DISPATCHES FROM THE GUILD CONFERENCE, SERIES #21

Biosimilars for the Treatment of Inflammatory Bowel Disease

April 2019 • Volume XLIII, Issue 4
Vivek A. Rudrapatna,Fernando Velayos

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Biosimilars are biologic products that are highly similar to a previously approved reference (or originator) biologic drug in terms of safety, purity, and potency (efficacy). These medications are increasingly being approved by global regulatory agencies in the hopes of reducing treatment costs. This review aims to answer common questions regarding biosimilars and their use for IBD. It is written in a question/answer format for easy reference and guides the reader from the basics of biosimilars, to clinically relevant questions encountered in the clinic, to their policy implications, among other topics.

Biosimilars are biologic products that are highly similar to a previously approved reference (or originator) biologic drug in terms of safety, purity, and potency (efficacy). These medications are increasingly being approved by global regulatory agencies in the hopes of reducing treatment costs. To date, six biosimilars in the United States have been approved for the treatment of inflammatory bowel disease (IBD). Despite their approval by regulatory bodies and several years-worth of ‘real world’ evidence supporting their use, this class of medications remain somewhat unfamiliar to many clinicians and patients. This review aims to answer common questions regarding biosimilars and their use for IBD. It is written in a question/ answer format for easy reference and guides the reader from the basics of biosimilars, to clinically relevant questions encountered in the clinic, to their policy implications, among other topics.

1Vivek A. Rudrapatna, MD 2Fernando Velayos, MD 1Division of Gastroenterology, Department of Medicine, University of California, San Francisco, CA 2Department of Gastroenterology, Kaiser Permanente Medical Group, San Francisco, CA

INTRODUCTION

This review addresses the use of biosimilars in patients with inflammatory bowel disease (IBD). Here we aim to guide the reader from the basics of biosimilars, to clinically relevant questions encountered in the clinic, to their policy implications, among other topics. The goal is to provide an evidence-based review of the topic that answers common questions and can be applied easily to the clinic, for both counseling IBD patients on the use of biosimilars and taking care of patients who are on biosimilars or considering a switch from an originator product. 

What are biosimilars?

Biosimilars are biologic products that are highly similar to a previously approved reference (or originator) biologic drug in terms of safety, purity, and potency (efficacy). In the United States (US), biosimilar products first entered regulatory pathways following the passage of the Affordable Care Act, which included the Biologics Price Competition and Innovation Act of 2009. This act created an abbreviated licensure pathway for new biologic products to be marketed as either biosimilar to or interchangeable with a previously approved reference product. Biosimilarity and Interchangeability (Table 1) are distinct and not synonymous marketing categories.

Although biosimilars might sound like another name for generics, they are in fact different. Understanding the difference relies on understanding the differences between biologics and small molecule drugs. Small molecules are the most common class of pharmacotherapies. They are small by atomic size (e.g. Aspirin, 21 atoms), structurally simple, and uniformly manufactured by a short, well-defined process of organic chemical synthesis leading to a homogenous product. By contrast, biologics such as vaccines, hormones (e.g. epoetin alfa), and monoclonal antibodies (e.g. infliximab) are large (∼103-104 atoms) and structurally complex. They are typically derived from living systems (e.g. cultured cells or organisms), and as such involve a more complex manufacturing process, continual surveillance for contamination, and regular assessment of batch-to-batch heterogeneity. The output is a product that is more immunogenic than small molecules, and considerably more expensive. As such, the process of ‘replicating’ a reference small molecule product (e.g. a generic) is much more straightforward and less expensive than the analogous process for a reference biologic (e.g. a biosimilar).

Is it possible to distinguish an originator from a biosimilar prescription?

In the US, six biosimilars have been approved by the Food and Drug Administration (FDA) as of December 2018 (Table 2). Three are infliximab biosimilars – Inflectra™ (infliximab-dyyb), Renflexis™ (infliximab-abda), and Ixfi™ (infliximab-qbtx) – and three are adalimumab biosimilars – Amjevita™ (adalimumab-atto), Cyltezo™ (adalimumab-adbm), and Hyrimoz™ (adalimumab-adaz). Each biosimilar has a unique, non-proprietary name designed to identify the base compound (i.e. infliximab) and distinguish it from the originator and from other biosimilars with the use of a four-letter suffix (that has no inherent meaning). Thus, when prescribing a biosimilar, the trade name or non-proprietary name with a four-letter suffix should be specified. Of the FDA approved biosimilars, only Inflectra™ (infliximab-dyyb) and Renflexis™ (infliximab-abda) have been marketed in the US. The adalimumab biosimilars appear to be in patent litigation with the likely possibility of no market competition until 2023.

How are biosimilars approved?

Recognizing the above differences in complexity and cost, global regulatory bodies such as the FDA and European Medicines Agency have outlined pathways to efficiently approve any new product shown to be sufficiently similar to a reference product that is no longer under patent protection. In order to achieve a balance between rapid approval and confidence in the new agent, the FDA’s current guidance relies on two principles: 1) explicit demonstration of substantial similarity between the proposed product and the reference, and 2) implicit reliance on the existing safety and efficacy evidence in support of the reference product across treatment indications. 

The abbreviated pathway for biosimilar approval acknowledges that the goals of biosimilar development are fundamentally different from that of novel agents; while new biologics must be demonstrated to be safe and efficacious for each proposed indication, the burden of proof for biosimilars primarily lies in demonstration of substantial similarity to the reference product (Figure 1). To demonstrate biosimilarity, the FDA has outlined a step-wise approach with a heavy emphasis on analytical assays and clinical pharmacology. The objectives of biochemical assays are to comprehensively characterize the attributes of the molecule, including any post-translational modifications (e.g. folding, subunit interactions, glycosylation) that might affect the immunogenicity of the product. Because biosimilars must be delivered using the same administration route, dose, and frequency as the reference product, they must be shown to have essentially equivalent pharmacokinetics. 

How were biosimilars approved for IBD?

A key distinction between applications for novel biologic therapies and biosimilars is that the latter can potentially be approved for all of the indications of the reference product without explicit safety and efficacy testing for each indication. This process, called extrapolation (Table 1), is contingent on a case-by-base assessment of the known mechanisms of action, pharmacokinetics, immunogenicity, and other factors. Take for instance the first biosimilar to be FDA-approved for IBD: infliximab-dyyb (i.e. CT-P13, Inflectra™). Although this agent was approved for all the indications of originator infliximab (including Crohn’s disease and ulcerative colitis), the only controlled testing of the drug at the time of approval included a phase 1 study for ankylosing spondylitis (PLANETAS1) and a phase 3 study for rheumatoid arthritis (PLANETRA2). 

The rationale in the approval process given by the FDA and other regulatory bodies is that the pre-clinical data as well as the clinical trial data for which infliximab-dyyb was formally tested (i.e. the totality of the data) supported its mechanism of action, pharmacokinetics, immunogenicity, and toxicity as being sufficiently similar to infliximab as used for IBD. While extrapolation for each indication is performed on a case-by-case basis based on the totality of the data, this process serves to accelerate the delivery of biosimilar products and to reduce costs by avoiding replicative clinical trials for each clinical indication for which the originator is approved.

Is there controlled trial evidencefor the use of biosimilars in IBD?

Although the approval of biosimilars for IBD has been based on extrapolated data, controlled trial data have emerged examining the use of biosimilars in IBD (Table 3). The NOR-SWITCH trial3 was a double-blind, non-inferiority study of patients receiving originator infliximab who were randomly assigned to either continue this treatment or switch to infliximab-dyyb. Of the 482 enrolled subjects who underwent randomization and treatment assignment, 155 had Crohn’s disease and 93 had ulcerative colitis. The primary endpoint was a composite endpoint disease worsening by non-invasive scores (including the Harvey-Bradshaw Index4 and partial Mayo score5 for the IBD subgroups, respectively). Subgroup analysis of the IBD patient population, analyzed by per-protocol analysis and adjusted for the duration of reference Infliximab use demonstrated non-inferiority both globally as well as within both IBD subgroups. Moreover, there were no systematic differences seen between groups for inflammatory markers (e.g. fecal calprotectin, c-reactive protein), anti-drug antibodies, pharmacokinetics, safety, or number of patients in clinical remission at one year.

A second randomized controlled trial of infliximab-dyyb in biologic-naive patients with active Crohn’s has recently been published.6 The study randomized patients to inflixmab vs infliximab-dyyb for 30 weeks, and subsequently re-randomized patients to continue versus crossover and continue through 54 total weeks of observation. The investigators assessed a primary endpoint of clinical response by Crohn’s Disease Activity Index-70 (CR-70) criteria at week 6; secondary endpoints included CR-70 at weeks 30 and 54. The investigators found that infliximab-dyyb met the non-inferiority margin of 20% and showed no concerning differences in safety compared to the originator infliximab.

What has been the real-world experience with IBD biosimilars from a safety and efficacy standpoint? 

A sizeable number of publications reporting real-world experience of switching IBD patients to biosimilars have already been published (Table3). Most of this data has come from Europe, where national healthcare payors exercise greater control over treatment options. 

The overall consensus from these studies, which range from studies of both new starts on infliximab products7 vs switching from the reference to the biosimilar in adults8-12 and children,9 is that biosimilars appear to have similar safety, efficacy, and immunogenicity as the reference. These findings have for the most part been consistent with the experience for rheumatological disease. Of note, all of these referenced studies are of infliximab products; very limited data of adalimumab biosimilars in IBD has been published thus far.

The largest of these studies to date was an administrative database study of infliximab-naive Crohn’s patients initiated on reference infliximab vs infliximab-dyyb.13 Time-to-event analysis for a primary composite endpoint of Crohn’s related surgery, all-cause hospitalization, and reimbursement for another biologic demonstrated non-inferiority of the biosimilar within a prespecified margin of 10% – an even tighter margin than that of the NOR-SWITCH trial. They additionally showed no signal for differences in safety between the biosimilar and reference product. Some open-label studies have suggested higher discontinuation rates upon switching to a biosimilar, especially in the setting of rheumatologic disease. These findings have raised the possibility of a significant nocebo effect14-15 – a diminished or negative effect of medical treatment resulting from adverse patient expectations. As such, increased patient education on biosimilars has been recommended as a means of mitigating this effect. 

Are biosimilars considered interchangeable with the reference product? Who determines what version of the drug my patient will get?

Although biosimilars are considered highly similar to the reference product, they are not considered interchangeable. Interchangeability as defined by the FDA is a more stringent standard, implying that 1) it would be expected to produce the same clinical result in any given patient as the reference, and 2) that the risks of safety or diminished efficacy resulting from alternating or switching between products is no greater than that of using the originator without switching. The consequences of interchangeability are that such biosimilars may be substituted for the reference without the intervention of the prescriber, subject to state pharmacy laws. Meeting this higher standard requires additional data and studies from the manufacturer of a proposed interchangeable product.

To date, no biologics for any indication have been approved by the FDA as interchangeable. This does not imply that patients should not be switched or newly initiated on biosimilar products, but rather that patients in the US will receive the specific version of a biologic prescribed by their provider, and switches between biologic cannot be done without the provider’s knowledge or approval. 

What is the position of gastroenterology societies and patient advocacy societies on switching from the originator to a biosimilar product for IBD?

While there are many high-quality patient and physician resources on the use of biologics from the American College of Gastroenterology and American Gastroenterology Association, formal position statements have been published by the Crohn’s and Colitis Foundation and the European Crohn’s and Colitis Organization on switching.16 (Table 3) The Crohn’s and Colitis Foundation does not oppose single transitions of stable patients from an originator to a biosimilar (or vice versa) by third parties (payers or pharmacies), but is opposed to multiple switches if the agents involved have not been designated as interchangeable by the FDA. They also endorse, when switches occur, that patients and providers are informed of the exact agent the patient is receiving and whether it has received an interchangeable designation.

The European Crohn’s and Colitis Organization (ECCO) reports that switching from the originator to a biosimilar in patients with IBD is acceptable.17 They highlight that scientific and clinical evidence is lacking regarding reverse switching, multiple switching and cross-switching among biosimilars. They endorse that switches should be performed that switches should be performed following appropriate discussions between patients and their physician and other team, members.

Can biosimilars be used in patients who have had a secondary loss of response or adverse reaction to an originator product? Can they be monitored using existing therapeutic drug monitoring assays?

A secondary loss of response to a biologic describes a common phenomenon whereby a patient experiences an adequate response when the therapy is started but then experiences either a subsequent waning response (symptoms recur before the next dose) or full flare at any point before the following dose. The most informative study related to this question was one that specifically tested the cross-reactivity of anti-infliximab antibodies to infliximab-dyyb in 125 IBD patients. The investigators found that sera from all of the patients with antibodies to the originator cross-reacted to infliximab-dyyb whereas none of the controls without anti-infliximab antibodies showed cross-reactivity. The anti-drug antibody titers against infliximab and infliximab-dyyb were almost perfectly correlated. Moreover, they showed that these antibodies showed similar functional competition for and inhibition of drug binding to tumor necrosis factor alpha (TNF-a).

Overall, the results suggest two important points. First, biosimilar drugs are sufficiently similar to the originator as to result in meaningful results when subject to existing assays for therapeutic drug monitoring and anti-drug antibodies against the reference product. Second, patients with non-response to the originator drug are unlikely to benefit from a trial of a biosimilar and may even be at increased risk for complications mediated by anti-drug antibodies such as anaphylaxis. Thus, we typically do not recommend using the biosimilar to an originator biologic in the patient who experiences a secondary loss of response or adverse reaction to the originator with the expectation that the outcome will be different than using the originator.

Have biosimilars lowered the cost of treatment and/or increased access to treatment?

Early and preliminary data from Europe have been optimistic regarding the cost savings resulting from the introduction of biosimilars into the market. At the 2018 Interdisciplinary Autoimmune Summit, Jonathan Kay reported that the Norwegian government was able to secure a 40% cost savings on infliximab as a result of a competitive bidding process.18 Cost projections published by authors from the RAND corporation proposed a potential windfall of $44.2 billion as in the US over a ten-year window.19 However, data supporting increased access to care because of widespread biosimilar entry into the marketplace is not yet available. 

CONCLUSION

In summary, biosimilars are biologic products that are highly similar to, and lacking in, clinically meaningful differences from the off-patent reference product. Six anti-TNF biosimilars have been approved in the US, but only the two infliximab biosimilars are widely available at this time. No currently approved biosimilar has a designation as interchangeable. Based on scientific extrapolation, evidence from controlled trials and real-world experience in IBD, data supports the use of biosimilars for both treatment initiation and switching as safe, effective, and potentially cheaper alternatives to the originator biologic.

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FRONTIERS IN ENDOSCOPY, SERIES #51

Pancreaticopleural Fistula: Diagnosis and Management of Three Cases

April 2019 • Volume XLIII, Issue 4
Douglas G. Adler,Linda Jo Taylor,Madeleine Birch

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Pancreaticopleural fistulas are uncommon complications of pancreatitis that occur when there is a disruption in the pancreatic duct, causing pancreatic fluid to track through the retroperitoneum and into the pleural cavities. Treatment of pancreaticopleural fistulas can include conservative medical therapy, ERCP intervention using pancreatic duct stent, and operative therapy which should be considered a last resort if all prior therapies fail. This manuscript serves to highlight why ERCP with pancreatic duct stenting should be considered first line therapy when treating a pancreaticopleural fistula.

