methods
Clinical Utility
Interfering Diseases or Substances that Alter Levels
Commonly Used Terms
Internet Links

REFERENCE METHODS	CHARACTERIZATION
ELISA
High diagnostic performance of ELISA detection of antibodies to citrullinated antigens in rheumatoid arthritis. Suzuki K, Sawada T, Murakami A, Matsui T, Tohma S, Nakazono K, Takemura M, Takasaki Y, Mimori T, Yamamoto K. Department of Allergy and Rheumatology, University of Tokyo School of Medicine, Tokyo, Japan	Scand J Rheumatol. 2003;32(4):197-204. Abstract quote   OBJECTIVE: We investigated the rheumatoid arthritis (RA) diagnostic performances of anti-cyclic citrullinated peptide antibody (anti-CCP) and antifilaggrin antibody (AFA) in comparison with RF and matrix metalloproteinase-3 (MMP-3). METHODS: We used a second generation enzyme-linked immunosorbent assay (ELISA) kit for the detection of anti-CCP. We constructed recombinant human filaggrin, which was citrullinated in vitro by human peptidylarginine deiminase, and subsequently used it as the coating antigen for AFA-ELISA. A total of 549 RA patients and 208 other rheumatic disease patients were included in the study. RESULTS: The specificities of anti-CCP (88.9%) and AFA (94.7%) were superior to those of RF (81.7%) and MMP-3 (49.5%). The sensitivity of anti-CCP (87.6%) was superior to all others. However, the sensitivity of AFA (68.7%) was inferior to those of RF (69.8%) and MMP-3 (75.7%). Furthermore, receiver operating characteristic curves of anti-CCP and AFA passed closer to the upper left corner than those of RF and MMP-3, and the areas under the curves (AUC) of AFA and anti-CCP were significantly larger. In addition, the AUC of anti-CCP was significantly larger than that of AFA. CONCLUSION: ELISA detection of antibodies to citrullinated antigens, especially a second generation anti-CCP, showed higher discriminative ability than other assays, including RF, and would be useful to aid the diagnosis of RA in clinical practice.

 

