BJD British Journal of Dermatology. Summary. What s already known about this topic? What does this study add? THERAPEUTICS

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1 THERAPEUTICS BJD British Journal of Dermatology improves nail disease in patients with moderate-to-severe psoriasis: results from PHOENIX 1 P. Rich, 1 M. Bourcier, 2 H. Sofen, 3 S. Fakharzadeh, 4 Y. Wasfi, 5 Y. Wang, 5 U. Kerkmann, 6 P.-D. Ghislain 7 and Y. Poulin; 8 on behalf of the PHOENIX 1 investigators 1 Dermatology and Clinical Research, Oregon Health Science University, 2565 NW Lovejoy Street, Suite 200, Portland, OR 97210, U.S.A. 2 Dermatology Clinic, Moncton, NB, Canada 3 UCLA School of Medicine, Los Angeles, CA, U.S.A. 4 Janssen Biotech, Inc., Horsham, PA, U.S.A. 5 Janssen Research & Development LLC, Spring House, PA, U.S.A. 6 Janssen Biologics BV, Leiden, The Netherlands 7 St-Luc University Hospital, Brussels, Belgium 8 Centre Dermatologique du Quebec Metropolitain, Quebec City, QC, Canada Summary Correspondence Phoebe Rich. phoeberich@aol.com Accepted for publication 11 September 2013 Funding sources This study was sponsored by Janssen Biotech, Inc., Spring House, Pennsylvania. Conflicts of interest Conflicts of interest statements can be found in the Appendix. DOI /bjd Background Most patients with psoriasis have nail changes, and treating nail psoriasis is challenging. Objectives To assess improvement in fingernail psoriasis with ustekinumab treatment in the PHOENIX 1 trial. Methods Patients received ustekinumab 45 mg or 90 mg, or placebo at weeks 0 and 4. -randomized patients continued maintenance dosing every 12 weeks, while patients receiving placebo crossed over to receive ustekinumab 45 mg or 90 mg at weeks 12/16 followed by dosing every 12 weeks. At week 40, initial responders [those with 75% improvement from baseline in Psoriasis Area and Severity Index (PASI 75)] were rerandomized either to continue maintenance dosing or to withdraw from treatment. Nail involvement was evaluated using the Nail Psoriasis Severity Index (NAPSI) on a target fingernail, Nail Physician s Global Assessment (Nail PGA) and mean number of nails involved. Results Of 766 randomized patients, 545 (711%) had nail psoriasis. At week 24, the percentage improvement from baseline NAPSI score was 465% (ustekinumab 45 mg) and 487% (ustekinumab 90 mg). Percentage improvements in NAPSI ranged from 297% (PASI < 50) to 573% (PASI 90). Mean NAPSI scores improved from 45 at baseline to 24 at week 24 (45 mg) and from 44 to22 (90 mg). Nail PGA scores and the mean number of psoriatic nails improved by week 24. Further improvement was observed for all end points among initial responders continuing maintenance treatment through week 52. Conclusions significantly improves nail psoriasis, and improvements continue over time until up to 1 year of treatment in those receiving maintenance treatment. What s already known about this topic? The majority of patients with moderate-to-severe psoriasis have nail manifestations, for which limited therapies are available. What does this study add? Beyond the recognized benefit to the skin in psoriasis, ustekinumab significantly improves nail psoriasis over time. Both nail and skin manifestations of psoriasis should be considered when choosing treatment. 398 British Journal of Dermatology (2014) 170, pp British Association of Dermatologists

2 effectively treats nail psoriasis, P. Rich et al. 399 While psoriasis is an inflammatory disorder with clinical features primarily involving the skin, nail involvement may be present in up to 80% of patients with psoriasis or psoriatic arthritis (PsA). 1 8 According to a survey of 1728 patients with nail psoriasis, 9 approximately half of the patients complained of pain and/or restrictions in their daily activities, and nearly all patients reported cosmetic problems due to nail disease. Additionally, a large proportion showed little or no improvement in nail symptoms with current therapies, and the majority were willing to consider additional treatment for their nail psoriasis. Several treatment options are available for nail psoriasis; however, these therapies vary in their efficacy, convenience and tolerability Nail psoriasis is typically difficult to treat and responds more slowly to therapy compared with skin disease, as nail growth is slow and complete nail replacement may take up to 55 months. 