Conclusion
Infections may trigger or contribute to the pathogenesis of arthritis. Thus, vaccines may prevent arthritis by protecting against natural infections. Rubella-containing vaccines (e.g. MMR) can cause mild, acute, transient arthralgia or arthritis, rarely in children but commonly in certain adult women (between 10-25% of adult female vaccinees without preexisting rubella immunity), usually beginning 1-3 weeks after vaccination and then persisting up to 3 weeks. Other vaccines currently routinely recommended to the general population in the U.S.* have not been shown to cause chronic arthralgia or arthritis.
Epidemiological Evidence
Mild, acute, transient arthralgia occurs in approximately 25% of adult women without preexisting rubella immunity after rubella vaccination, and mild, acute, transient arthritis occurs in approximately 10%, usually beginning 1-3 weeks after vaccination and then persisting up to 3 weeks. Both are less common in men and rare in children 1.
The 2012 report by the Institute of Medicine (IOM) 2, now called the National Academy of Medicine (NAM), described four studies in women 3-6 and seven studies in children 7-13 that generally reported an increased risk of transient arthralgia after rubella or MMR vaccination. Also described are two studies assessing chronic arthralgia and arthritis in women 5,6 and two studies assessing arthropathy in men 14,15 after rubella or MMR vaccination; one study assessing the association between HPV vaccine and transient arthralgia 16; one study assessing the association between hepatitis B vaccination and exacerbation of rheumatoid arthritis 17; and two studies assessing the association between diphtheria or tetanus toxoid vaccination and chronic arthritis 15,18; however, these studies did not provide convincing evidence due to a lack of validity and precision. The IOM found no relevant studies of quality in the literature providing evidence of an association between any other vaccines and chronic arthropathy 2.
Most studies published since the 2012 IOM report did not show a statistically significant association between influenza and HPV vaccines and arthralgia 19-22. A 2011 study found a relative risk of arthralgia of 2.0 (95% CI: 1.6-2.5) after receipt of a vero-cell culture-derived trivalent influenza vaccine 23, and another 2011 study found an odds ratio of grade 3 arthralgias of 2.68 (95% CI: 1.29-5.59) after receipt of the AS04-adjuvanted HPV-16/18 vaccine (Cervarix®) among women in Korea 24. No association has been found between vaccination and arthritis 25-29.
Studies in patients with autoimmune inflammatory arthritis showed no change in disease severity or relapse rates after influenza vaccination 30-36. A 2017 South Korean nationwide cohort study found no associations between HPV vaccination and 33 predefined serious adverse events (including arthritis) 37. A 2019 case-crossover study found vaccination associated with double the odds of gout flares among gout patients (95% CI: 1.01-3.89) 38. A 2019 self-controlled case series analysis among people with autoimmune rheumatic diseases in the UK found no association between influenza vaccination and rheumatoid arthritis flares 39. A 2019 systematic review concluded that the current evidence is too heterogeneous and incomplete to infer a causal association between vaccination and incident arthritis or worsening of arthritic conditions 40. A 2020 systematic review and meta-analysis found no association between HPV vaccines and many autoimmune or other rare diseases (including rheumatoid arthritis) 41.
Proposed Biological Mechanism
Environmental factors such as infections may trigger or contribute to the pathogenesis of arthritis; however, the exact mechanisms are still unclear 42-45.
Based on both cases reviewed and knowledge about the natural infection, the IOM concluded that there was some mechanistic evidence in support of a causal relationship between rubella vaccine in women and arthralgia 3,46-48; however, there was less evidence for a relationship between rubella vaccine in women and chronic arthralgia 48-50 or arthritis 47,50. There was little evidence for a relationship between rubella vaccine and arthropathy in men, transient arthralgia in children or chronic arthropathy in children 51,52, for influenza vaccine and onset or exacerbation of arthropathy 53, or for hepatitis B vaccine and onset or exacerbation of arthritis 54,55. The IOM also concluded that there was no mechanistic evidence for an association between all other vaccines and arthralgia, arthritis or arthropathy.
