Ustekinumab Improves Nail Disease in Patients with Moderate-To-Severe Psoriasis: Results from PHOENIX 1 P

BJD THERAPEUTICS British Journal of Dermatology Ustekinumab 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. Ghislain7 and Y. Poulin;8 on behalf of the PHOENIX 1 investigators 1Dermatology and Clinical Research, Oregon Health Science University, 2565 NW Lovejoy Street, Suite 200, Portland, OR 97210, U.S.A. 2Dermatology Clinic, Moncton, NB, Canada 3UCLA School of Medicine, Los Angeles, CA, U.S.A. 4Janssen Biotech, Inc., Horsham, PA, U.S.A. 5Janssen Research & Development LLC, Spring House, PA, U.S.A. 6Janssen Biologics BV, Leiden, The Netherlands 7St-Luc University Hospital, Brussels, Belgium 8Centre Dermatologique du Quebec Metropolitain, Quebec City, QC, Canada

Summary

Correspondence Background Most patients with psoriasis have nail changes, and treating nail psoria- Phoebe Rich. sis is challenging. E-mail: [email protected] Objectives To assess improvement in fingernail psoriasis with ustekinumab treatment in the PHOENIX 1 trial. Accepted for publication Methods Patients received ustekinumab 45 mg or 90 mg, or placebo at weeks 0 11 September 2013 and 4. Ustekinumab-randomized patients continued maintenance dosing every 12 weeks, while patients receiving placebo crossed over to receive ustekinumab Funding sources 45 mg or 90 mg at weeks 12/16 followed by dosing every 12 weeks. At week This study was sponsored by Janssen Biotech, Inc., ≥ Spring House, Pennsylvania. 40, initial responders [those with 75% improvement from baseline in Psoriasis Area and Severity Index (PASI 75)] were rerandomized either to continue main- Conflicts of interest tenance dosing or to withdraw from treatment. Nail involvement was evaluated Conflicts of interest statements can be found in the using the Nail Psoriasis Severity Index (NAPSI) on a target fingernail, Nail Physi- Appendix. cian’s Global Assessment (Nail PGA) and mean number of nails involved. Results Of 766 randomized patients, 545 (71Á1%) had nail psoriasis. At week 24, DOI 10.1111/bjd.12632 the percentage improvement from baseline NAPSI score was 46Á5% (ustekinumab 45 mg) and 48Á7% (ustekinumab 90 mg). Percentage improvements in NAPSI ranged from 29Á7% (PASI < 50) to 57Á3% (PASI ≥ 90). Mean NAPSI scores improved from 4Á5 at baseline to 2Á4 at week 24 (45 mg) and from 4Á4to2Á2 (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 Ustekinumab 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.