CLINICAL UTILITY	CHARACTERIZATION
JUVENILE IDIOPATHIC ARTHRITIS
Anti-cyclic citrullinated peptide antibodies in patients with juvenile idiopathic arthritis. Hromadnikova I, Stechova K, Pavla V, Hridelova D, Houbova B, Voslarova S, Nekvasilova H, Vavrinec J. 2nd Paediatric Clinic, University Hospital Motol, 2nd Medical Faculty, Charles University Prague, Prague, Czech Republic.	Autoimmunity. 2002 Sep;35(6):397-401. Abstract quote   We analysed the presence of anti-cyclic citrullinated peptide (anti-CCP) and anti-keratin (AKA) antibodies of the IgG class in sera of patients with defined juvenile idiopathic arthritis (JIA) of various subgroups with more than one year duration of the disease. Enzyme-linked immunosorbent assay (Immunoscan RA, Eurodiagnostica, The Netherlands) and an indirect immunofluorescence (IIF) test on rat oesophagus substrate (ImmuGloTM, Immco Diagnostics, Buffalo, USA) were used for the detection and quantification of anti-CCP and AKA antibodies in 140 patients with JIA (64 male and 76 female) aged 2-47 years (median 16.5 years). Overall, anti-CCP were found in 7/140 (5.0%) patients including 3/52 RF negative polyarthritis, 2/18 RF positive polyarthritis, 1/15 enthesitis related arthritis and 1/5 unclassifiable arthritis. AKA were detected in 40/140 patients (28.6%, p = 0.04) including 2/11 systemic arthritis, 2/32 oligoarthritis, 18/52 patients with RF negative polyarthritis (34.6%, p = 0.01), 14/18 RF positive polyarthritis (77.8%, p = 0.000002), 2/15 enthesitis related arthritis and 2/3 psoriatic arthritis. While simultaneous negativity for AKA and anti-CCP occurred in most (97/140; 69.3%) studied cases, simultaneous antibody positivity was found only in few (4/140; 2.9%) studied samples. We conclude that while AKA measured using IIF on rat esophagus can be detected approximately in one third of patients with definite JIA with more than 1 year duration of the disease, only rare occurrence of anti-CCP was observed. We conclude that AKA seem to be partly useful to confirm JIA diagnosis, however, useless to follow-up severity or activity in JIA patients. Anti-CCP do not have any additional value in MA cohort in comparison to RA where their diagnostic and prognostic importance was reported.
RHEUMATOID ARTHRITIS PROGNOSIS
Association between HLA class II genes and autoantibodies to cyclic citrullinated peptides (CCPs) influences the severity of rheumatoid arthritis. Van Gaalen FA, Van Aken J, Huizinga TW, Schreuder GM, Breedveld FC, Zanelli E, Van Venrooij WJ, Verweij CL, Toes RE, De Vries RR. Leiden University Medical Center, Leiden, The Netherlands.	Arthritis Rheum. 2004 Jul;50(7):2113-21. Abstract quote   OBJECTIVE: The functional role of HLA class II molecules in the pathogenesis of rheumatoid arthritis (RA) is unclear. HLA class II molecules are involved in the interaction between T and B lymphocytes required for long-lived B cell responses and generation of high-affinity IgG antibodies. We undertook this study to investigate the relationship between HLA class II gene polymorphisms and RA-specific IgG antibodies against cyclic citrullinated peptides (anti-CCP antibodies). METHODS: High-resolution HLA-DR and DQ typing and anti-CCP-2 antibody testing were performed on 268 RA patients from the Early Arthritis Clinic cohort at the Department of Rheumatology of the Leiden University Medical Center. The presence of anti-CCP antibodies was analyzed in carriers of the different DR and DQ alleles. Disease progression was measured over a period of 4 years by scoring radiographs of the hands and feet using the Sharp/van der Heijde method. RESULTS: Carriership of the individual alleles HLA-DRB1*0401, DRB1*1001, DQB1*0302, and DQB1*0501 was associated with the presence of anti-CCP antibodies. Carriers of DQ-DR genotypes containing proposed RA susceptibility alleles were significantly more often anti-CCP antibody positive. Carriership of one or two HLA-DRB1 shared epitope (SE) alleles was significantly associated with production of anti-CCP antibodies (odds ratio [OR] 3.3, 95% confidence interval [95% CI] 1.8-6.0 and OR 13.3, 95% CI 4.6-40.4, respectively). An increased rate of joint destruction was observed in SE+, anti-CCP+ patients (mean Sharp score 7.6 points per year) compared with that in SE-, anti-CCP+ patients (2.4 points per year) (P = 0.04), SE+, anti-CCP- patients (1.6 points per year) (P < 0.001), and SE-, anti-CCP- patients (1.6 points per year) (P < 0.001). CONCLUSION: HLA class II RA susceptibility alleles are associated with production of anti-CCP antibodies. Moreover, more severe disease progression is found in RA patients with both anti-CCP antibodies and SE alleles.
Value of antibodies to citrulline-containing peptides for diagnosing early rheumatoid arthritis. Saraux A, Berthelot JM, Devauchelle V, Bendaoud B, Chales G, Le Henaff C, Thorel JB, Hoang S, Jousse S, Baron D, Le Goff P, Youinou P. Unit of Rheumatology and the Laboratory of Immunology, Hopital de la Cavale Blanche, CHU Brest, BP 824, F-29609 Brest-Cedex, France.	J Rheumatol. 2003 Dec;30(12):2535-9. Abstract quote   OBJECTIVE: To compare the diagnostic values of antiperinuclear factor (APF), antikeratin antibody (AKA), and anti-cyclic citrullinated peptides (anti-CCP) to discriminate between patients with and without rheumatoid arthritis (RA) and to determine the diagnostic value of anti-CCP used alone or with other tests. METHODS: Two hundred and seventy patients with early arthritis underwent standardized investigations in 1995-1997. The clinical utility of APF, AKA, and anti-CCP in first-visit sera was evaluated using receiver-operating characteristic curves. Combinations of anti-CCP with other laboratory tests were assessed by multiple logistic regression. RESULTS: Anti-CCP, APF, and AKA were not perfectly correlated with one another. Anti-CCP with 53 UI as the cutoff was 47% sensitive and 93% specific, versus 52% and 79%, and 47% and 94%, for APF and AKA, respectively. Multiple logistic regression selected anti-CCP, AKA, IgM-rheumatoid factor (RF) ELISA, and the latex test. CONCLUSION: Rheumatologists can routinely use 2 or 3 tests for diagnosing RA (latex and/or IgM RF ELISA, and either AKA or anti-CCP ELISA) and can add a third or fourth test when the diagnosis remains in doubt.
SJOGREN'S SYNDROME
Prevalence of anti-cyclic citrullinated peptide and anti- keratin antibodies in patients with primary Sjogren's syndrome. Gottenberg JE, Mignot S, Nicaise-Rolland P, Cohen-Solal J, Aucouturier F, Goetz J, Labarre C, Meyer O, Sibilia J, Mariette X. Bicetre Hospital, Assistance Publique-Hopitaux de Paris (AP-HP), France.	Ann Rheum Dis. 2004 Jul 1 Abstract quote   OBJECTIVE: To investigate the prevalence of anti-cyclic citrullinated peptide (anti-CCP) and anti- keratin (AKA) antibodies in a cohort of patients with primary Sjogren's syndrome (pSS). METHODS: One hundred forty-nine patients with a diagnosis of pSS according to the European/American consensus criteria (four criteria with a focus score >/=1 or presence of anti-SSA/SSB antibodies) were recruited from three French medical centers. The presence of anti-CCP antibodies was determined by ELISA and that of AKA antibodies by indirect immunofluorescence. Radiographs of hands and feet were evaluated at the time of the anti-CCP analysis. RESULTS: Six patients with radiological erosions were reconsidered to have rheumatoid arthritis (RA) and secondary SS. Of the 134 pSS patients, not fulfilling ACR classification criteria for RA, studied (mean disease duration of 11.1 +/- 6.6 years), 80 patients tested positive for IgM rheumatoid factor (RF) (59%), 10 (7.5%) for anti-CCP antibodies, 7 (5.2%) for AKA antibodies, and 5 (3.7%) for both anti-CCP and AKA antibodies. There was no difference between anti-CCP positive and negative patients regarding clinical and biological features, including prevalence of RF. Additionally, we individualized a group of 9 anti-CCP positive patients fulfilling ACR classification criteria for RA but presenting like pSS patients with non erosive arthritis, whose response to DMARDs could be different from classical RA patients. CONCLUSION: In conclusion, the majority of pSS patients is negative for AKA and anti-CCP antibodies. However, positive test results for anti-CCP or AKA antibodies should not rule out the diagnosis of pSS. Anti-CCP-positive patients, who could be prone to develop RA, require a cautious clinical and radiographic follow-up to confirm the eventual evolution to RA in the future.
Antibodies against cyclic citrullinated peptide (CCP) and levels of cartilage oligomeric matrix protein (COMP) in very early arthritis: relation to diagnosis and disease activity. Soderlin MK, Kastbom A, Kautiainen H, Leirisalo-Repo M, Strandberg G, Skogh T. Department of Internal Medicine, Vaxjo Central Hospital, Vaxjo, Sweden.	Scand J Rheumatol. 2004;33(3):185-8. Abstract quote   OBJECTIVE: To measure serum levels of antibodies against cyclic citrullinated peptide (anti-CCP antibodies) and serum cartilage oligomeric matrix protein (COMP) in patients with early joint inflammation, and to study the correlation of these two tests with clinical measurements. METHODS: Adult patients with recent-onset arthritis, of <3 months' duration, were referred from primary healthcare centres to rheumatologists. Serum levels of anti-CCP antibodies and COMP at baseline were analysed by enzyme immunoassay (EIA) and compared with clinical baseline data. RESULTS: Sixty-nine patients were included. The specificity of the anti-CCP antibody test for RA was 96%, and the sensitivity was 44%. There was a significant difference between the four diagnosis groups in the anti-CCP antibody test, probability (p)<0.001, whereas no significant differences were found concerning COMP. The baseline serum COMP test correlated with age (p=0.0001), joint score for swollen joints (p=0.02), and C-reactive protein (CRP) (p=0.02). CONCLUSION: This study confirms the high diagnostic specificity of anti-CCP antibodies for rheumatoid arthritis (RA) in a prospective population-based study of very early arthritis. Raised serum COMP levels were common in all diagnosis groups in this series, indicating cartilage involvement in both self-limiting and non-erosive disease.

