The effect of infliximab dose escalation in inflammatory bowel disease patients with antibodies to infliximab.

BACKGROUND: Infliximab dose escalation (DE) can be used in inflammatory bowel disease patient; however, the long-term benefit remains unclear, especially in those with antibodies to infliximab (ATI). The aim was to assess the effect of DE in patients with ATI on drug level, clinical response and ATI status. METHODS: All patients undergoing infliximab DE (a reduction in dose interval between infusions <8 weeks ± an increase in dose up to 10 mg/kg) at a referral centre between April 2016 and August 2019 were included. RESULTS: Ninety-two patients were DE: 51 were men, 50 had CD and 63 were receiving immunosuppression. A total of 87 people received DE for a median of 44 weeks (range 4-176). Five stopped infliximab after 1 dose of DE: 2 for loss of response and 3 for infusion reaction. In patients with ATI ≤10 vs. >10 AU/mL, DE significantly increased drug levels: median infliximab levels of 1.4 and 0.9 at baseline, respectively, to 3.2 and 3.5 at week 24. After DE, 21/35 ATI-positive patients had a fall in ATI ≤10 AU/mL. At week 24 following DE 62/92 patients were in clinical remission. Duration of clinical remission was shorter in those with ATI >10 AU/mL (median 24 weeks, range 0-88) than in those with transient/ATI ≤10 AU/mL (median 36 weeks, range 0-126, P = 0.06). CONCLUSIONS: A strategy of DE for selected patients receiving infliximab is associated with an increase in drug levels and reduced ATI positivity. This is associated with clinical remission in approximately 70% of patients at 6 months.

Critical Role of the Disintegrin Metalloprotease ADAM-like Decysin-1 [ADAMDEC1] for Intestinal Immunity and Inflammation.

BACKGROUND AND AIMS: ADAM [A Disintegrin And Metalloproteinase] is a family of peptidase proteins which have diverse roles in tissue homeostasis and immunity. Here, we study ADAM-like DECysin-1 [ADAMDEC1] a unique member of the ADAM family. ADAMDEC1 expression is restricted to the macrophage/dendritic cell populations of the gastrointestinal tract and secondary lymphoid tissue. The biological function of ADAMDEC1 is unknown but it has been hypothesised to play a role in immunity. The identification of reduced ADAMDEC1 expression in Crohn's disease patients has provided evidence of a potential role in bowel inflammation. METHODS: Adamdec1-/- mice were exposed to dextran sodium sulphate or infected orally with Citrobacter rodentium or Salmonella typhimurium. The clinical response was monitored. RESULTS: The loss of Adamdec1 rendered mice more susceptible to the induction of bacterial and chemical induced colitis, as evidenced by increased neutrophil infiltration, greater IL-6 and IL-1ß secretion, more weight loss and increased mortality. In the absence of Adamdec1, greater numbers of Citrobacter rodentium were found in the spleen, suggestive of a breakdown in mucosal immunity which resulted in bacteraemia. CONCLUSION: In summary, ADAMDEC1 protects the bowel from chemical and bacterial insults, failure of which may predispose to Crohn's disease.

Optineurin deficiency in mice contributes to impaired cytokine secretion and neutrophil recruitment in bacteria-driven colitis.

Crohn's disease (CD) is associated with delayed neutrophil recruitment and bacterial clearance at sites of acute inflammation as a result of impaired secretion of proinflammatory cytokines by macrophages. To investigate the impaired cytokine secretion and confirm our previous findings, we performed transcriptomic analysis in macrophages and identified a subgroup of individuals with CD who had low expression of the autophagy receptor optineurin (OPTN). We then clarified the role of OPTN deficiency in: macrophage cytokine secretion; mouse models of bacteria-driven colitis and peritonitis; and zebrafish Salmonella infection. OPTN-deficient bone-marrow-derived macrophages (BMDMs) stimulated with heat-killed Escherichia coli secreted less proinflammatory TNFα and IL6 cytokines despite similar gene transcription, which normalised with lysosomal and autophagy inhibitors, suggesting that TNFα is mis-trafficked to lysosomes via bafilomycin-A-dependent pathways in the absence of OPTN. OPTN-deficient mice were more susceptible to Citrobacter colitis and E. coli peritonitis, and showed reduced levels of proinflammatory TNFα in serum, diminished neutrophil recruitment to sites of acute inflammation and greater mortality, compared with wild-type mice. Optn-knockdown zebrafish infected with Salmonella also had higher mortality. OPTN plays a role in acute inflammation and neutrophil recruitment, potentially via defective macrophage proinflammatory cytokine secretion, which suggests that diminished OPTN expression in humans might increase the risk of developing CD.

