Abstract
Genital psoriasis (GenPs) is common and distressing for patients, but is often not discussed with physicians, and no previous clinical trials have assessed the effects of biologics specifically on GenPs and its associated symptoms.
To report results for novel patient-reported outcomes (PROs) for the assessment of symptoms and the sexual impact of GenPs before and after treatment in the IXORA-Q study.
IXORA-Q (NCT02718898) was a phase III, randomized, double-blind, placebo-controlled study of ixekizumab (80 mg/2 weeks after 160-mg initial dose) vs placebo for GenPs. Men and women ≥18 years old with moderate-to-severe GenPs and body surface area (BSA) ≥1% were assessed through 12 weeks.
GenPs symptoms were assessed using the 8-item Genital Psoriasis Symptoms Scale (GPSS), Genital Psoriasis Sexual Frequency Questionnaire (GenPs-SFQ), and Genital Psoriasis Sexual Impact Scale (GPSIS) (validation data presented in the supplemental materials), and the Dermatology Life Quality Index (DLQI) item 9.
For patients receiving ixekizumab (N = 75) vs placebo (N = 74), statistically significant improvement in GenPs symptoms were seen from week 1 onward (GPSS total and individual items, all P < .005). Sexual activity avoidance owing to GenPs symptoms (GPSIS) decreased significantly with ixekizumab from week 4 onward (all P <.005), whereas impact of sexual activity on GenPs improved significantly with ixekizumab at weeks 2–8 (all P < 0.05). Ixekizumab resulted in significant improvement vs placebo by week 1 onward in limitations on frequency of sexual activity owing to GenPs (GenPs-SFQ item 2). Sexual difficulties caused by skin (DLQI item 9) decreased significantly with ixekizumab from week 2 onward (all P < .001).
Both GenPs symptoms and impact on sexual activity improved rapidly and significantly with ixekizumab vs placebo through 12 weeks in patients with moderate-to-severe GenPs and BSA ≥1%.
To our knowledge, this is the first phase III, randomized, placebo-controlled, double-blinded clinical trial to evaluate the effect of any treatment on the symptoms and sexual impact related to GenPs. The study did not include an active comparator owing to the lack of any well-established treatment for moderate-to-severe GenPs, and the period assessed herein was of relatively short duration.
These validated PRO measures may aid in future clinical studies of GenPs and in facilitating discussions of GenPs symptoms and their impact between patients and clinicians.
Introduction
Genital psoriasis (GenPs) is a common manifestation of psoriasis, with up to 63% of psoriasis patients reporting genital involvement at some time.1–3 GenPs is characterized by symptoms such as intense itch, pain, burning, dyspareunia, worsening of symptoms after sexual intercourse, and decreased frequency of intercourse. These symptoms can contribute to impairment of quality of life, sexual health, and activities of daily living.2 Thus, psoriasis patients with genital lesions report significantly worse health-related quality of life vs patients without genital involvement, as well as greater feelings of stigmatization and lower self-esteem.3–5
Despite its high prevalence and burden, GenPs often remains undiagnosed, in part because of a reluctance of both healthcare providers and patients to discuss GenPs, leading to insufficient evaluation of patients for genital involvement.6,7 Treatment of GenPs is also complicated by the sensitivity of genital skin, for which many standard topical or UV-based treatments for psoriasis are either contraindicated or poorly tolerated. Given the high patient burden and limited available treatment options, current treatment guidelines support the use of systemic therapies for GenPs when other treatment options fail, even in patients below otherwise indicated cutoffs of body surface area (BSA) involvement for systemic therapies (BSA <10%).7,8 However, despite the significant unmet clinical need for effective treatments of GenPs, there are few published clinical studies investigating therapies for GenPs or validated instruments to assess GenPs.9
Ixekizumab is a high-affinity monoclonal antibody that selectively targets interleukin-17A. The recommended dosing regimen of ixekizumab results in rapid achievement and maintenance of high clinical response rates for patients with moderate-to-severe plaque psoriasis.10–12 In addition, a recent randomized, double-blinded, placebo-controlled phase IIIb clinical trial (IXORA-Q) demonstrated that ixekizumab is superior to placebo for the treatment of moderate-to-severe GenPs.13 The goals of the present report were to assess the effects of ixekizumab on GenPs symptoms and sexual activity through week 12 in the IXORA-Q study based on several recently developed GenPs-specific PRO instruments and on the Dermatology Life Quality Index (DLQI) item 9 (sexual difficulties due to skin). A secondary aim was to provide data validating the psychometric properties of the novel patient-reported outcomes (PROs) (Supplemental Table 1 and Supplemental Figures 1-5).
Methods
Study Design
IXORA-Q was a 52-week, phase IIIb, randomized, double-blind, placebo-controlled study (NCT02718898) evaluating the efficacy and safety of ixekizumab in patients with moderate-to-severe GenPs.13 Patients were randomized in a 1:1 ratio to receive placebo or 80 mg ixekizumab every 2 weeks (Q2W) through week 12 following an initial dose of 160-mg ixekizumab; data for the randomized treatment period (through week 12) are assessed in this article.
