ACPA in rheumatism diagnostics: new and highly promising biomarkers for rheumatoid arthritis
The diagnosis and treatment of rheumatoid arthritis (RA) have made tremendous progress in the last few years. Experts are even suggesting that a paradigm shift has occurred in the field of rheumatology.
According to rheumatologists, this radical change can be seen in the completely new rheumatoid arthritis medications that have resulted in entirely new treatment options. Again and again, the paradigm shift in rheumatology is attributed to the new possibilities in rheumatoid arthritis diagnostics. Modern RA diagnostics are said to make it increasingly possible for rheumatologists to objectively determine the activity level of RA and thus to predict the progression of this autoimmune disease.
And indeed they do: Just a few years ago, a physician would be more likely to wait and see how rheumatoid arthritis would develop in a particular patient to know “whether it was really going to get that bad”. Estimation of RA disease progression, RA stratification, was completely impossible a few years ago. Unavoidably, doctor and patient were forced to accept the risk of grave and irreparable damage to the joints caused by aggressive progression of RA.
Things have changed. Through early – and if necessary sufficiently aggressive – treatment, the destruction of the joints so typical of advanced rheumatoid arthritis can now be significantly delayed. Sometimes it is even possible for rheumatoid arthritis to go into remission – not a cure of the autoimmune disease, but a cessation of progression. First and foremost, the absence of acute symptoms means an absence of pain for patients.
DMARDs offer new treatment options for rheumatoid arthritis
This is all made possible by completely new treatments with new drugs. Most crucial in this case are DMARD therapy (“DMARD” stands for “disease-modifying anti-rheumatic drug”) and the modern options for RA diagnostics. Taken together – the possibilities offered by innovative RA medications in combination with modern and effective RA diagnostics – these give rise to the approach of “hit hard and early”.
I have described how such “hit hard and early treatment” may look in cases of rheumatoid arthritis in a previous article here in the ORGENTEC Autoimmunity Blog (Recommendations on the Management of Rheumatoid Arthritis (RA) with DMARDs, posted on 18/06/2010). Without question, the main focus of such early arthritis treatment is the use of synthetic DMARDs, as recommended by researchers working with Joseph S. Smolen at the Medical University in Vienna in their article EULAR Recommendations for the Management of Rheumatoid Arthritis with Synthetic and Biological Disease-Modifiying Antirheumatic Drugs (Smolen et al. 2010):
1. Treatment with synthetic DMARDs should be started as soon as the diagnosis of RA is made, [ … ]
2. Treatment should be aimed at reaching a target of remission or low disease activity as soon as possible in every patient; as long as the target has not been reached, treatment should be adjusted by frequent (every 1–3 months) and strict monitoring.
from: Joseph S. Smolen et al., Ann Rheum Dis 2010; 69(6):964-75
A prerequisite for an early start to treatment for rheumatoid arthritis is unquestionably a reliable, and most importantly early, diagnosis of RA – and “early diagnosis” means the reliable recognition of the disease before the first serious symptoms appear, before damage to the joint cartilage or bone becomes manifest.
ACPA – new biomarkers for RA diagnostics
The development of effective diagnostic seromarkers and corresponding test systems, particularly ELISA test assays, represents enormous progress in RA diagnostics. Of immense importance in this field is the ACPA family of biomarkers, the “anti-citrullinated protein antibodies”.
The tremendous significance of ACPA detection for RA diagnostics is reflected in the new RA classification criteria of the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR), which were published in October 2010 in the journal Arthritis & Rheumatism (Aletaha et al. 2010). In this collaborative consensus report from both rheumatologic societies ACR and EULAR, serodiagnosis is finally officially given its due for diagnosis and classification. In my opinion, this is very overdue. According to the 2010 ACR-EULAR Classification Criteria for Rheumatoid Arthritis (what the official title of the publication is), the highly positive detection of rheumatoid factors (“high-positive RF”) and/or a highly positive serum titre for ACPA (“high-positive ACPA”) represent half of the point total required for a patient to be classified as a RA patient, 3 out of 6 points (the score developed by ACR and EULAR for the classification criteria can reach up to 10 points – you can find a summary of the 2010 RA classification criteria here on the Arthritis & Rheumatism website: 2010 ACR-EULAR Classification Criteria for Rheumatoid Arthritis – Excerpt).