Madeleine Birch, Linda Jo Taylor, Douglas G. Adler MD, FACG, AGAF, FASGE University of Utah School of Medicine, Salt Lake City, UT

INTRODUCTION

Pancreaticopleural fistulas are uncommon complications of pancreatitis that occur when there is a disruption in the pancreatic duct, causing pancreatic fluid to track through the retroperitoneum and into the pleural cavities.1 Treatment of pancreaticopleural fistulas can includemconservative medical therapy, ERCP intervention using pancreatic duct stent, and operative therapy which should be considered a last resort if all prior therapies fail. This manuscript serves to highlight why ERCP with pancreatic duct stenting should be considered first line therapy when treating a pancreaticopleural fistula.

CASE REPORT

Case #1

A 46-year-old male with a history of alcohol induced chronic pancreatitis and recurrent pleural effusions presented to the emergency department with severe septicemia, shortness of breath, chest pain and abdominal pain. On chest x-ray, patient was found to have a right-sided large pleural effusion and pleural empyema. Thoracentesis was performed, and the pleural fluid had high amylase level of 10,000 U/dL and the empyema was positive for Actinomyces. In addition to chest drainage, the patient was referred for pancreatic duct stenting via ERCP to reduce the intraductal pressure and divert pancreatic secretions away from the fistulous tract. The ERCP showed dye extravasation at the level of the pancreatic tail. (Figure 1) Ventral pancreatic sphincterotomy was made in the minor papilla and one 5 Fr by 15 cm stent with two external and two internal flaps was placed in a transampullary manner. Repeat ERCP was performed 8 weeks later and no extravasation of contrast dye was noted, suggestive of a healed fistulous tract. The pleural effusion resolved without recurrence. 

Case #2

A 39-year-old male with history of alcohol induced acute pancreatitis and pseudocysts presented to the emergency department with shortness of breath, right sided chest pain, and was found to have a large right-sided plural effusion. Thoracentesis was performed, and the pleural fluid was found to have an amylase level of > 2,500 U/dL. The patient was referred for ERCP and pancreatic duct stenting to redirect fluid flow into duodenum and allow the fistulous tract to heal over time. The ERCP showed a high pancreatic duct disruption with extravasation of dye toward the right hemidiaphragm just above the level of the ampulla. (Figure 2) One 5 Fr by 5 cm plastic stent with two external flaps and a single internal flap was placed in the ventral pancreatic duct. Repeat ERCP showed complete resolution of fistulous tract. 

Case #3

A 40-year-old female with history of idiopathic pancreatitis presented to the emergency department with shortness of breath, pleuritic chest pain and left abdominal and flank pain. The CXR showed a large, left sided pleural effusion. (Figure 3a) Patient underwent a thoracentesis which showed high amylase levels of 34,000 U/gL. The patient was referred for ERCP, which showed a high grade pancreatic duct leak at the level of the pancreatic tail. (Figure 3b) One 7 Fr by 9 cm plastic stent with two external flaps and two internal flaps was placed in the ventral pancreatic duct in the tail of her pancreas. On repeat ERCP six weeks later, a small persistent leak was noted and the decision was made to place a 5 Fr by 5 cm plastic stent with two external flaps and a single internal flap into the ventral pancreatic duct. Subsequent ERCP four weeks later showed complete resolution of the fistulous tract.

Discussion

Pancreaticopleural fistulas are a rare and severe manifestation of pancreatitis. They are most commonly associated with alcohol-induced acute or chronic pancreatitis but can be associated with trauma or iatrogenic injury, among other causes.2 The pathophysiology of a pancreatic fistulas results from underlying inflammation that disrupts the pancreatic duct resulting in the formation of an alternative drainage pathway where pancreatic secretions, containing digestive enzymes and bicarbonate, take the path of least resistance.3 If the disruption in the pancreatic duct tracks anteriorly, a pancreaticoperitoneal fistula can communicate freely with the peritoneal cavity, manifesting as pancreatic ascites.4 If the disruption occurs posteriorly, these fistulous tracts can dissect through the retroperitoneum and into the pleural cavity. Such communications can result in left or right sided pleural effusions that can require management and can be acute, subacute, or chronic.5 There are substantial mortality risks associated with the development of a pancreaticopleural fistulas. While patients can experience severe electrolyte losses related to loss of sodium and bicarbonate in pancreatic secretions, most deaths are attributable to sepsis or hemorrhage.6

Patients with pancreaticopleural fistulas often present with chest pain, shortness of breath, respiratory distress and cough. Simultaneous pancreatic ascites is present in 20% of reported cases.7 Abdominal pain can also be present.8 Pleural effusions are often diagnosed after a chest radiograph or CT scan but identifying the pancreas as the source of disease can remain difficult if there is no overt antecedent history of pancreatitis. 

Diagnosis of a pancreatiopleural fistula is often made by performing a throacocentesis with an associated pleural fluid analysis. The defining feature of a pancreaticopleural fistula is an exudative pleural fluid with a high amylase content (greater than 1000 U/dL).9High lipase and high albumin (greater than 3 g/dL) levels are also noted to be characteristic of a pancreaticopleural fistula.6 Serum amylase levels have no diagnostic reliability, may or may not be elevated, and are generally not clinically valuable.10 Once a diagnosis of a pancreatiopleural fistula has been made, ERCP is typically performed to identify the fistula directly and provide endoscopic treatment. 

Pancreaticopleural effusions can be difficult complications to manage; they are rare entities with no clear guideline for management. A study by Virgilio et al. reported a total of 74 documented cases worldwide.11 Initial intervention can include total parenteral nutrition and drugs such as somatostatin and its analogues to decrease basal and food-stimulated pancreatic secretions. Conservative treatments have a success rate of 25-60% if continued for one month.12 Still, these are often inadequate; in a study by Schweigert et al. nonoperative measurements extending for greater than 17 weeks were associated with a substantial increased risk of septic complications such as pleural empyema.13 Definitive interventional therapy is preferable in most cases. 

ERCP is performed to decompress the pancreatic duct and reduce the ductal pressure. A pancreatic stent is commonly placed to divert pancreatic secretions away from the fistulous tract and out through the pancreatic duct to the duodenal lumen.14 Operative management may rarely be needed if other conservative therapies fail to close the fistulous tract or if the patient has high grade strictures, a disconnected pancreatic duct, or in the event of an unsuccessful ERCP.15 Morbidity and mortality rates must be weighed against potential complications of operative treatment. Early operative intervention of distal pancreatectomy with or without splenectomy after failed endoscopic management is associated with fewer septic complications, but represents maximally invasive therapy.16

In a review reported by Altasan et al. 5%-15% of patients with acute pancreatitis will develop complications including pseudocyst, necrosis, or pancreaticopleural fistula. Pleural effusion was noted in 3%-17% of cases and was associated with a worse prognosis.17 The development of a fistulous tract is associated with pseudocyst formation in 77% of cases. Patient age of presentation ranged from 20-60 years in 95% of the reported cases.18 In a literature review reported by Ali et al. 52 cases of pancreaticopleural fistulas were reported. Patients presented with dyspnea in 65% of cases, abdominal pain in (29%) cough (27%) and chest pain (23%). ERCP diagnosed fistulous tracts in 25 (78%) of 32 patients, CT scan was used to diagnose the pancreatiopleural fistula in 8 of 17 patients, and magnetic resonance cholangiopancreatography was used for diagnosis in 8 of 10 patients. Medical therapy was successful in as a primary intervention in 61% of the cases. ERCP with pancreatic duct stent placement was performed without first giving Octeotride intervention in 13 (25%) cases as initial therapy and surgical intervention as primary treatment was performed in 13% of cases. Conservative medical therapy failed in 65% of the cases but resolved with ERCP and surgical intervention.19

Medical therapy alone including drainage of chest fluid carries high failure rates and greatly increases the patient’s chances of needing more aggressive definitive intervention.20 While ERCP is more invasive than conservative medical treatment alone, it carries significantly fewer risks than operative therapy. During ERCP, pancreatic duct stents can be placed to bridge the ductal disruption (if possible) or simply be placed in a transampullary manner thereby diverting pancreatic secretions away from the fistulous tract and out to the duodenum. All of these effects help facilitate fistula healing.21 Most fistula tracts develop in the head or body of the pancreas where bridging with a pancreatic stent is accessible.6 If the fistulous tract is present in the tail of the pancreas, the pancreatic duct stent should be placed as close to the ductal disruption as possible if bridging across the disruption cannot be accomplished. In a study reported by Pai et al., 28 patients who presented with PPF, 92.8% of patients had complete resolution of pancreatic ascites or pleural effusion after they underwent endoscopic stenting with pancreatic sphincterotomy. Therapeutic interventions consisted of a 5mm sphincterotomy and placement of a 7 Fr pancreatic stent.22 A high percentage of pancreatic stents occlude within 3 months of placement some authors suggest placing pancreatic duct stent in addition to performing a sphincterotomy, although it must be said that individual techniques vary and there are no strict guidelines for this situation.23-24 Pai et al. were unable to conclude if sphincterotomy performed as a single intervention without subsequent pancreatic duct stenting was successful in resolution of the fistula. 20 Neher et al. reported successful treatment of a pancreaticopleural fistula with placement of a 7F nasopancreatic drain after the fistulous tract persisted following 7F stent placement. Nasopancreatic drains allow for repeated pancreatograms without further procedures, although in practice they are rarely employed given the high level of patient inconvenience they create.25 Conservative medical therapy alone was previously only continued for 2 to 4 weeks. Due to the high success rate of conservative medical therapy combined with ERCP intervention, conservative management can be continued up to 2.5 to 6 months.19

In summary, pancreaticopleural fistulas resulting in pleural effusions are rare complications of pancreatitis. Pleural effusion with a history of alcohol use and/or pancreatitis should raise clinical suspicion for presence of a pancreaticopleural fistula. Nonoperative treatments are often successful in resolution of fistulous tracts, mostly via endoscopic means. ERCP and pancreatic duct stent placement with or without sphincterotomy should be considered first line therapy when approaching treatment of such fistulas.

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INFLAMMATORY BOWEL DISEASE: A PRACTICAL APPROACH, SERIES #106

The IBD Therapeutic Pipeline Is Primed to Produce

April 2019 • Volume XLIII, Issue 4
Calen A. Steiner,Jeffrey A. Berinstein,Peter D.R. Higgins

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There has not been a more exciting time in the treatment of inflammatory bowel disease (IBD) since the approval of infliximab in 1998. In addition to multiple recently approved medications including vedolizumab, ustekinumab, and recently tofacitinib, the IBD pipeline continues to expand at a remarkable rate. This review will provide an update on the current and future IBD drugs, focusing on promising therapies currently in late stage or advanced human clinical trials.

Jeffrey A. Berinstein, MD, Calen A. Steiner, MD, MS, Peter D.R. Higgins, MD, PhD, MSc Department of Internal Medicine, Division of Gastroenterology, Michigan Medicine, University of Michigan, Ann Arbor, MI.

INTRODUCTION

There has not been a more exciting time in the treatment of inflammatory bowel disease (IBD) since the approval of infliximab in 1998. In addition to multiple recently approved medications including vedolizumab, ustekinumab, and recently tofacitinib, the IBD pipeline continues to expand at a remarkable rate. There are multiple emerging therapies in known and effective drug classes as well as multiple potential therapies with novel mechanisms of action (MOA). Therapies currently on the market employ a variety of different MOAs including anti-tumor necrosis factor (TNF) (infliximab, adalimumab, certolizumab, and golimumab), immune system modulation (azathioprine, 6-MP), anti-integrin or anti-adhesion (vedolizumab), anti-interleukin 12/23 (ustekinumab), and Janus lkinase (JAK) inhibitors (tofacitinib). The IBD pipeline now boasts additional therapies in each of these broad MOA groups, as well as therapies with completely novel mechanisms including regenerative therapy, immune cell modulation, microbiome targeting, nutrition-based, apheresis, hormone modulation, and PDE-4 inhibitors. This review will provide an update on the current and future IBD drugs, focusing on promising therapies currently in late stage or advanced human clinical trials.

CYTOKINES

TNF-α Inhibitors

The modulation of cytokines is a pivotal modality for the treatment of inflammatory bowel disease, and there are several pipeline drugs targeting various different cytokines. While the intricate and complicated roles of many cytokines remain to be elucidated, several have emerged as targets in inflammatory diseases such as Crohn’s disease (CD) and ulcerative colitis (UC).

The first approved specific cytokine-targeting drug to treat inflammatory bowel disease was the TNF-α inhibitor infliximab. Infliximab was approved in the United States (US) for Crohn’s disease in 1998 under the trade name Remicade. Three other TNF-α inhibitors have since been approved for use in inflammatory bowel disease, adalimumab (Humira) for CD and UC, certolizumab (Cimzia) for CD, and golimumab (Simponi) for UC. At this time several new TNF-α inhibitors have been studied in Crohn’s disease. DLX 105 (ESBATech) is an anti-TNF-α antibody, and its use for fistulizing Crohn’s disease has been studied as a fistula-targeted local injection in a phase II trial (ClinicalTrials.gov NCT01624376), but no results are available. Two oral anti-TNF-α therapies, V565 (VHsquared) and OPRX-106 (Protalix Bio), are in the pipeline. V565 is currently recruiting for a phase II trial for patients with moderately to severely active CD (NCT02976129) after reportedly favorable results in a phase Ib trial (NCT03010787). OPRX-106 demonstrated efficacy in clinical and biomarker improvement in a phase II trial of patients with mild to moderate UC.1 These exciting therapies are worth watching as the oral mode of administration could be of clinical benefit with a much easier mode of administration than currently available TNF-α inhibitors. 

In addition to more novel TNF-α inhibitors, biosimilar agents to infliximab have recently entered the market. In 2016 the FDA approved Inflectra (Remsima)(Pfizer), a biosimilar of infliximab, and this has been followed by Renflexis (Flixabi)(Merck). The FDA approved Cyltezo (adalimumab-adbm) (Boehringer-Ingelheim) in 2017 and Hyrimoz (adalimumab-adaz) (Sandoz) in 2018, both biosimilars to Humira. In September of 2018, Hulio (Mylan and Fujifilm Kyowa Kirin Biologics), another biosimilar to adalimumab, was approved for use in IBD in Europe. 

The approval of biosimilars is based largely on extrapolation from efficacy trials in other inflammatory conditions, as the biosimilar is nearly identical to the reference medication and therefore should have the same clinical effects in the same diseases.2 While this rationale is not uncontested, early evidence in multiple studies from Europe supports their use.2-4 Furthermore, several clinical trials investigating the clinical use of biosimilars compared to infliximab in CD and UC are in progress (NCT02452151, NCT03308357, NCT02846961, NCT02998398, NCT02925338). Given the substantial cost of biologic medications and the ever-present need to provide cost-effective treatment strategies, the use of biosimilars is likely to increase, and many more biosimilar medications are likely to come to market in the near future.

