Rheumatoid Arthritis: van Venrooij WJ

van Venrooij WJ, Pruijn GJ. · No affiliation provided · Arthritis Res Ther. · Pubmed #18828887 links to  free full text

Abstract: In the previous issue of Arthritis Research & Therapy data are presented showing that circulating immune complexes containing citrullinated fibrin(ogen) are present in anti-citrullinated protein antibody-positive rheumatoid arthritis patients, and that such immune complexes co-localize with complement factor C3 in the rheumatoid synovium. These results corroborate the idea that citrullination is intimately involved in the pathophysiology of rheumatoid arthritis and complete our model (the rheumatoid arthritis cycle) for the development and chronic nature of this disease.

van Venrooij WJ, van Beers JJ, Pruijn GJ. · Department of Biomolecular Chemistry, Radboud University, Nijmegen, The Netherlands. · Ann N Y Acad Sci. · Pubmed #19076355 No free full text.

Abstract: Rheumatoid arthritis (RA) is a common autoimmune disease characterized by chronic inflammation of synovial joints. In most cases this will lead to the formation of pannus tissue, ultimately leading to joint destruction. Early diagnosis, coupled with aggressive use of disease-modifying antirheumatic drugs, has been shown to have a favorable effect on the course of the disease. Therefore, early and accurate diagnosis has become increasingly important. Several sets of criteria have been published to achieve such an early diagnosis, and all of them include measurement of antibodies directed to citrullinated peptides or proteins. This review summarizes our present knowledge about the most well-known and established test to measure these antibodies, the anti-CCP test, which measures antibodies directed to cyclic citrullinated peptides. We describe the current views on how these antibodies are generated and how genetic and environmental parameters are important in this process. The anti-CCP test is more specific than the commonly used RF test (95% versus less than 90%) and has a comparable sensitivity (more than 70%). These antibodies are detectable very early in the disease and are reported to predict the development of erosive RA. Increasing evidence supports a role for these antibodies in the pathology of the disease. In conclusion, testing for anti-CCP autoantibodies is widely accepted as an indispensable tool for diagnosis and early treatment in the management of rheumatoid arthritis patients.

van Venrooij WJ, Zendman AJ, Pruijn GJ. · Department of Biochemistry, Centre for Molecular Life Sciences, Radboud University Nijmegen, Nijmegen, The Netherlands. · Autoimmun Rev. · Pubmed #17110315 No free full text.

Abstract: Rheumatoid arthritis (RA) is a common, systemic autoimmune disease characterized by chronic inflammation of the synovium, that can lead to progressive joint destruction and in many cases results in severe disability and poor quality of life. With the availability of more sophisticated and effective therapies and with increasing evidence that the first few months of disease represent an unique therapeutic opportunity and that such early therapeutic intervention is crucial in preventing irreversible joint damage, it is widely accepted that early and accurate diagnosis of RA is critical in disease management. Within the last three years a growing number of publications have reported that the second generation anti-CCP (cyclic citrullinated peptide) test may become the marker of choice for diagnosing early RA as it appears to be highly specific for the disease with a sensitivity comparable to the widely used but less specific rheumatoid factor test. Additionally, anti-CCP2 positivity can predict future development of RA in both asymptomatic individuals and in patients with undifferentiated arthritis. Furthermore, antibody levels at presentation can correlate with progression to erosive disease.

Zendman AJ, van Venrooij WJ, Pruijn GJ. · Department of Biochemistry, Nijmegen Center for Molecular Life Sciences, Radboud University Nijmegen, The Netherlands. · Rheumatology (Oxford). · Pubmed #16188946 links to  free full text

This publication has no abstract.

Zendman AJ, Vossenaar ER, van Venrooij WJ. · Department of Biochemistry, Nijmegen Center for Molecular Life Science, University of Nijmegen, Nijmegen, The Netherlands. · Autoimmunity. · Pubmed #15518045 No free full text.

This publication has no abstract.

van Venrooij WJ, Vossenaar ER, Zendman AJ. · Department of Biochemistry 161, University of Nijmegen, Nijmegen, The Netherlands. · Autoimmun Rev. · Pubmed #15309772 No free full text.

