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Objectives The purpose of this analysis was to assess the frequency of inadequate response (IR) over 1 year from advanced therapy (AT) initiation among ulcerative colitis (UC) patients in the United States using a claims-based algorithm. Baseline factors associated with IR to an AT were also analyzed. Methods This was a retrospective cohort study using claims data from the HealthCore Integrated Research Database (HIRD®). Adult patients with UC who initiated an AT (TNFi: adalimumab, golimumab, infliximab; non-TNFi: vedolizumab; other agent: tofacitinib) from 7/1/2016 to 8/31/2018 and had continuous enrollment ≥6 months before and ≥12 months after index date (date of first AT claim) were included. The index AT was defined as the first AT prescribed during the study time period. The claims-based algorithm used in this study to identify IR was originally developed and validated in rheumatoid arthritis1, and was modified for UC patients. Patients were identified as having IR to their index AT if during the 12 months after index date they had one or more of the following: low adherence (defined as proportion of days covered (PDC) Results A total of 1,692 UC patients were included in this analysis. Mean age was 42 years, 52% were male, 78% initiated a TNFi, and 22% initiated a non-TNFi as their index AT (Table 1). Over the 1-year follow-up period, 63% of UC patients had an IR to their AT: 42% of patients had low adherence, 24% switched/added a new AT, 18% added a new conventional therapy, 13% had a dose/frequency increase of their index AT, 14% had an addition/dose increase of oral glucocorticoids, 8% used a new pain medication, and 2% had surgery. Inadequate responders were more likely to be prescribed a TNFi (odds ratio (OR)=2.76; p

Objectives The purpose of this analysis was to assess the frequency of inadequate response (IR) over 1 year from biologic initiation among Crohn’s disease (CD) patients in the United States using a claims-based algorithm. Baseline factors associated with IR to a biologic were also analyzed. Methods This was a retrospective cohort study using claims data from the HealthCore Integrated Research Database. Adult patients with CD who initiated a biologic (TNFi: adalimumab, certolizumab, infliximab; non-TNFi: natalizumab, ustekinumab, and vedolizumab) from 7/1/2016 to 8/31/2018 and had continuous enrollment ≥6 months before and ≥12 months after index date (date of first biologic claim) were included. The index biologic was defined as the first biologic prescribed during the study time period. The claims-based algorithm used in this study to identify IR was originally developed and validated in rheumatoid arthritis and was modified for CD patients. Patients were identified as having IR to their index biologic if during the 12 months after index date they had one or more of the following: low adherence (defined as proportion of days covered (PDC) Results A total of 2,437 CD patients were included in this analysis. Mean age was 41 years, 53% were female, 81% initiated a TNFi, and 19% initiated a non-TNFi as their index biologic (Table 1). Over the 1-year follow-up period, 62% of CD patients had an IR to their biologic: 41% of patients had low adherence, 14% switched/added a new biologic, 13% added a new conventional therapy, 12% had a dose/frequency increase of their index biologic, 12% had an addition/dose increase of oral glucocorticoids, 8% used a new pain medication, and 5% had surgery. Inadequate responders were more likely to be female (odds ratio (OR)=1.36; p Conclusion Over 62% of CD patients had an inadequate response to their index biologic within 1 year after initiation, mostly driven by low adherence. This modified claims-based algorithm for CD appears useful to classify inadequate responders in health plan claims data. Additional research is needed to further validate this algorithm in a clinical setting.

Background & Aims: The duodenum is a cystic fibrosis transmembrane conductance regulator (CFTR)-expressing epithelium with high bicarbonate secretory capacity. We aimed to define the role of CFTR in human duodenal epithelial bicarbonate secretion in normal (NL) subjects and patients with cystic fibrosis (CF). Methods: Endoscopic biopsy specimens of the duodenal bulb were obtained from 9 CF patients and 16 volunteers. Tissues were mounted in modified Ussing chambers. Bicarbonate secretion and short-circuit current (Isc) were quantitated under basal conditions and in response to dibutyryl adenosine 3',5'-cyclic monophosphate (db-cAMP), carbachol, and the heat-stable toxin of Escherichia coli (STa). Duodenocytes were also isolated and loaded with the pH-sensitive fluoroprobe BCECF/AM, and intracellular pH (pH i ) was measured at rest and after intracellular acidification and alkalinization. Results: Basal HCO 3 − secretion and Isc were significantly lower in the CF vs. NL duodenal mucosa. In contrast to NL, db-cAMP failed to alter either HCO 3 − or Isc in CF tissues. However, in CF, carbachol resulted in an electroneutral HCO 3 − secretion, whereas STa induced electrogenic HCO 3 − secretion that was similar to NL. In CF and NL duodenocytes, basal pH i and recovery from an acid load were comparable, but pH i recovery after an alkaline load in CF duodenocytes was Cl − dependent, whereas in NL duodenocytes it was Cl − independent. Conclusions: These findings implicate CFTR in NL duodenal alkaline transport and its absence in CF. Although duodenal bicarbonate secretion is impaired in CF tissues, alternate pathway(s) likely exist that can be activated by carbachol and STa. GASTROENTEROLOGY 2000;118:1051-1060

