Real‐world effectiveness of guselkumab in patients with psoriasis: Health‐related quality of life and efficacy data from the noninterventional, prospective, German multicenter PERSIST trial

Psoriasis is a common, chronic inflammatory skin disorder negatively impacting health‐related quality of life (HRQoL). Guselkumab, targeting interleukin‐23 (IL‐23), is an approved biologic therapy for psoriasis. PERSIST is an ongoing prospective, noninterventional, long‐term, German multicenter study evaluating the effect of guselkumab on HRQoL, and its efficacy and safety in patients with moderate‐to‐severe psoriasis in a real‐world setting. The primary endpoint is the proportion of patients with a Dermatology Life Quality Index (DLQI) score ≤ 1 at week 28. Of 303 patients enrolled and treated with guselkumab, mean age and disease duration were 49.7 and 21.0 years, respectively, and 51.2% (n = 155) of patients had received ≥1 prior biologic therapy. Mean baseline DLQI score was 13.7, and mean symptom and sign scores in the Psoriasis Symptoms and Signs Diary (PSSD) were 51.9 and 60.8, respectively. Baseline Psoriasis Area Severity Index (PASI) and body surface area (%) scores were 16.4 and 27.5. Following 28 weeks of guselkumab treatment, the mean DLQI score decreased to 2.8, and 56.8% of patients (n = 150) achieved DLQI ≤ 1. Mean PSSD symptom and sign scores also improved, decreasing to 12.5 and 15.9, respectively. At week 28, PASI 90 response was 55.3%; significant improvement was observed in patients with psoriasis in difficult‐to‐treat areas. Overall, analyses demonstrated that guselkumab was effective in the real‐world setting, as measured by HRQoL and skin improvements, even in patients with a high burden of disease and those who have received multiple biologic therapies. No new safety signals were observed.


| INTRODUC TI ON
Psoriasis is a chronic inflammatory skin disease with a prevalence of 2%-4% in Europe, and 2.5% in Germany. 1 Plaque psoriasis is the most frequent type, comprising more than 80% of all cases. Patients with moderate-to-severe psoriasis have an increased risk of developing comorbidities; as such, they usually require continuous therapy to limit the impact of the disease on health-related quality of life (HRQoL), including anxiety and depression. 2 However, severity of psoriasis is not a reliable predictor of the severity of psychological distress, disability, or impact on HRQoL. [3][4][5] Therefore, patient-reported outcomes (PROs) play a critical role during treatment evaluation. 6 The Dermatology Life Quality Index (DLQI), which evaluates patient perception of the impact of skin disease on HRQoL, and the Psoriasis Symptoms and Signs Diary (PSSD) are key tools for conducting patient-centric evaluations. [7][8][9][10] With increased understanding of the pathophysiology of psoriasis, several biologic therapies have been developed. Guselkumab, a fully human monoclonal antibody that binds to the p19 subunit of interleukin-23 (IL- 23), was approved in Europe in November 2017 for the treatment of moderate-to-severe psoriasis based on its significant superior efficacy versus placebo in the phase 3 double-blind VOYAGE 1 and VOYAGE 2 studies. 11,12 Long-term efficacy and safety with guselkumab treatment have since been demonstrated in these studies, 13,14 as well as in the phase 3 double-blind, head-to-head ECLIPSE study versus secukinumab. 15 However, patients treated in randomized controlled trials (RCTs) have often received fewer previous therapies and have fewer comorbidities than patients in the real-world setting. Therefore, PROs and real-world data from postmarketing studies and international or local registries are of great interest to the scientific community, providing crucial data in patients typically excluded from RCTs. 6,16,17 PERSIST is a noninterventional study investigating the effect of guselkumab and ustekinumab treatment on HRQoL, and their long-term efficacy and safety in patients with moderate-to-severe psoriasis, in routine clinical practice. This publication focuses on patients treated with guselkumab, at week 28.

