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Risk of Herpes Zoster in Patients Receiving Anti-TNF-α in the Prospective French RATIO Registry

2011; Elsevier BV; Volume: 132; Issue: 3 Linguagem: Inglês

10.1038/jid.2011.383

1523-1747

G Serac, Florence Tubach, Xavier Mariette, Dominique Salmon‐Céron, Philippe Ravaud, Frédéric Lioté, David Laharie, Jean-Marc Ziza, Laurent Marguerie, Christine Bonnet, Géraldine Falgarone, Nathalie Nicolas, Olivier Lortholary, O. Chosidow,

Ocular Diseases and Behçet’s Syndrome

adalimumab etanercept herpes zoster infliximab rheumatoid arthritis tumor necrosis factor-α varicella zoster virus Anti-tumor necrosis factor-α (TNF-α) drugs (mAbs infliximab (IFX) and adalimumab (ADA), and soluble TNF-α receptor etanercept (ETA)) are used for rheumatoid arthritis (RA), spondylarthropathies, psoriasis, Crohn's disease, and ulcerative colitis. These molecules increase the risk of various pathogens such as Mycobacterium tuberculosis (Flynn et al., 1995Flynn J.L. Goldstein M.M. Chan J. et al.Tumor necrosis factor-alpha is required in the protective immune response against Mycobacterium tuberculosis in mice.Immunity. 1995; 2: 561-572Abstract Full Text PDF PubMed Scopus (1368) Google Scholar; Tubach et al., 2009Tubach F. Salmon D. Ravaud P. et al.Risk of tuberculosis is higher with anti-tumor necrosis factor monoclonal antibody therapy than with soluble tumor necrosis factor receptor therapy: The three-year prospective French Research Axed on Tolerance of Biotherapies registry.Arthritis Rheum. 2009; 60: 1884-1894Crossref PubMed Scopus (532) Google Scholar) or trigger reactivation of varicella zoster virus (VZV) and subsequently herpes zoster (HZ). The Spanish registry showed more frequent hospitalizations because of VZV infection for patients receiving anti-TNF-α therapy than expected in the general population (García-Doval et al., 2010García-Doval I. Pérez-Zafrilla B. Descalzo M.A. et al.Incidence and risk of hospitalisation due to shingles and chickenpox in patients with rheumatic diseases treated with TNF antagonists.Ann Rheum Dis. 2010; 69: 1751-1755Crossref PubMed Scopus (84) Google Scholar), and the German registry demonstrated an increased risk of HZ and severe HZ as well (Strangfeld et al., 2009Strangfeld A. Listing J. Herzer P. et al.Risk of herpes zoster in patients with rheumatoid arthritis treated with anti-TNF-alpha agents.JAMA. 2009; 301: 737-744Crossref PubMed Scopus (460) Google Scholar). We aimed to identify the risk factors and describe the outcome of HZ for patients receiving TNF-α blockers for severe inflammatory conditions. The French RATIO registry was designed to prospectively collect all cases of opportunistic infections in metropolitan France from 1 February 2004 to 31 January 2007 in patients who were receiving or had received anti-TNF-α treatment. This registry includes cases from clinicians, pharmacovigilance centers of the French agency of drugs (Agence Française de Sécurité Sanitaire des Produits de Santé), and companies commercializing anti-TNF-α therapy. The methodological details have been described elsewhere (Tubach et al., 2005Tubach F. Salmon-Céron D. Ravaud P. et al.The RATIO observatory: French registry of opportunistic infections, severe bacterial infections, and lymphomas complicating anti-TnFalpha therapy.Joint Bone Spine. 2005; 72: 456-460Crossref PubMed Scopus (55) Google Scholar, Tubach et al., 2009Tubach F. Salmon D. Ravaud P. et al.Risk of tuberculosis is higher with anti-tumor necrosis factor monoclonal antibody therapy than with soluble tumor necrosis factor receptor therapy: The three-year prospective French Research Axed on Tolerance of Biotherapies registry.Arthritis Rheum. 