The primary and major secondary outcomes were reported previously, and included the percentage of patients at week 12 achieving clear or almost clear genital skin (static Physician’s Global Assessment [sPGA]-G 0/1), clear or almost clear overall skin (overall sPGA 0/1), ≥3-point improvement from baseline in GenPs itch numeric rating scale (NRS) in patients with score ≥3 at baseline, and a score of 0 or 1 in GenPs-Sexual Frequency Questionnaire (GenPs-SFQ) item 2 (0/1) in patients with score ≥2 at baseline.13 Safety data have also been published previously.13
This study was conducted in accordance with the ethical principles of the Declaration of Helsinki. All patients provided written informed consent before undergoing study-related procedures.
Participants
As previously described, participants were ≥18 years old, with a history of plaque psoriasis for ≥6 months.13 Participants were candidates for phototherapy or systemic therapy and had previously failed or were intolerant of ≥1 topical therapy (corticosteroids, calcineurin inhibitors, and vitamin D analogs) for their GenPs. At screening and baseline, subjects were required to have an overall sPGA ≥3, sPGA of Genitalia (sPGA-G) ≥3, plaque psoriasis in a non-genital area, and BSA involvement of ≥1%. Subjects were excluded for presence of pustules or vesicles in the genital area or previous treatment with IL-17 antagonists.
Outcome Measures for Results
GenPs symptoms were measured using several novel PRO measures, which were developed based on previous literature and clinician interviews, and responses during in-depth interviews of patients affected by GenPs.14 The validated (based on data from IXORA-Q) Genital Psoriasis Symptoms Scale (GPSS) uses an NRS (range, 0–10; 0 = no symptom, 10 = worst imaginable) for 8 common symptoms of GenPs (itch, pain, discomfort, stinging, burning, redness, scaling, and cracking) and also includes a total score (range 0–80).15 In accordance with published Food and Drug Administration (FDA) guidance, a clinically meaningful improvement in GPSS itch NRS was derived by anchoring the change of itch score on the clinician assessment sPGA-G; a ≥3-point improvement from baseline was thereby defined as clinically meaningful, and was assessed at week 12 as a prespecified major secondary end point of IXORA-Q.13,16 In addition, we completed a sensitivity analysis to evaluate response for genital itch (GPSS itch) ≥4 point improvement from baseline, as a 4-point improvement has historically been accepted by regulatory agencies such as the FDA. Psychometric validation data for the GPSS are provided in the Supplemental Materials.
The GenPs-SFQ PRO evaluates the impact of GenPs symptoms on sexual frequency based on 2 items. Item 1 asked how many times the patient engaged in sexual activity in the past week with response options of “none/0” (2), “once” (1), and “2 or more” (0).14 Item 2 assessed how often GenPs symptoms limited the frequency of sexual activity with response options ranging from 0 (never) to 4 (always). The individual item scores of the GenPs-SFQ were reported separately and no total score was calculated. Validation data for GenPs-SFQ item 2 are shown in the Supplemental Materials.
Avoidance of sexual activity and the impact of sexual activity on GenPs symptoms were assessed using the Genital Psoriasis Sexual Impact Scale (GPSIS) PRO, which comprises 2 subscales. The GPSIS Sexual Activity Avoidance Subscale asked whether the patient had been sexually active in the last week (item 1) with responses “yes,” “no due to my genital psoriasis,” and “no due to reasons other than my genital psoriasis,” and if “yes,” how often their GenPs symptoms had interfered with sexual activity (item 2), with answers ranging from never (1) to always (5) avoided sexual activity. For the GPSIS Impact of Sexual Activity on Genital Psoriasis Symptoms Subscale, patients who reported being sexually active on GPSIS item 1 were given the opportunity to respond to item 3. Item 3 asked the patient to select a response to reflect the level (degree) of worsening of GenPs symptoms during or following sexual activity: 1 = very low or not at all, 2 = low, 3 = moderate, 4 = high, 5 = very high. Validation data for the GPSIS are shown in the Supplemental Materials.
The DLQI is a well-established and validated 10-item instrument for assessing quality of life in patients with skin disease, including psoriasis.17 DLQI item 9 assesses the impact of skin on sexual difficulties by asking “Over the last week, how much has your skin caused any sexual difficulties?” with scores of 0 = not at all; 1 = a little; 2 = a lot; and 3 = very much (not relevant scored as 0).
Patients were asked to complete assessments of the impact of GenPs for the above outcomes (with the exception of DLQI item 9 that assesses the impact of skin overall). The genital area was defined as the labia majora (outer lips), labia minora (inner lips), and perineum (area between vagina and anus) for women, and the penis, scrotum, and perineum (area between the penis and anus) for men. The definition of sexual activity was not limited to intercourse and included activities such as masturbation. An electronic diary or tablet was used to collect PRO data from screening through week 12; for the GPSIS and SFQ, patients used a recall period of 1 week. The GPSS required a daily response.
