Cutaneous manifestations of inflammatory bowel disease: basic characteristics, therapy, and potential pathophysiological associations.

Inflammatory bowel disease (IBD) is a chronic inflammatory disease typically involving the gastrointestinal tract but not limited to it. IBD can be subdivided into Crohn's disease (CD) and ulcerative colitis (UC). Extraintestinal manifestations (EIMs) are observed in up to 47% of patients with IBD, with the most frequent reports of cutaneous manifestations. Among these, pyoderma gangrenosum (PG) and erythema nodosum (EN) are the two most common skin manifestations in IBD, and both are immune-related inflammatory skin diseases. The presence of cutaneous EIMs may either be concordant with intestinal disease activity or have an independent course. Despite some progress in research on EIMs, for instance, ectopic expression of gut-specific mucosal address cell adhesion molecule-1 (MAdCAM-1) and chemokine CCL25 on the vascular endothelium of the portal tract have been demonstrated in IBD-related primary sclerosing cholangitis (PSC), little is understood about the potential pathophysiological associations between IBD and cutaneous EIMs. Whether cutaneous EIMs are inflammatory events with a commonly shared genetic background or environmental risk factors with IBD but independent of IBD or are the result of an extraintestinal extension of intestinal inflammation, remains unclear. The review aims to provide an overview of the two most representative cutaneous manifestations of IBD, describe IBD's epidemiology, clinical characteristics, and histology, and discuss the immunopathophysiology and existing treatment strategies with biologic agents, with a focus on the potential pathophysiological associations between IBD and cutaneous EIMs.

Influence of Fibrinogen/Albumin Ratio and Fibrinogen/Pre-Albumin Ratio on Cardiac Autonomic Neuropathy in Type 2 Diabetes.

Purpose: Subclinical inflammation may be involved in the pathogenesis of diabetic cardiac autonomic neuropathy (DCAN). The purpose of the study is to explore the relationship between novel inflammation biomarkers fibrinogen-albumin ratio (FAR), fibrinogen-prealbumin ratio (FPR), and DCAN in type 2 diabetes mellitus (T2DM). Patients and Methods: A total of 715 T2DM patients were enrolled in this retrospective study, divided into non-DCAN (n=565) and DCAN (n=150) groups by Ewing's test. Serum fibrinogen, albumin, prealbumin, routine inflammatory and other biochemical markers were measured. Results: Patients with versus without DCAN had higher FAR (10.29 ± 4.83 vs 7.22 ± 2.56 g/g, P < 0.001) and FPR (2.19 ± 1.85 vs 1.43 ± 0.93 g/mg, P < 0.001). As FAR and FPR quartiles increased, the incidence of DCAN increased (Quartile 1 vs Quartile 4: 8.4 vs 42.7%, 9.6 vs 39.2%, respectively, P < 0.001), heart rate variability parameters decreased (P < 0.001); the incidence of diabetic nephropathy, retinopathy and peripheral neuropathy tended to be higher and inflammation factors were more active (P < 0.01). FAR (OR, 95% CI: 1.16, 1.08-1.25, P < 0.001) and FPR (OR, 95% CI: 1.22, 1.03-1.44, P = 0.021) were independent determinants of DCAN; the risk of DCAN increased by approximately 65% and 27% with each increase in the standard deviation (SD) of FAR (OR per SD, 95% CI: 1.65, 1.29-2.11, P < 0.001) and FPR (OR per SD, 95% CI: 1.27, 1.04-1.56, P = 0.021). Conclusion: FAR and FPR are independent risk factors and may influence DCAN development through inflammation.

Lower Limb Arterial Ischemia: An Independent Risk Factor of Sudomotor Dysfunction in Type 2 Diabetes.

Background: As an early manifestation of diabetic peripheral neuropathy (DPN), sudomotor dysfunction significantly increases the risk of diabetic foot ulcer. The pathogenesis of sudomotor dysfunction is still unclear. Lower limb ischemia may be related to sudomotor dysfunction, but few studies have explored it. The purpose of this study is to explore the relationship between sudomotor function and comprehensive lower limb arterial ischemia including large arteries, small arteries and microvascular in type 2 diabetes mellitus (T2DM). Patients and Methods: 511 T2DM patients were enrolled in this cross-sectional study. Sudomotor function was assessed qualitatively and quantitatively by Neuropad. Lower limb arterial ischemia was defined as any abnormality of the ankle brachial index (ABI), toe brachial index (TBI) or transcutaneous oxygen tension (TcPO2). Results: In this study, 75.1% of patients had sudomotor dysfunction. Compared with normal sudomotor function, patients with sudomotor dysfunction had a higher incidence of lower limb arterial ischemia (51.2% vs 36.2%, p = 0.004). Similarly, compared with the non-arterial ischemia group, the proportion of sudomotor disorders was higher in the arterial ischemia group (p = 0.004). Low TBI and low TcPO2 groups also had a higher proportion of sudomotor disorders (all p < 0.05).Compare with normal groups, low ABI, low TBI, and low TcPO2 groups had lower Slop4 which quantitatively reflecting Neuropad discoloration. Arterial ischemia was an independent risk factor for sudomotor dysfunction [OR = 1.754, p = 0.024]. Low TcPO2 also independently increased the risk of sudomotor disorders [OR = 2.231, p = 0.026]. Conclusion: Lower limb arterial ischemia is an independent risk factor of sudomotor dysfunction. Especially below the ankle (BTA) small arteries and microvascular ischemia may also be involved in the occurrence of sudomotor disorders.

