Real‐world treatment persistence of four commonly prescribed biologic therapies for moderate to severe psoriasis in Australia

Australian data comparing biologic treatments for moderate to severe chronic plaque psoriasis are lacking. We compared persistence on therapy across four biologic therapies (adalimumab, guselkumab, secukinumab and ustekinumab) used to treat chronic plaque psoriasis. The impact of prior biologic use on persistence was also investigated.


INTRODUCTION
Psoriasis is a chronic immune-mediated inflammatory skin condition increasingly recognised as a systemic disease.It increases the risk of psoriatic arthritis in particular, but is also associated with cardiovascular disease, metabolic disorders and inflammatory bowel disease. 1 It is also associated with lower quality of life and increased risk of anxiety, depression and suicide. 1,2About 2.5% of Australians have psoriasis, with chronic plaque psoriasis accounting for 80%-90% of cases.Of these, 20% have moderate to severe and 10% severe disease. 3tandard treatments for severe psoriasis include phototherapy, methotrexate, cyclosporin, apremilast and acitretin.In Australia, the government subsidises biologic therapies for chronic plaque psoriasis through the Pharmaceutical Benefits Scheme (PBS).Biologic therapies are registered for use in moderate to severe chronic plaque psoriasis.To be granted access, however, patients must meet stringent eligibility criteria regarding severity and treatment history limiting subsidised access to those with severe disease.Requirements include psoriasis lesions present for at least 6 months, plus failure to achieve an adequate psoriasis area and severity index (PASI) response to two of the five standard treatments (or be contraindicated or intolerant).Patients need to demonstrate severe chronic plaque psoriasis of the whole body, with a PASI>15, or present with regional chronic plaque psoriasis of the face, or a palm of a hand or the sole of a foot (2 of the 3 PASI symptom sub-scores rated as 'severe' or 'very severe' or affecting at least 30% of the area).To continue to access subsidised medication, patients are required to demonstrate and maintain an adequate response defined as a PASI 75 or greater improvement and/or 75% reduction in area of involvement or improvement of erythema, thickness and scaling for regional disease.Patient assessments need to be provided to the PBS after induction therapy and every 6 months thereafter.Patients can switch agents without having to experience disease exacerbation, safety concerns or drug toxicity.
Stopping or switching biologic therapies for psoriasis is common, mainly attributed to treatment failure, suboptimal disease control or lower than expected benefits to quality of life. 11,12Other reasons for not persisting with treatment include toxicities that may limit the dose and duration of therapy.For this reason, treatment persistence is considered to correlate well with other clinical outcomes such as treatment response and tolerability in a real-world setting. 12It is used as an endpoint in clinical trials and real-world evidence studies, particularly for biologic therapies, which tend to become less efficacious over time.
The primary objective of this study was to compare persistence to biologic therapies for adults with chronic plaque psoriasis in Australia.The most commonly prescribed therapy within each biologic treatment class was assessed: adalimumab, guselkumab, secukinumab and ustekinumab.Secondary objectives were to compare the persistence of therapy between patients without prior biologic experience (bio-naïve patients) and patients with prior biologic therapy experience (bio-experienced patients).The patient populations receiving each of the biologic therapies of interest were also described.A sensitivity analysis using an alternate definition of persistence assessed the impact of definitions on discontinuation of treatment timing.