Anti-Interleukins

Several interleukins (ILs), a subset of cytokines, play a critical role in gut inflammation and the pathogenesis of IBD and have been identified as important treatment targets. Perhaps the most promising target interleukin is IL23 with or without concomitant inhibition of IL12. IL23 and IL12 are critical mediators of T cell differentiation and function.5 While the exact role of IL12 and IL23 in the pathogenesis of Crohn’s disease is unclear, IL23 in particular is thought to be important in the pathogenesis of CD through induction of IL22 expression.6 Ustekinumab (Stelara) (Janssen) is an inhibitor of IL12 and IL23 through direct action on P40, a subunit of both interleukins.5 In 2016 ustekinumab became the only approved IL12/23 inhibitor in inflammatory bowel disease (CD), and a recent phase III long-term extension trial demonstrated reduction in the incidence of CD-related hospitalization, surgery, and alternative biologic therapy at two years in patients treated with ustekinumab compared to placebo.7

There are several specific IL23 inhibitors currently in clinical trials. Two of the most promising IL23 inhibitors currently in the pipeline, are MEDI2070 (brazikumab) (Allergan) and risankizumab (AbbVie). Both MEDI2070 and risankizumab are selective inhibitors of IL23 via selective binding of the p19 subunit, a component of IL23 but not IL12.6,8 MEDI2070 recently demonstrated efficacy in a phase IIa trial for patients with moderate to severe CD who had previously failed anti-TNF therapy.6 In this double-blind, placebo-controlled study, 119 patients received either placebo or 700mg MEDI2070 IV at weeks 0 and 4, followed by open-label MEDI2070 210 mg subcutaneously every 4 weeks from week 12-112. The primary outcome of clinical response at week 8, (either remission defined as a Crohn’s disease activity index [CDAI] score <150, or a decrease in CDAI score of 100 from baseline), was achieved in 49.2% of the MEDI2070 group compared to 26.7% of the placebo group (p=0.010). In the open label phase of this study, 53.8% of patients that continued to get MEDI2070 and 57.7% of patients who had received placebo then transitioned to open label MEDI2070 achieved clinical response at week 24. A phase IIb/III trial of MEDI2070 in patients with moderate to severe CD is currently active (NCT03759288) as is a phase II trial of MEDI2070 in patients with UC (NCT03616821).

More recently, risankizumab demonstrated efficacy in a phase II, randomized, double-blind, placebo-controlled trial for patients with moderate-to-severe CD.8 In this study 121 patients were randomized, and the primary outcome was clinical remission (CDAI score <150) at week 12. Patients received intravenous infusions of either risankizumab 200 mg, risankizumab 600 mg, or placebo at weeks 0, 4, and 8. The primary outcome was achieved in 31% of the pooled risankizumab arm versus 15% of the placebo arm (p = 0.0489). When separating the risankizumab dose groups, 24% of the 200mg group and 37% of the 600 mg risankizumab group achieved clinical remission (p = 0.31 and p = 0.0252 respectively). A long-term extension phase II trial of risankizumab in patients with moderately to severely active CD is currently underway (NCT02513459), as well as three phase III studies for use in CD that are currently either recruiting or planned (NCT03105128, NCT03104413, NCT03105102). 

Several other IL23 specific inhibitors are rapidly entering clinical trials for CD and UC, including mirikizumab (LY3074828) (Eli Lilly), tildrakizumab (Sun Pharma), and guselkumab (Janssen).9 Of the three, mirikizumab is farthest along in development with two phase II clinical trials recruiting, one for active CD (SERENITY) and another for moderate to severe UC (NCT02891226, NCT02589665 respectively). Guselkumab recently started recruiting for a combined phase II/phase III trial in CD (GALAXI)(NCT03466411) with an expected enrollment of over 2000 participants with a smaller phase IIa trial in UC patients (NCT03662542).

The selective inhibition of IL23 and sparing of IL12 may add increased safety, as IL12 plays a role in defense against intracellular pathogens and may be important in susceptibility to mycobacterial disease.9 Furthermore, risakizumab demonstrated superiority over ustekinumab in a phase II trial for patients with moderate-to-severe plaque psoriasis.10 This further supports the notion that selective IL23 blockade may be superior to combined IL12/23 inhibition for use in inflammatory or autoimmune conditions. The positioning of ustekinumab and other inhibitors of interleukin 23 for use in clinical practice is still being sorted out. One patient subset that may be ideally suited for use of IL12/23 inhibition is patients with CD as well as psoriasis, or those that develop psoriasis induced by TNF-α inhibitors. These assertions are supported by the efficacy of ustekinumab in patients with CD and severe psoriasiform lesions and/or alopecia secondary to TNF-α inhibitor use.9 Additionally, ustekinumab has been proposed as a potential first line agent for moderate to severe CD given comparable efficacy and more favorable safety profile than TNF-α inhibitors,9 although head-to-head data is lacking and more research is needed. 

In addition to the IL12/23 pathway, there is a drug in development that targets IL17 indirectly. Vidofludimus (4SC) is an oral inhibitor of dihydroorotate dehydrogenase (DHODH), which inhibits the proliferation of lymphocytes and IL17 production.11 In an open label, uncontrolled study (ENTRANCE), 8 out of 14 (57.1%) patients with CD and 6 out of 12 (50.0%) patients with UC experienced steroid-free clinical remission at week 12 using CDAI< 150 for CD and clinical activity index (CAI) < 4 for UC.12 Vidofludimus was also reported to be well tolerated, with no serious drug-related adverse events. A phase II dose finding clinical trial of IMU-838 (vidofludimus calcium) (Immunic Therapeutics) in patients with UC recently started recruiting (NCT03341962) with reported plans for a phase II trial in CD as well. 

Inhibition of the pro-inflammatory cytokine IL6 with the fully human monoclonal antibody PF-04236921(Pfizer) has shown promising results for the treatment of CD in phase II trials (ANDANTE I and II).13 These multicenter, randomized trials included an induction study and an open label extension. Patients in this trial had failed ≥ 1 anti-TNF therapy. This trial randomized 249 patients to receive placebo or treatment with PF-04236921 subcutaneously at doses of 10mg, 50mg, or 200mg on days 1 and 28, however enrollment in the 200mg group was discontinued early due to fatalities in a trial for aystemic lupus erythematosus (SLE), and this group was not included in the primary efficacy analysis. The primary endpoint for the induction study was CDAI-70 response rate at weeks 8 or 12, and the primary objective of the open label extension was safety. In the induction study PF-04236921 met the primary endpoint in 49.3% vs. 30.6% for placebo at week 8 (p < 0.05), and 47.4% vs. 28.6% at 12 weeks (p < 0.05). In the open label extension study, a one-time dose escalation to 100 mg was allowed for non-responders beginning at week 8, and 77.8% had their dose escalated to 100mg. Despite the drug’s efficacy, there is some concern regarding signals of gastrointestinal abscess and perforation, which have been reported with other IL6 inhibitors as well. While this does not exclude anti-IL6 therapy from consideration, especially in a treatment refractory population, careful patient selection may be prudent for anti-IL6 therapies going forward. 

An additional cytokine modulator in the pipeline is PF-06480605 (Pfizer). This therapy is also an inhibitor of a cytokine, a blocker of the TNF ligand known as TNFSF15 (TNF super family 15). A phase II trial for patients with UC has reportedly completed enrollment, however no data on efficacy has been published yet (NCT02840721).14

A phase II trial of GSK1070806 (GlaxoSmithKline), a monoclonal antibody to IL18, was recently registered for patients with moderate to severe CD after a single arm phase I trial demonstrated safety in healthy and obese subjects.15

Tumor necrosis factor receptors (TNFRs) have become targets for novel therapeutics. OX40 is a member of the TNFR family. The novel OX40 inhibitor KHK4083 (Kyowa Hakko Kirin) has demonstrated safety and tolerability in a phase I trial for patients with plaque psoriasis.16 KHK8043 is currently being investigated in a phase I (NCT02985593) and a phase II (NCT02647866) clinical trial for patients with UC. 

The importance of cytokines in the pathogenesis of inflammatory bowel disease is highlighted by the numerous promising therapeutics either in use or under investigation that target them. Cytokine modulation is and will certainly continue to be a cornerstone of the treatment of CD and UC. We anticipate that the cytokine modulator pipeline will continue to grow in this arena as our understanding of these pathways continues to evolve. 

Regeneration

Utilizing the innate potential of the stem cell, or modulating the body’s own regenerative capacity to heal disease, is an exciting and active area of research in many diseases including inflammatory bowel disease. Despite many inherent challenges to this type of therapy, advances are being made at a fast pace. It is likely that regenerative medicine will become a powerful and prominent tool for many disease states including inflammatory bowel disease. Stem cell therapy (SCT) for inflammatory bowel disease is beginning to emerge as a potentially viable treatment option for some patients. There are numerous clinical trials either published or registered with Clinicaltrials.gov for use of stem cells in CD and UC. Therapies may include stem cells that are hematopoietic, bone marrow-derived, adipose-derived, or mesenchymal. Both autologous and non-autologous stem cells have been studied. The route of administration can be either systemic or locally injected/delivered.

In March of 2018, the European Commision approved Alofisel (formerly Cx601) (Takeda, TiGenix), the allogeneic expanded, adipose-derived stem cell therapy for the treatment of complex perianal fistulas in adult patients with Crohn’s disease who have shown inadequate response to at least one conventional or biologic therapy. Approval was based on a randomized, double-blind, parallel-group, placebo-controlled phase III trial (ADMIRE-CD) of Cx601 injection for complex perianal fistulas in adult patients with Crohn’s disease demonstrating safety and efficacy.17 In this study 202 patients received a single injection of either Cx601 or placebo (saline solution) into the lesion. The primary endpoint was combined remission, defined as clinical closure of all treated external openings that were draining at baseline, and no collections of greater than 2 cm of treated fistulas on MRI. This was achieved in 50% of the treatment group compared to 34% of the placebo (p = 0.024). This study was also continued for a 52-week period evaluating efficacy endpoints of combined remission (as above), and clinical remission (absence of draining fistulas). At 52 weeks 56.3% of the treatment group achieved combined remission compared to 38.6% in the control group (p = 0.021); and 59.2% of the treatment group compared to 41.6% of the control group achieved clinical remission (p = 0.013). Cx601 also proved to be safe, with similar rates of adverse events in both groups.17 A large, multicenter, phase III trial (ADMIRE-CD II) in underway to gain FDA approval (NCT03279081). Additional promising stem cell therapies in the pipeline include Furestem-CD (Kangstem Biotech) (NCT02000362, NCT02926300) in phase I and II trials for CD, PROCHYMAL (NCT00482092, NCT00543374, NCT01233960) in phase III trials for CD, and MultiStem (NCT01240915) in a phase II trial for UC.

A recent meta-analysis of stem cell therapy (SCT) for CD analyzed 21 studies that included 514 patients.18 This study found that systemic infusion of SCT resulted in 56% of patients achieving clinical response using random-effects meta-analysis (95% confidence interval [CI] 33-76, n=150). Efficacy was also demonstrated when evaluating clinical and endoscopic remission, and for patients with perianal CD. This analysis suggests that SCT may be effective, however the rate of severe adverse events (SAEs) was also significant. In this meta-analysis, the overall pooled rate of SAEs was 12%. The pooled rate of SAEs related to SCT was 8%. Severe adverse effects of SCT could be a significant obstacle to the use of these therapies. The use of adipose-derived mesenchymal stem cells as intralesional injection therapy for perianal fistulae in CD is perhaps closest to mainstream clinical use in the US. These studies, combined with the meta-analysis previously discussed, enabled the use of this therapy in Europe, and suggests that intra-fistula injection of adipose-derived stem cells may soon become a readily available treatment options for these patients in the US. In addition to therapies that utilize administration of actual stem cells, several emerging therapies aim to modulate or induce the regenerative capacity of a patient’s own stem cells. Preliminary evidence suggests that regenerative therapies hold great promise as treatments for IBD. While many barriers to their widespread use remain, this is an area that is likely to occupy a significant role in the treatment of IBD in the future.

Barrier and Mucosal Agents

The use of barrier or mucosal augmentation agents to help reconstitute and protect the intestinal mucosa is an exciting potential therapeutic area under investigation. These are directly acting, mechanistically based, and ideally not systemically absorbed. The investigators postulate that barrier agents may be uniquely suited to be low toxicity augmentations to other therapies, or potentially non-systemic maintenance therapy.

For patients with ulcerative colitis, the administration of oral phosphatidylcholine represents perhaps the most promising potential barrier augmentation therapy. The concentration of phosphatidylcholine in intestinal mucous has been shown to be lower in patients with UC compared to both patients with Crohn’s disease and healthy controls.20 It is for this reason that re-constituting this barrier with delayed release phosphatidylcholine has been studied as a potential therapy in several clinical trials for patients with UC.21One such therapy is LT-02 (Nestlé Health Science), which demonstrated promising early results in clinical trials, including a phase II trial for UC patients refractory to mesalazine.22 This was a double-blind, randomized, placebo-controlled superiority study that analyzed 156 patients with UC and a deficient response to mesalazine therapy. Co-medication with 5-ASA, systemic steroids, azathioprine, and 6-mercaptopurine was allowed if specific dosing and duration criteria were met. Patients receiving rectally applied aminosalicylates or steroids, or oral topically acting steroids were excluded. The primary endpoint was change in the simple clinical colitis activity index (SCCAI). This study compared placebo to LT-02 doses of 0.8g, 1.6g, and 3.2g, and demonstrated a SCCAI score decrease of 33.3% in the placebo group vs. 44.3% in the 0.8g, 40.7% in the 1.6g, and 51.7% in the 3.2g doses (p>0.05, p>0.05, and p=0.030 respectively). Remission for placebo vs. 3.2g was 15% vs. 31.4% (p=0.089). Interestingly, despite a modest clinical improvement in patients receiving LT-02 vs. placebo, histologic remission was achieved in 20% of placebo patients compared to 40.5% LT-02 patients (p=0.016). Patients achieved mucosal healing in 32.5% for placebo vs. 47.4% for LT-02(p=0.098). Furthermore, the safety profile was very favorable. 

These promising results led to the study of LT-02 in phase III trials. Three phase III trials for LT-02 in UC have been initiated, PROTECT-1 (NCT02142725), PROTECT-2 (NCT02280629), and PROTECT-3 (NCT 02849951). PROTECT-1 investigated LT-02 at two doses compared to placebo for remission induction in patients with UC refractory to mesalamine, but was unfortunately terminated. PROTECT-2 is investigating LT-02 at the 3.2g dose for maintenance of remission over 48 weeks, and is currently recruiting. PROTECT-3 investigated LT-02 as an add-on therapy for the induction of remission in UC patients refractory to mesalamine, but unfortunately has also been terminated. Given the termination of two studies aimed at induction of remission, it is reasonable to deduct that LT-02 may have more promise as maintenance therapy with a favorable safety profile for UC patients already having achieved remission.