This publication has no abstract.

Vossenaar ER, van Venrooij WJ. · Department of Biochemistry, University of Nijmegen, Nijmegen, The Netherlands. · Arthritis Res Ther. · Pubmed #15142259 links to  free full text

Abstract: Antibodies directed to citrullinated proteins (e.g. anti-CCP [cyclic citrullinated peptide] antibodies) are highly specific for rheumatoid arthritis (RA). These antibodies are produced at the site of inflammation in RA, and therefore citrullinated antigens are also expected to be present in the inflamed synovium. We discuss literature showing that the presence of citrullinated proteins in the synovium is not specific for RA. The RA-specific antibodies are therefore most likely the result of an abnormal immune response that specifically occurs in RA patients. It was recently shown that presence of anti-CCP antibodies precedes the onset of clinical symptoms of RA by years. It thus appears that it may take years for initial events that cause the generation of anti-CCP antibodies to develop into full-blown disease.

Vossenaar ER, Zendman AJ, van Venrooij WJ, Pruijn GJ. · Department of Biochemistry, University of Nijmegen, Nijmegen, The Netherlands. · Bioessays. · Pubmed #14579251 No free full text.

Abstract: Peptidylarginine deiminase (PAD, EC 3.5.3.15) enzymes catalyze the conversion of protein-bound arginine to citrulline. This post-translational modification may have a big impact on the structure and function of the target protein. In this review, we will discuss the effects of citrullination and its involvement in several human diseases, including rheumatoid arthritis and multiple sclerosis. So far, four isotypes of PAD have been described in mammals. We describe the existence of PAD in non-mammalian vertebrates and the existence of a fifth mammalian PAD. In addition, tissue-specific expression, genomic organization and evolutionary conservation of the different PAD isotypes will be discussed in detail. This article contains supplementary material which may be viewed at the BioEssays website at http://www.interscience.wiley.com/jpages/0265-9247/suppmat/2003/25/v25.1106.html.

van Venrooij WJ, van de Putte LB. · Katholieke Universiteit, faculteit Natuurwetenschappen, Wiskunde en Informatica, afd. Biochemie, Postbus 9101, 6500 HB Nijmegen. · Ned Tijdschr Geneeskd. · Pubmed #12645351 No free full text.

Abstract: In patients with rheumatoid arthritis (RA), joint erosions occur at a very early stage of the disease before clinical symptoms can be detected. Early treatment with currently available antirheumatic drugs may stop or delay the development of such erosions. A simple and specific diagnostic test is needed for treatment to be initiated at an early stage. The specificity of the routinely used rheumatoid factor (RF) test is too low for that purpose. A novel autoantibody, directed to citrullinated antigens in the synovium, seems to provide a new starting point. These citrullinated autoantigens (e.g. fibrin) are specifically present in inflamed synovia and the antibodies for these are locally produced. The autoantibodies can be detected in the blood of the patients with RA years before the first clinical signs are manifest, and high titres appear to correlate strongly with erosive disease. The test for cyclic citrullinated peptide, which has recently become available, has a specificity of 98-99% and a sensitivity of 75-80%.

van Venrooij WJ, Hazes JM, Visser H. · Department of Biochemistry (161), University of Nijmegen, PO Box 9101, 6500 HB Nijmegen, the Netherlands. · Neth J Med. · Pubmed #12607587 links to  free full text

This publication has no abstract.

van Boekel MA, Vossenaar ER, van den Hoogen FH, van Venrooij WJ. · Department of Biochemistry, University of Nijmegen, PO Box 9101, 6500 HB Nijmegen, The Netherlands. · Arthritis Res. · Pubmed #11879544 links to  free full text

Abstract: The diagnosis of rheumatoid arthritis (RA) is primarily based on clinical symptoms, so it is often difficult to diagnose RA in very early stages of the disease. A disease-specific autoantibody that could be used as a serological marker would therefore be very useful. Most autoimmune diseases are characterized by a polyclonal B-cell response targeting multiple autoantigens. These immune responses are often not specific for a single disease. In this review, the most important autoantibody/autoantigen systems associated with RA are described and their utility as a diagnostic and prognostic tool, including their specificity, sensitivity and practical application, is discussed. We conclude that, at present, the antibody response directed to citrullinated antigens has the most valuable diagnostic and prognostic potential for RA.

