Jump to comment:

• Herpes zoster infection risk in patients with rheumatoid arthritis on tumor necrosis factor inhibitors Prabha Ranganathan MD, MS
  PRABHA RANGANATHAN
  Published on: 12 February 2013
• TNF antagonists and Shingles: Is Vaccination Advisable?
  Muhammad K Nisar
  Published on: 7 February 2013

• Published on: 12 February 2013

  Herpes zoster infection risk in patients with rheumatoid arthritis on tumor necrosis factor inhibitors Prabha Ranganathan MD, MS

  • PRABHA RANGANATHAN, Associate Professor of Medicine

  Dear Editor,

  We read with interest the study conducted by Galloway and colleagues on the risk of skin and soft tissue infections (SSTI) and herpes zoster (HZ) in patients with rheumatoid arthritis (RA) treated with tumor necrosis factor (TNF) antagonists versus non-biologic disease-modifying anti-rheumatic drugs (nbDMARDs). (1) This study highlights the occurrence of common infections such as SSTI and more unco...

  Show More

  Dear Editor,

  We read with interest the study conducted by Galloway and colleagues on the risk of skin and soft tissue infections (SSTI) and herpes zoster (HZ) in patients with rheumatoid arthritis (RA) treated with tumor necrosis factor (TNF) antagonists versus non-biologic disease-modifying anti-rheumatic drugs (nbDMARDs). (1) This study highlights the occurrence of common infections such as SSTI and more uncommon infections such as HZ, when TNF antagonists and nbDMARDs are used in patients with RA with several existing co-morbidities. The study revealed that TNF antagonists increased the risk of HZ with an adjusted hazard ratio (HR) of 1.8 (95% confidence intervals [CI] 1.2-2.8) with the highest risk occurring with infliximab (HR of 2.2; 95% CI 1.4-3.4) and the lowest with adalimumab (HR of 1.5; 95% CI 1.1-2.0).

  We would like to draw attention to our own retrospective cohort study of 20,357 patients with RA assembled from the Department of Veterans Affairs (VA) national administrative databases in the United States. Our study demonstrated similar results to those of Galloway et al. (2) Patients with RA treated with medications such as methotrexate, leflunomide, azathioprine, cyclophosphamide and anakinra had a HR of 1.34 (95% CI 1.13-1.59) for an increased risk of HZ, while those treated with TNF antagonists such as etanercept, adalimumab and infliximab had a HR of 1.38 (95% CI 1.08-1.77) when compared to patients treated with hydroxychloroquine, oral or injectable gold, sulfasalazine or penicillamine (reference group). Among the TNF antagonists, we found a lower risk for HZ with use of etanercept (HR of 0.62; 95% CI 0.40-0.95) and adalimumab (HR of 0.53; 95% CI 0.31-0.91) compared to infliximab, again mirroring the results obtained by Galloway et al. Thus although the design and methodology of the two studies were quite different, the results were remarkably similar.

  Hence based on published literature to date, TNF antagonists in patients with RA appear to increase the risk of HZ. This may be particularly relevant in older patients, those on steroids and those with a history of prior malignancies, and chronic lung, liver and kidney disease as demonstrated in our study. (2) Rheumatologists should be aware of this risk when using these biologic agents in RA.

  References

  1. Galloway JB, Mercer LK, Moseley A, et al. Risk of skin and soft tissue infections (including shingles) in patients exposed to anti-tumour necrosis factor therapy: results from the British Society for Rheumatology Biologics Register. Ann Rheum Dis. 2013 Feb;72(2):229-34. Epub 2012 Apr 24.

  2. McDonald JR, Zeringue AL, Caplan L, et al. Herpes zoster risk factors in a national cohort of veterans with rheumatoid arthritis. Clin Infect Dis. 2009 May 15;48(10):1364-71.

  Conflict of Interest:

  None declared

  Show Less

  Conflict of Interest:
  None declared.

  • Back to top
• Published on: 7 February 2013

  TNF antagonists and Shingles: Is Vaccination Advisable?

  • Muhammad K Nisar, Senior Registrar
  • Other Contributors:
    • Andrew JK Ostor

  Dear Editor,

  We read with interest the report by Galloway et al on the risk of skin and soft tissue infections (including shingles) in patients exposed to TNF antagonists from the BSRBR [1]. In the light of our recently published systematic literature review of the risk of shingles in rheumatoid arthritis (RA) patients, we would like to address several issues raised in the report [2]. The authors state that the inci...

  Show More

  Dear Editor,

  We read with interest the report by Galloway et al on the risk of skin and soft tissue infections (including shingles) in patients exposed to TNF antagonists from the BSRBR [1]. In the light of our recently published systematic literature review of the risk of shingles in rheumatoid arthritis (RA) patients, we would like to address several issues raised in the report [2]. The authors state that the incidence of shingles is 1.6/100 patient-year (PY) in anti-TNF cohort compared to 0.8/100PY in nbDMARD group. However, it is well established that RA patients have an inherently higher risk of shingles irrespective of treatment modality [3]. In a retrospective analysis of data from a US managed care database (n =122,272) and a UK general practice research database (n =38,621), an increased risk of shingles was found among all patients with RA compared with the general population (in the US, adjusted HR 1.91, 95% confidence interval [95% CI] 1.80-2.03; in the UK, adjusted HR 1.65, 95% CI 1.57- 1.75) [4]. In one study addressing this issue, shingles incidence rates in RA patients were 14.5 cases per 1,000 PY (9 cases of shingles in 187 patients) and 1.3-4.8 cases per 1,000 PY in the general population. In this study, no cases of systemic dissemination or further episodes of shingles infection were observed in the RA patients despite 27.4 years of cumulative follow up among patients who continued on MTX [5]. Thus the higher risk of shingles seen in patients on anti TNF agents in BSRBR might be a reflection of active RA as it is these patients who are most likely to receive TNF inhibitors.

