Integrated safety analysis: Frequency of urinary tract infections in patients with psoriasis treated with ixekizumab
Authors: Saxon D. Smith, Curdin Conrad, Michael Ramharter, Alice Benedix Gottlieb, Himanshu Patel, Wen Xu, Elisabeth Riedl, Christopher Schuster
Journal: Journal of the American Academy of Dermatology (2020)

To the Editor: Urinary tract infections (UTIs) occur very frequently, affecting approximately 150 million people globally each year, and are associated with significant societal and personal burden.1Flores-Mireles A.L. Walker J.N. Caparon M. Hultgren S.J. Urinary tract infections: epidemiology, mechanisms of infection and treatment options.Nat Rev Microbiol. 2015; 13: 269-284Crossref PubMed Scopus (1665) Google Scholar Lower UTIs, limited to the urethra and bladder, are generally uncomplicated and afebrile, whereas upper UTIs involving the kidneys and ureters are usually complicated and febrile. To date, clinical studies into interleukin 17 (IL-17) inhibitors have not identified UTI adverse events (AEs) as safety signals.2Langley R.G. Kimball A.B. Nak H. et al.Long-term safety profile of ixekizumab in patients with moderate-to-severe plaque psoriasis: an integrated analysis from 11 clinical trials.J Eur Acad Dermatol Venereol. 2019; 33: 333-339Crossref PubMed Scopus (44) Google Scholar,3Deodhar A. Mease P.J. McInnes I.B. et al.Long-term safety of secukinumab in patients with moderate-to-severe plaque psoriasis, psoriatic arthritis, and ankylosing spondylitis: integrated pooled clinical trial and post-marketing surveillance data.Arthritis Res Ther. 2019; 21: 111Crossref PubMed Scopus (176) Google Scholar One recent real-world evidence study identified 3 cases (incidence rate per 100 person-years [IR], 0.64; 95% confidence interval [CI], 0.2-2.0) of upper UTI in patients with psoriasis exposed to IL-17 inhibitors, suggesting that these may be class-specific AEs.4Sahuquillo-Torralba A. Carretero G. Rivera R. et al.The risk of urinary tract infections in patients with psoriasis on systemic medications in Biobadaderm registry: a prospective cohort study.J Am Acad Dermatol. 2019; 82: 738-741Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar We performed an integrated safety analysis of the frequency of UTIs in clinical trial patients with psoriasis treated with the IL-17A antagonist ixekizumab. Integrated analysis of 6091 patients with psoriasis (17,499 person-years) treated with ixekizumab in 14 clinical trials showed treatment-emergent AEs for upper UTI (n = 23; IR, 0.1; 95% CI, 0.1-0.2), lower UTI (n = 424; IR, 2.4; 95% CI, 2.2-2.7), and prostatitis (n = 12; IR, 0.1; 95% CI, 0.0-0.1). Analyses comparing UTI rates for ixekizumab, placebo, etanercept, and ustekinumab showed no statistical significance in IR between ixekizumab and other treatment groups (Table I).Table IUrinary tract infection (UTI) incidence rate per 100 person-years (IR) in patients with psoriasis in clinical trials who received placebo (PBO), ixekizumab (IXE), etanercept (ETN), or ustekinumab (UST)VariableDouble-blind 0-12 weeks: UNCOVER-2 (NCT01597245), UNCOVER-3 (NCT01646177)Double-blind 0-52 weeks: IXORA-S (NCT02561806)All IXE exposure up to 5 years∗Naïve pooling: Total of numerators divided by total of denominators. (14 psoriasis studies)†Psoriasis studies: I1F-EW-RHBZ, I1F-JE-RHAT, I1F-MC-RHAG, I1F-MC-RHAJ, I1F-MC-RHAZ, I1F-MC-RHBA, I1F-MC-RHBC, I1F-MC-RHBL, I1F-MC-RHBP, I1F-MC-RHBQ, I1F-MC-RHBS, I1F-MC-RHBU, I1F-MC-RHCD, I1F-US-RHBO.PBOIXEETNIXEUSTIXETotal patients, No.36014637391661356091Total person-years‡Total person-years: Total time at risk in years.83.2336.5169.2159.5131.417,499Patients with ≥1 upper UTI No.0100023 IR (95% CI)0.0 (NA)0.3 (0.04-2.11)0.0 (NA)0.0 (NA)0.0 (NA)0.1 (0.1-0.2)Patients with ≥1 lower UTI No.326745424 IR (95% CI)3.6 (1.16-11.2)7.7 (5.26-11.4)4.1 (1.97-8.68)2.5 (0.94-6.68)3.8 (1.58-9.15)2.4 (2.2-2.7)Patients with ≥1 prostatitis No.0101012 IR (95% CI)0.0 (NA)0.3 (0.04-2.11)0.0 (NA)0.6 (0.09-4.45)0.0 (NA)0.1 (0.0-0.1)CI, Confidence interval; NA, not available.∗ Naïve pooling: Total of numerators divided by total of denominators.† Psoriasis studies: I1F-EW-RHBZ, I1F-JE-RHAT, I1F-MC-RHAG, I1F-MC-RHAJ, I1F-MC-RHAZ, I1F-MC-RHBA, I1F-MC-RHBC, I1F-MC-RHBL, I1F-MC-RHBP, I1F-MC-RHBQ, I1F-MC-RHBS, I1F-MC-RHBU, I1F-MC-RHCD, I1F-US-RHBO.