 

INTERFERING DISEASES OR SUBSTANCES THAT ALTER LEVELS	CHARACTERIZATION
INFLIXIMAB
Autoantibody profile in rheumatoid arthritis during long-term infliximab treatment. Bobbio-Pallavicini F, Alpini C, Caporali R, Avalle S, Bugatti S, Montecucco C. Department of Rheumatology University of Pavia, IRCCS Policlinico S, Matteo, Pavia, Italy.	Arthritis Res Ther. 2004;6(3):R264-72. Epub 2004 Apr 26. Abstract quote   The aim of the present study was to investigate the effect of long-term infliximab treatment on various autoantibodies in patients with rheumatoid arthritis. Serum samples from 30 consecutive patients, who were prospectively followed during infliximab and methotrexate therapy for refractory rheumatoid arthritis, were tested at baseline and after 30, 54 and 78 weeks. At these points, median values of the Disease Activity Score were 6.38 (interquartile range 5.30-6.75), 3.69 (2.67-4.62), 2.9 (2.39-4.65) and 3.71 (2.62-5.06), respectively. Various autoantibodies were assessed by standard indirect immunofluorescence and/or ELISA. Initially, 50% of patients were positive for antinuclear antibodies, and this figure increased to 80% after 78 weeks (P = 0.029). A less marked, similar increase was found for IgG and IgM anticardiolipin antibody titre, whereas the frequency of anti-double-stranded DNA antibodies (by ELISA) exhibited a transient rise (up to 16.7%) at 54 weeks and dropped to 0% at 78 weeks. Antibodies to proteinase-3 and myeloperoxidase were not detected. The proportion of patients who were positive for rheumatoid factor (RF) was similar at baseline and at 78 weeks (87% and 80%, respectively). However, the median RF titre exhibited a progressive reduction from 128 IU/ml (interquartile range 47-290 IU/ml) to 53 IU/ml (18-106 IU/ml). Anti-cyclic citrullinated peptide (CCP) antibodies were found in 83% of patients before therapy; anti-CCP antibody titre significantly decreased at 30 weeks but returned to baseline thereafter. In conclusion, the presence of anti-double-stranded DNA antibodies is a transient phenomenon, despite a stable increase in antinuclear and anticardiolipin antibodies. Also, the evolution of RF titres and that of anti-CCP antibody titres differed during long-term infliximab therapy.

Henry JB. Clinical Diagnosis and Management by Laboratory Methods. Twentieth Edition. WB Saunders. 2001.

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Last Updated 7/15/2004

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