Greater Efficacy with Secukinumab Treatment is Associated with Greater Psoriasis Symptom Relief: Results from Secukinumab Clinical Trial Data

Abstract

Background

Psoriasis negatively affects patients’ quality of life. Secukinumab is a human interleukin-17A antagonist indicated for the treatment of moderate-to-severe plaque psoriasis.

Objectives

The current analysis evaluated the benefits of secukinumab by assessing relationships between disease severity and patient-reported symptoms.

Methods

Correlations between psoriasis-related itching, pain, and scaling and disease severity scores (Psoriasis Area and Severity Index [PASI] and Investigator's Global Assessment [IGA]) were evaluated at baseline, Week 12, and change from baseline to Week 12 using secukinumab clinical data from ERASURE and FIXTURE. Symptom responder status and PASI/IGA change were evaluated using logistic modeling.

Results

Correlation coefficients ranged 0.11-0.49 for PASI and 0.19-0.52 for IGA. Greater PASI response was related to greater symptom response/complete relief.

Conclusions

Results further demonstrate the relationship between traditional clinical measures of disease severity and patient-reported, psoriasis-related itching, pain, and scaling –- hence the need to consider both outcomes together to evaluate treatment effects in this disease fully.

Keywords

psoriasis secukinumab itching pain scaling PASI

Introduction

Psoriasis is a common, chronic, immune-mediated, inflammatory skin disease. It is mediated through the IL-23/Th17 pathway, with the key effector cytokine being IL-17.¹ Although the exact cause of psoriasis is not known, it is believed to be influenced by both genetic and environmental factors.² Plaque psoriasis is the most common form of the disease, occurring in more than 80% of patients with psoriasis. The clinical presentation of plaque psoriasis varies widely from minor cutaneous involvement to widespread coverage of body surfaces.³ Plaques commonly occur at the elbows, knees, lumbosacral region, genital area, and scalp, and distribution of lesions is often symmetrical.⁴

Psoriasis can have a profound negative impact on a patient's life. The skin lesions common with plaque psoriasis are associated with significant symptoms, such as itching and pain, which can ultimately affect a patient's emotional, social, occupational, and physical functioning.^5–8 While many patients, particularly those with the limited form of the disease, may be treated with topical therapy, those with extensive (moderate to severe) psoriasis typically require a more intensive therapy (i.e., phototherapy, oral systemics, biologics) to modulate the immune response adequately.⁹ Patients’ experiences with symptoms will guide them to seek medical care and influence the ultimate selection of a treatment option.⁹ Therefore, understanding the patient's experience of the illness and the treatment is a critical component of clinical research and practice.

Estimates of the strength of the relationship between clinical severity and the patients’ perspective of their disease severity have varied across psoriasis studies.^10–16 Although several studies report evidence of a moderate to strong association,¹³ others report that physical outcome measures, such as affected body surface area, do not correspond greatly with patient reports of the impact on health-related quality of life.^14,16 Furthermore, the relationship between clinically meaningful improvements based on the two different perspectives (clinician and patient) has not been widely investigated but is needed to gain a more complete understanding of treatment response.^12–13 As more efficacious treatments achieve greater skin clearance, this study provides an opportunity to explore complete skin clearance (as defined by Psoriasis Area and Severity Index [PASI] 100 response) and the associated degree of symptom relief.

Secukinumab is a fully human monoclonal antibody that selectively targets IL-17A and is highly efficacious in the treatment of moderate to severe psoriasis, providing high levels of skin clearance, with a sustained effect and favorable safety profile. Secukinumab is indicated for the treatment of moderate to severe plaque psoriasis in adult patients who are candidates for systemic therapy or phototherapy.¹⁷ Evaluations of secukinumab have included both traditional clinical assessments, including the PASI,¹⁸ and the Investigator's Global Assessment modified 2011 (IGA mod 2011)¹⁹ and patient assessments, including the Psoriasis Symptom Diary (PSD).^10,11 Phase 3 studies have shown that secukinumab effectively improves skin clearance, based on the PASI and the IGA mod 2011; provides significant improvements in patient-reported itching, pain, and scaling, based on the PSD; and has a favorable safety profile.^20,21

The primary objective of the current analysis was to use the pooled phase 3 trials (ERASURE and FIXTURE) to further evaluate the benefits of secukinumab by assessing the relationship between psoriasis disease severity and patient-reported symptoms (psoriasis-related pain, itching and scaling) among patients treated with secukinumab, especially for those achieving complete skin clearance.