2009; 60: 1884-1894Crossref PubMed Scopus (532) Google Scholar). A committee of three experts in opportunistic infections (OC, DS-C, and OL) reviewed detailed standardized case report forms and additional documents for all reported HZ cases. We conducted a case–control study to investigate the risk factors of HZ for patients receiving anti-TNF-α therapy. Cases were validated HZ cases being treated for a labeled indication, and controls were patients from centers involved in the RATIO registry who were being treated with anti-TNF-α therapy (current treatment or stopped for <24 months) for a labeled indication and never exhibited HZ during the follow-up period. The control pool has been described elsewhere (Salmon-Ceron et al., 2011Salmon-Ceron D. Tubach F. Lortholary O. et al.Drug-specific risk of non-tuberculosis opportunistic infections in patients receiving anti-TNF therapy reported to the 3-year prospective French RATIO registry.Ann Rheum Dis. 2011; 70: 616-623Crossref PubMed Scopus (222) Google Scholar). Four controls per case were matched by underlying inflammatory disease. We validated 24 HZ cases (18 women, mean age 54.4 years, 79% receiving anti-TNF-α therapy for RA, median time from onset of last anti-TNF agent to HZ occurrence 11.5 years (interquartile range 4.2–24.3)). Clinical characteristics and outcomes are shown in Table 1. The last anti-TNF agent received was ADA, IFX, and ETA in 10 (14.7%), 9 (37.5%), and 5 (20.8%) cases, respectively. Eight cases, involving at least two distinct episodes, more than one dermatome, the central nervous system, or the eye, were considered severe HZ, as recently defined by the RATIO group (Salmon-Ceron et al., 2011Salmon-Ceron D. Tubach F. Lortholary O. et al.Drug-specific risk of non-tuberculosis opportunistic infections in patients receiving anti-TNF therapy reported to the 3-year prospective French RATIO registry.Ann Rheum Dis. 2011; 70: 616-623Crossref PubMed Scopus (222) Google Scholar): one clinically symptomatic meningitis with positive local results on PCR, four multidermatomal locations, one secondary generalized and recurrent HZ, and three ophthalmic HZ (including two keratitis). After HZ diagnosis, anti-TNF-α therapy was stopped for 16 patients (66.7%), but was still ongoing for 7 patients (2 ETA and 5 IFX). After a median follow-up of 35.3 (29.9–36.5) months, one patient died from an HZ-unrelated cause, one experienced two relapses, despite receiving valaciclovir as chemoprophylaxis, and one presented postherpetic pain; the other cases were cured.Table 1Clinical characteristics and outcome of herpes zoster cases that occurred between February 2004 and January 2007 in patients who were receiving or had received anti-TNF therapy in FrancePatientAge (years)SexUnderlying diseaseCorticosteroid therapyMethotrexateAnti-TNF-α agentTreatment duration (weeks)1Previous anti-TNF agent(s).Clinical featuresTreatment (days)Anti-TNF-α withdrawalAnti-TNF-α restart, timeOutcomeFollow-up (months) 159FRAYesYesETA70DorsalHospit, VCV PONoRecovery30 229FCrohnNoNoIFX99NAVCV PONoRecovery— 325FCrohnNoNoIFX202LumbarVCV PO (7)NoRecovery, death—no link with VZV12 463FRAYesNoETA156TrigeminalVCV PO (15)YesYes, 1 monthPHP36 554FRAYesNoADA10LumbarVCV POYesYes, 3 weeksRecovery36 660FRAYesNoADA31DorsalVCV POYesYes, 3 weeksRecovery36 741FRAYesYesADA17Disseminated and ophthalmic (keratitis)Hospit, VCV PO J1 then ACV IV (10)YesYes, 2 monthsIntro preventive ttt, 2 disseminated recurrences36 882FRAYesYesADA30LumbarHospit, ttt NAYesYesRecovery36 947FRA; RPYesYesIFX13DorsalVCV PO (7)YesYes, 1 monthRecovery361049MRAYesYesADA (IFX, ETA)2Time from onset of last anti-TN-F-α agent to first symptoms of HZ.110Cervical MM hyperalgicHospit, ACV IV (10)YesYes, 1 monthRecovery Intro preventive ttt301171FRAYesYesETA (IFX)2Time from onset of last anti-TN-F-α agent to first symptoms of HZ.10Ophthalmic with keratitisHospit, NAYesNoSlow recovery (3–6 months)181235MCrohnNoNoIFX36DorsalHospit, ACV IV (10)NoRecovery361361FRAYesNoADA95LumbarACV POYesNoRecovery361464MASNoNoIFX78Dorsal MM, meningitisHospit, ACV IV (10), VCV PO (5)NoRecovery301568FRAYesYesIFX45CervicalAucunYesNoRecovery361643FRANoYesADA (IFX)2Time from onset of last anti-TN-F-α agent to first symptoms of HZ.30OphthalmicVCV PO (7)YesYes, 6 weeksRecovery361783FRAYesYesIFX189LumbarVCV POYesYes, 1 monthRecovery361843FRAYesYesADA130DorsalVCV PO (7)YesYes; ETA, 24 monthsRecovery361966FRAYesNoADA108 (Stopped for 14 weeks)CervicalVCV PO (10)Yes, before HZ for visceral tuberculosisNoRecovery242033MCrohnNoNoIFXNDCervical MMHospit, ACV IV (7), VCV PO (7)YesYes, 3 weeksRecovery62144FRAYesYesIFX8Cervical, bilateralHospit, VCV PONoRecovery302265FRANoNoETA54DorsalHospit, VCV PO (7)YesNoRecovery362337MRANoYesETA (IFX, ADA)2Time from onset of last anti-TN-F-α agent to first symptoms of HZ.50CervicalVCV PO (10)NoRecovery (recurrences of HSV)362467MRAYesYesADA (ETA)2Time from onset of last