PATIENTS AND METHODS
This study was a retrospective cohort analysis using data from the Australian Department of Human Services PBS 10% sample from 1 September 2015 to 31 December 2021.The PBS 10% sample data is a national record of pharmaceutical claims containing a systematic random sample of 10% of the Medicare-eligible Australian population and their reimbursed dispensations.It includes about 75% of prescribed medicine in Australia and does not include private prescriptions, or medicines supplied to public biologic therapy, guselkumab, psoriasis, retrospective studies, treatment switching hospital inpatients or over-the-counter.The 10% sample is available for the purposes of research via data custodians.This study was approved by the Australian Government Department of Human Services External Request Evaluation Committee (RMS2412).
Data extracted for this study were from patients who were at least 18 years of age at the time of first prescription of any biologic treatment for chronic plaque psoriasis.Included patients had also been prescribed at least one of the four biologic therapies of interest (adalimumab, guselkumab, secukinumab, ustekinumab) by a dermatologist during the study period.Patients must not have received the biologic therapy within the previous 6 months of the index date (date of first claim), to ensure the therapy was newly initiated.
Patients were defined as either biologic naïve (no evidence of biologic therapy use at any time before the index date; first-line therapy) or biologic experienced (at least one dispensing record for any biologic therapy [not limited to biologics of interest] before the index date; second or later line therapy).
Extracted data included gender, year of birth, state of filled prescription, date of claim and PBS item code.Variables of interest included gender, age group (18-29 years, 30-49 years, and 50 years and older), bio-naïve/ bio-experienced and time since first biologic therapy for bio-experienced patients, defined as time in years since the first purchase of any biologic medication to index date (0-2 years, 3-6 years, 7 or more years).

Analysis
Baseline demographics were summarised descriptively.
The Kaplan-Meier (KM) method was used to determine treatment persistence.Statistical testing between KM curves was conducted using the log-rank test.Persistence was defined as the time in consecutive days from the index date to the time of discontinuation of therapy, or censoring, measured in consecutive days.Patients were censored at the date of last data extraction or death.An event was defined as treatment cessation.Patients were considered to have ceased treatment if the index biologic therapy had not been dispensed for a fixed maximum allowable gap (MAG). 10The MAG used in the primary analysis was 180 days, 13 which equates to approximately two missed doses of the biologic with the longest interval between doses: ustekinumab.Missing two doses implies discontinuation rather than a short-term cessation.In the sensitivity analysis, the MAG was three times the maintenance dosing interval for each biologic: adalimumab = 42 days, guselkumab = 168 days, secukinumab = 84 days and ustekinumab = 252 days.
The KM method was also used to estimate the proportion of patients who were persistent with each therapy after 6, 12, 18 and 24 months of follow-up.
Differences in persistence on treatment between the biologics were explored using a Cox's proportional hazards model with covariates of gender, age at initiation of therapy, bio-naïve/bio-experienced and time since first biologic therapy, in the bio-experienced patients.
An alternative model used propensity score as a covariate, with matching performed by sex, age at initiation of therapy, bio-naïve/bio-experienced and time since first biologic therapy.The four biologics of interest were compared as pairs: adalimumab versus guselkumab; adalimumab versus secukinumab; adalimumab versus ustekinumab; guselkumab versus secukinumab; guselkumab versus ustekinumab; secukinumab versus ustekinumab.Propensity score(s) for each pair were estimated by logistic regression.Cohorts used for each pairwise comparison were matched one-to-one on estimated propensity score and the matched cohorts used in a KM analysis of treatment persistence.Log-rank tests were performed for each pair of biologics.
All statistical analyses and confounders were subject to sample size and available covariates within the datasets.All analyses were performed with p < 0.05 considered statistically significant.Analyses were conducted using R (R Foundation) and Python and PharmDash software.