While psoriasis is an inflammatory disorder with clinical fea- ≥ 75% improvement from baseline Psoriasis Area and Severity tures primarily involving the skin, nail involvement may be Index (PASI 75) at both weeks 28 and 40 (i.e. initial respond- present in up to 80% of patients with psoriasis or psoriatic ers) were rerandomized either to continue maintenance treat- – arthritis (PsA).1 8 According to a survey of 1728 patients with ment with ustekinumab or to withdraw from active treatment nail psoriasis,9 approximately half of the patients complained and receive placebo. Patients not achieving a PASI 75 response of pain and/or restrictions in their daily activities, and nearly at week 28 or 40 were not rerandomized, and their dosing was all patients reported cosmetic problems due to nail disease. either discontinued or modified (Fig. 1). Nail Psoriasis Severity Additionally, a large proportion showed little or no improve- Index (NAPSI)40 scores were assessed at baseline and weeks 12 ment in nail symptoms with current therapies, and the major- and 24 (before rerandomization at week 40) for all patients ity were willing to consider additional treatment for their nail with nail involvement (overall nail psoriasis population) and psoriasis. also at week 52 for initial responders. The extent and severity of Several treatment options are available for nail psoriasis; skin involvement was evaluated using PASI,41 and the presence however, these therapies vary in their efficacy, convenience of PsA was determined based on investigator review of medical – and tolerability.10 16 Nail psoriasis is typically difficult to treat history. and responds more slowly to therapy compared with skin disease, as nail growth is slow and complete nail replacement Nail evaluations may take up to 5Á5 months.17 While the use of conventional systemic therapies for psoriasis is typically reserved for All patients were assessed at study entry to determine whether treatment of moderate-to-severe skin or joint disease, such nail psoriasis was present, and only those with nail involve- treatments are used for nail involvement after topical or ment (i.e. the overall nail psoriasis population) were included intralesional treatments have failed. Biological agents may in the current analyses. Nail psoriasis was evaluated based on provide significant benefit in nail psoriasis and, thereby, the NAPSI, the Nail Physician’s Global Assessment (Nail PGA) decrease disease burden;18 however, such evidence is and the number of nails affected by psoriasis. Every effort was – limited19 25 and, to date, randomized and controlled studies made to ensure that the same evaluator performed assessments only for infliximab and etanercept have reported improvement throughout the study. The worst fingernail affected with pso- in nail psoriasis.1,26 riasis at baseline was identified as the target nail and followed Ustekinumab, a fully human monoclonal antibody against throughout the study for NAPSI and Nail PGA assessments. the p40 subunit shared by interleukins 12 and 23, has been NAPSI scores were determined as described by Rich and approved for the treatment of moderate-to-severe psoriasis. Scher.40 The Nail PGA score, which ranges from 1 to 5 (1, Studies of ustekinumab have shown significant efficacy in the none; 2, mild; 3, moderate; 4, severe; 5, very severe), was – treatment of skin psoriasis and PsA,27 31 and the emerging also used to evaluate psoriasis of the target fingernail. A safety profile for ustekinumab in psoriasis continues to be decrease of at least 1 point on the Nail PGA scale was consid- favourable over a 5-year period of treatment in clinical tri- ered improvement in nail psoriasis. The number of fingernails – als.32 36 While there is anecdotal evidence in the literature that with psoriatic involvement was also assessed, and a nail was – ustekinumab improves nail psoriasis,37 39 data from controlled considered ‘involved’ even with only minimal residual trials have not been published. We report findings on the changes. impact of ustekinumab on nail psoriasis for up to 52 weeks of treatment in a randomized, controlled trial (PHOENIX 1). Statistical methods

Patients and 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 Patients analysed according to the assigned treatment group. Data were PHOENIX 1 is a phase 3, double-blind, randomized, placebo- analysed at weeks 12 and 24 for the overall nail psoriasis pop- controlled, multicentre trial that evaluated the efficacy and safety ulation and at week 52 for initial responders. Missing data of ustekinumab in patients with moderate-to-severe psoriasis. were not imputed; the specific data handling rules have been As reported previously,27 the PHOENIX 1 study included four reported previously.27 distinct treatment periods (Fig. 1): placebo-controlled (weeks The mean percentage improvement in NAPSI score from 0–12), placebo crossover and active treatment (weeks 12–40), baseline to week 12 was compared between the placebo and randomized withdrawal (weeks 40–76) and long-term exten- ustekinumab 45 and 90 mg groups using an analysis of sion for up to 5 years. At baseline (week 0), patients were ran- variance on the van der Waerden normal scores. Spearman domized (1 : 1 : 1) to receive ustekinumab 45 mg or 90 mg correlation coefficients were calculated to assess the relation- (Janssen Biotech Inc., Malvern, PA, U.S.A.) at weeks 0, 4, 16 ship between improvements in PASI and NAPSI scores at week and 28, or placebo at weeks 0 and 4 followed by crossover to 24 among patients randomized to receive ustekinumab. In receive ustekinumab 45 mg or 90 mg at weeks 12, 16 and 28. addition, percentage improvement in NAPSI score was sum- At week 40, ustekinumab-randomized patients achieving marized at weeks 12 and 24 for patients with PsA.

