Niveles de autoanticuerpos anti-peptidos carbamilados y citrulinados y su relación con índices de actividad clínica reumática en pacientes con artritis reumatoide temprana y familiares en primer grado de consanguinidad de pacientes con artritis reumatoide, oriundos de Colombia

La Artritis Reumatoide (AR) es una enfermedad autoinmune sistémica caracterizada por un estado de inflamación crónica y deterioro progresivo de las articulaciones. Su diagnóstico se basa en una serie de criterios clínicos y pruebas de laboratorio. Este último ítem abarca la detección del Factor Reum...

Full description

Autores:
Ramos Casallas, Manuel Alejandro
Tipo de recurso:
Trabajo de grado de pregrado
Fecha de publicación:
2018
Institución:
Colegio Mayor de Cundinamarca
Repositorio:
Repositorio Colegio Mayor de Cundinamarca
Idioma:
spa
OAI Identifier:
oai:repositorio.unicolmayor.edu.co:unicolmayor/4792
Acceso en línea:
https://repositorio.unicolmayor.edu.co/handle/unicolmayor/4792
Palabra clave:
Enfermedad Autoinmune
Autoautoanticuerpos
Anticuerpos
Artritis
Autoinmunidad
Carbamilación
Diagnostico
Rights
closedAccess
License
Derechos Reservados - Universidad Colegio Mayor de Cundinamarca, 2018
id UCOLMAYOR2_4253ab4341adfc2f3abdea9a1e093a5a
oai_identifier_str oai:repositorio.unicolmayor.edu.co:unicolmayor/4792
network_acronym_str UCOLMAYOR2
network_name_str Repositorio Colegio Mayor de Cundinamarca
repository_id_str
dc.title.spa.fl_str_mv Niveles de autoanticuerpos anti-peptidos carbamilados y citrulinados y su relación con índices de actividad clínica reumática en pacientes con artritis reumatoide temprana y familiares en primer grado de consanguinidad de pacientes con artritis reumatoide, oriundos de Colombia
title Niveles de autoanticuerpos anti-peptidos carbamilados y citrulinados y su relación con índices de actividad clínica reumática en pacientes con artritis reumatoide temprana y familiares en primer grado de consanguinidad de pacientes con artritis reumatoide, oriundos de Colombia
spellingShingle Niveles de autoanticuerpos anti-peptidos carbamilados y citrulinados y su relación con índices de actividad clínica reumática en pacientes con artritis reumatoide temprana y familiares en primer grado de consanguinidad de pacientes con artritis reumatoide, oriundos de Colombia
Enfermedad Autoinmune
Autoautoanticuerpos
Anticuerpos
Artritis
Autoinmunidad
Carbamilación
Diagnostico
title_short Niveles de autoanticuerpos anti-peptidos carbamilados y citrulinados y su relación con índices de actividad clínica reumática en pacientes con artritis reumatoide temprana y familiares en primer grado de consanguinidad de pacientes con artritis reumatoide, oriundos de Colombia
title_full Niveles de autoanticuerpos anti-peptidos carbamilados y citrulinados y su relación con índices de actividad clínica reumática en pacientes con artritis reumatoide temprana y familiares en primer grado de consanguinidad de pacientes con artritis reumatoide, oriundos de Colombia
title_fullStr Niveles de autoanticuerpos anti-peptidos carbamilados y citrulinados y su relación con índices de actividad clínica reumática en pacientes con artritis reumatoide temprana y familiares en primer grado de consanguinidad de pacientes con artritis reumatoide, oriundos de Colombia
title_full_unstemmed Niveles de autoanticuerpos anti-peptidos carbamilados y citrulinados y su relación con índices de actividad clínica reumática en pacientes con artritis reumatoide temprana y familiares en primer grado de consanguinidad de pacientes con artritis reumatoide, oriundos de Colombia
title_sort Niveles de autoanticuerpos anti-peptidos carbamilados y citrulinados y su relación con índices de actividad clínica reumática en pacientes con artritis reumatoide temprana y familiares en primer grado de consanguinidad de pacientes con artritis reumatoide, oriundos de Colombia
dc.creator.fl_str_mv Ramos Casallas, Manuel Alejandro
dc.contributor.advisor.none.fl_str_mv Romero Sánchez, María Consuelo
Chila Moreno, Leidy Lorena
Muñoz Henao, Julián Esteban
dc.contributor.author.none.fl_str_mv Ramos Casallas, Manuel Alejandro
dc.subject.lemb.none.fl_str_mv Enfermedad Autoinmune
Autoautoanticuerpos
topic Enfermedad Autoinmune
Autoautoanticuerpos
Anticuerpos
Artritis
Autoinmunidad
Carbamilación
Diagnostico
dc.subject.proposal.spa.fl_str_mv Anticuerpos
Artritis
Autoinmunidad
Carbamilación
Diagnostico
description La Artritis Reumatoide (AR) es una enfermedad autoinmune sistémica caracterizada por un estado de inflamación crónica y deterioro progresivo de las articulaciones. Su diagnóstico se basa en una serie de criterios clínicos y pruebas de laboratorio. Este último ítem abarca la detección del Factor Reumatoide (FR) y/o los autoanticuerpos anti-proteínas citrulinadas (anti-CCP), asociados a la actividad de la enfermedad y al pronóstico de la misma. Sin embargo, existen grupos de pacientes con elevado daño articular y niveles indetectables de FR y/o autoautoanticuerpos anti-CCP, dificultando el diagnóstico y las opciones terapéuticas. De forma reciente se descubrieron los autoanticuerpos anti-proteínas carbamiladas (anti-CarP) asociados a esta enfermedad, los cuales permitirían tipificar la AR en estos grupos de pacientes e individuos con condiciones de riesgo, además de poder predecir el desenlace articular. De esta manera se facilitaría el diagnóstico, así como en el tratamiento y el pronóstico. En este estudio se midieron los niveles de autoautoanticuerpos anti-CCP. Así mismo, se midieron los niveles de autoanticuerpos frente al péptido carbamilado de fibrinógeno (empleando el péptido nativo como control), en pacientes con artritis reumatoide temprana y familiares en primer grado de consanguinidad, para establecer su asociación frente al daño reumatológico y periodontal. Los resultados resaltan la asociación entre el número de articulaciones dolorosas e inflamadas y el daño periodontal con la presencia de los anticuerpos anti-péptido de fibrinógeno carbamilado en el grupo de familiares en primer grado de consanguinidad. No hubo asociación entre estos autoanticuerpos y los autoautoanticuerpos anti-CCP en los pacientes con artritis reumatoide temprana. Como hallazgo adicional, se observó que los dos grupos de estudio presentan autoanticuerpos contra el péptido nativo de fibrinógeno. En conclusión, la presencia de autoanticuerpos contra péptidos/proteínas carbamiladas están presentes en la población colombiana con artritis reumatoide temprana y familiares en primer grado de consanguinidad; asociados a manifestaciones de daño articular y periodontal. Además, la presencia de autoanticuerpos frente al péptido de fibrinógeno nativo puede ser un indicio de desarrollo de la enfermedad.
publishDate 2018
dc.date.issued.none.fl_str_mv 2018-05
dc.date.accessioned.none.fl_str_mv 2022-03-09T16:33:00Z
dc.date.available.none.fl_str_mv 2022-03-09T16:33:00Z
dc.type.spa.fl_str_mv Trabajo de grado - Pregrado
dc.type.coar.spa.fl_str_mv http://purl.org/coar/resource_type/c_7a1f
dc.type.coarversion.spa.fl_str_mv http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.content.spa.fl_str_mv Text
dc.type.driver.spa.fl_str_mv info:eu-repo/semantics/bachelorThesis
dc.type.redcol.spa.fl_str_mv https://purl.org/redcol/resource_type/TP
dc.type.version.spa.fl_str_mv info:eu-repo/semantics/publishedVersion
format http://purl.org/coar/resource_type/c_7a1f
status_str publishedVersion
dc.identifier.uri.none.fl_str_mv https://repositorio.unicolmayor.edu.co/handle/unicolmayor/4792
dc.identifier.barcode.none.fl_str_mv 58418
url https://repositorio.unicolmayor.edu.co/handle/unicolmayor/4792
identifier_str_mv 58418
dc.language.iso.spa.fl_str_mv spa
language spa
dc.relation.references.spa.fl_str_mv Firestein GS. Evolving concepts of rheumatoid arthritis. Nature [Internet]. 2003 May 15;423(6937):356–61. Available from: http://www.nature.com/doifinder/10.1038/nature01661
Klareskog L, Rönnelid J, Lundberg K, Padyukov L, Alfredsson L. Immunity to citrullinated proteins in rheumatoid arthritis. Annu Rev Immunol [Internet]. 2008;26:651–75. Available from: http://www.ncbi.nlm.nih.gov/pubmed/18173373
Wegner N, Lundberg K, Kinloch A, Fisher B, Malmström V, Feldmann M, et al. Autoimmunity to specific citrullinated proteins gives the first clues to the etiology of rheumatoid arthritis. Immunol Rev. 2010;233(1):34–54.
Rosales-borjas DM, Arévalo MA, Ortiz-ortiz L. Artritis reumatoide: importancia de los antigenos citrulinados en el diagnostico del padecimiento. Rev Médica la Extensión Port. 2009;4(3):125–30.
Nishimura K, Sugiyama D, Kogata Y, Tsuji G, Nakazawa T, Kawano S, et al. Meta-analysis: diagnostic accuracy of anti-cyclic citrullinated peptide antibody and rheumatoid factor for rheumatoid arthritis. Ann Intern Med [Internet]. 2007 Jun 5;146(11):797–808. Available from: http://www.ncbi.nlm.nih.gov/pubmed/17548411
van Venrooij WJ, Hazes JM, Visser H. Anticitrullinated protein/peptide antibody and its role in the diagnosis and prognosis of early rheumatoid arthritis. Neth J Med. 2002;60(10):383–8.
Rantapää-Dahlqvist S, de Jong BAW, Berglin E, Hallmans G, Wadell G, Stenlund H, et al. Antibodies against cyclic citrullinated peptide and IgA rheumatoid factor predict the development of rheumatoid arthritis. Arthritis Rheum [Internet]. 2003 Oct;48(10):2741–9. Available from: http://www.ncbi.nlm.nih.gov/pubmed/14558078
van der Helm-van Mil AHM, Verpoort KN, Breedveld FC, Toes REM, Huizinga TWJ. Antibodies to citrullinated proteins and differences in clinical progression of rheumatoid arthritis. Arthritis Res Ther [Internet]. 2005;7(5):R949-58. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1257421&tool=pm centrez&rendertype=abstract
Van Der Woude D, Young A, Jayakumar K, Mertens BJ, Toes REM, Van Der Heijde D, et al. Prevalence of and predictive factors for sustained diseasemodifying antirheumatic drug-free remission in rheumatoid arthritis: Results from two large early arthritis cohorts. Arthritis Rheum [Internet]. 2009 Aug;60(8):2262–71. Available from: http://doi.wiley.com/10.1002/art.24661
Van Der Woude D, Young A, Jayakumar K, Mertens BJ, Toes REM, Van Der Heijde D, et al. Prevalence of and predictive factors for sustained diseasemodifying antirheumatic drug-free remission in rheumatoid arthritis: Results from two large early arthritis cohorts. Arthritis Rheum [Internet]. 2009 Aug;60(8):2262–71. Available from: http://doi.wiley.com/10.1002/art.24661
Nielen MMJ, van Schaardenburg D, Reesink HW, van de Stadt RJ, van der Horst-Bruinsma IE, de Koning MHMT, et al. Specific autoantibodies precede the symptoms of rheumatoid arthritis: a study of serial measurements in blood donors. Arthritis Rheum [Internet]. 2004 Feb;50(2):380–6. Available from: http://www.ncbi.nlm.nih.gov/pubmed/14872479
Willemze A, Trouw L a, Toes REM, Huizinga TWJ. The influence of ACPA status and characteristics on the course of RA. Nat Rev Rheumatol [Internet]. 2012;8(3):144–52. Available from: http://www.ncbi.nlm.nih.gov/pubmed/22293763
Berglin E, Johansson T, Sundin U, Jidell E, Wadell G, Hallmans G, et al. Radiological outcome in rheumatoid arthritis is predicted by presence of antibodies against cyclic citrullinated peptide before and at disease onset, and by IgA-RF at disease onset. Ann Rheum Dis [Internet]. 2006 Apr;65(4):453–8. Available from: http://www.ncbi.nlm.nih.gov/pubmed/16176994
Shi J, Knevel R, Suwannalai P, van der Linden MP, Janssen GMC, van Veelen P a., et al. Autoantibodies recognizing carbamylated proteins are present in sera of patients with rheumatoid arthritis and predict joint damage. Proc Natl Acad Sci. 2011;108(42):17372–7.
Steinbrecher UP, Fisher M, Witztum JL, Curtiss LK. Immunogenicity of homologous low density lipoprotein after methylation, ethylation, acetylation, or carbamylation: generation of antibodies specific for derivatized lysine. J Lipid Res [Internet]. 1984 Oct;25(10):1109–16. Available from: http://www.ncbi.nlm.nih.gov/pubmed/6439810
Mydel P, Wang Z, Brisslert M, Hellvard A, Dahlberg LE, Hazen SL, et al. Carbamylation-dependent activation of T cells: a novel mechanism in the pathogenesis of autoimmune arthritis. J Immunol [Internet]. 2010 Jun 15;184(12):6882–90. Available from: http://www.ncbi.nlm.nih.gov/pubmed/20488785
Shi J, Van De Stadt LA, Levarht EWN, Huizinga TWJ, Toes REM, Trouw LA, et al. Anti-carbamylated protein antibodies are present in arthralgia patients and predict the development of rheumatoid arthritis. Arthritis Rheum. 2013;65(4):911–5.
Yee A, Webb T, Seaman A, Infantino M, Meacci F, Manfredi M, et al. AntiCarP antibodies as promising marker to measure joint damage and disease activity in patients with rheumatoid arthritis. Immunol Res. 2014;61(1–2):24– 30.