| Study design
PERSIST is an ongoing, prospective, noninterventional, multicenter study investigating the impact of guselkumab and ustekinumab on HRQoL, and the long-term efficacy and safety of these treatments in a real-world setting, in patients with moderate-tosevere plaque psoriasis. First planned and started in 2016 with ustekinumab-treated patients, a study amendment was approved in January 2018 to also evaluate patients treated with guselkumab.

| Patients
Patients enrolled in PERSIST were ≥18 years old and had a diagnosis of moderate-to-severe plaque psoriasis for ≥2 years. All patients included in this analysis were prescribed guselkumab based on the treating physician's decision as per routine clinical practice, and according to the approved label. See Supporting Information for exclusion criteria.

| Endpoints and assessments
The primary endpoint was the proportion of patients with a DLQI score ≤ 1 at week 28. The DLQI comprises 10 questions that evaluate the impact of skin disease on the patient's life during the previous week, providing a score ranging from 0 to 30, where 0-1 indicates no effect on quality of life. Secondary endpoints included PSSD, Psoriasis Area Severity Index (PASI) and body area-specific Physician's Global Assessment (PGA) outcomes at week 28. The PSSD allows patient self-evaluation of symptoms and signs of psoriasis on a scale of 0-10, with higher scores indicating greater severity (see Supporting Information for additional assessment details).
Patients will be evaluated for 2 years, until consent withdrawal, or until beginning another systemic treatment for psoriasis.
Concomitant medications for psoriasis (excluding biologic therapy) were permitted. Safety was assessed at data cut-off (28 January 2020) by evaluating adverse events (AEs) using terms as defined by Medical Dictionary for Regulatory Activities (MedDRA v20.0).
Assessments were conducted on the full analysis population, comprising all patients treated with guselkumab, using available data without imputing missing values.

| Statistical analysis
A study sample size of ≥300 patients was selected for the group receiving guselkumab, consistent with the size of the ustekinumab study (see Supporting Information).

| Patients
Between January 2018 and May 2019, 303 patients were enrolled into PERSIST following routine prescription of guselkumab. There were 24 (7.9%) patient withdrawals before week 28, six (2.0%) be- At baseline, patient mean age was 49.7 years and mean duration of disease was 21.0 years ( Table 1). The mean DLQ I score was 13.7, and the mean (PSSD) symptom and sign scores were 51.9 and 60.8, respectively. Mean PASI score was 16  Coinciding with improvements in DLQI, the mean PSSD symptom score decreased from 51.9 at baseline to 12.5 (95% CI 10.3-14.7) at week 28, whereas the mean sign score decreased from 60.8 to 15.9 (95% CI 13.5-18.3; Figure S1a). Among patients who had PSSD scores ≥ 1 for itch, pain or scaling at baseline, the mean reductions in these item scores were −4.6 (n = 244), −4.4 (n = 210), and −5.1 (n = 242), respectively, each meeting the criteria for clinically meaningful improvement (≥4-point reduction). 18 Within this group, the proportion of patients achieving a score of 0 was 35.7% (n = 87) for itch, 65.2% (n = 137) for pain, and 37.2% (n = 90) for scaling; patients who achieved a PSSD score of 0 for these individual items were more likely to have a DLQI score of ≤ 1 versus > 1 ( Figure 3).
In line with PASI responses, progressive improvement was observed in patients with difficult-to-treat psoriasis. Among those with an area-specific PGA score ≥ 2 at baseline, severe involvement of the scalp, palmoplantar, and anogenital regions was observed in 23.5%

