Byron P. Vaughn

Proactive therapeutic concentration monitoring of infliximab may improve outcomes for patients with inflammatory bowel disease: results from a pilot observational study.

Background:Infliximab (IFX) is effective in the treatment of inflammatory bowel disease; however, the effect is often not durable. It is unknown if proactive therapeutic concentration monitoring (TCM) of IFX improves outcomes. Methods:This is a retrospective observational study examining the use of proactive TCM and titration of IFX to a target concentration for patients with inflammatory bowel disease in clinical remission at a tertiary care center. The primary aim was to describe the clinical course of patients who had proactive TCM. A secondary analysis was done to assess if this strategy was superior to the standard of care. Results:Forty-eight patients were identified as having proactive TCM. Fifteen percent had an initial undetectable trough concentration. Twenty-five percent (12 of 48) of patients escalated IFX after the first proactive TCM while 15% (7 of 48) of patients de-escalated IFX therapy over the study period. A control group of 78 patients was identified. Patients who had proactive TCM had a greater probability of remaining on IFX than controls (hazard ratio, 0.3; 95% confidence interval, 0.1–0.6; log rank test; P = 0.0006). The probability of remaining on IFX was greatest for patients who achieved a trough concentration >5 &mgr;g/mL (hazard ratio, 0.03; 95% confidence interval, 0.01–0.1; P < 0.0001 versus trough <5 &mgr;g/mL). Fewer patients in the proactive TCM group stopped IFX (10% versus 31%, P = 0.009). Conclusions:In this pilot observational study, proactive TCM of IFX frequently identified patients with low or undetectable trough concentrations and resulted in a greater probability of remaining on IFX.

Improved Long-term Outcomes of Patients With Inflammatory Bowel Disease Receiving Proactive Compared With Reactive Monitoring of Serum Concentrations of Infliximab

BACKGROUND & AIMS: Monitoring serum concentrations of tumor necrosis factor antagonists in patients receiving these drugs as treatment for inflammatory bowel disease (IBD), also called therapeutic drug monitoring, is performed either after patient loss of response (reactive drug monitoring) or in patients in clinical remission in which the drug is titrated to a target concentration (proactive drug monitoring). We compared long‐term outcomes of patients with IBD undergoing proactive vs reactive monitoring of serum concentrations of infliximab. METHODS: We performed a multicenter, retrospective study of 264 consecutive patients with IBD (167 with Crohns disease) receiving infliximab maintenance therapy. The subjects received proactive (n = 130) or reactive (n = 134) drug monitoring, based on measurements of first infliximab concentration and antibodies to infliximab, from September 2006 to January 2015; they were followed through December 2015 (median time of 2.4 years). We analyzed time to treatment failure, first IBD‐related surgery or hospitalization, serious infusion reaction, and detection of antibodies to infliximab. Treatment failure was defined as drug discontinuation for loss of response or serious adverse event, or need for surgery. RESULTS: Multiple Cox regression analysis independently associated proactive drug monitoring, compared with reactive monitoring, with reduced risk for treatment failure (hazard ratio [HR], 0.16; 95% confidence interval [CI], 0.09–0.27; P < .001), IBD‐related surgery (HR, 0.30; 95% CI, 0.11–0.80; P = .017), IBD‐related hospitalization (HR, 0.16; 95% CI, 0.07–0.33; P < .001), antibodies to infliximab (HR, 0.25; 95% CI, 0.07–0.84; P = .025), and serious infusion reaction (HR, 0.17; 95% CI, 0.04–0.78; P = .023). CONCLUSIONS: In a retrospective analysis of patients with IBD receiving proactive vs reactive monitoring of serum concentration of infliximab, proactive monitoring was associated with better clinical outcomes, including greater drug durability, less need for IBD‐related surgery or hospitalization, and lower risk of antibodies to infliximab or serious infusion reactions.

Screening for tuberculosis and hepatitis B prior to the initiation of anti-tumor necrosis therapy.

Background: Since the introduction of infliximab, anti‐tumor necrosis factor alpha (anti‐TNF‐&agr;) agents have been used with increasing frequency for the treatment of inflammatory bowel disease (IBD). Reactivation of latent Mycobacterium tuberculosis (TB) soon became recognized as a complication of therapy. More recently, reactivation of hepatitis B while on anti‐TNF therapy has been documented. The aim of this study was to assess the adherence to screening for latent TB and hepatitis B by gastroenterologists prior to initiation of an anti‐TNF. Methods: This is a retrospective analysis of all patients with IBD treated with an anti‐TNF at a large urban academic hospital. In our population, 65% of patients were screened for latent TB prior to the initiation of anti‐TNF therapy, while 25% of patients were screened for hepatitis B. Results: Failure to screen for latent TB was strongly correlated with prior exposure to an anti‐TNF (odds ratio [OR]: 5.3; P < 0.0001) and initiation of treatment prior to 2006 (OR: 5.8; P < 0.0001). Failure to screen for hepatitis B was associated with lack of an abnormal alanine aminotransferase (OR: 2.6; P = 0.005) and treatment prior to 2010 (OR: 3.3; P = 0.02). Providers who had been in practice longer were less likely screen for TB or hepatitis B. Conclusions: The rate of screening for both latent TB and hepatitis B in this study was inadequate. While the rate of screening is increasing, further systems improvements and physician education is needed. (Inflamm Bowel Dis 2012;)