* These conclusions do not necessarily consider vaccines recommended only for special populations in the United States such as Yellow Fever vaccine (international travelers) or Smallpox vaccine (military personnel), or vaccines no longer recommended to the public such as the Janssen (J&J) COVID-19 vaccine.
References
1. Epidemiology and Prevention of Vaccine-Preventable Diseases. Washington D.C.: Centers for Disease Control and Prevention, 2015.
2. Institute of Medicine. In: Stratton K, Ford A, Rusch E, Clayton EW, eds. Adverse Effects of Vaccines: Evidence and Causality. Washington (DC): National Academies Press (US); 2012.
3. Mitchell LA, Tingle AJ, MacWilliam L, Horne C, Keown P, Gaur LK, Nepom GT. HLA-DR class II associations with rubella vaccine-induced joint manifestations. The Journal of infectious diseases 1998; 177(1): 5-12.
4. Slater PE, Ben-Zvi T, Fogel A, Ehrenfeld M, Ever-Hadani S. Absence of an association between rubella vaccination and arthritis in underimmune postpartum women. Vaccine 1995; 13(16): 1529-32.
5. Ray P, Black S, Shinefield H, Dillon A, Schwalbe J, Holmes S, Hadler S, Chen R, Cochi S, Wassilak S. Risk of chronic arthropathy among women after rubella vaccination. Vaccine Safety Datalink Team. Jama 1997; 278(7): 551-6.
6. Tingle AJ, Mitchell LA, Grace M, Middleton P, Mathias R, MacWilliam L, Chalmers A. Randomised double-blind placebo-controlled study on adverse effects of rubella immunisation in seronegative women. Lancet 1997; 349(9061): 1277-81.
7. Benjamin CM, Chew GC, Silman AJ. Joint and limb symptoms in children after immunisation with measles, mumps, and rubella vaccine. BMJ 1992; 304(6834): 1075-8.
8. Davis RL, Marcuse E, Black S, Shinefield H, Givens B, Schwalbe J, Ray P, Thompson RS, Chen R. MMR2 immunization at 4 to 5 years and 10 to 12 years of age: a comparison of adverse clinical events after immunization in the Vaccine Safety Datalink project. The Vaccine Safety Datalink Team. Pediatrics 1997; 100(5): 767-71.
9. Dos Santos BA, Ranieri TS, Bercini M, Schermann MT, Famer S, Mohrdieck R, Maraskin T, Wagner MB. An evaluation of the adverse reaction potential of three measles-mumps-rubella combination vaccines. Rev Panam Salud Publica 2002; 12(4): 240-6.
10. Heijstek MW, Pileggi GC, Zonneveld-Huijssoon E, Armbrust W, Hoppenreijs EP, Uiterwaal CS, Kuis W, Wulffraat NM. Safety of measles, mumps and rubella vaccination in juvenile idiopathic arthritis. Ann Rheum Dis 2007; 66(10): 1384-7.
11. LeBaron CW, Bi D, Sullivan BJ, Beck C, Gargiullo P. Evaluation of potentially common adverse events associated with the first and second doses of measles-mumps-rubella vaccine. Pediatrics 2006; 118(4): 1422-30.
12. Peltola H, Heinonen OP. Frequency of true adverse reactions to measles-mumps-rubella vaccine. A double-blind placebo-controlled trial in twins. Lancet 1986; 1(8487): 939-42.
13. Virtanen M, Peltola H, Paunio M, Heinonen OP. Day-to-day reactogenicity and the healthy vaccinee effect of measles-mumps-rubella vaccination. Pediatrics 2000; 106(5): E62.
14. Chen RT, Moses JM, Markowitz LE, Orenstein WA. Adverse events following measles-mumps-rubella and measles vaccinations in college students. Vaccine 1991; 9(5): 297-9.
15. Pattison E, Harrison BJ, Griffiths CE, Silman AJ, Bruce IN. Environmental risk factors for the development of psoriatic arthritis: results from a case-control study. Ann Rheum Dis 2008; 67(5): 672-6.