Background & Aims: The gastroduodenal epithelium is protected from acid-peptic damage, in part, by its ability to secrete bicarbonate. Patients with duodenal ulcer disease have impaired proximal duodenal mucosal bicarbonate secretion. We have shown in vitro that histamine inhibits prostaglandin-stimulated bicarbonate secretion in rabbit duodenal mucosa via histamine H 2 receptors and enteric nerves. In this study we examined whether the proulcerogenic compounds aspirin or ethanol regulate duodenal bicarbonate secretion and the involvement of histamine. Methods: Bicarbonate secretion by rabbit proximal duodenal mucosa was examined in vitro in Ussing chambers. Results: Aspirin and ethanol decreased basal and prostaglandin-stimulated bicarbonate secretion; the latter effect was specific for prostaglandin. The inhibitory effects of the two ulcerogenic compounds were at least additive. Ranitidine and tetrodotoxin abolished the inhibitory effects on stimulated, but not basal, secretion. Aspirin and ethanol also induced release of duodenal histamine. Conclusions: Aspirin and ethanol act by two distinct pathways to impair duodenal bicarbonate secretion. Both agents inhibit basal secretion via a histamine-independent and neurally independent pathway while they inhibit prostaglandin E 2 –stimulated secretion via histamine release, likely from mast cells, and actions on enteric nerves. Our findings may be of relevance to the understanding and potential treatment of nonsteroidal anti-inflammatory drug–associated mucosal injury. GASTROENTEROLOGY 1998;114:527-535

BACKGROUND & AIMS: Eradication of Helicobacter pylori expedites duodenal ulcer healing and prevents recurrences. Most patients with duodenal ulcers have impaired proximal duodenal mucosal bicarbonate secretion (DMBS). In patients with inactive, healed duodenal ulcers and normal subjects, the effect of H. pylori infection on DMBS and proximal duodenal secretory function and structure were examined. METHODS: DMBS was quantitated before and after eradication of H. pylori. Mucosal structure (duodenal bulb histopathology) and function (DMBS at rest and stimulated, effect of active vs. healed ulcer and of age) were determined in patients with duodenal ulcers and normal subjects. RESULTS: In patients with duodenal ulcers, H. pylori eradication normalized proximal DMBS. Histological examination of duodenal biopsy samples was comparable in patients with duodenal ulcers and normal subjects without apparent relationship between inflammation and DMBS. Significantly impaired DMBS occurred in response to all agonists tested (luminal acid, prostaglandin E2, and cephalic-vagal stimulation) in patients with duodenal ulcers, suggesting a generalized secretory defect. Neither the presence of active (vs.inactive) ulcer nor age significantly affected bicarbonate secretion. CONCLUSIONS: In patients with duodenal ulcers, eradication of H. pylori normalized proximal DMBS and may thereby reduce ulcer recurrences. Altered DMBS in patients with duodenal ulcers was unrelated to histopathologic abnormalities. Impaired bicarbonate secretion in patients with duodenal ulcers could be caused by a cellular and/or physiological regulatory transport defect possibly related to H. pylori. (Gastroenterology 1996 Mar;110(3):705-16)