Statistical Methods for Results
All analyses were performed using SAS version 9.2 or higher. Baseline comparisons used Fisher’s exact test for categorical data and analysis of variance with treatment as a factor for continuous data. Efficacy analyses were performed for all randomized patients by assigned treatment group (intent-to-treat population). Categorical variables were analyzed using a logistic regression model accounting for missing data using non-responder imputation. Continuous variables were analyzed using a mixed-effects model for repeated measures (MMRM). Type III tests for the least squares means were used for statistical comparison between treatment groups for continuous variables. Both logistic and MMRM models included baseline BSA category (<10% vs ≥10%) as a covariate.
Results
Baseline Characteristics
As reported previously, baseline demographics and disease characteristics were similar between the placebo (N = 74) and ixekizumab (N = 75) groups. Overall, 75.8% of patients were men (including 1 transgender patient who identified as female but had male genitalia), 87.9% were white, mean (SD) age was 43.7 (12.7) years, and weight was 93.5 (24.7) kg. The mean (SD) duration of plaque psoriasis and GenPs was 16.5 (12.6) years and 8.8 (9.1) years, respectively, and 39.6% of patients had 1% to <10% BSA involvement. Systemic therapies had previously been used by 52.3% (non-biologic) and 19.5% (biologic) of patients.
Genital Psoriasis Symptoms Scale
Baseline overall values for the GPSS total and item scores are shown in Table 1 ; no significant differences were seen between treatment groups at baseline for the GPSS total or item scores (all P ≥ .276). At visits from week 1 to week 12, there was a statistically significantly greater improvement from baseline in the GPSS total score and in each item score (itch, pain, discomfort, stinging, burning, redness, scaling, and cracking) in patients receiving ixekizumab vs patients receiving placebo (P < .005; all items P < .001 from week 2–week 12; Figure 1 ). As reported previously for the GPSS itch item, among patients with a score ≥3 at baseline, ixekizumab resulted in significantly more patients achieving a ≥3-point (clinically meaningful) improvement from baseline (59.7%) compared with placebo (8.3%, P < .001) at week 12, and a significant improvement in genital itch was observed with ixekizumab as early as week 2 (ixekizumab: 33.9%, placebo: 5.0%, P < .001).13 For an improvement in GPSS itch of ≥4 points among patients with a score of ≥4 at baseline, ixekizumab resulted in a significantly greater proportion of patients achieving response at week 12 (55.4%) vs placebo (5.9%, P < .001), and a significant improvement was observed with ixekizumab from week 2 (ixekizumab: 23.2%, placebo: 2.0%, P = .012). Psychometric validation data for the GPSS are described in the Supplemental Materials.
Baseline values for GPSS total scores and item scores
| Item | Placebo (N = 74) | Ixekizumab Q2W (N = 75) | Total (N = 149) | |
|---|---|---|---|---|
| GPSS∗ | Total score | 45.4 (19.5) | 43.6 (18.4) | 44.5 (18.9) |
| Itch | 6.0 (2.4) | 5.9 (2.4) | 6.0 (2.4) | |
| Pain | 5.4 (2.7) | 5.2 (2.7) | 5.3 (2.7) | |
| Discomfort | 6.2 (2.5) | 6.0 (2.4) | 6.1 (2.5) | |
| Stinging | 5.3 (2.7) | 5.1 (2.7) | 5.2 (2.7) | |
| Burning | 5.4 (2.7) | 5.1 (2.7) | 5.2 (2.7) | |
| Redness | 6.2 (2.4) | 6.3 (2.2) | 6.2 (2.3) | |
| Scaling | 5.6 (2.5) | 5.1 (2.7) | 5.4 (2.6) | |
| Cracking | 5.3 (2.9) | 4.9 (2.7) | 5.1 (2.8) |
| Item | Placebo (N = 74) | Ixekizumab Q2W (N = 75) | Total (N = 149) | |
|---|---|---|---|---|
| GPSS∗ | Total score | 45.4 (19.5) | 43.6 (18.4) | 44.5 (18.9) |
| Itch | 6.0 (2.4) | 5.9 (2.4) | 6.0 (2.4) | |
| Pain | 5.4 (2.7) | 5.2 (2.7) | 5.3 (2.7) | |
| Discomfort | 6.2 (2.5) | 6.0 (2.4) | 6.1 (2.5) | |
| Stinging | 5.3 (2.7) | 5.1 (2.7) | 5.2 (2.7) | |
| Burning | 5.4 (2.7) | 5.1 (2.7) | 5.2 (2.7) | |
| Redness | 6.2 (2.4) | 6.3 (2.2) | 6.2 (2.3) | |
| Scaling | 5.6 (2.5) | 5.1 (2.7) | 5.4 (2.6) | |
| Cracking | 5.3 (2.9) | 4.9 (2.7) | 5.1 (2.8) |
Data are presented as mean (SD). No statistically significant differences were seen between groups.
GPSS = Genital Psoriasis Symptoms Scale; Q2W = every 2 weeks.
Entered prespecified minimum of 4 GPSS entries into daily diary over a 7-day period before study drug administration: Placebo, n = 68; Ixekizumab Q2W, n = 72; Total, n = 140.
