[Cost-Utility Analysis of Dupilumab for the Treatment of Severe Atopic Dermatitis in Children and Adolescents in Italy]

BACKGROUND AND OBJECTIVE: Atopic dermatitis (AD) is a chronic, multifactorial, inflammatory condition characterized by a significant impact on patients' quality of life. Dupilumab is reimbursed by the Italian Medicines Agency (AIFA) for the treatment of adolescent and adult patients with severe AD (according to AIFA registry criteria). Recently, dupilumab has been reimbursed in the treatment of children with severe AD. The objective of this analysis was to estimate the incremental cost-utility ratio (ICUR) of dupilumab compared to current supportive care (SC), for the treatment of severe AD in children (6-11 years) and adolescents (12-17 years) in Italy.MATERIALS AND METHODS: Cost-effectiveness analysis was conducted using a 1-year decision tree followed by a Markov model over a lifetime period. The base case analysis was performed on the overall population of the LIBERTY AD ADOL (NCT03054428) and LIBERTY AD PEDS (NCT03345914) studies, adopting the National Health Service (NHS) perspective. The following costs were considered: acquisition of treatment, management of disease, adverse events and complications. The robustness of the model was tested through sensitivity analysis. In addition, a scenario analysis adopting the social perspective was performed.RESULTS: In the base case, over a lifetime, dupilumab was more effective than SC in both children and adolescents (+2.44 and +1.62 quality-adjusted life years—QALYs, respectively). The introduction of dupilumab generated an increase in treatment costs (+€ 64,800 and +€ 52,853 € for children and adolescents, respectively), partially offset by a decrease in the costs of disease management and complications. Incremental cost-utility ratios (ICURs) were € 21,189 per QALY gained, for children, and € 26,569 per QALY gained, for adolescents. In both cases, the ICUR was lower than the willingness to pay threshold considered in Italy (€ 50,000 per QALY gained). Both the deterministic and probabilistic sensitivity analysis confirmed the robustness of the base case results. Finally, the scenario analysis, adopting the social perspective, showed coherent results compared to the base case.DISCUSSION: Dupilumab is a cost-effective option for the treatment of children and adolescents with severe AD eligible for systemic treatment in Italy compared to SC, from both the NHS and social perspective, confirming the results obtained in the adult population

The role of microvesicles derived from mesenchymal stem cells in tissue regeneration; a dream for tendon repair?

Tendon injuries represent even today a challenge as repair may be exceedingly slow and incomplete. Regenerative medicine and stem cell technology have shown to be of great promise. Here, we will review the current knowledge on the mechanisms of the regenerative potential of mesenchymal stem cells (MSCs) obtained from different sources (bone marrow, fat, cord blood, placenta). More specifically, we will devote attention to the current use of MSCs that have been used experimentally and in limited numbers of clinical cases for the surgical treatment of subchondral-bone cysts, bone-fracture repair and cartilage repair. Based on the recently emerging role in regenerative mechanisms of soluble factors and of extracellular vesicles, we will discuss the potential of non-cellular therapies in horse tendon injurie

Superior physical and mental health of healthy volunteers before and five years after mobilized stem cell donation

Background: Safety, tolerability and efficacy of granulocyte colony-stimulating factor (G-CSF) for mobilization of hematopoietic stem and progenitor cells (HSPCs) from healthy donors have been conclusively demonstrated. This explicitly includes, albeit for smaller cohorts and shorter observation periods, biosimilar G-CSFs. HSPC donation is non-remunerated, its sole reward being “warm glow”, hence harm to donors must be avoided with maximal certitude. To ascertain, therefore, long-term physical and mental health effects of HSPC donation, a cohort of G-CSF mobilized donors was followed longitudinally. Methods: We enrolled 245 healthy volunteers in this bi-centric long-term surveillance study. 244 healthy volunteers began mobilization with twice-daily Sandoz biosimilar filgrastim and 242 underwent apheresis after G-CSF mobilization. Physical and mental health were followed up over a period of 5-years using the validated SF-12 health questionnaire. Results: Baseline physical and mental health of HSPC donors was markedly better than in a healthy reference population matched for ethnicity, sex and age. Physical, but not mental health was sharply diminished at the time of apheresis, likely due to side effects of biosimilar G-CSF, however had returned to pre-apheresis values by the next follow-up appointment after 6 months. Physical and mental health slightly deteriorated over time with kinetics reflecting the known effects of aging. Hence, superior physical and mental health compared to the general healthy non-donor population was maintained over time. Conclusions: HSPC donors are of better overall physical and mental health than the average healthy non-donor. Superior well-being is maintained over time, supporting the favorable risk–benefit assessment of volunteer HSPC donation. Trial registration National Clinical Trial NCT0176693

Interplay between oncogene-induced DNA damage response and heterochromatin in senescence and cancer

Two major mechanisms have been causally implicated in the establishment of cellular senescence: the activation of the DNA damage response (DDR) pathway and the formation of senescence-associated heterochromatic foci (SAHF). Here we show that in human fibroblasts resistant to premature p16(INK4a) induction, SAHF are preferentially formed following oncogene activation but are not detected during replicative cellular senescence or on exposure to a variety of senescence-inducing stimuli. Oncogene-induced SAHF formation depends on DNA replication and ATR (ataxia telangiectasia and Rad3-related). Inactivation of ATM (ataxia telangiectasia mutated) or p53 allows the proliferation of oncogene-expressing cells that retain increased heterochromatin induction. In human cancers, levels of heterochromatin markers are higher than in normal tissues, and are independent of the proliferative index or stage of the tumours. Pharmacological and genetic perturbation of heterochromatin in oncogene-expressing cells increase DDR signalling and lead to apoptosis. In vivo, a histone deacetylase inhibitor (HDACi) causes heterochromatin relaxation, increased DDR, apoptosis and tumour regression. These results indicate that heterochromatin induced by oncogenic stress restrains DDR and suggest that the use of chromatin-modifying drugs in cancer therapies may benefit from the study of chromatin and DDR status of tumours