GLP-1 receptor agonist-associated tumor adverse events: A real-world study from 2004 to 2021 based on FAERS.

Background: GLP-1 receptor agonists (GLP-1RA) have demonstrated cardiovascular benefits, but the relationship between GLP-1RA and tumors is controversial. Recently, clinical trials reported higher rates of malignancy with semaglutide than control group. As real-world evidence of GLP-1RA-associated tumor risk is very limited, we explored the association of GLP-1RA and all types of neoplasms by mining the FDA Adverse Event Reporting System (FAERS) database. Methods: The FAERS data from the first quarter (Q1) of 2004 to the second quarter (Q2) of 2020 in the AERSMine were extracted to conduct disproportionality analysis, which was used by the proportional reporting ratio (PRR) to assess the relationship between GLP-1RA and all types of neoplasms. Then, the details of disproportionate GLP-1RA-associated tumor cases from Q1 2004 to Q2 2021 in the FAERS Public Dashboard were collected to analyze demographic characteristics. Results: A total of 8718 GLP-1RA-associated tumors were reported. Excluding cases with pre-existing tumors, other glucose-lowering drugs, and other GLP-1RA-related adverse events, diabetes cases with GLP-1RA as the main suspected drug were selected. GLP-1RA did not cause a disproportionate increase in all tumor cases (PRR 0.83) at the SOC level, and there was also no increase in most types of tumors associated with GLP-1RA at the HLGT/HLT levels. Significant signals were detected between GLP-1RA and certain tumors, including thyroid cancers [medullary thyroid cancer (PRR 27.43) and papillary thyroid cancer (PRR 8.68)], pancreatic neoplasms malignant (PRR 9.86), and islet cell neoplasms and APUDoma NEC (PRR 2.86). The combination of GLP-1RA with dipeptidyl-peptidase IV inhibitors (DPP4i) perhaps caused the increased reporting rate in some tumors. Conclusion: Our study provided new real-world evidence for oncology safety information of GLP-1RA. Given the wide use of GLP-1RA, clinicians should be well informed about important potential adverse events. Our pharmacovigilance analysis also prompted clinicians to raise concerns about potential tumor-related adverse effects when combining GLP-1RA with DPP4i.

Association of the gallbladder or biliary diseases with dipeptidyl peptidase 4 inhibitors in patients with type 2 diabetes: a meta-analysis of randomized controlled trials.

BACKGROUND: Previous studies have shown inconsistent conclusions regarding the association between incretin-based therapies and the risk of developing gallbladder or biliary diseases. We conducted a meta-analysis to evaluate the risk of gallbladder or biliary diseases associated with dipeptidyl peptidase 4 inhibitors (DPP4i) in patients with type 2 diabetes. METHODS: The PubMed, Embase, Cochrane Library, and ClinicalTrials.gov databases were searched (from inception up to March 14, 2022) for published randomized controlled trials (RCTs) that compared DPP4i with placebo or other glucose-lowering drugs in patients with type 2 diabetes. The outcomes of interest were cholecystitis, cholangitis, cholelithiasis, bile duct stones, and biliary colic. Relative risks (RRs) and 95% confidence intervals (CI) were pooled using a random-effects model. Subgroup analyses were performed according to patient age, trial duration, and types of DPP4i. RESULTS: In total, 97,150 participants from 75 eligible RCTs were included in the meta-analysis. DPP4i were associated with an increased risk of composite of gallbladder or biliary diseases (RR 1.20 [95% CI 1.01-1.42]) and cholecystitis (RR 1.38 [95% CI 1.08-1.75]). Among all included trials, DPP4i showed no association with the following manifestations of gallbladder or biliary diseases: cholelithiasis (RR 1.00 [95% CI 0.76-1.32]), cholangitis (RR 0.81 [95% CI 0.39-1.66]), bile duct stones (RR 1.08 [95% CI 0.57-2.05]), and biliary colic (RR 0.72 [95% CI 0.23-2.25]). Subgroup analyses showed that DPP4i were associated with a higher risk of cholecystitis in older patients (RR 1.37 [95% CI 1.03-1.83]) compared with younger patients (RR 1.08 [95% CI 0.89-2.18]) and in those with a longer duration of drug use (RR 1.43 [95% CI 1.08-1.89]) compared with shorter use (RR 1.23 [95% CI 0.74-2.03]). CONCLUSIONS: This systematic review and meta-analysis of RCTs found that the use of DPP4i was associated with an increased risk of cholecystitis, especially in patients of advanced age or in those who were exposed to the drugs for a long period of time.