Patient disposition and demographics
In the PBS 10% sample, there were 1969 patients who were at least 18 years of age when they were first prescribed biologic treatment for psoriasis.Of these, 1219 patients had at least one of the four specified biologic therapies (adalimumab, guselkumab, secukinumab and ustekinumab) between 1 September 2015 and 31 December 2021, and 1056 patients had at least one prescription from a dermatologist.Excluding patients who had been dispensed a biologic therapy of interest within the 6 months before the index date, there were 878 patients included in the study.These patients had 1131 index prescriptions for a biologic therapy of interest (some patients received more than one biologic therapy during the study period).
There were 105 index prescriptions for adalimumab, 385 for guselkumab, 305 for secukinumab and 336 for ustekinumab.Table 1 shows prescribing by age, gender, line of therapy and time from first biologic therapy to index therapy.Most patients (667; 76%) had only received one of the four biologic therapies during the study period.Four patients (0.5%) had received all four biologics of interest, 34 patients (3.9%) had received three and 173 patients (19.7%) had received two.
Guselkumab median persistence was not reached in the study period (n = 385; 75.8% persistence at 24 months).Median follow-up time for guselkumab (21 months) was shorter than that for adalimumab (44 months),   ustekinumab (46 months) or secukinumab (45 months) as it was listed on the PBS from February 2019.KM estimates of treatment persistence by the line of biologic therapy (bio-naïve/first-line or bio-experienced/ second or later line) are presented in Figure 2. Median persistence for each therapy is higher for bio-naïve patients; but the same relative order between biologic therapies is preserved across all populations examined.
In the adjusted Cox analysis of the total cohort, gender and age did not affect persistence (Figure 3a).Bioexperienced patients were more likely to discontinue their index treatment than bio-naïve patients, as were patients who received their first biologic therapy in the 2 years prior to the index date compared to patients who received their first biologic therapy 7 or more years before the index date.
In the adjusted Cox analysis of the bio-experienced cohort, gender did not affect persistence, whereas patients aged 18-29 years were more likely to discontinue treatment than those aged 50 years or older (Figure 3b).

Sensitivity analyses
When the MAG was defined as three times the labelrecommended dose interval of each biologic therapy of interest as a sensitivity analysis, adjusted Cox analysis found that persistence to guselkumab remained significantly greater than to adalimumab (HR 10.40 [95% CI 7.65-14.1],p < 0.001), secukinumab (HR 3.10 [95% CI 2.38-4.03],p < 0.001) and ustekinumab (HR 2.14 [95% CI 1.63-2.81],p < 0.001) (Figure 4).Ranked from highest to lowest persistence: guselkumab > ustekinumab > secukinumab > adalimumab, with each pairwise Log-rank comparison significant at p < 0.001, thus carrying significance even if adjusted for multiple statistical tests using a Bonferroni correction that lowers the p-value needed for significance to 0.007.
In the sensitivity analysis, bio-experienced patients also remained more likely to discontinue their index treatment, as were patients who received their first biologic therapy in the 2 years prior to the index date (Figure 5).

Propensity score matching
When analysed using populations matched by gender, age at initiation of therapy, bio-naïve/bio-experienced and time since first biologic therapy, persistence to guselkumab remained greater than to the other biologic therapies of interest.

DISCUSSION
Persistence on psoriasis therapy is utilised as a marker for continued disease control and perceived patient tolerability of the treatment.To continue on Australian PBSsubsidised therapy patients must maintain a PASI of 75% or greater severity improvement on their baseline at their 6 monthly reviews, or improved area or symptom subscore for face, hand and/or foot psoriasis.Limited treatment response is a common cause for ceasing or switching therapy and may occur if efficacy is lacking at the outset or is lost over time.Patients and physicians' threshold for