anti-TN-F-α agent to first symptoms of HZ.7DorsalHospit, ACV PO, then IV, then VCV POYesNDRecovery24Abbreviations: ACV, aciclovir; ADA, adalimumab; AS, ankylosing spondylitis; ETA, etanercept; F, female; Hospit, hospitalization; HSV, herpes simplex virus; HZ, herpes zoster, IFX, infliximab; Intro, introduction; IV, intravenously; M, male; MM, multimetameric; NA, not assessed; ND, not determined; PO, orally; PHP, postherpetic pain; RA, rheumatoid arthritis; RP, relapsing; TNF-α, tumor necrosis factor-α; ttt, treatment; VCV, Valaciclovir; VZV, varicella zoster virus.1 Previous anti-TNF agent(s).2 Time from onset of last anti-TN-F-α agent to first symptoms of HZ. Open table in a new tab Abbreviations: ACV, aciclovir; ADA, adalimumab; AS, ankylosing spondylitis; ETA, etanercept; F, female; Hospit, hospitalization; HSV, herpes simplex virus; HZ, herpes zoster, IFX, infliximab; Intro, introduction; IV, intravenously; M, male; MM, multimetameric; NA, not assessed; ND, not determined; PO, orally; PHP, postherpetic pain; RA, rheumatoid arthritis; RP, relapsing; TNF-α, tumor necrosis factor-α; ttt, treatment; VCV, Valaciclovir; VZV, varicella zoster virus. Multivariate analysis (Table 2) of data for the 24 HZ cases and 96 controls showed a decreased risk of HZ with increasing time since the last anti-TNF-α agent, with no significant difference by anti-TNF-α agent. When considering anti-TNF-α agents in two classes, the risk of HZ was significantly greater with monoclonal anti-TNF-α antibodies than with soluble receptor. Sensitivity analysis varying the definition of exposure (by anti-TNF-α agent, for patients currently receiving anti-TNF-α therapy, those who received anti-TNF-α therapy for at least 6 weeks, and those who received only one anti-TNF-α agent) showed a higher risk with ADA and IFX than ETA, statistically significant in only some subgroups. In the subgroup of severe HZ, the risk was higher, but not significant, with mAbs than with soluble receptor (P=0.06).Table 2Herpes zoster risk factors in patients receiving anti-TNF-α therapy considering anti-TNF-α agents in three molecules or two classes: multivariate analysisOR (95% CI)P-valueTime from onset of last anti-TNF-α agent (for a 1-month increase)0.96 (0.93–0.99)0.0088Last anti-TNF-α agent0.0974 Etanercept1— Adalimumab3.25 (0.93–11.36)0.0652 Infliximab3.94 (0.93–16.65)0.0619Time from onset of last anti-TNF-α agent (for a 1-month increase)0.96 (0.93–0.99)0.0078Class of last anti-TNF-α agent Soluble TNF-α receptor (etanercept)1— mAb (adalimumab or infliximab)3.49 (1.12–10.90)0.0316Abbreviations: CI, confidence interval; OR, odds ratio; TNF-α, tumor necrosis factor-α. Open table in a new tab Abbreviations: CI, confidence interval; OR, odds ratio; TNF-α, tumor necrosis factor-α. Our results suggest an increased risk of HZ with monoclonal anti-TNF-α antibodies than with soluble TNF-α receptor. This result agrees with those from the German register RABBIT (Strangfeld et al., 2009Strangfeld A. Listing J. Herzer P. et al.Risk of herpes zoster in patients with rheumatoid arthritis treated with anti-TNF-alpha agents.JAMA. 2009; 301: 737-744Crossref PubMed Scopus (460) Google Scholar). The difference in the risk of HZ between the two classes of anti-TNF-α therapy may be explained by their different mechanisms of action (Wallis, 2008Wallis R.S. Tumour necrosis factor antagonists: structure, function, and tuberculosis risks.Lancet Infect Dis. 2008; 8: 601-611Abstract Full Text Full Text PDF PubMed Scopus (226) Google Scholar). Moreover, a similar result was observed in the risk of tuberculosis reactivation (Dixon et al., 2007Dixon W.G. Symmons D.P.M. Lunt M. et al.Serious infection following anti-tumor necrosis factor alpha therapy in patients with rheumatoid arthritis: lessons from interpreting data from observational studies.Arthritis Rheum. 2007; 56: 2896-2904Crossref PubMed Scopus (267) Google Scholar; Tubach et al., 2009Tubach F. Salmon D. Ravaud P. et al.Risk of tuberculosis is higher with anti-tumor necrosis factor monoclonal antibody therapy than with soluble tumor necrosis factor receptor therapy: The three-year prospective French Research Axed on Tolerance of Biotherapies registry.Arthritis Rheum. 