Background & Aims: Duodenal bicarbonate secretion is impaired in patients with duodenal ulcer. Before characterization of any cellular transport defect is possible, the origin of duodenal bicarbonate (epithelial cells and/or Brunner's glands) must be determined. The aim of this study was to determine the role of Brunner's glands in duodenal bicarbonate secretion. Methods: Rats, which have Brunner's glands only in the proximal duodenum, and rabbits, which have Brunner's glands throughout the duodenum, were anesthetized. Basal and stimulated (with HCl, prostaglandin E 2 , and vasoactive intestinal polypeptide [VIP]) bicarbonate secretion was measured in three isolated intestinal segments: proximal duodenum, distal duodenum, and proximal jejunum. Mucosal surface area and Brunner's gland thickness was quantitated in each segment. Results: Secretion rates in proximal and distal duodenum and proximal jejunum were significantly different. Normalized proximal-to-distal duodenal gradients in bicarbonate secretion were similar in the two species despite significantly different gradients of Brunner's gland thickness. In rabbits, gradients of bicarbonate secretion and Brunner's gland thickness were not correlated. In both species, HCl, prostaglandin E 2 , and VIP stimulated secretion in all three segments. If the agonists specifically stimulated Brunner's gland bicarbonate secretion, relationships between gradients of bicarbonate secretion and Brunner's gland thickness would have been anticipated. This was not observed. Conclusions: The higher rates of bicarbonate secretion in the proximal duodenum than in the distal duodenum and proximal jejunum are independent of Brunner's glands.

Background/Aims: Carbonic anhydrase activity plays a role in electrolyte transport in many tissues. This study examined the effect of the carbonic anhydrase inhibitor acetazolamide on human basal and prostaglandin E2- and acid-stimulated duodenal mucosal bicarbonate secretion and transmucosal electrical potential difference. Methods: Seven healthy volunteers participated in four separate experiments. The variables included oral acetazolamide vs. control test and, as agonists of bicarbonate secretion, either luminal acidification or luminal prostaglandin E2. The proximal 4 cm of the duodenum (i.e., the duodenal bulb) was isolated between balloons as previously described and perfused with an HCO3−-containing (24 mmol/L) balanced electrolyte glucose-containing (10 mmol/L) solution. Results: Acetazolamide treatment significantly decreased mean basal HCO3− secretion and basal transmucosal potential difference. After luminal acidification, duodenal mucosal bicarbonate increased significantly after both acetazolamide treatment (mean, 626; 95% CI, 91–1160 μmol·cm−1·h−1) and in the control tests (mean, 868; 95% CI, 652–1084 μmol·cm−1·h−1). However, acetazolamide treatment significantly decreased prostaglandin E2-stimulated HCO3− secretion from 461 (95% CI, 307–615) to 222 (95% CI, 121–324) μmol·cm−1·h−1. Conclusions: Duodenal mucosal carbonic anhydrase activity has an important function in the regulation of basal and prostaglandin E2-stimulated human duodenal mucosal bicarbonate transport.

Background: Interaction of the enteric nerves in regulating mammalian duodenal mucosal bicarbonate secretion is not well understood. The purpose of the present experiments was to evaluate the role of the enteric nervous system on bicarbonate secretion from rabbit duodenal mucosa in vitro. Methods: Proximal duodenum from male New Zealand White rabbits was stripped of seromuscular layers, mounted in Ussing chambers, and studied under short-circuited conditions. Effects of electrical field stimulation, vasoactive intestinal polypeptide (VIP), carbachol, prostaglandin E2 (PGE2), dibutyryl-cyclic adenosine monophosphate (db-cAMP), and the neurotoxin tetrodotoxin (TTX) and muscarinic blockade by atropine were studied. Results: Electrical field stimulation significantly (P < 0.01) stimulated bicarbonate secretion, short-circuit current (Isc), and electrical potential difference (PD) that was sensitive to both TTX and atropine. VIP-stimulated bicarbonate secretion was significantly inhibited by TTX (−73%), yet Isc and PD remained unchanged. Atropine decreased VIP-induced bicarbonate secretion (−69%) and Isc (−43%). Carbachol-stimulated bicarbonate secretion, Isc, and PD were abolished by atropine, whereas TTX was without affect. Neither TTX nor atropine had a significant effect on PGE2 or db-cAMP-stimulated bicarbonate secretion. Conclusions: These results suggest that (1) enteric nerve stimulation activates an acetylcholine receptor that in turn stimulates duodenal epithelial bicarbonate secretion; (2) VIP stimulates bicarbonate secretion, in large part, via the enteric nervous system; and (3) PGE2 and cAMP stimulate bicarbonate secretion independent of the enteric nervous system.