I would argue that we here at ORGENTEC Diagnostika have played no small role in this development. With the Anti-MCV assay, we developed one of the two leading ACPA tests here in Mainz. And we were also involved in coining the term “ACPA” for the “anti-citrullinated protein antibodies”.
What are ACPAs all about?
The term anti-citrullinated protein antibodies, abbreviated as “ACPA”, includes all those autoantibodies that are directed against naturally occurring citrullinated epitopes of proteins (for example, mutated citrullinated vimentin, MCV) or against synthetic citrullinated peptides. For example, synthetically generated “cyclic citrullinated peptides”, CCP, are used as target antigens in various anti-CCP test systems.
Protein citrullination is a physiological process, meaning that it occurs naturally in the body. The process converts a specific amino acid, arginine, into the atypical amino acid citrulline (hence “citrullination”) (Vossenaar et al. 2004). The altered, citrullinated native protein is considered foreign by the immune system, which results in the formation of autoreactive (autoreactive = directed against the self) antibodies.
These autoantibodies attack the body’s own tissue and induce an inflammatory reaction. The consequence of citrullination can thus be an autoimmune disorder like rheumatoid arthritis, as described by Bence Gyorgy, Erzsébet Tóth, Edi Tarcsa, András Falus, and Edit I. Buzás in a review published in 2006 in the International Journal of Biochemistry & Cell Biology (Gyorgy et al. 2006). (Following this link you will find the abstract of the article: Citrullination: A Posttranslational Modification in Health and Disease.) Various different citrullinated proteins have been detected in the joints of patients with rheumatoid arthritis (Kinloch et al. 2008). One of these is citrullinated vimentin, which is identical to the Sa antigen first described in 1994 (Despres et al. 1994).
The processes that may be involved in the pathogenesis of rheumatoid arthritis were vividly described two years ago by my colleagues Holger Bang and Friederike Hammar in the article New Frontiers in Serodiagnosis of Rheumatoid Arthrits, presented in the October 2008 issue of the trade journal Clinical Laboratory International. This highly readable article also contains a figure depicting current thinking regarding the pathogenesis of rheumatoid arthritis, including the role played by citrullinated vimentin (link to Figure 3: Illustration of a model for the pathogenesis of rheumatoid arthritis involving mutated citrullinated vimentin (MCV).
The ACPA assay: from the Sa antibody to the Anti-MCV ELISA
Now a brief word about the history of anti-citrullinated protein antibodies, ACPA: Initially, ACPA were detected by means of immunofluorescence assays (IFA) and identified as anti-perinuclear factors and anti-keratin antibodies. Along with the Sa antibodies later described by Normand Després, Gilles Boire, F. Javier Lopez-Longo, and Henri A. Ménard in the article The Sa System: a Novel Antigen-Antibody System Specific for Rheumatoid Arthritis (Despres, Boire, Lopez-Longo, & Menard 1994), which are directed against citrullinated vimentin, these are specific markers of rheumatoid arthritis – though they have relatively low diagnostic sensitivity.
In Mutation and Citrullination Modifies Vimentin to a Novel Autoantigen for Rheumatoid Arthritis ORGENTEC associate Holger Bang then demonstrated that the properties of the citrullinated form of vimentin, the Sa antigen, are influenced by citrullination as well as various mutations (Bang et al. 2007). Based on these results, Holger developed an assay test that detects the autoantibodies against mutated citrullinated vimentin with high clinical specificity and good clinical sensitivity –ORGENTEC’s Anti-MCV ELISA test system for the sensitive and highly specific detection of ACPA was born.