17 While the use of conventional systemic therapies for psoriasis is typically reserved for treatment of moderate-to-severe skin or joint disease, such treatments are used for nail involvement after topical or intralesional treatments have failed. Biological agents may provide significant benefit in nail psoriasis and, thereby, decrease disease burden; 18 however, such evidence is limited and, to date, randomized and controlled studies only for infliximab and etanercept have reported improvement in nail psoriasis. 1,26, a fully human monoclonal antibody against the p40 subunit shared by interleukins 12 and 23, has been approved for the treatment of moderate-to-severe psoriasis. Studies of ustekinumab have shown significant efficacy in the treatment of skin psoriasis and PsA, and the emerging safety profile for ustekinumab in psoriasis continues to be favourable over a 5-year period of treatment in clinical trials While there is anecdotal evidence in the literature that ustekinumab improves nail psoriasis, data from controlled trials have not been published. We report findings on the impact of ustekinumab on nail psoriasis for up to 52 weeks of treatment in a randomized, controlled trial (PHOENIX 1). Patients and methods Patients PHOENIX 1 is a phase 3, double-blind, randomized, placebocontrolled, multicentre trial that evaluated the efficacy and safety of ustekinumab in patients with moderate-to-severe psoriasis. As reported previously, 27 the PHOENIX 1 study included four distinct treatment periods (Fig. 1): placebo-controlled (weeks 0 12), placebo crossover and active treatment (weeks 12 40), randomized withdrawal (weeks 40 76) and long-term extension for up to 5 years. At baseline (week 0), patients were randomized (1 : 1 : 1) to receive ustekinumab 45 mg or 90 mg (Janssen Biotech Inc., Malvern, PA, U.S.A.) at weeks 0, 4, 16 and 28, or placebo at weeks 0 and 4 followed by crossover to receive ustekinumab 45 mg or 90 mg at weeks 12, 16 and 28. At week 40, ustekinumab-randomized patients achieving 75% improvement from baseline Psoriasis Area and Severity Index (PASI 75) at both weeks 28 and 40 (i.e. initial responders) were rerandomized either to continue maintenance treatment with ustekinumab or to withdraw from active treatment and receive placebo. Patients not achieving a PASI 75 response at week 28 or 40 were not rerandomized, and their dosing was either discontinued or modified (Fig. 1). Nail Psoriasis Severity Index (NAPSI) 40 scores were assessed at baseline and weeks 12 and 24 (before rerandomization at week 40) for all patients with nail involvement (overall nail psoriasis population) and also at week 52 for initial responders. The extent and severity of skin involvement was evaluated using PASI, 41 and the presence of PsA was determined based on investigator review of medical history. Nail evaluations All patients were assessed at study entry to determine whether nail psoriasis was present, and only those with nail involvement (i.e. the overall nail psoriasis population) were included in the current analyses. Nail psoriasis was evaluated based on the NAPSI, the Nail Physician s Global Assessment (Nail PGA) and the number of nails affected by psoriasis. Every effort was made to ensure that the same evaluator performed assessments throughout the study. The worst fingernail affected with psoriasis at baseline was identified as the target nail and followed throughout the study for NAPSI and Nail PGA assessments. NAPSI scores were determined as described by Rich and Scher. 40 The Nail PGA score, which ranges from 1 to 5 (1, none; 2, mild; 3, moderate; 4, severe; 5, very severe), was also used to evaluate psoriasis of the target fingernail. A decrease of at least 1 point on the Nail PGA scale was considered improvement in nail psoriasis. The number of fingernails with psoriatic involvement was also assessed, and a nail was considered involved even with only minimal residual changes. Statistical methods Details pertaining to the randomization methods and sample size determinations have been provided elsewhere. 