Other therapies that address the unique needs of the inflamed colonic mucosa rather than creating a mechanical barrier have been investigated. Luminal short-chain fatty acids (SCFAs) are thought to be important for colonic integrity, blood flow, motility, and mucous.23,24 Two small studies of SCFA delivered topically as enemas have been performed without compelling evidence for efficacy.25,26 L-Carnitine is critical in fatty acid transport/metabolism, and propionyl-L-carnitine (PLC) is thought to potentially represent a colonic reserve of propionyl-coenzyme-A and L-carnitine in the colon of patients with UC.23 PLC is also thought to be anti-inflammatory and have antioxidant effects in the intestinal mucosa of UC patients.27 PLC has been studied in a phase II trial for patients with UC due these potential effects on SCFA metabolism as well as protective effects on reactive oxygen species present in states of inflammation.23 This double-blind, parallel-group trial randomized 121 patients with UC on stable aminosalicylate or thiopurine therapy to receive 1g/day PLC, 2g/day PLC, or placebo.23 The primary endpoint was “clinical/endoscopic response” using the disease activity index (DAI) as the measure. The study reported good results for both dose groups, with 72% of PLC treated patients achieving clinical/endoscopic response vs. 50% in the placebo group (p=0.02). The remission rates did not achieve statistical significance for PLC treated vs. placebo. Unfortunately, two phase III clinical trials of propionyl-L-carnitine hydrochloride (ST 261) were terminated due to low probability of success (NCT01538251, NCT01567956.) Despite these failures, the general concept of mucosal function augmentation with safe and tolerable oral supplementation such as PLC persists as a potential therapeutic avenue.

Alkaline phosphatase (AP) is a highly important and prevalent enzyme in many living organisms including humans.28 AP is expressed as an apical brush border enzyme in the intestinal tract and is thought to play an important role in mucosal defense through dephosphorylation of inflammatory molecules.28,29 An exploratory open label study of exogenous AP in 21 patients with refractory UC reported improvement in short term disease activity scores as well as lower levels of C-reactive protein(CRP) and fecal calprotectin.29 Of note, in this study the exogenous AP was administered intraduodenally via naso-duodenal tube daily for 7 days. Previously, exogenous AP has been studied intravenously for safety in a variety of conditions. Since then AM-Pharma has developed a fully human recombinant form of AP known as recAP, and is currently studying intravenous recAP in a phase II trial for acute kidney injury due to sepsis (NCT02182440).30 The authors could not find active clinical trials in UC. Alkaline phosphatase appears to be a promising agent to promote protection from inflammation at the mucosal barrier of the intestine, but there remain significant challenges in drug delivery. Should a stable intestinal-release oral formulation become feasible, human AP could represent another safe mucosal-based therapy for UC.

The future direction of barrier reconstitution and augmentation therapies appears promising, and the authors anticipate their incorporation into the UC armamentarium in the near future.

JAK Inhibitors 

Therapeutics targeting the Janus kinase (JAK) pathway offer a particularly promising class for the treatment of IBD. JAKs are a family of receptor-associated tyrosine kinases that are crucial in cytokine signaling.31 Their importance in cytokine signaling makes JAK signaling a key pathway in autoimmune disorders including rheumatoid arthritis and inflammatory bowel disease.31 JAK antagonists are actively being used or investigated for several disease states, including inflammatory bowel disease. Thus far several JAK inhibitors have demonstrated promising efficacy for the treatment of Crohn’s disease and ulcerative colitis, and their oral delivery represents an additional potential benefit. As a class, JAK inhibitors do exhibit significant side effects including lymphopenia, leukopenia, liver enzyme elevations, dyslipidemia and herpes zoster reactivation.32

Tofacitinib (Xeljanz) (Pfizer) is a pan-JAK inhibitor with a preference for JAK1 and JAK3 that has demonstrated efficacy in the treatment of ulcerative colitis.33 As a result, Tofacitinib was recently approved in the United States and Europe for moderate to severe active ulcerative colitis (UC) based on phase II and phase III trials. Phase III trials, titled Oral Clinical Trials for tofAcitinib in ulceratiVE colitis (OCTAVE), were published in May 2017. OCTAVE Induction 1 included 614 randomized patients assigned to placebo, tofacitinib 10 mg twice daily, or tofacitinib 15 mg twice daily. The primary endpoint was remission at 8 weeks, defined a Mayo score ≤ 2, no subscore > 1, and rectal bleeding subscore = 0. Mucosal healing, defined as a Mayo endoscopic subscore ≤1, was a secondary endpoint. Remission occurred in 18.5% of the 10 mg tofacitinib group compared to 8.2% of placebo (p=0.007). Mucosal healing was achieved in 31.3% in the 10 mg tofacitinib group vs. 15.6% in the placebo group(p<0.001). OCTAVE Induction 2 examined the same endpoints in 547 randomized patients. Remission was achieved in 16.6% of the 10 mg tofacitinib group vs. 3.6% of the placebo group(p<0.001). Mucosal healing was achieved in 28.4% of the 10 mg tofacitinib group vs. 11.6% of the placebo group (p<0.001).33

The OCTAVE Sustain trial randomized 593 patients that had completed OCTAVE Induction 1 or 2 and had a clinic response to receive placebo, tofacitinib 5 mg twice daily, or tofacitinib 10 mg twice daily. The primary endpoint of remission at 52 weeks was achieved in 11.1% of placebo, 34.3% of the tofacitinib 5 mg group, and 40.6% of the tofacitinib 10 mg group (p<0.001) for each treatment compared to placebo. The secondary endpoint of mucosal healing was also significantly higher for both treatments compared to placebo. Unfortunately tofacitinib failed to demonstrate efficacy based on the CDAI as induction or maintenance therapy in two phase II studies for moderate-to-severe Crohn’s disease, despite significant decreases in CRP and FCP.35,36

Another exciting JAK inhibitor is filgotinib (GLPG0634/GS-6034)(Galapagos), which is a selective inhibitor of JAK1.37 Filgotinib has demonstrated efficacy in several phase II trials for rheumatoid arthritis.38-40 Filgotinib also delivered promising results in a phase II clinical trial for moderate to severe Crohn’s disease.41 This trial was a randomized, double-blinded, placebo-controlled trial that enrolled 174 patients. This study compared filgotinib 200 mg daily given orally to placebo. The primary endpoint was clinical remission, defined as Crohn’s Disease Activity Index less than 150 at week ten. At week ten, 47% of the filgotinib group achieved clinical remission compared to 23% of the placebo group (p=0.0077). These early results are certainly promising, and there are currently multiple registered clinical trials for filgotinib in inflammatory bowel disease, all of which are currently recruiting. Phase II trials that are recruiting include studies investigating filgotinib for the treatment of small bowel Crohn’s disease (NCT03046056), and for perianal fistulizing Crohn’s disease (NCT03077412). Phase III trials include investigating filgotinib for moderately to severely active Crohn’s disease (NCT02914561), for moderately to severely active ulcerative colitis (NCT02914522), and long-term extensions for patients with Crohn’s disease (NCT02914600) and ulcerative colitis (NCT02914535). 

Upadacitinib (ABT-494) (AbbVie) is a more potent JAK1-selective inhibitor that is currently being investigated for use in Crohn’s disease, ulcerative colitis, rheumatoid arthritis, atopic dermatitis, and psoriatic arthritis.42 CELEST (NCT02365649) was a phase II, randomized, double-blinded, placebo-controlled study investigating upadacitinib for patients with moderately to severely active Crohn’s disease.43 The study which required intolerance or poor response to TNF inhibitors or immunomodulators, enrolled 220 patients, and investigated an array of dosages of upadacitinib compared to placebo. Efficacy was seen with regards to clinical response and remission as well as endoscopic remission at 16-weeks. Similarly, a 52 week maintenance extension showed maintenance of response at 52 weeks.44 A phase II study evaluating long term efficacy, safety and tolerability in patients with Crohn’s disease is ongoing with expected completion in 2022 (NCT02782663). Additionally, upadacitinib is being studied in a phase II trial for induction and maintenance in patients with moderately to severely active ulcerative colitis (NCT02819635). Currently recruiting/enrolling phase III trials of upadacitinib include a trial for patients with Crohn’s disease and intolerance or inadequate response to conventional therapies but not biologics (NCT03345849), a maintenance and long term extension study in patients with Crohn’s disease (NCT03345823), a study of patients with Crohn’s disease and inadequate response or intolerance to biologic therapy (NCT03345836), and a study of long term safety and efficacy in ulcerative colitis (NCT03006068). 

TD-1473 (Theravance Biopharma) is a gut-selective multi-JAK inhibitor that has reportedly demonstrated promise in a small phase Ib trial for moderate to severe UC according to a press release by Theravance Biopharma.45 While data is extremely preliminary, TD-1473 is gut-selective. The potential to avoid systemic side effects from JAK inhibition with a localized gut-selective agent is very appealing, making this agent another exciting pipeline therapy in the JAK inhibitor class. A phase IIb evaluation of the efficacy and safety of induction and maintenance therapy with TD-1473 in subjects with moderately-to-severely active ulcerative colitis was recently registered (NCT03758443), however recruitment has not started. 

In addition to the promising efficacy of JAK inhibitors in IBD, their oral delivery represents an additional potential benefit to both patients and physicians. These benefits must be weighed against factors such as cost, risks, and side effects. Shingles is the most prominent adverse event in tofacitinib trials, which seems likely to be ameliorated by prior use of the recombinant Shingrix vaccine. Similarly, it is expected that the JAK-1 specific inhibitors will have less occurrence of shingles, but this remains to be proven in clinical trials. The authors anticipate that additional selective JAK inhibitors will achieve approval for ulcerative colitis and Crohn’s disease in the near future.

Anti-Adhesion and Chemotaxis Therapies

Anti-adhesion therapies aim to prevent the interaction between adhesion molecules expressed on the endothelium of blood vessels and molecules expressed on the leukocyte cell surface, primarily integrins. By preventing this interaction, leukocytes are unable to migrate into gut tissue from the vasculature and propagate tissue inflammation. Natalizumab (Tysabri) was the first drug in this class to be approved for use in CD, after the phase III ENCORE trial demonstrated efficacy.46 As a monoclonal antibody targeting the a4 integrin subunit, it was designed to have broad effects, blocking the gut-specific a4β7 integrin for Crohn’s disease as well as the a4β1 integrin in the brain for multiple sclerosis. Unfortunately, long-term natalizumab use was associated with increased susceptibility to JC virus infection in the brain and subsequent development of progressive multifocal leukoencephalopathy (PML).47 As a result, the FDA suspended its use in general clinical practice and clinical trials in February of 2005 and it is currently restricted to registered providers in select circumstances through the TOUCH prescribing program.

Vedolizumab (Entyvio) (Takeda), a monoclonal antibody targeting the gut-specific a4β7 ?integrin, has since been developed and showed efficacy in phase III trials (GEMINI) for induction and maintenance in Crohn’s disease and ulcerative colitis and was approved by the FDA in May of 2014.48,49 Abrilumab (AMG 181/MEDI 7183) (Amgen) was designed as an antibody against gut specific a4β7?integrin with reduced immunogenicity as compared to Vedolizumab. Unfortunately, phase II trials failed to demonstrate efficacy in inducing remission rates at 8 weeks in moderate to severe Crohn’s disease, though modestly increased response rates were observed.50 Abrilumab demonstrated improved rates of remission, response, and mucosal healing at doses of 70mg and 210mg. This was seen in all subjects as well as subjects who previously failed anti-TNF.51 A phase II trial of PTG-100 (Protagonist Therapeutics)(NCT02895100), an oral gut-specific a4β7 ?integrin antagonist, was initially terminated due to lack of efficacy. However, an independent, blinded, re-read of endoscopies demonstrated higher rates of clinical remission relative to placebo. The initial lack of response was attributed usually high placebo effect due to “misread endoscopy reports”. An official report is expected to be published in 2019.

Etrolizumab (RG7413/rhuMAb Beta7) (Roche) is a monoclonal antibody that targets the β7 subunit of a4β7 and aEβ7 integrin (involved in T? cell retention via interaction with E-cadherin) on T lymphocytes. A phase II clinical trial, EUCALYPTUS, demonstrated efficacy of Etrolizumab in inducing and maintaining remission in patients with UC.52 The recently published phase III BERGAMOT trial demonstrated higher rates of symptomatic remission and endoscopic remission as early as 6 weeks and sustained through week 14 in CD patients refractory/intolerant.to anti-TNFa agents. The maintenance phase of this trial is still ongoing.53 Etrolizumab is currently being studied in seven additional phase III clinical trials in both UC and CD in both anti-TNF naive and exposed patients (NCT02100696, NCT02163759, NCT02171429, NCT02165215,, NCT02118584, NCT02136069, NCT02394028, NCT02403323).

AJM300 (Carotegrast) (EA Pharma) is an oral small molecule directed against the a4 integrin involved in lymphocyte homing to the gut and brain. Phase II clinical trials in UC demonstrated significantly higher rates of clinical response, remission, and mucosal healing at 8 weeks compared to placebo,54 however no significant difference was noted in patients with CD.55 Phase III development for ulcerative colitis is ongoing in Japan. Although there is a theoretical risk of PML with AJM300, given the presence of a4 in brain lymphocytes, the manufacturer speculated that the short half-life of this thrice daily small molecule could facilitate rapid cessation should PML occur, and that the subsequent resumption of immune activity might prevent significant brain damage. However, given the significant potential for harm caused by PML, the evidence level required for any future a4 agent to reach market is expected be extremely high.

Based on the success of targeting integrins, investigation has also focused on preventing lymphocyte migration and tissue infiltration by inhibiting the mucosal addressin-cell adhesion molecule 1 (MAdCAM-1) present on intestinal and colonic vascular endothelial cells. This molecule is the target of the a4β7 integrin blocked by vedolizumab and etrolizumab. SHP647 (previously known as PF-00547659) (Shire, previously Pfizer) is an anti-MadCAM-1 antibody that was shown in phase II studies to be significantly more effective than placebo in achieving clinical remission, clinical response, and mucosal healing in patients with UC who failed prior therapy (TURANDOT).56 Results of phase II studies in patients with CD (OPERA-1) did not show significant efficacy as induction therapy,57 however, the results of the maintenance part of the phase II study (OPERA-2) suggested sustained efficacy over 72 weeks, but not a clear dose-reponse signal.58 Phase III trials of SHP647 in patients with moderate to severe ulcerative colitis have recently started ruiting (NCT03259334, NCT03259308) with plans to start recruiting for a phase III long-term maintenance trial (CARMEN CD 305, 306 307) in patients with moderate to severe Crohn’s disease (NCT03345849, NCT03627091, NCT03559517). However, development of this promising therapy may be further slowed by the purchase of Shire by Takeda, and the required sale of this drug to another company as it competes with vedolizumab.

Eldelumab (BMS-936557) (Bristol-Myers Squibb) is a monoclonal antibody that binds to Interferon-y-inducible protein-10 (IP-10, also known as CXCL10) and blocks lymphocyte migration into intestinal epithelial cells. Results of phase II clinical trials of Eldelumab in UC and CD did not demonstrate significant efficacy in induction therapy.59,60

“Lymph node trapping” through modulation of sphingosine-1-?phosphate (S1P) receptors has emerged as an exciting target for modulating gut inflammation in IBD. S1P signaling is thought to play a critical role in migration of lymphocytes from peripheral lymph nodes to gut lymphoid tissue.61 Ozanimod (formerly RPC1063) (Celgene) is an oral S1PR1 and S1PR5 agonist, that produced increased clinical remission rates in ulcerative colitis after 8 weeks of induction(TOUCHSTONE) and Crohn’s disease (STEPSTONE) when compared to placebo in phase II clinical trials.62 Two phase III open-label extension studies are currently ongoing for patients with moderate to severe UC who were treated with ozanimod in previous trials (NCT02531126, NCT02435992). Phase II trials of Amiselimod (MT-1303) (Biogen), a S1PR1 modulator, were recently discontinued while phase II trials of Etrasimod (APD334) (Arena), another oral S1PR1 modulator, are still ongoing recently demonstrated positive results in patients in UC patients. Reportedly phase III trials are planned, however, have not been registered. 

