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ATLANTA - Anti tumor necrosis factor therapy increases the risk of developing varicella zoster virus infections, including shingles and chicken pox, according to research presented this week at the American College of Rheumatology Annual Scientific Meeting in Atlanta.

Rheumatoid arthritis is a chronic disease that causes pain, stiffness, swelling, and limitation in the motion and function of multiple joints. Though joints are the principal body parts affected by RA, inflammation can develop in other organs as well. An estimated 1.3 million Americans have RA, and the disease typically affects women twice as often as men.

Varicella zoster virus is a common viral infection. The initial infection typically occurs in childhood, causing chicken pox, and reactivation later in life results in herpes zoster (shingles). The body's immune defense against both chicken pox and herpes zoster relies on immune pathways that may be impaired by anti-TNF therapy - theoretically predisposing people who take anti-TNF therapy to varicella zoster-associated infection.

Using the British Society for Rheumatology Biologics Register—a registry that tracks the progress of patients with severe rheumatoid arthritis and other rheumatic conditions who are taking anti-TNF therapy—researchers recently looked at the association between anti-TNF therapy and varicella zoster infections.

They studied 11,864 people with RA who were undergoing anti-TNF therapy and compared them to 3,666 patients who were undergoing treatment with disease-modifying antirheumatic drugs (commonly called DMARDs). They began recruiting patients in October 2001 and continued to monitor them until the first episode of herpes zoster infection (which is caused by varicella zoster virus), death, or the end of 2009, whichever came first. A patient's health was monitored through questionnaires filled out by the patients and their physicians, and a varicella zoster infection was attributed to anti-TNF therapy if diagnosed while a patient was actively receiving the drug (up to the date of the first missed dose).

During the study, 322 herpes zoster infections occurred in the patients taking anti-TNF therapy and 46 infections occurred in the DMARD group. A greater proportion of the cases in the anti-TNF group were severe (defined as herpes zoster being a primary reason for hospitalization, requiring intravenous anti-viral medication, or being multi-dermatomal). Furthermore, 12 cases of chicken pox, presumably initial infection with the varicella zoster virus, were reported in the anti-TNF group and none in the DMARD group. These results suggest that anti-TNF therapy may be associated with both primary and recurrent infections with the varicella zoster virus.

"Anti-TNF therapy conferred more than a twofold increase in the risk of developing shingles in our dataset when compared to traditional DMARD therapy," explains James Galloway, MD, MBChB, MRCP, MSc; clinical research fellow; BSR Biologics Register; ARC unit; University of Manchester, Manchester, United Kingdom, and lead investigator in the study."Chicken pox was also observed more frequently in the anti-TNF cohort, although absolute numbers were small. This supports a recent similar observation from the Spanish Registry - BIOBADASER." Dr. Galloway adds. "The clinical message from this study is to be vigilant for shingles with anti-TNF therapy."

Dr. Galloway also suggests that the study's findings raise two important questions that warrant further research: Is there any value in screening people for immunity to the varicella zoster virus, and what role does vaccination have in preventing the VZV-associated infections?

TNF-antagonists (anti-TNF therapy; among drugs called biologics) are a class of drugs that have been used since 1998. Overall, they have been given to more than 600,000 people worldwide. These drugs are given to lessen inflammation by interfering with biologic substances that cause or worsen inflammation.

The American College of Rheumatology is an international professional medical society that represents more than 8,000 rheumatologists and rheumatology health professionals around the world. Its mission is to advance rheumatology. The ACR/ARHP Annual Scientific Meeting is the premier meeting in rheumatology. For more information about the meeting, visit Follow the meeting on twitter by using the official hashtag: #ACR2010.


Editor's Notes: James Galloway, MD, MBChB, MRCP, MSc will present this research during the ACR Annual Scientific Meeting at the Georgia World Congress Center from 9:00 - 11:00 AM on Monday, November 8 in Halls B1 & B2. Deborah Symmons, MD will be available for media questions and briefing at 8:30 AM on Tuesday, November 9 in the on-site press conference room, B 212.