Biologic Concentration Testing in Inflammatory Bowel Disease

Abstract:Anti-TNF medications have revolutionized the care of patients with inflammatory bowel disease. However, despite an initial robust effect, loss of response is common and long-term results are disappointing. Much of this lack of durability may be due to inadequate dose optimization, and recent studies suggest a correlation between serum drug concentrations and clinical outcomes. Currently, in clinical practice, measurement of drug concentrations and antibodies to drug are typically performed only when a patient presents with active inflammatory bowel disease symptoms or during a potential immune-mediated reaction to anti-TNF (“reactive” setting). However, proactive monitoring of anti-TNF concentrations with titration to a therapeutic window (i.e., therapeutic concentration monitoring) represents a new strategy with many potential clinical benefits including prevention of immunogenicity, less need for IFX rescue therapy, and greater durability of IFX treatment. This review will cover the salient features of anti-TNF pharmacokinetics and pharmacodynamics and provide a rational approach for the use of anti-TNF concentration testing in both the reactive and proactive settings.

Purinergic signalling in the liver in health and disease.

Purinergic signalling is involved in both the physiology and pathophysiology of the liver. Hepatocytes, Kupffer cells, vascular endothelial cells and smooth muscle cells, stellate cells and cholangiocytes all express purinoceptor subtypes activated by adenosine, adenosine 5′-triphosphate, adenosine diphosphate, uridine 5′-triphosphate or UDP. Purinoceptors mediate bile secretion, glycogen and lipid metabolism and indirectly release of insulin. Mechanical stress results in release of ATP from hepatocytes and Kupffer cells and ATP is also released as a cotransmitter with noradrenaline from sympathetic nerves supplying the liver. Ecto-nucleotidases play important roles in the signalling process. Changes in purinergic signalling occur in vascular injury, inflammation, insulin resistance, hepatic fibrosis, cirrhosis, diabetes, hepatitis, liver regeneration following injury or transplantation and cancer. Purinergic therapeutic strategies for the treatment of these pathologies are being explored.

Prevention of post-operative recurrence of Crohn's disease

Endoscopic and clinical recurrence of Crohns disease (CD) is a common occurrence after surgical resection. Smokers, those with perforating disease, and those with myenteric plexitis are all at higher risk of recurrence. A number of medical therapies have been shown to reduce this risk in clinical trials. Metronidazole, thiopurines and anti-tumour necrosis factors (TNFs) are all effective in reducing the risk of endoscopic or clinical recurrence of CD. Since these are preventative agents, the benefits of prophylaxis need to be weighed-against the risk of adverse events from, and costs of, therapy. Patients who are high risk for post-operative recurrence should be considered for early medical prophylaxis with an anti-TNF. Patients who have few to no risk factors are likely best served by a three-month course of antibiotics followed by tailored therapy based on endoscopy at one year. Clinical recurrence rates are variable, and methods to stratify patients into high and low risk populations combined with prophylaxis tailored to endoscopic recurrence would be an effective strategy in treating these patients.

Pathological roles of purinergic signaling in the liver.

Purinergic signaling has been postulated as a mechanism of cellular signaling since the early 1970s. Cellular responses triggered by extracellular nucleotides and nucleosides occur by defined adenosine (P1) and ATP (P2) receptors, respectively, and play a prominent role in many aspects of health and disease, including those involving the liver. In normal physiology, extracellular nucleotides modulate many of the normal biologic and hepatic metabolic processes such as gluconeogenesis and insulin responsiveness. Further, in multiple disease states, ATP and certain nucleotides serve as danger signals and are involved in heightened purinergic receptor activation in a myriad of pathologic processes. Recently, others and we have shown the regulation of purinergic signaling by ectonucleotidases to play an important role in the acute vascular pathobiology of liver inflammation, regeneration, and immunity, as in ischemia reperfusion and transplantation. Increased understanding into mechanisms of extracellular ATP metabolism by such ecto enzymes has also led to novel insights into the exquisite balance of nucleotide P2-receptor and adenosinergic P1-receptor signaling in those chronic hepatic diseases characterized by steatosis, fibrosis, and malignancy. This review will explore the developing role of purinergic signaling in the pathophysiology of liver disease and comment on potential future clinical applications.

