Effects of TNFi Therapy on Herpes Zoster Risk in Rheumatoid Arthritis

Herpes zoster (HZ) is an extremely painful acute and chronic infection resulting from reactivation of the varicella zoster virus (VZV), which can lead to postherpetic neuralgia (PHN) involving destruction and inflammation of the nerves.¹ An estimated 95% to 98% of the US population is infected with the VZV virus during childhood.^1,2

VZV is a cell-mediated infection exclusive to humans. Following primary infection, VZV gains access to epidermal cells, which erupt into the typical varicella rash. The virus enters mucocutaneous sites and travels along sensory nerves to the dorsal root ganglia adjacent to the spinal cord, where it establishes permanent latency in neuronal cell bodies.³ In most individuals, the latent virus will never be reactivated; however, approximately one-third of the general population will get HZV in their lifetime, usually decades after initial VZV infection.^3,4

Reinfection can last for months or even years; 1 in 4 infections will develop more serious complications,⁴ including PHN (with chronic pain, burning, allodynia, weight loss, sleep disturbances, and depression), as well as ocular complications, stroke, motor paresis, loss of hearing and/or balance, facial paralysis, meningoencephalitis, and secondary bacterial infection of the skin.^1,2

Risk Factors for Herpes Zoster

The primary risk attributed to HZV activation is reduced cell-mediated immunity (CMI) as a normal consequence of aging or due to immune-compromising diseases and/or treatments. The subgroups at highest risk for developing HZ include people older than 65 (and particularly >85); patients with human immunodeficiency virus infection, Hodgkin’s disease, non-Hodgkin’s lymphomas, leukemia, bone marrow and other organ transplants, systemic lupus erythematosus, rheumatoid arthritis; and individuals taking immunosuppressive medications, including tumor necrosis factor inhibitor (TNFi) drugs.^2,3

Patients who are diagnosed with RA have multiple risk factors for HZ starting at a much younger age than the general population. Because RA is associated with severe CMI impairment, the risk for HZV at age 40 is similar to that in people age 60 without RA.⁵ In addition, the drugs used to treat RA have been associated with VZV activation, the severity of which is tied to type and dosage of the agents used.⁵

Treatment-Associated Risks of HZV

Glucocorticoid therapy has been shown in multiple studies to increase the risk for HZ from 1.5 to 2.5 fold in a dose-dependent manner.⁵  Risks with DMARD therapies have also been widely observed, although studies are far less conclusive. A 2017 meta-analysis by Tran, et al⁵ concluded that the risk for VZV associated with immunomodulating agents seemed moderate, although the studies used may have lacked statistical power.

Impact of TNFi Therapies on Risks of HZV

Biologic anti-TNF drugs have demonstrated great success in reducing progression of RA and improving outcomes; however, a review by Cacciapaglia et al² determined that continued cases from clinical practice suggest that the relatively low reported rates from randomized clinical trials may underestimate the risks.

Lyn March, MB BS, MSc, PhD, FRACP, FAFPHM, professor of medicine, Florance and Cope Professorial Department of Rheumatology, Royal North Shore Hospital, Institute of Bone and Joint Research, University of Sydney, Australia. “In a real-world Australian cohort⁶ we identified a 2-fold increase in risk of HZ among RA patients on anti-TNFs compared with those not on anti-TNFs,” Dr March told Rheumatology Advisor. “People living with RA were at increased risk of HZ compared to the general population (likely secondary to effects of the disease itself and use of drugs such as glucocorticoids). We also identified that the RA patients who received biologics were at increased risk in the period before they started the anti-TNF.”

Cong Tri Tran, MD, of the Laboratoire de Virologie, CHU d’Angers, in France, and colleages, uncovered a pattern of conflicting results in which several studies showed a distinct increase in the risk for HZ directly associated with biologic anti-TNF agents compared with synthetic disease-modifying anti-rheumatic drugs (DMARDs), while others found no increase in the risk at all.⁵ Dr Tran reported that the potential risks appear to be higher with infliximab compared with other anti-TNF agents, although data conflicted on this point too.⁵

“Our study did not find an increased risk for infliximab but our numbers were small for this mediation,” Dr March observed. She pointed out that other studies, including meta-analyses, show that all TNFis appear to be at risk. “We did not explore combinations but anecdotally the concurrent use of glucocorticoids appears to increase the risk,” she said.

Treatment Strategies

Currently, no strong recommendations for or against the use of biologic anti-TNF therapies exist, and they are considered largely safe. Recommendations released in 2012 from the American College of Rheumatology⁷ provided only C-level evidence supporting switching from anti-TNF biologic therapies (adalimumab, certolizumab, etanercept, infliximab, golimumab) to a nonanti-TNF-biologic (abatacept, rituximab or tocilizumab) following the occurrence of a serious adverse event (AE) in a patient with continued high-level RA disease activity.⁷ Recommendations where failure of therapy was due to a non-serious AE were to switch to another non-TNF biologic or an anti-TNF biologic.

Dr March counseled that the latest research, while still inconclusive, can still contribute to selection of the safest therapy. “We recommend that this information should form part of the shared decision making and patient education before commencing biologic therapy.

Vaccination for VZV is being increasingly recommended prior to starting DMARD and bDMARD [biologic disease-modifying anti-rheumatic drug] therapy,” she said, adding that detailed clinical history of bacterial and viral infections (including VZV) and malignancy and blood serology for chronic viral exposures is an important screening procedure to determine who can safely be treated with anti-TNF therapies.

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References

1. Schmader K. Herpes Zoster. Clin Geriatr Med. 2016;32:539-553.
2. Cacciapaglia C, Zuccaro C, Iannone F. Varicella-zoster virus infection in rheumatoid arthritis patients in the anti-tumour necrosis factor era. Clin Exp Rheumatol. 2015;33(6):917-923.
3. Harpaz R, Ortega-Sanchez IR, Seward JF, et al. Prevention of herpes zoster: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2008;57(RR-5):1-30.
4. Yawn BP, Saddier P, Wollan PC, St. Sauver JL, Kurland MJ, Sy LS. A population-based study of the incidence and complication rates of herpes zoster before zoster vaccine introduction. Mayo Clin Proc. 2007;82:1341-1349.
5. Tran CT, Ducancelle  A, Masson C, Lunel-Fabiani F. Herpes zoster: risk and prevention during immunomodulating therapy. Joint Bone Spine. 2017;84:21-27.
6. Segan J, Staples MP, March L, Lassere M, Chakravarty EF, Buchbinder R. Risk factors for herpes zoster in rheumatoid arthritis patients: the role of tumour necrosis factor-α inhibitors. Intern Med J. 2015;45:310-308.
7. Singh JA, Furst DE, Bharat A, et al. 2012 update of the 2008 American College of Rheumatology recommendations for the use of disease-modifying antirheumatic drugs and biologic agents in the treatment of rheumatoid arthritis. Arthritis Care Res (Hoboken). 2012;64:625-639.