We assessed post-marketing safety of sodium-glucose co-transporter-2 inhibitors (SGLT2-Is) by analyzing adverse events (AEs) reported in international pharmacovigilance databases.
Eudravigilance, ...WHO-Vigibase (as of Feb 25, 2017) and the FDA Adverse Event Reporting System (FAERS, from 2004 to 2016 second quarter) were queried to extract AEs recording SGLT2-Is as suspect. Disproportionality analyses (case/non-case method) were performed in FAERS by calculating the reporting odds ratios (RORs) from System Organ Classes (SOCs) to Preferred Terms (PTs) (precise clinical entities). Potential signals were defined by statistically-significant ROR (lower limit of the 95% confidence interval – LL95%CI – >1) undetected by literature analysis (as of December 2016).
SGLT2-Is were recorded in 7972, 19,775, 11,137 reports (Eudravigilance, WHO-Vigibase and FAERS, respectively); in FAERS, statistically significant ROR emerged for the following SOCs: “infections and infestations” (N = 2162; LL95%CI = 3.25), “metabolism and nutrition disorders” (2278; 1.36), “renal and urinary disorders” (1665; 2.31), “reproductive system and breast disorders” (471; 4.85), “skin and subcutaneous tissue disorders” (1136; 1.52). Skin toxicity emerged as potential signal (e.g., rash, photosensitivity, urticaria as PTs), both for SGLT2-Is as a class and as individual drugs. Severe adverse skin events (81 reports, 7% of the skin cases) mainly occurred in females aged 18–65 using SGLT2-Is as single antidiabetic regimen.
Among antidiabetics, SGLT2-Is are associated with higher reporting of infections, metabolism, renal and reproductive AEs, corroborating clinical trial evidence. Their large reporting patterns and the unexpected signal of skin toxicity justify active vigilance by clinicians and “real-time” monitoring by pharmacovigilance experts.
•Multi-database pharmacovigilance analysis was performed to assess post-marketing safety of SGLT2-Is.•The majority of adverse events were predictable from pre-approval clinical evidence.•The unexpected signal of skin toxicity warrants active monitoring in the real-world.•Large analytical safety studies are needed for risk quantification.
Background
Anti‐nuclear antibodies (ANA), anti‐extractable nuclear antigens (ENA) and anti‐dsDNA antibodies are often associated with cutaneous lupus erythematosus (CLE), with variable frequency ...depending on skin subtype. However, specific data based on large case‐series on the pathogenetic, diagnostic and prognostic meaning of such autoantibodies are still lacking.
Objective
To characterize the correlations between CLE subtypes as well as LE‐non‐specific skin lesions and their autoantibody pattern.
Methods
Epidemiological, clinical and immunopathological data of 619 Italian patients with CLE and LE‐non‐specific skin lesions were analysed. Differences in age, sex, clinical features and autoantibody profile were evaluated in each LE subgroup.
Results
Anti‐nuclear antibodies (P < 0.0001), anti‐dsDNA (P < 0.0001), ENA (P = 0.001), anti‐Sm (P = 0.001), anti‐RNP (P = 0.004) and anti‐histone (P = 0.005) antibodies were associated with SLE. A strong association between ANA (P < 0.0001) and anti‐dsDNA (P < 0.0001) and female gender was also found: positive ANA and positive anti‐dsDNA had a higher prevalence among females. Chronic CLE resulted to be negatively associated with ENA (OR = 0.51, P < 0.0001), anti‐Ro/SSA (OR = 0.49, P < 0.0001) and anti‐dsDNA (OR = 0.37, P < 0.0001). Intermittent CLE resulted to be negatively associated with ENA (OR = 0.50, P = 0.007) and ANA (OR = 0.61, P = 0.025). Subacute CLE resulted to be associated with ENA (OR = 5.19, P < 0.0001), anti‐Ro/SSA (OR = 3.83, P < 0.0001), anti‐Smith (OR = 2.95, P = 0.004) and anti‐RNP (OR = 3.18, P = 0.007). Acute CLE resulted to be strongly associated with anti‐dsDNA (OR = 6.0, P < 0.0001) and ANA (OR = 18.1, P < 0.0001). LE‐non‐specific skin lesions resulted to be significantly associated with systemic involvement. Livedo reticularis was significantly associated with ENA (P = 0.007) and anti‐Ro/SSA (P = 0.036). Palpable purpura and periungual telangiectasia were significantly associated with ANA.
Conclusion
According to our findings, some well‐known associations between CLE subtypes and autoantibody profile were confirmed; moreover, specific association between autoantibodies and LE‐non‐specific skin lesions was highlighted. A strict association between anti‐ENA and anti‐Ro/SSA antibodies and livedo reticularis, ANA and palpable purpura, and ANA and periungual telangiectasia was evidenced.
Summary
Chloracne, also known as metabolizing acquired dioxin‐induced skin hamartomas (MADISH), is a rare disfiguring disease related to dioxin exposure. There is a paucity of literature on the ...clinical manifestations and pathogenesis of chloracne/MADISH. The aim of this study was to assess the clinical features of this very unusual acneiform eruption and to explore the pathogenesis of the disease. This was a retrospective, observational report study was conducted on five patients belonging to the same nuclear family (father, mother and three children) and a relative (father’s brother) living in the same house. Histopathological, immunohistochemical, laboratory and toxicological analyses were performed for all patients. The results suggest that CYP1A1 in human skin is a diagnostic biomarker in chloracne, and was positive for all the patients in our sample. Tetrachlorodibenzo‐p‐dioxin is the most investigated dioxin responsible for chloracne; however, several other agonists, whether dioxin‐like or not, can activate the aryl hydrocarbon receptor. To our knowledge, this Italian case series is the first study to suggest polychlorinated biphenyls as a possible cause of an overstimulation of aryl hydrocarbons causing the consequent acneiform eruption.
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