Methods

Study Design

Data from two 52-week, randomized, double-blind, double-dummy, placebo-controlled, multicenter phase 3 trials (ERASURE [N = 737] and FIXTURE [N = 1,305]) of secukinumab in patients with moderate to severe chronic plaque psoriasis were combined to perform the analyses. Langley and colleagues provide further details of the trials’ study designs, as well as the efficacy and safety results.²⁰ Inclusion criteria included having a diagnosis of chronic plaque psoriasis for at least 6 months before study entry, a PASI score of 12 or greater, an IGA mod 2011 score characterized as moderate to severe (> 3), and at least 10% of their body surface area involved with psoriasis lesions.

Subjects in ERASURE were randomly assigned 1:1:1 to receive subcutaneous secukinumab 300 mg, secukinumab 150 mg, or placebo with initial dosing at Weeks 0, 1, 2, and 3, followed by monthly maintenance dosing starting at Week 4. Subjects in FIXTURE were randomly assigned 1:1:1:1 to receive secukinumab 300 mg, secukinumab 150 mg, etanercept, or placebo.²⁰

All patients completed and signed informed consent forms, and each trial was conducted in accordance with International Conference on Harmonisation's Harmonised Tripartite Guidelines for Good Clinical Practice, with applicable local regulations (including European Directive 2001/20/EC, United States Code of Federal Regulations Title 21, and Japanese Ministry of Health, Labor, and Welfare), and with the ethical principles in the Declaration of Helsinki.

Sample

The current analysis was limited to subjects who were in the 300 mg or 150 mg secukinumab treatment groups and who completed the baseline and at least one post-baseline PSD assessment during the 12-week induction phase. Although investigators were encouraged to administer and subjects were encouraged to complete the PSD when available, its use was not mandatory in the trials. In addition, translations were not available for two countries and the electronic device used to administer the PSD was not available for two countries due to customs delays.

Measures

The PASI¹⁹ is a clinician-reported measure evaluating the head, trunk, upper limbs, and lower limbs for the severity and body surface area coverage of erythema, thickening (plaque elevation, induration), and scaling (desquamation). Subjects achieving a ≥ 75% improvement (reduction) in PASI score at Week 12 compared with baseline were identified as PASI 75 treatment responders (a coprimary endpoint in the phase 3 trials); subjects achieving a ≥ 90% improvement in PASI score at Week 12 compared with baseline were identified as PASI 90 responders (a key secondary endpoint in the phase 3 trials). For the current analyses, PASI responder groups were defined as PASI < 75 (subjects achieving < 75% improvement from baseline), PASI 75 to < 90 (subjects achieving ≥ 75% to < 90% improvement from baseline), and PASI ≥ 90 (subjects achieving ≥ 90% improvement from baseline). In addition, the subgroup achieving skin clearance, defined as PASI 100 (subjects achieving 100% improvement from baseline), was evaluated.

The IGA mod 2011 is a five-category scale indicating the physician's overall assessment of psoriasis severity, by induration, erythema, and scaling, evaluated with categories of “0 = clear,” “1 = almost clear,” “2 = mild,” “3 = moderate,” or “4 = severe.”¹⁹ A coprimary efficacy endpoint in the ERASURE and FIXTURE studies was based on the IGA mod 2011 as follows: A subject was considered as an “IGA 0 or 1” responder if the subject achieved a score of 0 (clear) or 1 (almost clear) and had improved by at least two points on the IGA mod 2011 scale compared with baseline.

Patient-Reported Outcomes

The PSD is a psoriasis-specific patient-reported measure designed to evaluate the daily patient reports of severity, bother, and impacts of key signs and symptoms of plaque psoriasis, including itching, stinging, burning, pain from skin cracking, psoriasis-related pain, scaling, and altered skin color.^6,11

The current analysis focused on three symptom items from the PSD –- itching, pain, and scaling –- included as key secondary endpoints in the two phase 3 trials. Previous studies have demonstrated adequate reliability, validity, and responsiveness of these measures using phase 2 data¹¹ as well as pooled phase 3 ERASURE and FIXTURE data.¹⁰

Subjects completed the PSD electronically once each evening from screening through Week 12, and a weekly average for each item was calculated. The weekly average was computed as the sum of the scored items over the course of the study week divided by the number of days on which the item was completed (4 completed days were required to derive a weekly score; 1 to 3 missed days, consecutive or nonconsecutive, were allowed). Cases for which a weekly score could not be calculated (e.g., fewer than 4 completed days in a study week) were set as missing and were excluded from the analysis.

