The devil is in the data: differences in drug persistence between <scp>SNIIRAM</scp> , the French national health insurance database, and psoriasis biologics intervention registers
Authors: Henry J. Grantham, Nick J. Reynolds
Journal: British Journal of Dermatology (2019)

Linked Article: Sbidian et al. Br J Dermatol 2019; 180:86-93. Although the era of biologics for psoriasis was ushered in through the serendipitous but astute observation of psoriasis improvement in a patient receiving infliximab for coexisting Crohn disease,1 increased understanding of the immunopathogenesis underlying psoriasis has subsequently resulted in bioengineered molecules that target aberrant immune pathways with precision.2 These biological therapies have dramatically altered treatment pathways and outcomes for patients. Nevertheless, small molecules are effective particularly in moderate disease; for example, 45% of patients treated with methotrexate achieve a 75% reduction in their Psoriasis Area and Severity Index score (PASI 75) according to a recent meta-analysis,3 and current therapy guidelines generally advocate use of (or contraindication to) conventional systemic therapy prior to biologics. In 2004, efalizumab and etanercept were the first biologics approved for the treatment of psoriasis in Europe, followed by infliximab soon after. Compared with small molecules, biologics are able to achieve PASI 75, 90 and 100 in a greater proportion of patients.4 However, they are not without significant potential risk, and as the majority of clinical trials are powered for treatment response rather than side-effects, postmarketing surveillance is crucial. For example, efalizumab was removed from the market worldwide in 2009 following reports of increased risk of progressive multifocal leucoencephalopathy.5 Around this time, treatment registries were created to record and analyse real-world data on biologics. Example databases include the PSOriasis Longitudinal Assessment and Registry (PSOLAR; an international database involving countries in the Americas, Eastern Europe and the Middle East), BIOBADADERM (Spain) and the British Association of Dermatologists Biologic Interventions Register (BADBIR; the U.K. and Ireland). In this issue of the British Journal of Dermatology, Sbidian et al. present their real-world analysis of drug persistence in biologic-naïve patients with psoriasis, using data obtained from the French National Health Insurance database, le Système National d'Information Interrégimes de l'Assurance Maladie (SNIIRAM).6 SNIIRAM includes 65 million individuals – over 98% of the French population – providing each with a unique, anonymous identifier.7 Data recorded include demographics (with the exception of smoking status); medical conditions, as recorded on inpatient discharge summaries; and reimbursed drug prescriptions. Long-term diseases with significant or costly health burden, such as diabetes mellitus and ischaemic heart disease, are also recorded. Interestingly, psoriasis is not included in this group, despite being a disease with significant burden and cost.8, 9 Thus, SNIIRAM is a resource of great potential for research. In the current study, the authors determined that a patient had psoriasis following the prescription of at least two topical vitamin D analogues within a 2-year period. Persistence was defined as the length of time from initiation of the biologic to discontinuation. This definition of persistence is in line with other drug survival studies.10-12 Discontinuation was defined as more than 90 days after the next dose would be due without a further prescription. There were 16 545 biologic-naïve patients in the cohort (6493 treated with adalimumab, 5524 with etanercept, 2023 with infliximab and 2505 with ustekinumab). Similar to other studies, ustekinumab had the highest recorded persistence rate,10-12 but this rate reduced faster than previously published (84% at 1 year, 65% at 2 years and 54% at 3 years). The authors also report an average persistence rate for biologics that is lower than previous studies (62% at 1 year, 43% at 2 years and 33% at 3 years).10-12 What are the possible reasons that may account for this? The authors suggest that previous studies may suffer from selection bias and question the representativeness of registries. However, they also explore the limitations of their study, which seem a more plausible explanation for the difference. The inherent limitations of SNIIRAM – as an insurance database rather than treatment registry – necessitated that the authors define psoriasis indirectly. This significant limitation could result in selection bias and confounders for numerous reasons. For example, this definition would exclude patients who had not been prescribed topical vitamin D analogues (perhaps due to the patient and clinician deciding on an alternate treatment). Additionally, there are numerous off-label indications for topical vitamin D analogues,13 potentially resulting in patients without psoriasis being included in the cohort. Sensitivity of their definition (the proportion of patients prescribed ustekinumab who had also been prescribed topical vitamin D analogues previously) was calculated as 84·5%. This would likely be lower still when considering the additional indications for all other biologics assessed in the study. To illustrate this, patients taking infliximab appear far more likely to have associated inflammatory bowel disease (18·6% vs. the average of 5·7%), whereas patients taking ustekinumab were far less likely to also have psoriatic arthritis (12·3% vs. the average of 33·6%). In other words, the analysis performed by Sbidian et al.6 may well include patients with psoriasis who were prescribed biological therapy primarily for one of their comorbid conditions. It is therefore perhaps not surprising that persistence rates were lower compared with those reported from psoriasis registries. Another reason for the difference in persistence rates could be due to the definition of drug discontinuation in this study. Revealingly, of the 8020 patients that discontinued their initial biologic within 1 year, 20% of these reinitiated the same biologic within the next 12 months – and in four out of five cases, this reintroduction was within 3 months (Tables 3 and 4 in Sbidian et al.6). This was as high as 40% for patients taking ustekinumab, which has the largest interval between doses of all assessed biologics. It seems highly likely that these ‘treatment re-initiations’ were in fact treatment continuations. If these patients who had ‘discontinued’ their medication instead remained in the ongoing treatment group, one would expect that the persistence rates would resemble data from previous studies far more closely. As a final point, the authors do not mention how missing data is handled. Taken together, these factors might go a long way towards explaining the marked difference in persistence rates compared with previous studies from psoriasis registries. In contrast, psoriasis biologics registries are longitudinal observational prospective studies. Within BADBIR for example, all registrants have a diagnosis of psoriasis made by a dermatologist, and all registrants in the biologic cohort have been prescribed biologics for their psoriasis; consequently, data can be evaluated directly. Registries are not randomized, but selection bias can be controlled for through propensity score modelling, which is a statistical method that accounts for confounding factors when estimating the effect on a study outcome.14 The design of registries is thus critical for the reliable interpretation of published data, enabling the busy dermatologist to have fully informed discussions surrounding treatments with patients in clinic. BADBIR now includes data from over 16 000 registrants and has resulted in more than 10 publications to date, reporting outcomes ranging from drug survival to risk of serious infections.10, 15 As registries continue to recruit patients, the applicability of this data will only increase in scale over time. The study by Sbidian et al.6 highlights the key differences between registries and health insurance databases and emphasizes the need for correctly unlocking routinely collected data. N.J.R. reports grants from PSORT industrial partners as listed (http://www.psort.org.uk/); other research grants from AstraZeneca, Novartis and Stiefel/GSK; and other income to Newcastle University from Almiral, Amgen, Janssen and Novartis for lectures/attendance at advisory boards. N.J.R. has been a member of the BADBIR Steering Committee since its inception and is Chair of the BADBIR research committee. H.J.G. reports no conflicts of interest.