van Jaarsveld CH, ter Borg EJ, Jacobs JW, Schellekens GA, Gmelig-Meyling FH, van Booma-Frankfort C, de Jong BA, van Venrooij WJ, Bijlsma JW. · Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, The Netherlands. · Clin Exp Rheumatol. · Pubmed #10609067 No free full text.

Abstract: OBJECTIVE: To study the prognostic value of the antiperinuclear factor (APF), determined by an indirect immunofluorescence test (IIF) and a recently developed anti-citrullinated cyclic peptide (CCP) ELISA, in combination with rheumatoid factor (RF) status, in early RA (< 1 year). METHODS: A total of 249 participants in a randomized trial of treatment strategies were divided into 4 groups according to their APF (or CCP) and RF status at baseline. Differences in disability, joint involvement and radiological damage over a 3-year period were analysed. RESULTS: APF-IIF results differed from CCP-ELISA in 42 cases (17%); 38 of the 42 had a positive IIF and negative ELISA value. Disability after 3 years did not differ significantly between the RF and APF groups. APF- patients had significantly lower Thompson joint scores compared to APF+ patients (6 vs 24 for CCP-ELISA; 2 vs 24 for IIF). RF+APF+ patients exhibited more radiological damage compared to RF-APF- patients. RF+APF- and RF-APF+ patients had intermediate scores. Within the RF+ and RF- groups, APF+ was associated with more radiological damage and thus yielded prognostic information in addition to RF. In this respect, the results of ELISA and IIF were comparable. Thirty percent of the RF+APF+ patients had a radiological score higher than 45, compared to 13% of the RF+APF-, none of the RF-APF+, and 2% of RF-APF- patients (p < 0.001). In addition, more large joints were affected in APF+ than in APF- patients, while no difference was observed between RF+ and RF- patients. CONCLUSION: APF has prognostic value in addition to RF for joint involvement and radiological damage in early RA. The CCP-ELISA technique for APF assessment may facilitate its use in clinical practice. However, the prognostic value of the two tests lies in their ability to predict mild disease. Reliable identification at baseline of individual patients with progressive disease is still not possible.

van Venrooij WJ, Zendman AJ. · Department of Biomolecular Chemistry, Radboud University Nijmegen, Nijmegen, The Netherlands, · Clin Rev Allergy Immunol. · Pubmed #18270856 links to  free full text

Abstract: The literature of the last 4 years confirms that the anti-CCP2 test is a very useful marker for the early and specific diagnosis of rheumatoid arthritis (RA). The anti-CCP2 test is very specific for RA (95-99%) and has sensitivity comparable to that of the rheumatoid factor (70-75%). The antibodies can be detected very early in the disease and can be used as an indicator for the progression and prognosis of RA. In this review, these interesting properties and some future possibilities of this diagnostic test are discussed.

Zendman AJ, Raijmakers R, Nijenhuis S, Vossenaar ER, Tillaart M, Chirivi RG, Raats JM, van Venrooij WJ, Drijfhout JW, Pruijn GJ. · Department of Biomolecular Chemistry, Nijmegen Center for Molecular Life Sciences, Institute for Molecules and Materials, Radboud University Nijmegen, Nijmegen NL-6500 HB, The Netherlands. · Anal Biochem. · Pubmed #17716614 No free full text.

Abstract: Members of the family of peptidylarginine deiminases (PADs, EC 3.5.3.15) catalyze the posttranslational modification of peptidylarginine into peptidylcitrulline. Citrulline-containing epitopes have been shown to be major and specific targets of autoantibodies produced by rheumatoid arthritis patients. Recently, the citrullination of histone proteins by PAD enzyme was reported to influence gene expression levels. These findings greatly increase the interest in the PAD enzymes and their activities. A few procedures to monitor PAD activity in biological samples have been described previously. However, these assays either have low sensitivity or are rather laborious. Here we describe a reliable and reproducible method for the determination of PAD activity in both purified and crude samples. The method is based on the quantification of PAD-dependent citrullination of peptides, immobilized in microtiter plates, using antibodies that are exclusively reactive with the reaction product(s). Our results demonstrate that this antibody-based assay for PAD activity, called ABAP, is very sensitive and can be applied to monitor PAD activity in biological samples.

