Reaching complete or near-complete resolution of psoriasis: benefit and risk considerations

Dear Editor, The incremental benefits of obtaining high levels of skin clearance for patients with psoriasis have been established across several patient‐reported outcomes (PROs). Patients who obtain clear or almost‐clear skin are more likely to report that psoriasis has no impact on their health‐related quality of life (HRQoL) and other measures of symptoms.1,2,3 Although the benefits of obtaining high skin clearance have been reported using different therapeutic agents, the question of whether the benefits of such high levels of response may be offset by an increased risk for adverse outcomes has not been fully explored with biologics.4 In this study improvements in HRQoL and psoriasis symptoms in patients with increased skin clearance were examined in relationship to adverse events (AEs) to determine whether higher levels of skin clearance were associated with greater risks for AEs. Data were obtained from two phase‐III trials of ixekizumab in patients with moderate‐to‐severe plaque psoriasis (UNCOVER‐2 and UNCOVER‐3). The primary study design and outcomes have been reported elsewhere.5,6 Efficacy of skin clearance was assessed using the Psoriasis Area and Severity Index (PASI). Following 12 weeks of treatment with a placebo, etanercept (ETN; 50‐mg twice weekly) or the interleukin (IL)‐17A antagonist, ixekizumab (80 mg every 2 weeks or every 4 weeks after a starting dose of 160 mg), data from all groups were combined and categorized into four groups by the percentage improvement in PASI achieved at week 12: PASI < 75 (< 75% improvement); PASI 75 to < 90 (improvement ≥ 75% but less than 90%); PASI 90 to < 100 (near‐complete resolution) and PASI 100 (complete resolution). PROs included the Dermatology Life Quality Index (DLQI; ≥ five‐point change = minimally clinical important difference);7,8 the Medical Outcomes Survey Short Form‐36 item (SF‐36), including mental and physical component summary scores;9 the itch numeric rating scale (NRS; ≥ four‐point change = minimally clinical important difference);10 and the skin–pain Visual Analogue Scale. Safety was assessed by the incidence of treatment‐emergent AEs (TEAEs), including infections, serious AEs (SAEs) and discontinuations of treatment due to AEs. Groups were formed based on PASI improvement scores at week 12 after the imputation of missing data using the last observation carried forward (LOCF). For categorical variables, associations between PASI improvement and PROs at week 12 (LOCF) were evaluated using the Cochran–Armitage trend test and logistic model. For continuous variables ancova models were used. Associations of safety events and PASI improvements were also assessed using the Cochran–Armitage trend test. At week 12 one‐third of patients had < 75% PASI improvement from baseline and two‐thirds had PASI improvements evenly distributed across higher levels of skin improvement (Table 1). Most patients with PASI < 75 were in the placebo (n = 341, 38%) or ETN (n = 380, 42%) groups, while most of the PASI 100 patients were in the ixekizumab every 4 weeks (n = 246, 42%) and ixekizumab every 2 weeks (n = 293, 50%) groups. Patient‐reported outcomes and safety analyses at week 12 AE, adverse event; DLQI, Dermatology Life Quality Index; LSM, least squares mean; PASI, Psoriasis Area Severity Index; SAEs, serious adverse events; SE, standard error; SF‐36, 36‐Item Short Form survey; SOC, system organ class; TEAEs, treatment‐emergent adverse effects; VAS, visual analogue scale. *P < 0·001 vs. < 75. †P < 0·001 vs. 75 to < 90. ‡P < 0·01 vs. 90 to < 100 via logistic regression for categorical data and ancova model (adjusting for PASI group, study, and baseline health outcome score) for continuous data. P‐values greater than 0·01 are significant. aAmong patients with a DLQI total score ≥ five at baseline. bAmong patients with itch numeric rating scale (NRS) ≥ four at baseline. cFor determining the percentages of each group, the numerator is the number of patients experiencing