Since that time, many other scientists have also demonstrated the diagnostic efficacy of our Anti-MCV test. In the last three years, many studies about the diagnostic power of that ACPA assay have been published, and the list of references on the ORGENTEC website relays only a small fraction of this very comprehensive list of literature (link to the ORGENTEC Literature Service: Anti-MCV and Antibodies against Citrullinated Protein/Peptide Antigens (ACPA).
Numerous completely independent research groups have since demonstrated that the anti-MCV antibodies, and thus our Anti-MCV test system, have diagnostic significance comparable to that of the previously known anti-CCP antibodies (“anti-CCP” means “antibodies against cyclic citrullinated peptides”). Various studies even prove that the anti-MCV antibodies broaden the diagnostic spectrum. The Anti-MCV test’s specificity is comparable to that for the anti-CCP antibodies – 95% versus 96% – but its sensitivity is considerably higher – 71% versus 58%. (I’ve taken these figures from the publication Antibodies Against Citrullinated Vimentin in Rheumatoid Arthritis by Linda Mathsson and co-workers, which appeared in 2007 in Arthritis & Rheumatism (Mathsson et al. 2007).
In this context, I also found the results reported by a research team working with Lena Innala in the article Antibodies against Mutated Citrullinated Vimentin Are a Better Predictor of Disease Activity at 24 Months in Early Rheumatoid Arthritis than Antibodies against Cyclic Citrullinated Peptides, which appeared in the April 2008 issue of The Journal of Rheumatology, to be particularly significant (Innala et al. 2008). The Scandinavian research results demonstrated a clear relationship between the anti-MCV antibody titre and the severity of rheumatoid arthritis, as well as a correlation between the anti-MCV autoantibody titre and disease activity as measured by the DAS28 score (DAS = “disease activity score”). In contrast to patients testing positive for anti-CCP antibodies, those positive for anti-MCV antibodies are characterized by a smaller reduction in disease activity (also measured by the DAS28 score) and a larger number of swollen joints.
And there’s more: Another follow-up study (Prediction of Radiographic Progression in Rheumatoid Arthritis and the Role of Antibodies against Mutated Citrullinated Vimentin: Results from a Ten-Year Prospective Study), which first appeared online in the Annals of the Rheumatoid Diseases, The EULAR journal, in July 2009, showed that patients with active rheumatoid arthritis have significantly higher serum titres of MCV antibodies than patients with mild rheumatoid arthritis (Syversen et al. 2009). The researchers were not able to achieve similar RA stratification with the anti-CCP test because the anti-CCP serum titres of both groups were nearly identical.
The upshot is that RA patients with a positive anti-MCV test result and negative anti-CCP test result experience a more aggressive progression of the disease than those patients who have a negative result for both antibodies. Also, the anti-MCV autoantibodies are clearly good markers for progression involving joint destruction in the early phase of rheumatoid arthritis.
I am thus curious to know if you are using ORGENTEC Diagnostika’s Anti-MCV assay for the diagnosis and stratification of rheumatoid arthritis? And I would also like to know what your experience with our test has been like!
Author of this article: Tobias Stolzenberg
Aletaha, D., Neogi, T., Silman, A.J., Funovits, J., Felson, D.T., Bingham, C.O., III, Birnbaum, N.S., Burmester, G.R., Bykerk, V.P., Cohen, M.D., Combe, B., Costenbader, K.H., Dougados, M., Emery, P., Ferraccioli, G., Hazes, J.M., Hobbs, K., Huizinga, T.W., Kavanaugh, A., Kay, J., Kvien, T.K., Laing, T., Mease, P., Menard, H.A., Moreland, L.W., Naden, R.L., Pincus, T., Smolen, J.S., Stanislawska-Biernat, E., Symmons, D., Tak, P.P., Upchurch, K.S., Vencovsky, J., Wolfe, F., & Hawker, G. 2010. 2010 Rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Ann Rheum Dis. 2010, 69, (9) 1580-1588 – free full text article available!