27 Efficacy data from all randomized patients with nail psoriasis were analysed according to the assigned treatment group. Data were analysed at weeks 12 and 24 for the overall nail psoriasis population and at week 52 for initial responders. Missing data were not imputed; the specific data handling rules have been reported previously. 27 The mean percentage improvement in NAPSI score from baseline to week 12 was compared between the placebo and ustekinumab 45 and 90 mg groups using an analysis of variance on the van der Waerden normal scores. Spearman correlation coefficients were calculated to assess the relationship between improvements in PASI and NAPSI scores at week 24 among patients randomized to receive ustekinumab. In addition, percentage improvement in NAPSI score was summarized at weeks 12 and 24 for patients with PsA British Association of Dermatologists British Journal of Dermatology (2014) 170, pp

3 400 effectively treats nail psoriasis, P. Rich et al. Screen a Placebo-controlled (Period 1) Placebo Crossover and Active Treatment (Period 2) Randomized Withdrawal (Period 3) Group 1 45 mg at Weeks 0, 4 q12 wk 45 mg q12 wk Group 2 90 mg at Weeks 0, 4 q12 wk 90 mg q12 wk Group 3 Placebo at Weeks 0, 4 3a 3b 45 mg at Weeks 12, 16 q12 wk 90 mg at Weeks 12, 16 q12 wk Week 28: b PASI < 50: D/C PASI 50 to < 75: q8 wk PASI 75: q12 wk Week 40: c PASI < 75: q8 wk PASI 75: entered randomized withdrawal Week Fig 1. Study design of the PHOENIX 1 trial from baseline to week 52. Reprinted from The Lancet Vol. 371 (9625), Leonardi et al., 27 Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 76-week results from a randomized, doubleblind, placebo-controlled trial (PHOENIX 1), pages , Copyright 2008, with permission from Elsevier. D/C, discontinued; PASI, Psoriasis Area and Severity Index; â, randomization; q8wk, every 8 weeks; q12wk, every 12 weeks. a Patients were ineligible if they had non plaque forms of psoriasis; had a recent serious systemic or local infection; had a history of tuberculosis (except latent tuberculosis that was concurrently treated), or a known malignancy (except treated basal cell skin cancer or squamous cell skin cancer for at least 5 years); had received previous treatment with any agent specially targeting interleukin-12 or interleukin-23; had received biologic or investigational agent; had received conventional systemic psoriasis therapy or phototherapy within the previous 4 weeks; or had received topical psoriasis treatment within the previous 2 weeks. b At week 28, in all groups, nonresponders (PASI < 50) discontinued study agent, partial responders (PASI 50 to < 75) began q8wk dosing, and PASI responders (PASI 75) received q12wk dosing. c At week 40, PASI responders to q12wk dosing in groups 1 and 2 were randomized to either placebo or continued q12wk ustekinumab (at their original dose), while those in group 3 received placebo. At loss of therapeutic effect, patients receiving placebo began retreatment at their dosing regimen prior to withdrawal. In all groups, nonresponders or partial responders (PASI < 75) were adjusted to q8wk dosing. Patients receiving q8wk dosing continued q8wk dosing. Results In total, 766 patients were randomized to receive ustekinumab 45 mg (n = 255), ustekinumab 90 mg (n = 256) or placebo (n = 255); of these, 545 (711%) had nail psoriasis (Fig. 2). The patient disposition for the entire study population has been reported elsewhere. 27 Baseline demographic and clinical nail characteristics and proportions of patients receiving previous treatments were generally similar across treatment groups (Table 1). About one-third of patients with nail psoriasis also had PsA, and 193 (751%) of 257 patients with PsA had nail involvement. The mean NAPSI score at baseline was 44, and Nail PGA scores indicated mild (score of 2), moderate (3) and severe or very severe (4 or 5) disease in approximately 50%, 40% and 10% of patients, respectively. The mean number of involved nails at baseline was 66 across treatment groups. Among ustekinumab-treated patients, the most common nail matrix and nail bed features were pitting and onycholysis, respectively (Table 