Learn more about living well with rheumatic disease as well as rheumatologists and the role they play in health care. Also, discover how the ACR Research and Education Foundation's Within Our Reach: Finding a Cure for Rheumatoid Arthritis campaign is accelerating RA research.

Presentation Number: 421

Varicella Zoster Virus (VZV) Infections Are Increased in Patients with Rheumatoid Arthritis (RA) Treated with Anti-TNF Therapy; Results from the British Society for Rheumatology Biologics Register (BSRBR).

James Galloway
(University of Manchester, Manchester)

Alison Moseley
(University of Manchester)

Lousie Mercer
(University of Manchester)

Will Dixon
(University of Manchester)

Bo Fu
(University of Manchester)

Andrew Ustianowski
(University of Manchester)

Kath Watson
(University of Manchester)

Mark Lunt
(University of Manchester)

BSRBR Control centre consortium
(University of Manchester)

Kimme Hyrich
(University of Manchester)

Deborah Symmons
(University of Manchester)

On behalf of the British Society for Rheumatology Biologics Register
(University of Manchester)

Introduction:VZV infection is highly prevalent with 95% of adults showing seropositivity. The initial infection typically occurs in childhood causing chicken pox. Reactivation later in life results in herpes zoster (shingles). The immune defence against both chicken pox and herpes zoster is T-cell mediated. Anti-TNF therapy interacts with this pathway and hence theoretically predisposes to VZV associated disease. The aim of this study was to compare rates of herpes zoster in rheumatoid arthritis (RA) patients treated with anti-TNF agents or non-biologic disease modifying anti-rheumatic drugs (DMARDs); and to compare the rates for the individual anti-TNF agents.

Methods: The BSRBR was established in 2001 to evaluate the safety of anti-TNF therapies etanercept (ETN), infliximab (INF) and adalimumab (ADA) in patients with RA. The anti-TNF treated cohort was recruited alongside a comparator group with active disease (DAS28 >4.2) treated with DMARDs. Patients were recruited between 01/10/2001 and 30/06/2008 and followed up by consultant and patient questionnaires. For this analysis patients were followed until the first episode of herpes zoster infection, death or 31/12/2009, whichever came first. An infection was attributed to anti-TNF if diagnosed while the patient was actively receiving the drug (up to the date of the first missed dose). A Cox proportional hazards model was used to compare rates between cohorts and adjustment was made for differences in baseline characteristics including age, gender, disease severity, disease duration, baseline steroid exposure and co-morbidity using an inverse probability of treatment weighting propensity model.

Results: (see table) Three hundred and twenty two herpes zoster infections occurred in the anti-TNF cohort: IR 7.8/1000 (pyrs) (95% CI 7.0, 8.7) and 46 in the DMARD cohort (IR 4.0/1000 pyrs (95% CI 3.0, 5.4) (Table). The adjusted hazard ratio for herpes zoster was 2.2 (95% CI 1.4, 3.6). A greater proportion of the cases in the anti-TNF cohort were severe (defined as herpes zoster being a primary reason for hospitalisation, requiring intravenous antivirals or being multidermatomal) 6% vs 0.02%. A similar pattern of risk was seen for each anti-TNF therapy with no statistical difference between etanercept and the monoclonal antibodies. In total, 12 cases of chicken pox infection were reported in the anti-TNF cohort and none in the DMARD cohort.

Conclusion: Anti-TNF therapy is associated with a significantly increased risk of VZV associated disease. This information would support the evaluation of VZV vaccination in an RA population.

Table. Baseline characteristics and incidence of VZV infections. Table:Baseline characteristics and incidence of VZV infections

Disclosure: James Galloway, nothing to disclose; Alison Moseley, nothing to disclose; Lousie Mercer, nothing to disclose; Will Dixon, nothing to disclose; Bo Fu, nothing to disclose; Andrew Ustianowski; nothing to disclose; Kath Watson, nothing to disclose; Mark Lunt, nothing to disclose; BSRBR Control centre consortium, nothing to disclose, Kimme Hyrich, nothing to disclose; Deborah Symmons, nothing to disclose; On behalf of the British Society for Rheumatology Biologics Register, British Society for Rheumatology: Research grants.

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