Risk of common infections among individuals with psoriasis in Sweden: A nationwide cohort study comparing secukinumab to ustekinumab

Abstract Purpose To determine risk of respiratory tract infections, urinary tract infections and candidiasis in secukinumab users compared to ustekinumab users among individuals with psoriasis in Sweden. Methods This was a Swedish population‐based register‐linked new‐user cohort study on individuals with psoriasis and psoriasis arthritis treated with secukinumab (2015‐2017) and ustekinumab (2009‐2017). Ever‐never exposure definition was used, that is, each individual's follow‐up time was attributed to the drug they were first exposed to. Risk of severe respiratory and urinary tract infections and candidiasis (diagnosis codes from out‐patient specialist visits and in‐patient hospitalisations) and respiratory and urinary tract infections treated in primary care (proxied by dispensation of antibiotics) was determined by adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) using Cox regression. We also give crude incidence rates and rate ratios. Results In total, 1955 new users of secukinumab (n = 848) and ustekinumab (n = 1107) were identified. There was a slightly increased risk of respiratory and urinary tract infections treated in primary care among secukinumab users compared to ustekinumab users (HR: 1.22, 95% CI: 1.03‐1.43). Non‐significant differences in estimated risk of severe respiratory and urinary tract infections (HR: 0.96, 95% CI: 0.57‐1.61) and candidiasis (HR: 1.80, 95% CI: 0.84‐3.84) treated in the hospital setting were observed. Conclusion We observed a slightly increased risk of respiratory and urinary tract infections treated in primary care among secukinumab users compared to ustekinumab users. Larger studies with longer follow‐up are needed to draw conclusions on relative safety.

psoriasis. 3 Also, external factors such as stress, infections and certain medications such as beta blockers and antimalarial drugs are known to aggravate the disease. 7 Exploring the function of T helper 17 cells in the inflammatory cascade has resulted in the identification of specific antibody treatments for multiple immune-mediated diseases including psoriasis. 8 Biologics offer target-specific immunosuppressive activity, improved safety profiles and better tolerability compared to traditional anti-inflammatory medications. 7,9,10 However, as biologics are inherently meant to act upon the immune system, they have the potential to cause other immune mediated effects besides their targeted action, including an increased susceptibility for infections. 11,12 Currently, interleukin (IL)-inhibitors ustekinumab and secukinumab are being favoured in psoriasis management, as they have demonstrated improved skin clearance compared to their predecessor tumour necrosis factor-α (TNF-α) inhibitors etanercept and infliximab. 9,[13][14][15][16][17] However, the implications of the long-term activity of IL-inhibitors outside of clinical trials is yet to be explored. [18][19][20][21] Secukinumab and ustekinumab act by targeting proinflammatory cytokines IL-17A and IL-12/23 respectively. 18,22 IL-17A is involved in host immune defence, with roles in granulopoiesis, neutrophil trafficking and mucocutaneous defence against fungi and bacteria; thusly, raising concerns with anti-IL-17A therapy and its potential for infections. 22 Risk of infections is also a concern among patients on anti-IL12/23 therapy, since genetic deficiencies of IL-12/23 can raise the risk of certain bacterial infections. 18 The European Medicines Agency (EMA) risk management plans (RMP) of both secukinumab and ustekinumab highlights the risk of infections, upper respiratory tract infections (RTI) in particular for secukinumab use. 23-25 Also, IL-related immune protection has been evidenced, especially against fungal infections caused by Candida species. Therefore, anti-IL therapy, puts patients at an increased risk of Candida infections due to their mode of action. [26][27][28] Previous studies have shown conflicting results regarding clinical superiority of secukinumab over ustekinumab with respect to achieving desired clinical endpoints, demonstrating higher efficacy and safety. 9,13,29 In a long-term study exploring the safety and efficacy of biologics in psoriasis, secukinumab had more adverse events compared to other agents including ustekinumab. 13 In a multicentre, randomised, double-blinded clinical trial, secukinumab demonstrated superior clinical efficacy with improved quality of life when compared to ustekinumab and showed a comparable safety profile with ustekinumab. 29 Since secukinumab is a relatively new drug, long-term surveillance data is lacking. [18][19][20][21] Also, studies comparing the safety profiles of both ustekinumab and secukinumab are limited. 13,29 Clinical trials are carried out on select populations with short follow-up not mirroring the clinical reality where the drugs are used once marketed. 30 Continuous post-marketing safety surveillance of drugs is crucial to capture clinical endpoints which are missed in conventional pre-market clinical trials. 30 The availability of register-linked information in Sweden provides a unique possibility of obtaining effective insights into safety comparisons between drugs. This study aimed at determining the risk of RTI and urinary tract infections (UTI) for secukinumab use compared to ustekinumab use among individuals with psoriasis, using population data on clinical diagnoses and dispensed antibiotic prescriptions used as proxies for infections treated in primary care from Swedish national registers. As a secondary aim, the risk of candidiasis was investigated using population data on clinical diagnoses. Chemical Classification System (ATC) index. 37 Information on migration was obtained from population registers of Statistics Sweden. 35,38 The SCR was used to obtain morphologically verified cancer diagnoses which could be potential confounders in the study. 33 The CDR was used to capture mortality data. 34 Data up to December 31, 2017

