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 very 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.
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 .
The 2012 report by the Institute of Medicine (IOM) , 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 ; one study assessing the association between hepatitis B vaccination and exacerbation of rheumatoid arthritis ; 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 .
Most studies published since the 2012 IOM report did not show a statistically significant association between influenza and HPV vaccines and arthralgia [19-22]. One 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 , and another 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 . 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].
Proposed Biological Mechanism
Environmental factors such as infections may trigger or contribute to the pathogenesis of arthritis; however, the exact mechanisms are still unclear [37-40].
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, 41-43]; however, there was less evidence for a relationship between rubella vaccine in women and chronic arthralgia [43-45] or arthritis [42, 45]. There was little evidence for a relationship between rubella vaccine and arthropathy in men, transient arthralgia in children or chronic arthropathy in children [46, 47], for influenza vaccine and onset or exacerbation of arthropathy , or for hepatitis B vaccine and onset or exacerbation of arthritis [49, 50]. The IOM also concluded that there was no mechanistic evidence for an association between all other vaccines and arthralgia, arthritis or arthropathy.
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, et al. HLA-DR class II associations with rubella vaccine-induced joint manifestations. The Journal of infectious diseases 1998;177:5-12.
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;13:1529-32.
5. Ray P, Black S, Shinefield H, et al. Risk of chronic arthropathy among women after rubella vaccination. Vaccine Safety Datalink Team. Jama 1997;278:551-6.
6. Tingle AJ, Mitchell LA, Grace M, et al. Randomised double-blind placebo-controlled study on adverse effects of rubella immunisation in seronegative women. Lancet 1997;349:1277-81.
7. Benjamin CM, Chew GC, Silman AJ. Joint and limb symptoms in children after immunisation with measles, mumps, and rubella vaccine. BMJ 1992;304:1075-8.
8. Davis RL, Marcuse E, Black S, et al. 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;100:767-71.
9. Dos Santos BA, Ranieri TS, Bercini M, et al. An evaluation of the adverse reaction potential of three measles-mumps-rubella combination vaccines. Rev Panam Salud Publica 2002;12:240-6.
10. Heijstek MW, Pileggi GC, Zonneveld-Huijssoon E, et al. Safety of measles, mumps and rubella vaccination in juvenile idiopathic arthritis. Ann Rheum Dis 2007;66:1384-7.
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;118:1422-30.
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;1:939-42.
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:E62.
14. Chen RT, Moses JM, Markowitz LE, Orenstein WA. Adverse events following measles-mumps-rubella and measles vaccinations in college students. Vaccine 1991;9:297-9.
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;67:672-6.
16. Bhatla N, Suri V, Basu P, et al. Immunogenicity and safety of human papillomavirus-16/18 AS04-adjuvanted cervical cancer vaccine in healthy Indian women. J Obstet Gynaecol Res 2010;36:123-32.
17. Elkayam O, Yaron M, Caspi D. Safety and efficacy of vaccination against hepatitis B in patients with rheumatoid arthritis. Ann Rheum Dis 2002;61:623-5.
18. Bengtsson C, Kapetanovic MC, Kallberg H, et al. Common vaccinations among adults do not increase the risk of developing rheumatoid arthritis: results from the Swedish EIRA study. Ann Rheum Dis 2010;69:1831-3.
19. Frey S, Vesikari T, Szymczakiewicz-Multanowska A, et al. 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;51:997-1004.
20. Jackson LA, Gaglani MJ, Keyserling HL, et al. 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, et al. 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;52:128-37.
22. Ngan HY, Cheung AN, Tam KF, et al. Human papillomavirus-16/18 AS04-adjuvanted cervical cancer vaccine: immunogenicity and safety in healthy Chinese women from Hong Kong. Hong Kong Med J 2010;16:171-9.
23. Barrett PN, Berezuk G, Fritsch S, et al. Efficacy, safety, and immunogenicity of a Vero-cell-culture-derived trivalent influenza vaccine: a multicentre, double-blind, randomised, placebo-controlled trial. Lancet 2011;377:751-9.