at least one TEAE in that PASI improvement group; the denominator is the total number of patients in each PASI improvement group. dCandida high‐level terms, with Medical Dictionary for Regulatory Activities preferred terms for TEAEs likely to represent Candida infections (fungal oesophagitis, oral fungal infection, oropharyngitis fungal, vulvovaginal mycotic infection). eOral candidiasis; oral fungal infection, oropharyngeal candidiasis. fP‐value derived from Cochran–Armitage Trend test for categorical responses and safety, and from the test of the overall PASI group effect with ancova model for continuous outcomes. Patient‐reported outcomes and safety analyses at week 12 AE, adverse event; DLQI, Dermatology Life Quality Index; LSM, least squares mean; PASI, Psoriasis Area Severity Index; SAEs, serious adverse events; SE, standard error; SF‐36, 36‐Item Short Form survey; SOC, system organ class; TEAEs, treatment‐emergent adverse effects; VAS, visual analogue scale. *P < 0·001 vs. < 75. †P < 0·001 vs. 75 to < 90. ‡P < 0·01 vs. 90 to < 100 via logistic regression for categorical data and ancova model (adjusting for PASI group, study, and baseline health outcome score) for continuous data. P‐values greater than 0·01 are significant. aAmong patients with a DLQI total score ≥ five at baseline. bAmong patients with itch numeric rating scale (NRS) ≥ four at baseline. cFor determining the percentages of each group, the numerator is the number of patients experiencing at least one TEAE in that PASI improvement group; the denominator is the total number of patients in each PASI improvement group. dCandida high‐level terms, with Medical Dictionary for Regulatory Activities preferred terms for TEAEs likely to represent Candida infections (fungal oesophagitis, oral fungal infection, oropharyngitis fungal, vulvovaginal mycotic infection). eOral candidiasis; oral fungal infection, oropharyngeal candidiasis. fP‐value derived from Cochran–Armitage Trend test for categorical responses and safety, and from the test of the overall PASI group effect with ancova model for continuous outcomes. At week 12, significantly better PROs were found in the groups with greater PASI improvements than those with lower PASI responses (Table 1). Specifically, for itch NRS outcomes and DLQI (0, 1), each incremental increase in PASI response was associated with significantly better PROs. With regard to safety, the frequency of patients reporting at least one TEAE was significantly greater (P < 0·008) in those with higher levels of improvement in their skin. However, significantly fewer patients with higher levels of skin improvement reported at least one severe TEAE (P = 0·021) or discontinued treatment due to AEs (P = 0·038; Table 1). There were no statistically significant associations between skin improvements and infections or SAEs (Table 1, Fig. 1). Among patients treated with ixekizumab there were no significant associations between skin improvements and rates of TEAEs or SAEs (every 4 weeks: TEAE P = 0·818, SAE P = 0·368, every 2 weeks: TEAE P = 0·099, SAE P = 0·255). Severity and frequency of overall adverse events, serious adverse events, and infections among Psoriasis Area and Severity Index (PASI) improvement groups. (a) Percentage of patients in each PASI improvement group reporting at least one treatment‐emergent adverse event (TEAE) (left) or at least one mild, moderate or severe TEAE at week 12. (b) Percentage of patients in each PASI improvement group reporting at least one infection by week 12. (c) Percentage of patients in each PASI improvement group reporting at least one severe adverse event (SAE) at week 12 (left) or at least one SAE of infection (right). For all charts, P‐values were determined by Cochran–Armitage trend tests. The findings of the present study indicate that patients attaining near‐complete or complete resolution of psoriasis had more beneficial PROs than patients who had lower levels of skin improvement. The increased benefits observed in patients with higher levels of improvement (i.e. PASI ≥ 90) suggest