Cellular immune response to pneumococcal vaccination in patients with rheumatoid arthritis receiving methotrexate and rituximab (Literature review)
https://doi.org/10.34215/1609-1175-2026-2-33-40
Abstract
Patients with rheumatoid arthritis (RA) are at an increased risk for invasive pneumococcal infections due to immune system characteristics related to the disease and its treatment. Treatment options include disease-modifying antirheumatic drugs, such as methotrexate (MTX), and anti-B-cell therapy drugs, such as rituximab (RTX). Therefore, vaccination holds significant preventive value. Previous studies indicate that RTX impairs the cellular and humoral response to PPV23 in patients with RA. In RA patients, MTX led to decreased vaccine-specific antibody response and functionality, reduced Th17 cell numbers, and blocked plasma cell activation and switched memory B cell activation following PCV13 administration. Due to its ability to suppress peripheral blood monocyte concentration, MTX may serve as a biomarker for identifying RA patients who will be resistant to PKV13.
About the Authors
A. D. Shmitko
I. Mechnikov Scientific Research Institute of Vaccines and Serums
Russian Federation
Russian Federation
Anna D. Shmitko - Cand. Sci. (Med.), Senior Research, Laboratory of Vaccination and Immunotherapy of Allergic Diseases.
5A Maly Kazenny per., Moscow 105064
A. A. Tarasova
Privolzhsky Research Medical University
Russian Federation
Russian Federation
Nizhny Novgorod
B. Ts. Batozhargalova
I. Mechnikov Scientific Research Institute of Vaccines and Serums
Russian Federation
Russian Federation
Moscow
M. P. Kostinov
I. Mechnikov Scientific Research Institute of Vaccines and Serums; I.M. Sechenov First Moscow State Medical University
Russian Federation
Russian Federation
Moscow
References
1. Plotkin SA. Recent updates on correlates of vaccine-induced protection. Front. Immunol. 2023;13:1081107. doi: 10.3389/fimmu.2022.1081107
2. Chuchalin AG, Briko NI, Avdeev SN, Belevskiy AS, Bilichenko TN, Demko IV et al. Federal clinical guidelines on preventive vaccination against pneumococcal infections in adults. Pul`monologiya. 2019;29(1):19–34 (In Russ.). doi: 10.18093/0869-0189-2019-29-1-19-34
3. Baranov AA, Namazova-Baranova LS, Brico NI, Lobzin YuV, Коzlov RS, Kostinov MP et al. Vaccine prevention of pneumococcal infection in children. Pediatric Pharmacology. 2018;15(3):200–211 (In Russ.). doi: 10.15690/pf.v15i3.1899
4. Peset Llopis MJ, Harms G, Hardonk MJ, Timens W. Human immune response to pneumococcal polysaccharides: complementmediated localization preferentially on CD21-positive splenic marginal zone B cells and follicular dendritic cells. J. Allergy Clin. Immunol. 1996;97(4):1015–1024. doi: 10.1016/s00916749(96)80078-9
5. Pollard AJ, Perrett KP, Beverley PC. Maintaining protection against invasive bacteria with protein-polysaccharide conjugate vaccines. Nat. Rev. Immunol. 2009;9(3):213–220. doi: 10.1038/nri2494
6. Yoshida T, Mei H, Dörner T, Hiepe F, Radbruch A, Fillatreau S, Hoyer BF. Memory B and memory plasma cells. Immunol. Rev. 2010;237:117–139. doi: 10.1111/j.1600-065X.2010.00938.x
7. Clutterbuck EA, Lazarus R, Yu L, Bowman J, Bateman EAL, Diggle L et al. Pneumococcal conjugate and plain polysaccharide vaccines have divergent effects on antigen-specific B cells. J. Infect. Dis. 2012;205(9):1408–1416. doi: 10.1093/infdis/jis212
