Research letters 865 centres. Randomized controlled studies are required to confirm Funding sources: none. that our patients should be offered more individualized treat- ment regimens. Conflicts of interest: the authors declare they have no conflicts of interest. Acknowledgments: the authors recognize the contributions of Drs Raffaele Dante Caposiena Caro, Giovanni Damiani, Isabelle Delorme, Jose Carlos Pascual, Ziad Reguiai, Anastasia Trigoni Integrated safety analysis of treatment- and Eva Vilarrasa in providing patients’ data for the study by emergent eczematous reactions in patients Zouboulis et al.4 The Departments of Dermatology, Venereol- with moderate-to-severe psoriasis treated with ogy, Allergology and Immunology, Dessau Medical Center, ixekizumab, etanercept and ustekinumab Dessau, Germany are healthcare providers of the European DOI: 10.1111/bjd.20527 Reference Network for Rare and Complex Skin Diseases (ERN Skin – ALLOCATE Skin group). DEAR EDITOR, Eczema and eczematous reactions induced by inter- leukin (IL)-17 inhibitors in patients with psoriasis are estab- lished adverse events.1 They may be reported as adverse events E.M. Sanchez Martınez iD ,1 G. Murray iD ,2 F. Alfageme (AEs) in up to 121% of patients on anti-IL-17 treatment in con- Roldan,3 R. Garcıa Ruiz,1 A.M. Tobin2,4 and C.C. Zouboulis4,5 trolled clinical trials.2–5 We performed an integrated safety anal- 1 Department of Dermatology, University Hospital Doctor Peset, Valencia, ysis of 13 clinical studies to evaluate the frequency and Spain; 2Department of Dermatology, Tallaght University Hospital, Dublin, management of the treatment-emergent AEs (TEAEs) of eczema Ireland; 3Department of Dermatology, University Hospital Puerta De Hierro and clinical variants in patients with moderate-to-severe psoria- Majadahonda, Madrid, Spain; 4European Hidradenitis Suppurativa Foundation sis treated with ixekizumab (IXE), a selective inhibitor of IL- e.V., Dessau, Germany; and 5Departments of Dermatology, Venereology, 17A, to understand better the nature of these events. Allergology and Immunology, Dessau Medical Center, Brandenburg Medical Integrated analysis of 5930 patients with psoriasis (17 367 School Theodor Fontane and Faculty of Health Sciences Brandenburg, Dessau, patient-years) treated with IXE for up to 5 years in a clinical trial Germany setting showed that 361 patients (61%) had TEAEs. These events Email: eva.sanchez.m.92@gmail.com were defined by the Medical Dictionary for Regulatory Activities (MedDRA) preferred terms of eczema, dermatitis, dyshidrotic References eczema, allergic dermatitis, atopic dermatitis, asteatotic eczema, neurodermatitis, hand dermatitis, nummular eczema and vesicular 1 Kimball AB, Okun MM, Williams DA et al. Two phase 3 trials of eczema. Of these 361 patients, 335 (928%) were < 65 years old, adalimumab for hidradenitis suppurativa. N Engl J Med 2016; 245 (679%) were male, and 289 (801%) were of white ethnic- 375:422–34. 2 Zouboulis CC, Okun MM, Prens EP et al. Long-term adalimumab ity. The baseline characteristics are reflective of the entire study efficacy in patients with moderate-to-severe hidradenitis suppura- population. At the time of IXE treatment initiation, 78 patients tiva/acne inversa: 3-year results of a phase 3 open-label extension (216%) had undergone previous treatment with biologics, and study. J Am Acad Dermatol 2019; 80:60–9. 74 (205%) had a history of atopy and/or allergic disease. 3 Marzano AV, Genovese G, Casazza G et al. Evidence for a ‘window of Of the 361 patients with eczematous reactions, 268 (742%) opportunity’ in hidradenitis suppurativa treated with adalimumab: a retro- experienced one event; the mean number of events per patient spective, real-life multicentre cohort study. Br J Dermatol 2021; 184:133–40. experiencing at least one eczematous reaction was 14. Events 4 Zouboulis CC, Hansen H, Caposiena Caro RD et al. Adalimumab dose intensification in recalcitrant hidradenitis suppurativa/acne were mostly mild, and three patients (08%) discontinued IXE inversa. Dermatology 2020; 236:25–30. due to eczematous reactions. Significant differences were 5 Morita A, Takahashi H, Ozawa K et al. Long-term analysis of adali- observed between patients who experienced eczematous reactions mumab in Japanese patients with moderate to severe hidradenitis and those who did not for baseline alcohol use (349% vs. suppurativa: open-label phase 3 results. J Dermatol 2021; 48:3–13. 