Baseline values for GPSS total scores and item scores
| Item | Placebo (N = 74) | Ixekizumab Q2W (N = 75) | Total (N = 149) | |
|---|---|---|---|---|
| GPSS∗ | Total score | 45.4 (19.5) | 43.6 (18.4) | 44.5 (18.9) |
| Itch | 6.0 (2.4) | 5.9 (2.4) | 6.0 (2.4) | |
| Pain | 5.4 (2.7) | 5.2 (2.7) | 5.3 (2.7) | |
| Discomfort | 6.2 (2.5) | 6.0 (2.4) | 6.1 (2.5) | |
| Stinging | 5.3 (2.7) | 5.1 (2.7) | 5.2 (2.7) | |
| Burning | 5.4 (2.7) | 5.1 (2.7) | 5.2 (2.7) | |
| Redness | 6.2 (2.4) | 6.3 (2.2) | 6.2 (2.3) | |
| Scaling | 5.6 (2.5) | 5.1 (2.7) | 5.4 (2.6) | |
| Cracking | 5.3 (2.9) | 4.9 (2.7) | 5.1 (2.8) |
| Item | Placebo (N = 74) | Ixekizumab Q2W (N = 75) | Total (N = 149) | |
|---|---|---|---|---|
| GPSS∗ | Total score | 45.4 (19.5) | 43.6 (18.4) | 44.5 (18.9) |
| Itch | 6.0 (2.4) | 5.9 (2.4) | 6.0 (2.4) | |
| Pain | 5.4 (2.7) | 5.2 (2.7) | 5.3 (2.7) | |
| Discomfort | 6.2 (2.5) | 6.0 (2.4) | 6.1 (2.5) | |
| Stinging | 5.3 (2.7) | 5.1 (2.7) | 5.2 (2.7) | |
| Burning | 5.4 (2.7) | 5.1 (2.7) | 5.2 (2.7) | |
| Redness | 6.2 (2.4) | 6.3 (2.2) | 6.2 (2.3) | |
| Scaling | 5.6 (2.5) | 5.1 (2.7) | 5.4 (2.6) | |
| Cracking | 5.3 (2.9) | 4.9 (2.7) | 5.1 (2.8) |
Data are presented as mean (SD). No statistically significant differences were seen between groups.
GPSS = Genital Psoriasis Symptoms Scale; Q2W = every 2 weeks.
Entered prespecified minimum of 4 GPSS entries into daily diary over a 7-day period before study drug administration: Placebo, n = 68; Ixekizumab Q2W, n = 72; Total, n = 140.
Genital Psoriasis Symptom Score (GPSS) total score and item scores change from baseline by study week. Shown are least squares mean changes from baseline based on mixed-modeling of repeated measures. LSM = least squares mean; PBO = placebo. †P < .005, ‡P < .001.
GenPs-SFQ
Baseline overall values for GenPs-SFQ items 1 and 2, the GPSIS subscales, and DLQI item 9 are shown in Table 2 ; no significant differences were seen between the treatment groups in the distribution of patients across categories (P value range .242–> .999, data not shown). The frequency of sexual activity (none/0, once, ≥2) did not change significantly through 12 weeks of treatment for patients receiving ixekizumab vs placebo, although by week 12, 17% fewer ixekizumab than placebo patients reported no sexual activity in the previous week (GenPs-SFQ item 1; data not shown). Results regarding the effect of ixekizumab on the impact of GenPs on the frequency of sexual activity (GenPs-SFQ item 2) have been presented previously and are addressed in this article.13 Psychometric validation data for GenPs-SFQ item 2 are presented in the Supplemental Materials.
Baseline values for GPSIS, DLQI item 9, and GenPs-SFQ
| Measure | Response | Placebo (N = 74) | Ixekizumab Q2W (N = 75) | Total (N = 149) |
|---|---|---|---|---|
| GPSIS, Sexual Activity Avoidance Subscale∗ | 1, never | 27 (39.1) | 33 (45.2) | 60 (42.3) |
| 2, rarely | 7 (10.1) | 10 (13.7) | 17 (12.0) | |
| 3, sometimes | 7 (10.1) | 4 (5.5) | 11 (7.7) | |
| 4, often | 8 (11.6) | 3 (4.1) | 11 (7.7) | |
| 5, always | 20 (29.0) | 23 (31.5) | 43 (30.3) | |