8. Kostinov MP, Protasov AD, Zhestkov AV, Shteyner ML, Tezikov YuV., Lipatov IS. The effect of different regimens of vaccination against pneumococcal infection on the clinical course of chronic obstructive pulmonary disease: Focus on changes in sputum microorganism population. Tuberculosis and Lung Diseases. 2021;99(7):7–17 (In Russ.). doi: 10.21292/2075-1230-2021-99-7-7-17
9. Protasov AD, Kostinov MP, Zhestkov AV, Shteyner ML, Magarshak OO, Kostinova TA et al. Choice of optimal vaccination tactics against pneumococcal infection from immunological and clinical standpoints in patients with chronic obstructive pulmonary disease. Therapeutic Archive. 2016;88(5):62–69. (In Russ.). doi: 10.17116/terarkh201688562-69
10. Kostinov AM, Kostinov MP. Susceptibility of people vaccinated against S. pneumoniae to SARS-CoV-2 – mechanisms of nonspecific action of pneumococcal vaccine. Pediatrics. Journal named after G.N. Speransky. 2020;99(6):183–189 (In Russ.). doi: 10.24110/0031-403X-2020-99-6-183-189
11. Kostinov AM, Konishcheva AY, Protasov AD, Kostinov MP, Polishchuk VB, Zhestkov AV et al. Specific Features of Immune Response in Patients with Different Asthma Endotypes Following Immunization with a Conjugate Pneumococcal Vaccine. Vaccines. 2025;13:459. doi: 10.3390/vaccines13050459
12. Pollard AJ, Bijker EM. A guide to vaccinology: from basic principles to new developments. Nat. Rev. Immunol. 2021;21(2):83–100. doi: 10.1038/s41577-020-00479-7
13. Malley R, Trzcinski K, Srivastava A, Thompson CM, Anderson PW, Lipsitch M. CD4+ T cells mediate antibody-independent acquired immunity to pneumococcal colonization. Proc. Natl. Acad. Sci. USA. 2005;102(13):4848–4853. doi: 10.1073/pnas.0501254102
14. Backhaus E, Berg S, Andersson R, Ockborn G, Malmström P, Dahl M et al. Epidemiology of invasive pneumococcal infections: manifestations, incidence and case fatality rate correlated to age, gender and risk factors. BMC Infect. Dis. 2016;16:367. doi: 10.1186/s12879-016-1648-2
15. Shigayeva A, Rudnick W, Green K, Chen DK, Demczuk W, Gold WL et al. Toronto invasive bacterial diseases network. Invasive pneumococcal disease among immunocompromised persons: implications for vaccination programs. Clin. Infect. Dis. 2016;62(2):139–147. doi: 10.1093/cid/civ803
16. Gupta P, Padhan P, Bhargava N, Behera PK, Tripathy KP, Panda SS. Spectrum of infections occurring in patients of autoimmune rheumatic diseases on treatment with biological versus conventional disease-modifying antirheumatic drugs: A comparative study. J. Family Med. Prim. Care. 2022;11(7):3575–3583. doi: 10.4103/jfmpc.jfmpc_2147_21
17. Rutherford AI, Subesinghe S, Hyrich KL, Galloway JB. Serious infection across biologic-treated patients with rheumatoid arthritis: results from the british society for rheumatology biologics register for rheumatoid arthritis. Ann. Rheum. Dis. 2018;77(6):905–910. doi: 10.1136/annrheumdis-2017-212825
18. Cecconi M, Ranza R, Titton DC, Moraes JCB, Bertolo M, Bianchi W et al. Incidence of infectious adverse events in patients with rheumatoid arthritis and spondyloarthritis on biologic drugs-data from the Brazilian registry for biologics monitoring. J. Clin. Rheumatol. 2020;26(2):73–78. doi: 10.1097/RHU.0000000000000935