Placebo-controlled Placebo Crossover and Active Treatment Randomized Withdrawal Screena (Period 1) (Period 2) (Period 3)

Placebo → Retreatment Group 1 ® Ustekinumab 45 mg at Weeks 0, 4 → q12 wk 45 mg q12 wk

Placebo → Retreatment Group 2 ® ® Ustekinumab 90 mg at Weeks 0, 4 → q12 wk 90 mg q12 wk

3a Ustekinumab 45 mg at Weeks 12, 16 → q12 wk Placebo → Retreatment Group 3 Placebo at 3b Weeks 0, 4 Ustekinumab 90 mg at Weeks 12, 16 → q12 wk Placebo → Retreatment

Week 28: b Week 40: c PASI < 50: D/C PASI < 75: q8 wk PASI 50 to < 75: q8 wk PASI ≥ 75: entered PASI ≥ 75: q12 wk randomized withdrawal

Week–4 0 12 28 40 76

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, double- blind, placebo-controlled trial (PHOENIX 1), pages 1665–74, 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. aPatients 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. bAt 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. cAt 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 Nail Psoriasis Severity Index

In total, 766 patients were randomized to receive ustekinumab In the overall population of patients with nail psoriasis, 45 mg (n = 255), ustekinumab 90 mg (n = 256) or placebo NAPSI scores were signiﬁcantly improved from baseline as (n = 255); of these, 545 (71Á1%) had nail psoriasis (Fig. 2). early as week 12 for both ustekinumab 45 mg [percentage The patient disposition for the entire study population has improvement 26Á7%, 95% conﬁdence interval (CI) 18Á5– been reported elsewhere.27 Baseline demographic and clinical 35Á0; P < 0Á001 vs. placebo] and 90 mg (24Á9%, 95% CI nail characteristics and proportions of patients receiving 17Á8–32Á0; P = 0Á001 vs. placebo), compared with placebo previous treatments were generally similar across treatment (11Á8%, 95% CI 4Á2–19Á3) (Fig. 3). Percentage improve- groups (Table 1). About one-third of patients with nail ments in NAPSI score from baseline continued to improve psoriasis also had PsA, and 193 (75Á1%) of 257 patients with through to week 24 in ustekinumab-treated patients on PsA had nail involvement. The mean NAPSI score at baseline 45 mg (46Á5%, 95% CI 39Á5–53Á4) and 90 mg (48Á7%, was 4Á4, and Nail PGA scores indicated mild (score of 2), 95% CI 42Á0–55Á3) (Fig. 3). Among patients receiving moderate (3) and severe or very severe (4 or 5) disease in placebo who crossed over to receive ustekinumab at week approximately 50%, 40% and 10% of patients, respectively. 12, percentage improvements in NAPSI scores at week 24 The mean number of involved nails at baseline was 6Á6 across were generally comparable with the week-12 results for treatment groups. Among ustekinumab-treated patients, the patients initially randomized to receive ustekinumab 45 mg most common nail matrix and nail bed features were pitting (29Á1%, 95% CI 16Á5–41Á7) and 90 mg (40Á5%, 95% CI and onycholysis, respectively (Table 2). 30Á8–50Á2) (Fig 3).

766 psoriasis patients randomized

545 with nail psoriasis

176 placebo 182 ustekinumab 45 mg q12 wk regimen 187 ustekinumab 90 mg q12 wk regimen

10 D/C study agent 1 D/C study agent 8 D/C study agent 2 Lack of efficacy 0 Lack of efficacy 1 Lack of efficacy 5 Adverse event 0 Adverse event 2 Adverse event Placebo 3 Other 1 Other 5 Other Crossover (Week 12)

89 Crossed over to 45 mg 77 Crossed over to 90 mg ustekinumab q12 wk regimen ustekinumab q12 wk regimen

8 D/C study agent 4 D/C study agent 27 D/C study agent 10 D/C study agent 6 Lack of efficacy 2 Lack of efficacy 15 Lack of efficacy 4 Lack of efficacy 1 Adverse event 0 Adverse event 8 Adverse event 4 Adverse event 1 Other 2 Other 4 Other 2 Other 35 Adjusted to q8 wk 17 Adjusted to q8 wk 55 Adjusted to q8 wk 48 Adjusted to q8 wk dosing at week 28 dosing at week 28 dosing at week 28 dosing at week 28 Randomized or week 40 or week 40 or week 40 or week 40 Withdrawal (Week 40)

46 Switched to 56 Switched to 49 Randomized to 50 Randomized to 57 Randomized to 64 Randomized to Placebo → Retreatment Placebo → Retreatment Placebo → Retreatment 45 mg q12 wk Placebo → Retreatment 90 mg q12 wk