| GPSIS, Impact of Sexual Activity on Genital Psoriasis Symptoms Subscale† (sexually active patients only) | 1, very low or not at all | 5 (16.1) | 5 (15.6) | 10 (15.9) |
| 2, low | 3 (9.7) | 8 (25.0) | 11 (17.5) | |
| 3, moderate | 12 (38.7) | 11 (34.4) | 23 (36.5) | |
| 4, high | 9 (29.0) | 8 (25.0) | 17 (27.0) | |
| 5, very high | 2 (6.5) | 0 | 2 (3.2) | |
| DLQI item 9‡ | 0, not at all | 18 (24.3) | 24 (32.0) | 42 (28.2) |
| 1, a little | 18 (24.3) | 21 (28.0) | 39 (26.2) | |
| 2, a lot | 19 (25.7) | 9 (12.0) | 28 (18.8) | |
| 3, very much | 15 (20.3) | 14 (18.7) | 29 (19.5) | |
| 0, not relevant | 4 (5.4) | 7 (9.3) | 11 (7.4) | |
| GenPs-SFQ item 1∗ | 0 (≥2) | 17 (24.6) | 17 (23.3) | 34 (23.9) |
| 1 (once) | 17 (24.6) | 19 (26.0) | 36 (25.4) | |
| 2 (none/0) | 35 (50.7) | 37 (50.7) | 72 (50.7) | |
| GenPs-SFQ item 2∗ | 0, never | 19 (27.5) | 25 (34.2) | 44 (31.0) |
| 1, rarely | 8 (11.6) | 11 (15.1) | 19 (13.4) | |
| 2, sometimes | 14 (20.3) | 9 (12.3) | 23 (16.2) | |
| 3, often | 11 (15.9) | 8 (11.0) | 19 (13.4) | |
| 4, always | 17 (24.6) | 20 (27.4) | 37 (26.1) | |
| Mean (SD) | 2.0 (1.6) | 1.8 (1.7) | 1.9 (1.6) |
| Measure | Response | Placebo (N = 74) | Ixekizumab Q2W (N = 75) | Total (N = 149) |
|---|---|---|---|---|
| GPSIS, Sexual Activity Avoidance Subscale∗ | 1, never | 27 (39.1) | 33 (45.2) | 60 (42.3) |
| 2, rarely | 7 (10.1) | 10 (13.7) | 17 (12.0) | |
| 3, sometimes | 7 (10.1) | 4 (5.5) | 11 (7.7) | |
| 4, often | 8 (11.6) | 3 (4.1) | 11 (7.7) | |
| 5, always | 20 (29.0) | 23 (31.5) | 43 (30.3) | |
| GPSIS, Impact of Sexual Activity on Genital Psoriasis Symptoms Subscale† (sexually active patients only) | 1, very low or not at all | 5 (16.1) | 5 (15.6) | 10 (15.9) |
| 2, low | 3 (9.7) | 8 (25.0) | 11 (17.5) | |
| 3, moderate | 12 (38.7) | 11 (34.4) | 23 (36.5) | |
| 4, high | 9 (29.0) | 8 (25.0) | 17 (27.0) | |
| 5, very high | 2 (6.5) | 0 | 2 (3.2) | |
| DLQI item 9‡ | 0, not at all | 18 (24.3) | 24 (32.0) | 42 (28.2) |
| 1, a little | 18 (24.3) | 21 (28.0) | 39 (26.2) | |
| 2, a lot | 19 (25.7) | 9 (12.0) | 28 (18.8) | |
| 3, very much | 15 (20.3) | 14 (18.7) | 29 (19.5) | |
| 0, not relevant | 4 (5.4) | 7 (9.3) | 11 (7.4) | |
| GenPs-SFQ item 1∗ | 0 (≥2) | 17 (24.6) | 17 (23.3) | 34 (23.9) |
| 1 (once) | 17 (24.6) | 19 (26.0) | 36 (25.4) | |
| 2 (none/0) | 35 (50.7) | 37 (50.7) | 72 (50.7) | |
| GenPs-SFQ item 2∗ | 0, never | 19 (27.5) | 25 (34.2) | 44 (31.0) |
| 1, rarely | 8 (11.6) | 11 (15.1) | 19 (13.4) | |
| 2, sometimes | 14 (20.3) | 9 (12.3) | 23 (16.2) | |
| 3, often | 11 (15.9) | 8 (11.0) | 19 (13.4) | |
| 4, always | 17 (24.6) | 20 (27.4) | 37 (26.1) | |
| Mean (SD) | 2.0 (1.6) | 1.8 (1.7) | 1.9 (1.6) |
Data are presented as n (%). No statistically significant differences were seen between groups.
DLQI = Dermatology Life Quality Index; GenPs-SFQ = Genital Psoriasis Sexual Frequency Questionnaire; GPSIS = Genital Psoriasis Sexual Impact Scale; Q2W = every 2 weeks.
Numbers of patients who were eligible and entered data in diary:
Placebo, n = 69; Ixekizumab Q2W, n = 73; Total, n = 142.
Placebo, n = 31; Ixekizumab Q2W, n = 32; Total, n = 63.
Placebo, n = 74; Ixekizumab Q2W, n = 75; Total, n = 149.