24. Kim SC, Song YS, Kim YT, et al. Human papillomavirus 16/18 AS04-adjuvanted cervical cancer vaccine: immunogenicity and safety in 15-25 years old healthy Korean women. J Gynecol Oncol 2011;22:67-75.
25. Chao C, Klein NP, Velicer CM, et al. Surveillance of autoimmune conditions following routine use of quadrivalent human papillomavirus vaccine. J Intern Med 2012;271:193-203.
26. Eder L, Law T, Chandran V, et al. Association between environmental factors and onset of psoriatic arthritis in patients with psoriasis. Arthritis Care Res (Hoboken) 2011;63:1091-7.
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, et al. A postmarketing evaluation of the safety of Ann Arbor strain live attenuated influenza vaccine in children 5 through 17 years of age. Vaccine 2012;30:2989-98.
29. Ray P, Black S, Shinefield H, et al. Risk of rheumatoid arthritis following vaccination with tetanus, influenza and hepatitis B vaccines among persons 15-59 years of age. Vaccine 2011;29:6592-7.
30. Aikawa NE, Campos LM, Silva CA, et al. Glucocorticoid: major factor for reduced immunogenicity of 2009 influenza A (H1N1) vaccine in patients with juvenile autoimmune rheumatic disease. The Journal of rheumatology 2012;39:167-73.
31. Gabay C, Bel M, Combescure C, et al. 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;63:1486-96.
32. Muller RB, Maier R, Hoschler K, et al. Efficient boosting of the antiviral T cell response in B cell-depleted patients with autoimmune rheumatic diseases following influenza vaccination. Clin Exp Rheumatol 2013;31:723-30.
33. Oren S, Mandelboim M, Braun-Moscovici Y, et al. Vaccination against influenza in patients with rheumatoid arthritis: the effect of rituximab on the humoral response. Ann Rheum Dis 2008;67:937-41.
34. Saad CG, Borba EF, Aikawa NE, et al. Immunogenicity and safety of the 2009 non-adjuvanted influenza A/H1N1 vaccine in a large cohort of autoimmune rheumatic diseases. Ann Rheum Dis 2011;70:1068-73.
35. Shinoki T, Hara R, Kaneko U, et al. Safety and response to influenza vaccine in patients with systemic-onset juvenile idiopathic arthritis receiving tocilizumab. Mod Rheumatol 2012;22:871-6.
36. Toplak N, Subelj V, Kveder T, et al. Safety and efficacy of influenza vaccination in a prospective longitudinal study of 31 children with juvenile idiopathic arthritis. Clin Exp Rheumatol 2012;30:436-44.
37. Angeles-Han S, Prahalad S. The genetics of juvenile idiopathic arthritis: what is new in 2010? Curr Rheumatol Rep 2010;12:87-93.
38. Berkun Y, Padeh S. Environmental factors and the geoepidemiology of juvenile idiopathic arthritis. Autoimmun Rev 2010;9:A319-24.
39. Aslan M, Kasapcopur O, Yasar H, et al. Do infections trigger juvenile idiopathic arthritis? Rheumatol Int 2011;31:215-20.
40. 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;22:287-94.
41. Best JM, Banatvala JE, Bowen JM. New Japanese rubella vaccine: comparative trials. Br Med J 1974;3:221-4.
42. 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;40:22-8.
43. 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;27:418-23.
44. Mitchell LA, Tingle AJ, Shukin R, Sangeorzan JA, McCune J, Braun DK. Chronic rubella vaccine-associated arthropathy. Arch Intern Med 1993;153:2268-74.
45. 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;152:606-12.
46. 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;47:442-4.
47. Peters ME, Horowitz S. Bone changes after rubella vaccination. AJR Am J Roentgenol 1984;143:27-8.
48. 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;36:120-3.
49. Biasi D, De Sandre G, Bambara LM, et al. A new case of reactive arthritis after hepatitis B vaccination. Clin Exp Rheumatol 1993;11:215.
50. Maillefert JF, Sibilia J, Toussirot E, et al. Rheumatic disorders developed after hepatitis B vaccination. Rheumatology (Oxford) 1999;38:978-83.