1 D/C study agent 1 Received no treatment 1 Received no treatment 0 D/C study agent 0 Lack of efficacy 0 D/C study agent 0 D/C study agent 2 D/C study agent 0 D/C study agent 0 Adverse event 0 Lack of efficacy 1 Other 2 Adverse event 0 Other

46 Completed study 55 Completed study 48 Completed study 50 Completed study 57 Completed study 61 Completed study agent through week 52 agent through week 52 agent through week 52 agent through week 52 agent through week 52 agent through week 52 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 popula- percentage improvements in NAPSI score at week 24 prior to tion also showed improvement at weeks 12 and 24. At week rerandomization (55Á3% and 56Á9%, respectively). However, 12, NAPSI scores Æ SD improved from 4Á5 Æ 2Á01 at baseline at week 52 the percentage improvements from baseline NAPSI to 3Á2 Æ 2Á06 in the 45-mg group and from 4Á4 Æ 1Á81 to score for the maintenance group [n = 114; 68Á6% (45 mg) 3Á3 Æ 2Á08 in the 90-mg group; the corresponding NAPSI and 68Á5% (90 mg)] were 10–15% higher than those for the scores in the placebo group were 4Á3 Æ 1Á81 at baseline and withdrawal group [n = 106; 54Á0% (45 mg) and 58Á5% 3Á8 Æ 2Á12 at week 12. The mean NAPSI scores were further (90 mg)]. The absolute NAPSI scores Æ SD for initial reduced from baseline to week 24: from 4Á5 Æ 2Á01 to responders improved from 4Á2 Æ 1Á84 at baseline to 1Á1 Æ 2Á4 Æ 2Á08 in the 45-mg group, from 4Á4 Æ 1Á81 to 1Á47 at week 52 in the maintenance group, compared with 2Á2 Æ 1Á89 in the 90-mg group, from 4Á2 Æ 1Á91 to 4Á7 Æ 1Á77 to 1Á9 Æ 1Á96 in the withdrawal group. 2Á9 Æ 2Á23 in the placebo?45-mg group and from 4Á4 Æ 1Á69 to 2Á6 Æ 1Á98 in the placebo?90-mg group. Nail Physician’s Global Assessment The proportions of patients randomized to ustekinumab with each of the nail bed and nail matrix features assessed by Improvements in Nail PGA scores were generally not observed the NAPSI were lower at week 12 compared with baseline, in the overall nail psoriasis population at week 12 (data not and continued to decrease through to week 24 (Table 2). shown), which was not unexpected given the lower sensitivity Compared with baseline, the proportion of ustekinumab-trea- of the Nail PGA relative to NAPSI. However, substantial ted patients with pitting decreased by approximately 20%, and improvements in Nail PGA scores were observed in us- the proportion with onycholysis decreased by over 30% at tekinumab-treated patients at week 24 (Fig. 4), with the week 24 in both the 45- and 90-mg groups (Table 2). The majority of patients with a baseline Nail PGA score of ≥ 3 proportions of patients receiving placebo with these nail fea- (moderate) achieving improvement by at least 1 point. Among tures at baseline were similar to those for ustekinumab-ran- patients with a baseline Nail PGA score of 2 (mild disease), domized patients and did not change substantially through to 21% and 12% of patients in the 45-mg and 90-mg groups, week 12 (Table 2); improvements in each feature were noted respectively, improved to a Nail PGA score of 1 (no psoriasis) by week 24 after crossover to receive ustekinumab (data not at week 24. In the subset of patients with moderate nail dis- shown). ease (Nail PGA score of 3) at baseline, Nail PGA scores Initial responders rerandomized either to continue mainte- improved to mild or clear at week 24 in approximately three- nance therapy or to withdraw from treatment showed similar quarters of patients (i.e. 77Á0% and 75Á0% in the 45-mg and