Baseline values for GPSIS, DLQI item 9, and GenPs-SFQ
| Measure | Response | Placebo (N = 74) | Ixekizumab Q2W (N = 75) | Total (N = 149) |
|---|---|---|---|---|
| GPSIS, Sexual Activity Avoidance Subscale∗ | 1, never | 27 (39.1) | 33 (45.2) | 60 (42.3) |
| 2, rarely | 7 (10.1) | 10 (13.7) | 17 (12.0) | |
| 3, sometimes | 7 (10.1) | 4 (5.5) | 11 (7.7) | |
| 4, often | 8 (11.6) | 3 (4.1) | 11 (7.7) | |
| 5, always | 20 (29.0) | 23 (31.5) | 43 (30.3) | |
| GPSIS, Impact of Sexual Activity on Genital Psoriasis Symptoms Subscale† (sexually active patients only) | 1, very low or not at all | 5 (16.1) | 5 (15.6) | 10 (15.9) |
| 2, low | 3 (9.7) | 8 (25.0) | 11 (17.5) | |
| 3, moderate | 12 (38.7) | 11 (34.4) | 23 (36.5) | |
| 4, high | 9 (29.0) | 8 (25.0) | 17 (27.0) | |
| 5, very high | 2 (6.5) | 0 | 2 (3.2) | |
| DLQI item 9‡ | 0, not at all | 18 (24.3) | 24 (32.0) | 42 (28.2) |
| 1, a little | 18 (24.3) | 21 (28.0) | 39 (26.2) | |
| 2, a lot | 19 (25.7) | 9 (12.0) | 28 (18.8) | |
| 3, very much | 15 (20.3) | 14 (18.7) | 29 (19.5) | |
| 0, not relevant | 4 (5.4) | 7 (9.3) | 11 (7.4) | |
| GenPs-SFQ item 1∗ | 0 (≥2) | 17 (24.6) | 17 (23.3) | 34 (23.9) |
| 1 (once) | 17 (24.6) | 19 (26.0) | 36 (25.4) | |
| 2 (none/0) | 35 (50.7) | 37 (50.7) | 72 (50.7) | |
| GenPs-SFQ item 2∗ | 0, never | 19 (27.5) | 25 (34.2) | 44 (31.0) |
| 1, rarely | 8 (11.6) | 11 (15.1) | 19 (13.4) | |
| 2, sometimes | 14 (20.3) | 9 (12.3) | 23 (16.2) | |
| 3, often | 11 (15.9) | 8 (11.0) | 19 (13.4) | |
| 4, always | 17 (24.6) | 20 (27.4) | 37 (26.1) | |
| Mean (SD) | 2.0 (1.6) | 1.8 (1.7) | 1.9 (1.6) |
| Measure | Response | Placebo (N = 74) | Ixekizumab Q2W (N = 75) | Total (N = 149) |
|---|---|---|---|---|
| GPSIS, Sexual Activity Avoidance Subscale∗ | 1, never | 27 (39.1) | 33 (45.2) | 60 (42.3) |
| 2, rarely | 7 (10.1) | 10 (13.7) | 17 (12.0) | |
| 3, sometimes | 7 (10.1) | 4 (5.5) | 11 (7.7) | |
| 4, often | 8 (11.6) | 3 (4.1) | 11 (7.7) | |
| 5, always | 20 (29.0) | 23 (31.5) | 43 (30.3) | |
| GPSIS, Impact of Sexual Activity on Genital Psoriasis Symptoms Subscale† (sexually active patients only) | 1, very low or not at all | 5 (16.1) | 5 (15.6) | 10 (15.9) |
| 2, low | 3 (9.7) | 8 (25.0) | 11 (17.5) | |
| 3, moderate | 12 (38.7) | 11 (34.4) | 23 (36.5) | |
| 4, high | 9 (29.0) | 8 (25.0) | 17 (27.0) | |
| 5, very high | 2 (6.5) | 0 | 2 (3.2) | |
| DLQI item 9‡ | 0, not at all | 18 (24.3) | 24 (32.0) | 42 (28.2) |
| 1, a little | 18 (24.3) | 21 (28.0) | 39 (26.2) | |
| 2, a lot | 19 (25.7) | 9 (12.0) | 28 (18.8) | |
| 3, very much | 15 (20.3) | 14 (18.7) | 29 (19.5) | |
| 0, not relevant | 4 (5.4) | 7 (9.3) | 11 (7.4) | |
| GenPs-SFQ item 1∗ | 0 (≥2) | 17 (24.6) | 17 (23.3) | 34 (23.9) |
| 1 (once) | 17 (24.6) | 19 (26.0) | 36 (25.4) | |
| 2 (none/0) | 35 (50.7) | 37 (50.7) | 72 (50.7) | |
| GenPs-SFQ item 2∗ | 0, never | 19 (27.5) | 25 (34.2) | 44 (31.0) |
| 1, rarely | 8 (11.6) | 11 (15.1) | 19 (13.4) | |
| 2, sometimes | 14 (20.3) | 9 (12.3) | 23 (16.2) | |
| 3, often | 11 (15.9) | 8 (11.0) | 19 (13.4) | |
| 4, always | 17 (24.6) | 20 (27.4) | 37 (26.1) | |
| Mean (SD) | 2.0 (1.6) | 1.8 (1.7) | 1.9 (1.6) |
Data are presented as n (%). No statistically significant differences were seen between groups.
DLQI = Dermatology Life Quality Index; GenPs-SFQ = Genital Psoriasis Sexual Frequency Questionnaire; GPSIS = Genital Psoriasis Sexual Impact Scale; Q2W = every 2 weeks.
Numbers of patients who were eligible and entered data in diary:
Placebo, n = 69; Ixekizumab Q2W, n = 73; Total, n = 142.
Placebo, n = 31; Ixekizumab Q2W, n = 32; Total, n = 63.
Placebo, n = 74; Ixekizumab Q2W, n = 75; Total, n = 149.
