Secukinumab improves the quality ‐ of ‐ life of family members and partners of people with psoriasis: Family Dermatology Life Quality Index (FDLQI) results from a randomised open ‐ label study (SIGNATURE)

Background: The Family Dermatology Life Quality Index (FDLQI) was developed to meet a need for a dermatology ‐ specific family member/partner quality ‐ of ‐ life (QoL) measure. This paper focuses on the analysis and interpretation of FDLQI data (used as an exploratory outcome) collected in the SIGNATURE study. Objectives: To measure the impact of secukinumab therapy for moderate to severe plaque psoriasis on the QoL of family members/partners of patients. Methods: Randomised, open ‐ label, non ‐ comparator study in 53 dermatology centres in the UK and Republic of Ireland. Patients received secukinumab


INTRODUCTION
Family members/partners of psoriasis patients experience many quality-of-life (QoL) impacts. 1 Biologic therapy improves patients' QoL 2-4 but it is unclear if effective patient treatment also decreases the burden on family members/partners. 5 It is important to identify the burden of psoriasis not only on patients but also on their family members/partners, the "Greater Patient," as this allows appropriate care strategies to be developed. 6,7 A large-scale multi-specialty study (144 diagnoses across 26 specialties) showed the significant impact chronic illnesses have on the QoL of family members/partners. 8 A review of the impact of dermatological conditions on this group identified 15 papers describing nine different instruments. 9 The Family Dermatology Life Quality Index (FDLQI) 10 is a simple, effective, and practical tool to assess the QoL impact on family members/partners of people affected by a range of skin diseases. 5,[11][12][13] It measures the impact over the previous 30 days of any skin disease and can be used by family members/partners aged ≥16 years. [10][11][12] When the study protocol was written, the FDLQI was chosen as the family measure: family members of psoriasis patients had been involved in the creation of the FDLQI. At that time neither of the psoriasis-specific measures PFI-14 nor FamilyPso had been published.
The aim of this analysis focused on the FDLQI data from the SIGNATURE study, 3,14 was to measure the impact of secukinumab therapy for moderate to severe plaque psoriasis on family member/partner QoL and to further demonstrate the responsiveness to change of the FDLQI.

Study design
This 72-week, multicentre, open-label, non-comparator study of 235 patients with moderate to severe chronic plaque psoriasis was conducted in 53 centres in the UK and Republic of Ireland. Independent ethics committee approval was obtained and all patients provided written informed consent. The primary study data were described in detail previously. 3 Patients were randomised to receive either secukinumab 300 or 150 mg and stratified into 1 of 3 sub-groups, in line with the National Institute for Health and Care Excellence (NICE) definitions for patients failing tumour necrosis factor-α (TNF-α)-inhibitor therapy: • Inadequate responder (IR) after single anti-TNF-α therapy-primary IR. • IR after single anti-TNF-α therapy (after initially achieving a good primary response)-secondary IR. • IR after >1 anti-TNF-α therapy.
There were five periods: a 28-day screening period, a baseline period, an initiation period (Weeks 1-16), maintenance period 1 (Weeks 17-48), and maintenance period 2 (Weeks 49-72). Patients who responded (i.e., achieved 75% reduction in PASI from baseline or 50% reduction and a 5-point reduction in DLQI) after the initiation period or maintenance period 1 continued on study treatment for 32 weeks (maintenance period 1) or 24 weeks (maintenance period 2), respectively. Patients on the 150 mg dose not responding after the initiation period or maintenance period 1 could increase to 300 mg. After each study period, non-responders on 300 mg returned to routine clinical care (Figure 1).
Key inclusion criteria for patients: • Age ≥18 years with chronic plaque psoriasis >6 months. • Moderate to severe disease: Psoriasis Area Severity Index (PASI) ≥ 10 and Dermatology Life Quality Index (DLQI) > 10. • Previously treated with ≥1 anti-TNF-α therapy for moderate to severe psoriasis and either a primary or secondary non-responder.

Endpoints
The primary endpoint was to assess the % of patients on secukinumab 300 mg achieving PASI 75 at Week 16 compared to baseline. Key secondary endpoints assessed PASI 75 response after 16 weeks with 150 mg and in the three sub-groups, and with both doses after 2, 4, 8, 12, 24, 48, and 72 weeks.