233%, respectively, P < 0001), tobacco use (211% vs. 143%, 6 Bettoli V, Manfredini M, Calamo G et al. Long-term adalimumab P < 0001) and history of eczema (30% vs. 08%, P < 0001). treatment of hidradenitis suppurativa: results and practical Patients with eczema [n = 169, incidence rate per 100 patient- insights from a real-life experience. Dermatol Ther 2018; 31: e12737. years (IR) 10, 95% confidence interval (CI) 08–1.1] and der- 7 Frew JW, Jiang CS, Singh N et al. Clinical response rates, placebo matitis (n = 92, IR 05, 95% CI 04–06) accounted for the response rates, and significantly associated covariates are dependent majority of the 361 patients with eczematous reactions (Table 1). on choice of outcome measure in hidradenitis suppurativa: a post The median times to onset for eczema and dermatitis were 292 hoc analysis of PIONEER 1 and 2 individual patient data. J Am Acad and 466 days, respectively. The median duration of AEs was Dermatol 2020; 82:1150–7. 121 weeks (range 01–274). Of the 361 patients with eczema- 8 Caposiena Caro RD, Chiricozzi A, Sechi A et al. Factors related to tous reactions, 645% received some treatment, with topical cor- the onset and recurrence of flares in hidradenitis suppurativa patients treated with adalimumab. Ital J Dermatol Venerol 2021; ticosteroids (TCS) as the predominant therapy (468%). The https://doi.org/10.23736/S2784-8671.21.06966-8 median duration of TCS use was 46 weeks (range 03–267). © 2021 Eli Lilly and Company. British Journal of Dermatology British Journal of Dermatology (2021) 185, pp840–867 published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. 866 Research letters Table 1 Incidence rates of cutaneous adverse events (AEs) in patients with psoriasis in clinical trials who received either placebo (PBO), etanercept (ETN), ixekizumab (IXE) or ustekinumab (UST) Double-blind 0–12 weeks UNCOVER-2 (NCT01597245) Double-blind 0–52 weeks UNCOVER-3 (NCT01646177) IXORA-S (NCT02561806) All IXE exposure up to 5 years Parameter PBO ETNa IXE USTb IXE IXEc Total patients 360 739 1463 166 135 5930 Total patient-yearsd 832 1692 3365 1595 1314 17 367 AEse,f 0 5 (30) 13 (39) 2 (13) 5 (38) 361 (21) Eczema 0 3 (18) 5 (15) 0 2 (15) 169 (10) Dermatitisg 0 2 (12) 6 (18) 0 1 (08) 92 (05) Dyshidrotic eczema 0 0 1 (03) 0 1 (08) 33 (02) Allergic dermatitis 0 0 0 0 0 26 (01) Atopic dermatitis 0 0 0 0 0 20 (01) Asteatotic eczema 0 0 0 1 (06) 0 19 (01) Neurodermatitis 0 0 0 1 (06) 1 (08) 19 (01) Hand dermatitis 0 0 1 (03) 0 0 17 (01) Nummular eczema 0 0 0 0 0 7 (00) Vesicular eczema 0 0 0 0 0 1 (0) Relative risks for all AEs IXE vs. ETN: 1.3 IXE vs. UST: 30 IXE vs. PBO: not applicable The results are descriptive and presented as n (incidence rate per 100 patient-years) unless noted otherwise. The psoriasis studies are 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 and I1F-US-RHBO. aEtanercept 50 mg twice weekly. bUstekinumab 45 mg or 90 mg at weeks 0, 4, 16, 28 and 40. cIxekizumab 80 mg every 2 weeks or every 4 weeks after a 160-mg starting dose. dTotal time patients were in each treat- ment period. eAdverse events are coded using Medical Dictionary for Regulatory Activities version 221. fContact dermatitis was not included. g Dermatitis did not include psoriasis. Analyses comparing rates for IXE, placebo (PBO), etanercept inhibitors, can sometimes resemble eczema, and differentiation (ETN) and ustekinumab (UST) showed no clinically meaningful in the clinical setting could be ambiguous.6 Also, the patient- differences in overall IRs for eczematous reactions between IXE years method used in reporting AEs may potentially miss early- and other treatments (Table 1). onset or late-onset AEs.7 While the difference was not statisti- With increased use of biologic therapies for psoriasis, reports of cally significant, numerically more events were reported for eczematous reactions potentially associated with their use have patients receiving IXE than those receiving ETN or UST. been observed, in some cases in up to 121% of patients. Here we In summary, trial data comprising 17 367 patient-years report an integrated safety analysis from 13 psoriasis studies demonstrated that the overall frequency of eczematous reactions regarding the frequency, clinical subtypes, predisposing factors, was low across the treatments, and no statistically significant dif- time of onset and treatment discontinuations in patients develop- ferences were noted between IXE, ETN and UST. The events were ing eczematous reactions while receiving IXE and, for comparison, generally mild in nature, appeared more often in patients with a PBO, ETN and UST. Numerical values for history of allergic events history of eczema, and rarely led to treatment discontinuation. and history of eczema were