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Cytokines (IL-15, IL-21, and IFN-γ) in rheumatoid arthritis: association with positivity to autoantibodies (RF, anti-CCP, anti-MCV, and anti-PADI4) and clinical activity

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Abstract

Introduction

Rheumatoid arthritis (RA) is an autoimmune disease characterized by synovial membrane damage and autoantibody production. RA is a heterogeneous disease, where cytokines such as IL-15, IL-21, and IFN-γ have been associated. However, their association with the autoantibodies has not been clearly described. The aim of this study was to evaluate the relationship between the cytokines IL-15, IL-21, and IFN-γ with the autoantibodies (RF, anti-CCP, anti-MCV, and anti-PADI4) in RA and disease activity.

Methodology

This study included 153 RA patients and 80 control subjects (CS). The levels of IL-15, IL-21, IFN-γ, anti-CCP, anti-MCV, and anti-PADI4 were quantified by ELISA, whereas RF was quantified by turbidimetry. The disease activity was evaluated by the indices disease activity score 28-erythrocyte sedimentation rate (DAS28-ESR), clinical disease activity index (CDAI), and simple disease activity index (SDAI).

Results

The serum levels of IL-15, IL-21, and IFN-γ, and autoantibodies were increased in RA patients, compared with CS (p < 0.05). A correlation was found between IL-21 and anti-CCP and anti-MCV (p < 0.05). According to RA evolution, RF, anti-CCP, and anti-MCV had higher levels in early RA. In addition, increased levels of IL-21 were observed in RA seropositive patients (RF/anti-CCP/anti-MCV). The higher levels of both cytokines and autoantibodies were observed in moderate activity, evaluated by the three indices.

Conclusions

Our results suggest that the increased soluble levels of IL-15, IL-21, and IFN-γ are involved in the inflammatory network in RA. However, IL-21 serum levels are associated with higher titers of autoantibodies (RF, anti-CCP, and anti-MCV) and IL-15 with moderate activity.

Key Points

• IL-15, IL-21, and IFN-y are associated with the immunopathology of RA, but not significantly with the evolution of the disease.

• RF, anti-CCP, and anti-MCV had higher levels in early than established RA.

• IL-21 has an association with RF, anti-CCP, and anti-MCVand, for this reason, could be proposed as a disease biomarker.

• Patients with activity moderate of disease showed higher levels of RF, anti-CCP, anti-MCV, and IL-15.

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References

  1. Smolen JS, Aletaha D, Barton A, Burmester GR, Emery P, Firestein GS, Kavanaugh A, McInnes IB, Solomon DH, Strand V, Yamamoto K (2018) Rheumatoid arthritis. Nat Rev Dis Prim 4:1–23. https://doi.org/10.1038/nrdp.2018.1

    Article  Google Scholar 

  2. Moreno-Montoya J, Alvarez-Nemegyei J, Sanin LH, Pérez-Barbosa L, Trejo-Valdivia B, Santana N, Goycochea-Robles MV, Cardiel MH, Riega-Torres J, Maradiaga M, Burgos-Vargas R, Peláez-Ballestas I, GEEMA (Grupo de Estudio Epidemiológico de Enfermedades Músculo Articulares) (2015) Association of regional and cultural factors with the prevalence of rheumatoid arthritis in the Mexican population. JCR J Clin Rheumatol 21:57–62. https://doi.org/10.1097/RHU.0000000000000223

    Article  PubMed  Google Scholar 

  3. Peláez-Ballestas I, Granados Y, Quintana R, Loyola-Sánchez A, Julián-Santiago F, Rosillo C, Gastelum-Strozzi A, Alvarez-Nemegyei J, Santana N, Silvestre A, Pacheco-Tena C, Goñi M, García-García C, Cedeño L, Pons-Éstel BA (2018) Epidemiology and socioeconomic impact of the rheumatic diseases on indigenous people: an invisible syndemic public health problem. Ann Rheum Dis:1–8. https://doi.org/10.1136/annrheumdis-2018-213625