2009; 60: 1884-1894Crossref PubMed Scopus (532) Google Scholar), legionellosis, and other severe opportunistic infections (Salmon-Ceron et al., 2011Salmon-Ceron D. Tubach F. Lortholary O. et al.Drug-specific risk of non-tuberculosis opportunistic infections in patients receiving anti-TNF therapy reported to the 3-year prospective French RATIO registry.Ann Rheum Dis. 2011; 70: 616-623Crossref PubMed Scopus (222) Google Scholar). In addition, we found that the risk of HZ was higher at the beginning of anti-TNF-α therapy. This result agrees with those from a Swedish study suggesting increased risk of hospitalization with infection in general in the first year of anti-TNF-α therapy, but decreased thereafter (Askling et al., 2007Askling J. Fored C.M. Brandt L. et al.Time-dependent increase in risk of hospitalisation with infection among Swedish RA patients treated with TNF antagonists.Ann Rheum Dis. 2007; 66: 1339-1344Crossref PubMed Scopus (287) Google Scholar). HZ, which results from the reactivation of VZV, occurs early during immunosuppression, after bone marrow transplantation (Steer et al., 2000Steer C.B. Szer J. Sasadeusz J. et al.Varicella-zoster infection after allogeneic bone marrow transplantation: incidence, risk factors and prevention with low-dose aciclovir and ganciclovir.Bone Marrow Transplant. 2000; 25: 657-664Crossref PubMed Scopus (116) Google Scholar), solid organ transplantation (Gourishankar et al., 2004Gourishankar S. McDermid J.C. Jhangri G.S. et al.Herpes zoster infection following solid organ transplantation: incidence, risk factors and outcomes in the current immunosuppressive era.Am J Transplant. 2004; 4: 108-115Crossref PubMed Scopus (198) Google Scholar), or during HIV infection, when CD4 cell count might still be relatively preserved (Moore and Chaisson, 1996Moore R.D. Chaisson R.E. Natural history of opportunistic disease in an HIV-infected urban clinical cohort.Ann Intern Med. 1996; 124: 633-642Crossref PubMed Scopus (259) Google Scholar). One-third of our HZ patients receiving anti-TNF-α agents showed severe HZ. For these cases, subgroup analysis also showed a higher risk, but not significant, with mAbs than with soluble receptor. Some HZ cases reported in trials are severe and may present as encephalitis with neurological sequelae (Keystone et al., 2004Keystone E.C. Kavanaugh A.F. Sharp J.T. et al.Radiographic, clinical, and functional outcomes of treatment with adalimumab (a human anti-tumor necrosis factor monoclonal antibody) in patients with active rheumatoid arthritis receiving concomitant methotrexate therapy: a randomized, placebo-controlled, 52-week trial.Arthritis Rheum. 2004; 50: 1400-1411Crossref PubMed Scopus (1047) Google Scholar), with one report of death due to bacterial superinfection complicated by necrotizing fasciitis (Furst et al., 2003Furst D.E. Schiff M.H. Fleischmann R.M. et al.Adalimumab, a fully human anti tumor necrosis factor-alpha monoclonal antibody, and concomitant standard antirheumatic therapy for the treatment of rheumatoid arthritis: results of STAR (Safety Trial of Adalimumab in Rheumatoid Arthritis).J Rheumatol. 2003; 30: 2563-2571PubMed Google Scholar). The German register RABBIT reported 15 cases of multidermatomal or HZ ophthalmicus, with an incidence of 2.5/1,000 patient-years for patients receiving anti-TNF-α agents: 3.7 for mAbs, 0.8 for ETA, and 0.9 for controls (Strangfeld et al., 2009Strangfeld A. Listing J. Herzer P. et al.Risk of herpes zoster in patients with rheumatoid arthritis treated with anti-TNF-alpha agents.JAMA. 2009; 301: 737-744Crossref PubMed Scopus (460) Google Scholar). The main limitation of this study analysis is that our data for HZ episodes may not be exhaustive because of underreporting; therefore, we did not aim to determine HZ incidence in patients receiving anti-TNF-α agents, and the sample size was very limited. More severe infections were more likely to be reported (relative overrepresentation of severe cases because of lack of exhaustivity of nonsevere cases), but probably did not differ by anti-TNF-α agent. The next step should be better management of prevention and treatment of HZ in patients receiving anti-TNF-α agents, including the value of vaccination before treatment. The pharmaceutical companies Abbott, Schering Plough, and Wyeth had no role in the study design, data collection, data analysis, data interpretation, or writing of the report.