Shi J, van de Stadt L a, Levarht EWN, Huizinga TWJ, Hamann D, van Schaardenburg D, et al. Anti-carbamylated protein (anti-CarP) antibodies precede the onset of rheumatoid arthritis. Ann Rheum Dis [Internet]. 2014;73(4):780–3. Available from: http://www.ncbi.nlm.nih.gov/pubmed/24336334
Brink M, Verheul MK, Rönnelid J, Berglin E, Holmdahl R, Toes REM, et al. Anti-carbamylated protein antibodies in the pre-symptomatic phase of rheumatoid arthritis, their relationship with multiple anti-citrulline peptide antibodies and association with radiological damage. Arthritis Res Ther [Internet]. 2015;17:25. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=4350267&tool=pm centrez&rendertype=abstract
Jiang X, Trouw L a, van Wesemael TJ, Shi J, Bengtsson C, Källberg H, et al. Anti-CarP antibodies in two large cohorts of patients with rheumatoid arthritis and their relationship to genetic risk factors, cigarette smoking and other autoantibodies. Ann Rheum Dis [Internet]. 2014;1761–8. Available from: http://www.ncbi.nlm.nih.gov/pubmed/24812286
Gan RW, Trouw LA, Shi J, Toes REM, Huizinga TWJ, Demoruelle MK, et al. Anti-carbamylated Protein Antibodies Are Present Prior to Rheumatoid Arthritis and Are Associated with Its Future Diagnosis. J Rheumatol [Internet]. 2015 Apr 1;42(4):572–9. Available from: http://www.jrheum.org/cgi/doi/10.3899/jrheum.140767
Shi J, van Steenbergen HW, van Nies JAB, Levarht EWN, Huizinga TWJ, van der Helm-van Mil AHM, et al. The specificity of anti-carbamylated protein antibodies for rheumatoid arthritis in a setting of early arthritis. Arthritis Res Ther [Internet]. 2015;17(1):339. Available from: http://arthritisresearch.com/content/17/1/339
Alessandri C, Bartosiewicz I, Pendolino M, Mancini R, Colasanti T, Pecani A, et al. Anti-carbamylated protein antibodies in unaffected first-degree relatives of rheumatoid arthritis patients: Lack of correlation with anti-cyclic citrullinated protein antibodies and rheumatoid factor. Clin Exp Rheumatol. 2015;33(6):824–30.
Koppejan H, Trouw LA, Sokolove J, Lahey LJ, Huizinga TJW, Smolik IA, et al. Role of Anti-Carbamylated Protein Antibodies Compared to Anti- Citrullinated Protein Antibodies in Indigenous North Americans With Rheumatoid Arthritis, Their First-Degree Relatives, and Healthy Controls. Arthritis Rheumatol [Internet]. 2016 Sep;68(9):2090–8. Available from: http://doi.wiley.com/10.1002/art.39664
Reed E, Jiang X, Kharlamova N, Ytterberg AJ, Catrina AI, Israelsson L, et al. Antibodies to carbamylated α -enolase epitopes in rheumatoid arthritis also bind citrullinated epitopes and are largely indistinct from anti-citrullinated protein antibodies. Arthritis Res Ther [Internet]. 2016;1–9. Available from: http://dx.doi.org/10.1186/s13075-016-1001-6
Montes A, Regueiro C, Perez-Pampin E, Boveda MD, Gomez-Reino JJ, Gonzalez A. Anti-Carbamylated Protein Antibodies as a Reproducible Independent Type of Rheumatoid Arthritis Autoantibodies. Kuwana M, editor. PLoS One [Internet]. 2016 Aug 18;11(8):e0161141. Available from: http://dx.plos.org/10.1371/journal.pone.0161141
Gibofsky A. Overview of epidemiology, pathophysiology, and diagnosis of rheumatoid arthritis. Am J Manag Care [Internet]. 2012 Dec;18(13 Suppl):S295-302. Available from: http://www.ncbi.nlm.nih.gov/pubmed/23327517
McInnes IB, Schett G. The Pathogenesis of Rheumatoid Arthritis. N Engl J Med [Internet]. 2011 Dec 8;365(23):2205–19. Available from: http://rcnpublishing.com/doi/abs/10.7748/phc2011.11.21.9.29.c8797
Burska AN, Hunt L, Boissinot M, Strollo R, Ryan BJ, Vital E, et al. Autoantibodies to Posttranslational Modifications in Rheumatoid Arthritis. Mediators Inflamm [Internet]. 2014;2014:1–19. Available from: http://www.hindawi.com/journals/mi/2014/492873/
Nissim A, Winyard PG, Corrigall V, Fatah R, Perrett D, Panayi G, et al. Generation of neoantigenic epitopes after posttranslational modification of type II collagen by factors present within the inflamed joint. Arthritis Rheum [Internet]. 2005 Dec;52(12):3829–38. Available from: http://doi.wiley.com/10.1002/art.21479
Marcinkiewicz J, Biedroń R, Maresz K, Kwaśny-Krochin B, Bobek M, Kontny E, et al. Oxidative modification of type II collagen differentially affects its arthritogenic and tolerogenic capacity in experimental arthritis. Arch Immunol Ther Exp (Warsz) [Internet]. 52(4):284–91. Available from: http://www.ncbi.nlm.nih.gov/pubmed/15467493
Anderton SM. Post-translational modifications of self antigens: implications for autoimmunity. Curr Opin Immunol [Internet]. 2004 Dec;16(6):753–8. Available from: http://linkinghub.elsevier.com/retrieve/pii/S0952791504001451
Eggleton P, Nissim A, Ryan BJ, Whiteman M, Winyard PG. Detection and isolation of human serum autoantibodies that recognize oxidatively modified autoantigens. Free Radic Biol Med [Internet]. 2013 Apr;57:79–91. Available from: http://linkinghub.elsevier.com/retrieve/pii/S0891584912018060
Valesini G, Gerardi MC, Iannuccelli C, Pacucci VA, Pendolino M, Shoenfeld Y. Citrullination and autoimmunity. Autoimmun Rev [Internet]. 2015 Jun;14(6):490–7. Available from: http://linkinghub.elsevier.com/retrieve/pii/S1568997215000282
Baka Z, György B, Géher P, Buzás EI, Falus A, Nagy G. Citrullination under physiological and pathological conditions. Jt Bone Spine [Internet]. 2012 Oct;79(5):431–6. Available from: http://linkinghub.elsevier.com/retrieve/pii/S1297319X12000127
Cantagrel A, Degboé Y. New autoantibodies associated with rheumatoid arthritis recognize posttranslationally modified self-proteins. Joint Bone Spine [Internet]. 2015;83(1):11–7. Available from: http://www.ncbi.nlm.nih.gov/pubmed/26639222
Gerlag DM, Raza K, van Baarsen LGM, Brouwer E, Buckley CD, Burmester GR, et al. EULAR recommendations for terminology and research in individuals at risk of rheumatoid arthritis: report from the Study Group for Risk Factors for Rheumatoid Arthritis. Ann Rheum Dis. 2012;71(5):638–41.
Aletaha D, Neogi T, Silman AJ, Funovits J, Felson DT, Bingham CO, et al. 2010 Rheumatoid arthritis classification criteria: An American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheum. 2010;62(9):2569–81.
O’Dell J. Rheumatoid arthritis. In: Goldman L, Schafer AI E, editor. Goldman’s Cecil Medicine. 25th ed. Philadelphia: Elsevier Saunders; 2016.
Gregersen PK, Silver J, Winchester RJ. The shared epitope hypothesis. An approach to understanding the molecular genetics of susceptibility to rheumatoid arthritis. Arthritis Rheum [Internet]. 1987 Nov;30(11):1205–13. Available from: http://www.ncbi.nlm.nih.gov/pubmed/2446635
Bax M, van Heemst J, Huizinga TWJ, Toes REM. Genetics of rheumatoid arthritis: what have we learned? Immunogenetics [Internet]. 2011 Aug 10;63(8):459–66. Available from: http://link.springer.com/10.1007/s00251- 011-0528-6
Hutchinson D, Shepstone L, Moots R, Lear JT, Lynch MP. Heavy cigarette smoking is strongly associated with rheumatoid arthritis (RA), particularly in patients without a family history of RA. Ann Rheum Dis [Internet]. 2001 Mar;60(3):223–7. Available from: http://www.ncbi.nlm.nih.gov/pubmed/11171682
Källberg H, Ding B, Padyukov L, Bengtsson C, Rönnelid J, Klareskog L, et al. Smoking is a major preventable risk factor for rheumatoid arthritis: estimations of risks after various exposures to cigarette smoke. Ann Rheum Dis [Internet]. 2011 Mar;70(3):508–11. Available from: http://www.ncbi.nlm.nih.gov/pubmed/21149499
Karlson EW, Lee IM, Cook NR, Manson JE, Buring JE, Hennekens CH. A retrospective cohort study of cigarette smoking and risk of rheumatoid arthritis in female health professionals. Arthritis Rheum [Internet]. 1999 May;42(5):910–7. Available from: http://www.ncbi.nlm.nih.gov/pubmed/10323446
Kochi Y, Suzuki A, Yamamoto K. Genetic basis of rheumatoid arthritis: A current review. Biochem Biophys Res Commun [Internet]. 2014;452(2):254– 62. Available from: http://dx.doi.org/10.1016/j.bbrc.2014.07.085
Suzuki A, Yamada R, Chang X, Tokuhiro S, Sawada T, Suzuki M, et al. Functional haplotypes of PADI4, encoding citrullinating enzyme peptidylarginine deiminase 4, are associated with rheumatoid arthritis. Nat Genet [Internet]. 2003 Aug 29;34(4):395–402. Available from: http://www.nature.com/doifinder/10.1038/ng1206
Kochi Y, Suzuki A, Yamada R, Yamamoto K. Ethnogenetic heterogeneity of rheumatoid arthritis—implications for pathogenesis. Nat Rev Rheumatol [Internet]. 2010 May 16;6(5):290–5. Available from: http://www.nature.com/doifinder/10.1038/nrrheum.2010.23
Nakashima K, Hagiwara T, Ishigami A, Nagata S, Asaga H, Kuramoto M, et al. Molecular characterization of peptidylarginine deiminase in HL-60 cells induced by retinoic acid and 1alpha,25-dihydroxyvitamin D(3). J Biol Chem [Internet]. 1999 Sep 24;274(39):27786–92. Available from: http://www.ncbi.nlm.nih.gov/pubmed/10488123
Irigoyen P, Lee AT, Wener MH, Li W, Kern M, Batliwalla F, et al. Regulation of anti-cyclic citrullinated peptide antibodies in rheumatoid arthritis: Contrasting effects of HLA-DR3 and the shared epitope alleles. Arthritis Rheum [Internet]. 2005 Dec;52(12):3813–8. Available from: http://doi.wiley.com/10.1002/art.21419
Cha S, Choi C-B, Han T-U, Kang CP, Kang C, Bae S-C. Association of Anti– Cyclic citrullinated peptide antibody levels with PADI4 haplotypes in early rheumatoid arthritis and with shared epitope alleles in very late rheumatoid arthritis. Arthritis Rheum [Internet]. 2007 May;56(5):1454–63. Available from: http://doi.wiley.com/10.1002/art.22570
Gregersen PK, Lee H-S, Batliwalla F, Begovich AB. PTPN22: Setting thresholds for autoimmunity. Semin Immunol [Internet]. 2006 Aug;18(4):214– 23. Available from: http://linkinghub.elsevier.com/retrieve/pii/S1044532306000467
Cohen S, Dadi H, Shaoul E, Sharfe N, Roifman CM. Cloning and characterization of a lymphoid-specific, inducible human protein tyrosine phosphatase, Lyp. Blood [Internet]. 1999 Mar 15;93(6):2013–24. Available from: http://www.ncbi.nlm.nih.gov/pubmed/10068674
Vang T, Miletic A V, Arimura Y, Tautz L, Rickert RC, Mustelin T. Protein tyrosine phosphatases in autoimmunity. Annu Rev Immunol [Internet]. 2008;26:29–55. Available from: http://www.ncbi.nlm.nih.gov/pubmed/18303998
Thomson W, Barton A, Ke X, Eyre S, Hinks A, Bowes J, et al. Rheumatoid arthritis association at 6q23. Nat Genet [Internet]. 2007 Dec 4;39(12):1431– 3. Available from: http://www.nature.com/doifinder/10.1038/ng.2007.32
Thomson W, Barton A, Ke X, Eyre S, Hinks A, Bowes J, et al. Rheumatoid arthritis association at 6q23. Nat Genet [Internet]. 2007 Dec 4;39(12):1431– 3. Available from: http://www.nature.com/doifinder/10.1038/ng.2007.32
Musone SL, Taylor KE, Lu TT, Nititham J, Ferreira RC, Ortmann W, et al. Multiple polymorphisms in the TNFAIP3 region are independently associated with systemic lupus erythematosus. Nat Genet [Internet]. 2008 Sep 1;40(9):1062–4. Available from: http://www.nature.com/doifinder/10.1038/ng.202
Matmati M, Jacques P, Maelfait J, Verheugen E, Kool M, Sze M, et al. A20 (TNFAIP3) deficiency in myeloid cells triggers erosive polyarthritis resembling rheumatoid arthritis. Nat Genet [Internet]. 2011 Aug 14;43(9):908–12. Available from: http://www.nature.com/doifinder/10.1038/ng.874
Adrianto I, Wen F, Templeton A, Wiley G, King JB, Lessard CJ, et al. Association of a functional variant downstream of TNFAIP3 with systemic lupus erythematosus. Nat Genet [Internet]. 2011 Mar 20;43(3):253–8. Available from: http://www.nature.com/doifinder/10.1038/ng.766
Zheng J, Yin J, Huang R, Petersen F, Yu X. Meta-analysis reveals an association of STAT4 polymorphisms with systemic autoimmune disorders and anti-dsDNA antibody. Hum Immunol [Internet]. 2013 Aug;74(8):986–92. Available from: http://linkinghub.elsevier.com/retrieve/pii/S0198885913001201
Kariuki SN, Kirou KA, MacDermott EJ, Barillas-Arias L, Crow MK, Niewold TB. Cutting Edge: Autoimmune Disease Risk Variant of STAT4 Confers Increased Sensitivity to IFN- in Lupus Patients In Vivo. J Immunol [Internet]. 2009 Jan 1;182(1):34–8. Available from: http://www.jimmunol.org/cgi/doi/10.4049/jimmunol.182.1.34
Hirota K, Yoshitomi H, Hashimoto M, Maeda S, Teradaira S, Sugimoto N, et al. Preferential recruitment of CCR6-expressing Th17 cells to inflamed joints via CCL20 in rheumatoid arthritis and its animal model. J Exp Med [Internet]. 2007 Nov 26;204(12):2803–12. Available from: http://www.jem.org/lookup/doi/10.1084/jem.20071397
Nagpal R, Yamashiro Y, Izumi Y. The Two-Way Association of Periodontal Infection with Systemic Disorders: An Overview. Mediators Inflamm [Internet]. 2015;2015:1–9. Available from: http://www.hindawi.com/journals/mi/2015/793898/
Liubomorova I. State of periodontium in patients affected with rheumatism. Stomatologiia (Mosk). 1964;33 – 37.