KEY POINTS
• Biologics secukinumab and ustekinumab are effective for psoriasis management. However, clinical trials of these biologicals highlight safety concerns such as respiratory tract infections, urinary tract infections and candidiasis.
• Health and population data from Swedish national registers provide a unique opportunity to investigate the safety of biologics in a real-world setting.
• A slight increased risk of respiratory tract infections and urinary tract infections treated in primary care was observed among secukinumab users compared to ustekinumab users.
• Although both immune dysregulation and interleukinantagonist therapy can raise the risk of Candida infections, our findings showed no remarkable risk of candidiasis among secukinumab users compared to ustekinumab users.
were included for all the data sources except for data from Statistics Sweden where data up to December 31, 2016 were included.

| Outcomes
The outcome measured was common infections (see Appendix, Table S2). This comprised of upper and lower RTI, UTI and candidiasis.
The RMPs for secukinumab and ustekinumab highlight upper RTI as a common safety event. 24,25 UTI were added since they are a common group of infections especially in primary care. 39 Additionally, we stud-

| Covariates
Information on sociodemographic covariates including age, sex, education, income, occupation, civil status and region, was obtained from NPR and population registers of Statistics Sweden. 31,35,38 Clinical covariates related to both psoriasis and the exposure drugs were considered as potential confounders. All the covariates were included in the study based on existing knowledge from relevant scientific literature. Information on these clinical covariates was obtained from NPR and SCR. Sociodemographic covariates were assessed 1 year before index date and clinical covariates were assessed starting from 1997.
Missingness is a minor problem in the Swedish national registers. If information on a variable, for example, diagnosis, was available, patients were coded as not having the diagnosis if that specific diagnosis code was not found. For other types of variables where "miss- ing" was one of the possible values, for example, for geographical area, the category "missing" was used; geographical area can be "predominantly urban," "intermediate," "predominantly rural" or "missing."    (Table 2).