Alicaforsen (ISIS 2302) (ISIS Pharmaceuticals) is a 20-base antisense oligonucleotide that is highly selective for intercellular adhesion molecule-1(ICAM-1) mRNA resulting in ICAM-1 down regulation. ICAM-1 is an adhesion molecule involved in leukocyte migration and trafficking in the gut. While phase II trials demonstrated that topical alicaforsen was more effective than placebo in inducing long term remission in patients with distal UC, there was no significant difference when compared to mesalamine enemas.63 Results of a phase II clinical trial investigating IV Alicaforsen in patients with CD were similarly disappointing.64 There is evidence that Alicaforsen may be effective in chronic refractory pouchitis.65 Vercinon (CCX282-B) (GSK-1605786) (GlaxoSmithKline) is an oral small molecule that binds to and blocks CCR9 receptors on the surface of lymphocytes which are involved in lymphocyte trafficking. This was studied in a phase III clinical trial (SHIELD-1), however results did not show significant efficacy compared to placebo in patients with CD and the program was discontinued in August of 2013.66

Immune Cell Modulation

Lymphocytes play a critical role in gut inflammation and the pathogenesis of IBD. Therapeutic strategies targeting aberrant lymphocyte differentiation, activation, survival, and functioning represent an important area of interest with variable success. Early attempts at modulating lymphocyte function with rituximab, (an anti-CD20 monoclonal antibody),67 and lenalidomide, (a derivative of thalidomide used in multiple myeloma),68demonstrated no efficacy in treating IBD. IL2 plays an important role in promoting regulatory T cell (Treg) proliferation and survival as well as differentiation into proinflammatory effector T cells including Th17. Unfortunately, daclizumab, a monoclonal antibody to the IL2 receptor (CD25) showed no effect in phase II trials in UC.69

T cell activation occurs by simultaneous engagement of the T cell receptor, co-receptor complex (CD3), and co-stimulatory molecule (CD28) by antigen presenting cells. Both CD3 and CD28 have been proposed as therapeutic targets. Visilizumab (HuM291) (Nuvion) is a monoclonal antibody to the CD3 chain of the T-cell receptor complex which has been shown to diminish cytokine release and T cell activation while inducing T cell apoptosis. Unfortunately, visilizumab was not effective for severe, corticosteroid-refractory UC and was associated with increased infectious, cardiac, and vascular adverse events70 despite positive phase I and phase II studies at higher doses.71,72 As a consequence, the clinical development of visilizumab was halted. 

Another T cell targeting agent, foralumab (NI-0401/TZLS-401) (Tiziana), a human anti-CD3 antibody was evaluated in a phase II clinical trial in patients with moderate to severely active Crohn’s disease (NCT00630643), however results of this study remain unpublished. Abatacept (BMS-188667) (Orencia) (Bristol-Myers Squibb), which inhibits T cell co-stimulatory signaling by binding to C80/CD86 on antigen presenting cells, thus preventing CD28-mediated co-stimulation, was also unsuccessful in phase III trials of patients with moderate to severe UC and CD.73

Laquinimod (TV-5600, previously ABR-215062) (TEVA) is a novel oral therapy with a proposed mechanism of direct inhibitory effect on antigen presenting cells and T cells, resulting in downregulation of pro-inflammatory cytokines. Phase II trials demonstrated significantly higher rates of remission and response compared to placebo in patients with CD.74 Currently phase III trials are underway for MS but no trials are registered at clinicaltrials.gov for IBD as of yet. 

Upregulation of immunoregulatory cytokines, such as TGF-?, has been an exciting area of investigation. TGF-? suppresses the activation and functioning of pro-inflammatory effector T cells. High concentrations of intracellular SMAD7 inhibit TGF-? pathways leading to development of colitis in animal models75. Mongersen (Formerly GED-0301) (Celgene) is an oral pH controlled 21base single-stranded oligonucleotide that binds and facilitates degradation of SMAD7 mRNA. Phase II trials demonstrated significant efficacy in clinical remission compared to placebo,76,77 with minimal data on biologic remission. After studies including an endoscopic endpoint in 2017, Celgene shut down four planned and ongoing phase III clinical trials testing the safety and efficacy of mongersen (NCT02641392, NCT02685683, NCT02596893, and NCT02974322). 

Kappaproct (Cobitolimod) (DIMS0150) (InDex) is a locally administered DNA-based immunomodulatory sequence that binds to the toll-like receptor 9 (TLR9). This leads to the release of anti-inflammatory cytokines such IL10 and type I interferons to reduce intestinal inflammation and induce mucosal healing.78,79 A phase III clinical study demonstrated increased rates of symptomatic remission as well as histological remission compared to placebo in patients with ulcerative colitis at week four. This was seen after two doses of topically administered drug during colonoscopy at weeks 0 and 4.80 It remains to be seen whether oral administration will have comparable efficacy with results expected by the end of 2018. Another interesting approach currently being investigated involves hampering Th2-mediated inflammation which has been shown to play a role in the pathogenesis of UC. SB012 (Sterna Biologicals) is a rectally delivered DNAzyme-based GATA-3 antagonist. GATA-3 is a transcription factor that plays a key role in regulating Th2 differentiation, activation, and proinflammatory cytokine release such as IL4, IL5, and IL13. Preclinical studies demonstrated that inhibition of GATA-3 mRNA expression in T cells resulted in suppressed colitis in experimental mice models.81 In May of 2014 recruitment for a phase II trial, 

SECURE (NCT02129439) was initiated in patients with UC which recently concluded in March of 2018 with published abstract suggesting safety and efficacy in disease activity improvement at 28 and 56 days.82

In addition to lymphocytes, the activity of macrophages and NK cells is being investigated as an area of interest. ABX464 (Abivax) is an oral small molecule that has been shown in mouse models to reduce colonic production of macrophage-induced inflammatory cytokines such as IL6 and TNF-α and increase tissue repair via cytokine IL22.83 A recent phase 2a induction trial of ABX464 reportedly demonstrated significant increase in clinical remission and mucosal healing over placebo in patients with moderate to severe active ulcerative colitis who failed or were intolerant to other therapy with an extension study evaluating the long-term safety and efficacy currently recruiting (NCT03368118). Interestingly, ABX464 is also currently being investigated in HIV due to its ability to block HIV replication. In March of 2017 recruiting for a phase IIa trial (NCT03093259) of Abivax in moderate-to-severe active UC began.

Another cell-targeting therapy, NNC0142-0002 (Janssen) is an antibody directed against the natural killer group 2D (NKG2D) protein, demonstrated increased clinical remission after week 12 in patients with CD in a phase II study as well as a significant improvement in a biologic non-failure subgroup from week one onward despite not meeting their primary endpoints (clinical response at 4 weeks).84 Two new clinical studies with the anti-NKG2D biologic have reportedly been planned for moderately to severely active Crohn’s, but as yet they have not been registered with clinicaltrials.gov. 

Bertilimumab (Immune Pharmaceuticals) is a monoclonal antibody that targets eotaxin-1, a chemokine involved in eosinophils migration to inflamed tissue. A randomized, double blind phase 2 trial is actively enrolling patients with severe UC (NCT01671956), however recruitment has been ongoing for over 2 years. 

TOP1288 (TopiVert Pharma) is a rectally administered, non-absorbed, narrow spectrum protein kinase inhibitor (NSKI) that has been shown to be effective in reducing inflammation in mouse models of colitis.85 TOP1288 is currently undergoing a randomized, double-blind, placebo-controlled multicenter phase IIa clinical trial for patients with moderate to severe UC (NCT02888379) and a phase I clinical trial with the non-absorbed oral formulation (NCT03071081).

P28GST (Satt Nord) is a recombinant protein glutathione-S-transferase. It is found in the intestinal helminth parasite Schistosoma. It has been shown to promote Th2 mediated cytokine release and reduce intestinal inflammation as well as decrease colitis in experimental mouse models.86,87 This is currently being investigated as a therapeutic vaccine in a phase II, multicenter clinical trial in patients with moderate CD (NCT02281916).

GSK2982772 (GlaxoSmithKline) is a first in class small molecule inhibitor of receptor-interacting protein-1 (RIP1) kinase, which is involved in necroptosis (programed inflammatory cell death) and inflammation via TNF dependent cellular responses.88Currently GSK2982772 is being evaluated in a phase II, multicenter, randomized, placebo-controlled study is patients with UC (NCT02903966). 

LYC-30937-EC (Lycera) is a first in class, oral, gut-directed ATPase modulator, designed to selectively target and induce apoptosis in lymphocytes. Currently two phase II trials have completed recruiting in patients with active UC (NCT02762500, NCT02764229), but did not show statistically significant benefits.

QBECO SSI (Qu Biologics) is an investigational immunotherapy that is derived from inactivated E. coli bacteria and is designed to restore innate immune function in the gastrointestinal (GI) tract. Phase I/II trials demonstrated safety and efficacy in patients with both CD and UC. A larger phase II trial of both induction and maintenance therapy in patients with moderate to severe CD is currently recruiting at five centers in Canada (NCT03472690).

Microbiome Targeted Therapies

Multiple studies have demonstrated that intestinal dysbiosis plays a key role in the development and exacerbation of IBD through aberrant mucosal inflammation.89 As a result, various therapeutic strategies aimed at manipulating the intestinal microbiome are currently in development. Investigation has focused on diet, probiotics, prebiotics, antibiotics, and fecal microbiota transplant (FMT).

Diet and Nutritional Supplementation

Dietary approaches to managing IBD represent an under-resourced, difficult, but important area of study. This was highlighted by an online questionnaire showing that 71% of IBD patients believe that diet affects their disease and that 61% of patients believe their specialist disregarded the importance of diet the management of their disease.90Despite the patient perspective on diet and nutritional supplementation in the management of IBD, very few rigorously designed prospective trials exist. 

Diets of popular interest include the semi-vegetarian diet (SVD), the specific carbohydrate diet (SCD), the exclusive enteral nutrition (EEN), the low fermentable oligosaccharide, disaccharide, monosaccharide, and polyol (FODMAP) diet, and the allergen elimination diet. A small prospective trial in Japan demonstrated that a semi-vegetarian diet, with small portions of meat offered once every two weeks and fish weekly, had higher rates of remission and prevention of relapse compared to omnivores in hospitalized patients with CD.91,92 Exclusive enteral nutrition (EEN) has been shown in pediatric CD patients to be as effective as corticosteroids in inducing disease remission with higher rates of histological improvement.93 Unfortunately, these results have not been reproduced in adult studies.94 Specific carbohydrate diets, consisting of mostly meat, fruits, vegetables, nuts, oils, and honey with the elimination of most grains, have shown some efficacy in pediatric patients with IBD in retrospective and small single arm clinical trials.95,96Multiple additional early phase trials have been registered and are recruiting in both pediatric (NCT02610101, NCT03301311) and adult patients (NCT03058679, NCT02412553, NCT02858557). Multiple small observational studies 97,98 and one small randomized cross-over study99 have demonstrated that low FODMAP diets (elimination of poorly absorbed short-chain carbohydrates) are effective in improving clinical symptoms of pain, bloating, and distention in patients with IBD, however larger prospective clinical trials are needed. Currently a 30 participant randomized trial of a low FODMAP diet compared to a control diet is recruiting patients with UC (NCT02469220). A large, randomized, controlled trial, conducted at three London teaching hospitals showed improvement in quality of life in CD patients with the implementation of an IgG4-targeted elimination diet. The research group used IgG4 reactivity to guide exclusion of the four food types with the highest IgG4 titers in the treatment group compared to the elimination of the four food types with the lowest IgG4 titers in the sham control group.100

Omega-3 free fatty acids (Epanova) (AstraZeneca) were evaluated in Crohn’s disease patients in two large randomized, double-blind, placebo-controlled studies (EPIC-1 and EPIC-2), and did not show efficacy in maintaining remission.101 However, recently published results of a phase II clinical trial evaluating the efficacy of eicosapentaenoic acid (TP-252) (Thetis) in maintaining remission for patients with UC, the major component of fish oil, demonstrated significant improvements in fecal calprotectin levels and maintenance of clinical remission at six months.102

A large, multi-center, randomized, control trial of curcumin, the biologically active component of turmeric with anti-inflammatory and antioxidant effects, showed higher rates of remission as well as improved clinical and endoscopic scores in patients with UC when added to standard therapy compared to standard therapy alone.103 Additional phase III clinical trials evaluating the efficacy of curcumin have recently been registered in both pediatric (NCT02277223) and adult patients (NCT02683759) with UC. A randomized, double-blind, placebo-controlled study of vitamin D administration (2000.IU/day) demonstrated increased plasma cathelicidin, improved intestinal permeability (measured by urinary sugar excretion), lower CRP, and higher QoL in patients with CD.104

Andrographis paniculata extract (HMPL-004) (Hutchison Medi Pharma), a plant extract with broad anti-inflammatory properties (inhibiting TNF-α, NF-κB, and ILβ),105demonstrated efficacy in phase II clinical trials.106 However phase III clinical trials further evaluating effectiveness of HMPL-004 in induction therapy (NCT01805791) and maintenance therapy (NCT01882764) were terminated due to an interim analysis which demonstrated futility in continuing its development. AndoSan (ACE Co. Ltd) is an extract from the Agaricus blazei Murill, a mushroom from Brazil with anti-inflammatory properties that has been evaluated in a phase II/phase III trial. This randomized, single-blinded, placebo controlled trial demonstrated improvement in symptom score, fatigue, and health related quality of life compared to placebo in patients with UC.107 Additional trials of anti-bacterial and anti-inflammatory mastiha gum, derived from the mastic tree in Greece, are currently ongoing (NCT02796339), as are studies of the effects of citrus extract (NCT03225261) and flaxseed lignan-enriched complex (NCT02201758).

Probiotics and Prebiotics

Augmentation of the protective functions of “good” bacteria in the GI tract through the use of probiotics and prebiotics have recently emergent as an area of interest. Single probiotic strains of non-pathogenic E. coli Nissle 1917108 and Lactobacillus GG109 demonstrated effectiveness in single trials in maintenance of remission in UC patients. Several trials have demonstrated that VSL#3 (a cocktail of eight different bacteria species) may be effective in inducing and maintaining remission in UC110,111 and preventing the development and recurrence of pouchitis.112-114 Several clinical trials investigating the role of probiotics for CD induction and maintenance therapy have failed to yield positive results.115,116

Another multi-probiotic, SER-287 (Seres Therapeutics), consists of live bacterial spores that proliferate and replace pathogenic “bad” gut bacteria. SER-287 reportedly showed benefit in clinical remission rates and endoscopic scores in patients with UC in a phase Ib placebo-controlled trial (NCT02618187). 