Genital Psoriasis Sexual Impact Scale
Improvement in the GPSIS sexual activity avoidance subscale were assessed based on change from avoiding sometimes (3), often (4), or always (5) at baseline to avoiding rarely (1) or never (0) at follow-up. The proportion of patients improving to 0/1 was significantly greater with ixekizumab vs placebo from week 4 to week 12 (all P < .005; Figure 2 A). Among patients who were sexually active, the Impact of Sexual Activity on Genital Psoriasis Symptoms Subscale improved significantly with ixekizumab vs placebo at weeks 2, 4, and 8 (all P < .05) but not week 12 (Figure 2B). Psychometric validation data for the GPSIS are presented in the Supplemental Materials.
Proportion of patients with improvement in the Genital Psoriasis Sexual Impact Scale (GPSIS) from ≥3 at baseline to 0 or 1 during treatment by study week. (A) sexual activity avoidance subscale; (B) sexual activity impact subscale. IXE Q2W = ixekizumab every 2 weeks; PBO = placebo. *P < .05, †P < .005, ‡P < .001.
DLQI Item 9
At baseline there was no significant difference between treatment arms in the distribution of responses to DLQI item 9. Following treatment, the proportion with DLQI item 9 scores of 0 or 1 was significantly greater with ixekizumab vs placebo from week 2–week 12 (all P < .001; Figure 3 ).
Percentage of patients with Dermatology Life Quality Index (DLQI) item 9 score 0 or 1 by study week. IXE Q2W = ixekizumab every 2 weeks; PBO = placebo. ‡P < .001.
Analyses by Gender
At baseline, the PRO instruments generally showed trends toward differences in responses based on gender. In particular, for the GPSS, all item scores had higher values (worse symptoms) for women. The impact of GenPs on sexual activity was also greater for women than men at baseline (Supplemental Table 2).
Changes from baseline at week 12 were statistically significantly greater with ixekizumab Q2W versus placebo regardless of gender for all GPSS items, the GPSIS avoidance subscale, and GenPs-SFQ item 2 (Supplemental Table 3).
Discussion
The primary and major secondary results of the IXORA-Q study indicated that ixekizumab rapidly and significantly improved both genital and overall psoriasis symptoms vs placebo in patients with moderate-to-severe psoriasis with BSA ≥1% based on physician-rated response and on multiple PRO instruments.13 Here we focused on novel PRO measures for the assessment of GenPs symptoms and impact on sexual health. At baseline, women were generally more profoundly impacted by GenPs symptoms than men. Following treatment, the GenPs symptoms of itch, pain, discomfort, stinging, burning, redness, scaling, and cracking all improved rapidly and significantly (by week 1) with ixekizumab vs placebo. At weeks 4–12, ixekizumab significantly reduced (vs placebo) avoidance of sexual activity owing to GenPs and at weeks 2–8 significantly reduced worsening of GenPs symptoms during or after sexual activity. Although the frequency of sexual activity did not show a statistically significant increase with ixekizumab vs placebo in the overall patient population (GenPs-SFQ item 1, data not shown), as previously reported, among patients who reported that GenPs symptoms affected sexual activity “sometimes,” “often,” or “always” at baseline (GenPs-SFQ item 2), ixekizumab resulted in rapid and significant improvement in the impact of GenPs symptoms on the frequency of sexual activity through week 12.13 This difference in response likely reflects the nearly 25% of patients who reported no sexual activity at baseline owing to reasons other than GenPs. The improvements observed with ixekizumab vs placebo were also seen among both women and men for the GPSS, GPSIS avoidance subscale, and GenPs-SFQ. In addition, rapid and significant improvements were seen in the impact of skin on sexual difficulties as determined by item 9 of the DLQI. These data based on PROs are fully consistent with results presented previously based on physician-reported measures.13
Almost two-thirds of psoriasis patients will experience involvement of the genital area at some time, yet there are currently few published interventional studies of treatments for GenPs. Furthermore, patients perceive the attention given to GenPs symptoms in clinical care as insufficient, and most have never been asked about their sexual health by their doctor.4,18 This is consistent with inadequacies previously described for the clinical care of men with erectile dysfunction.19,20 Thus, the profound impact of GenPs on patients’ well-being may not be appreciated among healthcare providers. Notably, in a recent study of 20 patients’ perspectives on the impact of GenPs, all patients preferred telephone over in-person interviews, which may reflect patients’ discomfort with discussing GenPs symptoms.2 In this context, the use of ≥1 PRO instruments may help facilitate discussion of genital symptoms between patients and healthcare providers. However, there were previously no validated instruments to assess symptoms specifically or the sexual impact of GenPs. Herein we provide data showing the validation of the psychometric properties, as well as the first application in a clinical trial of the GPSS, GPSIS, and GenPs-SFQ, providing valuable support for their use in further clinical studies of GenPs and possibly in clinical practice.
