Hidradenitis suppurativa (HS) is a debilitating chronic inflammatory skin disease characterized by chronic abscess formation and development of multiple draining sinus tracts in the groin, axillae, and perineum. Using proteomic and transcriptomic approaches, we characterized the inflammatory responses in HS in depth, revealing immune responses centered on IFN-γ, IL-36, and TNF, with lesser contribution from IL-17A. We further identified B cells and plasma cells, with associated increases in immunoglobulin production and complement activation, as pivotal players in HS pathogenesis, with Bruton’s tyrosine kinase (BTK) and spleen tyrosine kinase (SYK) pathway activation as a central signal transduction network in HS. These data provide preclinical evidence to accelerate the path toward clinical trials targeting BTK and SYK signaling in moderate-to-severe HS.

ImportanceCrohn disease, a chronic gastrointestinal inflammatory disease, is increasing in incidence and prevalence in many parts of the world. Uncontrolled inflammation leads to long-term complications, including fibrotic strictures, enteric fistulae, and intestinal neoplasia. Therefore, early and effective control of inflammation is of critical importance.ObservationsThe optimal management approach for Crohn disease incorporates patient risk stratification, patient preference, and clinical factors in therapeutic decision-making. First-line therapy generally consists of steroids for rapid palliation of symptoms during initiation of anti–tumor necrosis factor α therapy. Other treatments may include monoclonal antibodies to IL-12/23 or integrin α4β7, immunomodulators, combination therapies, or surgery. Effective control of inflammation reduces the risk of penetrating complications (such as intra-abdominal abscesses and fistulae), although more than half of patients will develop complications that require surgery. Adverse reactions to therapy include antibody formation and infusion reactions, infections, and cancers associated with immune modulators and biologics and toxicity to the bone marrow and the liver. Both Crohn disease and corticosteroid use are associated with osteoporosis. Vaccinations to prevent infections, such as influenza, pneumonia, and herpes zoster, are important components of health maintenance for patients with Crohn disease, although live vaccines are contraindicated for patients receiving immune suppression therapy.Conclusions and RelevanceThe treatment of patients with Crohn disease depends on disease severity, patient risk stratification, patient preference, and clinical factors, including age of onset and penetrating complications, and includes treatment with steroids, monoclonal antibody therapies, immunomodulators, and surgery. Physicians should be familiar with the advantages and disadvantages of each therapy to best counsel their patients.

Baseline depression is associated with a higher risk for aggressive IBD at follow-up. A single question is not a sensitive method of assessing depression. Providers should consider administering the PHQ-8 to capture those at greater risk for aggressive disease.

Background:The older patient group with inflammatory bowel diseases (IBD) is particularly vulnerable to consequences of disease and therapy-related side effects but little is known about the best treatment options in this population. Aim:To compare safety and efficacy of tumor necrosis factor α antagonist (anti-TNF) or vedolizumab (VDZ) in patients with IBD >60 years of age.Methods: This retrospective study included patients with Crohn's disease (CD) or ulcerative colitis (UC) initiating anti-TNF or VDZ therapy ≥60 years of age at three study sites. We examined occurrence of infection or malignancy within 1 year after therapy as our primary outcome. Our efficacy outcomes included clinical remission at 3, 6 and 12 months. Multivariable logistic regression models adjusting for relevant confounders estimated odds ratios (OR) and 95% confidence intervals. Results:The study included 131 anti-TNF and 103 VDZ initiated patients (age range 60-88 years). Approximately half had CD. At 1 year, there were no significant differences in safety profile between the two therapeutic classes. Infections were observed in 20% of anti-TNF-treated and 17% of VDZ-treated patients (P = 0.54).Pneumonia was the most common infection in both groups. While more anti-TNFtreated CD patients were in remission at 3 months compared to VDZ (OR 2.82, 95% CI 1.18-6.76), this difference was not maintained at 6 and 12 months suggesting similar efficacy of both classes. Conclusions:Both anti-TNF and VDZ therapy were similarly effective and safe in elderly IBD patients.