  4. Aletaha D, Neogi T, Silman AJ, Funovits J, Felson DT, Bingham CO III, Birnbaum NS, Burmester GR, Bykerk VP, Cohen MD, Combe B, Costenbader KH, Dougados M, Emery P, Ferraccioli G, Hazes JMW, Hobbs K, Huizinga TWJ, Kavanaugh A, Kay J, Kvien TK, Laing T, Mease P, Ménard HA, Moreland LW, Naden RL, Pincus T, Smolen JS, Stanislawska-Biernat E, Symmons D, Tak PP, Upchurch KS, Vencovský J, Wolfe F, Hawker G (2010) 2010 Rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheum 62:2569–2581. https://doi.org/10.1002/art.27584

  5. Jabri B, Abadie V (2015) IL-15 functions as a danger signal to regulate tissue-resident T cells and tissue destruction HHS Public Access. Nat Rev Immunol 15:771–783. https://doi.org/10.1038/nri3919

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Goldbergova MP, Pavek N, Lipkova J et al (2012) Circulating cytokine pattern and factors describing rheumatoid arthritis : IL-15 as one of the biomarkers for RA ?, Biomarkers 17:655–662. https://doi.org/10.3109/1354750X.2012.719036

  7. Yang X, Xu W, Leng R et al (2015) Therapeutic potential of IL-15 in rheumatoid arthritis. Hum Immunol 76:812–818. https://doi.org/10.1016/j.humimm.2015.09.041

    Article  CAS  PubMed  Google Scholar 

  8. Dinesh P, Rasool M (2018) Multifaceted role of IL-21 in rheumatoid arthritis: current understanding and future perspectives. J Cell Physiol 233:3918–3928. https://doi.org/10.1002/jcp.26158

    Article  CAS  PubMed  Google Scholar 

  9. Ettinger R, Kuchen S, Lipsky PE (2008) The role of IL-21 in regulating B-cell function in health and disease. Immunol Rev 223:60–86. https://doi.org/10.1111/j.1600-065X.2008.00631.x

    Article  CAS  PubMed  Google Scholar 

  10. Gottenberg J, Dayer J, Lukas C et al (2012) Serum IL-6 and IL-21 are associated with markers of B cell activation and structural progression in early rheumatoid arthritis : results from the ESPOIR cohort. Annals of the Rheumatic Diseases 71:1243–1248. https://doi.org/10.1136/annrheumdis-2011-200975

  11. Kak G, Raza M, Tiwari BK (2018) Interferon-gamma (IFN-γ): exploring its implications in infectious diseases. Biomol Concepts 9:64–79. https://doi.org/10.1515/bmc-2018-0007

    Article  CAS  PubMed  Google Scholar 

  12. Mata-Espinosa DA, Hernández-Pando R (2008) Interferón gamma: aspectos básicos, importancia clínica y usos terapéuticos. Rev Invest Clin 60:421–431.

  13. Gavrilă BI, Ciofu C, Stoica V (2016) Biomarkers in rheumatoid arthritis, what is new? J Med Life 9:144–148

    PubMed  PubMed Central  Google Scholar 

  14. Willemze A, Toes REM, Huizinga TWJ, Trouw LA (2012) New biomarkers in rheumatoid arthritis. Neth J Med 70:392–399

    CAS  PubMed  Google Scholar 

  15. Farid SS, Azizi G, Mirshafiey A (2013) Anti-citrullinated protein antibodies and their clinical utility in rheumatoid arthritis. Int J Rheum Dis 16:379–386. https://doi.org/10.1111/1756-185X.12129

    Article  CAS  PubMed  Google Scholar 

  16. Van Venrooij WJ, Van Beers JJBC, Pruijn GJM (2011) Anti-CCP antibodies: the past, the present and the future. Nat Rev Rheumatol 7:391–398. https://doi.org/10.1038/nrrheum.2011.76

    Article  CAS  PubMed  Google Scholar 

  17. Bidkar M, Vassallo R, Luckey D, Smart M, Mouapi K, Taneja V (2016) Cigarette smoke induces immune responses to vimentin in both, arthritis-susceptible and -resistant humanized mice. PLoS One 11:1–15. https://doi.org/10.1371/journal.pone.0162341