Table 1 Demographic and baseline disease Ustekinumab characteristics: patients with nail psoriasis Placebo 45 mg 90 mg Patients randomized, n 255 255 256 Patients with nail psoriasis, n 176 182 187 Age (years) 45Á1 Æ 11Á145Á9 Æ 12Á346Á0 Æ 10Á9 Male sex, n (%) 137 (77Á8) 138 (75Á8) 144 (77Á0) Weight (kg) 95Á4 Æ 22Á895Á2 Æ 23Á395Á0 Æ 23Á2 Duration of psoriasis (years) 21Á2 Æ 11Á120Á2 Æ 11Á419Á9 Æ 10Á7 Patients with psoriatic arthritis, n (%) 65 (36Á9) 57 (31Á3) 71 (38Á0) Number of nails involved 6Á6 Æ 3Á46Á6 Æ 3Á56Á7 Æ 3Á3 NAPSI score (0–8) 4Á3 Æ 1Á84Á5 Æ 2Á04Á4 Æ 1Á8 Nail matrix score (0–4) 2Á6 Æ 1Á52Á7 Æ 1Á52Á5 Æ 1Á5 Nail bed score (0–4) 1Á8 Æ 1Á21Á9 Æ 1Á21Á9 Æ 1Á2 Nail PGA score, n (%) 1, None 0 (0Á0) 0 (0Á0) 0 (0Á0) 2, Mild 84 (47Á7) 91 (50Á0) 89 (47Á6) 3, Moderate 71 (40Á3) 66 (36Á3) 77 (41Á2) 4, Severe 19 (10Á8) 18 (9Á9) 18 (9Á6) 5, Very severe 2 (1Á1) 7 (3Á8) 3 (1Á6) Prior treatment, n (%) Topical agents 166 (94Á3) 175 (96Á2) 172 (92Á0) Phototherapya 107 (60Á8) 118 (64Á8) 126 (67Á4) Conventional systemic agentsb 110 (62Á5) 103 (56Á6) 110 (58Á8) Biological agentsc 97 (55Á1) 102 (56Á0) 97 (51Á9)

NAPSI, Nail Psoriasis Severity Index; PGA, Physician’s Global Assessment. Values are expressed as mean Æ SD unless otherwise indicated. aPhototherapy includes psoralen ultraviolet A (PUVA) and ultraviolet B therapy. bConventional systemic agents include acitretin, ciclosporin, methotrexate and PUVA. cBiological agents include adalimumab, alefacept, efalizumab, etanercept and inﬂiximab.

90-mg groups, respectively). Among patients with severe or cebo?45 mg) and from 6Á7 Æ 3Á50 to 5Á5 Æ 3Á69 (pla- very severe nail disease (Nail PGA score of 4 or 5) at baseline, cebo?90 mg). Among initial responders, the mean number Nail PGA scores had improved to moderate or better in 72Á0% of nails involved at week 52 decreased from 5Á7 Æ 3Á51 at of patients in the 45-mg group and 95Á0% of patients in the baseline to 3Á8 Æ 3Á82 (45 mg) and from 5Á9 Æ 3Á74 to 90-mg group at week 24. Few patients in any treatment group 2Á6 Æ 3Á13 (90 mg) in the maintenance group, and from were observed to have worsening of Nail PGA scores at week 7Á0 Æ 3Á38 to 3Á9 Æ 3Á55 (45 mg) and from 7Á0 Æ 3Á10 to 24. The proportions of initial responders continuing mainte- 4Á3 Æ 3Á38 (90 mg) in the withdrawal group. nance treatment with a Nail PGA rating of 1 (no nail psoria- In the overall nail psoriasis population, full clearance (no sis) at week 52 were 26Á0% (45 mg) and 36Á5% (90 mg), nail involvement) was achieved at week 12 in 9Á3%, 5Á4% compared with 18Á4% (45 mg) and 12Á3% (90 mg) for those and 4Á0% of patients for the ustekinumab 45 mg, withdrawn from treatment. ustekinumab 90 mg and placebo groups, respectively; at week 24, the proportions increased to 15Á2% (45 mg), 8Á8% (90 mg), 12Á5% (placebo?45 mg) and 10Á4% (placebo? Number of nails with psoriasis and full nail clearance 90 mg). Among initial responders, 32Á4% in the maintenance In the overall nail psoriasis population, the mean number of group achieved full nail clearance at week 52 compared with nails with psoriasis generally showed improvement in 15Á7% in the withdrawal group. Examples of improvement in ustekinumab-treated patients at week 12 [from 6Á6 Æ 3Á46 at common features of nail psoriasis (i.e. pitting, onycholysis baseline to 6Á1 Æ 3Á68 (45 mg) and from 6Á7 Æ 3Á31 to and hyperkeratosis) through to week 52 are illustrated in 6Á0 Æ 3Á54 (90 mg)] compared with placebo (from Figure 5. 6Á6 Æ 3Á39 to 6Á5 Æ 3Á49). However, the mean number of nails involved continued to decrease through to week 24 in Psoriatic arthritis the ustekinumab groups [from 6Á6 Æ 3Á46 at baseline to 5Á1 Æ 3Á78 (45 mg) and from 6Á7 Æ 3Á31 to 5Á3 Æ 3Á57 At week 12, percentage improvements in NAPSI score in (90 mg)]. In the placebo crossover groups, the mean number patients either with or without PsA, respectively, in the overall of nails involved at week 24 (i.e. after 12 weeks of treatment) nail psoriasis population were 12Á2% or 11Á5% (placebo), decreased from 6Á4 Æ 3Á30 at baseline to 5Á8 Æ 3Á73 (pla- 18Á1% or 30Á7% (45 mg) and 27Á0% or 23Á7% (90 mg).

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 24a Ustekinumab Ustekinumab Ustekinumab Ustekinumab Ustekinumab Ustekinumab Placebo 45 mg 90 mg Placebo 45 mg 90 mg 45 mg 90 mg Patients, n 176 182 187 174 182 183 177 180 Nail matrix features Pitting 134 (76Á1) 140 (76Á9) 134 (71Á7) 124 (71Á3) 121 (66Á5) 123 (67Á2) 99 (55Á9) 91 (50Á6) Leuconychia 58 (33Á0) 59 (32Á4) 53 (28Á3) 43 (24Á7) 32 (17Á6) 38 (20Á8) 26 (14Á7) 27 (15Á0) Red spots in 9(5Á1) 25 (13Á7) 15 (8Á0) 10 (5Á7) 7 (3Á8) 7 (3Á8) 9 (5Á1) 3 (1Á7) the lunula Nail plate 41 (23Á3) 41 (22Á5) 51 (27Á3) 37 (21Á3) 30 (16Á5) 28 (15Á3) 20 (11Á3) 15 (8Á3) crumbling Nail bed features Onycholysis 122 (69Á3) 129 (70Á9) 136 (72Á7) 111 (63Á8) 93 (51Á1) 86 (47Á0) 64 (36Á2) 74 (41Á1) Nail splinter 45 (25Á6) 48 (26Á4) 50 (26Á7) 38 (21Á8) 32 (17Á6) 23 (12Á6) 28 (15Á8) 25 (13Á9) haemorrhages Nail oil drop 70 (39Á8) 68 (37Á4) 88 (47Á1) 61 (35Á1) 34 (18Á7) 33 (18Á0) 33 (18Á6) 27 (15Á0) discoloration Nail bed 50 (28Á4) 57 (31Á3) 59 (31Á6) 40 (23Á0) 35 (19Á2) 23 (12Á6) 25 (14Á1) 18 (10Á0) hyperkeratosis

Values are expressed as n (%). aAt 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.

Correlation of Nail Psoriasis Severity Index and Psoriasis 100 Area and Severity Index scores a P < 0·001 vs. placebo b P = 0·001 vs. placebo 80 Evaluation of percentage improvement in NAPSI by PASI response at weeks 12 and 24 showed that improvements in 46·5 48·7 (42·0, 55·3) 60 40·5 (39·5, 53·4) nail psoriasis correlated with skin responses in the overall nail (30·8, 50·2) 29·1 psoriasis population (Table 3). Percentage improvements from 26·7 a (16·5, 41·7) 40 (18·5, 35·0) 24·9 b baseline NAPSI score at week 12 were lower in patients who (17·8, 32·0) 11·8 achieved less than PASI 75 response [9Á1% (PASI < 50) and (4·2, 19·3) 20 13Á4% (PASI 50–75)] compared with those achieving at least PASI 75 response [32Á2% (PASI 75–90) and 34Á6% 0 0115_v2 ≥ Mean percentage improvement, 95% CI Week 12 Week 24 (PASI 90)]. By week 24, percentage improvements from baseline NAPSI scores were greater at all PASI response levels

Placebo Ust 45 mg Ust 90 mg compared with week 12; however, lower improvements in Placebo → Ust 45 mg Placebo → Ust 90 mg NAPSI scores were similarly observed for patients with lower PASI responses [29Á7% (PASI < 50) and 29Á3% (PASI 50–75) compared with 43Á3% (PASI 75–90) and 57Á3% (PASI ≥ 90)]. Fig 3. Mean percentage improvement and conﬁdence intervals (CIs) in Nail Psoriasis and Severity Index from baseline to weeks 12 and 24 The correlation between percentage improvements in PASI and by treatment group: patients randomized at baseline. Ust, NAPSI scores increased over time for ustekinumab-treated ustekinumab. patients, with a Spearman correlation coefﬁcient of 0Á22 at week 12 and 0Á29 at week 24. Among initial responders in the maintenance group, the mean percentage improvements in Improvements continued to week 24 for all groups, regardless NAPSI score from baseline were 69Á4% (45 mg) and 72Á2% of PsA status: ustekinumab 45 mg (44Á3% for PsA vs. 47Á4% (90 mg) at week 52 for those with a PASI 75 response, and for non-PsA), ustekinumab 90 mg (46Á8% vs. 49Á8%), pla- 89Á7% (45 mg) and 75Á9% (90 mg) for those with a PASI 90 cebo?ustekinumab 45 mg (40Á0% vs. 22Á1%) and placebo? response. ustekinumab 90 mg (34Á8% vs. 43Á4%). Among initial responders in the maintenance group, the percentage Discussion improvement in NAPSI was lower for patients with PsA (62Á6%; n = 36) compared with those without PsA (71Á5%; The PHOENIX 1 study is one of only a few randomized con- n = 74) at week 52. trolled trials prospectively designed to evaluate nail psoriasis.

(a)Patients with baseline Nail PGA of 2 (b) Patients with baseline Nail PGA of 3 (c) Patients with baseline Nail PGA of 4-5 100 100 100

83·5 80 80 80 70·8 71·1 66·2

60 60 60

45·0 40·0 40 40 40 36·0 32·0 28·0 21·3 23·1 22·4 Proportion of patients Proportion of patients Proportion of patients 20 20 20 11·8 10·8 10·0 4·5 5·0 3·5 3·4 3·9 2·6 4·0 1·2 0·0 0 0 0 UST-1-8_v2

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 0/62/76 5 n = 1/25 2/20 9/25 9/20 8/25 8/20 7/25 1/20 None Mild Moderate Severe None Mild Moderate Severe None Mild Moderate Severe (1) (2) (3) (4-5) (1) (2) (3) (4-5) (1) (2) (3) (4-5)

Ustekinumab 45 mg Ustekinumab 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 (71Á1%) of the 766 patients enrolled in In general, nail responses were considerably slower than this large, randomized, placebo-controlled trial had nail skin responses. At week 12, the percentage improvements involvement, which is similar to rates of up to 80% reported from baseline in NAPSI scores were significantly less than the elsewhere.1,2,8 Similarly consistent with previous reports,3 nail percentage improvements in PASI scores.27 Although nail features of pitting and onycholysis were reported most fre- changes continued to improve, they lagged behind cutaneous quently (i.e. in nearly three-quarters of patients) at baseline. responses over time. The need for longer treatment to Taken together, these data indicate that the PHOENIX 1 study improve nail involvement may reflect the fact that some fea- population is reflective of the general psoriasis population tures of nail psoriasis require replacement of the dysmorphic with respect to nail involvement. Furthermore, our findings portion of the nail plate.17 demonstrate that ustekinumab significantly improves nail Nonetheless, nail and skin manifestations of psoriasis gener- involvement in patients with moderate-to-severe psoriasis. The ally improved in parallel based on correlation between NAPSI onset of response in nail psoriasis was evident after only two and PASI responses over time. Overall, patients with greater doses (week 12) in some patients. Improvement continued skin responses also demonstrated better nail responses. Specifi- with an additional dose (at week 16) through to week 24 in cally, at incremental levels of skin response ranging from the overall nail psoriasis population and through to 1 year of PASI < 50 to PASI ≥ 90, the mean percentage improvement in treatment in the subgroup of initial responders who continued NAPSI increased from 9Á1to34Á6 at week 12 and from 29Á7 therapy without interruption. to 57Á3 at week 24. Moreover, these results demonstrate that