Vannini A, Cheung K, Fusconi M, Stammen-Vogelzangs J, Drenth JP, Dall'Aglio AC, Bianchi FB, Bakker-Jonges LE, van Venrooij WJ, Pruijn GJ, Zendman AJ. · Department of Internal Medicine, Cardioangiology, Hepatology, University of Bologna, and Azienda Ospedaliero-Universitaria S. Orsola-Malpighi, Bologna, Italy. · Ann Rheum Dis. · Pubmed #16984940 No free full text.

Abstract: BACKGROUND: Antibodies directed against citrullinated proteins (eg anti-cyclic citrullinated peptide (CCP)) have excellent diagnostic and good prognostic potential for rheumatoid arthritis. Type 1 autoimmune hepatitis (AIH-1) is a chronic liver disease characterised by a variety of serum autoantibodies. Recently, in a large group of patients with AIH-1 without clear rheumatoid arthritis overlap, a relatively high percentage (9%) of anti-CCP2 positivity was scored. OBJECTIVES: To characterise the citrulline-dependence of the observed anti-CCP2 positivity in AIH-1 sera as well as in other groups of patients without rheumatoid arthritis (mainly rheumatic diseases). METHODS: Serum samples of 57 patients with AIH-1 and 66 patients without rheumatoid arthritis, most of them reported as anti-CCP positive, were tested for citrulline-specific reactivity with a second generation anti-CCP kit, with the citrullinated and the corresponding non-citrullinated (arginine-containing) antigen. A subset of AIH-1 sera was also tested with a CCP1 ELISA (and arginine control). RESULTS: The anti-CCP2 reactivity of most non-rheumatoid arthritis rheumatic diseases samples (87-93%) was citrulline-specific, whereas a relatively high percentage of AIH-1 samples (42-50%) turned out to be reactive in a citrulline-independent manner. The use of citrullinated and non-citrullinated CCP1 peptides confirmed a high occurrence of citrulline-independent reactivity in AIH-1 samples. CONCLUSIONS: In rheumatoid arthritis and most non-rheumatoid arthritis rheumatologic disease sera, anti-CCP positivity is citrulline-dependent. However in some patients, particularly patients with AIH-1, citrulline-independent reactivity in the anti-CCP2 test can occur. A positive CCP test in a non-rheumatic disease (eg liver disease) should therefore be interpreted with care, and preferably followed by a control ELISA with a non-citrullinated antigen.

van Venrooij WJ, van de Putte LB. · Department of Biochemistry, Radboud University, Nijmegen, Netherlands. · Nat Clin Pract Rheumatol. · Pubmed #16932618 No free full text.

This publication has no abstract.

Hueber W, Tomooka BH, Zhao X, Kidd BA, Drijfhout JW, Fries JF, van Venrooij WJ, Metzger AL, Genovese MC, Robinson WH. · Division of Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine, and Palo Alto VA Health Care System, MC 154R, 3801 Miranda Avenue, Palo Alto, CA 94304, USA. · Ann Rheum Dis. · Pubmed #16901957 No free full text.