2). British Journal of Dermatology (2014) 170, pp Nail Psoriasis Severity Index In the overall population of patients with nail psoriasis, NAPSI scores were significantly improved from baseline as early as week 12 for both ustekinumab 45 mg [percentage improvement 267%, 95% confidence interval (CI) ; P < 0001 vs. placebo] and 90 mg (249%, 95% CI ; P = 0001 vs. placebo), compared with placebo (118%, 95% CI ) (Fig. 3). Percentage improvements in NAPSI score from baseline continued to improve through to week 24 in ustekinumab-treated patients on 45 mg (465%, 95% CI ) and 90 mg (487%, 95% CI ) (Fig. 3). Among patients receiving placebo who crossed over to receive ustekinumab at week 12, percentage improvements in NAPSI scores at week 24 were generally comparable with the week-12 results for patients initially randomized to receive ustekinumab 45 mg (291%, 95% CI ) and 90 mg (405%, 95% CI ) (Fig 3) British Association of Dermatologists

4 effectively treats nail psoriasis, P. Rich et al psoriasis patients randomized 545 with nail psoriasis 176 placebo 182 ustekinumab 45 mg q12 wk regimen 187 ustekinumab 90 mg q12 wk regimen Placebo Crossover (Week 12) 10 D/C study agent 2 Lack of efficacy 5 Adverse event 3 Other 1 D/C study agent 0 Lack of efficacy 0 Adverse event 1 Other 8 D/C study agent 1 Lack of efficacy 2 Adverse event 5 Other 89 Crossed over to 45 mg ustekinumab q12 wk regimen 77 Crossed over to 90 mg ustekinumab q12 wk regimen Randomized Withdrawal (Week 40) 8 D/C study agent 6 Lack of efficacy 1 Adverse event 1 Other 35 Adjusted to q8 wk dosing at week 28 or week 40 4 D/C study agent 2 Lack of efficacy 0 Adverse event 2 Other 17 Adjusted to q8 wk dosing at week 28 or week D/C study agent 15 Lack of efficacy 8 Adverse event 4 Other 55 Adjusted to q8 wk dosing at week 28 or week D/C study agent 4 Lack of efficacy 4 Adverse event 2 Other 48 Adjusted to q8 wk dosing at week 28 or week Switched to 56 Switched to 49 Randomized to 50 Randomized to 45 mg q12 wk 57 Randomized to 64 Randomized to 90 mg q12 wk 0 D/C study agent 1 Received no treatment 0 D/C study agent 1 D/C study agent 0 Lack of efficacy 0 Adverse event 1 Other 0 D/C study agent 0 D/C study agent 1 Received no treatment 2 D/C study agent 0 Lack of efficacy 2 Adverse event 0 Other 46 Completed study 55 Completed study 48 Completed study 50 Completed study 57 Completed study 61 Completed study UST-1-8_v1 Fig 2. Patient disposition from baseline to week 52 in the PHOENIX 1 trial. D/C, discontinued; q8wk, every 8 weeks; q12wk, every 12 weeks. Absolute NAPSI scores in the overall nail psoriasis population also showed improvement at weeks 12 and 24. At week 12, NAPSI scores SD improved from at baseline to in the 45-mg group and from to in the 90-mg group; the corresponding NAPSI scores in the placebo group were at baseline and at week 12. The mean NAPSI scores were further reduced from baseline to week 24: from to in the 45-mg group, from to in the 90-mg group, from to in the placebo?45-mg group and from to in the placebo?90-mg group. The proportions of patients randomized to ustekinumab with each of the nail bed and nail matrix features assessed by the NAPSI were lower at week 12 compared with baseline, and continued to decrease through to week 24 (Table 2). Compared with baseline, the proportion of ustekinumab-treated patients with pitting decreased by approximately 20%, and the proportion with onycholysis decreased by over 30% at week 24 in both the 45- and 90-mg groups (Table 2). The proportions of patients receiving placebo with these nail features at baseline were similar to those for ustekinumab-randomized patients and did not change substantially through to week 12 (Table 2); improvements in each feature were noted by week 24 after crossover to receive ustekinumab (data not shown). Initial responders rerandomized either to continue maintenance therapy or to withdraw from treatment showed similar percentage improvements in NAPSI score at week 24 prior to rerandomization (553% and 569%, respectively). However, at week 52 the percentage improvements from baseline NAPSI score for the maintenance group [n = 114; 686% (45 mg) and 685% (90 mg)] were 10 15% higher than those for the withdrawal