We investigated proteinase-activated receptor-2 (PAR 2 )-triggered signal transduction pathways causing increased prostaglandin E 2 (PGE 2 ) formation in human lung-derived A549 epithelial cells. The PAR 2 agonist, SLIGRL-NH 2 (Ser-Leu-Ile-Gly-Arg-Leu-amide), evoked immediate cytosolic Ca 2ϩ mobilization and delayed (0.5-3 h) PGE 2 formation. The PAR 2 -triggered PGE 2 formation was attenuated by inhibition of the following signal pathway enzymes: cyclooxygenases 1 and 2 (COX-1 and COX-2, respectively), cytosolic Ca 2ϩ -dependent phospholipase A 2 (cPLA 2 ), the mitogenactivated protein kinases (MAPKs), mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEK)-extracellular signal-regulated kinase (ERK) and p38 MAPK, Src family tyrosine kinase, epidermal growth factor (EGF) receptor tyrosine kinase (EGFRK), and protein kinase C (PKC), but not by inhibition of matrix metalloproteinases. SLIGRL-NH 2 caused prompt (5 min) and transient ERK phosphorylation, blocked in part by inhibitors of PKC and tyrosine kinases but not by an EGFRK inhibitor. SLIGRL-NH 2 also evoked a relatively delayed (15 min) and persistent (30 min) phosphorylation of p38 MAPK, blocked by inhibitors of Src and EGFRK but not by inhibitors of COX-1 or COX-2. SLIGRL-NH 2 elicited a Src inhibitor-blocked prompt (5 min) and transient phosphorylation of the EGFRK. SLIGRL-NH 2 up-regulated COX-2 protein and/or mRNA levels that were blocked by inhibition of p38 MAPK, EGFRK, Src, and COX-2 but not MEK-ERK. SLIGRL-NH 2 also caused COX-1-dependent up-regulation of microsomal PGE synthase-1 (mPGES-1). We conclude that PAR 2 -triggered PGE 2 formation in A549 cells involves a coordinated up-regulation of COX-2 and mPGES-1 involving cPLA 2 , increased cytosolic Ca 2ϩ , PKC, Src, MEK-ERK, p38 MAPK, Src-mediated EGF receptor trans-activation, and also metabolic products of both COX-1 and COX-2.Proteinase-activated receptors (PARs), a family of G protein-coupled seven-trans-membrane domain receptors, consisting of PARs 1 to 4, are now known to mediate a variety of intracellular signaling and subsequent cellular events caused by specific extracellular proteinases (Hollenberg