The Strober and colleagues study¹¹ used an anchor-based method and phase 2 data to determine treatment responder thresholds for itching, pain, and scaling. The primary anchor measure was a patient global impression of change (PGIC), which asked patients to rate the overall impact of psoriasis on their life at week 12 in comparison to the start of the study. The anchor was a response of “a little better” on the PGIC and subsequent responder thresholds were defined based on the mean change for the subgroup of patients with “a little better” as their response. These thresholds were applied to the current analysis. Specifically, symptom response was defined as an improvement (reduction between baseline and Week 12) of at least 2.2 points in itching, 2.2 points in pain, and 2.3 points in scaling. Furthermore, complete symptom relief was defined as “no itching,” “no pain,” or “no scaling” and corresponded to a weekly average value of less than 0.5 on the 0-10 scale.

Analytic Methods

Statistical Methods

Correlations were computed between itching, pain, scaling and the PASI and the IGA mod 2011 at baseline, Week 12, and change from baseline to Week 12. Pearson correlation coefficients were computed for the PASI and Spearman correlation coefficients were computed for the IGA mod 2011 values. Correlation coefficients ranged from 0 (no correlation) to 1 (perfect correlation). Cohen²² provides a general rule of thumb for evaluating the magnitude of correlation coefficients: values 0.1-0.3 are considered “small association,” values 0.3-0.5 are “medium association,” and values > 0.5 are indicative of “strong association.”

Logistic models were conducted for the itching, pain, and scaling responder status (at least 2.2 points for itching, 2.2 points for pain, and 2.3 points for scaling, respectively from baseline) at Week 12 with percentage change from baseline to Week 12 in the PASI value as a predictor. In addition, the weekly percentage of itching, pain, and scaling responders from Week 1 to Week 12 was compared by Week 12 PASI responder group status (PASI < 75, PASI 75 to < 90, and PASI ≥ 90) using a Cochran-Mantel-Haenszel test stratified by geographic region and body weight. As treatment goals increased to include skin clearance, symptom response from Week 1 to 12 was further evaluated for the subgroup of patients who achieved PASI 100 response. To provide an evaluation of complete symptom relief, the analyses were repeated for subjects reporting itching, pain, and scaling complete relief (defined as “no itching,” “no pain,” “no scaling” = a weekly value of less than 0.5 on the 0-10 PSD item scale).

Missing PASI and IGA mod 2011 data were imputed using the last-observation-carried-forward method. Because the analyses were exploratory in nature, significance testing results were not adjusted for multiple comparisons.

Results

Subject Characteristics

Of the 1,144 subjects randomly assigned to secukinumab, 39.6% (453/1,144) completed the PSD at baseline and at least once during the 12-week induction phase. Baseline demographics for secukinumab subjects who completed the PSD were similar across secukinumab dose groups (Table 1) and similar to those previously reported in the overall trial population.²⁰ The mean age of subjects ranged from 43.0 years (secukinumab 300 mg group) to 45.7 years (secukinumab 150 mg group). Mean PASI scores at baseline were 21.9 and 21.8 for the secukinumab 300 mg and 150 mg groups, respectively, and based on the IGA mod 2011, the majority of subjects had moderate disease (i.e., 3 based on 0-4 scale). Baseline item scores for itching, pain, and scaling were similar across groups.