group [n = 106; 540% (45 mg) and 585% (90 mg)]. The absolute NAPSI scores SD for initial responders improved from at baseline to at week 52 in the maintenance group, compared with to in the withdrawal group. Nail Physician s Global Assessment Improvements in Nail PGA scores were generally not observed in the overall nail psoriasis population at week 12 (data not shown), which was not unexpected given the lower sensitivity of the Nail PGA relative to NAPSI. However, substantial improvements in Nail PGA scores were observed in ustekinumab-treated patients at week 24 (Fig. 4), with the majority of patients with a baseline Nail PGA score of 3 (moderate) achieving improvement by at least 1 point. Among patients with a baseline Nail PGA score of 2 (mild disease), 21% and 12% of patients in the 45-mg and 90-mg groups, respectively, improved to a Nail PGA score of 1 (no psoriasis) at week 24. In the subset of patients with moderate nail disease (Nail PGA score of 3) at baseline, Nail PGA scores improved to mild or clear at week 24 in approximately threequarters of patients (i.e. 770% and 750% in the 45-mg and 2013 British Association of Dermatologists British Journal of Dermatology (2014) 170, pp

5 402 effectively treats nail psoriasis, P. Rich et al. Placebo 45 mg 90 mg Patients randomized, n Patients with nail psoriasis, n Age (years) Male sex, n (%) 137 (778) 138 (758) 144 (770) Weight (kg) Duration of psoriasis (years) Patients with psoriatic arthritis, n (%) 65 (369) 57 (313) 71 (380) Number of nails involved NAPSI score (0 8) Nail matrix score (0 4) Nail bed score (0 4) Nail PGA score, n (%) 1, None 0 (00) 0 (00) 0 (00) 2, Mild 84 (477) 91 (500) 89 (476) 3, Moderate 71 (403) 66 (363) 77 (412) 4, Severe 19 (108) 18 (99) 18 (96) 5, Very severe 2 (11) 7 (38) 3 (16) Prior treatment, n (%) Topical agents 166 (943) 175 (962) 172 (920) Phototherapy a 107 (608) 118 (648) 126 (674) Conventional systemic agents b 110 (625) 103 (566) 110 (588) Biological agents c 97 (551) 102 (560) 97 (519) Table 1 Demographic and baseline disease characteristics: patients with nail psoriasis NAPSI, Nail Psoriasis Severity Index; PGA, Physician s Global Assessment. Values are expressed as mean SD unless otherwise indicated. a Phototherapy includes psoralen ultraviolet A (PUVA) and ultraviolet B therapy. b Conventional systemic agents include acitretin, ciclosporin, methotrexate and PUVA. c Biological agents include adalimumab, alefacept, efalizumab, etanercept and infliximab. 90-mg groups, respectively). Among patients with severe or very severe nail disease (Nail PGA score of 4 or 5) at baseline, Nail PGA scores had improved to moderate or better in 720% of patients in the 45-mg group and 950% of patients in the 90-mg group at week 24. Few patients in any treatment group were observed to have worsening of Nail PGA scores at week 24. The proportions of initial responders continuing maintenance treatment with a Nail PGA rating of 1 (no nail psoriasis) at week 52 were 260% (45 mg) and 365% (90 mg), compared with 184% (45 mg) and 123% (90 mg) for those withdrawn from treatment. Number of nails with psoriasis and full nail clearance British Journal of Dermatology (2014) 170, pp In the overall nail psoriasis population, the mean number of nails with psoriasis generally showed improvement in ustekinumab-treated patients at week 12 [from at baseline to (45 mg) and from to (90 mg)] compared with placebo (from to ). However, the mean number of nails involved continued to decrease through to week 24 in the ustekinumab groups [from at baseline to (45 mg) and from to (90 mg)]. In the placebo crossover groups, the mean number of nails involved at week 24 (i.e. after 12 weeks of treatment) decreased from at baseline to (placebo?45 mg) and from to (placebo?90 mg). Among initial responders, the mean number of nails involved at week 52 decreased from at baseline to (45 mg) and from to (90 mg) in the maintenance group, and from to (45 mg) and from to (90 mg) in the withdrawal group. In the overall nail psoriasis population, full clearance (no nail involvement) was achieved at week 12 in 93%, 54% and 40% of patients for the ustekinumab 45 mg, ustekinumab 90 mg and placebo groups, respectively; at week 24, the proportions increased to 152% (45 mg), 88% (90 mg), 125% (placebo?45 mg) and 104% (placebo? 