In recent years, attention has shifted to prebiotics, which are non-digested compounds that shift microbial composition to promote protective “good bacteria” growth. This is achieved by serving as preferential metabolites for these bacteria. In preclinical studies, prebiotics have shown improved growth of “good bacteria”,118,119 reduced inflammatory cytokine production,120 and reduced fecal calprotectin levels.121 Clinical use has been limited by high participant dropout due to bloating and discomfort among IBD patients.122,123 Currently, a phase II, single-group, clinical trial of Synergy-1, which is a combination of a probiotics and prebiotic (known as a synbiotic) containing a 1:1 oligosaccharide/inulin mixture, has been completed without published results for patients with mild to moderately active UC (NCT02093767). An additional randomized placebo-controlled trial evaluating the efficacy of Synergy-1 for maintenance therapy in patients with UC is currently recruiting (NCT02865707). 

Antimicrobial Therapy

Antimicrobial therapy aims to alter the composition of the microbiota by reducing the concentration of potentially pathogenic bacteria that may be playing a role in the pathogenesis and disease course of patients with IBD. While the use of ciprofloxacin and metronidazole have demonstrated modest efficacy in inducing and maintaining remission in patients with active colonic Crohn’s disease and in preventing postoperative recurrence in patients with ileocolonic anastomosis, their routine use is not recommended outside of suppurative complications.124 Rifaximin, a minimally absorbed antibiotic, has gained attention recently due to its efficacy in other intestinal diseases. Several studies have shown that rifaximin may be effective in inducing and maintaining clinical remission in patients with CD compared to placebo,125,126 however studies have thus far failed to show improvement in patients with UC.127 Multiple additional trials of Rifaximin for induction therapy in CD patients (NCT02240108, NCT00603616, NCT02240121) and in the prevention of postoperative recurrence in CD patients (NCT03185624, NCT03185611) are currently underway. Additional studies investigating the role of antibiotics in IBD include the use of wide-spectrum antibiotic cocktails with doxycycline, amoxicillin, and metronidazole (NCT02345733) and oral vancomycin, neomycin, ciprofloxacin, lavage with PEG, +/- fluconazole in active CD that is refractory to conventional immunosuppressive therapy (NCT02765256). 

Antimicrobial therapy targeting specific aberrant bacterial triggers of IBD is currently under investigation. Specifically, the ongoing randomized controlled trial TEOREM (Evaluation of Adherent Invasive E coli Eradication in Adult Crohn Disease) plans to assess whether 12 weeks of treatment with ciprofloxacin and rifaximin is superior to placebo in obtaining endoscopic remission in patients with ileal Crohn’s disease colonized with adherent invasive E coli (NCT02620007). Adherent invasive E coli is a bacteria which has been associated with the pathogenesis of IBD. RHB-104 (Redhill Biopharma) is a fixed oral antibiotic combination therapy of clarithromycin, rifabutin, and clofazimine with potent intracellular, anti-mycobacterial, and anti-inflammatory properties that targets Mycobacterium avium subspecies paratuberculosis (MAP). MAP may play a role in the pathogenesis of Crohn’s disease.128 RHB-104 has recently completed a phase III clinical trials (MAPUS) in patients with CD (NCT01951326). 

Fecal Microbiota Transplant

Fecal microbiota transplant (FMT) has the potential to restore microbial diversity that is often lost in IBD patients and has gained significant attention due its low cost, “ick factor”, and relative safety profile.129 In February of 2017, the FOCUS study demonstrated improved steroid-free clinical remission, steroid-free clinical response, and steroid-free endoscopic response at 8 weeks in patients who received one multi-donor FMT colonic infusion followed by multi-donor FMT enemas 5 days per week for 8 weeks.130 The success of this trial was attributed to the intensity of the FMT administration. These results were also supported by a phase III uncontrolled trial in Turkey, where a single 500.mL fecal suspension was endoscopically delivered into the proximal terminal ileum along with loperamide (to provide adequate time for colonization). This study showed a 70% clinical response with 13% having clinical and endoscopic remission at 12 weeks.131

An earlier trial conducted in Canada demonstrated a significantly higher frequency of clinical and endoscopic remission in patients with UC at 7 weeks compared to placebo after receiving one FMT enema per week for 6 weeks.132 A recently published abstract demonstrated that FMT can be effective with shorter duration and lower intensity protocols as well. This multi-center, randomized, placebo-controlled trial demonstrated that FMT delivered as one week of induction therapy, (administered via colonoscopy on day 0 followed by two enemas by day 7), had higher rates of steroid-free clinical and endoscopic remission compared to placebo (autologous FMT).133 Given the invasive and “icky” nature of FMT administered by endoscopy, enteral access, or enema, there is currently a phase II trial evaluating the effectiveness of fecal transplantation via oral frozen capsules (NCT03273465). 

Currently there is no published data on the efficacy of FMT in Crohn’s disease, however there are currently multiple trials underway (NCT02227342, NCT02330211, NCT03078803, NCT02417974). A phase II trial of FMT in UC-associated pouchitis is currently recruiting as well (NCT02049502). Two studies looking at antimicrobial ablation with FMT rescue therapy in IBD patients are currently underway (NCT02606032, NCT02033408). Several additional studies with variations in FMT protocols are underway as well.

Extracorporeal Leukocytapheresis and Small Molecule Absorbents

Leukocytapheresis is a non-pharmacologic approach to the treatment of IBD that purportedly works by removing activated circulating leukocytes in the colonic mucosa through the use of beads or filters.134 Leukocytapheresis has the potential for improved treatment efficacy in steroid refractory and steroid dependent patients as well as improved safety through steroid and biologic sparing. Adacolumn (JIMRO) is a device column packed with cellulose acetate beads capable of extracting granulocytes and monocytes from the patient’s plasma. Cellsorba (Asahi KASEI) is a leukocyte apheresis device consisting of fine polyester fibers that removes lymphocytes in addition to granulocytes and monocytes. Small uncontrolled studies, primarily conducted in Japan, have demonstrated some efficacy as a steroid-sparing treatment modality.135 However larger, sham-randomized phase III North American trials failed to demonstrate any efficacy of the Adacolumn for induction therapy for patients with moderate-to-severe UC136 or active CD.137 Two recent single group assignment trials have shown efficacy in inducing remission for steroid dependent ulcerative colitis demonstrating a potential role in this subclass of patients.138,139

ST-120 is a spherical carbon adsorbent that absorbs small molecular weight toxins, inflammatory mediators, and bile acids in the GI tract. ST-120 demonstrated significant efficacy in fistulizing CD in small Japanese studies.140 Unfortunately, a large phase III, multicenter, randomized, placebo-controlled study (FHAST-1) did not meet primary endpoints (50% reduction in the number of draining fistula) in patients with active fistulizing CD.141

Phosphodiesterase 4 (PDE4) inhibitors

Phosphodiesterase 4 (PDE4) inhibitors block the breakdown of cAMP, which is an important intracellular signaling molecule that plays a role in the suppression of the NF-.B dependent inflammation including TNF-α production.142 Apremilast (Otezla) (Celgene), is a PDE4 inhibitor approved by the FDA for psoriasis and psoriatic arthritis. A recent phase II, multicenter, randomized, placebo-controlled trial demonstrated significantly higher rates of clinical remission, mucosal healing, and biomarker improvement in patients with UC.143

While PDE4 inhibition represents a potentially efficacious target in IBD pathogenesis, multiple phase II and phase III trials of the PDE4 inhibitor tetomilast (OPC-6535) (Otsuka Pharma) failed to show any difference compared to placebo in patients with UC.144,145The trial was limited by high drop-out rate due to upper gastrointestinal symptoms, and a post hoc analysis suggests that tetomilast may have some clinical efficacy in those able to tolerate the drug. 

Hyperbaric Oxygen Therapy

Hyperbaric oxygen therapy (HBOT) was investigated in a small phase II clinical trial based on systematic review suggesting improvement in clinical response.146 HBOT has been shown to reduce pro-inflammatory cytokines, improve microbiome diversity, and increase growth factor synthesis. A recent phase 2A, randomized, double-blind, sham-controlled trial demonstrated significantly higher rates of clinical remission at 5 and 10 days in patients hospitalized for moderate-severe UC flare treated with HBOT and steroids compared to sham plus steroids despite early termination due to poor recruitment.147Despite these encouraging results, availability and costs of administering hyperbaric oxygen therapy remains a major barrier to widespread use outside of highly specialized academic centers. 

CONCLUSION

Advances in our understanding of the pathogenesis of IBD have begun to unravel the complexity of gut inflammation. With contributions from the immune system, genetics, microbiome, pathogens, and the environment, the multiple facets of IBD can be daunting. This complexity also allows for immense opportunity, offering multiple targets on which to intervene. The IBD pipeline can therefore be expected to continue to grow and mature. Identifying safe and efficacious targets is only the first hurdle. Critical questions regarding optimal overall treatment approach and drug selection remain unanswered. The question of which therapy to initiate in the treatment naive patient, or which drug to try next, remain largely uninformed and often clinical practice relies on anecdotal or cost-driven step-up therapy in the absence of an evidence-based overall strategy. Studies aimed at answering these questions have been performed and some headway has been made, particularly with regard to the benefits of combination therapy demonstrated in the SONIC148 trial for CD and the SUCCESS149 trial for UC. Newer studies, including REACT150 and CALM,151 have shown benefit in rapid step-up and treat-to-target strategies. REACT was an open-label, cluster randomized controlled trial that compared early combined immunotherapy (ECI) with an anti-TNF-α and an antimetabolite therapy to conventional management. This study found that ECI was not more effective than conventional management for symptom control in CD, but had improved rates of major adverse outcomes. 150 CALM was an open-label, randomized phase III study comparing a ‘tight control’ management strategy that utilized the biomarkers fecal calprotectin and C-reactive protein in conjunction with clinical symptoms vs. a strategy using only clinical symptoms. This study found that patients in the tight control group had better clinical and endoscopic outcomes than those in the clinical management alone, supporting a treat-to-target strategy that utilizes biomarkers in conjunction with clinical evaluation.151

Optimal treatment strategies remain elusive due to a number of factors including an incomplete understanding of the pathogenesis of IBD, a lack of head to head treatment trials (further complicated by the rate of emerging new therapies), and the mixed data on prospective drug levels. The field will benefit from head to head treatment trials and algorithmic strategy studies at the population level. However, the heterogeneity of patient response highlights the need for predictive models that can identify the next optimal therapy for each patient.

As our understanding of IBD expands, so too does the drug pipeline but also the number of unanswered questions regarding the best way to use these treatments. These complex diseases offer many challenges, but great opportunity to improve patients’ quality of life and outcomes. This is an exciting time in the treatment of IBD, and we are only just beginning.

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MEDICAL BULLETIN BOARD

Compulink Showcases Smart EHR Multi-Specialty Solution At HIMSS 2019

March 2019 • Volume XLIII, Issue 3

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Newbury Park, CA—Compulink Healthcare Solutions, the creator of Advantage SMARTPractice®, an all-in-one EHR and practice management solution powered by artificialintelligence (AI), demonstrated its multi-specialtysolution, Compulink AdvantageTM at HIMSS Annual Conference & Exhibition.

Advantage uses AI technology and real-time data from the clinic to completely automate tasks such as billing, along with eliminating steps toimprove patient flow.

Among the innovative AI-driven features demonstrated:

Advantage SMART Workflow®:

Advantage knows which patients are being seen based on their room assignment and automatically displays their record when needed. The system also lets providers and staff know who is waiting, where they need to go next, and keeps them constantlyinformed for maximum efficiency.

SMART Automated Billing, Eligibility & ERA Posting:

Using the Advantage PracticeWatch® task automation engine, staff can schedule eligibility, claims submission, and remittance posting to run unattended. Advantage also automatically populates a claim edit worklist to quickly identify and correct issues.

Advantage SMART Patient EngagementTM:

Advantage automatically communicates personalized content directly to the patient’s mobile device. This includes information about productsand services specific to each individual patient as they arrive at the office and move through the normal patient workflow.

“We expect this release to take our client’sefficiency across their entire clinic to a whole new level,” said Link Wilson, CEO and founder of Compulink. “Our SMART billing features willreduce the amount of time required to generateand work claims by about 90%. With our SMART workflow engine, we’re looking for patientthroughput to increase by as much as 15% or more. And with our mobile patient engagement, the ability to engage patients in their own care while growing your patient base is really limitless.”

Among Compulink’s key innovations is a single database architecture that allows Advantageto serve up templates, workflow, and content(e.g. diagnosis codes) to support the provider’s individual specialty, while allowing the entire care team to easily share information.

The company’s 2015 ONC Certified systemis used by more than 20,000 providers in over 4,700 locations and 40 ASC. Its all-in-onesolution includes specialty-specific EHR for 18specialties, practice management, ASC, inventorymanagement, patient engagement and workflowoptimization. The company also provides an expert revenue cycle management service for its clients.

About Compulink Healthcare Solutions

A leader in specialty-specific, all-in-one EHRand Practice Management solutions for 34 years,Compulink’s Advantage SMART Practice® usesartificial intelligence to improve clinical and financial results. Designed to maximize your time while seeing patients, Advantage includes everything you need to optimize workflow including EHR, PM, ASC, patient engagement, and RCM.

For additional information, visit: Compulink Advantage’s website

FRONTIERS IN ENDOSCOPY, SERIES #50

Endoscopic Diagnosis and Management of Cholangiocarcinoma

March 2019 • Volume XLIII, Issue 3
Dan McEntire,Douglas G. Adler

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Although Cholangiocarcinoma (CCA) is an uncommon disease, it frequently presents at an advanced stage. This emphasizes the need for accurate diagnostic techniques and beneficial palliative therapy. This article reviews several endoscopic diagnostic techniques relevant to CCA

Cholangiocarcinoma (CCA) is a cancer of the biliary tract. Although it is an uncommon disease, it frequently presents at an advanced stage, which precludes surgical resection and carries a poor prognosis. This emphasizes the need for accurate diagnostic techniques and beneficial palliative therapy. This article reviews several endoscopic diagnostic techniques relevant to CCA including brush cytology, transpapillary forceps biopsy, endoscopic ultrasound, cholangioscopy, probe-based confocal laser endomicroscopy and optical coherence tomography. Additionally, this article discusses biliary stenting, endoscopic biliary radiofrequency ablation and photodynamic therapy.

Dan McEntire MD, Douglas G. Adler MD, FACG, AGAF, FASGE University of Utah School of Medicine, Salt Lake City, UT

INTRODUCTION

Cholangiocarcinoma (CCA) is a rare cancer that arises from biliary epithelium. The incidence is increasing and is more common in underdeveloped countries, and the prognosis is often poor.1,2 The clinical manifestations of CCA depend on the stage and tumor characteristics, but include jaundice, pale stools, abdominal pain, and constitutional symptoms. CCA is classified as intrahepatic or extrahepatic; extrahepatic is subdivided into perihilar and distal CCA. Extrahepatic CCA is more common than intrahepatic.2 The diagnostic workup of CCA includes radiographic imaging, which may demonstrate characteristic findings and delineate the relationship of the mass to the biliary tree and nearby vasculature. When imaging reveals a highly suspicious lesion that appears amenable to resection, timely surgical intervention is indicated.3 However, for patients that are not surgical candidates, or when imaging is non-diagnostic, confirmation with tissue diagnosis is essential prior to pursuing aggressive treatments (e.g., chemoradiation).3,4 In general, a tissue diagnosis is obtained prior to any treatment. Several endoscopic techniques have been developed to maximize diagnosis of CCA, provide symptomatic relief, acquire valuable information about tumor characteristics, and potentially offer non-surgical interventions. This article reviews endoscopic diagnosis and management of cholangiocarcinoma.