Mikuls TR, Payne JB, Yu F, Thiele GM, Reynolds RJ, Cannon GW, et al. Periodontitis and Porphyromonas gingivalis in Patients With Rheumatoid Arthritis. Arthritis Rheumatol [Internet]. 2014 May;66(5):1090–100. Available from: http://doi.wiley.com/10.1002/art.38348
Mercado F, Marshall RI, Klestov AC, Bartold PM. Is there a relationship between rheumatoid arthritis and periodontal disease? J Clin Periodontol [Internet]. 2000 Apr;27(4):267–72. Available from: http://www.ncbi.nlm.nih.gov/pubmed/10783841
Mercado F, Marshall RI, Klestov AC, Bartold PM. Is there a relationship between rheumatoid arthritis and periodontal disease? J Clin Periodontol [Internet]. 2000 Apr;27(4):267–72. Available from: http://www.ncbi.nlm.nih.gov/pubmed/10783841
Arkema E V., Karlson EW, Costenbader KH. A Prospective Study of Periodontal Disease and Risk of Rheumatoid Arthritis. J Rheumatol [Internet]. 2010 Sep 1;37(9):1800–4. Available from: http://www.jrheum.org/cgi/doi/10.3899/jrheum.091398
Abdelsalam SK, Hashim NT, Elsalamabi EM, Gismalla BG. Periodontal status of rheumatoid arthritis patients in khartoum state. BMC Res Notes [Internet]. 2011;4(1):460. Available from: http://bmcresnotes.biomedcentral.com/articles/10.1186/1756-0500-4-460
Gleissner C, Willershausen B, Kaesser U, Bolten WW. The role of risk factors for periodontal disease in patients with rheumatoid arthritis. Eur J Med Res [Internet]. 1998 Aug 18;3(8):387–92. Available from: http://www.ncbi.nlm.nih.gov/pubmed/9707521
Kässer UR, Gleissner C, Dehne F, Michel A, Willershausen-Zönnchen B, Bolten WW. Risk for periodontal disease in patients with longstanding rheumatoid arthritis. Arthritis Rheum [Internet]. 1997 Dec;40(12):2248–51. Available from: http://www.ncbi.nlm.nih.gov/pubmed/9416864
Cooles FAH, Isaacs JD. Pathophysiology of rheumatoid arthritis. Curr Opin Rheumatol [Internet]. 2011 May;23(3):233–40. Available from: http://www.ncbi.nlm.nih.gov/pubmed/21427580
Socransky SS, Haffajee AD. Effect of Therapy on Periodontal Infections. J Periodontol [Internet]. 1993 Aug;64(8s):754–9. Available from: http://www.joponline.org/doi/10.1902/jop.1993.64.8s.754
Holt SC, Kesavalu L, Walker S, Genco CA. Virulence factors of Porphyromonas gingivalis. Periodontol 2000 [Internet]. 1999 Jun;20:168– 238. Available from: http://www.ncbi.nlm.nih.gov/pubmed/10522227
Kesavalu L, Holt SC, Ebersole JL. Trypsin-like protease activity of Porphyromonas gingivalis as a potential virulence factor in a murine lesion model. Microb Pathog [Internet]. 1996 Jan;20(1):1–10. Available from: http://www.ncbi.nlm.nih.gov/pubmed/8692006
Birkedal-Hansen H, Taylor RE, Zambon JJ, Barwa PK, Neiders ME. Characterization of collagenolytic activity from strains of Bacteroides gingivalis. J Periodontal Res [Internet]. 1988 Jul;23(4):258–64. Available from: http://www.ncbi.nlm.nih.gov/pubmed/2846816
Lamont RJ, Jenkinson HF. Life below the gum line: pathogenic mechanisms of Porphyromonas gingivalis. Microbiol Mol Biol Rev [Internet]. 1998 Dec;62(4):1244–63. Available from: http://www.ncbi.nlm.nih.gov/pubmed/9841671
McGraw WT, Potempa J, Farley D, Travis J. Purification, characterization, and sequence analysis of a potential virulence factor from Porphyromonas gingivalis, peptidylarginine deiminase. Infect Immun [Internet]. 1999 Jul;67(7):3248–56. Available from: http://www.ncbi.nlm.nih.gov/pubmed/10377098
Wegner N, Wait R, Sroka A, Eick S, Nguyen K-A, Lundberg K, et al. Peptidylarginine deiminase from Porphyromonas gingivalis citrullinates human fibrinogen and α-enolase: implications for autoimmunity in rheumatoid arthritis. Arthritis Rheum [Internet]. 2010 Sep;62(9):2662–72. Available from: http://www.ncbi.nlm.nih.gov/pubmed/20506214
Batool H, Afzal N, Shahzad F, Kashif M. Relationship between rheumatoid arthritis and chronic periodontitis. J Med Radiol Pathol Surg [Internet]. 2016;2(6):11–4. Available from: http://www.joponline.org/doi/abs/10.1902/jop.2001.72.6.779%5Cnhttp://www. ncbi.nlm.nih.gov/pubmed/11453241
Koziel J, Mydel P, Potempa J. The link between periodontal disease and rheumatoid arthritis: an updated review. Curr Rheumatol Rep [Internet]. 2014 Mar;16(3):408. Available from: http://www.ncbi.nlm.nih.gov/pubmed/24458478
Mangat P, Wegner N, Venables PJ, Potempa J. Bacterial and human peptidylarginine deiminases: targets for inhibiting the autoimmune response in rheumatoid arthritis? Arthritis Res Ther [Internet]. 2010;12(3):209. Available from: http://arthritisresearch.biomedcentral.com/articles/10.1186/ar3000
Rodríguez SB, Stitt BL, Ash DE. Cysteine 351 is an essential nucleophile in catalysis by Porphyromonas gingivalis peptidylarginine deiminase. Arch Biochem Biophys [Internet]. 2010 Dec;504(2):190–6. Available from: http://linkinghub.elsevier.com/retrieve/pii/S0003986110003838
Farquharson D, Butcher JP, Culshaw S. Periodontitis, Porphyromonas, and the pathogenesis of rheumatoid arthritis. Mucosal Immunol [Internet]. 2012;5(2):112–20. Available from: http://www.ncbi.nlm.nih.gov/pubmed/22274780
Brinkmann V. Neutrophil Extracellular Traps Kill Bacteria. Science (80- ) [Internet]. 2004 Mar 5;303(5663):1532–5. Available from: http://www.sciencemag.org/cgi/doi/10.1126/science.1092385
Brinkmann V, Zychlinsky A. Beneficial suicide: why neutrophils die to make NETs. Nat Rev Microbiol [Internet]. 2007 Aug;5(8):577–82. Available from: http://www.nature.com/doifinder/10.1038/nrmicro1710
Neeli I, Khan SN, Radic M. Histone deimination as a response to inflammatory stimuli in neutrophils. J Immunol [Internet]. 2008 Feb 1;180(3):1895–902. Available from: http://www.ncbi.nlm.nih.gov/pubmed/18209087
Klareskog L, Malmström V, Lundberg K, Padyukov L, Alfredsson L. Smoking, citrullination and genetic variability in the immunopathogenesis of rheumatoid arthritis. Semin Immunol [Internet]. 2011 Apr;23(2):92–8. Available from: http://linkinghub.elsevier.com/retrieve/pii/S1044532311000157
Klareskog L, Stolt P, Lundberg K, Källberg H, Bengtsson C, Grunewald J, et al. A new model for an etiology of rheumatoid arthritis: Smoking may trigger HLA–DR (shared epitope)–restricted immune reactions to autoantigens modified by citrullination. Arthritis Rheum [Internet]. 2006 Jan;54(1):38–46. Available from: http://doi.wiley.com/10.1002/art.21575
Makrygiannakis D, Hermansson M, Ulfgren A-K, Nicholas AP, Zendman AJW, Eklund A, et al. Smoking increases peptidylarginine deiminase 2 enzyme expression in human lungs and increases citrullination in BAL cells. Ann Rheum Dis [Internet]. 2008 Oct 1;67(10):1488–92. Available from: http://ard.bmj.com/cgi/doi/10.1136/ard.2007.075192
Padyukov L, Silva C, Stolt P, Alfredsson L, Klareskog L. A gene-environment interaction between smoking and shared epitope genes in HLA-DR provides a high risk of seropositive rheumatoid arthritis. Arthritis Rheum [Internet]. 2004 Oct;50(10):3085–92. Available from: http://doi.wiley.com/10.1002/art.20553
Linn-Rasker SP. Smoking is a risk factor for anti-CCP antibodies only in rheumatoid arthritis patients who carry HLA-DRB1 shared epitope alleles. Ann Rheum Dis [Internet]. 2006 Mar 1;65(3):366–71. Available from: http://ard.bmj.com/cgi/doi/10.1136/ard.2005.041079
Pedersen M, Jacobsen S, Garred P, Madsen HO, Klarlund M, Svejgaard A, et al. Strong combined gene–environment effects in anti–cyclic citrullinated peptide–positive rheumatoid arthritis: A nationwide case–control study in Denmark. Arthritis Rheum [Internet]. 2007 May;56(5):1446–53. Available from: http://doi.wiley.com/10.1002/art.22597
Lundström E, Källberg H, Alfredsson L, Klareskog L, Padyukov L. Geneenvironment interaction between the DRB1 shared epitope and smoking in the risk of anti-citrullinated protein antibody-positive rheumatoid arthritis: All alleles are important. Arthritis Rheum [Internet]. 2009 Jun;60(6):1597–603. Available from: http://doi.wiley.com/10.1002/art.24572
Anaya JM, Correa PA, Mantilla R, Jiménez F, Kuffner T MJ. Rheumatoid arthritis in African Colombians from Quibdó. Semin Arthritis Rheum [Internet]. 2001;31:191–8. Available from: http://www.semarthritisrheumatism.com/article/S0049-0172(01)33477- 7/abstract
Diaz JA, Dávila-Ramírez FA, Quintana-López G, Aristizábal-Gutiérrez F, Brown P. Prevalencia de artritis reumatoide en Colombia: Una aproximación basada en la carga de la enfermedad año 2005. Rheumatoid Arthritis prevalence in Colombia: An approach based on burden of disease study 2005. 2015;3(1):11–6.
Machado-Alba JE, Ruiz AF, Medina Morales DA. The epidemiology of rheumatoid arthritis in a cohort of Colombian patients. Rev Colomb Reumatol [Internet]. 2015;22(3):148–52. Available from: http://www.sciencedirect.com/science/article/pii/S012181231500047X
Muñetón, G. A.; Quintana G. La epidemiología de la artritis reumatoide. Rev Colomb Reumatol [Internet]. 2016;2(3):145–7. Available from: http://www.scielo.org.co/pdf/rcre/v22n3/v22n3a01.pdf
Bright R, Proudman SM, Rosenstein ED, Bartold PM. Is there a link between carbamylation and citrullination in periodontal disease and rheumatoid arthritis? Med Hypotheses [Internet]. 2015 Jun;84(6):570–6. Available from: http://linkinghub.elsevier.com/retrieve/pii/S0306987715001115
Kroot EJ, de Jong BA, van Leeuwen MA, Swinkels H, van den Hoogen FH, van’t Hof M, et al. The prognostic value of anti-cyclic citrullinated peptide antibody in patients with recent-onset rheumatoid arthritis. Arthritis Rheum [Internet]. 2000 Aug;43(8):1831–5. Available from: http://www.ncbi.nlm.nih.gov/pubmed/10943873
Kroot EJ, de Jong BA, van Leeuwen MA, Swinkels H, van den Hoogen FH, van’t Hof M, et al. The prognostic value of anti-cyclic citrullinated peptide antibody in patients with recent-onset rheumatoid arthritis. Arthritis Rheum [Internet]. 2000 Aug;43(8):1831–5. Available from: http://www.ncbi.nlm.nih.gov/pubmed/10943873
Aggarwal R, Liao K, Nair R, Ringold S, Costenbander KH. Anti-citrullinated peptide antibody assays and their role in the diagnosis of rheumatoid arthritis. Arthritis Care Res (Hoboken) [Internet]. 2009 Nov 15;61(11):1472– 83. Available from: http://doi.wiley.com/10.1002/art.24827
Liao F, Li Z, Wang Y, Shi B, Gong Z, Cheng X. Porphyromonas gingivalis may play an important role in the pathogenesis of periodontitis-associated rheumatoid arthritis. Med Hypotheses [Internet]. 2009 Jun;72(6):732–5. Available from: http://linkinghub.elsevier.com/retrieve/pii/S0306987709000504
Orgován G, Noszál B. The complete microspeciation of arginine and citrulline. J Pharm Biomed Anal [Internet]. 2011 Apr;54(5):965–71. Available from: http://linkinghub.elsevier.com/retrieve/pii/S0731708510006667
Carrasco-Marín E, Paz-Miguel JE, López-Mato P, Alvarez-Domínguez C, Leyva-Cobián F. Oxidation of defined antigens allows protein unfolding and increases both proteolytic processing and exposes peptide epitopes which are recognized by specific T cells. Immunology [Internet]. 1998 Nov;95(3):314–21. Available from: http://www.ncbi.nlm.nih.gov/pubmed/9824492
Szodoray P, Szabó Z, Kapitány A, Gyetvai Á, Lakos G, Szántó S, et al. Anticitrullinated protein/peptide autoantibodies in association with genetic and environmental factors as indicators of disease outcome in rheumatoid arthritis. Autoimmun Rev [Internet]. 2010 Jan;9(3):140–3. Available from: http://linkinghub.elsevier.com/retrieve/pii/S1568997209001116
Nagata S, Yamagiwa M, Inoue K, Senshu T. Estrogen regulates peptidylarginine deiminase levels in a rat pituitary cell line in culture. J Cell Physiol [Internet]. 1990 Nov;145(2):333–9. Available from: http://doi.wiley.com/10.1002/jcp.1041450219
Sebbag M, Chapuy-Regaud S, Auger I, Petit-Texeira E, Clavel C, Nogueira L, et al. Clinical and pathophysiological significance of the autoimmune response to citrullinated proteins in rheumatoid arthritis. Jt Bone Spine [Internet]. 2004 Nov;71(6):493–502. Available from: http://linkinghub.elsevier.com/retrieve/pii/S1297319X04001460
Masson-Bessiere C, Sebbag M, Girbal-Neuhauser E, Nogueira L, Vincent C, Senshu T, et al. The Major Synovial Targets of the Rheumatoid ArthritisSpecific Antifilaggrin Autoantibodies Are Deiminated Forms of the - and - Chains of Fibrin. J Immunol [Internet]. 2001 Mar 15;166(6):4177–84. Available from: http://www.jimmunol.org/cgi/doi/10.4049/jimmunol.166.6.4177
Sebbag M, Moinard N, Auger I, Clavel C, Arnaud J, Nogueira L, et al. Epitopes of human fibrin recognized by the rheumatoid arthritis-specific autoantibodies to citrullinated proteins. Eur J Immunol [Internet]. 2006 Aug;36(8):2250–63. Available from: http://doi.wiley.com/10.1002/eji.200535790
Bang H, Egerer K, Gauliard A, Lüthke K, Rudolph PE, Fredenhagen G, et al. Mutation and citrullination modifies vimentin to a novel autoantigen for rheumatoid arthritis. Arthritis Rheum [Internet]. 2007 Aug;56(8):2503–11. Available from: http://doi.wiley.com/10.1002/art.22817
Kinloch A, Tatzer V, Wait R, Peston D, Lundberg K, Donatien P, et al. Identification of citrullinated alpha-enolase as a candidate autoantigen in rheumatoid arthritis. Arthritis Res Ther [Internet]. 2005;7(6):R1421-9. Available from: http://arthritisresearch.biomedcentral.com/articles/10.1186/ar1845
Foulquier C, Sebbag M, Clavel C, Chapuy-Regaud S, Al Badine R, Méchin M-C, et al. Peptidyl arginine deiminase type 2 (PAD-2) and PAD-4 but not PAD-1, PAD-3, and PAD-6 are expressed in rheumatoid arthritis synovium in close association with tissue inflammation. Arthritis Rheum [Internet]. 2007 Nov;56(11):3541–53. Available from: http://doi.wiley.com/10.1002/art.22983
Quirke A-M, Fisher BAC, Kinloch AJ, Venables PJ. Citrullination of autoantigens: Upstream of TNFα in the pathogenesis of rheumatoid arthritis. FEBS Lett [Internet]. 2011 Dec 1;585(23):3681–8. Available from: http://doi.wiley.com/10.1016/j.febslet.2011.06.006
Vander Cruyssen B, Cantaert T, Nogueira L, Clavel C, De Rycke L, Dendoven A, et al. Diagnostic value of anti-human citrullinated fibrinogen ELISA and comparison with four other anti-citrullinated protein assays. Arthritis Res Ther [Internet]. 2006;8(4):R122. Available from: http://www.ncbi.nlm.nih.gov/pubmed/16859515
Chapuy-Regaud S, Nogueira L, Clavel C, Sebbag M, Vincent C, Serre G. IgG subclass distribution of the rheumatoid arthritis-specific autoantibodies to citrullinated fibrin. Clin Exp Immunol [Internet]. 2005 Mar;139(3):542–50. Available from: http://www.ncbi.nlm.nih.gov/pubmed/15730401
Berlyne GM. Carbamylated proteins and peptides in health and in uremia. Nephron [Internet]. 1998;79(2):125–30. Available from: http://www.ncbi.nlm.nih.gov/pubmed/9647489
Nolte W. Microbiología Odontológica. México: Editorial Interamericana; 1985.
