Global Risk of Bacterial Skin Infections and Herpesviridae Infections with Ustekinumab, Secukinumab, and Tumour Necrosis Factor-alpha Inhibitors: Spontaneous Reports of Adverse Drug Reactions from the World Health Organization Pharmacovigilance Center


  • Linda Davidson Department of Internal Medicine and Radboudumc Center for Infectious diseases (RCI), Radboud University Medical Center, Geert Grooteplein Zuid 10, NL-6525 GA Nijmegen, The Netherlands
  • Juul M.P.A. van den Reek
  • Florence van Hunsel
  • Elke M.G.J. de Jong
  • Bart Jan Kullberg



IL-12/23 inhibitors, IL-17 inhibitors, ustekinumab, secukinumab, bacterial skin infection, herpesviridae infection


Genetic defects in interleukin-12/23/17 immunity are associated with an increased risk of Staphylococcus aureus and herpesvirus skin infections. This study analysed spontaneous safety reports from the WHO Pharmacovigilance Center of bacterial skin or herpesvirus infections associated with secukinumab, ustekinumab and tumour necrosis factor-α inhibitors. Associations found in disproportionality analyses were expressed as reporting odds ratios (ROR). For bacterial skin infections, ustekinumab showed the strongest association (ROR 6.09; 95% confidence interval (95% CI) 5.44–6.81), and, among the tumour necrosis factor-α inhibitors, infliximab showed the strongest association (ROR 4.18; 95% CI 3.97–4.40). Risk was comparable between infliximab and secukinumab (ROR 3.51; 95% CI 3.00–4.09). Secukinumab showed the strongest association with herpes simplex infection (ROR 4.80; 95% CI 3.78–6.10). All biologics were equally associated with herpes zoster. Infliximab was the only biologic associated with cytomegalovirus infection (ROR 5.66; 95% CI 5.08–6.31) and had the strongest association with Epstein-Barr virus infection (ROR 6.90; 95% CI 6.03–7.90). All biologics evaluated were positively associated with bacterial skin infections, herpes simplex, and herpes zoster, compared with all other drugs in the WHO database for which individual case safety reports were collected. The possibility of under-reporting, reporting bias and difference in causality assessment between countries and reporters must be taken into account when interpreting the results of disproportionality analyses. 


Download data is not yet available.


Triplett KD, Pokhrel S, Castleman MJ, Daly SM, Elmore BO, Joyner JA, et al. GPER activation protects against epithelial barrier disruption by Staphylococcus aureus alpha-toxin. Sci Rep 2019; 9: 1343.

Fatahzadeh M, Schwartz RA. Human herpes simplex virus infections: epidemiology, pathogenesis, symptomatology, diagnosis, and management. J Am Acad Dermatol 2007; 57: 737-763; quiz 64-66.

Johnson BH, Palmer L, Gatwood J, Lenhart G, Kawai K, Acosta CJ. Annual incidence rates of herpes zoster among an immunocompetent population in the United States. BMC Infect Dis 2015; 15: 502.

Ahmed AM, Brantley JS, Madkan V, Mendoza N, Tyring SK. Managing herpes zoster in immunocompromised patients. Herpes 2007; 14: 32-36.

Fujisato S, Urushibara T, Kasai H, Ishi D, Inafuku K, Fujinuma Y, et al. A Fatal case of atypical disseminated Herpes zoster in a patient with meningoencephalitis and seizures associated with steroid immunosuppression. Am J Case Rep 2018; 19: 1162-1167.

Meesilpavikkai K, Dik WA, Schrijver B, Nagtzaam NM, van Rijswijk A, Driessen GJ, et al. A novel heterozygous mutation in the STAT1 SH2 domain causes chronic mucocutaneous candidiasis, atypically diverse infections, autoimmunity, and impaired cytokine regulation. Front Immunol 2017; 8: 274.

Toubiana J, Okada S, Hiller J, Oleastro M, Lagos Gomez M, Aldave Becerra JC, et al. Heterozygous STAT1 gain-of-function mutations underlie an unexpectedly broad clinical phenotype. Blood 2016; 127: 3154-3164.

Okada S, Puel A, Casanova JL, Kobayashi M. Chronic mucocutaneous candidiasis disease associated with inborn errors of IL-17 immunity. Clin Transl Immunology 2016; 5: e114.

Puel A, Cypowyj S, Bustamante J, Wright JF, Liu L, Lim HK, et al. Chronic mucocutaneous candidiasis in humans with inborn errors of interleukin-17 immunity. Science 2011; 332: 65-68.

Puel A, Cypowyj S, Marodi L, Abel L, Picard C, Casanova JL. Inborn errors of human IL-17 immunity underlie chronic mucocutaneous candidiasis. Curr Opin Allergy Clin Immunol 2012; 12: 616-622.

Netea MG, Joosten LA, van der Meer JW, Kullberg BJ, van de Veerdonk FL. Immune defence against Candida fungal infections. Nat Rev Immunol 2015; 15: 630-642.

Jeon C, Sekhon S, Yan D, Afifi L, Nakamura M, Bhutani T. Monoclonal antibodies inhibiting IL-12, -23, and -17 for the treatment of psoriasis. Hum Vaccin Immunother 2017; 13: 2247-2259.

Failla V, Nikkels AF. Ustekinumab and herpes zoster. Dermatology 2011; 222: 119-122.

Joost I, Steinfurt J, Meyer PT, Kern WV, Rieg S. Staphylococcus aureus bacteremia with iliac artery endarteritis in a patient receiving ustekinumab. BMC Infect Dis 2016; 16: 586.