Biliary Brush Cytology

Acquisition of cellular material for cytologic analysis is typically obtained during routine endoscopic retrograde cholangiopancreatography (ERCP) via routine brush cytology. (Figure 1) After fluoroscopic visualization of a biliary stricture, a brush is introduced and moved across the lesion several times, with surface cells being captured in the brush and then sent for analysis. Brush cytology is still widely performed as it is very safe and has a low cost. However, this technique yields positive results in less than 50% of CCA cases.4 This may, in part, be due to the desmoplastic nature of these cancers resulting in hypocellular specimens. Several studies have noted low diagnostic sensitivity (5.5% to 60%) and high sensitivity (94.7% to 99%).5,6,7,8,9,10 These values indicate that negative results do not reliably rule out CCA. A variation of this procedure involves biliary fluid aspiration rather than brushings. One study noted that aspiration of biliary fluids, alone or in combination with brushings, yielded sensitivities of 72.8% to 89%.8,11

Fluorescence in Situ Hybridization

Fluorescence in situ hybridization (FISH) is an ancillary test that applies fluorescence-labeled DNA probes to nuclear material generally obtained via brush cytology. Demonstration of aneuploidy of chromosome 3, 7, or 17 or 9p21 deletion are the best characterized abnormalities in biliary cancers that can be exploited for improved diagnosis. It is estimated that 39-80% of biliary tract cancers demonstrate aneuploidy or aneusomy.12 Several studies have demonstrated that the addition to FISH to brush cytology can greatly improve diagnostic sensitivity, while maintaining high specificity.10,13,14,15,16,17 FISH also enhances detection of CCA in patients with primary sclerosing cholangitis (PSC), a notoriously difficult population to accurately diagnose with malignancy given their baseline abnormal biliary ductal epithelium and high potential risk of developing CCA.14 Additionally, emerging data related to identification of epidermal growth factor receptors (EGFR or HER) via FISH may guide potential treatment options.18,19 A recent publication found that polysomy 7 was independently predictive of poor outcomes in CCA. Taken together, these data indicate a routine role for FISH in the diagnosis and management of CCA.

Transpapillary Forceps Biopsy

Transpapillary forceps biopsy (TPB) can be performed during ERCP in conjunction with biliary brushing. Closed forceps are introduced into the papilla and guided to the stricture under fluoroscopy. The forceps are then opened and pushed into the stricture to maximize tissue acquisition. These samples are then sent for histologic analysis. Forceps are not wire guided and often have difficulties in reaching and sampling lesions that are not readily accessible in the common bile duct or the common hepatic duct. In one study, use of TPB to diagnose CCA revealed sensitivity 73%, specificity 100%, positive predictive value 100%, and negative predictive value 31.2%.20 Several other studies demonstrate similar characteristics, and additionally provide evidence that TPB in combination with other diagnostic modalities (e.g., brush or aspiration cytology, FISH), greatly improves the diagnostic sensitivity without compromising specificity.6,7,8,21 Importantly, Kawashima et al.22 noted a 40% false negative rate when a single biopsy was taken. This group recommended that at least three biopsies should be acquired and analyzed if TPB was utilized.22 Proximal lesions can represent a difficult or impossible target to reach via TPB. 

Endoscopic Ultrasound

Endoscopic ultrasound (EUS), with or without fine needle aspiration (FNA) and/or fine needle biopsy (FNB), is an advanced procedure that can be performed as a primary diagnostic method or when pathology results of biliary brushings or biopsy are inconclusive and clinical suspicion for malignancy remains high. In addition to diagnostic utility, EUS can assist in gathering essential tumor characteristics, and provides unique approaches to biliary drainage. 

Diagnostic Use of EUS

The diagnostic use of endosonography in suspected CCA entails visualization of a biliary stricture of mass or abnormal perilesional lymph nodes, as well as FNA or FNB for histologic analysis. The exam is performed after introducing the echoendoscope, equipped with either a radial or linear array probe, and tracing the biliary tree from the duodenal bulb as well as the ampullary region. The linear array probe allows the endoscopist to perform FNA/FNB. 

Features suggestive of malignant strictures include visualization of duct wall thickness >3mm and irregularity of the outer bile duct wall.23 A meta-analysis of EUS in evaluation of biliary obstruction noted 78% sensitivity and 84% specificity in identifying malignant causes, although the data are not specific to CCA.24 EUS is generally a safe procedure, without apparent risks beyond that of routine EGD, and with diagnostic characteristics similar to that of magnetic resonance cholangiopancreatography (MCRP) but with the potential for tissue sampling.24

A meta-analysis of 284 patients reviewed the performance of EUS-FNA in detecting malignant biliary strictures, and determined 84% and 100% sensitivity and specificity, respectively.25 A prospective study of 51 patients with suspected biliary malignancy compared EUS-FNA to ERCP techniques (brush cytology and TPB) and found 94% vs 50% sensitivity.26 However, only 14 of these patients were determined to have bile duct cancer; EUS-FNA and ERCP characteristics in this small subgroup were very similar.26

One consideration relevant to EUS is the location of the lesion of interest, as EUS tends to perform better with distal as compared to proximal lesions. Accordingly, Mohamadnejad et al.27 found 81% and 59% sensitivity in proximal versus distal CCA. Another potential limitation is the concern for peritoneal tumor seeding during EUS-FNA. Despite a small sample size, Heimbach et al.28 concluded that EUS-FNA should be viewed as a contraindication to a potentially curative liver transplant. In general, most endosonographers will not perform EUS FNA/FNB of a primary suspected CCA if the patient is felt to be a candidate for surgery or transplantation given concerns about tumor seeding along the needle track, and in most patients the primary role of EUS with regards to tissue acquisition is to sample adenopathy. 

A similar endoscopic procedure is intraductal ultrasound (IDUS). In this procedure, the biliary tract is cannulated via ERCP and an ultrathin radial ultrasound probe is introduced over a guidewire to generate EUS images from within the biliary tree itself. Similar to EUS, there are sonographic findings that can suggest malignancy (e.g., increased wall thickness, longer stricture length).29 One group compared EUS to IDUS in evaluation of biliary strictures and found IDUS to be more accurate (89.1 versus 75.6%) and more sensitive (91.1% versus 75.7%).30 Despite these findings, IDUS is rarely used in clinical practice given the need for the specialized IDUS probe and a second ultrasound processor. This may also be because poor imaging depth is achieved, limiting evaluation to the biliary wall and its immediate surroundings.30

EUS Assessment Of Surgical Resectability

Although various imaging modalities can assist in identifying factors that determine surgical resectability, some cases are not deemed unresectable until the time of surgery. Some endoscopic techniques, with the majority of data related to EUS, are emerging as options to determine tumor characteristics and aid in surgical planning. A few reports evaluated patients with suspected CCA and found that EUS not only accurately diagnoses malignancy, but also reliably identifies unresectable disease.27,31 EUS allows for visualization and biopsy of liver nodules or non-regional (aortocaval or celiac) lymph nodes, ascites indicative of peritoneal carcinomatosis, or adherence to or invasion of the portal vein and hepatic artery; any of which signifies unresectable disease.27 (Figure 2)

Cholangioscopy

Cholangioscopy is an endoscopic technique that allows endoscopists to directly inspect biliary epithelium and vasculature, visualize strictures or masses, and obtain precisely targeted biopsies via miniaturized forceps. Traditional cholangioscopy is performed by two endoscopists; one managing the duodenoscope and the other managing the cholangioscope. Modern cholangioscopy is a single operator procedure. A small caliber endoscope is introduced into the biliary tree through the accessory channel of the duodenoscope. Advances in cholangioscopy include develop of a single-operator system, progression from fiberoptic to digital imaging, and ultrathin upper-endoscopes that can pass directly into the biliary tree (direct peroral cholangioscopy). Cholangioscopy data relevant to CCA are limited but promising. In a study of 30 patients where both ERCP and EUS-FNA were non-diagnostic, cholangioscopy with intraductal biopsy diagnosed 23 cases of CCA.32 Similarly sized studies indicate 76.5% to 86% sensitivity.5,32,33,39,41

Probe-Based Confocal Laser Endomicroscopy

Probe-based confocal laser endomicroscopy (pCLE) is an ERCP-based technique designed to allow the clinician to potentially make diagnoses in vivo. The probe emits laser light of a defined wavelength to illuminate the tissue of interest, and then detects reflected fluorescent light allowing for real time examination of cellular and subcellular structures. This procedure requires systemic or topical administration of fluorescein to enhance image quality, though there are limited data to suggest that nonmalignant hepatic cells demonstrate adequate autofluorescence in cases of intrahepatic CCA.34

As with many diagnostic procedures, pCLE is subject to significant interobserver variability that improves substantially with standardized training.35 For this reason, a standard classification system has been proposed. The Miami classification describes 5 features to distinguish benign from malignant cells: thick white bands >20mm, thick dark bands >40mm, epithelial structures, dark clumps, and fluorescein leakage.36 Combining two or more of these criteria provided a sensitivity and specificity of 97% and 33%, respectively.36 Work by Caillol et al.37 noted this low specificity, due largely to false positive results in benign inflammatory conditions, and identified additional characteristics of malignancy such as vascular congestion, dark granular patterns, increased inter-glandular space, and thickened reticular structures. Several studies have evaluated the diagnostic characteristics of pCLE in cases of pancreaticobiliary strictures and found sensitivity of 74.6% to 98%, specificity of 33% to 97%, positive predictive value (PPV) of 71% to 80%, and negative predictive value (NPV) of 97% to 100%.36,38,39,40,41,42 The uniformly high NPV of pCLE have led some to suggest that this method may be a useful tool in patients with benign inflammatory conditions such as PSC.42 pCLE is not widely used at this time and should still be considered experimental. 

Optical Coherence Tomography

Optical coherence tomography (OCT) was first used to evaluate CCA in 2002.43 Miniature probes have been developed that can be passed through the ERCP working channel. Analogous to ultrasonography, OCT detects back-scattered infrared light to produce high-resolution, cross-sectional images in-vivo that are similar in appearance to histologic sections. OCT remains experimental and the available literature relevant to CCA primarily describes image features (e.g., unrecognizable tissue layer architecture, papillary structures) that are suggestive of malignancy.43,44,45

ERCP-Guided Biliary Stent Placement

Endoscopic biliary drainage is performed to manage cholangitis, provide palliative relief of cholestasis, and is routinely performed prior to neoadjuvant chemotherapy and hepatic resection in patients with obstructive jaundice.46 Most oncologists will not administer chemotherapy in the setting of jaundice. There are several methods available to achieve endoscopic biliary drainage, but most frequently involves ERCP-guided stent placement.

Biliary Stents

There are a variety of stents available, broadly categorized into plastic and metal stents. Plastic stents are smaller in diameter compared to self-expandable metal stents (SEMS). For this reason, a major disadvantage to plastic stents is early occlusion (1-3 months) due to accumulation of biliary sludge and thus plastic stents require periodic replacement.47,48SEMS are available uncovered (an open frame meshwork) or covered by a thin membrane. Either variety remains patent significantly longer than plastic stents.47 The open meshwork of uncovered SEMS allows tissue ingrowth, which prevents migration of the stent, but this also leads to earlier stent occlusion (compared to covered SEMS) and precludes future removal.49 The thin membrane over covered SEMS mitigates stent occlusion but results in more frequent migration and are more expensive. In general, preoperative patients are treated with plastic stents and nonoperative patients are treated with metal stents. Also, given that most patients with cholangiocarcinoma have proximal biliary obstruction, uncovered stents are typically warranted in these patients. 

Palliative Biliary Drainage

For patients with unresectable CCA, palliative drainage with stent placement can relieve jaundice and pruritis and extend life. A number of recent meta-analyses have compared plastic versus uncovered SEMS for palliative drainage.50,51,52 The overall findings advocate the use of uncovered SEMS due to lower overall stent dysfunction, longer stent patency, fewer required re-interventions, and increased survival time.50,51,52 An interesting area of research which could further prolong palliation involves the development of radiation-emitting and drug-eluting biliary stents.53,54,55 Despite interest in these devices for years, they remain experimental. 

There has been controversy regarding whether standard practice for endoscopic palliative biliary drainage in patients with hilar obstruction should be unilateral or bilateral. (Figure 3) Three recent meta-analyses analyzed several retrospective cohorts patients with hilar obstruction (of any Bismuth type) and generally found that although unilateral stent placement was technically more successful, bilateral drainage resulted in better drainage and longer stent patency.52,56,57 Mortality and complication rates were no different. In the only prospective, randomized trial relevant to this topic, 133 patients (with Bismuth type 2-4 obstruction) were randomized to unilateral or bilateral metal stenting.58 Technical success rates were not different, but bilateral drainage relieved jaundice more effectively and the biliary tree remained patent significantly longer.58 Nonetheless, the question remains controversial and highly debated, and in practice many patients only receive unilateral stents and achieve adequate biliary drainage given the technical difficulties inherent in bilateral stent placement. Most endoscopists who do not perform high volumes of ERCP are uncomfortable placing bilateral stents. Studies into this question are ongoing. 

Preoperative Biliary Drainage in Perihilar CCA

In operative candidates with perihilar CCA that present with obstructive jaundice, preoperative biliary drainage is routinely performed to restore hepatic function to an optimal state prior to major resection. Notably, two meta-analyses, by Liu et al.59 and Celotti et al.60, identified an increased risk of postoperative infection in patients that received preoperative endoscopic biliary drainage. However, hepatic resection of a jaundiced patient is associated with higher rates of significant adverse events and perioperative mortality.61,62 A major cause of death is hepatic failure.63 For this and other reasons, the current accepted practice is to preoperatively drain segments of the future remnant liver and is especially important when the predicted volume of the future liver remnant is <50%.64 Antibiotic administration during and after ERCP in these patients is usually performed to reduce the risk of infectious complications. 