Shi J, van Veelen PA, Mahler M, Janssen GMC, Drijfhout JW, Huizinga TWJ, et al. Carbamylation and antibodies against carbamylated proteins in autoimmunity and other pathologies. Autoimmun Rev [Internet]. 2014;13(3):225–30. Available from: http://dx.doi.org/10.1016/j.autrev.2013.10.008
Trepanier DJ, Thibert RJ. Carbamylation of erythrocyte membrane aminophospholipids: an in vitro and in vivo study. Clin Biochem [Internet]. 1996 Aug;29(4):333–45. Available from: http://linkinghub.elsevier.com/retrieve/pii/0009912096000185
Lapko VN, Smith DL, Smith JB. Methylation and carbamylation of human γcrystallins. Protein Sci [Internet]. 2003 Aug;12(8):1762–74. Available from: http://doi.wiley.com/10.1110/ps.0305403
Wang Z, Nicholls SJ, Rodriguez ER, Kummu O, Hörkkö S, Barnard J, et al. Protein carbamylation links inflammation, smoking, uremia and atherogenesis. Nat Med [Internet]. 2007;13(10):1176–84. Available from: http://www.ncbi.nlm.nih.gov/pubmed/17828273
Holzer M, Zangger K, El-Gamal D, Binder V, Curcic S, Konya V, et al. Myeloperoxidase-Derived Chlorinating Species Induce Protein Carbamylation Through Decomposition of Thiocyanate and Urea: Novel Pathways Generating Dysfunctional High-Density Lipoprotein. Antioxid Redox Signal [Internet]. 2012 Oct 15;17(8):1043–52. Available from: http://online.liebertpub.com/doi/abs/10.1089/ars.2011.4403
Kalmár J, Woldegiorgis KL, Biri B, Ashby MT. Mechanism of Decomposition of the Human Defense Factor Hypothiocyanite Near Physiological pH. J Am Chem Soc [Internet]. 2011 Dec 14;133(49):19911–21. Available from: http://pubs.acs.org/doi/abs/10.1021/ja2083152
Klebanoff SJ. Myeloperoxidase: friend and foe. J Leukoc Biol [Internet]. 2005 Jan 26;77(5):598–625. Available from: http://www.jleukbio.org/cgi/doi/10.1189/jlb.1204697
Jaisson S, Pietrement C, Gillery P. Carbamylation-Derived Products: Bioactive Compounds and Potential Biomarkers in Chronic Renal Failure and Atherosclerosis. Clin Chem [Internet]. 2011 Nov 1;57(11):1499–505. Available from: http://www.clinchem.org/cgi/doi/10.1373/clinchem.2011.163188
Jaisson S, Gillery P. Evaluation of Nonenzymatic Posttranslational Modification-Derived Products as Biomarkers of Molecular Aging of Proteins. Clin Chem [Internet]. 2010 Sep 1;56(9):1401–12. Available from: http://www.clinchem.org/cgi/doi/10.1373/clinchem.2010.145201
Song YW, Kang EH. Autoantibodies in rheumatoid arthritis: rheumatoid factors and anticitrullinated protein antibodies. QJM [Internet]. 2010 Mar 1;103(3):139–46. Available from: https://academic.oup.com/qjmed/articlelookup/doi/10.1093/qjmed/hcp165
Wernick RM, Lipsky PE, Marban-Arcos E, Maliakkal JJ, Edelbaum D, Ziff M. IgG and IgM rheumatoid factor synthesis in rheumatoid synovial membrane cell cultures. Arthritis Rheum [Internet]. 1985 Jul;28(7):742–52. Available from: http://www.ncbi.nlm.nih.gov/pubmed/4015721
Jones V, Taylor PC, Jacoby RK, Wallington TB. Synovial synthesis of rheumatoid factors and immune complex constituents in early arthritis. Ann Rheum Dis [Internet]. 1984 Apr;43(2):235–9. Available from: http://www.ncbi.nlm.nih.gov/pubmed/6712294
Nell VPK. Autoantibody profiling as early diagnostic and prognostic tool for rheumatoid arthritis. Ann Rheum Dis [Internet]. 2005 Dec 1;64(12):1731–6. Available from: http://ard.bmj.com/cgi/doi/10.1136/ard.2005.035691
Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum [Internet]. 1988 Mar;31(3):315–24. Available from: http://www.ncbi.nlm.nih.gov/pubmed/3358796
Arend WP, Firestein GS. Pre-rheumatoid arthritis: predisposition and transition to clinical synovitis. Nat Rev Rheumatol [Internet]. 2012;8(10):573– 86. Available from: http://dx.doi.org/10.1038/nrrheum.2012.134
Otterness IG. The value of C-reactive protein measurement in rheumatoid arthritis. Semin Arthritis Rheum [Internet]. 1994 Oct;24(2):91–104. Available from: http://www.ncbi.nlm.nih.gov/pubmed/7839158
Brigden M. The erythrocyte sedimentation rate. Postgrad Med [Internet]. 1998 May 30;103(5):257–74. Available from: http://www.sciencedirect.com/science/article/pii/S0736467997001972%5Cnh ttp://www.ncbi.nlm.nih.gov/pubmed/9404806
Kushner I. C-reactive protein in rheumatology. Arthritis Rheum [Internet]. 1991 Aug;34(8):1065–8. Available from: http://doi.wiley.com/10.1002/art.1780340819
Bedell SE, Bush BT. Erythrocyte sedimentation rate. From folklore to facts. Am J Med [Internet]. 1985 Jun;78(6 Pt 1):1001–9. Available from: http://www.ncbi.nlm.nih.gov/pubmed/4014259
Shearn MA, Kang IY. Effect of age and sex on the erythrocyte sedimentation rate. J Rheumatol [Internet]. 1986 Apr;13(2):297–8. Available from: http://www.ncbi.nlm.nih.gov/pubmed/3723495
Fabry TL. Mechanism of erythrocyte aggregation and sedimentation. Blood [Internet]. 1987 Nov;70(5):1572–6. Available from: http://www.ncbi.nlm.nih.gov/pubmed/3663946
Fabry TL. Mechanism of erythrocyte aggregation and sedimentation. Blood [Internet]. 1987 Nov;70(5):1572–6. Available from: http://www.ncbi.nlm.nih.gov/pubmed/3663946
Pepys MB. C-reactive protein fifty years on. Lancet (London, England) [Internet]. 1981 Mar 21;1(8221):653–7. Available from: http://www.ncbi.nlm.nih.gov/pubmed/6110874
Gewurz H, Mold C, Siegel J, Fiedel B. C-reactive protein and the acute phase response. Adv Intern Med [Internet]. 1982;27:345–72. Available from: http://www.ncbi.nlm.nih.gov/pubmed/7041546
Tishler M, Caspi D, Yaron M. C-reactive protein levels in patients with rheumatoid arthritis: the impact of therapy. Clin Rheumatol [Internet]. 1985 Sep;4(3):321–4. Available from: http://link.springer.com/10.1007/BF02031616
Larsen A. The relation of radiographic changes to serum acute-phase proteins and rheumatoid factor in 200 patients with rheumatoid arthritis. Scand J Rheumatol [Internet]. 1988;17(2):123–9. Available from: http://www.ncbi.nlm.nih.gov/pubmed/3387929
Im CH, Kang EH, Ryu HJ, Lee JH, Lee EY, Lee YJ, et al. Anti-cyclic citrullinated peptide antibody is associated with radiographic erosion in rheumatoid arthritis independently of shared epitope status. Rheumatol Int [Internet]. 2009 Jan;29(3):251–6. Available from: http://www.ncbi.nlm.nih.gov/pubmed/18751982
Wilder RL, Sternberg EM. Neuroendocrine hormonal factors in rheumatoid arthritis and related conditions. Curr Opin Rheumatol [Internet]. 1990 Jun;2(3):436–40. Available from: http://www.ncbi.nlm.nih.gov/pubmed/2203424
Ahmed SA, Hissong BD, Verthelyi D, Donner K, Becker K, Karpuzoglu-Sahin E. Gender and risk of autoimmune diseases: Possible role of estrogenic compounds. Environ Health Perspect. 1999;107(SUPPL. 5):681–6.
Feng J, Chen Q, Yu F, Wang Z, Chen S, Jin Z, et al. Body Mass Index and Risk of Rheumatoid Arthritis: A Meta-Analysis of Observational Studies. Medicine (Baltimore) [Internet]. 2016;95(8):e2859. Available from: http://www.ncbi.nlm.nih.gov/pubmed/26937917
Unriza-Puin S, Bautista-Molano W, Lafaurie GI, Valle-O??ate R, Chalem P, Chila-Moreno L, et al. Are obesity, ACPAs and periodontitis conditions that influence the risk of developing rheumatoid arthritis in first-degree relatives? Clin Rheumatol [Internet]. 2017;36(4):799–806. Available from: http://dx.doi.org/10.1007/s10067-016-3519-z
Gremese E, Tolusso B, Gigante MR, Ferraccioli G. Obesity as a Risk and Severity Factor in Rheumatic Diseases (Autoimmune Chronic Inflammatory Diseases). Front Immunol [Internet]. 2014 Nov 11;5. Available from: http://journal.frontiersin.org/article/10.3389/fimmu.2014.00576/abstract
Bello-Gualtero JM, Lafaurie GI, Hoyos LX, Castillo DM, De-Avila J, Munevar JC, et al. Periodontal Disease in Individuals With a Genetic Risk of Developing Arthritis and Early Rheumatoid Arthritis: A Cross-Sectional Study. J Periodontol [Internet]. 2016 Apr;87(4):346–56. Available from: http://doi.wiley.com/10.1902/jop.2015.150455
Auger I, Sebbag M, Vincent C, Balandraud N, Guis S, Nogueira L, et al. Influence of HLA-DR genes on the production of rheumatoid arthritis-specific autoantibodies to citrullinated fibrinogen. Arthritis Rheum [Internet]. 2005 Nov;52(11):3424–32. Available from: http://doi.wiley.com/10.1002/art.21391
Bright R, Thiele GM, Manavis J, Mikuls TR, Payne JB, Bartold PM. Gingival tissue, an extrasynovial source of malondialdehyde-acetaldehyde adducts, citrullinated and carbamylated proteins. J Periodontal Res [Internet]. 2017 Oct 17; Available from: http://doi.wiley.com/10.1111/jre.12486
Freire MO, Van Dyke TE. Natural resolution of inflammation. Periodontol 2000 [Internet]. 2013 Oct;63(1):149–64. Available from: http://doi.wiley.com/10.1111/prd.12034
dc.rights.spa.fl_str_mv Derechos Reservados - Universidad Colegio Mayor de Cundinamarca, 2018
dc.rights.uri.spa.fl_str_mv https://creativecommons.org/licenses/by-nc-sa/4.0/
dc.rights.accessrights.spa.fl_str_mv info:eu-repo/semantics/closedAccess
dc.rights.creativecommons.spa.fl_str_mv Atribución-NoComercial-CompartirIgual 4.0 Internacional (CC BY-NC-SA 4.0)
dc.rights.coar.spa.fl_str_mv http://purl.org/coar/access_right/c_14cb
rights_invalid_str_mv Derechos Reservados - Universidad Colegio Mayor de Cundinamarca, 2018
https://creativecommons.org/licenses/by-nc-sa/4.0/
Atribución-NoComercial-CompartirIgual 4.0 Internacional (CC BY-NC-SA 4.0)
http://purl.org/coar/access_right/c_14cb
eu_rights_str_mv closedAccess
dc.format.extent.spa.fl_str_mv 117p.