| Statistical analysis
We report crude and adjusted analyses using Cox proportionalhazards models, comparing secukinumab users with ustekinumab users ( Baseline comorbidities are clinical conditions recorded before index drug use. This includes -(major adverse cardiovascular events (MACE), angina, coronary artery disease (CAD), cancer, immunocompromised status, diabetes, chronic obstructive pulmonary disease (COPD), dyslipidemia, hypertension, HIV, arrhythmias, arthritis, rheumatoid diseases, Crohn's disease, ulcerative colitis, liver diseases, renal diseases, psoriatic arthritis, asthma) before index. with psoriasis. Our study findings showed secukinumab users with a higher risk of infections treated in primary care compared to ustekinumab users. This is consistent with the results from the 52-week CLEAR RCT on secukinumab and ustekinumab use, where the safety profiles of both drugs were found to be comparable with a slightly higher proportion of adverse events among the secukinumab group (64.2%) compared to the ustekinumab group (58.3%), with non-serious infections being the most common adverse events. 41 Infections in our study were largely driven by the increased risk of RTI treated in primary care, although not statistically significant. Similarly, a previous long-term pooled safety analysis of secukinumab highlights upper RTI as one of the most common adverse events for secukinumab (3.3%). 22 As for ustekinumab, a long-term analysis of ustekinumab demonstrated no elevated risk of infections after 5 years of ustekinumab exposure. 18 Another large analysis of safety data from clinical trials and post-marketing surveillance database reports the association of secukinumab with fewer adverse events, with upper RTI being the most frequent. 42 For severe RTI and UTI observed in our study, there were no significant differences in the risk of infections possibly due to the smaller number of events. Immune dysregulation in psoriasis is known to cause increased production of pro-inflammatory cytokines. Some of these cytokines (eg, IL-22, IL-23, IL-17) have significant roles in immune defence mechanisms against pathogens such as Candida albicans. Therefore, patients treated with IL-antagonists, are at a higher risk of developing Candida infections. 27 A study exploring previously conducted clinical trials to measure the risk of candidiasis among patients treated with IL-targeted therapies, presents 1.7% overall incidence of candidiasis among secukinumab users and 2.3% overall incidence of candidiasis among ustekinumab users. 26 In our study, for candidiasis treated in hospital care we found a slightly elevated but statistically insignificant risk in secukinumab users as compared to ustekinumab users. The majority of cases were vaginal candidiasis followed by oral candidiasis (data not shown). When restricting the study period to the first 3 years of market availability for both drugs, no differences were found indicating that potential channelling bias had little impact on the main results.
Our study has multiple strengths. Firstly, the study population included all psoriasis patients treated with secukinumab and ustekinumab during the study period in Sweden; minimising the potential for selection bias. Secondly, register-based data covers people from all regions in Sweden; increasing the generalizability of the findings to Sweden and/or to countries with similar healthcare systems and populations. Thirdly, data on baseline characteristics and clinical comorbidities were collected from linking of multiple registers, to ensure completeness of information and to avoid differential misclassification. In addition to severe RTI and UTI diagnosed from NPR, RTI and UTI treated in primary care were captured using antibiotics use recorded in PDR as proxies. The completeness of pharmacy records is guaranteed as they reflect drug dispensation received by patients. Although prescriptions do not reflect actual medication taking behaviour, they do confirm the occurrence of infections which necessitated antibiotics' prescriptions. Similar to our study, antibiotics' prescriptions have been previously used as proxy measures to capture infections. [43][44][45] Additionally, to the best of our knowledge, this is the first post-marketing study comparing the use of secukinumab and ustekinumab and risk of RTI, UTI and candidiasis outside of clinical trials. Also, the use of active comparator design that is, ustekinumab being compared to secukinumab among individuals with the same disease, reduces the potential for confounding by indication. 46 However, this study has its share of limitations. The ustekinumab group had a longer follow-up period compared to the secukinumab group. This could potentially introduce bias in the study results pro- However, the overall proportion of drug switchers during the study period was quite low (~12%, data not shown). Although there were some differences in the baseline comorbidities among the study drug groups, all baseline comorbidities were adjusted for in the final model. Nevertheless, risk for residual confounding and unmeasured confounding (eg, lifestyle factors, body mass index) cannot be ruled out.
Also, baseline disease severity of both treatment groups was not accounted for. However, as both groups are treated with biologics, we expect them to have fairly similar severity of disease. Additionally, indications for which the antibiotics were prescribed are unknown.
Antibiotic prescription rates can vary between practitioners and across counties in Sweden. 47,48 Although we have not explored the difference in prescription rates among specific practitioners, we have adjusted for different counties in Sweden. This will capture most of the potential variation. Lastly, our data coverage ended December 2017, since the national Swedish registers are updated annually, for example, NPR is available the earliest in September the next year. Moreover, the process for data application and delivery takes about 1 year. Allowing time for data cleaning, analysis and manuscript writing, we used data available to us early 2019, that is, data availability beyond December 31, 2017 was impossible to obtain.

| CONCLUSION
The study findings provide real-world evidence on the adverse events -RTI, UTI and candidiasis among secukinumab and ustekinumab users treated for psoriasis and psoriatic arthritis. Specifically, secukinumab users had a slightly increased risk of infections treated in primary care compared to ustekinumab users. Infections are events of clinical significance as they cause varying burden among affected individuals.
Continuous, long-term, comparative safety studies with multiple biologic therapies, among different population groups are needed to validate our study findings and to obtain robust data, which can help develop optimal therapeutic guidelines.
T A B L E 2 Number of events and crude incidence rates of RTI, UTI and candidiasis per 1000 person-days, incidence rate ratios of RTI, UTI and candidiasis per 1000 person-days and crude and adjusted hazard ratios (HR, Cox proportional hazards model, 95% CI) for secukinumab use and ustekinumab use