Tiago Torres

The Protective Role of HLA-DRB1∗13 in Autoimmune Diseases

Autoimmune diseases (AIDs) are characterized by a multifactorial aetiology and a complex genetic background, with the MHC region playing a major role. We genotyped for HLA-DRB1 locus 1228 patients with AIDs-213 with Systemic Lupus Erythematosus (SLE), 166 with Psoriasis or Psoriatic Arthritis (Ps + PsA), 153 with Rheumatoid Arthritis (RA), 67 with Systemic Sclerosis (SSc), 536 with Multiple Sclerosis (MS), and 93 with Myasthenia Gravis (MG) and 282 unrelated controls. We confirmed previously established associations of HLA-DRB1∗15 (OR = 2.17) and HLA-DRB1∗03 (OR = 1.81) alleles with MS, HLA-DRB1∗03 with SLE (OR = 2.49), HLA-DRB1∗01 (OR = 1.79) and HLA-DRB1∗04 (OR = 2.81) with RA, HLA-DRB1∗07 with Ps + PsA (OR = 1.79), HLA-DRB1∗01 (OR = 2.28) and HLA-DRB1∗08 (OR = 3.01) with SSc, and HLA-DRB1∗03 with MG (OR = 2.98). We further observed a consistent negative association of HLA-DRB1∗13 allele with SLE, Ps + PsA, RA, and SSc (18.3%, 19.3%, 16.3%, and 11.9%, resp., versus 29.8% in controls). HLA-DRB1∗13 frequency in the AIDs group was 20.0% (OR = 0.58). Although different alleles were associated with particular AIDs, the same allele, HLA-DRB1∗13, was underrepresented in all of the six diseases analysed. This observation suggests that this allele may confer protection for AIDs, particularly for systemic and rheumatic disease. The protective effect of HLA-DRB1∗13 could be explained by a more proficient antigen presentation by these molecules, favouring efficient clonal deletion during thymic selection.

Toxicity screening of diclofenac, propranolol, sertraline and simvastatin using Danio rerio and Paracentrotus lividus embryo bioassays.

Early life-stage bioassays have been used as an alternative to short-term adult toxicity tests since they are cost-effective. A single couple can produce hundreds or thousands of embryos and hence can be used as a simple high-throughput approach in toxicity studies. In the present study, zebrafish and sea urchin embryo bioassays were used to test the toxicity of four pharmaceuticals belonging to different therapeutic classes: diclofenac, propranolol, simvastatin and sertraline. Simvastatin was the most toxic tested compound for zebrafish embryo, followed by diclofenac. Sertraline was the most toxic drug to sea urchin embryos, inducing development abnormalities at the ng/L range. Overall, our results highlight the potential of sea urchin embryo bioassay as a promising and sensitive approach for the high-throughput methods to test the toxicity of new chemicals, including pharmaceuticals, and identify several drugs that should go through more detailed toxicity assays.

Safety of Anti-TNF Therapies in Immune-Mediated Inflammatory Diseases: Focus on Infections and Malignancy.

Preclinical Research

A revolutionary therapeutic approach for psoriasis: bispecific biological agents.

Psoriasis is a chronic inflammatory skin disorder affecting 2.5% of the population worldwide.Its pathogenic mechanism involves tissue cells, in particular keratinocytes, and a wide array of immune ...

Effects of Tributyltin and Other Retinoid Receptor Agonists in Reproductive-Related Endpoints in the Zebrafish (Danio rerio).

Both field and experimental data examined the influence of exposure to environmental contaminant tributyltin (TBT) on marine organisms. Although most attention focused on the imposex phenomenon in gastropods, adverse effects were also observed in other taxonomic groups. It has been shown that imposex induction involves modulation of retinoid signaling in gastropods. Whether TBT influences similar pathways in fish is yet to be addressed. In this study, larvae of the model teleost Danio rerio were exposed to natural retinoids, all-trans-retinoic acid, 9-cis-retinoic acid, and all-trans-retinol, as well as to the RXR synthetic pan-agonist methoprene acid (MA) and to TBT. Larvae were exposed to TBT from 5 days post fertilization (dpf) to adulthood, and reproductive capacity was assessed and correlated with mode of action. TBT significantly decreased fecundity at environmentally relevant levels at 1 μg TBT Sn/g in diet. Interestingly, in contrast to previous reports, TBT altered zebrafish sex ratio toward females, whereas MA exposure biased sex toward males. Since fecundity was significantly altered in the TBT-exposed group with up to 62% decrease, the potentially affected pathways were investigated. Significant downregulation was observed in brain mRNA levels of aromatase b (CYP19a1b) in females and peroxisome proliferator activated receptor gamma (PPARg) in both males and females, suggesting an involvement of these pathways in reproductive impairment associated with TBT.

Epicardial adipose tissue and coronary artery calcification in psoriasis patients.

Psoriasis is a chronic, immune‐mediated disease associated with several cardio‐metabolic comorbidities, accelerated atherosclerosis and cardiovascular disease (CVD). Other causes beyond systemic inflammation and traditional cardiovascular risk factors (CVRF) may be implicated in the increased risk of CVD observed in these patients. Epicardial adipose tissue (EAT), a type of visceral adipose tissue surrounding the heart and coronary vessels has been implicated in the development of coronary artery disease, by endocrine mechanisms, but particularly by local inflammation.