dc.format.mimetype.spa.fl_str_mv application/pdf
dc.publisher.spa.fl_str_mv Universidad Colegio Mayor de Cundinamarca
dc.publisher.faculty.spa.fl_str_mv Facultad de Ciencias de la Salud
dc.publisher.place.spa.fl_str_mv Bogotá D.C
dc.publisher.program.spa.fl_str_mv Bacteriología y Laboratorio Clínico
institution Colegio Mayor de Cundinamarca
bitstream.url.fl_str_mv https://repositorio.unicolmayor.edu.co/bitstream/unicolmayor/4792/1/Presentaci%c3%b3n%20final.pdf
https://repositorio.unicolmayor.edu.co/bitstream/unicolmayor/4792/2/Documento%20final%20modificado.pdf
https://repositorio.unicolmayor.edu.co/bitstream/unicolmayor/4792/3/Documento%20final%20modificado%20FORMATO%20DERECHOS%20DE%20AUTOR.pdf
https://repositorio.unicolmayor.edu.co/bitstream/unicolmayor/4792/4/license.txt
https://repositorio.unicolmayor.edu.co/bitstream/unicolmayor/4792/5/Presentaci%c3%b3n%20final.pdf.txt
https://repositorio.unicolmayor.edu.co/bitstream/unicolmayor/4792/7/Documento%20final%20modificado.pdf.txt
https://repositorio.unicolmayor.edu.co/bitstream/unicolmayor/4792/9/Documento%20final%20modificado%20FORMATO%20DERECHOS%20DE%20AUTOR.pdf.txt
https://repositorio.unicolmayor.edu.co/bitstream/unicolmayor/4792/6/Presentaci%c3%b3n%20final.pdf.jpg
https://repositorio.unicolmayor.edu.co/bitstream/unicolmayor/4792/8/Documento%20final%20modificado.pdf.jpg
https://repositorio.unicolmayor.edu.co/bitstream/unicolmayor/4792/10/Documento%20final%20modificado%20FORMATO%20DERECHOS%20DE%20AUTOR.pdf.jpg
bitstream.checksum.fl_str_mv 1687d7c9cf19ab7d690aa3d3ab156605
f35c30e133170f778b066597705ac4ef
ce598a53a5b1f110d330c15aeb4c2e11
2f9959eaf5b71fae44bbf9ec84150c7a
ce632dd036e1bb528f7c982974b02856
fa025ebf3073a97ae284501729e3b071
462717b648a4e1f31197195266e891b0
93748c5ca4c32bf552e12ae0db8acff6
361367a55746171217ad9e2739c8b5ad
4fa4c3a9ebf54be7811fc69544a7b50f
bitstream.checksumAlgorithm.fl_str_mv MD5
MD5
MD5
MD5
MD5
MD5
MD5
MD5
MD5
MD5
repository.name.fl_str_mv Biblioteca Digital Unicolmayor
repository.mail.fl_str_mv repositorio@unicolmayor.edu.co
_version_ 1807009059208953856
spelling Romero Sánchez, María Consueloadef63ccda8465428682bb4b85aab02bChila Moreno, Leidy Lorena4cf9279b88e653b3ab1a8b78e5bf2628Muñoz Henao, Julián Esteban8c3a047deeb142fcc831a877d6096885Ramos Casallas, Manuel Alejandro020df3abddf85c632fbe164fbcd63ec42022-03-09T16:33:00Z2022-03-09T16:33:00Z2018-05https://repositorio.unicolmayor.edu.co/handle/unicolmayor/479258418La Artritis Reumatoide (AR) es una enfermedad autoinmune sistémica caracterizada por un estado de inflamación crónica y deterioro progresivo de las articulaciones. Su diagnóstico se basa en una serie de criterios clínicos y pruebas de laboratorio. Este último ítem abarca la detección del Factor Reumatoide (FR) y/o los autoanticuerpos anti-proteínas citrulinadas (anti-CCP), asociados a la actividad de la enfermedad y al pronóstico de la misma. Sin embargo, existen grupos de pacientes con elevado daño articular y niveles indetectables de FR y/o autoautoanticuerpos anti-CCP, dificultando el diagnóstico y las opciones terapéuticas. De forma reciente se descubrieron los autoanticuerpos anti-proteínas carbamiladas (anti-CarP) asociados a esta enfermedad, los cuales permitirían tipificar la AR en estos grupos de pacientes e individuos con condiciones de riesgo, además de poder predecir el desenlace articular. De esta manera se facilitaría el diagnóstico, así como en el tratamiento y el pronóstico. En este estudio se midieron los niveles de autoautoanticuerpos anti-CCP. Así mismo, se midieron los niveles de autoanticuerpos frente al péptido carbamilado de fibrinógeno (empleando el péptido nativo como control), en pacientes con artritis reumatoide temprana y familiares en primer grado de consanguinidad, para establecer su asociación frente al daño reumatológico y periodontal. Los resultados resaltan la asociación entre el número de articulaciones dolorosas e inflamadas y el daño periodontal con la presencia de los anticuerpos anti-péptido de fibrinógeno carbamilado en el grupo de familiares en primer grado de consanguinidad. No hubo asociación entre estos autoanticuerpos y los autoautoanticuerpos anti-CCP en los pacientes con artritis reumatoide temprana. Como hallazgo adicional, se observó que los dos grupos de estudio presentan autoanticuerpos contra el péptido nativo de fibrinógeno. En conclusión, la presencia de autoanticuerpos contra péptidos/proteínas carbamiladas están presentes en la población colombiana con artritis reumatoide temprana y familiares en primer grado de consanguinidad; asociados a manifestaciones de daño articular y periodontal. Además, la presencia de autoanticuerpos frente al péptido de fibrinógeno nativo puede ser un indicio de desarrollo de la enfermedad.TABLA DE CONTENIDO RESUMEN EJECUTIVO 11 INTRODUCCIÓN 13 1. OBJETIVOS 15 1.1. OBJETIVO PRINCIPAL (GENERAL )15 1.2. OBJETIVOS SECUNDARIOS (ESPECÍFICOS)15 2. ANTECEDENTES 17 3. MARCO TEÓRICO 24 3.1. DEFINICIÓN DE ARTRITIS REUMATOIDE 24 3.2. MANIFESTACIONES CLÍNICAS 27 3.3. FACTORES DE RIESGO 28 3.4. EPIDEMIOLOGÍA DE LA ENFERMEDAD EN COLOMBIA. 34 3.5. DIAGNÓSTICO 35 4. METODOLOGÍA 44 4.1. TIPO DE INVESTIGACIÓN 44 4.2. POBLACIÓN 44 4.3. MUESTRA 44 4.4. SELECCIÓN DE LA MUESTRA 44 4.5. CRITERIOS DE INCLUSIÓN 45 4.6. CRITERIOS DE EXCLUSIÓN 45 4.7. HIPÓTESIS 47 4.8. TÉCNICAS Y PROCEDIMIENTOS 48 4.9. ANÁLISIS ESTADÍSTICO 51 5. RESULTADOS 52 6. DISCUSIÓN 86 7. CONCLUSIONES 91 8. REFERENCIAS 92 9. ANEXOS 116 9.1. FORMATO DE CRITERIOS DE EXCLUSION 116 9.2. FORMATO DE RECOLECCION DE DATOS PACIENTES CON AR Y FAMILIARES: 117PregradoBacteriólogo(a) y Laboratorista Clínico117p.application/pdfspaUniversidad Colegio Mayor de CundinamarcaFacultad de Ciencias de la SaludBogotá D.CBacteriología y Laboratorio ClínicoDerechos Reservados - Universidad Colegio Mayor de Cundinamarca, 2018https://creativecommons.org/licenses/by-nc-sa/4.0/info:eu-repo/semantics/closedAccessAtribución-NoComercial-CompartirIgual 4.0 Internacional (CC BY-NC-SA 4.0)http://purl.org/coar/access_right/c_14cbNiveles de autoanticuerpos anti-peptidos carbamilados y citrulinados y su relación con índices de actividad clínica reumática en pacientes con artritis reumatoide temprana y familiares en primer grado de consanguinidad de pacientes con artritis reumatoide, oriundos de ColombiaTrabajo de grado - Pregradohttp://purl.org/coar/resource_type/c_7a1fhttp://purl.org/coar/version/c_970fb48d4fbd8a85Textinfo:eu-repo/semantics/bachelorThesishttps://purl.org/redcol/resource_type/TPinfo:eu-repo/semantics/publishedVersionFirestein GS. Evolving concepts of rheumatoid arthritis. Nature [Internet]. 2003 May 15;423(6937):356–61. Available from: http://www.nature.com/doifinder/10.1038/nature01661Klareskog L, Rönnelid J, Lundberg K, Padyukov L, Alfredsson L. Immunity to citrullinated proteins in rheumatoid arthritis. Annu Rev Immunol [Internet]. 2008;26:651–75. Available from: http://www.ncbi.nlm.nih.gov/pubmed/18173373Wegner N, Lundberg K, Kinloch A, Fisher B, Malmström V, Feldmann M, et al. Autoimmunity to specific citrullinated proteins gives the first clues to the etiology of rheumatoid arthritis. Immunol Rev. 2010;233(1):34–54.Rosales-borjas DM, Arévalo MA, Ortiz-ortiz L. Artritis reumatoide: importancia de los antigenos citrulinados en el diagnostico del padecimiento. Rev Médica la Extensión Port. 2009;4(3):125–30.Nishimura K, Sugiyama D, Kogata Y, Tsuji G, Nakazawa T, Kawano S, et al. Meta-analysis: diagnostic accuracy of anti-cyclic citrullinated peptide antibody and rheumatoid factor for rheumatoid arthritis. Ann Intern Med [Internet]. 2007 Jun 5;146(11):797–808. Available from: http://www.ncbi.nlm.nih.gov/pubmed/17548411van Venrooij WJ, Hazes JM, Visser H. Anticitrullinated protein/peptide antibody and its role in the diagnosis and prognosis of early rheumatoid arthritis. Neth J Med. 2002;60(10):383–8.Rantapää-Dahlqvist S, de Jong BAW, Berglin E, Hallmans G, Wadell G, Stenlund H, et al. Antibodies against cyclic citrullinated peptide and IgA rheumatoid factor predict the development of rheumatoid arthritis. Arthritis Rheum [Internet]. 2003 Oct;48(10):2741–9. Available from: http://www.ncbi.nlm.nih.gov/pubmed/14558078van der Helm-van Mil AHM, Verpoort KN, Breedveld FC, Toes REM, Huizinga TWJ. Antibodies to citrullinated proteins and differences in clinical progression of rheumatoid arthritis. Arthritis Res Ther [Internet]. 2005;7(5):R949-58. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1257421&tool=pm centrez&rendertype=abstractVan Der Woude D, Young A, Jayakumar K, Mertens BJ, Toes REM, Van Der Heijde D, et al. Prevalence of and predictive factors for sustained diseasemodifying antirheumatic drug-free remission in rheumatoid arthritis: Results from two large early arthritis cohorts. Arthritis Rheum [Internet]. 2009 Aug;60(8):2262–71. Available from: http://doi.wiley.com/10.1002/art.24661Van Der Woude D, Young A, Jayakumar K, Mertens BJ, Toes REM, Van Der Heijde D, et al. Prevalence of and predictive factors for sustained diseasemodifying antirheumatic drug-free remission in rheumatoid arthritis: Results from two large early arthritis cohorts. Arthritis Rheum [Internet]. 2009 Aug;60(8):2262–71. Available from: http://doi.wiley.com/10.1002/art.24661Nielen MMJ, van Schaardenburg D, Reesink HW, van de Stadt RJ, van der Horst-Bruinsma IE, de Koning MHMT, et al. Specific autoantibodies precede the symptoms of rheumatoid arthritis: a study of serial measurements in blood donors. Arthritis Rheum [Internet]. 2004 Feb;50(2):380–6. Available from: http://www.ncbi.nlm.nih.gov/pubmed/14872479Willemze A, Trouw L a, Toes REM, Huizinga TWJ. The influence of ACPA status and characteristics on the course of RA. Nat Rev Rheumatol [Internet]. 2012;8(3):144–52. Available from: http://www.ncbi.nlm.nih.gov/pubmed/22293763Berglin E, Johansson T, Sundin U, Jidell E, Wadell G, Hallmans G, et al. Radiological outcome in rheumatoid arthritis is predicted by presence of antibodies against cyclic citrullinated peptide before and at disease onset, and by IgA-RF at disease onset. Ann Rheum Dis [Internet]. 2006 Apr;65(4):453–8. Available from: http://www.ncbi.nlm.nih.gov/pubmed/16176994Shi J, Knevel R, Suwannalai P, van der Linden MP, Janssen GMC, van Veelen P a., et al. Autoantibodies recognizing carbamylated proteins are present in sera of patients with rheumatoid arthritis and predict joint damage. Proc Natl Acad Sci. 2011;108(42):17372–7.Steinbrecher UP, Fisher M, Witztum JL, Curtiss LK. Immunogenicity of homologous low density lipoprotein after methylation, ethylation, acetylation, or carbamylation: generation of antibodies specific for derivatized lysine. J Lipid Res [Internet]. 1984 Oct;25(10):1109–16. Available from: http://www.ncbi.nlm.nih.gov/pubmed/6439810Mydel P, Wang Z, Brisslert M, Hellvard A, Dahlberg LE, Hazen SL, et al. Carbamylation-dependent activation of T cells: a novel mechanism in the pathogenesis of autoimmune arthritis. J Immunol [Internet]. 2010 Jun 15;184(12):6882–90. Available from: http://www.ncbi.nlm.nih.gov/pubmed/20488785Shi J, Van De Stadt LA, Levarht EWN, Huizinga TWJ, Toes REM, Trouw LA, et al. Anti-carbamylated protein antibodies are present in arthralgia patients and predict the development of rheumatoid arthritis. Arthritis Rheum. 2013;65(4):911–5.Yee A, Webb T, Seaman A, Infantino M, Meacci F, Manfredi M, et al. AntiCarP antibodies as promising marker to measure joint damage and disease activity in patients with rheumatoid arthritis. Immunol Res. 2014;61(1–2):24– 30.Shi J, van de Stadt L a, Levarht EWN, Huizinga TWJ, Hamann D, van Schaardenburg D, et al. Anti-carbamylated protein (anti-CarP) antibodies precede the onset of rheumatoid arthritis. Ann Rheum Dis [Internet]. 2014;73(4):780–3. Available from: http://www.ncbi.nlm.nih.gov/pubmed/24336334Brink M, Verheul MK, Rönnelid J, Berglin E, Holmdahl R, Toes REM, et al. Anti-carbamylated protein antibodies in the pre-symptomatic phase of rheumatoid arthritis, their relationship with multiple anti-citrulline peptide antibodies and association with radiological damage. Arthritis Res Ther [Internet]. 2015;17:25. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=4350267&tool=pm centrez&rendertype=abstractJiang X, Trouw L a, van Wesemael TJ, Shi J, Bengtsson C, Källberg H, et al. Anti-CarP antibodies in two large cohorts of patients with rheumatoid arthritis and their relationship to genetic risk factors, cigarette smoking and other autoantibodies. Ann Rheum Dis [Internet]. 