There were several limitations of this study. The study did not include an active comparator, in part owing to a lack of well-established treatments for moderate-to-severe GenPs. Approximately 75% of the study population was men; although GenPs is somewhat more common in male vs female psoriasis patients,9,21 this could have impacted the lack of significant difference in sexual activity based on GenPs-SFQ item 1 in particular, because in a small recent study in patients with GenPs symptoms, men were less likely than women to forgo sexual activity altogether.2,9,21 In addition, this report assessed response only through 12 weeks; the long-term impact of ixekizumab on genital symptoms and sexual activity merits further study, particularly because the impact of avoidance of sexual activity in a relationship might be expected to lag symptom improvement in some cases. Notably, validation of the GPSS, GPSIS, and GenPs-SFQ was based on use in this 1 trial through week 12; analysis over longer treatment durations may further validate the reliability of the change in symptoms over time, as well as the sensitivity to change, of these instruments. Finally, it would be of interest in future studies to assess these instruments for GenPs alongside established instruments for assessing sexual function and satisfaction such as the International Index of Erectile Function and the Female Sexual Function Index.
Conclusion
The GPSS, GPSIS, and GenPs-SFQ are PRO measures of GenPs symptom severity and impact on sexual health with appropriate psychometric properties for use in assessing response to GenPs treatment. To our knowledge these are the first validated measures designed to assess GenPs symptoms specifically and the impact of GenPs on sexual activity (and vice versa). In the present study, patients with moderate-to-severe GenPs and BSA ≥1% receiving ixekizumab had rapid and significantly greater improvements in the severity of GenPs symptoms and impact of GenPs on sexual health compared with those receiving placebo as measured by GPSS, GPSIS, and GenPs-SFQ, as well as by DLQI item 9. These findings support the use of customized treatment for psoriasis patients with genital involvement and lower BSA involvement. These PRO-based findings were fully consistent with the primary and major secondary results of the IXORA-Q study, which included physician-reported assessments. Data following longer duration of therapy will be needed to assess the long-term impact of ixekizumab therapy in alleviating GenPs symptoms. Further discussion also is needed on how best to improve communication between healthcare providers and patients regarding the sensitive topic of GenPs symptoms.
Statement of authorship
Category 1
Conception and Design
Allison Potts Bleakman; Russel Burge
Acquisition of Data
Peter Foley
Analysis and Interpretation of Data
Gil Yosipovitch; Peter Foley; Catriona Ryan; Jennifer Cather; Kim Meeuwis; Russel Burge; Allison Potts Bleakman; Chen-Yen Lin; William Malatestinic; Alice Gottlieb
Category 2
Revising It for Intellectual Content
Gil Yosipovitch; Peter Foley; Catriona Ryan; Jennifer Cather; Kim Meeuwis; Russel Burge; Allison Potts Bleakman; Chen-Yen Lin; William Malatestinic; Alice Gottlieb
Category 3
Final Approval of the Completed Article
Gil Yosipovitch; Peter Foley; Catriona Ryan; Jennifer Cather; Kim Meeuwis; Russel Burge; Allison Potts Bleakman; Chen-Yen Lin; William Malatestinic; Alice Gottlieb
Supplementary Data
Supplementary data related to this article can be found at https://doi.org/10.1016/j.jsxm.2018.09.004.
Funding
This study was funded by Eli Lilly and Company.
Acknowledgment
Thomas Melby (Syneos Health) drafted the manuscript under contract to Eli Lilly and Company.
References
Author notes
Conflict of Interest: G. Yosipovitch: Consultant and scientific advisory board member to Eli Lilly and Co (Lilly), and Opko, TREVI, Menlo, Sienna, Sanofi Regeneron, Novartis, Pfizer, and Galderma, and is supported by Leo Foundation, Pfizer, research funding from Sun Pharma. P. Foley: Investigator, speaker, advisor, or received travel/grant/research support from 3M/iNova/Valeant, Abbott/AbbVie, Amgen, Ascent, Aspen, Australian Ultraviolet Services, Biogen Idec, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Clinuvel, Cutanea, Dermira, CSL, Lilly, Galderma, GlaxoSmithKline/Stiefel, Janssen-Cilag, Leo Pharma/Peplin, Merck Serono, Novartis, Regeneron, Roche, Sanofi, Schering-Plough/MSD, UCB Pharma, Valeant, and Wyeth/Pfizer. C. Ryan: Honoraria as a consultant or speaker for AbbVie, Boehringer Ingelheim, Dermira, Dr. Reddy’s Laboratories, Janssen, Leo, Lilly, Medimetriks, Novartis, Regeneron/Sanofi, and UCB Pharma. J.C. Cather: Grant support and honoraria as an investigator, speaker, and advisory board member for AbbVie, Celgene, Lilly, and Regeneron-Sanofi Genzyme; honoraria as a speaker and advisory board member for Actelion; and grant support as an investigator for Amgen, Boehringer Ingelheim, Dermira, Galderma, Janssen, and Sun Pharmaceuticals. K.A. Meeuwis: Consultant and received honoraria from Lilly and Eucerin and advisor for Eucerin, Netherlands. R. Burge, A.P. Bleakman, C-Y. Lin, and W. Malatestinic are employees of Eli Lilly and Co. A. Gottlieb: Current consulting/advisory board agreements/or speakers bureau for Janssen, Celgene, Bristol-Myers Squibb, Beiersdorf, AbbVie, UCB Pharma, Novartis, Incyte, Lilly, Reddy Labs, Valeant, Dermira, Allergan, and Sun Pharmaceuticals, and research/educational grants from Janssen, Incyte, Lilly, Novartis, Allergan, and Leo.