higher for those patients who devel- oped eczematous reactions. Numerical differences in alcohol and tobacco consumption were also noted, although the significance Acknowledgments: we would like to thank Chenyun Tan, of these associations is not clear. Our findings differ from previ- PharmD, an employee of Eli Lilly and Company, for medical ously published data;5 however, those results were limited by a writing assistance. small sample size and no information about predisposing factors. Real-world evidence depicts data from more diversified set- tings than clinical trials. While the two types of data supplement P.M. Brunner iD ,1 C. Conrad,2 R. Vender iD ,3 S. Grond,4 each other, data from clinical trials allow for more stringent C. Schuster,1,4 H. Patel,4 W. Xu4 and J.M. Carrascosa Carrillo5 1 analysis due to the controlled environment. Although patients in Department of Dermatology, Medical University of Vienna, Vienna, Austria; 2 clinical trials may not entirely reflect real-world patient popula- Department of Dermatology, Lausanne University Hospital CHUV, Lausanne, tions, our integrated safety analysis included 5930 patients, Switzerland; 3Dermatrials Research Inc, Hamilton, ON, Canada; 4Eli Lilly minimizing selection and information bias. Limitations of this and Company, Indianapolis, IN, USA; and 5Department of Dermatology, analysis include potential misdiagnosis or reporting error of Hospital Universitari Germans Trias I Pujol, Universitat Autonoma de eczematous reactions. For instance, paradoxical psoriasis, an Barcelona, Barcelona, Spain adverse event more specific for tumour necrosis factor-a Email: patrick.brunner@meduniwien.ac.at British Journal of Dermatology (2021) 185, pp840–867 © 2021 Eli Lilly and Company. British Journal of Dermatology published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists Research letters 867 7 Paterson KR. Events per person year. Can obscure the true risk of References certain adverse drug reactions. BMJ 1995; 310:1470. 1 Lai F, Higgins E, Smith C et al. Morphologic switch from psoriasi- form to eczematous dermatitis after anti-IL-17 therapy: a case ser- Funding sources: Eli Lilly and Company. ies. JAMA Dermatol 2019; 155:1082–4. 2 Napolitano M, Megna M, Fabbrocini G et al. Eczematous eruption Conflicts of interest: P.M.B. is an employee of the Medical University during anti-interleukin 17 treatment of psoriasis: an emerging con- of Vienna; has received personal fees from LEO Pharma, Pfizer, Sanofi, dition. Br J Dermatol 2019; 181:604–6. Eli Lilly and Company, Novartis, Celgene, UCB Pharma, Biotest, Boeh- 3 Caldarola G, Pirro F, Di Stefani A et al. Clinical and histopathological ringer Ingelheim, AbbVie, Amgen and Arena Pharmaceuticals; is an characterization of eczematous eruptions occurring in course of anti investigator for Novartis (grant paid to his institution); and has IL-17 treatment: a case series and review of the literature. Expert Opin received a grant from Celgene (paid to his institution). C.C. has served Biol Ther 2020; 20:665–72. as a scientific adviser and/or clinical study investigator for AbbVie, 4 Al-Janabi A, Foulkes AC, Mason K et al. Phenotypic switch to Actelion, Almirall, Amgen, Celgene, Eli Lilly and Company, Galderma, eczema in patients receiving biologics for plaque psoriasis: a sys- Janssen, LEO Pharma, MSD, Novartis, Pfizer and UCB. R.V. has partici- tematic review. J Eur Acad Dermatol Venereol 2020; 34:1440–8. pated in clinical trials and has received honoraria for acting as a con- 5 Saeki H, Nakagawa H, Nakajo K et al. Efficacy and safety of ixek- sultant for and/or as a speaker at events sponsored by AbbVie, izumab treatment for Japanese patients with moderate to severe pla- Amgen, Boehringer Ingelheim, Celgene, Eli Lilly, Galderma, GSK, Jans- que psoriasis, erythrodermic psoriasis and generalized pustular sen, LEO Pharma, MSD, Novartis, Pfizer and UCB. S.G., C.S., H.P. and psoriasis: results from a 52-week, open-label, phase 3 study W.X. are employees and minor stockholders of Eli Lilly and Company. (UNCOVER-J). J Dermatol 2017; 44:355–62. J.M.C.C. has received speaker and consultant fees from Sanofi and as 6 Conrad C, Di Domizio J, Mylonas A et al. TNF blockade induces a dysregulated type I interferon response without autoimmunity in an investigator in clinical trials for Sanofi, Eli Lilly and Company, LEO paradoxical psoriasis. Nat Commun 2018; 9:25. Pharma, Pfizer and Amgen. © 2021 Eli Lilly and Company. British Journal of Dermatology British Journal of Dermatology (2021) 185, pp840–867 published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists