Assessing the Impact of Efalizumab on Nail, Scalp and Palmoplantar Psoriasis and on Quality of Life: Results from a Multicentre, Open-label, Phase IIIb/IV Trial

This post-approval, open-label trial (n = 1266) assessed the efficacy of efalizumab, administered in accordance with the European label at that time, in patients with concomitant nail, scalp or palmoplantar psoriasis. Patients received subcutaneous efalizumab 1.0 mg/kg weekly for up to 20 weeks. By Week 12, an improvement from baseline of 50% or more was observed in 21.4% (181/844) of patients with nail psoriasis, 62.4% (718/1150) of patients with scalp psoriasis, and 51.4% (127/247) of patients with palmoplantar psoriasis. Quality of life improved throughout the trial, with a 50% median improvement in DLQI score after 12 weeks of treatment. Efalizumab showed promising efficacy in the treatment of nail, scalp and palmoplantar psoriasis, which was reflected in improvements in quality of life.


Introduction
P soriasis frequently affects the nails, scalp, palms of the hands and soles of the feet, which can have disabling consequences and a considerable negative impact on a patient's quality of life (QoL) [1][2][3][4][5][6]. It can be very difficult to treat; in particular, the nails and scalp are not amenable to many topical psoriasis treatments or phototherapy because the nail plate or hair, respectively, prevent adequate contact with the affected tissue [2,[5][6][7].
Efalizumab is a recombinant monoclonal immunoglobulin G1 antibody that binds to the CD11a subunit of lymphocyte function-associated antigen type 1. Until early 2009 it was approved in Europe for the treatment of adults suffering from moderate-to-severe chronic plaque psoriasis. This study reports data from a large-scale, prospective post-approval trial, the first of its kind in psoriasis patients, which assessed the efficacy and safety of efalizumab therapy in patients treated according to the European label at that time. Separately reported findings from this trial indicated that efalizumab effectively controlled psoriasis in twothirds of patients within 12 weeks, and that this was maintained in over three-quarters of patients who continued to receive treatment for a total of 20 weeks [8]. In this article we present results from this trial for patient subgroups presenting with nail, scalp or palmoplantar psoriasis, as well as QoL outcomes for the entire patient population.

Patients
The trial included patients aged Ն18 years with a diagnosis of moderate-to-severe plaque psoriasis who had failed to respond to, were contraindicated for, or were intolerant of other systemic therapies, including ciclosporin, methotrexate and psoralen plus ultraviolet (UV)A phototherapy. Key exclusion criteria included guttate, erythrodermic or pustular psoriasis as the sole or predominant form of psoriasis; withdrawal from previous efalizumab treatment as a result of lack of efficacy or an adverse event; history of opportunistic infections or ongoing uncontrolled infections or active tuberculosis (TB), or treatment for TB within 1 year prior to entry. Written informed consent was obtained from all patients enrolled in the trial.

Trial Design
The trial design is described in detail elsewhere [8]. Briefly, after a single subcutaneous (s.c.) conditioning dose of efalizumab 0.7 mg/kg, eligible patients received open-label s.c. efalizumab 1.0 mg/kg once weekly for a further 11 weeks (first-treatment period). At Week 12, responders could opt to continue with efalizumab treatment for a further 8 weeks while nonresponders switched to an alternative approved anti-psoriasis medication for up to 12 weeks. Regardless of their response, patients could choose to discontinue anti-psoriasis medication at Week 12; these patients entered the observation period and were monitored without treatment for up to 8 weeks or until signs of worsening psoriasis were observed. Patients who responded during the first-treatment period but experienced worsening psoriasis during the observation period could then receive further treatment with weekly open-label s.c. efalizumab 1.0 mg/kg for a further 12 weeks. The trial was performed in accordance with the Declaration of Helsinki Guidelines for Good Clinical Practice, with approval by the independent ethics committee/institutional review board for each participating country.

Assessments of Nail, Scalp and Palmoplantar Psoriasis
Nail Psoriasis Severity Index (NAPSI) assessments were made at baseline and at Week 12 of the trial.
Psoriasis Scalp Severity Index (PSSI) assessments and Palmoplantar Pustulosis Psoriasis Area and Severity Index (PPPASI) assessments were made at baseline and at Weeks 4, 8 and 12. In each case, higher scores indicate greater disease severity.

Assessment of Quality of Life
QoL was assessed at baseline and Weeks 2, 4, 8, 12 and 20 using the Dermatology Life Quality Index (DLQI) and the Medical Outcomes Study Short Form-36 (SF-36).