Table 1

Subject Demographic and Clinical Characteristics at Baseline for Those Completing the PSD by Secukinumab Dose

Demographics and Characteristics	Secukinumab 300 mg (n = 224)	Secukinumab 150 mg (n = 229)
Male, n (%)	140 (62.5%)	151 (65.9%)
Age, mean (SD)	43.0 (13.1)	45.7 (12.9)
Body weight, mean (SD)	90.3 (23.1)	89.3 (22.2)
PASI
Mean (SD)	21.9 (9.0)	21.8 (9.0)
Range	12.0-64.2	12.0-69.6
IGA mod 2011, n (%)
Moderate (level = 3)	141 (63.0%)	152 (66.4%)
Severe (level = 4)	83 (37.1%)	77 (33.6%)
PSD, mean (SD)
Itching	6.4 (2.4)	6.5 (2.4)
Pain	5.5 (3.0)	5.3 (3.1)
Scaling	6.4 (2.6)	6.5 (2.4)

IGA mod 2011 = Investigator's Global Assessment modified 2011; PASI = Psoriasis Area and Severity Index; PSD = Psoriasis Symptom Diary; SD = standard deviation.

Correlation Analyses Results

The correlation coefficients for itching, pain, and scaling ranged from 0.11 to 0.16 for the PASI and from 0.19 to 0.21 for the IGA mod 2011 (0: no correlation; 1: perfect correlation) at baseline, 0.32 to 0.49 for the PASI and 0.38 to 0.52 for the IGA mod 2011 at Week 12, and 0.18 to 0.22 for the PASI and 0.26 to 0.30 for the IGA mod 2011 for the Week 12 change from baseline (data not shown). The values, while not trivial, were not large, indicating that the concepts measured by the PASI and the IGA mod 2011 differ from those measured by the itching, pain, and scaling severity items. The positive sign of the correlation coefficient values indicated that (1) the higher the PASI or IGA mod 2011 values (increased severity), the higher score values for the itching, pain, and scaling items (more severe symptoms); and (2) larger improvements for the itching, pain, and scaling items (reduction of the scores) were associated with larger improvements on the PASI or IGA mod 2011 (reduction of the scores).

Itching, Pain, and Scaling Responders

The likelihood of achieving a psoriasis-related itching, pain, and scaling response at Week 12 increased as the Week 12 PASI response (from baseline) increased (Figure 1). For itching, the probability of a response was 77.7% for a PASI 75 response and increased to 85.9% for a PASI 90 response. Results were similar for pain and scaling, with 65.9% and 72.6% for pain and 77.7% and 86.1% for scaling, for PASI 75 response and PASI 90 response, respectively. Complete skin clearance (PASI 100 response) provided further benefit, with probability of response ranging from 76.6% for pain to 90.1% for scaling.

Figure 1

Probability of Itching, Pain, and Scaling Responder Status Predicted by PASI Response Among Subjects Randomly Assigned to Receive Secukinumab 300 mg or 150 mg at Week 12

Figure 2 provides the percentage of subjects achieving itching, pain, and scaling response from Week 1 to Week 12 by PASI response groups at Week 12. As expected, a greater PASI improvement was related to a greater percentage of symptom responders (starting at Week 2 for itching and pain and at Week 4 for scaling). In addition, generally as treatment duration increased, the percentage of itching, pain, and scaling responders increased for all PASI responder groups. By Week 12, 64% of subjects in the PASI < 75 response group had achieved itching response, 55.3% for pain response, and 63.2% for scaling response. With a PASI 75 to < 90 response, these percentages increased to 81.3% for itching response, 71.1% for pain, and 82.8% for scaling at Week 12. The largest percentage of symptom responders was at Week 12 for the PASI ≥ 90 group: 90% for itching, 76.1% for pain, and 89.5% for scaling. (PASI ≥ 90 vs. PASI < 75: all comparisons were significant at P < 0.05; PASI ≥ 90 vs. PASI 75 to < 90: all comparisons were significant at P < 0.05 for itching except Week 9 and for scaling except Weeks 6, 11, and 12 but were only significant for pain at Weeks 2-4). Figure 3 provides the percentage of subjects achieving itching, pain, and scaling response from Week 1 to Week 12 for the subgroup of subjects who achieved PASI 100 response at Week 12.

Figure 2

Percentage of Subjects Achieving Itching, Pain, and Scaling Responder Status by Week 12 PASI Response Groups

Figure 3

Probability of Subjects Reporting Complete Relief in Itching, Pain, and Scaling Predicted by PASI Response Among Subjects Randomly Assigned to Receive Secukinumab 300 mg or 150 mg at Week 12

Complete Relief of Itching, Pain, and Scaling

The likelihood of achieving complete relief of itching, pain, and scaling at Week 12 increased as the Week 12 PASI response increased (Figure 4). For itching, the probability of a response was 30.9% for a PASI 75 response and increased to 47.9% for a PASI 90 response. Results were higher for pain and similar for scaling, with 51.4% and 65.3% for pain and 24.8% and 44.4% for scaling for PASI 75 response and PASI 90 response, respectively. Complete skin clearance (PASI 100 response) provided further benefit, with probability of complete relief ranging from 59.1% for scaling to 73.4% for pain.

