Boehringer Ingelheim (Argentina)

Introduction: Generalized pustular psoriasis (GPP) is a heterogeneous, systemic, neutrophilic, inflammatory disease associated with chronic symptoms and periods of flaring. Spesolimab is an anti-interleukin-36 receptor monoclonal antibody approved for the treatment of flares in adult patients with GPP in Argentina (17 Aug 2023).1 Here, we present safety data from a real-world expanded access program (EAP: 22 Feb 2023–10 Jan 2024) in Argentina which provided early access to spesolimab intravenous (IV) for GPP patients presenting with a flare with no other treatment options. Methods: Patients (18–75 years old) diagnosed with GPP received a 900mg dose of spesolimab IV for flare treatment, with an optional second dose after 1 week for persistent flare symptoms. Adverse events (AEs), serious AEs (SAEs), and AEs of special interest (AESIs) were recorded for up to 16 weeks after the last spesolimab infusion.Results: Six female patients were treated with spesolimab IV (1 dose, n=2; 2 doses, n=4).Mean (standard deviation [SD]) age: 49.3 (11.5) years (range: 30–60 years), mean (SD) body mass index: 28.1 (5.8) kg/m2, and mean (SD) follow-up: 3.85 (0.11) months. At baseline, GPP had been diagnosed within ≤1 year (n=2), >1–≤5 years (n=1), and >10 years (n=3). Reported flare triggers were stress (n=2), treatment withdrawal (n=1), heat (n=1), lack of current treatment efficacy (n=1), and unknown (n=1). At baseline, 4 patients had ≥1 comorbidity, including hypertension (n=2), tachycardia, hypothyroidism, chronic gastritis, arthritis, and epilepsy (each n=1). Five patients reported use of ≥1 concomitant medication (including immunosuppressants and corticosteroids) during the EAP; 1 patient had discontinued ustekinumab (biologic). Three patients had signs of plaque psoriasis within the past year and had received treatment for plaque psoriasis; 1 patient had ongoing plaque psoriasis. In total, 4 patients had any AEs (all 4 patients had mild AEs [influenza, catarrh, pruritis, rash, pain] and 1 of these patients also had a moderate AE [headache]). Two drug-related AEs (pruritus and rash) were reported in 1 patient. The hypersensitivity event (rash) was non-serious. There were no reports of SAEs, AESIs, or AEs that led to discontinuation/death. Conclusion: Spesolimab showed a favorable safety profile in patients with GPP, including patients with comorbidities and those taking concomitant medication. Findings were comparable with a Phase 2a randomized controlled trial in patients with GPP flares (EFFISAYIL 1).

Abstract Disclosure: M. Rojo: None. A.L. Millán: None. H. Pérez: None. C.M. Pautasso: None. P.N. Maidana: None. M.G. Emily: None. G.E. Cerrone: None. G.D. Frechtel: None. Polycystic ovary syndrome (PCOS) is characterized by the presence of obesity and/or metabolic syndrome that can influence mitochondrial DNA content. Objective: To evaluate the mitochondrial DNA mass in women with PCOS in comparison with control women and its relationship with metabolic parameters and absolute telomeric length (aTL). Materials and methods: We studied 81 women with PCOS and 57 control women aged 16 to 46 years. The copy number of mitochondrial DNA (mtDNA) was determinated in peripheral blood leukocytes by quantitative PCR in real time, SYBR Green method. The relationship between mtDNA copy number and copy number of the single copy β2 microglobulin gene was measured. Anthropometric, metabolic and hormonal variables (PCOS) were studied to carry out linear regression between the ADNmt content and the distinct comparative form variables between the distinct groups. Statistical analysis was carried out in SPSS version 25 with a significance level of 0.05. Results: Compared to controls, PCOS patients have higher body mass index (BMI), waist circumference (WC), levels of TG, LDL-c, total cholesterol, fasting plasma glucose, and lower levels of HDL-c. We observed that mitochondrial DNA mass was significantly lower in the presence of PCOS (216,40±140,9 vs 164.59 ± 102.07; p = 0.020). When corrected for age, this result is still significant. PCOS women were classified as metabolically healthy PCOS (PCOS-MH) and PCOS with metabolic syndrome (PCOS-SM). We observed a progressive decrease in mtDNA content between control, PCOS-MH, and PCOS-SM (215,42±143,39; 179,64±106,12; 149,69±93,13), with statistical significance between control and PCOS-SM (p=0,044), maintained after age correction (p=0,023). By linear regression we found association of mtDNA mass with BMI (p=0,013) and WC (p=0,030). An association tendency was observed between lower mitochondrial DNA mass and higher HOMA index (p=0,086), also, with longer aTL (p = 0.088). Conclusion PCOS-MH was defined as an intermediate phenotype between controls and PCO-SM, when mass mtDNA mass, aTL and metabolic variables were studied, reflecting the oxidative stress associated with PCOS that could cause damage mtDNA, proteins and lipids. Presentation: Saturday, June 17, 2023

Click to increase image sizeClick to decrease image size Disclosure statementNo potential conflict of interest was reported by the author(s).Additional informationFundingThe author(s) reported that there is no funding associated with the work featured in this article.

Hyperglycemia is associated with an increased risk of cardiovascular disease, and the consequences of intensive therapy may depend on the mechanism of the anti-diabetic agent(s) used to achieve a tight control. In animal models, stable analogues of glucagon-like peptide-1 (GLP-1) were able to reduce body weight and blood pressure and also had favorable effects on ischemia following coronary reperfusion. In a similar way, dipeptidyl peptidase IV (DPP-IV) showed to have favorable effects in animal models of ischemia/reperfusion. This could be due to the fact that DPP-IV inhibitors were able to prevent the breakdown of GLP-1 and glucose-dependent insulinotropic polypeptide, but they also decreased the degradation of several vasoactive peptides. Preclinical data for GLP-1, its derivatives and inhibitors of the DPP-IV enzyme degradation suggests that these agents may be able to, besides controlling glycaemia, induce cardio-protective and vasodilator effects. Notwithstanding the many favorable cardiovascular effects of GLP-1/incretins reported in different studies, many questions remain unanswered due the limited number of studies in human beings that aim to examine the effects of GLP-1 on cardiovascular endpoints. For this reason, long-term trials searching for positive cardiovascular effects are now in process, such as the CAROLINA and CARMELINA trials, which are supported by small pilot studies performed in humans (and many more animal studies) with incretin-based therapies. On the other hand, selective renal sodium-glucose co-transporter 2 inhibitors were also evaluated in the prevention of cardiovascular outcomes in type 2 diabetes. However, it is quite early to draw conclusions, since data on cardiovascular outcomes and cardiovascular death are limited and long-term studies are still ongoing. In this review, we will analyze the mechanisms underlying the cardiovascular effects of incretins and, at the same time, we will present a critical position about the real value of these compounds in the cardiovascular system and its protection.

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