90 mg). Among initial responders, 324% in the maintenance group achieved full nail clearance at week 52 compared with 157% in the withdrawal group. Examples of improvement in common features of nail psoriasis (i.e. pitting, onycholysis and hyperkeratosis) through to week 52 are illustrated in Figure 5. Psoriatic arthritis At week 12, percentage improvements in NAPSI score in patients either with or without PsA, respectively, in the overall nail psoriasis population were 122% or 115% (placebo), 181% or 307% (45 mg) and 270% or 237% (90 mg) British Association of Dermatologists

6 effectively treats nail psoriasis, P. Rich et al. 403 Table 2 Proportion of patients with individual nail matrix and nail bed features of the Nail Psoriasis Severity Index over time: patients with nail psoriasis at baseline Baseline Week 12 Week 24 a Placebo 45 mg 90 mg Placebo 45 mg 90 mg 45 mg 90 mg Patients, n Nail matrix features Pitting 134 (761) 140 (769) 134 (717) 124 (713) 121 (665) 123 (672) 99 (559) 91 (506) Leuconychia 58 (330) 59 (324) 53 (283) 43 (247) 32 (176) 38 (208) 26 (147) 27 (150) Red spots in 9(51) 25 (137) 15 (80) 10 (57) 7 (38) 7 (38) 9 (51) 3 (17) the lunula Nail plate 41 (233) 41 (225) 51 (273) 37 (213) 30 (165) 28 (153) 20 (113) 15 (83) crumbling Nail bed features Onycholysis 122 (693) 129 (709) 136 (727) 111 (638) 93 (511) 86 (470) 64 (362) 74 (411) Nail splinter 45 (256) 48 (264) 50 (267) 38 (218) 32 (176) 23 (126) 28 (158) 25 (139) haemorrhages Nail oil drop 70 (398) 68 (374) 88 (471) 61 (351) 34 (187) 33 (180) 33 (186) 27 (150) discoloration Nail bed hyperkeratosis 50 (284) 57 (313) 59 (316) 40 (230) 35 (192) 23 (126) 25 (141) 18 (100) Values are expressed as n (%). a At week 24 (i.e. 12 weeks after crossing over to receive ustekinumab) the proportions of patients with individual nail features in the placebo crossover groups were generally similar to both ustekinumab-randomized groups at week 12. Mean percentage improvement, 95% CI (4 2, 19 3) 26 7 a (18 5, 35 0) 24 9 b (17 8, 32 0) Week 12 Week 24 Placebo Ust 45 mg Ust 90 mg Placebo Ust 45 mg a P < vs. placebo b P = vs. placebo (39 5, 53 4) (30 8, 50 2) 29 1 (16 5, 41 7) Placebo Ust 90 mg 48 7 (42 0, 55 3) Fig 3. Mean percentage improvement and confidence intervals (CIs) in Nail Psoriasis and Severity Index from baseline to weeks 12 and 24 by treatment group: patients randomized at baseline. Ust, ustekinumab. Improvements continued to week 24 for all groups, regardless of PsA status: ustekinumab 45 mg (443% for PsA vs. 474% for non-psa), ustekinumab 90 mg (468% vs. 498%), placebo?ustekinumab 45 mg (400% vs. 221%) and placebo? ustekinumab 90 mg (348% vs. 434%). Among initial responders in the maintenance group, the percentage improvement in NAPSI was lower for patients with PsA (626%; n = 36) compared with those without PsA (715%; n = 74) at week _v2 Correlation of Nail Psoriasis Severity Index and Psoriasis Area and Severity Index scores Evaluation of percentage improvement in NAPSI by PASI response at weeks 12 and 24 showed that improvements in nail psoriasis correlated with skin responses in the overall nail psoriasis population (Table 3). Percentage improvements from baseline NAPSI score at week 12 were lower in patients who achieved less than PASI 75 response [91% (PASI < 50) and 134% (PASI 50 75)] compared with those achieving at least PASI 75 response [322% (PASI 75 90) and 346% (PASI 90)]. By week 24, percentage improvements from baseline NAPSI scores were greater at all PASI response levels compared with week 12; however, lower improvements in NAPSI scores were similarly observed for patients with lower PASI responses [297% (PASI < 50) and 293% (PASI 50 75) compared with 433% (PASI 75 90) and 573% (PASI 90)]. The correlation between percentage improvements in PASI and NAPSI scores increased over time for ustekinumab-treated patients, with a Spearman correlation coefficient of 022 at week 12 and 029 at week 24. Among initial responders in the maintenance group, the mean percentage improvements in NAPSI score from baseline were 694% (45 mg) and 722% (90 mg) at week 52 for those with a PASI 75 response, and 897% (45 mg) and 759% (90 mg) for those with a PASI 90 response. Discussion The PHOENIX 1 study is one of only a few randomized controlled trials prospectively designed to evaluate nail psoriasis British Association of Dermatologists British Journal of Dermatology (2014) 170, pp