Figure 4

Percentage of Subjects Reporting Complete Relief in Itching, Pain, and Scaling by Week 12 PASI Response Groups

Figure 5 provides the percentage of subjects achieving complete symptom relief from Week 1 to Week 12 by Week 12 PASI response group. Similar to the itching, pain, and scaling responder analysis shown in Figure 2, a greater PASI improvement was related to a greater percentage of subjects reporting complete relief. Generally, as treatment duration increased, the percentage of subjects reporting complete symptom relief increased for all PASI responder groups. By Week 12, 18.4% of subjects in the PASI < 75 response group had reported complete itching relief, 34.2% achieved complete pain relief, and 14% achieved complete scaling relief. With a PASI 75 to < 90 response, these percentages increased to 27.3% for itching, 48.4% for pain, and 28.9% for scaling at Week 12. The largest percentage of subjects reporting complete symptom relief was at Week 12 for the PASI ≥ 90 group: 59.3% for itching, 72.2% for pain, and 53.1% for scaling. Figure 6 provides the percentage of subjects achieving complete relief of itching, pain, and scaling from Week 1 to Week 12 for the subgroup of subjects who achieved complete skin clearance (PASI 100 response) at Week 12.

Discussion

Historically, improvements in clinician ratings on the PASI and the IGA mod 2011 have been used as the key criteria to assess treatment efficacy in psoriasis clinical trials. More recently, patient-reported severity, bothersomeness, and daily impacts of key signs and symptoms of plaque psoriasis have been used in conjunction with the clinician ratings.^20,21,23 The treatment benefit of secukinumab versus etanercept and placebo has been previously reported using PASI, the IGA mod 2011, and psoriasis symptoms.^20,24 The current analysis focused on the relationship between improvements in psoriasis disease severity and patient-reported, psoriasis-related itching, pain, and scaling symptoms.

The analysis included an evaluation of whether PASI responders also are pain, itching, and scaling responders. Using data from two phase 3 clinical trials of secukinumab (ERASURE and FIXTURE), the correlation between scores and changes from baseline in psoriasis-related itching, pain, and scaling (based on the PSD) versus PASI and IGA mod 2011 ratings were compared. Small to medium correlation coefficients at baseline, Week 12, and change from baseline to Week 12 between the PASI, the IGA mod 2011, and the symptom items indicated that these measures are positively related but not fully overlapping evaluations of secukinumab's efficacy. Each provides unique information. The likelihood of achieving itching, pain, or scaling response was associated positively with the level of PASI response. Achieving PASI 90 response, for example, provided better outcomes on the symptom measures than achieving PASI 75 response. However, total skin clearance (PASI 100 response) did not equate perfectly to itching, pain, and scaling response –- not all PASI 100 responders were itching, pain, and scaling responders, and not all itching, pain, and scaling responders were PASI 100 responders –- rather greater skin clearance, as measured by the PASI, was positively related to symptom response.

There are a number of potential reasons why a patient classified as a PASI 100 responder may not be classified as an itching, pain, or scaling responder. For example, a patient may be at the beginning of a psoriasis flare that is not observable by the clinician, or a lesion may have been present but was missed due to its location during the clinical exam, or a symptom may be neurogenic in nature, or a symptom may be caused by something besides psoriasis (even though the patient is directed to only report psoriasis-related symptoms). Furthermore, based on the data in this study, complete skin clearance was more associated with itching and scaling response than with pain response (i.e., PASI 100 response was associated with approximately 90% probability of itching and scaling response and less than 80% probability of pain response). Data were not available to test any of the potential reasons for the differences. However, the presence of the differences between the clinical and patient-reported measures provided further support that both should be collected. Investigating the relationships among these different endpoints and furthermore how the relationships may change over time is important when making treatment decisions, planning a clinical trial program, or conducting an evaluation of therapies using multiple data sources, including the patient's perspective, especially in light of new treatments achieving greater skin clearance. Within these data, the correspondence of improvement over time appeared early in the treatment period as has been reported by Sobell and colleagues.²⁵ For these reasons, within the area of drug development, including drug development in psoriasis, it has become common practice for patient-reported outcomes to be included as supportive or as secondary endpoints to the clinical and/or biomarker outcomes.²⁶ This analysis has demonstrated the value of reviewing both aspects to provide a more comprehensive understanding of psoriasis.