16. Bhatla N, Suri V, Basu P, Shastri S, Datta SK, Bi D, Descamps DJ, Bock HL. Immunogenicity and safety of human papillomavirus-16/18 AS04-adjuvanted cervical cancer vaccine in healthy Indian women. J Obstet Gynaecol Res 2010; 36(1): 123-32.
17. Elkayam O, Yaron M, Caspi D. Safety and efficacy of vaccination against hepatitis B in patients with rheumatoid arthritis. Ann Rheum Dis 2002; 61(7): 623-5.
18. Bengtsson C, Kapetanovic MC, Kallberg H, Sverdrup B, Nordmark B, Klareskog L, Alfredsson L. Common vaccinations among adults do not increase the risk of developing rheumatoid arthritis: results from the Swedish EIRA study. Ann Rheum Dis 2010; 69(10): 1831-3.
19. Frey S, Vesikari T, Szymczakiewicz-Multanowska A, Lattanzi M, Izu A, Groth N, Holmes S. Clinical efficacy of cell culture-derived and egg-derived inactivated subunit influenza vaccines in healthy adults. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 2010; 51(9): 997-1004.
20. Jackson LA, Gaglani MJ, Keyserling HL, Balser J, Bouveret N, Fries L, Treanor JJ. Safety, efficacy, and immunogenicity of an inactivated influenza vaccine in healthy adults: a randomized, placebo-controlled trial over two influenza seasons. BMC Infect Dis 2010; 10: 71.
21. Madhi SA, Maskew M, Koen A, Kuwanda L, Besselaar TG, Naidoo D, Cohen C, Valette M, Cutland CL, Sanne I. Trivalent inactivated influenza vaccine in African adults infected with human immunodeficient virus: double blind, randomized clinical trial of efficacy, immunogenicity, and safety. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 2011; 52(1): 128-37.
22. Ngan HY, Cheung AN, Tam KF, Chan KK, Tang HW, Bi D, Descamps D, Bock HL. Human papillomavirus-16/18 AS04-adjuvanted cervical cancer vaccine: immunogenicity and safety in healthy Chinese women from Hong Kong. Hong Kong Med J 2010; 16(3): 171-9.
23. Barrett PN, Berezuk G, Fritsch S, Aichinger G, Hart MK, El-Amin W, Kistner O, Ehrlich HJ. Efficacy, safety, and immunogenicity of a Vero-cell-culture-derived trivalent influenza vaccine: a multicentre, double-blind, randomised, placebo-controlled trial. Lancet 2011; 377(9767): 751-9.
24. Kim SC, Song YS, Kim YT, Kim YT, Ryu KS, Gunapalaiah B, Bi D, Bock HL, Park JS. Human papillomavirus 16/18 AS04-adjuvanted cervical cancer vaccine: immunogenicity and safety in 15-25 years old healthy Korean women. J Gynecol Oncol 2011; 22(2): 67-75.
25. Chao C, Klein NP, Velicer CM, Sy LS, Slezak JM, Takhar H, Ackerson B, Cheetham TC, Hansen J, Deosaransingh K, Emery M, Liaw KL, Jacobsen SJ. Surveillance of autoimmune conditions following routine use of quadrivalent human papillomavirus vaccine. J Intern Med 2012; 271(2): 193-203.
26. Eder L, Law T, Chandran V, Shanmugarajah S, Shen H, Rosen CF, Cook RJ, Gladman DD. Association between environmental factors and onset of psoriatic arthritis in patients with psoriasis. Arthritis Care Res (Hoboken) 2011; 63(8): 1091-7.
27. Bardage C, Persson I, Ortqvist A, Bergman U, Ludvigsson JF, Granath F. Neurological and autoimmune disorders after vaccination against pandemic influenza A (H1N1) with a monovalent adjuvanted vaccine: population based cohort study in Stockholm, Sweden. Bmj 2011; 343: d5956.
28. Baxter R, Toback SL, Sifakis F, Hansen J, Bartlett J, Aukes L, Lewis N, Wu X, Ambrose CS. A postmarketing evaluation of the safety of Ann Arbor strain live attenuated influenza vaccine in children 5 through 17 years of age. Vaccine 2012; 30(19): 2989-98.
