Scd1 and monounsaturated lipids are required for autophagy and survival of adipocytes.

OBJECTIVE: Exposure of adipocytes to 'cool' temperatures often found in the periphery of the body induces expression of Stearoyl-CoA Desaturase-1 (Scd1), an enzyme that converts saturated fatty acids to monounsaturated fatty acids. The goal of this study is to further investigate the roles of Scd in adipocytes. METHOD: In this study, we employed Scd1 knockout cells and mouse models, along with pharmacological Scd1 inhibition to dissect the enzyme's function in adipocyte physiology. RESULTS: Our study reveals that production of monounsaturated lipids by Scd1 is necessary for fusion of autophagosomes to lysosomes and that with a Scd1-deficiency, autophagosomes accumulate. In addition, Scd1-deficiency impairs lysosomal and autolysosomal acidification resulting in vacuole accumulation and eventual cell death. Blocking autophagosome formation or supplementation with monounsaturated fatty acids maintains vitality of Scd1-deficient adipocytes. CONCLUSION: This study demonstrates the indispensable role of Scd1 in adipocyte survival, with its inhibition in vivo triggering autophagy-dependent cell death and its depletion in vivo leading to the loss of bone marrow adipocytes.

SCD1 and monounsaturated lipids are required for autophagy and survival of adipocytes.

Exposure of adipocytes to 'cool' temperatures often found in the periphery of the body induces expression of Stearoyl-CoA Desaturase-1 (SCD1), an enzyme that converts saturated fatty acids to monounsaturated fatty acids. In this study, we employed Scd1 knockout cells and mouse models, along with pharmacological SCD1 inhibition, to investigate further the roles of SCD1 in adipocytes. Our study reveals that production of monounsaturated lipids by SCD1 is necessary for fusion of autophagosomes to lysosomes and that with a SCD1-deficiency, autophagosomes accumulate. In addition, SCD1-deficiency impairs lysosomal and autolysosomal acidification resulting in vacuole accumulation and eventual cell death. Blocking autophagosome formation or supplementation with monounsaturated fatty acids maintains vitality of SCD1-deficient adipocytes. Taken together, our results demonstrate that in vitro inhibition of SCD1 in adipocytes leads to autophagy-dependent cell death, and in vivo depletion leads to loss of bone marrow adipocytes.

Cost-effectiveness of the fixed-dose combination tiotropium/olodaterol versus tiotropium monotherapy or a fixed-dose combination of long-acting ß2-agonist/inhaled corticosteroid for COPD in Finland, Sweden and the Netherlands: a model-based study.

OBJECTIVES: Chronic obstructive pulmonary disease (COPD) guidelines advocate treatment with combinations of long-acting bronchodilators for patients with COPD who have persistent symptoms or continue to have exacerbations while using a single bronchodilator. This study assessed the cost-utility of the fixed dose combination of the bronchodilators tiotropium and olodaterol versus two comparators, tiotropium monotherapy and long-acting ß2 agonist/inhaled corticosteroid (LABA/ICS) combinations, in three European countries: Finland, Sweden and the Netherlands. METHODS: A previously published COPD patient-level discrete event simulation model was updated with most recent evidence to estimate lifetime quality-adjusted life years (QALYs) and costs for COPD patients receiving either tiotropium/olodaterol, tiotropium monotherapy or LABA/ICS. Treatment efficacy covered impact on trough forced expiratory volume in 1 s (FEV1), total and severe exacerbations and pneumonias. The unit costs of medication, maintenance treatment, exacerbations and pneumonias were obtained for each country. The country-specific analyses adhered to the Finnish, Swedish and Dutch pharmacoeconomic guidelines, respectively. RESULTS: Treatment with tiotropium/olodaterol gained QALYs ranging from 0.09 (Finland and Sweden) to 0.11 (the Netherlands) versus tiotropium and 0.23 (Finland and Sweden) to 0.28 (the Netherlands) versus LABA/ICS. The Finnish payer's incremental cost-effectiveness ratio (ICER) of tiotropium/olodaterol was €11 000/QALY versus tiotropium and dominant versus LABA/ICS. The Swedish ICERs were €6200/QALY and dominant, respectively (societal perspective). The Dutch ICERs were €14 400 and €9200, respectively (societal perspective). The probability that tiotropium/olodaterol was cost-effective compared with tiotropium at the country-specific (unofficial) threshold values for the maximum willingness to pay for a QALY was 84% for Finland, 98% for Sweden and 99% for the Netherlands. Compared with LABA/ICS, this probability was 100% for all three countries. CONCLUSIONS: Based on the simulations, tiotropium/olodaterol is a cost-effective treatment option versus tiotropium or LABA/ICS in all three countries. In both Finland and Sweden, tiotropium/olodaterol is more effective and cost saving (ie, dominant) in comparison with LABA/ICS.

Corrigendum to: Persistence of biologic treatments in psoriatic arthritis: a population-based study in Sweden.

[This corrects the article DOI: 10.1093/rap/rkaa070.][This corrects the article DOI: 10.1093/rap/rkaa070.].

Persistence of biologic treatments in psoriatic arthritis: a population-based study in Sweden.

OBJECTIVES: TNF inhibitors (TNFis) and IL inhibitors are effective treatments for PsA. Treatment non-persistence (drug survival, discontinuation) is a measure of effectiveness, tolerability and patient satisfaction or preferences in real-world clinical practice. Persistence on these treatments is not well understood in European PsA populations. The aim of this study was to compare time to non-persistence for either ustekinumab (IL-12/23 inhibitor) or secukinumab (IL-17 inhibitor) to a reference group of adalimumab (TNFi) treatment exposures in PsA patients and identify risk factors for non-persistence. METHODS: A total of 4649 exposures of adalimumab, ustekinumab, and secukinumab in 3918 PsA patients were identified in Swedish longitudinal population-based registry data. Kaplan-Meier curves were constructed to measure treatment-specific real-world risk of non-persistence and adjusted Cox proportional hazards models were estimated to identify risk factors associated with non-persistence. RESULTS: Ustekinumab was associated with a lower risk of non-persistence relative to adalimumab in biologic-naïve [hazard ratio (HR) 0.48 (95% CI 0.33, 0.69)] and biologic-experienced patients [HR 0.65 (95% CI 0.56, 0.76)], while secukinumab was associated with a lower risk in biologic-naïve patients [HR 0.65 (95% CI 0.49, 0.86)] but a higher risk of non-persistence in biologic-experienced patients [HR 1.20 (95% CI 1.03, 1.40)]. Biologic non-persistence was also associated with female sex, axial involvement, recent disease onset, biologic treatment experience and no psoriasis. CONCLUSION: Ustekinumab exhibits a favourable treatment persistency profile relative to adalimumab overall and across lines of treatment. The performance of secukinumab is dependent on biologic experience. Persistence and risk factors for non-persistence should be accounted for when determining an optimal treatment plan for patients.