Drug Persistence of Biologic Treatments in Psoriasis: A Swedish National Population Study

Biologic therapies with diverse mechanisms of action have been developed to treat moderate-to-severe psoriasis. Targets for biologics are cytokines involved in psoriasis pathology: anti–tumour necrosis factor (TNF), anti–interleukin (IL)-12/23, anti–IL-23, and anti–IL-17 [1, 2]. Agents in the newer classes targeting IL-17 or IL-23 show greater efficacy in phase III clinical trials than the biologics that target TNF [1, 3‐6] or IL-12/23 [1, 4, 7, 8].

Treatment persistence, or drug survival, represents an important parameter related to long-term therapeutic performance in the real-life setting [9]. Biologic treatments for psoriasis are discontinued or switched in most patients, due to either to lack or loss of efficacy or tolerability issues or other complex reasons, including patient motivation [9‐14]. Studies on the real-world persistence of anti-TNF and newer biologics show greater persistence for the newer agents [10‐12, 15‐23]. While persistence with biologics is assumed to be closely related to therapeutic performance [18], experience from other medical specialties shows that treatment patterns are influenced by many additional factors, such as patient characteristics, dosing regimens and formulations, the availability of alternative agents, and market factors, including reimbursement, pricing and marketing [22, 24, 25].

The biologics landscape in psoriasis treatment has changed markedly in the past decade. In the European Union, four biologics targeting TNF (infliximab, etanercept, adalimumab and certolizumab pegol) were launched for this indication in 1999, 2000, 2003 and 2018, respectively, followed by patent expiry in 2015, 2015, 2018, and 2021 and the launch of biosimilars [26]. One IL‐12/23 inhibitor (ustekinumab), two IL-17A inhibitors (secukinumab and ixekizumab), and one IL-17A receptor subunit blocker (brodalumab) were launched in 2009, 2015, 2016 and 2019, respectively. Three IL-23 inhibitors (guselkumab, tildrakizumab, and risankizumab) were launched in 2017, 2018 and 2019, respectively.

The impact of newly developed biologics and biosimilars on the persistence of individual agents has not been sufficiently studied. The objective of this study was to analyse the real-world persistence of biologic therapy over time in psoriasis treatment based on national registries in Sweden.

In this retrospective, observational registry study in Sweden we assessed treatment persistence and change in persistence over time for individual biologics used in the treatment of psoriasis. The patients assessed had broadly similar demographic and clinical characteristics across the biologic groups analysed.

Overall, the median persistence for biologics was approximately 2 years. Because psoriasis is a chronic disease that usually requires lifelong treatment, this level of persistence can be considered low. Greater persistence was seen for ustekinumab (IL-12/23 inhibitor) and secukinumab (IL-17A inhibitor) than for the anti-TNF biologics etanercept and adalimumab. Our observations on the persistence of ustekinumab are consistent with those from previous real-world studies, which also reported greater persistence with ustekinumab than with TNF biologics [9, 11, 23, 31]. For secukinumab, our results contrast with those of earlier studies reporting low persistence [11, 16], although these reports were potentially influenced by the high proportion of biologic-experienced patients who were treated with secukinumab [10]. Our observations on the IL-17A inhibitor ixekizumab indicated low levels of persistence comparable to that with etanercept. However, these observations were based on very few patients with limited time in the database; therefore, more data are needed to draw conclusions on its persistence. Other real-world studies have reported greater persistence for ixekizumab than for adalimumab or secukinumab [17, 18].

For each of the biologics analysed, median persistence was greater in biologic-naive than biologic-exposed patients, in agreement with findings from previous studies [9, 10, 15, 32, 33]. One explanation for the reduction in persistence in biologic-exposed patients is that patients requiring second-line treatment might have more refractory disease [22]. Specifically, in relation to biologic-naive patients in our analysis, persistence was higher for ustekinumab and secukinumab, and lower for adalimumab and etanercept, consistent with our overall findings. Analysis of the biologic-naive ixekizumab group included only six patients, which influences the robustness of these outcomes.