2014;1761–8. Available from: http://www.ncbi.nlm.nih.gov/pubmed/24812286Gan RW, Trouw LA, Shi J, Toes REM, Huizinga TWJ, Demoruelle MK, et al. Anti-carbamylated Protein Antibodies Are Present Prior to Rheumatoid Arthritis and Are Associated with Its Future Diagnosis. J Rheumatol [Internet]. 2015 Apr 1;42(4):572–9. Available from: http://www.jrheum.org/cgi/doi/10.3899/jrheum.140767Shi J, van Steenbergen HW, van Nies JAB, Levarht EWN, Huizinga TWJ, van der Helm-van Mil AHM, et al. The specificity of anti-carbamylated protein antibodies for rheumatoid arthritis in a setting of early arthritis. Arthritis Res Ther [Internet]. 2015;17(1):339. Available from: http://arthritisresearch.com/content/17/1/339Alessandri C, Bartosiewicz I, Pendolino M, Mancini R, Colasanti T, Pecani A, et al. Anti-carbamylated protein antibodies in unaffected first-degree relatives of rheumatoid arthritis patients: Lack of correlation with anti-cyclic citrullinated protein antibodies and rheumatoid factor. Clin Exp Rheumatol. 2015;33(6):824–30.Koppejan H, Trouw LA, Sokolove J, Lahey LJ, Huizinga TJW, Smolik IA, et al. Role of Anti-Carbamylated Protein Antibodies Compared to Anti- Citrullinated Protein Antibodies in Indigenous North Americans With Rheumatoid Arthritis, Their First-Degree Relatives, and Healthy Controls. Arthritis Rheumatol [Internet]. 2016 Sep;68(9):2090–8. Available from: http://doi.wiley.com/10.1002/art.39664Reed E, Jiang X, Kharlamova N, Ytterberg AJ, Catrina AI, Israelsson L, et al. Antibodies to carbamylated α -enolase epitopes in rheumatoid arthritis also bind citrullinated epitopes and are largely indistinct from anti-citrullinated protein antibodies. Arthritis Res Ther [Internet]. 2016;1–9. Available from: http://dx.doi.org/10.1186/s13075-016-1001-6Montes A, Regueiro C, Perez-Pampin E, Boveda MD, Gomez-Reino JJ, Gonzalez A. Anti-Carbamylated Protein Antibodies as a Reproducible Independent Type of Rheumatoid Arthritis Autoantibodies. Kuwana M, editor. PLoS One [Internet]. 2016 Aug 18;11(8):e0161141. Available from: http://dx.plos.org/10.1371/journal.pone.0161141Gibofsky A. Overview of epidemiology, pathophysiology, and diagnosis of rheumatoid arthritis. Am J Manag Care [Internet]. 2012 Dec;18(13 Suppl):S295-302. Available from: http://www.ncbi.nlm.nih.gov/pubmed/23327517McInnes IB, Schett G. The Pathogenesis of Rheumatoid Arthritis. N Engl J Med [Internet]. 2011 Dec 8;365(23):2205–19. Available from: http://rcnpublishing.com/doi/abs/10.7748/phc2011.11.21.9.29.c8797Burska AN, Hunt L, Boissinot M, Strollo R, Ryan BJ, Vital E, et al. Autoantibodies to Posttranslational Modifications in Rheumatoid Arthritis. Mediators Inflamm [Internet]. 2014;2014:1–19. Available from: http://www.hindawi.com/journals/mi/2014/492873/Nissim A, Winyard PG, Corrigall V, Fatah R, Perrett D, Panayi G, et al. Generation of neoantigenic epitopes after posttranslational modification of type II collagen by factors present within the inflamed joint. Arthritis Rheum [Internet]. 2005 Dec;52(12):3829–38. Available from: http://doi.wiley.com/10.1002/art.21479Marcinkiewicz J, Biedroń R, Maresz K, Kwaśny-Krochin B, Bobek M, Kontny E, et al. Oxidative modification of type II collagen differentially affects its arthritogenic and tolerogenic capacity in experimental arthritis. Arch Immunol Ther Exp (Warsz) [Internet]. 52(4):284–91. Available from: http://www.ncbi.nlm.nih.gov/pubmed/15467493Anderton SM. Post-translational modifications of self antigens: implications for autoimmunity. Curr Opin Immunol [Internet]. 2004 Dec;16(6):753–8. Available from: http://linkinghub.elsevier.com/retrieve/pii/S0952791504001451Eggleton P, Nissim A, Ryan BJ, Whiteman M, Winyard PG. Detection and isolation of human serum autoantibodies that recognize oxidatively modified autoantigens. Free Radic Biol Med [Internet]. 2013 Apr;57:79–91. Available from: http://linkinghub.elsevier.com/retrieve/pii/S0891584912018060Valesini G, Gerardi MC, Iannuccelli C, Pacucci VA, Pendolino M, Shoenfeld Y. Citrullination and autoimmunity. Autoimmun Rev [Internet]. 2015 Jun;14(6):490–7. Available from: http://linkinghub.elsevier.com/retrieve/pii/S1568997215000282Baka Z, György B, Géher P, Buzás EI, Falus A, Nagy G. Citrullination under physiological and pathological conditions. Jt Bone Spine [Internet]. 2012 Oct;79(5):431–6. Available from: http://linkinghub.elsevier.com/retrieve/pii/S1297319X12000127Cantagrel A, Degboé Y. New autoantibodies associated with rheumatoid arthritis recognize posttranslationally modified self-proteins. Joint Bone Spine [Internet]. 2015;83(1):11–7. Available from: http://www.ncbi.nlm.nih.gov/pubmed/26639222Gerlag DM, Raza K, van Baarsen LGM, Brouwer E, Buckley CD, Burmester GR, et al. EULAR recommendations for terminology and research in individuals at risk of rheumatoid arthritis: report from the Study Group for Risk Factors for Rheumatoid Arthritis. Ann Rheum Dis. 2012;71(5):638–41.Aletaha D, Neogi T, Silman AJ, Funovits J, Felson DT, Bingham CO, et al. 2010 Rheumatoid arthritis classification criteria: An American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheum. 2010;62(9):2569–81.O’Dell J. Rheumatoid arthritis. In: Goldman L, Schafer AI E, editor. Goldman’s Cecil Medicine. 25th ed. Philadelphia: Elsevier Saunders; 2016.Gregersen PK, Silver J, Winchester RJ. The shared epitope hypothesis. An approach to understanding the molecular genetics of susceptibility to rheumatoid arthritis. Arthritis Rheum [Internet]. 1987 Nov;30(11):1205–13. Available from: http://www.ncbi.nlm.nih.gov/pubmed/2446635Bax M, van Heemst J, Huizinga TWJ, Toes REM. Genetics of rheumatoid arthritis: what have we learned? Immunogenetics [Internet]. 2011 Aug 10;63(8):459–66. Available from: http://link.springer.com/10.1007/s00251- 011-0528-6Hutchinson D, Shepstone L, Moots R, Lear JT, Lynch MP. Heavy cigarette smoking is strongly associated with rheumatoid arthritis (RA), particularly in patients without a family history of RA. Ann Rheum Dis [Internet]. 2001 Mar;60(3):223–7. Available from: http://www.ncbi.nlm.nih.gov/pubmed/11171682Källberg H, Ding B, Padyukov L, Bengtsson C, Rönnelid J, Klareskog L, et al. Smoking is a major preventable risk factor for rheumatoid arthritis: estimations of risks after various exposures to cigarette smoke. Ann Rheum Dis [Internet]. 2011 Mar;70(3):508–11. Available from: http://www.ncbi.nlm.nih.gov/pubmed/21149499Karlson EW, Lee IM, Cook NR, Manson JE, Buring JE, Hennekens CH. A retrospective cohort study of cigarette smoking and risk of rheumatoid arthritis in female health professionals. Arthritis Rheum [Internet]. 1999 May;42(5):910–7. Available from: http://www.ncbi.nlm.nih.gov/pubmed/10323446Kochi Y, Suzuki A, Yamamoto K. Genetic basis of rheumatoid arthritis: A current review. Biochem Biophys Res Commun [Internet]. 2014;452(2):254– 62. Available from: http://dx.doi.org/10.1016/j.bbrc.2014.07.085Suzuki A, Yamada R, Chang X, Tokuhiro S, Sawada T, Suzuki M, et al. Functional haplotypes of PADI4, encoding citrullinating enzyme peptidylarginine deiminase 4, are associated with rheumatoid arthritis. Nat Genet [Internet]. 2003 Aug 29;34(4):395–402. Available from: http://www.nature.com/doifinder/10.1038/ng1206Kochi Y, Suzuki A, Yamada R, Yamamoto K. Ethnogenetic heterogeneity of rheumatoid arthritis—implications for pathogenesis. Nat Rev Rheumatol [Internet]. 2010 May 16;6(5):290–5. Available from: http://www.nature.com/doifinder/10.1038/nrrheum.2010.23Nakashima K, Hagiwara T, Ishigami A, Nagata S, Asaga H, Kuramoto M, et al. Molecular characterization of peptidylarginine deiminase in HL-60 cells induced by retinoic acid and 1alpha,25-dihydroxyvitamin D(3). J Biol Chem [Internet]. 1999 Sep 24;274(39):27786–92. Available from: http://www.ncbi.nlm.nih.gov/pubmed/10488123Irigoyen P, Lee AT, Wener MH, Li W, Kern M, Batliwalla F, et al. Regulation of anti-cyclic citrullinated peptide antibodies in rheumatoid arthritis: Contrasting effects of HLA-DR3 and the shared epitope alleles. Arthritis Rheum [Internet]. 2005 Dec;52(12):3813–8. Available from: http://doi.wiley.com/10.1002/art.21419Cha S, Choi C-B, Han T-U, Kang CP, Kang C, Bae S-C. Association of Anti– Cyclic citrullinated peptide antibody levels with PADI4 haplotypes in early rheumatoid arthritis and with shared epitope alleles in very late rheumatoid arthritis. Arthritis Rheum [Internet]. 2007 May;56(5):1454–63. Available from: http://doi.wiley.com/10.1002/art.22570Gregersen PK, Lee H-S, Batliwalla F, Begovich AB. PTPN22: Setting thresholds for autoimmunity. Semin Immunol [Internet]. 2006 Aug;18(4):214– 23. Available from: http://linkinghub.elsevier.com/retrieve/pii/S1044532306000467Cohen S, Dadi H, Shaoul E, Sharfe N, Roifman CM. Cloning and characterization of a lymphoid-specific, inducible human protein tyrosine phosphatase, Lyp. Blood [Internet]. 1999 Mar 15;93(6):2013–24. Available from: http://www.ncbi.nlm.nih.gov/pubmed/10068674Vang T, Miletic A V, Arimura Y, Tautz L, Rickert RC, Mustelin T. Protein tyrosine phosphatases in autoimmunity. Annu Rev Immunol [Internet]. 2008;26:29–55. Available from: http://www.ncbi.nlm.nih.gov/pubmed/18303998Thomson W, Barton A, Ke X, Eyre S, Hinks A, Bowes J, et al. Rheumatoid arthritis association at 6q23. Nat Genet [Internet]. 2007 Dec 4;39(12):1431– 3. Available from: http://www.nature.com/doifinder/10.1038/ng.2007.32Thomson W, Barton A, Ke X, Eyre S, Hinks A, Bowes J, et al. Rheumatoid arthritis association at 6q23. Nat Genet [Internet]. 2007 Dec 4;39(12):1431– 3. Available from: http://www.nature.com/doifinder/10.1038/ng.2007.32Musone SL, Taylor KE, Lu TT, Nititham J, Ferreira RC, Ortmann W, et al. Multiple polymorphisms in the TNFAIP3 region are independently associated with systemic lupus erythematosus. Nat Genet [Internet]. 2008 Sep 1;40(9):1062–4. Available from: http://www.nature.com/doifinder/10.1038/ng.202Matmati M, Jacques P, Maelfait J, Verheugen E, Kool M, Sze M, et al. A20 (TNFAIP3) deficiency in myeloid cells triggers erosive polyarthritis resembling rheumatoid arthritis. Nat Genet [Internet]. 2011 Aug 14;43(9):908–12. Available from: http://www.nature.com/doifinder/10.1038/ng.874Adrianto I, Wen F, Templeton A, Wiley G, King JB, Lessard CJ, et al. Association of a functional variant downstream of TNFAIP3 with systemic lupus erythematosus. Nat Genet [Internet]. 2011 Mar 20;43(3):253–8. Available from: http://www.nature.com/doifinder/10.1038/ng.766Zheng J, Yin J, Huang R, Petersen F, Yu X. Meta-analysis reveals an association of STAT4 polymorphisms with systemic autoimmune disorders and anti-dsDNA antibody. Hum Immunol [Internet]. 2013 Aug;74(8):986–92. Available from: http://linkinghub.elsevier.com/retrieve/pii/S0198885913001201Kariuki SN, Kirou KA, MacDermott EJ, Barillas-Arias L, Crow MK, Niewold TB. Cutting Edge: Autoimmune Disease Risk Variant of STAT4 Confers Increased Sensitivity to IFN- in Lupus Patients In Vivo. J Immunol [Internet]. 2009 Jan 1;182(1):34–8. Available from: http://www.jimmunol.org/cgi/doi/10.4049/jimmunol.182.1.34Hirota K, Yoshitomi H, Hashimoto M, Maeda S, Teradaira S, Sugimoto N, et al. Preferential recruitment of CCR6-expressing Th17 cells to inflamed joints via CCL20 in rheumatoid arthritis and its animal model. J Exp Med [Internet]. 2007 Nov 26;204(12):2803–12. Available from: http://www.jem.org/lookup/doi/10.1084/jem.20071397Nagpal R, Yamashiro Y, Izumi Y. The Two-Way Association of Periodontal Infection with Systemic Disorders: An Overview. Mediators Inflamm [Internet]. 2015;2015:1–9. Available from: http://www.hindawi.com/journals/mi/2015/793898/Liubomorova I. State of periodontium in patients affected with rheumatism. Stomatologiia (Mosk). 1964;33 – 37.Mikuls TR, Payne JB, Yu F, Thiele GM, Reynolds RJ, Cannon GW, et al. Periodontitis and Porphyromonas gingivalis in Patients With Rheumatoid Arthritis. Arthritis Rheumatol [Internet]. 2014 May;66(5):1090–100. Available from: http://doi.wiley.com/10.1002/art.38348Mercado F, Marshall RI, Klestov AC, Bartold PM. Is there a relationship between rheumatoid arthritis and periodontal disease? J Clin Periodontol [Internet]. 2000 Apr;27(4):267–72. Available from: http://www.ncbi.nlm.nih.gov/pubmed/10783841Mercado F, Marshall RI, Klestov AC, Bartold PM. Is there a relationship between rheumatoid arthritis and periodontal disease? J Clin Periodontol [Internet]. 2000 Apr;27(4):267–72. Available from: http://www.ncbi.nlm.nih.gov/pubmed/10783841Arkema E V., Karlson EW, Costenbader KH. A Prospective Study of Periodontal Disease and Risk of Rheumatoid Arthritis. J Rheumatol [Internet]. 