IL-4/13 Blockade and sleep-related adverse drug reactions in over 37,000 Dupilumab reports from the World Health Organization Individual Case Safety reporting pharmacovigilance database (VigiBase™): a big data and machine learning analysis (Preprint)

BACKGROUND Atopic dermatitis displays a relevant sleep burden sustained by clinical (i.e., itch), psychological (i.e., inadequate coping strategies) and therapeutic (i.e. frequent loss of drug response) triggers. Dupilumab, the first biologic approved for atopic dermatitis, showed excellent effects on improving pruritus and sleep after only two weeks of treatment but, in some cases, may have paradoxical effects. OBJECTIVE The rate of sleep-related side-effects remains unknown. More specifically, adverse-drug reactions (ADRs) related to dupilumab have been investigated during the safety phase of randomized clinical trials or in small retrospective epidemiological surveys, but little is known about sleep-related ADRs in real-life settings. Therefore, we took advantage of a global large-scale pharmacovigilance database, carrying out a comprehensive data mining analysis to look at different sleep-related ADRs reported among patients under anti IL-4/13 therapy. METHODS We analysed individual case study reports (ICSRs) in VigiBase, the World Health Organization (WHO) global pharmacovigilance database of ADRs collected by national drug authorities in >140 countries (>90% of the world population). We looked for patterns of potentially sleep-related ADRs and we applied a disproportionality analysis based on Bayesian Confidence Propagation Neural Network (BCPNN). A meta-analytical approach was used to synthesize the overall effect size of sleep-related ADRs potentially associated to Dupilumab administration. RESULTS From inception up to March 9, 2021, 94,065 ADRs from 37,848 unique reports were included and analyzed in the present paper: 1,294 of them (1.4%) concerned sleep disturbances (n=27). Most of sleep-related complaints were generic sleep disorders (n=630), followed by insomnia (n=312), somnolence (n=81), lethargy (n=60), night sweats (n=30), middle insomnia (n=39), hypersomnia (n=25), poor quality sleep (n=21), initial insomnia (n=17), sleep apnoea syndrome (n=13), nightmares (n=11) and sleep deficit (n=11). Interestingly, restlessness and restless leg syndrome, nocturnal dyspnoea, narcolepsy and bruxism were reported in 7, 6, 5, 4 and 3 cases, respectively. Only sleep deficit (OR 15.67 [CrI 8.61-28.51]; IC 3.24 [CrI 2.26-3.97]), generic sleep disorder (OR 6.22 [CrI 5.74-6.73]; IC 2.60 [CrI 2.48-2.71]), and nocturnal dyspnoea (OR 3.68 [CrI 1.53-8.87]; IC 1.56 [CrI 0.03-2.56]) achieved the statistical significance threshold. CONCLUSIONS In this work, we identified over 37,000 unique case-reports of Dupilumab side-effects reported on the WHO pharmacovigilance database. We specifically categorised those related to sleep issues, which were 1,294. Our findings from large numbers of cases provide data supporting the clinical observations that Dupilumab is usually effective in improving sleep quality and sleep disturbances/impairments but sometimes may impair circadian rhythm and sleep. Further work is needed to closely scrutinise the impact of Dupilumab on sleep, in terms of underlying mechanisms, and to better understand residual sleep disorders in patients with atopic dermatitis and other allergic diseases treated with Dupilumab. Thus, sleep monitoring may be helpful for dermatologists in managing atopic dermatitis patients treated with dupilumab. The limitations of spontaneous reporting systems including underreporting and reporting bias, heterogeneity of sources and impossibility to infer any causal relationship merit consideration and further research is needed.