Kaplan–Meier analysis showed that persistence at 1, 2, and 5 years ranged from highest rates for ustekinumab (79.9, 64.8, 41.6%, respectively) to the lowest rates for etanercept (57.8, 39.7, 16.8%). These rates confirm that patients are likely to receive multiple different treatments in the course of their disease and underline the importance of selecting the right treatment options at an early stage.

In the 3-year running cohorts between 2010 and 2018, we observed a notable, progressive decrease in the median persistence for ustekinumab. This decrease, starting with the 2011–2013 cohort [ending persistence in 2015–2017 (median 50.3 months later)] and decreasing even more in the 2012–2014 cohort [ending persistence in 2015–2017 (median 32.2 months later)], coincided with the entry of newer biologics and the availability of biosimilars. It might be speculated that the availability of new biologics for patients who had run out of treatment options facilitated switching in this period. For etanercept, persistence initially increased for the 2012–2014 cohort (ending persistence 13.2 months later), then decreased and then increased again for the 2016–2018 cohort to approximately double the lowest level observed, potentially reflecting changes in the cost of this biologic at the introduction of biosimilars and confidential side agreements and discounts. Physicians continued to use adalimumab in a relatively stable way throughout the study period. It can be speculated that persistence was higher for newer drugs during initial treatment due to launch excitement and the close monitoring of patients with a high level of patience by clinicians. Complex interactions, including perceptions of relative therapeutic performance and market dynamics, are likely to play a part in changing persistence over time for each biologic.

The primary strength of this study is that it analysed the entire Swedish population using prescription data rich in detail and prescriptions linked with diagnoses at the individual level, enabling an accurate selection of patients with psoriasis. The limitations of real-world studies also apply to our analyses. As this was a retrospective observational study, the data were not specifically collected for the purpose of the study, treatment groups were not matched for patient characteristics or previous biologic treatment history and the duration of treatment differed among biologics. It was not possible to assess the reasons for initiating and discontinuing individual biologics and the role of patient characteristics or market factors, such as reimbursement decisions and price negotiations, in determining persistence. Together with persistence, adherence to therapy is important for optimizing patient care and therapeutic outcomes. However, analysis of adherence to the dosing scheme was not possible in this study, as information on the dose taken was not available in the national patient registries. It was assumed that all dispensed drugs were taken and that the date of dispensation was also a date of treatment use. Additionally, our study included a 90-day grace period to account for any gaps in adherence. Differences among biologics were not statistically evaluated, although the trends observed offer robust insights into real-world treatment patterns for biologics to treat psoriasis in Sweden. Finally, although we used a 90-day grace period as in previous literature and evaluated the level through sensitivity analyses, there are still patients who likely did not discontinue but rather had a long ‘drug holiday.’

Our results suggest that the clinical real-world persistence for interleukin inhibitors might not be as long as reported previously, which is a problem because treatment persistence has often been associated with treatment success. Our findings suggest that clinicians might have kept patients on these biologics because they were the best choices available at a given time. With newly available treatment alternatives, more recent data on persistence will provide a better estimate of treatment success in psoriasis.

Specifically, this analysis suggests that the persistence for ustekinumab has decreased over time, which might be explained by the introduction of more biologic treatment options from 2015 forward. Hence, the greater overall persistence for ustekinumab might be explained by the fact that ustekinumab was the only interleukin inhibitor on the market between 2009 and 2015 in Sweden.

This analysis of Swedish registry data shows that the persistence of biologic therapy for psoriasis is low on average (approximately 2 years) given that psoriasis can be considered to be a chronic disease that usually requires lifelong treatment. Our findings suggest that overall persistence is greater for newer interleukin inhibitor biologics than for TNF inhibitors. Thereby, this study contributes to the body of evidence on the overall persistence for biologics with important evidence on the differential persistence over time for each biologic.

These results indicate that persistence has changed over time for some biologics and that future studies on persistence should include analyses of persistence over time to provide an accurate picture of the current treatment landscape. This may help clinicians to make informed decisions when choosing a biologic treatment for their patients with psoriasis.