Abstract: OBJECTIVES: To identify peripheral blood autoantibody and cytokine profiles that characterise clinically relevant subgroups of patients with early rheumatoid arthritis using arthritis antigen microarrays and a multiplex cytokine assay. METHODS: Serum samples from 56 patients with a diagnosis of rheumatoid arthritis of <6 months' duration were tested. Cytokine profiles were also determined in samples from patients with psoriatic arthritis (PsA) and ankylosing spondylitis (n = 21), and from healthy individuals (n = 19). Data were analysed using Kruskal-Wallis test with Dunn's adjustment for multiple comparisons, linear correlation tests, significance analysis of microarrays (SAM) and hierarchical clustering software. RESULTS: Distinct antibody profiles were associated with subgroups of patients who exhibited high serum levels of tumour necrosis factor (TNF)alpha, interleukin (IL)1beta, IL6, IL13, IL15 and granulocyte macrophage colony-stimulating factor. Significantly increased autoantibody reactivity against citrullinated epitopes was observed in patients within the cytokine "high" subgroup. Increased levels of TNFalpha, IL1alpha, IL12p40 and IL13, and the chemokines eotaxin/CCL11, monocyte chemoattractant protein-1 and interferon-inducible protein 10, were present in early rheumatoid arthritis as compared with controls (p<0.001). Chemokines showed some of the most impressive differences. Only IL8/CXCL8 concentrations were higher in patients with PsA/ankylosing spondylitis (p = 0.02). CONCLUSIONS: Increased blood levels of proinflammatory cytokines are associated with autoantibody targeting of citrullinated antigens and surrogate markers of disease activity in patients with early rheumatoid arthritis. Proteomic analysis of serum autoantibodies, cytokines and chemokines enables stratification of patients with early rheumatoid arthritis into molecular subgroups.

Hueber W, Kidd BA, Tomooka BH, Lee BJ, Bruce B, Fries JF, Sønderstrup G, Monach P, Drijfhout JW, van Venrooij WJ, Utz PJ, Genovese MC, Robinson WH. · Division of Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine, Stanford, California, USA. · Arthritis Rheum. · Pubmed #16142722 links to  free full text

Abstract: OBJECTIVE: Because rheumatoid arthritis (RA) is a heterogeneous autoimmune disease in terms of disease manifestations, clinical outcomes, and therapeutic responses, we developed and applied a novel antigen microarray technology to identify distinct serum antibody profiles in patients with RA. METHODS: Synovial proteome microarrays, containing 225 peptides and proteins that represent candidate and control antigens, were developed. These arrays were used to profile autoantibodies in randomly selected sera from 2 different cohorts of patients: the Stanford Arthritis Center inception cohort, comprising 18 patients with established RA and 38 controls, and the Arthritis, Rheumatism, and Aging Medical Information System cohort, comprising 58 patients with a clinical diagnosis of RA of <6 months duration. Data were analyzed using the significance analysis of microarrays algorithm, the prediction analysis of microarrays algorithm, and Cluster software. RESULTS: Antigen microarrays demonstrated that autoreactive B cell responses targeting citrullinated epitopes were present in a subset of patients with early RA with features predictive of the development of severe RA. In contrast, autoimmune targeting of the native epitopes contained on synovial arrays, including several human cartilage gp39 peptides and type II collagen, were associated with features predictive of less severe RA. CONCLUSION: Proteomic analysis of autoantibody reactivities provides diagnostic information and allows stratification of patients with early RA into clinically relevant disease subsets.

Lundberg K, Nijenhuis S, Vossenaar ER, Palmblad K, van Venrooij WJ, Klareskog L, Zendman AJ, Harris HE. · Rheumatology Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden. · Arthritis Res Ther. · Pubmed #15899032 links to  free full text