F I G U R E 5
Adjusted Cox analysis of effect of type of biologic therapy and other covariates on #persistence in the total cohort (sensitivity analysis; three times maintenance days).^First biologic therapy for chronic plaque psoriasis.# Persistence = the number of consecutive days from the index date to the time of discontinuation (>3 times maintenance days without filling a prescription) or censoring (date of last data extraction or death).
switching due to unmet expectations may be lower when alternative biologics are available. 14A rapidly evolving therapeutic landscape provides more treatment options to switch between, which allows for greater flexibility to cater to patient and prescriber preferences. 15Other reasons for switching or ceasing therapy include drug holidays (e.g.pregnancy), intolerance or toxicity to therapy or developing concurrent disease.
In this study, we compared the persistence of treatment among the most commonly prescribed biologic from each class (IL-23, TNF-α, IL-17 and IL-12/23 inhibitors) prescribed for chronic plaque psoriasis in Australia.Persistence to treatment with guselkumab was greater than that observed with adalimumab, secukinumab or ustekinumab in both the unadjusted and adjusted analyses of Australian nationally representative data.This was also true when the population was matched by gender, age, previous biologic experience and time between the previous biologic for chronic plaque psoriasis.
Consistent with previous findings, bio-experienced patients were more likely to discontinue their index treatment than bio-naïve patients.Patients who received their first biologic within 2 years of their index therapy also had higher discontinuation rates which may be due to greater expectations from a broader treatment choice. 11,14,15Age was also a significant predictor of persistence to index treatment among bio-experienced patients, with younger patients (<30 years of age) less persistent or more likely to switch biologic than older patients (>50 years of age).When considering treatment selection, younger patients value higher skin clearance, 16 and older psoriasis patients are more influenced by safety concerns over symptom improvement. 17he primary analysis (180-day MAG) found that ustekinumab had lower persistence than adalimumab and secukinumab.In the sensitivity analysis (MAG defined as three times maintenance dose), persistence to ustekinumab was greater than persistence to adalimumab or secukinumab.This may be because the MAG chosen for the main analysis (180 days) disproportionately favours biologic therapies with shorter dosing schedules, for example, adalimumab (14 days), compared to ustekinumab (84 days).
Higher persistence to ustekinumab compared to adalimumab or secukinumab is consistent with prior research.For example, one US study of the MarketScan Commercial database. 10In the main analysis, the authors defined the MAG as the FDA label-recommended maintenance dosing, and found that persistence at 9 months was greatest among those treated with guselkumab (65.9%) and ustekinumab (65.7%), followed by ixekizumab (48.8%), secukinumab (48.3%), adalimumab (30.7%), certolizumab (14.8%) and etanercept (13.2%). 10he pattern of treatment persistence stayed the same when the MAG was defined as twice the labelrecommended dosing interval. 10n addition, our results are comparable to other recently published registry data. 18,19For example, prior to the availability of guselkumab, data from the PSO-LAR registry indicated persistence to ustekinumab was longer than infliximab, adalimumab and etanercept. 11his trend was observed regardless of whether it was the patient's first biologic therapy or not.More recently, a 2022 analysis of the British Association of Dermatologists Biologic Interventions Register (BADBIR) 18 compared guselkumab, ixekizumab, secukinumab and adalimumab to ustekinumab in psoriasis using a fixed 90-day MAG.In line with the current study findings, guselkumab had the greatest persistence in the BADBIR registry, followed by ustekinumab (adjusted HR, 0.13; 95% CI, 0.03-0.56compared to ustekinumab).Adalimumab had the lowest persistence, though had a similar estimated 2-year survival as ixekizumab.Seen in both the BADBIR and PSOLAR registries, significant effects modifiers for biologic persistence included psoriatic arthritis, nail involvement, previous biologic exposure and ethnicity. 11,12While our results are broadly comparable to what has been observed in other international studies, this was the first Australian study to examine covariates such as bio-experience and time since first biologic therapy on biologic treatment persistence for chronic plaque psoriasis.