Statistical Considerations
The intent-to-treat (ITT) population included all patients who received at least one dose of efalizumab and had at least one post-dose efficacy assessment.
Descriptive statistics were presented for SF-36 and DLQI data. For SF-36, a subscale score was included for patients who responded to at least half of the questions in that subscale; the mean score was calculated from the available responses.
For categorical data analyses, patients missing Week 12 data were considered to be nonresponders (worst-outcome imputation). For continuous data, patients with a missing value were excluded from the analysis at the time point for which the data were missing.

Patients
Of the 1266 patients enrolled to the trial, 11 were excluded due to lack of post-baseline efficacy assessment data. Thus the ITT population comprised 1255 patients (68.5% male; mean age 46.2 years). Of these, 1084 completed the first 12 weeks of treatment, with 171 patients withdrawing from treatment for the following reasons: adverse event (n = 81); lost to follow-up (n = 8); protocol violation (n = 3); lack of efficacy (n = 52); other (n = 27). A total of 688 patients, most of whom had responded to treatment during the initial 12-week treatment period, continued to receive efalizumab for a further 8 weeks, for a total of 20 weeks of efalizumab therapy.

Efficacy in Scalp Psoriasis
A PSSI score greater than zero was recorded for 1150 patients at baseline (Table 1) In many cases, a response to efalizumab was apparent early in treatment (Table 2), with over half of the patients classified as PSSI 50 responders at Week 12 having already achieved this response by Week 4 (n = 425).

Efficacy in Palmoplantar Psoriasis
There were 247 patients with a PPPASI score greater than zero at baseline (Table 1).

Quality of Life
Dermatology Life Quality Index A total of 1192 patients from the ITT population had DLQI data at baseline while 1044 patients had DLQI data at Week 12. DLQI scores ranged from 0 to 30 at baseline, with a median of 10 (IQR 5.0-16.0). Median DLQI scores improved steadily from baseline to Week 12 (Figure 2a). Among patients from the ITT population who had DLQI data at Week 12, the median improvement from baseline was 5 points (IQR 1.0-10.0).

Figure 1
Proportions of patients achieving a 50% or 75% improvement from baseline to Week 12 in Nail Psoriasis Severity Index (NAPSI), Psoriasis Scalp Severity Index (PSSI), or Palmoplantar Pustulosis Psoriasis Area and Severity Index (PPPASI) score; intent-to-treat populations.  Week 20, which was a 9.4% improvement from baseline.

Safety
Efalizumab was well tolerated. Full safety data are reported in the primary trial publication [8].

Discussion
This report describes the results arising from the secondary analysis of a large-scale prospective post-approval trial examining the efficacy and safety of efalizumab in patients with moderate-tosevere, chronic plaque psoriasis who had failed to respond to, had contraindications for, or were intolerant of other systemic therapies, including ciclosporin, methotrexate and psoralen plus UVA phototherapy. Evaluation of the primary endpoints of this trial have shown the safety and efficacy of efalizumab across the patient population as a whole [8].
A subgroup analysis of patients presenting with nail, scalp or palmoplantar psoriasis within this same trial are described herein. The data presented indicate that treatment with efalizumab for 12 weeks also resulted in a marked improvement in these conditions. In patients with scalp or palmoplantar involvement, over 40% of patients achieved at least a 75% improvement in symptoms by Week 12. Similarly, of the patients with nail involvement, more than one-fifth achieved at least a 50% improvement in symptoms by Week 12. These results support and extend the favourable findings of earlier smaller-scale trials reported in the Latin American CONTROL I trial [9] or the placebo-controlled Phase IV hand and foot plaque psoriasis trial [10].
Psoriasis can greatly influence a patient's selfesteem and sense of well-being, and consequently is detrimental to their QoL. The beneficial effects of efalizumab in the patients enrolled in this trial were paralleled by steady improvements in QoL throughout the initial 12-week efalizumab treatment period. This trend, along with the 50% (5-point) improvement in DLQI score from baseline to Week 12 of efalizumab treatment, is also in accordance with the results of previous studies examining QoL following treatment in psoriasis patients [11][12][13][14][15].
In light of post-marketing surveillance of patients with psoriasis receiving efalizumab continuously for more than 3 years, in which opportunistic infections were reported, and in particular cases of JC virus infection resulting in progressive multifocal leucoencephalopathy (PML), the European Medicines Agency evaluated all safety data. It concluded that the benefits of efalizumab treatment no longer outweighed the risks associated with the drug and recommended suspension of marketing authorization on 19 February 2009. This trial has confirmed that efalizumab, administered in accordance with the European label available at that time, provided effective control of moderate-to-severe plaque psoriasis. This latest analysis indicates that efalizumab can also be an effective treatment in difficult-to-treat forms of the disease, including nail, scalp or palmoplantar psoriasis, with profound effects on a patient's QoL.