19. Cronstein BN, Aune TM. Methotrexate and its mechanisms of action in inflammatory arthritis. Nat. Rev. Rheumatol. 2020;16(3):145-54. doi: 10.1038/s41584-020-0373-9
20. Wessels JA, Huizinga TW, Guchelaar HJ. Recent insights in the pharmacological actions of methotrexate in the treatment of rheumatoid arthritis. Rheumatology (Oxford). 2008;47:249–255. doi: 10.1093/rheumatology/kem279
21. Cribbs AP, Kennedy A, Penn H, Amjadi P, Green P, Read JE et al. Methotrexate restores regulatory T cell function through demethylation of the foxP3 upstream enhancer in patients with rheumatoid arthritis. Arthritis Rheumatol. 2015;67:1182– 1192. doi: 10.1002/art.39031
22. Glaesener S, Quách TD, Onken N, Weller-Heinemann F, Dressler F, Huppertz HI et al. Distinct effects of methotrexate and etanercept on the B cell compartment in juvenile idiopathic arthritis. Arthritis Rheumatol. 2014;66:2590–2600. doi: 10.1002/art.38736
23. Kapetanovic MC, Saxne T, Sjöholm A, Truedsson L, Jönsson G, Geborek P. Influence of methotrexate, TNF-blocker and prednisolone on antibody responses to pneumococcal polysacharide vaccine in patients with rheumatoid arthritis. Rheumatology. 2006;45:106–111. doi: 10.1093/rheumatology/kei193
24. Shi Y, Wu Y, Ren Y, Jiang Y, Chen Y. Infection risks of rituximab versus non-rituximab treatment for rheumatoid arthritis: A systematic review and meta-analysis. Int. J. Rheum. Dis. 2019;22(8):1361–1370. doi: 10.1111/1756-185X.13596
25. Fraenkel L, Bathon JM, England BR, St. Clair EW, Arayssi T, Carandang K et al. 2021 American college of rheumatology guideline for the treatment of rheumatoid arthritis. Arthritis Rheumatol. 2021;73(7):1108–1123. doi: 10.1002/art.41752
26. Stashenko P, Nadler LM, Hardy R, Schlossman SF. Characterization of a human B lymphocyte-specific antigen. J. Immunol. 1980;125(4):1678–1685.
27. DiLillo DJ, Hamaguchi Y, Ueda Y, Yang K, Uchida J, Haas KM et al. Maintenance of long-lived plasma cells and serological memory despite mature and memory B cell depletion during CD20 immunotherapy in mice. J. Immunol. 2008;180:361–371. doi: 10.4049/jimmunol.180.1.361
28. Belov BS, Tarasova GM, Murav'eva NV. Vaccination in rheumatology (the 2019 update of EULAR recommendations). Rheumatology Science and Practice. 2019;57(6):618–625 (In Russ.). doi: 10.14412/1995-4484-2019-618-625
29. Furer V, Rondaan C, Heijstek MW, van Assen S, Marc Bijl M, Agmon-Levin N et al. Incidence and prevalence of vaccine preventable infections in adult patients with autoimmune inflammatory rheumatic diseases (AIIRD): a systemic literature review informing the 2019 update of the EULAR recommendations for vaccination in adult patients with AIIRD. RMD Open 2019;5(2):e001041. doi: 10.1136/rmdopen-2019-001041
30. Bass AR, Chakravarty E, Akl EA, Bingham CO, Calabrese L, Cappelli LC, Johnson SR et al. 2022 American college of rheumatology guideline for vaccinations in patients with rheumatic and musculoskeletal diseases. Arthritis Care Res. (Hoboken). 2023. doi: 10.1002/acr.25045
31. Kapetanovic MC, Nagel J, Nordström I, Saxne T, Geborek P, Rudin A. Methotrexate reduces vaccine-specific immunoglobulin levels but not numbers of circulating antibody-producing B cells in rheumatoid arthritis after vaccination with a conjugate pneumococcal vaccine. Vaccine. 2017;35(6):903–908. doi: 10.1016/j.vaccine.2016.12.068