Sands BE, Sandborn WJ, Panaccione R, O'Brien CD, Zhang H, Johanns J, et al. Ustekinumab as induction and maintenance therapy for ulcerative colitis. N Engl J Med 2019; 381: 1201-1214.

van de Kerkhof PC, Griffiths CE, Reich K, Leonardi CL, Blauvelt A, Tsai TF, et al. Secukinumab long-term safety experience: a pooled analysis of 10 phase II and III clinical studies in patients with moderate to severe plaque psoriasis. J Am Acad Dermatol 2016; 75: 83-98.e4.

Lindquist M. VigiBase, the WHO Global ICSR database system: basic facts. Drug Informat J 2008; 42: 409-419.

World Health Organization. Uppsala Monitoring Center, Vigibase® 2019 [accessed April 12, 2019] Available from: https: //

Medical Dictionary for Regulatory Activities (MedDRA). 2019 [accessed April 12, 2019] Available from: https: //

World Health Organization, WHODrug Global. 2019 [accessed April 12, 2019] Available from: https: //

Cho JS, Pietras EM, Garcia NC, Ramos RI, Farzam DM, Monroe HR, et al. IL-17 is essential for host defense against cutaneous Staphylococcus aureus infection in mice. J Clin Invest 2010; 120: 1762-1773.

Kang S, Brown HM, Hwang S. Direct antiviral mechanisms of interferon-gamma. Immune Netw 2018; 18: e33.

Archer NK, Adappa ND, Palmer JN, Cohen NA, Harro JM, Lee SK, et al. Interleukin-17A (IL-17A) and IL-17F are critical for antimicrobial peptide production and clearance of staphylococcus aureus nasal colonization. Infect Immun 2016; 84: 3575-3583.

Krishna S, Miller LS. Innate and adaptive immune responses against Staphylococcus aureus skin infections. Semin Immunopathol 2012; 34: 261-280.

Sastalla I, Williams KW, Anderson ED, Myles IA, Reckhow JD, Espinoza-Moraga M, et al. Molecular typing of staphylococcus aureus isolated from patients with autosomal dominant hyper IgE syndrome. Pathogens 2017; 6: 23.

Bagri P, Anipindi VC, Nguyen PV, Vitali D, Stampfli MR, Kaushic C. Novel role for interleukin-17 in enhancing type 1 helper t cell immunity in the female genital tract following mucosal herpes simplex virus 2 vaccination. J Virol. 2017; 91: e01234-17.

Patel NU, Vera NC, Shealy ER, Wetzel M, Feldman SR. A review of the use of secukinumab for psoriatic arthritis. Rheumatol Ther 2017; 4: 233-246.

Ghosh S, Gensler LS, Yang ZJ, Gasink C, Chakravarty SD, Farahi K, et al. Ustekinumab safety in psoriasis, psoriatic arthritis, and crohn's disease: an integrated analysis of phase ii/iii clinical development programs (vol 42, pg 751, 2019). Drug Safety 2019; 42: 809.

Wegscheider BJ, El-Shabrawi L, Weger M, Ardjomand N, Hermann J, Aberer E, et al. Adverse skin reactions to infliximab in the treatment of intraocular inflammation. Eye 2007; 21: 547-549.

Lee HH, Song IH, Friedrich M, Gauliard A, Detert J, Rowert J, et al. Cutaneous side-effects in patients with rheumatic diseases during application of tumour necrosis factor-alpha antagonists. Brit J Dermatol 2007; 156: 486-491.

Wu KK, Lee MP, Lee EB, Wu JJ. Risk of herpes zoster with IL-17 inhibitor therapy for psoriasis and other inflammatory conditions. J Dermatolog Treat 2020; 31: 359-365.

Shalom G, Naldi L, Lebwohl M, Nikkels A, de Jong E, Fakharzadeh S, et al. Biological treatment for psoriasis and the risk of herpes zoster: results from the Psoriasis Longitudinal Assessment and Registry (PSOLAR). J Dermatolog Treat 2019; 30: 534-539.

Failla V, Jacques J, Castronovo C, Nikkels AF. Herpes zoster in patients treated with biologicals. Dermatology 2012; 224: 251-256.

Adelzadeh L, Jourabchi N, Wu JJ. The risk of herpes zoster during biological therapy for psoriasis and other inflammatory conditions. J Eur Acad Dermatol Venereol 2014; 28: 846-852.

Ueda M, Tateishi T, Shigeto H, Yamasaki R, Ohyagi Y, Kira J. [A case of acute disseminated encephalomyelitis associated with Epstein-Barr virus reactivation during infliximab therapy]. Rinsho Shinkeigaku 2010; 50: 461-466 (in Japanese).

Helbling D, Breitbach TH, Krause M. Disseminated cytomegalovirus infection in Crohn's disease following anti-tumour necrosis factor therapy. Eur J Gastroenterol Hepatol 2002; 14: 1393-1395.

Reich K, Papp KA, Blauvelt A, Langley RG, Armstrong A, Warren RB, et al. Bimekizumab versus ustekinumab for the treatment of moderate to severe plaque psoriasis (BE VIVID): efficacy and safety from a 52-week, multicentre, double-blind, active comparator and placebo controlled phase 3 trial. Lancet 2021; 397: 487-498.




How to Cite

Davidson, L., van den Reek, J. M., van Hunsel, F., de Jong, E. M., & Kullberg, B. J. (2022). Global Risk of Bacterial Skin Infections and Herpesviridae Infections with Ustekinumab, Secukinumab, and Tumour Necrosis Factor-alpha Inhibitors: Spontaneous Reports of Adverse Drug Reactions from the World Health Organization Pharmacovigilance Center. Acta Dermato-Venereologica, 102, adv00648.