Abstract: Autoantibodies directed against citrulline-containing proteins have an impressive specificity of nearly 100% in patients with rheumatoid arthritis and have been suggested to be involved in the disease pathogenesis. The targeted epitopes are generated by a post-translational modification catalysed by the calcium-dependent enzyme peptidyl arginine deiminase (PAD), which converts positively charged arginine to polar but uncharged citrulline. The aim of this study was to explore the effects of citrullination on the immunogenicity of autoantigens as well as on potential arthritogenicity. Thus, immune responses to citrullinated rat serum albumin (Cit-RSA) and to unmodified rat serum albumin (RSA) were examined as well as arthritis development induced by immunisation with citrullinated rat collagen type II (Cit-CII) or unmodified CII. In addition, to correlate the presence of citrullinated proteins and the enzyme PAD4 with different stages of arthritis, synovial tissues obtained at different time points from rats with collagen-induced arthritis were examined immunohistochemically. Our results demonstrate that citrullination of the endogenous antigen RSA broke immunological tolerance, as was evident by the generation of antibodies directed against the modified protein and cross-reacting with the native protein. Furthermore we could demonstrate that Cit-CII induced arthritis with higher incidence and earlier onset than did the native counterpart. Finally, this study reveals that clinical signs of arthritis precede the presence of citrullinated proteins and the enzyme PAD4. As disease progressed into a more severe and chronic state, products of citrullination appeared specifically in the joints. Citrullinated proteins were detected mainly in extracellular deposits but could also be found in infiltrating cells and on the cartilage surface. PAD4 was detected in the cytoplasm of infiltrating mononuclear cells, from day 21 after immunisation and onwards. In conclusion, our data reveal the potency of citrullination to break tolerance against the self antigen RSA and to increase the arthritogenic properties of the cartilage antigen CII. We also show that citrullinated proteins and the enzyme PAD4 are not detectable in healthy joints, and that the appearance and amounts in arthritic joints of experimental animals are correlated with the severity of inflammation.

Vossenaar ER, Smeets TJ, Kraan MC, Raats JM, van Venrooij WJ, Tak PP. · Department of Biochemistry 161, Radboud University Nijmegen, NL-6500 HB Nijmegen, The Netherlands. · Arthritis Rheum. · Pubmed #15529392 links to  free full text

Abstract: OBJECTIVE: Antibodies directed toward citrullinated proteins (e.g., anti-cyclic citrullinated peptide antibodies) are highly specific for rheumatoid arthritis (RA) and are produced locally at the site of inflammation. Although the presence of citrullinated proteins in rheumatoid synovium has been described in the literature, it is uncertain whether their presence is specific for RA. The present study was undertaken to investigate this. METHODS: The local production of the anti-citrullinated protein antibodies was investigated by comparing the concentration of the antibodies (corrected for the total amount of IgG present) in paired samples of serum and synovial fluid from RA patients. The presence of citrullinated proteins in the synovial tissue was investigated by immunohistochemical analysis of synovial tissue from RA patients and from patients with other arthropathies, using a variety of specific antibodies to citrullinated proteins. RESULTS: In RA patients, anti-citrullinated protein antibodies constituted a 1.4-fold higher proportion of IgG in synovial fluid compared with serum, which is indicative of a local production of the antibodies. Immunohistochemical staining of citrullinated proteins was observed in the lining layer, the sublining layer, and in extravascular fibrin deposits in inflamed synovial tissue from RA as well as non-RA patients. CONCLUSION: The presence of citrullinated proteins in the inflamed synovium is not specific for RA, but rather, it may be an inflammation-associated phenomenon. The high specificity of the anti-citrullinated protein antibodies is, therefore, most likely the result of an abnormal humoral response to these proteins.

Vossenaar ER, van Boekel MA, van Venrooij WJ, López-Hoyoz M, Merino J, Merino R, Joosten LA. · University of Nijmegen, Nijmegen, The Netherlands. · Arthritis Rheum. · Pubmed #15248238 links to  free full text

This publication has no abstract.

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. · Pubmed #15248208 links to  free full text

Abstract: 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.

Vossenaar ER, Després N, Lapointe E, van der Heijden A, Lora M, Senshu T, van Venrooij WJ, Ménard HA. · Department of Biochemistry, University of Nijmegen, Nijmegen, The Netherlands. · Arthritis Res Ther. · Pubmed #15059278 links to  free full text

Abstract: Antibodies directed to the Sa antigen are highly specific for rheumatoid arthritis (RA) and can be detected in approximately 40% of RA sera. The antigen, a doublet of protein bands of about 50 kDa, is present in placenta and in RA synovial tissue. Although it has been stated that the Sa antigen is citrullinated vimentin, experimental proof for this claim has never been published. In this study, we investigated the precise nature of the antigen. Peptide sequences that were obtained from highly purified Sa antigen were unique to vimentin. Recombinant vimentin, however, was not recognized by anti-Sa reference sera. In vivo, vimentin is subjected to various post-translational modifications, including citrullination. Since antibodies to citrullinated proteins are known to be highly specific for RA, we investigated whether Sa is citrullinated and found that Sa indeed is citrullinated vimentin. Anti-Sa antibodies thus belong to the family of anticitrullinated protein/peptide antibodies. The presence of the Sa antigen in RA synovial tissue, and the recent observation that vimentin is citrullinated in dying human macrophages, make citrullinated vimentin an interesting candidate autoantigen in RA and may provide new insights into the potential role of citrullinated synovial antigens and the antibodies directed to them in the pathophysiology of RA.