Distribution and function of the cannabinoid-1 receptor in the modulation of ion transport in the guinea pig ileum: relationship to capsaicin-sensitive nerves. Am J Physiol Gastrointest Liver Physiol 286: G863-G871, 2004. First published December 30, 2003 10.1152/ ajpgi.00482.2003.-We investigated the distribution and function of cannabinoid (CB)1 receptors in the submucosal plexus of the guinea pig ileum. CB 1 receptors were found on both types of submucosal secretomotor neurons, colocalizing with VIP and neuropeptide Y (NPY), the noncholinergic and cholinergic secretomotor neurons, respectively. CB1 receptors colocalized with transient receptor potential vanilloid-1 receptors on paravascular nerves and fibers in the submucosal plexus. In the submucosal ganglia, these nerves were preferentially localized at the periphery of the ganglia. In denervated ileal segments, CB1 receptor immunoreactivity in submucosal neurons was not modified, but paravascular and intraganglionic fiber staining was absent. Short-circuit current (I sc) was measured as an indicator of net electrogenic ion transport in Ussing chambers. In the ion-transport studies, I sc responses to capsaicin, which activates extrinsic primary afferents, and to electrical field stimulation (EFS) were reduced by pretreatment with the muscarinic antagonist atropine, abolished by tetrodotoxin, but were unaffected by VIP receptor desensitization, hexamethonium, ␣-amino-3-hydroxy-5-methlisoxazole-4-proprionic acid, or N-methyl-D-aspartate glutamate receptor antagonists. The responses to capsaicin and EFS were reduced by 47 Ϯ 12 and 30 Ϯ 14%, respectively, by the CB1 receptor agonist WIN 55,212-2. This inhibitory effect was blocked by the CB 1 receptor antagonist, SR 141716A. I sc responses to forskolin or carbachol, which act directly on the epithelium, were not affected by WIN 55,212-2. The inhibitory effect of WIN 55,212-2 on EFS-evoked secretion was not observed in extrinsically denervated segments of ileum. Taken together, these data show cannabinoids act at CB1 receptors on extrinsic primary afferent nerves, inhibiting the release of transmitters that act on cholinergic secretomotor pathways. submucosal plexus; vasoactive intestinal peptide; neuropeptide Y; transient receptor potential vanilloid-1 receptor THE ENTERIC NERVOUS SYSTEM exerts tight control over electrolyte and water transport by the intestinal epithelium (5, 7). Specifically, submucosal secretomotor neurons release vasoactive intestinal polypeptide and acetylcholine to activate cAMP-or Ca 2ϩ -dependent pathways, respectively, which control the gating of chloride transport through apically situated chloride transporters in enterocytes. The apically directed transport of chloride occurs predominantly via the cystic fibrosis transmembrane conductance regulator or a member of the calciumdependent chloride channel family (4). Whereas the intrinsic properties of these transporters have been, and continue to be, the subject of numerous studies, less well documented are the inputs that control the a...

The role of nitric oxide (NO) derived from the inducible isoform of NO synthase (iNOS) in epithelial transport dysfunction was studied in a model of colitis induced in mice by intrarectal 2,4,6-trinitrobenzenesulfonic acid in 30% ethanol. Expression of iNOS mRNA was determined by RT-PCR. Electrolyte transport studies were conducted in Ussing chambers in which segments of inflamed colon were incubated with or without the selective iNOS inhibitorl- N 6-(1-iminoethyl)lysine (l-NIL). Seven days after the induction of colitis, colonic tissue exhibited increased myeloperoxidase activity compared with saline controls. There was a detectable basal expression of iNOS mRNA, but expression was increased 3.7-fold in inflamed colons. Inflammation also caused an increase in iNOS activity and a concomitant decrease in constitutive NOS activity. In Ussing chamber experiments, there was a decreased response to electrical field stimulation in inflamed tissue, which was partially reversed by pretreatment of the tissue withl-NIL. The short-circuit current response to the muscarinic agonist carbachol was also reduced in inflammation, but this was not reversed byl-NIL. In summary, NO derived from iNOS mediates, in part, inflammation-induced suppression of neurally evoked electrolyte transport.

Left ventricular assist devices (LVADs) are an increasingly prevalent form of mechanical support for patients with end-stage heart failure. These devices can be implanted both as a bridge to transplant or definitive/destination therapy. Gastrointestinal (GI) bleeding is one of the most common and recalcitrant long-term complications following LVAD implantation, with an incidence approaching 30%. The pathophysiology of bleeding is multifactorial, with hemodynamic alterations, acquired von Willebrand factor deficiency, and coagulopathy being most often implicated. The majority of bleeding events in this population result from angioectasias and gastro-duodenal erosive disease. While these bleeding events are significant and often require transfusion therapy, they are rarely life threatening. Endoscopy remains the standard of care with upper endoscopy offering the highest diagnostic yield in these patients. However, the effectiveness of endoscopic hemostasis in this population is not well established. A small number of studies have evaluated medical therapy and alterations in LVAD settings as a means of preventing or treating bleeding with variable results. In summary, GI bleeding with LVADs is a common occurrence and will continue to be as more LVADs are being performed for destination therapy. This review will discuss what is known about the pathophysiology of GI bleeding in LVADs and the currently available options for medical and/or endoscopic management.