FormalPara Key Summary Points

Why carry out this study?

Patients with plaque psoriasis who are more severely affected and whose disease cannot be managed with conventional systemic therapy require biological treatment.

Treatment patterns and treatment discontinuation in patients with plaque psoriasis and biologic therapy have not sufficiently been investigated under routine care conditions in Germany.

What was learned from this study?

Approximately half of the patients receiving biologic therapy for plaque psoriasis discontinue treatment within 365 days of initiation, with variations among different biologic agents.

Notably, patients treated with the anti-interleukin-23 monoclonal antibody risankizumab had a statistically significant lower probability of treatment discontinuation compared to other biologic agents, with the exception of the anti-interleukin-12/23 monoclonal antibody ustekinumab.

Introduction

Plaque psoriasis is a common, often debilitating, chronic autoimmune inflammatory disease [1]. It has an incidence of 521.1 per 100,000 person years and, among adults, a lifetime prevalence of 2.2% in Germany [2, 3]. According to the European guideline for the management of psoriasis, phototherapy and systemic conventional therapy are recommended for moderate-to-severe forms which affects 20–30% of the patients [4, 5]. In cases of actual or probable failure of conventional systemic therapy, the guideline suggests the use of biological agents such as anti-interleukin (anti-IL) and anti-tumor necrosis factor (anti-TNF) antibodies [4].

The treatment landscape for moderate-to-severe psoriasis has been significantly transformed by these biologics. However, some patients may not respond adequately to initial biologic therapy, develop resistance to specific biologics over time, or face contraindications to treatment [6]. The consequence may be treatment discontinuation or switching in order to achieve satisfactory outcomes [1, 7]. Further, patients may wish to discontinue their biologic therapies when psoriasis lesions are completely cleared. Current guidelines are unclear regarding the duration of biologic therapy for psoriasis [8].

Previous international studies on single biologics suggest that treatment discontinuation is common and that a significant proportion of patients with psoriasis discontinue biologic treatment within the first year [9, 10]. However, there are very little data showing the frequency of discontinuation in biologic treatment of psoriasis in the German healthcare context. A better understanding of the characteristics of patients with psoriasis who discontinue their biologic treatment may provide relevant insights for clinicians.

To that end, we assessed the frequencies and the time until treatment discontinuation in patients with plaque psoriasis initiating biologic treatment and compared discontinuation rates between the different biologics during a 365-day period following treatment initiation in Germany.

Methods

Study Design

This study was conducted in a retrospective, non-interventional cohort design based on health claims data from the German statutory health insurance (SHI). The source of data was the sample database of the Institute for Applied Health Research Berlin (InGef) which comprises anonymized, longitudinal, and nationwide health claims from approximately four million individuals insured by the German SHI [11]. The database has been shown to be representative of the German population in terms of age and sex and shows high external validity regarding hospitalization and overall mortality rates [11]. The database contains individual-level information on hospitalizations (including inpatient diagnoses), outpatient services (including outpatient diagnoses), outpatient prescription drug data (including prescription and date of dispensation, anatomical therapeutic chemical [ATC] code, dispensed defined daily dose [DDD]), and socioeconomic information (including age and sex) [11]. All diagnoses in the database are coded using the German modification of the 10th version of the International Classification of Diseases (ICD-10-GM) [12]. The study included the data years 2016 to 2021.

Since all patient-level data in the database are anonymized to comply with German data protection regulations and German federal law, approval of an ethics committee was not required.

Study Population

Patients were included into drug-specific cohorts when they met the following criteria:

  1. 1.

    They had a dispensation with a specific anti-IL/anti-TNF agent (adalimumab, brodalumab, certolizumab, etanercept, guselkumab, infliximab, ixekizumab, risankizumab, secukinumab, tildrakizumab, ustekinumab) after its approval date for the treatment of psoriasis during the index period (2016–2021, index date).

  2. 2.

    They had ≥ 182 days of continuous insurance coverage prior to the index date (baseline period) and ≥ 365 days of continuous insurance coverage after the index date or until death (follow-up period) (Fig. S1).

  3. 3.

    They had ≥ 1 claim with a diagnosis code for psoriasis (ICD-10-GM diagnosis codes L40.0-L40.4, L40.8, and L40.9) in the quarter of the dispensation and/or during the baseline period.

  4. 4.

    They were ≥ 18 years old at the index date.

  5. 5.

    They had no claim with a diagnosis code for a comorbidity that can also be treated with the respective biologic (e.g., other immune-mediated inflammatory diseases) (Table S1).

  6. 6.

    They had no dispensation with this biologic during the baseline period.

Patients could be included in multiple drug-specific cohorts if they initiated treatment with different biologic therapies during the index period. Additionally, patients may be included in the same drug-specific cohort multiple times.

Ascertainment of Treatment Discontinuation

Discontinuation was defined as a gap in treatment equal to 150% of the assumed day supply of the last dispensed package (i.e., the number of days the dispensed package was assumed to last) (sensitivity analysis, 200%). This was calculated by the overall dose of the package at the dispensation date divided by the label-recommended daily dose during the maintenance phase (Fig. S2). The start date of treatment discontinuation was the run-out date of the last dispensed package. The time until treatment discontinuation was defined as the time from the index date to the date of discontinuation during the 365-day follow-up period. After a treatment discontinuation during the 365-day follow-up period, we assessed whether patients (1) restarted treatment with the same biologic, (2) switched to another biologic, or (3) received no further biologic therapy.

Statistical Analyses

Using descriptive analyses, we summarized categorical variables by frequencies and percentages, and continuous variables were summarized as mean and standard deviation. For each drug-specific cohort, the time to first treatment discontinuation after treatment initiation (post index) was assessed using Kaplan–Meier analyses. Analyses were adjusted for censoring due to death. Statistically significant differences in discontinuation rates were tested using a multivariate Cox proportional hazards model adjusted for age, sex, Charlson Comorbidity Index (CCI), systemic treatment during the baseline period, and treatment with biologics during the baseline period.

Results

Baseline Characteristics

The study included 2565 patients with psoriasis treated with secukinumab (n = 612), adalimumab (n = 454), guselkumab (n = 354), ixekizumab (n = 259), ustekinumab (n = 241), tildrakizumab (n = 205), etanercept (n = 166), risankizumab (n = 145), etanercept (n = 91), certolizumab (n = 29), and infliximab (n = 9) (selection steps are shown in Table S2). The mean age of patients was 47.85 (± 14.88) years (Table S3); 36.6% were female. Cardiovascular disease (44.5%), hypertension (36.5%), and hyperlipidemia (23.0%) were the most frequently observed pre-defined comorbidities. Topical treatment was given to 57.1% of the patients during the baseline period.

Discontinuation of Treatment During Follow-up

A total of 1290 patients (50.29%) discontinued treatment during the follow-up period (sensitivity analysis, 38.48%). The proportions varied across the biologic agents and ranged from 30.34% (risankizumab) to 69.23% (etanercept) (sensitivity analysis, 21.38% [risankizumab] to 60.44% [etanercept]). The median time until treatment discontinuation among those who discontinued ranged from 102 days (etanercept) to 208 days (risankizumab) (sensitivity analysis, 92 days [certolizumab] to 208 days [risankizumab]) (Tables 1 and S4).

Table 1 Drug-specific frequencies of treatment discontinuation and mean time to treatment discontinuation
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After discontinuing treatment during the 365-day follow-up, 45.05% of the patients restarted their treatment with the same biologic agent (sensitivity analysis, 26.96%), 23.10% switched to another biologic agent (sensitivity analysis, 30.19%), and 31.86% received no further biologic treatment (sensitivity analysis, 42.88%) (Tables 2 and S5). The proportion of patients with a restart of treatment with the same biologic ranged from 25.58% (tildrakizumab) to 60.00% (guselkumab). Switching to another biologic agent after a treatment discontinuation was most frequently observed in patients treated with brodalumab (38.95%) and least frequently observed in patients treated with guselkumab (13.71%). The share of patients with no further biologic treatment ranged from 18.95% (brodalumab) to 45.45% (risankizumab).

Table 2 Drug-specific frequencies of treatment options after discontinuation
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The probability of not discontinuing treatment at 365 days after the index date was highest for risankizumab (69.2%), ustekinumab (61.0%), and tildrakizumab (58.1%) (Fig. 1).

Fig. 1
figure 1

Kaplan–Meier curves for treatment discontinuation during the 365-day follow-up

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Certolizumab and infliximab were excluded from the regression analysis because of small patient numbers. The regression analysis revealed a significantly lower rate of treatment discontinuation in patients treated with risankizumab (p < 0.05) than in patients treated with other biologic agents except ustekinumab (p = 0.12; Table 3).

Table 3 Hazard ratio estimates for treatment discontinuation during the 365-day follow-up period
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Discussion

In this retrospective cohort study based on German health claims data, 50.29% of patients with plaque psoriasis who started a biologic treatment discontinued their treatment during the 365-day period. The probability of a treatment discontinuation during the 365-day follow-up period differed between biologics and, compared to other biologics, was significantly lower in patients treated with risankizumab (an anti-IL-23 biologic agent), except for ustekinumab. After treatment discontinuation during the 365-day follow-up period, 45.05% restarted biologic treatment with the same agent, 31.86% did not receive another biologic, and 23.10% switched to a different biologic.

The observed frequency of patients discontinuing biologic therapy during 365 days of follow-up in this study was within the range of that seen in other studies. In a retrospective analysis of healthcare administrative data covering the years 2010–2014 in Italy, the authors found that 31.8% of patients with psoriasis discontinued therapy during the first year of biologic treatment with adalimumab, ustekinumab, infliximab, etanercept, and golimumab [13]. A retrospective claims database analysis from Japan covering the years 2016–2020 showed that 63.7% of patients with psoriasis receiving systemic therapy, including biologic treatment, discontinued their systemic therapy during the 365-day follow-up [14]. The percentage of treatment discontinuation among the biologic treatments ranged from 12.3% (anti-IL-12/23 inhibitor) to 72.0% (TNFα inhibitor), mirroring our findings which identified the highest discontinuation rates for etanercept and adalimumab (anti-TNFα) and the lowest discontinuation rates for risankizumab (anti-IL-23) and ustekinumab (anti-IL-12/23). Largely consistent with our results, another claims data analysis from Japan found the lowest discontinuation rates for risankizumab (12%) and ustekinumab (24%) compared to other IL-inhibitors at 12 months of follow-up [15].

In contrast to other studies, we found that in our study a higher proportion of patients (23.10%) switched to another biologic after discontinuing treatment during the 365-day follow-up period. Another retrospective analysis of claims data reported that only 10% of patients with psoriasis receiving systemic therapy (including biologics) switched to another systemic therapy within 60 days after treatment discontinuation [14]. A British cohort study found that 17.5% of patients with psoriasis receiving biologic therapy with adalimumab, etanercept, or ustekinumab switched biologic treatment during a 12-month follow-up period [16]. A higher frequency of switching after discontinuation may contribute to the increased economic burden associated with treatment switching among biologics, which has been reported in multiple studies [14, 17, 18]. In our study, 45.05% of the patients restarted biologic therapy after discontinuing treatment (sensitivity analysis, 26.96%), which may indicate intermittent biologic treatment. A review of clinical trials investigating the efficacy and safety of intermittent biologic treatment of psoriasis reported that, although the majority of the studies indicated that the efficacy of biologic agents was greater, when administered continuously than intermittently, intermittent biologic treatment may be more feasible in the real-world setting as a result of patient preference, scheduled surgery, or adverse events [19]. Another aspect to consider is dose optimization through extended administration intervals. However, in Germany, this practice is considered off-label use and may entail the risk of subsequent claims for the prescribing physician, as SHI companies can submit a review request for unauthorized off-label prescriptions. Consequently, its relevance is deemed to be rather low.

Limitations

We recognize several limitations of our study. First, to increase the sample size, patients could be included into multiple drug-specific cohorts and/or into the same cohort multiple times, which may have introduced bias because different lines of therapy could have been compared.

Second, it should also be noted that German claims data do not contain information on whether a dispensed drug was taken and whether a dose was taken as prescribed or the reason for drug prescriptions. Therefore, patients with concomitant diseases, for which the biologics assessed in our study are also approved, were excluded to ensure psoriasis-related prescriptions as the basis for data analysis. This may have led to selection bias. Further, claims data do not provide sufficient clinical detail to adequately ascertain the underlying reasons for treatment discontinuation (e.g., information on disease severity, treatment response, safety aspects, or patient preferences).

Third, we inferred the dosage information from the dates of dispensation and package size. Some of the biologic therapies analyzed are also approved for other diseases, sometimes with different dosing regimens (e.g., rheumatoid arthritis). However, to ensure that a prescription was likely for psoriasis, patients with a concomitant diagnosis of one of these conditions were excluded from the respective drug-specific cohort.

Fourth, the follow-up period was limited to 365 days. Thus, the analysis of what happened after a discontinuation was limited to the remaining days until follow-up ended at 365 days.

Additionally, the relatively short baseline period may have introduced bias. For example, this might cause previous concomitant diagnoses, for which the respective agent is also an approved therapy option, to be overlooked.

Conclusions

Approximately half of patients receiving biologic therapy for plaque psoriasis discontinue treatment within 365 days of starting therapy, with variation in the probability of discontinuation observed with different agents. We found that patients treated with risankizumab had a statistically lower probability of treatment discontinuation compared to patients treated with other biologic agents with the exception of ustekinumab. Further research should focus on understanding the reasons for treatment discontinuation to gain insights into patient needs and further optimize biological treatment of patients with plaque psoriasis who are more severely affected.