Disruption of macrophage pro-inflammatory cytokine release in Crohn's disease is associated with reduced optineurin expression in a subset of patients.

Crohn's disease (CD) is a complex and highly heterogeneous chronic inflammatory disorder, primarily affecting the gastrointestinal tract. Genetic and functional studies have highlighted a key role for innate immunity in its pathogenesis. Profound systemic defects in innate immunity and acute inflammation are understood to result in markedly delayed clearance of bacteria from the tissues, leading to local chronic granulomatous inflammation and compensatory adaptive immunological changes. Macrophages, key orchestrators of acute inflammation, are likely to play an important role in the initial impaired innate immune response. Monocyte-derived macrophages from CD patients stimulated with Escherichia coli were shown to release attenuated levels of tumour necrosis factor and interferon-γ with normal secretion of interleukin-8 (IL-8), IL-10 and IL-6. In controls, the secretion of these cytokines was strongly positively correlated, which was not seen with CD macrophages. The transcriptomes of CD and control macrophages were examined in an attempt to understand the molecular basis of this defect. There were no differentially expressed genes identified between the two groups, consistent with genetic heterogeneity; however, a number of molecules were found to be under-expressed in subgroups of CD patients. The most common of these was optineurin (OPTN) which was under-expressed in approximately 10% of the CD patients. Reduced OPTN expression coincided with lower intracellular protein levels and diminished cytokine secretion after bacterial stimulation both in the patients and with small interfering RNA knockdown in THP-1 cells. Identifying and studying subgroups of patients with shared defective gene expression could aid our understanding of the mechanisms underlying highly heterogeneous diseases such as CD.

Is there a role for routine duodenal biopsy in diagnosing giardiasis in a European population?

OBJECTIVE: Giardia lamblia is the most common enteric protozoan world-wide. The prevalence varies internationally. Patients with giardiasis typically have diarrhoea but may have atypical symptoms when referred for endoscopy. The purpose of this study was to investigate whether a policy of routine duodenal biopsies increased the yield of diagnosing Giardia and whether treatment improved the patient's presenting symptoms. MATERIAL AND METHODS: Our hospital endoscopy database was examined retrospectively, from January 2003 to January 2004, to identify patients who had undergone gastroscopy and targeted duodenal biopsies. Thereafter, routine duodenal biopsies were carried out prospectively on unselected adult patients referred for gastroscopy from January 2004 to April 2006. Patients diagnosed with Giardia were assessed for symptoms and response to treatment. RESULTS: In the retrospective group, of the 5979 gastroscopies performed, 1464 duodenal biopsies were carried out; 5 patients had giardiasis, a prevalence of 0.08%, CI 0.01-0.16%. In the prospective group, 2000 gastroscopies with duodenal biopsies were performed; 9 patients had giardiasis, a prevalence of 0.45%, CI 0.16-0.74%. The difference in prevalence was 0.37%, CI 0.06-0.67%, which was statistically significant with a Yates' chi(2)(CC) of 9.49, p<0.005. On comparing response to treatment, the Fisher exact test revealed a proportional difference that was not statistically significant. CONCLUSIONS: In a UK population, the prevalence of Giardia was low. Although a policy of routine duodenal biopsy resulted in more cases of Giardia being identified, this increase in detection did not correspond with an improvement in patients' symptoms. This suggests that Giardia may be a coincidental finding. This study does not support the approach of routine duodenal biopsy in diagnosing giardiasis.