    Article  CAS  Google Scholar 

  18. Lee YH, Bae S-C, Song GG (2015) Diagnostic accuracy of anti-MCV and anti-CCP antibodies in rheumatoid arthritis. Z Rheumatol 74:911–918. https://doi.org/10.1007/s00393-015-1598-x

    Article  CAS  PubMed  Google Scholar 

  19. Ikari K, Kuwahara M, Nakamura T, Momohara S, Hara M, Yamanaka H, Tomatsu T, Kamatani N (2005) Association between PADI4 and rheumatoid arthritis: a replication study. Arthritis Rheum 52:3054–3057. https://doi.org/10.1002/art.21309

    Article  CAS  PubMed  Google Scholar 

  20. Suzuki T, Ikari K, Yano K, Inoue E, Toyama Y, Taniguchi A, Yamanaka H, Momohara S (2013) PADI4 and HLA-DRB1 are genetic risks for radiographic progression in RA patients, independent of ACPA status: results from the IORRA cohort study. PLoS One 8:2–9. https://doi.org/10.1371/journal.pone.0061045

    Article  CAS  Google Scholar 

  21. Seri Y, Shoda H, Suzuki A, Matsumoto I, Sumida T, Fujio K, Yamamoto K (2015) Peptidylarginine deiminase type 4 deficiency reduced arthritis severity in a glucose-6-phosphate isomerase-induced arthritis model. Sci Rep 5:1–7. https://doi.org/10.1038/srep13041

    Article  CAS  Google Scholar 

  22. Hernández-Bello J, Baños-Hernández CJ, Palafox-Sánchez CA, Navarro-Zarza JE, Reyes-Castillo Z, Muñoz Valle JF (2018) Combinaciones de autoanticuerpos y su asociación con variables clínicas en artritis reumatoidea. Acta Bioquím. Clín. Latinoam 52(1): 49–60.

  23. van Riel PLCM, Renskers L The Disease Activity Score (DAS) and the Disease Activity Score using 28 joint counts (DAS28) in the management of rheumatoid arthritis. Clin Exp Rheumatol 34:S40–S44

  24. Aletaha D, Bécède M, Smolen JS (2016) Information technology concerning SDAI and CDAI. Clin Exp Rheumatol 34:S45–S48

  25. Park MK, Her Y-M, La Cho M et al (2011) IL-15 promotes osteoclastogenesis via the PLD pathway in rheumatoid arthritis. Immunol Lett 139:42–51. https://doi.org/10.1016/j.imlet.2011.04.013

    Article  CAS  PubMed  Google Scholar 

  26. Liu R, Wu Q, Su D, et al (2012) A regulatory effect of IL-21 on T follicular helper-like cell and B cell in rheumatoid arthritis. Arthritis Res Ther. 14: R255. https://doi.org/10.1186/ar4100

  27. Xing R, Yang L, Jin Y, Sun L, Li C, Li Z, Zhao J, Liu X (2016) Interleukin-21 induces proliferation and proinflammatory cytokine profile of fibroblast-like synoviocytes of patients with rheumatoid arthritis. Scand J Immunol 83:64–71. https://doi.org/10.1111/sji.12396

    Article  CAS  PubMed  Google Scholar 

  28. Di Fusco D, Izzo R, Figliuzzi MM et al (2014) IL-21 as a therapeutic target in inflammatory disorders. Expert Opin Ther Targets 18:1329–1338. https://doi.org/10.1517/14728222.2014.945426

    Article  CAS  PubMed  Google Scholar 

  29. Lim SA, Nam DH, Lee JH, Kwok SK, Park SH, Chung SH (2015) Association of IL-21 cytokine with severity of primary Sjögren syndrome dry eye. Cornea 34:248–252. https://doi.org/10.1097/ICO.0000000000000363

    Article  PubMed  Google Scholar 

  30. Wang H-X, Chu S, Li J, Lai WN, Wang HX, Wu XJ, Kang X, Qiu YR (2014) Increased IL-17 and IL-21 producing TCRαβ + CD4 − CD8 − T cells in Chinese systemic lupus erythematosus patients. Lupus 23:643–654. https://doi.org/10.1177/0961203314524467