No meaningful association between suicidal behavior and the use of IL-17A-neutralizing or IL-17RA-blocking agents

ABSTRACT Introduction: An emerging class of agents blocking IL-17 signaling represents a very promising therapeutic approach. One of these agents, brodalumab, has been associated with an increased risk of suicide behavior. Areas covered: This review sought to provide an overview strictly focused on suicide behavior signals related to the use of IL-17 agents. Data collection regarding this peculiar safety aspect was primarily based on: (i) a revision of safety outcomes belonging to phase II and phase III trials; (ii) a systematic search using the Pubmed Medline database; and (iii) collecting recent data issued as posters or communications in eminent international meetings. Expert opinion: Whilst secukinumab and ixekizumab were not associated with increased signal of suicidal behavior, being recently approved for the treatment of psoriasis by EMA and FDA, brodalumab raised concern because of suicide behavior cases that led to pause momentarily its development program during pre-marketing stage before obtaining the positive recommendation by an FDA advisory panel for its approval. Indeed, a careful re-evaluation of brodalumab safety profile is being performed and no evidence clarified a significant association or a pathogenic mechanism linking brodalumab treatment to the risk of suicidal behavior, suggesting that cases of suicidal behavior accidentally occurred during brodalumab trials.

Cardiovascular comorbidities in childhood psoriasis

BackgroundPsoriasis is a common, chronic, systemic inflammatory skin disease associated with numerous cardiovascular comorbidities. Much evidence of this association exists in the adult population, data available in childhood psoriasis is more limited.ObjectivesTo analyze the prevalence of excess adiposity, cardiovascular risk factors, metabolic syndrome and lipid profile in children with psoriasis comparing to control group with similar age and sex distribution.Materials & methodsA case-control study was conducted with children, 5–15 year-sold, with moderate-to-severe plaque-type psoriasis and a control group comprising children with other skin diseases without systemic inflammatory diseases.ResultsPsoriatic children had a significantly higher prevalence and greater odds of excess adiposity compared to controls: BMI (≥85th percentile; OR 4.4; 95%CI 1.2–15.6), waist circumference (>75th percentile; OR 7.4; 95%CI 2.0–27.7) and waist-to-height ratio (>0.490; OR 4.6; 95%CI 1.3–17.0). A higher prevalence of metabolic syndrome was observed in children with psoriasis compared to controls (25% vs 3.7%;P=0.07), and two components of the metabolic syndrome were significantly higher in the psoriasis group: waist circumference (75% vs 29.6%; P = 0.002) and the high blood pressure component (30% vs 3.7%P=0.032). Finally, an altered and more atherogenic lipid profile was observed among psoriatic patients without excess adiposity.ConclusionThis study demonstrates that comorbidities known to be associated with adult psoriasis are also observed in childhood psoriasis, reinforcing the need for screening cardiovascular comorbidities in children with psoriasis and promoting healthy lifestyle choices in these patients. Moreover, it also suggests that its association with psoriasis may be in part genetically determined rather than uniquely acquired.

Framingham Risk Score underestimates cardiovascular disease risk in severe psoriatic patients: implications in cardiovascular risk factors management and primary prevention of cardiovascular disease.

Severe psoriasis has been associated with increase cardiovascular mortality, due to a higher prevalence of traditional cardiovascular risk factors and premature atherosclerosis, as a consequence of its systemic inflammation. Recently, it has been estimated that severe psoriasis may confer an increased 6.2% on long‐term risk of cardiovascular disease based on Framingham Risk Score, which can have practical implications in the treatment of cardiovascular risk factors and primary prevention of cardiovascular disease, as treatment guidelines account for the risk of cardiovascular disease in treatment goals. The aim of this study was to analyze the influence of the attributable risk of severe psoriasis on long‐term risk of cardiovascular disease and its implication on the correct treatment of cardiovascular risk factors and primary prevention of cardiovascular disease on a real‐world cohort of patients. One hundred severe psoriasis patients without psoriatic arthritis or previous cardiovascular disease were evaluated and it was found that more than half of the patients were reclassified to a higher cardiovascular risk category with important clinical implications on the correct management of their cardiovascular risk factors and primary prevention of cardiovascular disease, as a considerable proportion of patients with hypertension, hypercholesterolemia and coronary heart disease equivalent risk were not being correctly managed.

Maintenance treatment of psoriasis with cyclosporine A: Comparison between continuous and weekend therapy

coding, chart reviews to ensure proper documentation, problem-based learning sessions, conferences with the billing department, and active daily feedback on resident coding and documentation by attendings during clinics. Although teaching and learning these topics requires time and effort, improper coding and billing can lead to the downfall of a practice. Brief and repeated didactic sessions early in residency will likely leave a long-term impact by creating a foundation to build upon postresidency. More importantly, making sure residents understand documentation, coding, and billing will ensure that academic dermatology practices can be sustained.