7 404 effectively treats nail psoriasis, P. Rich et al. (a) Patients with baseline Nail PGA of 2 (b) Patients with baseline Nail PGA of 3 (c) Patients with baseline Nail PGA of Proportion of patients Proportion of patients n = 19/89 10/85 63/89 71/85 4/89 3/85 3/89 1/85 n = 7/65 3/76 43/65 54/76 15/65 17/76 0/6 2/765 n = 1/25 2/20 9/25 9/20 8/25 8/20 7/25 1/20 None (1) Mild (2) Moderate (3) Severe (4-5) None (1) Mild (2) Moderate (3) Proportion of patients Severe (4-5) None (1) Mild (2) Moderate (3) Severe (4-5) UST-1-8_v2 45 mg 90 mg Fig 4. Proportion of patients with each Nail Physician Global Assessment (Nail PGA) score at week 24 by baseline Nail PGA score and treatment group: patients randomized at baseline. Severe (4 5) includes severe and very severe scores. (a) (b) (c) (d) (e) (f) (g) (h) (i) Fig 5. Clearance of common nail features, including pitting (a c), onycholysis (d f) and hyperkeratosis (g i) in patients treated with ustekinumab through to week 52. A high proportion (711%) of the 766 patients enrolled in this large, randomized, placebo-controlled trial had nail involvement, which is similar to rates of up to 80% reported elsewhere. 1,2,8 Similarly consistent with previous reports, 3 nail features of pitting and onycholysis were reported most frequently (i.e. in nearly three-quarters of patients) at baseline. Taken together, these data indicate that the PHOENIX 1 study population is reflective of the general psoriasis population with respect to nail involvement. Furthermore, our findings demonstrate that ustekinumab significantly improves nail involvement in patients with moderate-to-severe psoriasis. The onset of response in nail psoriasis was evident after only two doses (week 12) in some patients. Improvement continued with an additional dose (at week 16) through to week 24 in the overall nail psoriasis population and through to 1 year of treatment in the subgroup of initial responders who continued therapy without interruption. British Journal of Dermatology (2014) 170, pp In general, nail responses were considerably slower than skin responses. At week 12, the percentage improvements from baseline in NAPSI scores were significantly less than the percentage improvements in PASI scores. 27 Although nail changes continued to improve, they lagged behind cutaneous responses over time. The need for longer treatment to improve nail involvement may reflect the fact that some features of nail psoriasis require replacement of the dysmorphic portion of the nail plate. 17 Nonetheless, nail and skin manifestations of psoriasis generally improved in parallel based on correlation between NAPSI and PASI responses over time. Overall, patients with greater skin responses also demonstrated better nail responses. Specifically, at incremental levels of skin response ranging from PASI < 50 to PASI 90, the mean percentage improvement in NAPSI increased from 91 to346 at week 12 and from 297 to 573 at week 24. Moreover, these results demonstrate that 2013 British Association of Dermatologists

8 effectively treats nail psoriasis, P. Rich et al. 405 Table 3 Mean percentage improvement from baseline in Nail Psoriasis Severity Index (NAPSI) by Psoriasis Area and Severity Index (PASI) response at weeks 12 and 24: patients with nail psoriasis at baseline Combined ustekinumab group Overall PASI < 50 PASI PASI PASI > 90 Week 12 Number of patients Mean percentage improvement Spearman correlation a 022 Week 24 Number of patients Mean percentage improvement Spearman correlation a 029 PASI 50, at least 50% improvement from baseline in PASI. a Spearman correlations were calculated between percentage improvement from baseline in NAPSI and percentage improvement from baseline in PASI. the degree of correlation between skin and nail improvements, although modest, became stronger over time. These observations are consistent with those reported in the EXPRESS study, in which the correlation between percentage improvement in PASI and NAPSI scores increased with time in infliximab-treated patients. 