    Article  CAS  PubMed  Google Scholar 

  31. Cui D, Zhang L, Chen J, Zhu M, Hou L, Chen B, Shen B (2015) Changes in regulatory B cells and their relationship with rheumatoid arthritis disease activity. Clin Exp Med 15:285–292. https://doi.org/10.1007/s10238-014-0310-9

    Article  CAS  PubMed  Google Scholar 

  32. Ahern DJ, Brennan FM (2011) The role of natural killer cells in the pathogenesis of rheumatoid arthritis: major contributors or essential homeostatic modulators? Immunol Lett 136:115–121. https://doi.org/10.1016/j.imlet.2010.11.001

    Article  CAS  PubMed  Google Scholar 

  33. Kim EY, Moudgil KD (2017) Immunomodulation of autoimmune arthritis by pro-inflammatory cytokines. Cytokine 98:87–96. https://doi.org/10.1016/j.cyto.2017.04.012

  34. Pavlovic V, Dimic A, Milenkovic S, Krtinic D (2014) Serum levels of IL-17, IL-4, and INFγ in Serbian patients with early rheumatoid arthritis. J Res Med Sci 19:18–22

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Alam J, Jantan I, Bukhari SNA (2017) Rheumatoid arthritis: recent advances on its etiology, role of cytokines and pharmacotherapy. Biomed Pharmacother 92:615–633. https://doi.org/10.1016/j.biopha.2017.05.055

  36. Osiri M, Wongpiyabovorn J, Sattayasomboon Y, Thammacharoenrach N (2016) Inflammatory cytokine levels, disease activity, and function of patients with rheumatoid arthritis treated with combined conventional disease-modifying antirheumatic drugs or biologics. Clin Rheumatol 35:1673–1681. https://doi.org/10.1007/s10067-016-3306-x

    Article  PubMed  Google Scholar 

  37. Krol A, Garred P, Heegaard NHH, Christensen AF, Hetland ML, Stengaard-Pedersen K, Junker P, Madsen HO, Lottenburger T, Ellingsen T, Andersen LS, Hansen I, Pedersen JK, Svendsen AJ, Tarp U, Pødenphant J, Lindegaard H, Østergaard M, Hørslev-Petersen K, Jacobsen S (2015) Interactions between smoking, increased serum levels of anti-CCP antibodies, rheumatoid factors, and erosive joint disease in patients with early, untreated rheumatoid arthritis. Scand J Rheumatol 44:8–12. https://doi.org/10.3109/03009742.2014.918651

    Article  CAS  PubMed  Google Scholar 

  38. Siloşi I, Boldeanu MV, Cojocaru M, Biciuşcă V, Pădureanu V, Bogdan M, Badea RG, Avramescu C, Petrescu IO, Petrescu F, Siloşi CA (2016) The relationship of cytokines IL-13 and IL-17 with autoantibodies profile in early rheumatoid arthritis. J Immunol Res 2016:1–10. https://doi.org/10.1155/2016/3109135

    Article  CAS  Google Scholar 

  39. Porto LSS, Tavares WC, Costa DA et al (2017) Anti-CCP antibodies are not a marker of severity in established rheumatoid arthritis: a magnetic resonance imaging study. Rev Bras Reumatol (English Ed) 57:15–22. https://doi.org/10.1016/j.rbre.2015.07.018

    Article  Google Scholar 

  40. Reyes-Castillo Z, Palafox-Sánchez CA, Parra-Rojas I, Martínez-Bonilla GE, del Toro-Arreola S, Ramírez-Dueñas MG, Ocampo-Bermudes G, Muñoz-Valle JF (2015) Comparative analysis of autoantibodies targeting peptidylarginine deiminase type 4, mutated citrullinated vimentin and cyclic citrullinated peptides in rheumatoid arthritis: associations with cytokine profiles, clinical and genetic features. Clin Exp Immunol 182:119–131. https://doi.org/10.1111/cei.12677

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Barouta G, Katsiari CG, Alexiou I, Liaskos C, Varna A, Bogdanos DP, Germenis AE, Sakkas LI (2017) Anti-MCV antibodies predict radiographic progression in Greek patients with very early (<3 months duration) rheumatoid arthritis. Clin Rheumatol 36:885–894. https://doi.org/10.1007/s10067-016-3494-4