Acid-Suppressive Medication Use and the Risk for Nosocomial Gastrointestinal Tract Bleeding

BACKGROUND Acid-suppressive medications are increasingly prescribed for noncritically ill hospitalized patients, although the incidence of nosocomial gastrointestinal (GI) tract bleeding (GI bleeding) and magnitude of potential benefit from this practice are unknown. We aimed to define the incidence of nosocomial GI bleeding outside of the intensive care unit and examine the association between acid-suppressive medication use and this complication. METHODS We conducted a pharmacoepidemiologic cohort study of patients admitted to an academic medical center from 2004 through 2007, at least 18 years of age, and hospitalized for 3 or more days. Admissions with a primary diagnosis of GI bleeding were excluded. Acid-suppressive medication use was defined as any order for a proton pump inhibitor or histamine-2-receptor antagonist. The main outcome measure was nosocomial GI bleeding. A propensity matched generalized estimating equation was used to control for confounders. RESULTS The final cohort included 78,394 admissions (median age, 56 years; 41% men). Acid-suppressive medication was ordered in 59% of admissions, and nosocomial GI bleeding occurred in 224 admissions (0.29%). After matching on the propensity score, the adjusted odds ratio for nosocomial GI bleeding in the group exposed to acid-suppressive medication relative to the unexposed group was 0.63 (95% confidence interval, 0.42-0.93). The number needed to treat to prevent 1 episode of nosocomial GI bleeding was 770. CONCLUSIONS Nosocomial GI bleeding outside of the intensive care unit was rare. Despite a protective effect of acid-suppressive medication, the number needed to treat to prevent 1 case of nosocomial GI bleeding was relatively high, supporting the recommendation against routine use of prophylactic acid-suppressive medication in noncritically ill hospitalized patients.

Abdominal phlegmons in Crohn's disease: outcomes following antitumor necrosis factor therapy.

Background: An abdominal phlegmon is an inflammatory mass that can develop in the setting of penetrating Crohns disease (CD). Anti‐tumor necrosis factor (TNF) antibody therapy is typically avoided in CD complicated by phlegmon because of concern for peritoneal infection but may offer an effective alternative to surgical resection after infection has been controlled with antibiotics. The aim of this study was to examine outcomes for patients with CD who developed an abdominal phlegmon that was subsequently treated with an anti‐TNF antibody. Methods: We retrospectively reviewed the records of all CD patients attending Beth Israel Deaconess Medical Center between 2004 and 2010 with an abdominal phlegmon who were treated with an anti‐TNF antibody in order to evaluate the safety and efficacy of this treatment regimen. Results: There were 13 patients with CD complicated by a phlegmon treated with antibiotics and an anti‐TNF antibody at our center between 2004 and 2010. Ten were male. Median time (interquartile range) from diagnosis to development of the phlegmon was 5.9 (1.9–22.7) years. The phlegmon was associated with an abscess in 12 patients. In addition to anti‐TNF therapy, all patients were treated with broad‐spectrum antibiotics. Anti‐TNF therapy was effective without complications in all subjects. Two patients eventually had surgery more than a year after initiating anti‐TNF treatment. Conclusions: Penetrating CD complicated by phlegmon formation may be safely and effectively managed with a combination of antibiotics and anti‐TNF therapy. Larger, prospective trials are required to confirm these initial findings. (Inflamm Bowel Dis 2011;)

Successful Resolution of Recurrent Clostridium difficile Infection using Freeze-Dried, Encapsulated Fecal Microbiota; Pragmatic Cohort Study

OBJECTIVES:Fecal microbiota transplantation (FMT) is increasingly being used for treatment of recurrent Clostridium difficile infection (R-CDI) that cannot be cured with antibiotics alone. In addition, FMT is being investigated for a variety of indications where restoration or restructuring of the gut microbial community is hypothesized to be beneficial. We sought to develop a stable, freeze-dried encapsulated preparation of standardized fecal microbiota that can be used for FMT with ease and convenience in clinical practice and research.METHODS:We systematically developed a lyophilization protocol that preserved the viability of bacteria across the taxonomic spectrum found in fecal microbiota and yielded physicochemical properties that enabled consistent encapsulation. We also treated a cohort of R-CDI patients with a range of doses of encapsulated microbiota and analyzed the associated changes in the fecal microbiome of the recipients.RESULTS:The optimized lyophilized preparation satisfied all our preset goals for physicochemical properties, encapsulation ease, stability at different temperatures, and microbiota viability in vitro and in vivo (germ-free mice). The capsule treatment was administered to 49 patients. Overall, 43/49 (88%) of patients achieved a clinical success, defined as no recurrence of CDI over 2 months. Analysis of the fecal microbiome demonstrated near normalization of the fecal microbial community by 1 month following FMT treatment. The simplest protocol using the lowest dose (2.1–2.5 × 1011 bacteria in 2–3 capsules) without any colon purgative performed equally well in terms of clinical outcomes and microbiota engraftment.CONCLUSIONS:A single administration of encapsulated, freeze-dried fecal microbiota from a healthy donor was highly successful in treating antibiotic-refractory R-CDI syndrome.