29. Ray P, Black S, Shinefield H, Dillon A, Carpenter D, Lewis E, Ross P, Chen RT, Klein NP, Baxter R. Risk of rheumatoid arthritis following vaccination with tetanus, influenza and hepatitis B vaccines among persons 15-59 years of age. Vaccine 2011; 29(38): 6592-7.
30. Aikawa NE, Campos LM, Silva CA, Carvalho JF, Saad CG, Trudes G, Duarte A, Miraglia JL, Timenetsky Mdo C, Viana VS, Franca IL, Bonfa E, Pereira RM. Glucocorticoid: major factor for reduced immunogenicity of 2009 influenza A (H1N1) vaccine in patients with juvenile autoimmune rheumatic disease. The Journal of rheumatology 2012; 39(1): 167-73.
31. Gabay C, Bel M, Combescure C, Ribi C, Meier S, Posfay-Barbe K, Grillet S, Seebach JD, Kaiser L, Wunderli W, Guerne PA, Siegrist CA. Impact of synthetic and biologic disease-modifying antirheumatic drugs on antibody responses to the AS03-adjuvanted pandemic influenza vaccine: a prospective, open-label, parallel-cohort, single-center study. Arthritis Rheum 2011; 63(6): 1486-96.
32. Muller RB, Maier R, Hoschler K, Zambon M, Ludewig B, Herrmann M, Schulze-Koops H, von Kempis J. Efficient boosting of the antiviral T cell response in B cell-depleted patients with autoimmune rheumatic diseases following influenza vaccination. Clin Exp Rheumatol 2013; 31(5): 723-30.
33. Oren S, Mandelboim M, Braun-Moscovici Y, Paran D, Ablin J, Litinsky I, Comaneshter D, Levartovsky D, Mendelson E, Azar R, Wigler I, Balbir-Gurman A, Caspi D, Elkayam O. Vaccination against influenza in patients with rheumatoid arthritis: the effect of rituximab on the humoral response. Ann Rheum Dis 2008; 67(7): 937-41.
34. Saad CG, Borba EF, Aikawa NE, Silva CA, Pereira RM, Calich AL, Moraes JC, Ribeiro AC, Viana VS, Pasoto SG, Carvalho JF, Franca IL, Guedes LK, Shinjo SK, Sampaio-Barros PD, Caleiro MT, Goncalves CR, Fuller R, Levy-Neto M, Timenetsky Mdo C, Precioso AR, Bonfa E. Immunogenicity and safety of the 2009 non-adjuvanted influenza A/H1N1 vaccine in a large cohort of autoimmune rheumatic diseases. Ann Rheum Dis 2011; 70(6): 1068-73.
35. Shinoki T, Hara R, Kaneko U, Miyamae T, Imagawa T, Mori M, Yokota S. Safety and response to influenza vaccine in patients with systemic-onset juvenile idiopathic arthritis receiving tocilizumab. Mod Rheumatol 2012; 22(6): 871-6.
36. Toplak N, Subelj V, Kveder T, Cucnik S, Prosenc K, Trampus-Bakija A, Todorovski L, Avcin T. Safety and efficacy of influenza vaccination in a prospective longitudinal study of 31 children with juvenile idiopathic arthritis. Clin Exp Rheumatol 2012; 30(3): 436-44.
37. Yoon D, Lee JH, Lee H, Shin JY. Association between human papillomavirus vaccination and serious adverse events in South Korean adolescent girls: nationwide cohort study. BMJ (Clinical research ed) 2021; 372: m4931.
38. Yokose C, McCormick N, Chen C, Neogi T, Chaisson C, Terkeltaub R, Hunter DJ, Zhang Y, Choi H. Risk of gout flares after vaccination: a prospective case cross-over study. Annals of the rheumatic diseases 2019; 78(11): 1601-4.
39. Nakafero G, Grainge MJ, Myles PR, Mallen CD, Zhang W, Doherty M, Nguyen-Van-Tam JS, Abhishek A. Association between inactivated influenza vaccine and primary care consultations for autoimmune rheumatic disease flares: a self-controlled case series study using data from the Clinical Practice Research Datalink. Annals of the rheumatic diseases 2019; 78(8): 1122-6.