  The authors' recommendation of shingles vaccination prior to commencing TNF antagonists has a number of limitations. Firstly the uptake of vaccines in RA patients, as authors suggested, is poor [6]. Secondly, most of these patients would have failed on nbDMARDs thus requiring rapid escalation of therapy. The BSR states that live vaccines (such as the shingles vaccine) should be given at least two weeks, and preferably four weeks, prior to immunosuppressive therapy [7]. The ACR recommends avoidance of live viral vaccine preparations with "all biologic agents", but does not specify whether live vaccines are safe with MTX [8]. EULAR state that live attenuated vaccines should be avoided whenever possible in immunosuppressed patients with autoimmune inflammatory rheumatic diseases. However, they suggest that VZV, shingles and MMR vaccines might be exceptions to the rule and may be considered in the 'mildly immunosuppressed' [9].

  If a patient were to be vaccinated whilst receiving MTX to avoid treatment delay (as suggested by EULAR), data is conflicting as to its efficacy [9]. The CDC ACIP states that patients vaccinated whilst on immunosuppressive therapy should be considered non-immune and should be revaccinated at least 3 months after their therapy is discontinued [10]. Secondly, the shingles vaccine should be given at least two weeks (and preferably one month) prior to receiving immunosuppressive medications [11]. This would delay further the initiation of anti-TNF treatment for a patient with aggressive disease and would be contrary to the 'treatment to target' model.

  In addition, the safety of vaccination must be considered with respect to both the immune dysfunction of RA itself and potential immunosuppression if administered during MTX therapy. A theoretical possibility exists, for example that stimulating a deregulated immune system may cause deleterious effects [12]. As such, EULAR suggest that vaccination in patients with autoimmune inflammatory rheumatic disease should ideally be administered when the disease is quiescent [9].

  A more pragmatic approach would be to rely on post-exposure management thereby removing the issues posed above as well as circumventing deviation from the current model of early aggressive therapy of RA. An option would be vaccination following exposure as with varicella zoster vaccine. However, no data exists regarding shingles vaccine post- exposure. An alternative could be administration of VZIg following exposure to shingles or VZV, although estimations of its efficacy vary. Levin et al found only 20% of immunocompromised children developed clinical varicella if VZIg was administered within 96 hours of exposure [13]. However, Evans et al reported that 56% of immunosuppressed patients developed clinical varicella with post-exposure VZIg [14].

  We conclude that at this point in time it is premature to recommend VZ vaccination for RA patients prior to starting biologic therapy.  

  References

  1. Galloway JB, Mercer LK, Moseley A et al. Risk of skin and soft tissue infections (including shingles) in patients exposed to anti-tumour necrosis factor therapy: results from the British Society for Rheumatology Biologics Register. Ann Rheum Dis. 2013;72:229-234

  2. Zhang N, Wilkinson S, Riaz M, et al. Does methotrexate increase the risk of varicella or herpes zoster infection in patients with rheumatoid arthritis? A systematic literature review. Clin Exp Rheumatol. 2012;30(6):962-71

  3. Glück T, Müller-Ladner U. Vaccination in patients with chronic rheumatic or autoimmune diseases. Clinical infectious diseases: an official publication of the Infectious Diseases Society of America. 2008;46(9):1459-65.

  4. Smitten AL, Choi HK, Hochberg MC, et al. The risk of herpes zoster in patients with rheumatoid arthritis in the United States and the United Kingdom. Arthritis rheum 2007;57(8):1431-8.

  5. Antonelli MA, Moreland LW, Brick JE. Herpes zoster in patients with rheumatoid arthritis treated with weekly, low-dose methotrexate. The American journal of medicine. 1991;90(3):295-8.

  6. Zhang J, Delzell E, Xie F, et al. The use, safety, and effectiveness of herpes zoster vaccination in individuals with inflammatory and autoimmune diseases: a longitudinal observational study. Arthritis Res Ther 2011;13:R174

  7. BSR. Vaccinations in the immunocompromised person -Guidelines for the patient taking immunosuppressants, steroids and the new biologic therapies. 2002

  8. Guidelines for the management of rheumatoid arthritis: 2002 Update. Arthritis rheum 2002;46(2):328-46.

  9. van Assen S, Agmon-Levin N, Elkayam O, et al. EULAR recommendations for vaccination in adult patients with autoimmune inflammatory rheumatic diseases. Ann rheum dis 2011;70(3):414-22.

  10. ACIP. Recommendations of the Advisory Committee on Immunization Practices (ACIP): Use of Vaccines and Immune Globulins in Persons with Altered Immunocompetence. MMWR. 1993;42(RR-4).

  11. Harpaz R, Ortega-Sanchez IR, Seward JF. Prevention of herpes zoster: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR. Recommendations and reports: Morbidity and mortality weekly report. Recommendations and reports / Centers for Disease Control. 2008 ;57(RR-5):1-30; quiz CE2-4.

  12. Wraith DC, Goldman M, Lambert PH. Vaccination and autoimmune disease: what is the evidence? Lancet 2003;362(9396):1659-66.

  13. Levin MJ, Nelson WL, Preblud SR et al. Clinical trials with varicella-zoster immunoglobulins. London: Academic Press Inc., Ltd; 1986.

  14. Evans EB, Pollock TM, Cradock-Watson JE, et al. Human anti- chickenpox immunoglobulin in the prevention of chickenpox. Lancet. 1980;315(8164):354-6.

  Conflict of Interest:

  None declared

  Show Less

  Conflict of Interest:
  None declared.

  • Back to top