FDLQI
Patients were asked to consent that the FDLQI was handed to a family member. If the patient gave consent, the chosen family member could be given further information about the study and given the FDLQI to complete. Family members/partners of patients with psoriasis completed FDLQI at baseline and at Weeks 12, 16, 48, and 72. For each question, the higher the score the more the QoL was impaired (Table 1). If one FDLQI item was left blank, the summed score from the other nine items was used. If more than one item was left blank, that FDLQI was considered invalid and not scored.

Statistical analysis
Relationship between PASI 75 response and change from baseline in FDLQI total score

Baseline characteristics
Of the 235 patients randomised between October 2013 and July 2016 (300 mg: 119, 150 mg: 116), 233 received ≥1 dose of study drug and 199 were stratified into subgroups. Demographic characteristics were well-balanced between the groups. 3

FDLQI from baseline to 72 weeks
The mean family member FDLQI scores were 12.6 (n = 61), 4.6 (n = 54), and 4.1 (n = 49) at baseline, Week Change from baseline FDLQI total score versus PASI 75 response The family members of both PASI 75 responders and nonresponders showed improved FDLQI at Weeks 12 and 16 compared to baseline; the improvement was greater for family members of responders (mean total score improvement: -9.1 for responders vs. -7.5 for non-responders, difference in improvement = 1.6, p = 0.0036) ( Table 3).

Individual questions
The decreasing radar plot mapping footprints of the two scales between baseline and Weeks 12 and 16 reflect the decreasing scores ( Figure 2). The Spearman correlation coefficient analysis showed positive correlations across all mapped FDLQI and DLQI questions ( Figure 3). The correlations were stronger for some mapped questions than others. The strongest correlation was between FDLQI Question 1 (emotional distress) and DLQI Question 2 at Weeks 12 and 16 (Spearman's rank correlation coefficient [Rs] >0.5). The stronger correlations (Rs > 0.4) were observed between FDLQI Question 9 (job/ study) and DLQI Question 7 at baseline, FDLQI Question 6 (recreation/leisure) and DLQI Question 6 at Week 12, FDLQI Question 7 (time looking after) and DLQI Question 10 at Week 16, and FDLQI Question 8 (extra housework) and DLQI Question 3 at Week 16.
Questions score changes FDLQI Overall, there was an improvement for all FDLQI questions at Week 16. The smallest mean improvement was for Question 9 (0.4) and the largest improvement was for Question 8 (1.1). The mean total score change was 8.2 (Table 4).
Most family subjects had an improved score for all FDLQI questions, ranging from 75.4% of subjects (Question 6) to 91.4% (Question 9) at Week 12, and 77.2% (Question 6) to 90.6% (Question 9) at Week 16. The proportion of subjects with worsening scores was small, ranging from 2.4% to 11.1% at Week 12 and 3.8% to 10.0% at Week 16 (Table 5).
FDLQI-in family subjects with corresponding patient visit DLQI total score >10 Overall, there was an improvement for all FDLQI questions at Week 16. The smallest mean improvement was for Questions 2 (physical well-being), 7, and 8 (0.3) and the largest was for Question 9 (0.8). The mean total score change was 5.2 ( Table 6).
The number of subjects was comparatively small so the proportions should be treated with caution.