van Gaalen FA, Linn-Rasker SP, van Venrooij WJ, de Jong BA, Breedveld FC, Verweij CL, Toes RE, Huizinga TW. · Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands. · Arthritis Rheum. · Pubmed #15022309 links to  free full text

Abstract: OBJECTIVE: Rheumatoid arthritis (RA) is a common, severe, chronic inflammatory joint disease. Since the disease may initially be indistinguishable from other forms of arthritis, early diagnosis can be difficult. Autoantibodies seen in RA can be detected years before clinical symptoms develop. In an inception cohort of patients with recent-onset arthritis, we undertook this study to assess the predictive value of RA-specific autoantibodies to cyclic citrullinated peptides (CCPs) in patients with undifferentiated arthritis (UA). METHODS: Anti-CCP2 antibody tests were performed at baseline in 936 consecutive, newly referred patients with recent-onset arthritis. Patients who could not be properly classified 2 weeks after inclusion were categorized as having UA. Patients with UA were followed up for 3 years and evaluated for progression of their disease to RA as defined by the American College of Rheumatology (ACR) 1987 revised criteria. RESULTS: Three hundred eighteen of 936 patients with recent-onset arthritis were classified as having UA and were available for analysis. After 3 years of followup, 127 of 318 UA patients (40%) had been classified as having RA. RA had developed in 63 of 249 patients (25%) with a negative anti-CCP test and in 64 of 69 patients (93%) with a positive anti-CCP test (odds ratio 37.8 [95% confidence interval 13.8-111.9]). Multivariate analysis of the presence of anti-CCP antibodies and parameters from the ACR criteria identified polyarthritis, symmetric arthritis, erosions on radiographs, and anti-CCP antibodies as significant predictors of RA. CONCLUSION: Testing for anti-CCP antibodies in UA allows accurate prediction of a substantial number of patients who will fulfill the ACR criteria for RA.

Vossenaar ER, Radstake TR, van der Heijden A, van Mansum MA, Dieteren C, de Rooij DJ, Barrera P, Zendman AJ, van Venrooij WJ. · Department of Biochemistry, University of Nijmegen, Nijmegen, The Netherlands. · Ann Rheum Dis. · Pubmed #15020330 links to  free full text

Abstract: BACKGROUND: Antibodies directed to proteins containing the non-standard amino acid citrulline, are extremely specific for rheumatoid arthritis (RA). Peptidylcitrulline can be generated by post-translational conversion of arginine residues. This process, citrullination, is catalysed by a group of calcium dependent peptidylarginine deiminase (PAD) enzymes. OBJECTIVE: To investigate the expression and activity of four isotypes of PAD in peripheral blood and synovial fluid cells of patients with RA. RESULTS: The data presented here show that citrullination of proteins by PAD enzymes is a process regulated at three levels: transcription-in peripheral blood PAD2 and PAD4 mRNAs are expressed predominantly in monocytes; PAD4 mRNA is not detectable in macrophages, translation-translation of PAD2 mRNA is subject to differentiation stage-specific regulation by its 3' UTR, and activation-the PAD proteins are only activated when sufficient Ca(2+) is available. Such high Ca(2+) concentrations are normally not present in living cells. In macrophages, which are abundant in the inflamed RA synovium, vimentin is specifically citrullinated after Ca(2+) influx. CONCLUSION: PAD2 and PAD4 are the most likely candidate PAD isotypes for the citrullination of synovial proteins in RA. Our results indicate that citrullinated vimentin is a candidate autoantigen in RA.