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 50–75 PASI 75–90 PASI > 90 Week 12 Number of patients 369 61 70 106 132 Mean percentage improvement 25Á89Á113Á432Á234Á6 Spearman correlationa 0Á22 Week 24 Number of patients 361 28 55 85 193 Mean percentage improvement 47Á629Á729Á343Á357Á3 Spearman correlationa 0Á29

PASI 50, at least 50% improvement from baseline in PASI. aSpearman 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, psoriasis therapies on nail disease and to identify treatments although modest, became stronger over time. These observa- that are effective for both skin and nail psoriasis. Of note, a tions are consistent with those reported in the EXPRESS study, recent report by a consortium of dermatologists described an in which the correlation between percentage improvement in algorithm for the management of moderate-to-severe PASI and NAPSI scores increased with time in infliximab-trea- psoriasis in patients with nail disease, suggesting that nail ted patients.1 These results suggest that high levels of skin responses should be considered when deciding whether to response may be predictive of marked nail responses in adjust treatment.46 This represents a shift in the current patients with psoriasis with both cutaneous and nail manifes- treatment paradigm for psoriasis, which focuses largely on tations. cutaneous response to manage disease. Initial responders who were rerandomized to continue Limitations of this study include the restriction of longer- maintenance dosing showed further improvement in NAPSI term analyses to initial responders only, the relatively small scores for up to 1 year of ustekinumab treatment, while those number of patients followed for 1 year, and the lack of data who were withdrawn from treatment showed no further for patients treated beyond 1 year. In addition, although the improvement. These findings suggest that continued treatment NAPSI scoring system is a validated and reliable instrument for with ustekinumab may provide further improvement in nail measuring the extent of nail disease and has been shown to response through to 1 year. Because nail response data were be simple and objective in its practical use,47,48 it may be not systematically collected beyond week 52, we could not somewhat limited in its capacity to provide detailed assess- assess whether nail responses would continue to improve with ment.49 Nevertheless, the Nail PGA results corroborate further long-term ustekinumab treatment. responses observed with the more sensitive NAPSI, and, taken Given that nail involvement may be associated with together, these data provide a comprehensive assessment of subsequent development of joint disease in patients with nail disease and the positive nail responses observed with psoriasis,5 we compared nail responses in patients with and ustekinumab treatment. without PsA. Overall, 74Á8% of patients with PsA had nail In conclusion, this analysis from the PHOENIX 1 study con- involvement, which is similar to other studies reporting nail firms a high incidence of nail psoriasis in patients with moder- – involvement in up to 80% of patients with PsA.3 8 Conversely, ate-to-severe skin disease, shows that ustekinumab improves the more than one-third of patients with nail involvement had nail manifestations of psoriasis over time for up to 1 year, and PsA, which is also similar to the findings reported elsewhere.1 indicates that skin and nail responses to ustekinumab treatment As demonstrated here, ustekinumab effectively improved nail may be correlated. These assessments represent the only broad- disease over time, regardless of the presence or absence of scoped evaluation of the effect of ustekinumab on nail psoriasis PsA. Furthermore, a recently published study indicated that and demonstrate a significant nail response in patients treated ustekinumab may be a therapeutic option for the treatment of with ustekinumab for moderate-to-severe psoriasis. PsA.31 Few detailed assessments of biological treatments have Acknowledgments concentrated solely on nail disease, and most were either patient case reports or open label or retrospective in The authors would like to thank Cynthia Arnold, BS, of Jans- – design.19 25,42,43 The burden of nail disease is becoming bet- sen Services LLC, Spring House, PA, for her writing and edito- ter understood in terms of its association with more severe rial support and Yin You, MS, of Janssen Research & – psoriasis,3 with PsA3 7 and with quality of life.9,39,44,45 In Development LLC, Spring House, PA, for her programming turn, it is increasingly important to understand the effect of and analyses support.

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