| Safety outcomes
Thirty-nine patients (12.9%) experienced at least one treatmentrelated AE. Most AEs were mild or moderate (   in PERSIST achieved a DLQI score of 0-1 (56.8% by week 28) as in VOYAGE 1 (60.9%) and 2 (57.6%) at week 24. 11,12 In PERSIST, improvements in DLQI score were also observed over time in patients with psoriasis in difficult-to-treat areas, which can profoundly impact on HRQoL. [22][23][24] PERSIST is the first real-world study to report on the effectiveness of guselkumab on HRQoL in patients with anogenital psoriasis, an indication that is particularly debilitating because sexual functioning is impacted in up to 90% of patients with genital psoriasis. 25 Moreover, psoriasis patients with anogenital involvement have significantly greater treatment needs than those without. 23 Findings from PERSIST may further support the effectiveness of guselkumab in patients who have a high burden of disease and impaired quality of life caused by psoriasis in difficult-to-treat areas. Improvement in PSSD scores was also observed in PERSIST, with mean changes consistent with both VOYAGE studies. 11,12 However, although baseline single-item scores in PERSIST and VOYAGE 1 were similar, the proportions of patients achieving a PSSD score of 0 (among those with a baseline score ≥ 1) differed ( 26 Overall, guselkumab-treated patients reported improvements in symptoms and signs, as well as HRQoL, demonstrating its effectiveness even in a population that has received previous biologic therapies. Although the PASI 90 response rate in PERSIST (55.3% at week 28) was not as high as that observed in two smaller RWE studies, where PASI 90 was achieved by 72.5% (N = 52) 27  As previously discussed, baseline patient characteristics could account for differences in response between PERSIST and RCTs.
In particular, a greater proportion of patients had received conventional systemic and biologic therapies; notably, such patients were less likely to achieve PASI 90 response (Figure 4b), a finding also observed in the RWE study by Galluzzo et al. 27 Other patient characteristics could account for the lower PASI response in PERSIST compared with other studies, including lower baseline PASI score (16.4 vs 20.0-22.1, respectively). 11,12,15,27 Analyses of data from the PsoReg registry determined that a high absolute PASI score before biologic treatment is associated with a higher PASI response. 30 A higher baseline value increases the likelihood of achieving relative endpoints, even if the absolute value remains high after treatment.
PERSIST also had a greater proportion of patients with ≥1 comorbidity compared with RCTs (e.g. 27.7% vs 17.9%-19.5% patients with PsA, respectively), 11,12,15 and this can negatively impact PASI response and drug survival. 31 The PSO-BIO-REAL study -a large multinational RWE study that examined the impact of biologic therapies (excluding IL-23 inhibitors) on skin clearance -demonstrated that 46.0% of patients without comorbidities achieved at least a PASI 90 response following biologic therapy versus 31.0% of patients with just one comorbidity. 32 Nevertheless, the presence of PsA in patients in PERSIST did not appear to hinder the ability to achieve a PASI 90 or 100 response. Lastly, an association between PASI response and BMI was observed in PERSIST; patients with a BMI < 25 were more likely to achieve a PASI 90 response than patients with a BMI > 30.
Indeed, obesity is reported to be a negative prognostic factor for achieving a clinical response with treatment of psoriasis. 33

TA B L E 2
Most common treatmentrelated adverse events (AEs; ≥1%) by severity (n = 303) AEs were mild or moderate in severity, were consistent with those observed in the VOYAGE 1, VOYAGE 2, and ECLIPSE studies, and occurred at a similar or lower rate. 13,15,35 The limitations of PERSIST include the lack of a comparator study arm. A comparison between outcomes for guselkumab and ustekinumab, noting limitations pertaining to differences in time periods when patients were treated, may be considered in future analyses of PERSIST data. In addition, as PERSIST is a German registry, the results may not be generalizable to patients in other countries.
In conclusion, guselkumab has a positive impact on both physician-assessed and patient-reported outcomes in real-world use. Guselkumab is efficacious and well tolerated, even for patients who have received several previous biologic therapies or have psoriasis in difficult-to-treat areas. While the data presented here provide important insights, longer-term data from PERSIST and other sources will expand understanding of the real-world performance profile of guselkumab for treatment of psoriasis.