Conclusion

In secukinumab trials, health-related quality of life has been shown to improve in parallel with improvement in skin clearance and disease severity in patients with moderate to severe psoriasis. Results of this analysis further emphasize this knowledge by demonstrating the correlation between traditional clinical measures of disease severity and patient-reported, psoriasis-related itching, pain, and scaling symptoms –- hence the need to consider both outcomes together to fully appreciate treatment effects in this disease.

Footnotes

Dr. Gottlieb has consulted or served on advisory boards through Tufts Medical Center or New York Medical College for Amgen, Astellas, Akros, Centocor (Janssen), Celgene Corporation, Bristol Myers Squibb, Beiersdorf, Abbott Labs (AbbVie), TEVA, Actelion, UCB, Novo Nordisk, Novartis, Dermipsor Limited, Incyte, Pfizer, Canfite, Eli Lilly, Coronado, Vertex, Karyopharm, CSL Behring Biotherapies for Life, GlaxoSmithKline, Xenoport, Catabasis, Meiji Seika Pharma Co., Ltd., Takeda, Mitsubishi Tanabe Pharma Development America, Inc., Genentech, and Baxalta. Dr. Gottlieb has participated in research/educational grants through Tufts Medical Center for Centocor (Janssen), Amgen, Abbott (AbbVie), Novartis, Celgene, Pfizer, Eli Lilly, Coronado, Levia, Merck, Xenoport, Dermira, and Baxalta. Dr. Strober has served as part of the Speakers’ Bureau for AbbVie; as a consultant for AbbVie, Amgen, Celgene Corporation, Dermira, Janssen, Leo Pharmaceuticals, Eli Lilly, Maruho, Medac, Merck, Novartis, Pfizer, Stiefel/GlaxoSmithKline, and UCB; as an investigator for AbbVie, Amgen, Novartis, Eli Lilly, Janssen, and Merck; as a scientific director for CORRONA Psoriasis Registry; and receives grant support through the University of Connecticut from AbbVie and Janssen.

Dr. Lebwohl is an employee of Icahn School of Medicine at Mount Sinai, which receives research funds from Amgen, Anacor Pharmaceuticals, Boehringer Ingelheim, Celgene Corporation, Eli Lilly, Janssen Biotech, Kadmon, LEO Pharmaceuticals, Medimmune, Novartis, Pfizer, Sun Pharmaceuticals, and Valeant.

Dr. Pariser has been an investigator or consultant for Brickell Biotechnology, Biofrontera AG, Celgene Corporation, Dermira, DUSA Pharmaceuticals, LEO Pharmaceuticals, Novartis Pharmaceuticals Corporation, Pfizer, Inc., Valeant Pharmaceuticals, Abbott/AbbVie, Eli Lilly and Company, Novo Nordisk, Peplin Inc., Photocure ASA, Procter & Gamble, and Stiefel, a GSK Company.

Dr. Narbutas has served as a consultant/investigator for Novartis.

Drs. Nyirady, Zhao, and Herrera are full-time employees of Novartis Pharmaceuticals Corporation.

Dr. McLeod and Ms. Odom are full-time employees of RTI Health Solutions.

Dr. Elewski has received grants and/or fees from Novartis Pharma AG, Janssen Pharma, Eli Lilly, Pfizer, Merck, AbbVie, and Amgen. Dr. Lebwohl has received grants, consulted for, been an investigator for, and/or received honoraria from Amgen, Celgene Corporation, Janssen Ortho Biotech, LEO Pharmaceuticals, Abbott, Anacor Pharmaceuticals Inc., BioLineRX Ltd., Coronado Biosciences, Galderma, Maruho Co. Ltd., Meda Pharmaceuticals, Novartis, Pfizer, Valeant, Ranbaxy, Dermipsor, and GlaxoSmithKline-Stiefel.

Acknowledgements

The authors would like to thank the subjects and the investigators who participated in the studies.

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