that, while PASI 75 remains a clinically meaningful response to treatment, physicians should also recognize the benefits of attaining greater clearance with treatment. The increased benefit of skin clearance resulted in clinically important and meaningful improvements in patients’ lives and they could be obtained within an acceptable safety profile. This conclusion should be considered within the context of the limitations stemming from the short‐term treatment period in this study (i.e. a potential selection bias in PASI groupings, lack of power for detecting rare safety events and the use of high‐level safety outcomes). Future studies are needed to understand the associations between long‐term skin improvement and long‐term safety. With the novel biological therapies that are being developed and approved for use in psoriasis, including IL‐17 antagonists, physicians can now recommend treatments that provide the highest levels of skin improvements seen to date. Although higher levels of efficacy associated with nonbiologic systemic therapies, such as methotrexate and ciclosporin, have been associated with higher risks of AEs and SAEs,4 the present study provides additional evidence to support a paradigm shift when considering this issue in the context of biological therapy. The study protocols were approved by the ethical review board at each study centre. The studies were conducted in full accordance with the Good Clinical Practice: Consolidated Guidance that was approved by the International Conference on Harmonization and applicable laws or regulations. Written, informed consent was obtained from each patient at study entry before any study procedures took place. Trial registration nos: NCT01597245, NCT01646177. The authors would like to thank Dr. Kristin Hollister, PhD, for her writing and editorial support on this manuscript. C.E.M.G. is a National Institute for Health Research Senior Investigator. Funding sources: This study was funded in full by Eli Lilly and Co., Indianapolis, IN, U.S.A. Conflicts of interest: A.B. has served as a scientific adviser and clinical study investigator for Amgen, AbbVie, Boehringer Ingelheim, Celgene, Dermira, Genentech, GlaxoSmithKline, Janssen, Eli Lilly and Co., Merck, Novartis, Pfizer, Regeneron, Sandoz, Sanofi Genzyme, Sun Pharma, USB and Valeant, and as a paid speaker for Eli Lilly and Co., Regeneron and Sanofi Genzyme; C.E.M.G. has received honoraria or research funds from AbbVie, Actelion, Amgen, Celgene, Janssen, LEO Pharma, Eli Lilly and Co., MSD, Novartis, Pfizer, Regeneron, Roche, Sandoz and UCB Pharma; M.L. is an employee of the Mount Sinai Medical Center, which receives research funds from Amgen, Anacor, Boehringer Ingelheim, Celgene, Lilly, Janssen Biotech, Kadmon, LEO Pharma, Medimmune, Novartis, Pfizer, Sun Pharmaceuticals and Valeant; U.M. has been an advisor or received speakers’ honoraria or grants, or participated in clinical trials of the following companies: Abbott/AbbVie, Almirall‐Hermal, Amgen, BASF, Biogen Idec, Boehringer‐Ingelheim, Celgene, Centocor, Eli Lilly and Co., Foamix, Forward Pharma, Galderma, Janssen, LEO Pharma, Medac, MSD, Miltenyi Biotech, Novartis, Pfizer, Teva, VBL and XenoPort; L.P. has participated in clinical trials or received honoraria as a consultant, investigator, speaker or advisory board member from AbbVie, Amgen, Biogen, Boehringer Ingelheim, Celgene, Janssen, Eli Lilly and Co., LEO Pharma, Merck‐Serono, MSD, Novartis, Pfizer, Regeneron, Roche and VBL; E.E.‐H., B.Z., E.N., L.Z., C‐Y.L., S.B., M.W., D.D. and L.M. are employees of Eli Lilly and Co. and therefore receive salaries and own stock in the company; K.R. has served as advisor or paid speaker, or participated in clinical trials sponsored by AbbVie, Amgen, Biogen, Boehringer Ingelheim Pharma, Celgene, Centocor, Covagen, Forward Pharma, GlaxoSmithKline, Janssen‐Cilag, LEO Pharma, Eli Lilly and Co., Medac, Merck Sharp & Dohme Corp., Novartis, Ocean Pharma, Pfizer, Regeneron, Takeda, UCB Pharma and XenoPort.

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