    Article  PubMed  Google Scholar 

  42. Avdeeva AS, Aleksandrova EN, Novikov AA, Smirnov AV, Cherkasova MV, Nasonov EL (2014) The relationship of antibodies to modified citrullinated vimentin and markers of bone and cartilage destruction in rheumatoid arthritis. Int J Rheumatol:7. https://doi.org/10.1155/2014/464585

  43. El Shazly RI, Hussein SA, Raslan HZ, Elgogary AA (2014) Anti-mutated citrullinated vimentin antibodies in rheumatoid arthritis patients: relation to disease activity and manifestations. Egypt Rheumatol 36:65–70. https://doi.org/10.1016/j.ejr.2013.12.009

    Article  Google Scholar 

  44. Gonzalez-Lopez L, Rocha-Muñoz AD, Ponce-Guarneros M et al (2014) Anti-cyclic citrullinated peptide (anti-CCP) and anti-mutated citrullinated vimentin (anti-MCV) relation with extra-articular manifestations in rheumatoid arthritis. J Immunol Res. https://doi.org/10.1155/2014/536050

  45. Jilani AA, Mackworth-Young CG (2015) The role of citrullinated protein antibodies in predicting erosive disease in rheumatoid arthritis: a systematic literature review and meta-analysis. Int J Rheumatol 2015:1–8. https://doi.org/10.1155/2015/728610

    Article  CAS  Google Scholar 

  46. Halvorsen EH, Pollmann S, Gilboe I-M, van der Heijde D, Landewe R, Odegard S, Kvien TK, Molberg O (2007) Serum IgG antibodies to peptidylarginine deiminase 4 in rheumatoid arthritis and associations with disease severity. Ann Rheum Dis 67:414–417. https://doi.org/10.1136/ard.2007.080267

    Article  PubMed  Google Scholar 

  47. Kolfenbach JR, Deane KD, Derber LA, et al (2010) Autoimmunity to peptidyl arginine deiminase type 4 precedes clinical onset of rheumatoid arthritis. Arthritis Rheum. 62(9):2633–2639. https://doi.org/10.1002/art.27570

  48. Syversen SW, Goll GL, van der Heijde D, Landewe R, Lie BA, Odegard S, Uhlig T, Gaarder PI, Kvien TK (2010) Prediction of radiographic progression in rheumatoid arthritis and the role of antibodies against mutated citrullinated vimentin: results from a 10-year prospective study. Ann Rheum Dis 69:345–351. https://doi.org/10.1136/ard.2009.113092

    Article  CAS  PubMed  Google Scholar 

  49. Bernasconi NL, Traggiai E, Lanzavecchia A (2002) Maintenance of serological memory by polyclonal activation of human memory B cells. Science 298:2199–2202. https://doi.org/10.1126/science.1076071

    Article  CAS  PubMed  Google Scholar 

  50. Davis MR, Zhu Z, Hansen DM, Bai Q, Fang Y (2015) The role of IL-21 in immunity and cancer. Cancer Lett 358:107–114. https://doi.org/10.1016/j.canlet.2014.12.047

    Article  CAS  PubMed  Google Scholar 

  51. Koenders MI, Van Den Berg WB (2015) Novel therapeutic targets in rheumatoid arthritis. Trends Pharmacol Sci 36:189–195. https://doi.org/10.1016/j.tips.2015.02.001

    Article  CAS  PubMed  Google Scholar 

  52. Fillatreau S (2015) Pathogenic functions of B cells in autoimmune diseases: IFN-γ production joins the criminal gang. Eur J Immunol 45:966–970. https://doi.org/10.1002/eji.201545544

    Article  CAS  PubMed  Google Scholar 

  53. An L-F, Zhang X-H, Sun X-T, Zhao LH, Li S, Wang WH (2015) Unexplained infertility patients have increased serum IL-2, IL-4, IL-6, IL-8, IL-21, TNFα, IFNγ and increased Tfh/CD4 T cell ratio: increased Tfh and IL-21 strongly correlate with presence of autoantibodies. Immunol Investig 44:164–173. https://doi.org/10.3109/08820139.2014.932377