‡ Total person-years: Total time at risk in years. Open table in a new tab CI, Confidence interval; NA, not available. Of 14 upper UTIs deemed serious AEs (SAEs), a review of patient histories showed 12 patients (85.7%) had a history of UTI or predisposing factors, or both, 9 (64.3%) were categorized with obesity (body mass index ≥30.0 kg/m2), and 9 (64.3%) were aged >50 years (Table II). None of the patients received additional immunosuppressive treatment (eg, methotrexate) or were otherwise immunocompromised (eg, HIV, diabetes).Table IIIndividual patient profiles for upper urinary tract infection (UTI) serious adverse events in patients with psoriasis treated with ixekizumab∗Data shown are upper UTI serious adverse events data arising from 6091 patients across 14 psoriasis studies: I1F-EW-RHBZ, I1F-JE-RHAT, I1F-MC-RHAG, I1F-MC-RHAJ, I1F-MC-RHAZ, I1F-MC-RHBA, I1F-MC-RHBC, I1F-MC-RHBL, I1F-MC-RHBP, I1F-MC-RHBQ, I1F-MC-RHBS, I1F-MC-RHBU, I1F-MC-RHCD, and I1F-US-RHBO.Age (y)SexBaseline BMI (kg/m2)Infective agentUTI historyPredisposing factors54M24.2E coliKidney stones74F34.0E coliUTIs in medical history38F22.1E coli38M44.1E coli21F29.2E coliChalices neck stenosis58F39.6E coliKidney stones54F49.6E coliAtrophic left kidney, chronic renal failure73M37.2E faecalisUTIs in medical historyBenign prostatic hyperplasia66F33.8K pneumoniaeBladder neck polyps72M29.2K pneumoniaeTURP71M30.1MRSABenign prostatic hyperplasia50F47.3UnknownUTIs in medical historyKidney stones26M33.2UnknownKidney stones32F27.4UnknownUTIs in medical historyBMI, Body mass index; E coli, Escherichia coli; E faecalis, Enterococcus faecalis; K pneumoniae, Klebsiella pneumoniae; MRSA, methicillin-resistant Staphylococcus aureus; TURP, transurethral resection of the prostate.∗ Data shown are upper UTI serious adverse events data arising from 6091 patients across 14 psoriasis studies: I1F-EW-RHBZ, I1F-JE-RHAT, I1F-MC-RHAG, I1F-MC-RHAJ, I1F-MC-RHAZ, I1F-MC-RHBA, I1F-MC-RHBC, I1F-MC-RHBL, I1F-MC-RHBP, I1F-MC-RHBQ, I1F-MC-RHBS, I1F-MC-RHBU, I1F-MC-RHCD, and I1F-US-RHBO. Open table in a new tab BMI, Body mass index; E coli, Escherichia coli; E faecalis, Enterococcus faecalis; K pneumoniae, Klebsiella pneumoniae; MRSA, methicillin-resistant Staphylococcus aureus; TURP, transurethral resection of the prostate. This integrated safety analysis found that the reported UTI IR with ixekizumab is low, and so contrasts with the Spanish registry data that showed increased febrile UTI with anti–IL-17 use.4Sahuquillo-Torralba A. Carretero G. Rivera R. et al.The risk of urinary tract infections in patients with psoriasis on systemic medications in Biobadaderm registry: a prospective cohort study.J Am Acad Dermatol. 2019; 82: 738-741Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar However, comparing both outcomes is difficult because the registry data used grouped analysis of multiple unspecified anti–IL-17 agents and short sampling duration (466 person-years), and clinical trials may not adequately represent all patient groups.5Garcia-Doval I. Carretero G. Vanaclocha F. et al.Risk of serious adverse events associated with biologic and nonbiologic psoriasis systemic therapy: patients ineligible vs eligible for randomized controlled trials.Arch Dermatol. 2012; 148: 463-470Crossref PubMed Scopus (139) Google Scholar Review of the medical histories of ixekizumab-treated patients who developed upper UTI SAEs in our clinical studies (Table II) showed most patients had known risk factors to UTI development (increased age, high body mass index, UTI history, predisposing factors, or a combination of these). UTI SAEs were caused by Escherichia coli, Klebsiella pneumoniae, and Enterococcus faecalis, which is expected given their dominance as drivers of UTI.1Flores-Mireles A.L. Walker J.N. Caparon M. Hultgren S.J. Urinary tract infections: epidemiology, mechanisms of infection and treatment options.Nat Rev Microbiol. 2015; 13: 269-284Crossref PubMed Scopus (1665) Google Scholar Although clinical trial populations may not represent typical real-world patient populations, trial data comprising 17,499 person-years shows that ixekizumab treatment carries a low overall UTI rate and does not show ixekizumab is related to an increased UTI rate vs placebo, etanercept, or ustekinumab. In UTI SAEs that occurred in the ixekizumab-treated trial population, an in-depth analysis of patient histories revealed most patients were predisposed to UTIs based on known risk factors. Considering predisposing factors is important when evaluating infection rates in patients with psoriasis and when judging the suitability of anti–IL-17 agents or any other biologic for patients with psoriasis. The authors would like to thank Omar Mahfoud, PhD, an employee of Eli Lilly and Company, for writing and editorial contributions.