Limitations
Biologic treatments available in Australia and the year they became reimbursed through the PBS are adalimumab (2009), etanercept (2006), guselkumab (2019), infliximab (2007), ixekizumab (2017), secukinumab (2015), risankizumab (2019), tildrakizumab (2019) and ustekinumab (2010).As guselkumab is the most recently available of the four biologic therapies for psoriasis discussed in this analysis, it may have benefitted more from censoring because of a shorter follow-up time.Additionally, only the most commonly prescribed treatment in each biologic class was included in this analysis.This is a retrospective study based on available data in the PBS 10% sample.The analyses are, therefore, limited by the availability of data in the database.The PBS 10% dataset does not provide clinical details such as severity of disease and, therefore, the line of therapy has been used as a surrogate.Other clinical details such as diagnosis with psoriatic arthritis and reason(s) for therapy discontinuation are also not provided in the dataset.
There is currently no ICD-10 code to identify patients with chronic plaque psoriasis in the PBS 10% data.Identifying eligible cases within the administrative dataset relied heavily on PBS authorities for psoriasis.Only the biologic therapies prescribed by dermatologists were included in the present study. 20Unlike in some other countries, only dermatologists can prescribe biologics for psoriasis in Australia, and biologics for psoriatic arthritis are prescribed by rheumatologists or clinical immunologists.To initiate biologic therapy on the PBS, the dermatologist must submit a signed declaration that the patient has severe chronic plaque psoriasis and meets the stringent eligibility criteria.Adalimumab is also PBS approved to treat hidradenitis suppurativa, but a different application form and scoring system are used, thus largely precluding incorrect coding as psoriasis in the PBS data.

CONCLUSIONS
Using a large nationally representative longitudinal data set, the results of this study allow us to compare the real-world differences between commonly prescribed biologics in Australia.Consistent with prior international studies, our findings suggested a greater persistence for guselkumab compared to ustekinumab, secukinumab or adalimumab.Results were robust in both unadjusted and adjusted analyses.In an increasingly crowded field with many biologic options available, patients and clinicians may benefit from understanding the comparative persistence on therapies used to treat psoriasis.The PBS 10% data in addition to registry data are suitable datasets to continue to monitor prescribing trends and real-world persistence to biological therapies for psoriasis.

ACKNO WLE DGE MENTS
The authors thank Sophie Gibb, PhD CMPP and Robyn Ordman of WriteSource Medical Pty Ltd, Sydney, Australia, for providing medical writing services funded by Janssen-Cilag Pty Ltd in accordance with Good Publication Practice (GPP 2022) guidelines (https://www.ismpp.org/gpp-2022).The authors thank Anthony Yeo for his help in preparing the statistical analysis plan for this project.The authors also thank Prospection Pty Ltd. for conducting the statistical analysis to address the key research questions in this study.Prospection Pty Ltd is a health analytics company approved to undertake analytics on the PBS 10% dataset under a licence agreement with Services Australia.The main contributors to be acknowledged from Prospection are Piotr Wargocki, Yi Lung Chen and Mahsa Hosseini Kouhkamari.Prospection Pty Ltd was funded by Janssen-Cilag Pty Ltd Australia to perform the analysis in this study.

T A B L E 1
Patient demographics and prior experience of biologic therapies for chronic plaque psoriasis.

F I G U R E 1
Kaplan-Meier estimate of overall # persistence to adalimumab, guselkumab, secukinumab and ustekinumab.# Persistence = the number of consecutive days from the index date to the time of discontinuation (>180 days without filling a prescription) or censoring (date of last data extraction or death).

F I G U R E 2
Kaplan-Meier estimate of #persistence to adalimumab, guselkumab, secukinumab and ustekinumab by line of therapy: (a) bio-naïve patients and (b) bio-experienced patients.# Persistence = the number of consecutive days from the index date to the time of discontinuation (>180 days without filling a prescription) or censoring (date of last data extraction or death).

F I G U R E 3
Adjusted Cox analysis of effect of type of biologic therapy and other covariates on #persistence in the: (a) Whole cohort and (b) Bio-experienced cohort.^First biologic therapy for chronic plaque psoriasis.# Persistence = the number of consecutive days from the index date to the time of discontinuation (>180 days without filling a prescription) or censoring (date of last data extraction or death).

F
I G U R E 4 Kaplan-Meier estimate of overall #persistence for adalimumab, guselkumab, secukinumab and ustekinumab (sensitivity analysis; three times maintenance days).# Persistence = the number of consecutive days from the index date to the time of discontinuation (>3 times maintenance days without filling a prescription) or censoring (date of last data extraction or death).*Denotes significance at a p-value <0.007 which accounts for a Bonferroni correction for multiple statistical tests.