Bang, H., Egerer, K., Gauliard, A., Luthke, K., Rudolph, P.E., Fredenhagen, G., Berg, W., Feist, E., & Burmester, G.R. 2007. Mutation and citrullination modifies vimentin to a novel autoantigen for rheumatoid arthritis. Arthritis Rheum., 56, (8) 2503-2511 – free full text article available!
Despres, N., Boire, G., Lopez-Longo, F.J., & Menard, H.A. 1994. The Sa system: a novel antigen-antibody system specific for rheumatoid arthritis. J.Rheumatol., 21, (6) 1027-1033. – external link will open the abstract
Gyorgy, B., Toth, E., Tarcsa, E., Falus, A., & Buzas, E.I. 2006. Citrullination: a posttranslational modification in health and disease. Int.J Biochem.Cell Biol., 38, (10) 1662-1677. – external link will open the abstract
Innala, L., Kokkonen, H., Eriksson, C., Jidell, E., Berglin, E., & Dahlqvst, S.R. 2008. Antibodies Against Mutated Citrullinated Vimentin Are a Better Predictor of Disease Activity at 24 Months in Early Rheumatoid Arthritis Than Antibodies Against Cyclic Citrullinated Peptides. J Rheumatol., 35, 6 – external link will open the abstract
Kinloch, A., Lundberg, K., Wait, R., Wegner, N., Lim, N.H., Zendman, A.J., Saxne, T., Malmstr, V., & Venables, P.J. 2008. Synovial fluid is a site of citrullination of autoantigens in inflammatory arthritis. Arthritis Rheum, 58, (8) 2287-2295. – external link will open the abstract
Mathsson, L., Mullazehi, M., Wick, M.C., Sjoberg, O., van, V.R., Klareskog, L., & Ronnelid, J. 2007. Antibodies against citrullinated vimentin in rheumatoid arthritis: Higher sensitivity and extended prognostic value concerning future radiographic progression as compared with antibodies against cyclic citrullinated peptides. Arthritis Rheum, 58, (1) 36-45. – free full text article available!
Smolen, J.S., Landewe, R., Breedveld, F.C., Dougados, M., Emery, P., Gaujoux-Viala, C., Gorter, S., Knevel, R., Nam, J., Schoels, M., Aletaha, D., Buch, M., Gossec, L., Huizinga, T., Bijlsma, J.W., Burmester, G., Combe, B., Cutolo, M., Gabay, C., Gomez-Reino, J., Kouloumas, M., Kvien, T.K., Martin-Mola, E., Mcinnes, I., Pavelka, K., van, R.P., Scholte, M., Scott, D.L., Sokka, T., Valesini, G., van, V.R., Winthrop, K.L., Wong, J., Zink, A., & van der Heijde, D. 2010. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs. Ann Rheum Dis., 69, (6) 964-975 – free full text article available!
Syversen, S.W., Goll, G.L., van der Heijde, D., Landewe, R., Lie, B.A., Odegard, S., Uhlig, T., Gaarder, P.I., & Kvien, T.K. 2009. Prediction of radiographic progression in rheumatoid arthritis and the role of antibodies against mutated citrullinated vimentin: results from a ten-year prospective study. Ann.Rheum.Dis., 69, (2) 345-351. – link will open the abstract
Vossenaar, E.R., Radstake, T.R., Van Der, H.A., van Mansum, M.A., Dieteren, C., de Rooij, D.J., Barrera, P., Zendman, A.J., & van Venrooij, W.J. 2004. Expression and activity of citrullinating peptidylarginine deiminase enzymes in monocytes and macrophages. Ann.Rheum.Dis., 63, (4) 373-381 – free full text article available!
ORGENTEC Diagnostika Literature Service: Anti-MCV and antibodies against citrullinated protein / peptide antigens (ACPA)
blog post on ORGENTEC’s Autoimmunity Blog, posted 18/06/2010, by Tobias Stolzenberg: Recommendations on the Management of Rheumatoid Arthritis (RA) with DMARDs
H. Bang and F. Hammar. New frontiers in serodiagnosis of rheumatoid arthritis. Clinical Laboratory International, October 2008, Vol. 32, Issue 6.