Background: Duodenal surface cells secrete bicarbonate that provides a barrier against injury. The current experiments were performed to identify duodenal bicarbonate regulatory and transport pathways. Methods: Rabbit proximal duodenal mucosa were mounted in chambers under short-circuited conditions. Bicarbonate transport, short-circuit current (Isc), and potential difference (PD) were quantitated in response to prostaglandin E 2 (PGE 2 ), vasoactive intestinal polypeptide (VIP), and dibutyryl cyclic adenosine monophosphate (db-cAMP). Anoxia (N 2 ), 4,4′-diisothiocyanostilbene-2,2′-disulfonic acid (DIDS) and Cl − free solutions, ouabain, and Na-free solutions were also studied, as was the effect of VIP and PGE 2 on duodenocyte cAMP. Results: PGE 2 , VIP, db-cAMP, and theophylline significantly increased bicarbonate secretion, Isc, and PD. Ouabain, Na + -free bathing solutions, and anoxia (N 2 ) inhibited the responses. DIDS and Cl − -free solutions abolished the PGE 2 -induced response, reduced the response to VIP by about 50%, and had no effect on the response to db-cAMP. After PGE 2 and VIP, cAMP concentration increased, yet was likely independent of bicarbonate secretion. Conclusions: Mammalian duodenal HCO 3 − transport requires Na + , Na+K+-adenosine triphospatase and O 2 -dependent metabolic pathways and is stimulated by PGE 2 , VIP, and cAMP, acting by distinct pathways.

Gastric acid enters the proximal duodenum both as free and buffered H+. The procedures in this study were threefold: (a) to determine the pH threshold for duodenal mucosal bicarbonate secretion, iso-osmolar citric acid (pH 2.5-4.0; H+, 1.1 mmol) was infused; (b) to examine the effect of varying acid loads (H+, 0.4-5.1 mmol), citric acid (pH 3.0) was perfused; and (c) to quantitate duodenal diffusion of CO2, citric acid (pH 5.0) gassed with CO2 (PCO2, 0-210 mm Hg) was tested. Basal bicarbonate secretion was similar on each test day, 230 mumol/cm.h. Citric acid at pH 2.5 and 3.0 increased bicarbonate output equally to about 560 mumol/cm.h (similar to 2 mmol of 100 mmol/L HCl); citric acid at pH 3.5 and 4.0 had no effect. Varying the acid load increased bicarbonate output similarly. Duodenal loss of CO2 was minimal (4%) with infusion of 50 mm Hg PCO2 and increased to approximately 25% (15 mm Hg/min) at higher PCO2 values. It is concluded that (a) the pH threshold for human duodenal mucosal bicarbonate secretion is 3.0; (b) a pH-sensitive, rather than an acid load-sensitive, regulatory process exists; and (c) CO2 loss plateaus at 15 mm Hg/min at a PCO2 of 200 mm Hg. (Gastroenterology 1992 Apr;102(4 Pt 1):1252-8)

When the proximal duodenum of animals or humans is perfused with isoosmolar NaCl, bicarbonate enters the luminal effluent. In addition, duodenal bicarbonate output is stimulated by luminal acidification and prostaglandins of the E class. The hypothesis that in vivo human duodenal bicarbonate transport persists in the absence of a plasma-to-lumen bicarbonate gradient and therefore is probably an active transport process was tested. In healthy subjects, a 4-cm segment of the proximal duodenum was isolated from gastric and pancreaticobillary secretions. Net duodenal bicarbonate secretion remained similar to basal levels during luminal perfusion with either 24 or 32 mM bicarbonate (each isoosmolar with plasma by the addition of NaCl). In addition, peak increases in acid-induced bicarbonate outputs with luminal perfusion of 154 mM NaCl and 32 mM NaHCO3 (+122 mM NaCl) were similar. Moreover, prostaglandin E2-stimulated bicarbonate secretion with perfusion of 154 mM NaCl and 32 mM NaHCO3 (+122 mM NaCl) was similar. It was concluded that in humans, proximal duodenal mucosal bicarbonate transport remains unaltered in the absence of a plasma-to-lumen bicarbonate gradient at rest and after stimulation with HCl or prostaglandin E2. These observations suggest that human proximal duodenal bicarbonate secretion involves active transport.