40. Panozzo CA, Pourmalek F, Brauchli Pernus Y, Pileggi GS, Woerner A, Bonhoeffer J. Arthritis and arthralgia as an adverse event following immunization: A systematic literature review. Vaccine 2019; 37(2): 372-83.
41. Willame C, Gadroen K, Bramer W, Weibel D, Sturkenboom M. Systematic Review and Meta-analysis of Postlicensure Observational Studies on Human Papillomavirus Vaccination and Autoimmune and Other Rare Adverse Events. The Pediatric infectious disease journal 2020; 39(4): 287-93.
42. Angeles-Han S, Prahalad S. The genetics of juvenile idiopathic arthritis: what is new in 2010? Curr Rheumatol Rep 2010; 12(2): 87-93.
43. Berkun Y, Padeh S. Environmental factors and the geoepidemiology of juvenile idiopathic arthritis. Autoimmun Rev 2010; 9(5): A319-24.
44. Aslan M, Kasapcopur O, Yasar H, Polat E, Saribas S, Cakan H, Dirican A, Torun MM, Arisoy N, Kocazeybek B. Do infections trigger juvenile idiopathic arthritis? Rheumatol Int 2011; 31(2): 215-20.
45. Frenkel LM, Nielsen K, Garakian A, Jin R, Wolinsky JS, Cherry JD. A search for persistent rubella virus infection in persons with chronic symptoms after rubella and rubella immunization and in patients with juvenile rheumatoid arthritis. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 1996; 22(2): 287-94.
46. Best JM, Banatvala JE, Bowen JM. New Japanese rubella vaccine: comparative trials. Br Med J 1974; 3(5925): 221-4.
47. Tingle AJ, Yang T, Allen M, Kettyls GD, Larke RP, Schulzer M. Prospective immunological assessment of arthritis induced by rubella vaccine. Infection and immunity 1983; 40(1): 22-8.
48. Mitchell LA, Tingle AJ, Grace M, Middleton P, Chalmers AC. Rubella virus vaccine associated arthropathy in postpartum immunized women: influence of preimmunization serologic status on development of joint manifestations. The Journal of rheumatology 2000; 27(2): 418-23.
49. Mitchell LA, Tingle AJ, Shukin R, Sangeorzan JA, McCune J, Braun DK. Chronic rubella vaccine-associated arthropathy. Arch Intern Med 1993; 153(19): 2268-74.
50. Tingle AJ, Chantler JK, Pot KH, Paty DW, Ford DK. Postpartum rubella immunization: association with development of prolonged arthritis, neurological sequelae, and chronic rubella viremia. J Infect Dis 1985; 152(3): 606-12.
51. Geiger R, Fink FM, Solder B, Sailer M, Enders G. Persistent rubella infection after erroneous vaccination in an immunocompromised patient with acute lymphoblastic leukemia in remission. J Med Virol 1995; 47(4): 442-4.
52. Peters ME, Horowitz S. Bone changes after rubella vaccination. AJR Am J Roentgenol 1984; 143(1): 27-8.
53. Thurairajan G, Hope-Ross MW, Situnayake RD, Murray PI. Polyarthropathy, orbital myositis and posterior scleritis: an unusual adverse reaction to influenza vaccine. Br J Rheumatol 1997; 36(1): 120-3.
54. Biasi D, De Sandre G, Bambara LM, Carletto A, Caramaschi P, Zanoni G, Tridente G. A new case of reactive arthritis after hepatitis B vaccination. Clin Exp Rheumatol 1993; 11(2): 215.
55. Maillefert JF, Sibilia J, Toussirot E, Vignon E, Eschard JP, Lorcerie B, Juvin R, Parchin-Geneste N, Piroth C, Wendling D, Kuntz JL, Tavernier C, Gaudin P. Rheumatic disorders developed after hepatitis B vaccination. Rheumatology (Oxford) 1999; 38(10): 978-83.