2010 Sep 1;37(9):1800–4. Available from: http://www.jrheum.org/cgi/doi/10.3899/jrheum.091398Abdelsalam SK, Hashim NT, Elsalamabi EM, Gismalla BG. Periodontal status of rheumatoid arthritis patients in khartoum state. BMC Res Notes [Internet]. 2011;4(1):460. Available from: http://bmcresnotes.biomedcentral.com/articles/10.1186/1756-0500-4-460Gleissner C, Willershausen B, Kaesser U, Bolten WW. The role of risk factors for periodontal disease in patients with rheumatoid arthritis. Eur J Med Res [Internet]. 1998 Aug 18;3(8):387–92. Available from: http://www.ncbi.nlm.nih.gov/pubmed/9707521Kässer UR, Gleissner C, Dehne F, Michel A, Willershausen-Zönnchen B, Bolten WW. Risk for periodontal disease in patients with longstanding rheumatoid arthritis. Arthritis Rheum [Internet]. 1997 Dec;40(12):2248–51. Available from: http://www.ncbi.nlm.nih.gov/pubmed/9416864Cooles FAH, Isaacs JD. Pathophysiology of rheumatoid arthritis. Curr Opin Rheumatol [Internet]. 2011 May;23(3):233–40. Available from: http://www.ncbi.nlm.nih.gov/pubmed/21427580Socransky SS, Haffajee AD. Effect of Therapy on Periodontal Infections. J Periodontol [Internet]. 1993 Aug;64(8s):754–9. Available from: http://www.joponline.org/doi/10.1902/jop.1993.64.8s.754Holt SC, Kesavalu L, Walker S, Genco CA. Virulence factors of Porphyromonas gingivalis. Periodontol 2000 [Internet]. 1999 Jun;20:168– 238. Available from: http://www.ncbi.nlm.nih.gov/pubmed/10522227Kesavalu L, Holt SC, Ebersole JL. Trypsin-like protease activity of Porphyromonas gingivalis as a potential virulence factor in a murine lesion model. Microb Pathog [Internet]. 1996 Jan;20(1):1–10. Available from: http://www.ncbi.nlm.nih.gov/pubmed/8692006Birkedal-Hansen H, Taylor RE, Zambon JJ, Barwa PK, Neiders ME. Characterization of collagenolytic activity from strains of Bacteroides gingivalis. J Periodontal Res [Internet]. 1988 Jul;23(4):258–64. Available from: http://www.ncbi.nlm.nih.gov/pubmed/2846816Lamont RJ, Jenkinson HF. Life below the gum line: pathogenic mechanisms of Porphyromonas gingivalis. Microbiol Mol Biol Rev [Internet]. 1998 Dec;62(4):1244–63. Available from: http://www.ncbi.nlm.nih.gov/pubmed/9841671McGraw WT, Potempa J, Farley D, Travis J. Purification, characterization, and sequence analysis of a potential virulence factor from Porphyromonas gingivalis, peptidylarginine deiminase. Infect Immun [Internet]. 1999 Jul;67(7):3248–56. Available from: http://www.ncbi.nlm.nih.gov/pubmed/10377098Wegner N, Wait R, Sroka A, Eick S, Nguyen K-A, Lundberg K, et al. Peptidylarginine deiminase from Porphyromonas gingivalis citrullinates human fibrinogen and α-enolase: implications for autoimmunity in rheumatoid arthritis. Arthritis Rheum [Internet]. 2010 Sep;62(9):2662–72. Available from: http://www.ncbi.nlm.nih.gov/pubmed/20506214Batool H, Afzal N, Shahzad F, Kashif M. Relationship between rheumatoid arthritis and chronic periodontitis. J Med Radiol Pathol Surg [Internet]. 2016;2(6):11–4. Available from: http://www.joponline.org/doi/abs/10.1902/jop.2001.72.6.779%5Cnhttp://www. ncbi.nlm.nih.gov/pubmed/11453241Koziel J, Mydel P, Potempa J. The link between periodontal disease and rheumatoid arthritis: an updated review. Curr Rheumatol Rep [Internet]. 2014 Mar;16(3):408. Available from: http://www.ncbi.nlm.nih.gov/pubmed/24458478Mangat P, Wegner N, Venables PJ, Potempa J. Bacterial and human peptidylarginine deiminases: targets for inhibiting the autoimmune response in rheumatoid arthritis? Arthritis Res Ther [Internet]. 2010;12(3):209. Available from: http://arthritisresearch.biomedcentral.com/articles/10.1186/ar3000Rodríguez SB, Stitt BL, Ash DE. Cysteine 351 is an essential nucleophile in catalysis by Porphyromonas gingivalis peptidylarginine deiminase. Arch Biochem Biophys [Internet]. 2010 Dec;504(2):190–6. Available from: http://linkinghub.elsevier.com/retrieve/pii/S0003986110003838Farquharson D, Butcher JP, Culshaw S. Periodontitis, Porphyromonas, and the pathogenesis of rheumatoid arthritis. Mucosal Immunol [Internet]. 2012;5(2):112–20. Available from: http://www.ncbi.nlm.nih.gov/pubmed/22274780Brinkmann V. Neutrophil Extracellular Traps Kill Bacteria. Science (80- ) [Internet]. 2004 Mar 5;303(5663):1532–5. Available from: http://www.sciencemag.org/cgi/doi/10.1126/science.1092385Brinkmann V, Zychlinsky A. Beneficial suicide: why neutrophils die to make NETs. Nat Rev Microbiol [Internet]. 2007 Aug;5(8):577–82. Available from: http://www.nature.com/doifinder/10.1038/nrmicro1710Neeli I, Khan SN, Radic M. Histone deimination as a response to inflammatory stimuli in neutrophils. J Immunol [Internet]. 2008 Feb 1;180(3):1895–902. Available from: http://www.ncbi.nlm.nih.gov/pubmed/18209087Klareskog L, Malmström V, Lundberg K, Padyukov L, Alfredsson L. Smoking, citrullination and genetic variability in the immunopathogenesis of rheumatoid arthritis. Semin Immunol [Internet]. 2011 Apr;23(2):92–8. Available from: http://linkinghub.elsevier.com/retrieve/pii/S1044532311000157Klareskog L, Stolt P, Lundberg K, Källberg H, Bengtsson C, Grunewald J, et al. A new model for an etiology of rheumatoid arthritis: Smoking may trigger HLA–DR (shared epitope)–restricted immune reactions to autoantigens modified by citrullination. Arthritis Rheum [Internet]. 2006 Jan;54(1):38–46. Available from: http://doi.wiley.com/10.1002/art.21575Makrygiannakis D, Hermansson M, Ulfgren A-K, Nicholas AP, Zendman AJW, Eklund A, et al. Smoking increases peptidylarginine deiminase 2 enzyme expression in human lungs and increases citrullination in BAL cells. Ann Rheum Dis [Internet]. 2008 Oct 1;67(10):1488–92. Available from: http://ard.bmj.com/cgi/doi/10.1136/ard.2007.075192Padyukov L, Silva C, Stolt P, Alfredsson L, Klareskog L. A gene-environment interaction between smoking and shared epitope genes in HLA-DR provides a high risk of seropositive rheumatoid arthritis. Arthritis Rheum [Internet]. 2004 Oct;50(10):3085–92. Available from: http://doi.wiley.com/10.1002/art.20553Linn-Rasker SP. Smoking is a risk factor for anti-CCP antibodies only in rheumatoid arthritis patients who carry HLA-DRB1 shared epitope alleles. Ann Rheum Dis [Internet]. 2006 Mar 1;65(3):366–71. Available from: http://ard.bmj.com/cgi/doi/10.1136/ard.2005.041079Pedersen M, Jacobsen S, Garred P, Madsen HO, Klarlund M, Svejgaard A, et al. Strong combined gene–environment effects in anti–cyclic citrullinated peptide–positive rheumatoid arthritis: A nationwide case–control study in Denmark. Arthritis Rheum [Internet]. 2007 May;56(5):1446–53. Available from: http://doi.wiley.com/10.1002/art.22597Lundström E, Källberg H, Alfredsson L, Klareskog L, Padyukov L. Geneenvironment interaction between the DRB1 shared epitope and smoking in the risk of anti-citrullinated protein antibody-positive rheumatoid arthritis: All alleles are important. Arthritis Rheum [Internet]. 2009 Jun;60(6):1597–603. Available from: http://doi.wiley.com/10.1002/art.24572Anaya JM, Correa PA, Mantilla R, Jiménez F, Kuffner T MJ. Rheumatoid arthritis in African Colombians from Quibdó. Semin Arthritis Rheum [Internet]. 2001;31:191–8. Available from: http://www.semarthritisrheumatism.com/article/S0049-0172(01)33477- 7/abstractDiaz JA, Dávila-Ramírez FA, Quintana-López G, Aristizábal-Gutiérrez F, Brown P. Prevalencia de artritis reumatoide en Colombia: Una aproximación basada en la carga de la enfermedad año 2005. Rheumatoid Arthritis prevalence in Colombia: An approach based on burden of disease study 2005. 2015;3(1):11–6.Machado-Alba JE, Ruiz AF, Medina Morales DA. The epidemiology of rheumatoid arthritis in a cohort of Colombian patients. Rev Colomb Reumatol [Internet]. 2015;22(3):148–52. Available from: http://www.sciencedirect.com/science/article/pii/S012181231500047XMuñetón, G. A.; Quintana G. La epidemiología de la artritis reumatoide. Rev Colomb Reumatol [Internet]. 2016;2(3):145–7. Available from: http://www.scielo.org.co/pdf/rcre/v22n3/v22n3a01.pdfBright R, Proudman SM, Rosenstein ED, Bartold PM. Is there a link between carbamylation and citrullination in periodontal disease and rheumatoid arthritis? Med Hypotheses [Internet]. 2015 Jun;84(6):570–6. Available from: http://linkinghub.elsevier.com/retrieve/pii/S0306987715001115Kroot EJ, de Jong BA, van Leeuwen MA, Swinkels H, van den Hoogen FH, van’t Hof M, et al. The prognostic value of anti-cyclic citrullinated peptide antibody in patients with recent-onset rheumatoid arthritis. Arthritis Rheum [Internet]. 2000 Aug;43(8):1831–5. Available from: http://www.ncbi.nlm.nih.gov/pubmed/10943873Kroot EJ, de Jong BA, van Leeuwen MA, Swinkels H, van den Hoogen FH, van’t Hof M, et al. The prognostic value of anti-cyclic citrullinated peptide antibody in patients with recent-onset rheumatoid arthritis. Arthritis Rheum [Internet]. 2000 Aug;43(8):1831–5. Available from: http://www.ncbi.nlm.nih.gov/pubmed/10943873Aggarwal R, Liao K, Nair R, Ringold S, Costenbander KH. Anti-citrullinated peptide antibody assays and their role in the diagnosis of rheumatoid arthritis. Arthritis Care Res (Hoboken) [Internet]. 2009 Nov 15;61(11):1472– 83. Available from: http://doi.wiley.com/10.1002/art.24827Liao F, Li Z, Wang Y, Shi B, Gong Z, Cheng X. Porphyromonas gingivalis may play an important role in the pathogenesis of periodontitis-associated rheumatoid arthritis. Med Hypotheses [Internet]. 2009 Jun;72(6):732–5. Available from: http://linkinghub.elsevier.com/retrieve/pii/S0306987709000504Orgován G, Noszál B. The complete microspeciation of arginine and citrulline. J Pharm Biomed Anal [Internet]. 2011 Apr;54(5):965–71. Available from: http://linkinghub.elsevier.com/retrieve/pii/S0731708510006667Carrasco-Marín E, Paz-Miguel JE, López-Mato P, Alvarez-Domínguez C, Leyva-Cobián F. Oxidation of defined antigens allows protein unfolding and increases both proteolytic processing and exposes peptide epitopes which are recognized by specific T cells. Immunology [Internet]. 1998 Nov;95(3):314–21. Available from: http://www.ncbi.nlm.nih.gov/pubmed/9824492Szodoray P, Szabó Z, Kapitány A, Gyetvai Á, Lakos G, Szántó S, et al. Anticitrullinated protein/peptide autoantibodies in association with genetic and environmental factors as indicators of disease outcome in rheumatoid arthritis. Autoimmun Rev [Internet]. 2010 Jan;9(3):140–3. Available from: http://linkinghub.elsevier.com/retrieve/pii/S1568997209001116Nagata S, Yamagiwa M, Inoue K, Senshu T. Estrogen regulates peptidylarginine deiminase levels in a rat pituitary cell line in culture. J Cell Physiol [Internet]. 1990 Nov;145(2):333–9. Available from: http://doi.wiley.com/10.1002/jcp.1041450219Sebbag M, Chapuy-Regaud S, Auger I, Petit-Texeira E, Clavel C, Nogueira L, et al. Clinical and pathophysiological significance of the autoimmune response to citrullinated proteins in rheumatoid arthritis. Jt Bone Spine [Internet]. 2004 Nov;71(6):493–502. Available from: http://linkinghub.elsevier.com/retrieve/pii/S1297319X04001460Masson-Bessiere C, Sebbag M, Girbal-Neuhauser E, Nogueira L, Vincent C, Senshu T, et al. The Major Synovial Targets of the Rheumatoid ArthritisSpecific Antifilaggrin Autoantibodies Are Deiminated Forms of the - and - Chains of Fibrin. J Immunol [Internet]. 2001 Mar 15;166(6):4177–84. Available from: http://www.jimmunol.org/cgi/doi/10.4049/jimmunol.166.6.4177Sebbag M, Moinard N, Auger I, Clavel C, Arnaud J, Nogueira L, et al. Epitopes of human fibrin recognized by the rheumatoid arthritis-specific autoantibodies to citrullinated proteins. Eur J Immunol [Internet]. 2006 Aug;36(8):2250–63. Available from: http://doi.wiley.com/10.1002/eji.200535790Bang H, Egerer K, Gauliard A, Lüthke K, Rudolph PE, Fredenhagen G, et al. Mutation and citrullination modifies vimentin to a novel autoantigen for rheumatoid arthritis. Arthritis Rheum [Internet]. 2007 Aug;56(8):2503–11. Available from: http://doi.wiley.com/10.1002/art.22817Kinloch A, Tatzer V, Wait R, Peston D, Lundberg K, Donatien P, et al. Identification of citrullinated alpha-enolase as a candidate autoantigen in rheumatoid arthritis. Arthritis Res Ther [Internet]. 2005;7(6):R1421-9. Available from: http://arthritisresearch.biomedcentral.com/articles/10.1186/ar1845Foulquier C, Sebbag M, Clavel C, Chapuy-Regaud S, Al Badine R, Méchin M-C, et al. Peptidyl arginine deiminase type 2 (PAD-2) and PAD-4 but not PAD-1, PAD-3, and PAD-6 are expressed in rheumatoid arthritis synovium in close association with tissue inflammation. Arthritis Rheum [Internet]. 2007 Nov;56(11):3541–53. Available from: http://doi.wiley.com/10.1002/art.22983Quirke A-M, Fisher BAC, Kinloch AJ, Venables PJ. Citrullination of autoantigens: Upstream of TNFα in the pathogenesis of rheumatoid arthritis. FEBS Lett [Internet]. 