32. Nived P, Pettersson Å, Jönsson G, Bengtsson A, Settergren B, Skattum L et al. Methotrexate reduces circulating Th17 cells and impairs plasmablast and memory B cell expansions following pneumococcal conjugate immunization in RA patients. Sci. Rep. 2021;11(1):9199. doi: 10.1038/s41598-021-88491-2
33. Schaerli P, Willimann K, Lang AB, Lipp M, Loetscher P, Moser B. CXC chemokine receptor 5 expression defines follicular homing T cells with B cell helper function. J. Exp. Med. 2000;192(11):1553–1562. doi: 10.1084/jem.192.11.1553
34. Morita R, Schmitt N, Bentebibel S, Ranganathan R, Bourdery L, Zurawski G et al. Human blood CXCR5(+)CD4(+) T cells are counterparts of T follicular cells and contain specific subsets that differentially support antibody secretion. Immunity. 2011;34(1):108–121. doi: 10.1016/j.immuni.2010.12.012
35. Locci M, Havenar-Daughton C, Landais E, Wu J, Kroenke MA, Arlehamn CL et al. Human circulating PD-1+CXCR3-CXCR5+ memory Tfh cells are highly functional and correlate with broadly neutralizing HIV antibody responses. Immunity. 2013;39(4):758–769. doi: 10.1016/j.immuni.2013.08.031
36. Elmér E, Nived P, Pettersson A, Skattum L, Hellmark T, Kapetanovic MC, Johansson ACM. Methotrexate treatment suppresses monocytes in nonresponders to pneumococcal conjugate vaccine in rheumatoid arthritis patients. J. Immunol. Res. 2022;2022:7561661. doi: 10.1155/2022/7561661
37. Zisapel M, Daphna Paran D, Elkayam O. Rituximab in rheumatoid arthritis – therapeutic aspects based on 18 years of global experience. Harefuah. 2019;158(9):595–600.
38. Hua C, Barnetche T, Combe B, Morel J. Effect of methotrexate, anti-tumor necrosis factor α, and rituximab on the immune response to influenza and pneumococcal vaccines in patients with rheumatoid arthritis: a systematic review and metaanalysis. Arthritis Care Res. (Hoboken). 2014;66(7):1016–1026. doi: 10.1002/acr.22246
39. Subesinghe S, Bechman K, Rutherford AI, Goldblatt D, Galloway JB. A systematic review and metaanalysis of antirheumatic drugs and vaccine immunogenicity in rheumatoid arthritis. J. Rheumatol. 2018;45(6):733–744. doi: 10.3899/jrheum.170710
40. Rehnberg M, Brisslert M, Amu S, Zendjanchi K, Håwi G, Bokarewa MI Vaccination response to protein and carbohydrate antigens in patients with rheumatoid arthritis after rituximab treatment. Arthritis Res. Ther. 2010;12(3):R111. doi: 10.1186/ar3047
41. Trollmo C, Sollerman C, Carlsten H, Tarkowski A. The gut as an inductive site for synovial and extra-articular immune responses in rheumatoid arthritis. Ann. Rheum. Dis. 1994;53:377–382. doi: 10.1136/ard.53.6.377
42. Bingham CO, Looney RJ, Deodhar A, Halsey N, Greenwald M, Codding C et al. Immunization responses in rheumatoid arthritis patients treated with rituximab: results from a controlled clinical trial. Arthritis Rheum. 2010;62(1):64–74. doi: 10.1002/art.25034
Review
For citations:
Shmitko A.D., Tarasova A.A., Batozhargalova B.Ts., Kostinov M.P. Cellular immune response to pneumococcal vaccination in patients with rheumatoid arthritis receiving methotrexate and rituximab (Literature review). Pacific Medical Journal. 2026;(2):33-40. (In Russ.) https://doi.org/10.34215/1609-1175-2026-2-33-40
Views:
38
JATS XML
Email this article 