    Article  CAS  Google Scholar 

  54. Deng X-M, Yan S-X, Wei W (2015) IL-21 acts as a promising therapeutic target in systemic lupus erythematosus by regulating plasma cell differentiation. Cell Mol Immunol 12:31–39. https://doi.org/10.1038/cmi.2014.58

    Article  CAS  PubMed  Google Scholar 

  55. Pfeifle R, Rothe T, Ipseiz N, Scherer HU, Culemann S, Harre U, Ackermann JA, Seefried M, Kleyer A, Uderhardt S, Haugg B, Hueber AJ, Daum P, Heidkamp GF, Ge C, Böhm S, Lux A, Schuh W, Magorivska I, Nandakumar KS, Lönnblom E, Becker C, Dudziak D, Wuhrer M, Rombouts Y, Koeleman CA, Toes R, Winkler TH, Holmdahl R, Herrmann M, Blüml S, Nimmerjahn F, Schett G, Krönke G (2017) Regulation of autoantibody activity by the IL-23–TH17 axis determines the onset of autoimmune disease. Nat Immunol 18:104–113. https://doi.org/10.1038/ni.3579

    Article  CAS  PubMed  Google Scholar 

  56. Rasmussen TK, Andersen T, HVID M et al (2010) Increased interleukin 21 (IL-21) and IL-23 are associated with increased disease activity and with radiographic status in patients with early rheumatoid arthritis. J Rheumatol 37:2014–2020. https://doi.org/10.3899/jrheum.100259

    Article  CAS  PubMed  Google Scholar 

  57. Xing R, Sun L, Wu D, Jin Y, Li C, Liu X, Zhao J (2018) Autoantibodies against interleukin-21 correlate with disease activity in patients with rheumatoid arthritis. Clin Rheumatol 37:75–80. https://doi.org/10.1007/s10067-017-3862-8

    Article  PubMed  Google Scholar 

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Acknowledgments

RPIV was a Ph.D. CONACYT fellow (Reg. 575070).

Funding

This research was performed with the financial support of the PRO-SNI 2016-2017 program from Universidad de Guadalajara granted to SHPE and RDMG.

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Author notes

  1. Sánchez-Hernández, Pedro Ernesto and Ramírez-Dueñas, María Guadalupe contributed equally as senior authors.

Authors and Affiliations

  1. Laboratorio de Inmunología, Departamento de Fisiología, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, No. 950, 44340, Guadalajara, Jalisco, Mexico

    Itzel Viridiana Reyes-Pérez, Pedro Ernesto Sánchez-Hernández, Trinidad García-Iglesias & María Guadalupe Ramírez-Dueñas

  2. Instituto de Investigación en Ciencias Biomédicas, Departamento de Clínicas Médicas, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara, Jalisco, Mexico

    José Francisco Muñoz-Valle & Samuel García-Arellano

  3. Servicio de Reumatología, Hospital Civil Fray Antonio Alcalde, Guadalajara, Jalisco, Mexico

    Gloria Esther Martínez-Bonilla, Verónica González-Díaz, Sergio Cerpa-Cruz & Julissa Polanco-Cruz

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Correspondence to Pedro Ernesto Sánchez-Hernández or María Guadalupe Ramírez-Dueñas.

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All individuals have written an informed consent letter, in agreement with the Code of Ethics of the World Medical Association (Declaration of Helsinki, Brazil 2013). The ethics, research, and biosafety committees of Hospital Civil de Guadalajara “Fray Antonio Alcalde” (Reg. No. 037/16) approved this study.

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Reyes-Pérez, I.V., Sánchez-Hernández, P.E., Muñoz-Valle, J.F. et al. Cytokines (IL-15, IL-21, and IFN-γ) in rheumatoid arthritis: association with positivity to autoantibodies (RF, anti-CCP, anti-MCV, and anti-PADI4) and clinical activity. Clin Rheumatol 38, 3061–3071 (2019). https://doi.org/10.1007/s10067-019-04681-4

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