DISCUSSION
Relationships between an individual and their family members/partners are multi-faceted. Patients with psoriasis have an added layer of complexity with differing impacts of psoriasis on those close to them. Differing attitudes between the patient and the family members/ partners towards the disease may adversely influence adjustment to the condition. 18 The lack of understanding of the psoriasis patient's family member/partner's experience became apparent in a qualitative study 6,19 when nearly all stated it was the first time any health care worker had enquired about their well-being, and recounted the many ways their lives were affected. A psoriasis-specific questionnaire, the Psoriasis Family Index-14 (PFI-14), 1,20 was developed from that study 6 and a further questionnaire, FamilyPso, has also been described. 21 The PFI-14 and Family PsO are specific to psoriasis whereas FDLQI is applicable in any skin condition thereby allowing comparisons of the impact of different conditions on family members/partners. Previous studies have shown FDLQI to effectively assess the QoL of family members/partners of patients with skin diseases. FDLQI previously demonstrated that 90% of the participating family members/partners of 80 patients felt that their relative's psoriasis affected their own QoL. 22 In the PROSE study (NCT02752776), secukinumab treatment completely normalised QoL in most psoriasis patients, and this was reflected by FDLQI scores showing an early and sustained improvement in partner/family member's QoL. 23 This study confirms these earlier findings that severe psoriasis has a major impact on QoL of family members/partners and that this improves with effective therapy. Additionally, this study mapped family members/partners' FDLQI scores to patients' DLQI scores, clarifying the association between different QoL domains in patients and family members. Furthermore, it highlights the impact of psoriasis on family members and may ultimately enhance patient consultation quality, particularly initially.
The SIGNATURE study data showed the responsiveness of the FDLQI to effective patient treatment, specifically with secukinumab, adding to this measure's validation and demonstrating the wider benefit of a highly effective therapy for plaque psoriasis to improve the impaired QoL of family members/partners. However, the data challenge dermatology teams treating psoriasis patients because understanding the QoL impact of psoriasis must be balanced with practical aspects of measurement and the associated burden of completing questionnaires. The study  Abbreviations: FAS, full analysis set; FDLQI, Family Dermatology Life Quality Index; N, the number of subjects in the analysis set; n, number of subjects included in the analysis; SD, standard deviation. a Subjects with a score at baseline other than "not at all" and the Week 12/16 assessment.
b Subjects with a score at baseline and the Week 12/16 assessment. c Subjects with score at baseline other than "very much" and Week 12/16 assessment.
was not designed to assess FDLQI use in routine clinical practice but the correlation between DLQI and FDLQI indicates that if a patient's DLQI score is high, it is very likely that family members/partners' QoL is also impaired. This suggests that separate assessment of family members/ partners' QoL may enhance physician understanding and improve quality of care.
There is no excuse to ignore the issue through ignorance of the extent or nature of the impact. Family members/partners are often crucial frontline carers (therapy encouragers) of severe psoriasis patients and it may be that therapy adherence is enhanced if their needs are understood and supported.
Those QoL aspects most affected or least improved following effective therapy may be those requiring most attention (job/study, personal relationships, and physical well-being). However, specific issues experienced by individual patients and their family members/partners must always be placed ahead of cohort-based conclusions. A wider framework of care for psoriasis patients and their family members/partners may be needed to formulate and test possible strategies aimed at addressing these different affected life aspects.
The strengths of the study were that analyses were conducted in a randomised clinical trial of a high-need population who had previously failed treatment, and that there was direct FDLQI versus DLQI comparison.
Study limitations were that the absence of a control group without therapy means that improvement in DLQI and FDLQI due to other factors cannot be excluded. Also, clinical meaning of FDLQI scores could not be compared with an established minimal clinically important difference because this has not been defined for FDLQI. However, as this is typically about 10% of the total score range for a clinical measure, it might be expected to be 3 to 4. Similarly, the relationships between patients and family members/partners may have varied. Caution is needed when describing high FDLQI to DLQI correlations because of small patient numbers. These analyses compared FDLQI changes in family members/partners of patients with a corresponding visit DLQI > 10 with the overall population but comparisons with other subgroups may have been useful. Patients chose which family member/partner could complete FDLQI but because this relationship was not recorded it could not be differentially analysed. A study limitation is that no characteristics of the family member respondents were collected: parameters such as the relationship to the patient, employment and household situation can be confounders. No specific instructions were given to family members about completing the FDLQI independently and so for some family respondents there may have been influence from the patient.
The overall FDLQI completion rates were approximately 50%, but there is no information as to why for the other patients, no family member completed the FDLQI. It is not known how representative the family members who did contribute were of those who did not contribute. As there is little experience of the use of a family reported outcome measure as part of a clinical trial, it is not known what completion rates to expect. Gathering data from family members involves several complex practical and ethical issues not normally encountered in clinical trials and it is likely that completion rates for family measures will be lower than for patient completed measures. This may partially explain the FDLQI completion rates of around 50% in this study. The DLQI and FDLQI total scores were calculated by summing all answered questions, as recommended by the original authors. The impact of questions answered 'not at all/not relevant' is not known. However, overall scores were initially high, confirming a large impairment of QoL of family members, which greatly improved following effective patient therapy.
Although the FDLQI has been used in cross-sectional studies of psoriasis in several countries, there is very little experience of its use to assess the impact following effective therapy of patients, and therefore the generalisability of this study is not known.
The finding that responders and non-responders showed similar improvements in FDLQI score is surprising and may be an effect of participating in a T A B L E 7 FDLQI questions score shifts from baseline to Weeks 12 and 16-corresponding visit DLQI total score >10 (FAS)

Question
Week Improved n/N a (%) Unchanged n/N b (%) Worsened n/N c (%) research study and/or the knowledge that a novel treatment was being used. Novel strategies to care for the wider impacts of psoriasis on family members/partners are needed and may contribute to better therapy compliance. The FDLQI questionnaire responds well and appropriately to major changes in the disease severity of those affected by psoriasis.