Does methotrexate increase the risk of varicella or herpes zoster infection in patients with rheumatoid arthritis? A systematic literature review

Clin Exp Rheumatol. 2012 Nov-Dec;30(6):962-71. Epub 2012 Dec 17.


Objectives: Methotrexate (MTX) has become the foundation disease-modifying anti-rheumatic drug (DMARD) for RA. However, concern exists regarding its possible association with infectious complications including varicella zoster virus (VZV) and herpes zoster (HZ). Furthermore, no consensus exists regarding pre-MTX VZV screening or the use of VZV vaccine.

Methods: We undertook systematic literature review (SLR) investigating the relationship between the use of MTX in patients with RA and VZV and HZ infection. Additionally, the European Centre for Disease Prevention and Control, HPA, the CDC, Rheumatology societies and WHO web sites and publications were consulted.

Results: Thirty-five studies fulfilled the inclusion criteria comprising 29 observational studies and 6 case reports. The case reports and 13 observation studies considered the association between MTX and HZ. Three of the observational studies reported a positive association although in 5 cases, patients were concurrently treated with prednisolone. Five studies concluded that there was no association between HZ and MTX. Three studies comparing the infection rates of MTX with other RA therapies found that MTX did not result in higher HZ infection rates. Three studies examining the association between HZ and MTX treatment duration failed to show a link.

Conclusions: No evidence exists to support an association between MTX and VZV infection in RA patients and the data regarding the role of MTX in HZ development is conflicting. The role of pre-MTX VZV screening is controversial and, as it may delay initiation of RA treatment, we suggest against VZV screening in this context.

Publication types

  • Review
  • Systematic Review

MeSH terms

  • Adult
  • Aged
  • Antirheumatic Agents / adverse effects*
  • Arthritis, Rheumatoid / drug therapy*
  • Chickenpox / chemically induced*
  • Chickenpox / diagnosis
  • Chickenpox / virology
  • Herpes Zoster / chemically induced*
  • Herpes Zoster / diagnosis
  • Herpes Zoster / virology
  • Humans
  • Methotrexate / adverse effects*
  • Middle Aged
  • Risk Assessment
  • Risk Factors


  • Antirheumatic Agents
  • Methotrexate