Background & Aims: Gastroesophageal reflux disease is a condition frequently associated with esophagitis and motor abnormalities. Recent evidence suggests that proinflammatory cytokines, such as interleukin (IL)-1β and IL-6, may be implicated because they reduce esophageal muscle contractility, but these results derive from in vitro or animal models of esophagitis. This study used human esophageal cells and tissues to identify the cellular source of cytokines in human esophagitis investigate whether cytokines can be induced by gastric refluxate, and examine whether esophageal tissue– or cell-derived mediators affect muscle contractility. Methods: Endoscopic mucosal biopsy specimens were obtained from patients with and without esophagitis, organ-cultured, and undernatants were assessed for cytokine content. The cytokine profile of esophageal epithelial, fibroblast, and muscle cells was analyzed, and esophageal mucosa and cell products were tested in an esophageal circular muscle contraction assay. Results: The mucosa of esophagitis patients produced significantly greater amounts of IL-1β and IL-6 compared with those of control patients. Cultured esophageal epithelial cells produced IL-6, as did fibroblasts and muscle cells. Epithelial cells exposed to buffered, but not denatured, gastric juice produced IL-6. Undernatants of mucosal biopsy cultures from esophagitis patients reduced esophageal muscle contraction, as did supernatants from esophageal epithelial cell cultures. Conclusions: The human esophagus produces cytokines capable of reducing contractility of esophageal muscle cells. Exposure to gastric juice is sufficient to stimulate esophageal epithelial cells to produce IL-6, a cytokine able to alter esophageal contractility. These results indicate that classic cytokines are important mediators of the motor disturbances associated with human esophageal inflammation.

5-hydroxytryptamine (5-HT) is an important neurotransmitter and intercellular messenger that modulates many gastrointestinal functions. Because little is known about the role of 5-HT in the regulation of duodenal bicarbonate secretion, we examined the role of 5-HT on duodenal bicarbonate secretion and define neural pathways involved in the actions of 5-HT.Duodenal mucosa from National Institutes of Health Swiss mice was stripped of seromuscular layers and mounted in Ussing chambers. The effect of 5-HT on duodenal bicarbonate secretion was determined by the pH stat technique. Acetylcholine (ACh) release from duodenal mucosa was assessed by preincubating the tissue with [(3)H] choline and measuring 5-HT-evoked release of tritium.5-HT added to the serosal bath markedly stimulated duodenal bicarbonate secretion and short circuit current (Isc) in a dose-dependent manner (10(-7) mol/L to 10(-3) mol/L; P0.0001), whereas mucosally added 5-HT was without effect. 5-HT-stimulated bicarbonate secretion was independent of luminal Cl(-). Pretreatment with tetrodotoxin (TTX) (10(-6) mol/L) or atropine (10(-5) mol/L) markedly reduced 5-HT-stimulated duodenal bicarbonate secretion (by 60% and 65%, respectively; P0.001) and Isc (by 45% and 27%, respectively; P0.001 and P0.05). Pretreatment with N(omega)-nitro-l-arginine methyl ester (l-NAME) (10(-3) mol/L), propranolol (10(-5) mol/L), or phentolamine (10(-5) mol/L) did not significantly alter 5-HT-stimulated duodenal mucosal bicarbonate secretion or Isc. 5-HT concentration-dependently evoked ACh release from duodenal mucosal preparations (P0.0001). TTX markedly inhibited 5-HT-evoked ACh release (P0.001).5-HT is a potent activator of duodenal mucosal bicarbonate secretion in mice. Duodenal bicarbonate secretion induced by 5-HT in vitro occurs principally via a cholinergic neural pathway.

Background/Aims: The gastroduodenal epithelium is protected from acid peptic damage by an adherent mucus-bicarbonate layer. Bicarbonate is secreted by the surface epithelial cells into this mucus layer. Patients with duodenal ulcer disease have impaired proximal duodenal bicarbonate secretion. Mast cells, present in large numbers in the duodenal mucosa, release a number of inflammatory mediators, including histamine. Release of such mast cell mediators has been implicated in ulcer disease. In this study, the ability of histamine to regulate bicarbonate secretion was examined. Methods: Bicarbonate secretion by rabbit proximal duodenal mucosa was examined in vitro, and the effects of histamine, its agonists, and its antagonists were studied. Results: Histamine essentially eliminated prostaglandin E 2 -stimulated duodenal mucosal bicarbonate secretion, an effect reversed both by the neurotoxin, tetrodotoxin, and the histamine H 2 -receptor antagonist, cimetidine, as well as reproduced by the H 2 -receptor agonist, dimaprit. Conclusions: In addition to the stimulatory action of histamine on gastric acid secretion, histamine expresses an additional antidefensive action by inhibiting prostaglandin E 2 -stimulated duodenal epithelial bicarbonate secretion. This effect of histamine is likely mediated via H 2 receptors located on enteric nerves.