2011 Dec 1;585(23):3681–8. Available from: http://doi.wiley.com/10.1016/j.febslet.2011.06.006Vander Cruyssen B, Cantaert T, Nogueira L, Clavel C, De Rycke L, Dendoven A, et al. Diagnostic value of anti-human citrullinated fibrinogen ELISA and comparison with four other anti-citrullinated protein assays. Arthritis Res Ther [Internet]. 2006;8(4):R122. Available from: http://www.ncbi.nlm.nih.gov/pubmed/16859515Chapuy-Regaud S, Nogueira L, Clavel C, Sebbag M, Vincent C, Serre G. IgG subclass distribution of the rheumatoid arthritis-specific autoantibodies to citrullinated fibrin. Clin Exp Immunol [Internet]. 2005 Mar;139(3):542–50. Available from: http://www.ncbi.nlm.nih.gov/pubmed/15730401Berlyne GM. Carbamylated proteins and peptides in health and in uremia. Nephron [Internet]. 1998;79(2):125–30. Available from: http://www.ncbi.nlm.nih.gov/pubmed/9647489Nolte W. Microbiología Odontológica. México: Editorial Interamericana; 1985.Shi J, van Veelen PA, Mahler M, Janssen GMC, Drijfhout JW, Huizinga TWJ, et al. Carbamylation and antibodies against carbamylated proteins in autoimmunity and other pathologies. Autoimmun Rev [Internet]. 2014;13(3):225–30. Available from: http://dx.doi.org/10.1016/j.autrev.2013.10.008Trepanier DJ, Thibert RJ. Carbamylation of erythrocyte membrane aminophospholipids: an in vitro and in vivo study. Clin Biochem [Internet]. 1996 Aug;29(4):333–45. Available from: http://linkinghub.elsevier.com/retrieve/pii/0009912096000185Lapko VN, Smith DL, Smith JB. Methylation and carbamylation of human γcrystallins. Protein Sci [Internet]. 2003 Aug;12(8):1762–74. Available from: http://doi.wiley.com/10.1110/ps.0305403Wang Z, Nicholls SJ, Rodriguez ER, Kummu O, Hörkkö S, Barnard J, et al. Protein carbamylation links inflammation, smoking, uremia and atherogenesis. Nat Med [Internet]. 2007;13(10):1176–84. Available from: http://www.ncbi.nlm.nih.gov/pubmed/17828273Holzer M, Zangger K, El-Gamal D, Binder V, Curcic S, Konya V, et al. Myeloperoxidase-Derived Chlorinating Species Induce Protein Carbamylation Through Decomposition of Thiocyanate and Urea: Novel Pathways Generating Dysfunctional High-Density Lipoprotein. Antioxid Redox Signal [Internet]. 2012 Oct 15;17(8):1043–52. Available from: http://online.liebertpub.com/doi/abs/10.1089/ars.2011.4403Kalmár J, Woldegiorgis KL, Biri B, Ashby MT. Mechanism of Decomposition of the Human Defense Factor Hypothiocyanite Near Physiological pH. J Am Chem Soc [Internet]. 2011 Dec 14;133(49):19911–21. Available from: http://pubs.acs.org/doi/abs/10.1021/ja2083152Klebanoff SJ. Myeloperoxidase: friend and foe. J Leukoc Biol [Internet]. 2005 Jan 26;77(5):598–625. Available from: http://www.jleukbio.org/cgi/doi/10.1189/jlb.1204697Jaisson S, Pietrement C, Gillery P. Carbamylation-Derived Products: Bioactive Compounds and Potential Biomarkers in Chronic Renal Failure and Atherosclerosis. Clin Chem [Internet]. 2011 Nov 1;57(11):1499–505. Available from: http://www.clinchem.org/cgi/doi/10.1373/clinchem.2011.163188Jaisson S, Gillery P. Evaluation of Nonenzymatic Posttranslational Modification-Derived Products as Biomarkers of Molecular Aging of Proteins. Clin Chem [Internet]. 2010 Sep 1;56(9):1401–12. Available from: http://www.clinchem.org/cgi/doi/10.1373/clinchem.2010.145201Song YW, Kang EH. Autoantibodies in rheumatoid arthritis: rheumatoid factors and anticitrullinated protein antibodies. QJM [Internet]. 2010 Mar 1;103(3):139–46. Available from: https://academic.oup.com/qjmed/articlelookup/doi/10.1093/qjmed/hcp165Wernick RM, Lipsky PE, Marban-Arcos E, Maliakkal JJ, Edelbaum D, Ziff M. IgG and IgM rheumatoid factor synthesis in rheumatoid synovial membrane cell cultures. Arthritis Rheum [Internet]. 1985 Jul;28(7):742–52. Available from: http://www.ncbi.nlm.nih.gov/pubmed/4015721Jones V, Taylor PC, Jacoby RK, Wallington TB. Synovial synthesis of rheumatoid factors and immune complex constituents in early arthritis. Ann Rheum Dis [Internet]. 1984 Apr;43(2):235–9. Available from: http://www.ncbi.nlm.nih.gov/pubmed/6712294Nell VPK. Autoantibody profiling as early diagnostic and prognostic tool for rheumatoid arthritis. Ann Rheum Dis [Internet]. 2005 Dec 1;64(12):1731–6. Available from: http://ard.bmj.com/cgi/doi/10.1136/ard.2005.035691Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum [Internet]. 1988 Mar;31(3):315–24. Available from: http://www.ncbi.nlm.nih.gov/pubmed/3358796Arend WP, Firestein GS. Pre-rheumatoid arthritis: predisposition and transition to clinical synovitis. Nat Rev Rheumatol [Internet]. 2012;8(10):573– 86. Available from: http://dx.doi.org/10.1038/nrrheum.2012.134Otterness IG. The value of C-reactive protein measurement in rheumatoid arthritis. Semin Arthritis Rheum [Internet]. 1994 Oct;24(2):91–104. Available from: http://www.ncbi.nlm.nih.gov/pubmed/7839158Brigden M. The erythrocyte sedimentation rate. Postgrad Med [Internet]. 1998 May 30;103(5):257–74. Available from: http://www.sciencedirect.com/science/article/pii/S0736467997001972%5Cnh ttp://www.ncbi.nlm.nih.gov/pubmed/9404806Kushner I. C-reactive protein in rheumatology. Arthritis Rheum [Internet]. 1991 Aug;34(8):1065–8. Available from: http://doi.wiley.com/10.1002/art.1780340819Bedell SE, Bush BT. Erythrocyte sedimentation rate. From folklore to facts. Am J Med [Internet]. 1985 Jun;78(6 Pt 1):1001–9. Available from: http://www.ncbi.nlm.nih.gov/pubmed/4014259Shearn MA, Kang IY. Effect of age and sex on the erythrocyte sedimentation rate. J Rheumatol [Internet]. 1986 Apr;13(2):297–8. Available from: http://www.ncbi.nlm.nih.gov/pubmed/3723495Fabry TL. Mechanism of erythrocyte aggregation and sedimentation. Blood [Internet]. 1987 Nov;70(5):1572–6. Available from: http://www.ncbi.nlm.nih.gov/pubmed/3663946Fabry TL. Mechanism of erythrocyte aggregation and sedimentation. Blood [Internet]. 1987 Nov;70(5):1572–6. Available from: http://www.ncbi.nlm.nih.gov/pubmed/3663946Pepys MB. C-reactive protein fifty years on. Lancet (London, England) [Internet]. 1981 Mar 21;1(8221):653–7. Available from: http://www.ncbi.nlm.nih.gov/pubmed/6110874Gewurz H, Mold C, Siegel J, Fiedel B. C-reactive protein and the acute phase response. Adv Intern Med [Internet]. 1982;27:345–72. Available from: http://www.ncbi.nlm.nih.gov/pubmed/7041546Tishler M, Caspi D, Yaron M. C-reactive protein levels in patients with rheumatoid arthritis: the impact of therapy. Clin Rheumatol [Internet]. 1985 Sep;4(3):321–4. Available from: http://link.springer.com/10.1007/BF02031616Larsen A. The relation of radiographic changes to serum acute-phase proteins and rheumatoid factor in 200 patients with rheumatoid arthritis. Scand J Rheumatol [Internet]. 1988;17(2):123–9. Available from: http://www.ncbi.nlm.nih.gov/pubmed/3387929Im CH, Kang EH, Ryu HJ, Lee JH, Lee EY, Lee YJ, et al. Anti-cyclic citrullinated peptide antibody is associated with radiographic erosion in rheumatoid arthritis independently of shared epitope status. Rheumatol Int [Internet]. 2009 Jan;29(3):251–6. Available from: http://www.ncbi.nlm.nih.gov/pubmed/18751982Wilder RL, Sternberg EM. Neuroendocrine hormonal factors in rheumatoid arthritis and related conditions. Curr Opin Rheumatol [Internet]. 1990 Jun;2(3):436–40. Available from: http://www.ncbi.nlm.nih.gov/pubmed/2203424Ahmed SA, Hissong BD, Verthelyi D, Donner K, Becker K, Karpuzoglu-Sahin E. Gender and risk of autoimmune diseases: Possible role of estrogenic compounds. Environ Health Perspect. 1999;107(SUPPL. 5):681–6.Feng J, Chen Q, Yu F, Wang Z, Chen S, Jin Z, et al. Body Mass Index and Risk of Rheumatoid Arthritis: A Meta-Analysis of Observational Studies. Medicine (Baltimore) [Internet]. 2016;95(8):e2859. Available from: http://www.ncbi.nlm.nih.gov/pubmed/26937917Unriza-Puin S, Bautista-Molano W, Lafaurie GI, Valle-O??ate R, Chalem P, Chila-Moreno L, et al. Are obesity, ACPAs and periodontitis conditions that influence the risk of developing rheumatoid arthritis in first-degree relatives? Clin Rheumatol [Internet]. 2017;36(4):799–806. Available from: http://dx.doi.org/10.1007/s10067-016-3519-zGremese E, Tolusso B, Gigante MR, Ferraccioli G. Obesity as a Risk and Severity Factor in Rheumatic Diseases (Autoimmune Chronic Inflammatory Diseases). Front Immunol [Internet]. 2014 Nov 11;5. Available from: http://journal.frontiersin.org/article/10.3389/fimmu.2014.00576/abstractBello-Gualtero JM, Lafaurie GI, Hoyos LX, Castillo DM, De-Avila J, Munevar JC, et al. Periodontal Disease in Individuals With a Genetic Risk of Developing Arthritis and Early Rheumatoid Arthritis: A Cross-Sectional Study. J Periodontol [Internet]. 2016 Apr;87(4):346–56. Available from: http://doi.wiley.com/10.1902/jop.2015.150455Auger I, Sebbag M, Vincent C, Balandraud N, Guis S, Nogueira L, et al. Influence of HLA-DR genes on the production of rheumatoid arthritis-specific autoantibodies to citrullinated fibrinogen. Arthritis Rheum [Internet]. 2005 Nov;52(11):3424–32. Available from: http://doi.wiley.com/10.1002/art.21391Bright R, Thiele GM, Manavis J, Mikuls TR, Payne JB, Bartold PM. Gingival tissue, an extrasynovial source of malondialdehyde-acetaldehyde adducts, citrullinated and carbamylated proteins. J Periodontal Res [Internet]. 2017 Oct 17; Available from: http://doi.wiley.com/10.1111/jre.12486Freire MO, Van Dyke TE. Natural resolution of inflammation. Periodontol 2000 [Internet]. 2013 Oct;63(1):149–64. Available from: http://doi.wiley.com/10.1111/prd.12034Enfermedad AutoinmuneAutoautoanticuerposAnticuerposArtritisAutoinmunidadCarbamilaciónDiagnosticoORIGINALPresentación final.pdfPresentación final.pdfapplication/pdf1108059https://repositorio.unicolmayor.edu.co/bitstream/unicolmayor/4792/1/Presentaci%c3%b3n%20final.pdf1687d7c9cf19ab7d690aa3d3ab156605MD51open accessDocumento final modificado.pdfDocumento final modificado.pdfapplication/pdf1129593https://repositorio.unicolmayor.edu.co/bitstream/unicolmayor/4792/2/Documento%20final%20modificado.pdff35c30e133170f778b066597705ac4efMD52open accessDocumento final modificado FORMATO DERECHOS DE AUTOR.pdfDocumento final modificado FORMATO DERECHOS DE AUTOR.pdfapplication/pdf315131https://repositorio.unicolmayor.edu.co/bitstream/unicolmayor/4792/3/Documento%20final%20modificado%20FORMATO%20DERECHOS%20DE%20AUTOR.pdfce598a53a5b1f110d330c15aeb4c2e11MD53metadata only accessLICENSElicense.txtlicense.txttext/plain; charset=utf-814828https://repositorio.unicolmayor.edu.co/bitstream/unicolmayor/4792/4/license.txt2f9959eaf5b71fae44bbf9ec84150c7aMD54open accessTEXTPresentación final.pdf.txtPresentación final.pdf.txtExtracted texttext/plain8025https://repositorio.unicolmayor.edu.co/bitstream/unicolmayor/4792/5/Presentaci%c3%b3n%20final.pdf.txtce632dd036e1bb528f7c982974b02856MD55open accessDocumento final modificado.pdf.txtDocumento final modificado.pdf.txtExtracted texttext/plain178155https://repositorio.unicolmayor.edu.co/bitstream/unicolmayor/4792/7/Documento%20final%20modificado.pdf.txtfa025ebf3073a97ae284501729e3b071MD57open accessDocumento final modificado FORMATO DERECHOS DE AUTOR.pdf.txtDocumento final modificado FORMATO DERECHOS DE AUTOR.pdf.txtExtracted texttext/plain14https://repositorio.unicolmayor.edu.co/bitstream/unicolmayor/4792/9/Documento%20final%20modificado%20FORMATO%20DERECHOS%20DE%20AUTOR.pdf.txt462717b648a4e1f31197195266e891b0MD59metadata only accessTHUMBNAILPresentación final.pdf.jpgPresentación final.pdf.jpgGenerated Thumbnailimage/jpeg7917https://repositorio.unicolmayor.edu.co/bitstream/unicolmayor/4792/6/Presentaci%c3%b3n%20final.pdf.jpg93748c5ca4c32bf552e12ae0db8acff6MD56open accessDocumento final modificado.pdf.jpgDocumento final modificado.pdf.jpgGenerated Thumbnailimage/jpeg9452https://repositorio.unicolmayor.edu.co/bitstream/unicolmayor/4792/8/Documento%20final%20modificado.pdf.jpg361367a55746171217ad9e2739c8b5adMD58open accessDocumento final modificado FORMATO DERECHOS DE AUTOR.pdf.jpgDocumento final modificado FORMATO DERECHOS DE AUTOR.pdf.jpgGenerated Thumbnailimage/jpeg7066https://repositorio.unicolmayor.edu.co/bitstream/unicolmayor/4792/10/Documento%20final%20modificado%20FORMATO%20DERECHOS%20DE%20AUTOR.pdf.jpg4fa4c3a9ebf54be7811fc69544a7b50fMD510metadata only accessunicolmayor/4792oai:repositorio.unicolmayor.edu.co:unicolmayor/47922022-03-10 03:00:41.895An error occurred on the license name.|||https://creativecommons.org/licenses/by-nc-sa/4.0/open accessBiblioteca Digital Unicolmayorrepositorio@unicolmayor.edu.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