1 These results suggest that high levels of skin response may be predictive of marked nail responses in patients with psoriasis with both cutaneous and nail manifestations. Initial responders who were rerandomized to continue maintenance dosing showed further improvement in NAPSI scores for up to 1 year of ustekinumab treatment, while those who were withdrawn from treatment showed no further improvement. These findings suggest that continued treatment with ustekinumab may provide further improvement in nail response through to 1 year. Because nail response data were not systematically collected beyond week 52, we could not assess whether nail responses would continue to improve with further long-term ustekinumab treatment. Given that nail involvement may be associated with subsequent development of joint disease in patients with psoriasis, 5 we compared nail responses in patients with and without PsA. Overall, 748% of patients with PsA had nail involvement, which is similar to other studies reporting nail involvement in up to 80% of patients with PsA. 3 8 Conversely, more than one-third of patients with nail involvement had PsA, which is also similar to the findings reported elsewhere. 1 As demonstrated here, ustekinumab effectively improved nail disease over time, regardless of the presence or absence of PsA. Furthermore, a recently published study indicated that ustekinumab may be a therapeutic option for the treatment of PsA. 31 Few detailed assessments of biological treatments have concentrated solely on nail disease, and most were either patient case reports or open label or retrospective in design ,42,43 The burden of nail disease is becoming better understood in terms of its association with more severe psoriasis, 3 with PsA 3 7 and with quality of life. 9,39,44,45 In turn, it is increasingly important to understand the effect of psoriasis therapies on nail disease and to identify treatments that are effective for both skin and nail psoriasis. Of note, a recent report by a consortium of dermatologists described an algorithm for the management of moderate-to-severe psoriasis in patients with nail disease, suggesting that nail responses should be considered when deciding whether to adjust treatment. 46 This represents a shift in the current treatment paradigm for psoriasis, which focuses largely on cutaneous response to manage disease. Limitations of this study include the restriction of longerterm analyses to initial responders only, the relatively small number of patients followed for 1 year, and the lack of data for patients treated beyond 1 year. In addition, although the NAPSI scoring system is a validated and reliable instrument for measuring the extent of nail disease and has been shown to be simple and objective in its practical use, 47,48 it may be somewhat limited in its capacity to provide detailed assessment. 49 Nevertheless, the Nail PGA results corroborate responses observed with the more sensitive NAPSI, and, taken together, these data provide a comprehensive assessment of nail disease and the positive nail responses observed with ustekinumab treatment. In conclusion, this analysis from the PHOENIX 1 study confirms a high incidence of nail psoriasis in patients with moderate-to-severe skin disease, shows that ustekinumab improves the nail manifestations of psoriasis over time for up to 1 year, and indicates that skin and nail responses to ustekinumab treatment may be correlated. These assessments represent the only broadscoped evaluation of the effect of ustekinumab on nail psoriasis and demonstrate a significant nail response in patients treated with ustekinumab for moderate-to-severe psoriasis. Acknowledgments The authors would like to thank Cynthia Arnold, BS, of Janssen Services LLC, Spring House, PA, for her writing and editorial support and Yin You, MS, of Janssen Research & Development LLC, Spring House, PA, for her programming and analyses support British Association of Dermatologists British Journal of Dermatology (2014) 170, pp

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