In preoperative patients with perihilar disease, plastic stents are preferred due to easy endoscopic or intraoperative retrieval to avoid interference with resection. Tissue ingrowth through uncovered SEMS can often render resection impossible, and use of SEMS in preoperative patients with perihilar CCA is, in general, not advised (SEMS are routinely used in nonoperative patients).46,65 It should be recognized the plastic stents need maintenance and periodic removal and replacement to avoid recurrent biliary obstruction.66

Endoscopic Interventions

There are a few endoscopic interventions, most commonly radiofrequency ablation (RFA) and photodynamic therapy (PDT), that are clinically useful in CCA, most commonly used in patients who are not felt to be surgical candidates. The utility of non-surgical treatment is highlighted by a report that over two-thirds of patients (in a cohort with greater than 6000 patients) with intrahepatic CCA were not considered surgical candidates, and that local treatment (such as RFA) significantly prolonged life.67

Endoscopic Biliary Radiofrequency Ablation (RFA)

Biliary RFA is an endoscopic technique used to provide local therapy to a malignant stricture. Performed as part of a standard ERCP, a radiofrequency catheter is introduced to the biliary tree to the level of a target lesion and, using an electrosurgical generator as a power source, emits heat to induce coagulative necrosis directly at the site of the malignant stricture. RFA is primarily used in CCA as a palliative technique and is generally performed prior to placement of a SEMS to prolong patency. RFA is considered a safe procedure and has been shown not only to prolong stent patency and improve drainage but can also significantly prolong life.67,68,69 In patients with stage I intrahepatic CCA, RFA increased median survival time from 0.7 to 2.1 years.67 A retrospective study by Sharaiha et al.68 included 37 patients with extrahepatic CCA and compared RFA plus SEMS to SEMS alone. Increased survival time (17.7 months versus 6.2 months) was noted in the RFA plus SEMS group, with no difference in adverse events.68 Stent patency time was unchanged.68In one of the only prospective studies relevant to this topic, 65 patients with perihilar (Bismuth type I or II) or distal CCA were randomized to endoscopic RFA and placement of a plastic stent, or placement of a plastic stent only.69 RFA with stent placement increased median survival to 13.2 months (versus 8.3 months), and increased stent patency to 6.8 months (versus 3.4 months), and there was no difference in adverse event rates.69 Interestingly, the longer survival time was attributed to slowed tumor growth and later occurrence of metastasis.69 This may be explained by findings that local tumor ablation therapies increase tumor immunogenicity, inducing a temporary anti-tumor immune response, although this is largely conjecture.70In cases of occluded SEMS, management has historically included insertion of additional stents or percutaneous biliary drainage. RFA of tumerous ingrowth in an uncovered SEMS has been shown to restore biliary drainage, and performance of RFA for this indication is now commonly performed. The effect of RFA is attenuated by the presence of a SEMS, limiting its effect to cancerous tissue within the stent.71 A small, retrospective study included 50 patients with an occluded SEMS: 25 underwent RFA and the remaining 25 underwent placement of a plastic stent.72 Biliary drainage was immediately apparent in all patients, but patency was significantly longer in the RFA group (119 days versus 65 days).72 Altogether, the use of endoscopic RFA in CCA is emerging as a valuable therapy.

Endoscopic Photodynamic Therapy (PDT)

ERCP-directed PDT is an ablative therapy similar in concept to RFA. This procedure requires intravenous administration of a photosensitizing agent (hematoporphyrin or chlorine derivatives) that preferentially accumulates in neoplastic cells and is typically injected 48-hours prior to PDT.73 The procedure involves direction of the laser light-emitting PDT catheter to the lesion of interest and emission of light to the sensitized tissue. Activation of the sensitizer, via exposure to specific wavelengths of light, is thought to produce reactive oxygen species, which interacts with cell membranes and activates inflammatory pathways, resulting in cellular death.74 To maximize the therapeutic effect of PDT, supplemental oxygen is frequently administered during the procedure.73

Endoscopic PDT is considered a palliative treatment and has been shown to extend survival time, prolong stent patency, and improve quality of life.73,75,76 Kahelah et al.75reported prospective data on 48 patients with unresectable hilar CCA: 29 patients received biliary stents, and 19 underwent PDT and stent placement. Median survival time was 16.2 months in the PDT plus stent group, compared to 7.4 months in the stented group.75Significant and similar serum bilirubin reduction was noted in both groups.75

In a similar study, 184 patients with unresectable hilar CCA received either PDT with stent placement or stents only.76 In the PDT group, statistically significant findings included longer life, (12 versus 6.4 months), lower serum bilirubin values, and significantly improved quality of life.76 A randomized, controlled trial studied patients with unresectable perihilar CCA in which 39 patients were randomized to PDT with bilateral stent placement or bilateral stenting alone.73 In the PDT group, survival time was extended (median of 493 days versus 98 days), a greater percentage of patients demonstrated resolution of hyperbilirubinemia, and improved quality of life was reported.73 Non-fatal adverse events were relatively uncommon, but did include mild-to-moderate cases of skin photosensitivity.73 Studies that compared endoscopic RFA to PDT did not find significantly different survival times, though RFA was superior in terms of bilirubin reduction and unplanned stent replacement.77,78 RFA is also technically easier and faster to perform and carries no risk of photosensitization. 

CONCLUSION

Cholangiocarcinoma is a rare malignancy with a historically dismal prognosis due to diagnosis at advanced stages. There are several endoscopic diagnostic techniques that are continually improving, and a number of newer techniques are emerging to assist in an early and accurate diagnosis. Endoscopic interventions such as biliary stenting, RFA, and PDT are useful palliative techniques that improve quality of life and extend survival time.

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DISPATCHES FROM THE GUILD CONFERENCE, SERIES #20

Update in the Diagnosis and Treatment of Esophageal Motility Disorders

March 2019 • Volume XLIII, Issue 3
John DeWitt

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In this review, the epidemiology, pathophysiology and presentation of most common esophageal motility disorders (EMDs) will be addressed. Achalasia is the most well-described disorder of the group and its features will be highlighted. Due to the increasing diagnostic and treatment options of EMDs, a multidisciplinary approach is required and referral to gastroenterology or surgery is strongly recommended for further management of these disorders.

Esophageal motility disorders (EMDs) represent a diverse group of conditions that alter normal peristalsis and passage of food from the esophagus into the stomach. Symptoms most commonly include dysphagia and chest pain. Differentiation from other common conditions such as coronary artery disease, gastroesophageal reflux disease and malignancy may be difficult. Standard evaluation includes upper endoscopy, barium esophagram and high-resolution esophageal manometry. The best-characterized EMD is achalasia, which causes esophageal aperistalsis and a poorly relaxing lower esophageal sphincter (LES). Treatment of achalasia focuses on reducing the pressure of the LES to allow gravity to enable passage of food into the stomach. Pneumatic dilation and laparoscopic Heller myotomy (LHM) with fundoplication are the standard treatments for achalasia. Per-oral endoscopic myotomy (POEM) represents the newest endoscopic treatment for achalasia and early data suggests efficacy comparable to that of Heller myotomy.

John DeWitt MD, FACG, FACP, FASGE, AGAF Professor of Medicine, Director of Endoscopic Ultrasound , Department of Medicine, Division of Gastroenterology & Hepatology, Indiana University Health Medical Center, Indianapolis, IN.

INTRODUCTION

The esophagus serves as a conduit for passage of food from the mouth to the stomach. The upper and lower esophageal sphincter, which are located on the proximal and distal ends of the esophagus, regulate passage of food into and out of the esophagus. Under normal circumstances swallowing occurs in a coordinated, sequential fashion using the musculature of the esophageal wall. This process is called peristalsis. The lower esophageal sphincter maintains a baseline tone to prevent gastroesophageal reflux disease. When peristalsis propels food to the lower esophageal sphincter, the muscle relaxes to permit food to pass into the stomach before re-establishing its baseline tone. Esophageal motility disorders (EMDs) are rare disorders of esophageal peristalsis and the lower esophageal sphincter. Although sometimes asymptomatic, they are usually characterized by symptoms of dysphagia, chest pain, regurgitation, and if severe may manifest as weight loss, aspiration pneumonia and malnutrition. Primary EMDs are not associated with systemic diseases whereas secondary motility disorders accompany a systemic disease such as scleroderma or malignancy.

In this review, the epidemiology, pathophysiology and presentation of most common EMDs will be addressed. Achalasia is the most well-described disorder of the group and its features will be highlighted. Workup for these conditions includes upper endoscopy, barium esophagram and high-resolution esophageal manometry. Management including the role of medications, injection of medications, dilation, surgery and novel endoscopic treatments will be addressed. Due to the increasing diagnostic and treatment options of EMDs, a multidisciplinary approach is required and referral to gastroenterology or surgery is strongly recommended for further management of these disorders.

Epidemiology

Esophageal motility disorders are rare. Achalasia, the best characterized disorder in this group, occurs in 1-2 persons per 100,000 population.10 More common disorders include esophageal spasm or ineffective motility disorder and are poorly characterized and described. There are some recent data suggesting that these disorders – achalasia in particular – may be increasing in incidence.2-3 However, this is most likely due to the increased use of high-resolution manometry which improves characterization and diagnosis of these conditions. Due to the rare nature of these disorders, demographic information is poorly understood. Achalasia occurs most commonly during the 4th and 5th decade however it can occur in children and in patients exceeding 90 years of age.

Pathogenesis

Esophageal motility disorders are disorders of the muscle that lines the esophageal wall. In achalasia, the neurons of the myenteric plexus are destroyed by chronic inflammation which results in esophageal aperistalsis and poor relaxation of the lower esophageal sphincter.4,5 The trigger for the chronic inflammation is unknown but is likely an infectious agent in a genetically susceptible individual. In South America, an achalasia-like disorder called Chaga’s disease is caused by infection of the protozoan T. cruzi. Similar to idiopathic achalasia, this disorder causes inflammation in the esophageal myenteric plexus with resultant esophageal aperistalsis and non-relaxation of the lower esophageal sphincter (LES). Patients with spastic disorders of the esophagus however have a normal myenteric plexus. The etiology of these motility disorders may be due to fragmentation of vagal nerve endings and mitochondria, esophageal muscle hypertrophy and anxiety.

Clinical Presentation

The classic presenting symptoms for achalasia are dysphagia to solids greater than liquids which often occurs for many years prior to diagnosis. Patients often learn to accommodate the dysphagia by altering their diet or performing physical maneuvers that help improve swallowing. Dysphagia is often accompanied by effortless regurgitation of poorly digested food or fluid and is usually worse in the supine position or after eating large meals. Occasionally regurgitation can lead to aspiration pneumonia. With poor nutrition, weight loss is inevitable. Patients with achalasia or spastic motility disorders may complain of chest pain which may or may not worsen with swallowing. Chest pain is often incorrectly attributed to gastro-esophageal reflux disease (GERD) which is rare in these patients with increased lower esophageal sphincter pressure.

Differential Diagnosis

When middle-aged patients report chest pain as part of their symptom complex, coronary artery disease (CAD) and GERD must be initially considered. Difficulty distinguishing motility disorders from CAD is particularly difficult in patients who may have other risk factors for CAD such as diabetes, hypertension, tobacco use or family history. However, chest pain with esophageal motility disorders often accompanies food intake and is often sharp, non-radiating and rarely lasts for longer than a few minutes. This is in contrast to chest pain from angina which is often related to exercise and exertion and is a long lasting, crescendo, dull or heavy chest pain that may radiate to the jaw or left arm.

Patients with esophageal motility disorders are often incorrectly diagnosed with GERD and placed on anti-secretory therapy with H2 receptor antagonists or proton pump inhibitors. These medications usually provide no benefit for the reported symptoms which may be the first clue that reflux of gastric acid is not a contributing factor to the patient’s illness. Patients with a hypertensive lower esophageal sphincter (i.e. achalasia) experience regurgitation rather than GERD and a careful history can usually distinguish between the two symptoms. Regurgitation is the effortless return of liquid or poorly digested food from the esophagus proximally higher into the upper esophagus or mouth. The contents do not have gastric acid, therefore there is usually no reported or burning sensation. GERD, on the other hand requires a loose or intermittently relaxed lower esophageal sphincter. The passage of gastric contents into the esophagus usually is accompanied by a burning sensation in the chest or mouth and is usually well controlled with the addition of H2 blockers or PPIs.

Dysphagia and weight loss are common symptoms of achalasia but also primary esophageal or gastro-esophageal junction malignancy. Gastroesophageal junction malignancy can cause rapid weight loss and dysphagia and is termed pseudo-achalasia. These symptoms may also be seen in esophageal strictures, esophagitis, esophageal ulceration or extrinsic compression from a mediastinal mass.

Testing

Upper endoscopy (EGD) and esophagram are often the first tests performed in patients with suspected achalasia or EMDs. Patients with achalasia have a nonperistaltic (atonic) esophagus which may be dilated with retained fluid or food. The hypertonic LES makes it difficult for ingested oral contrast or an endoscope to pass into the stomach. Ingested barium often produces the classic “bird’s beak” appearance at gastroesophageal junction. 

Other motility disorders such as esophageal spasm or jackhammer esophagus usually demonstrate random, haphazard esophageal contractions seen on endoscopy or esophagram.

The most important test for the diagnosis of esophageal motility disorders is high resolution esophageal manometry (HRM).6 This test requires passage of a soft flexible catheter through the nose and into the upper stomach. The catheter has pressure sensors every 1-2 cm. During HRM the patient is asked to ingest about 10 liquid swallows. Machine software generates topographs showing time, length and pressure which are used to further subclassify these disorders. The most commonly used classification system is termed the Chicago Classification version 3.0.7 In this classification, disorders of esophagogastric junction (EGJ) outflow obstruction are defined as having an elevated integrated relaxation pressure (IRP) at the lower esophageal sphincter and include the three subtypes of achalasia and EGJ outflow obstruction (EGJOO). Major motility disorders have normal IRPs and are termed aperistalsis, distal esophageal spasm and hypercontractile (Jackhammer) esophagus. Minor disorders include ineffective esophageal motility or fragmented peristalsis. 

Treatment

Therapy for esophageal motility disorders focuses initially on the status of the pressure in the lower esophageal sphincter. If the pressure is elevated then medical or surgical treatment aimed at lowering this pressure is required. In the spastic motility disorders (jackhammer esophagus, type III achalasia, esophageal spasm), treatment may also focus on relaxing the muscle of the esophageal body.

Medications

Pharmacologic therapy to lower the esophageal sphincter is currently limited to nitrates such as isosorbide dinitrate and calcium channel blockers like diltiazem or nifedipine. These medications may lower pressure and improve swallowing in some patients. However, adverse events such as dizziness, orthostasis and hypotension limit their use in this population. Noncardiac chest pain in spastic esophageal disorders may respond to treatment with tricyclic antidepressants (TCAs) or selective serotonin reuptake inhibitors (SSRIs). These medications may also often successfully treat anxiety that often accompanies these disorders. The lowest dose required to successfully treat the chest pain is recommended. 

Proton pump inhibitors (PPIs) and H2 receptor antagonist have essentially no role in treating esophageal motility disorders. Acid reflux does not readily occur in patients with achalasia who have a hypertensive lower esophageal sphincters. Patients with EMDs and a normal LES pressure (normal IRP on HRM) may occasionally have GERD and therefore rarely esophagitis which may respond to anti-secretory therapy. The diagnosis of GERD can usually be elucidated with upper endoscopy but may require formal esophageal pH testing or evaluation of a response to PPI therapy to accurately diagnose.

Endoscopy

Injection of botulinum toxin into a hypertensive LES or spastic esophageal body during upper endoscopy has been used for decades to treat esophageal motility disorders. Botulinum toxin is an inhibitor of acetylcholine release from neurons and when placed into the esophageal body or LES, it will lower the amplitude of contractions and sphincter pressure, respectively. Standard injection dose is 80-100 units in four quadrants about 1-2 cm above the LES. This leads to rapid improvement in about 80% of patients with achalasia.8 However, at 12 months following injection, only 40-50% of patients maintain response and require repeat injections to maintain efficacy. Therefore, treatment for a hypertensive LES (achalasia or EGJOO) with botulinum toxin in 2019 is reserved for diagnostic purposes or for patients averse to or high risk for laparoscopic surgery (e.g. elderly with extensive comorbidities). For spastic esophageal disorders, injection of 100 units of botulinum toxin into the mid- or distal esophagus may decrease chest pain but similarly requires repeat treatment in most patients for maintenance of response.

Endoscopic pneumatic dilation for achalasia or EGJOO utilizes balloons that measure 30mm, 35mm, or 40mm in diameter, which are larger than those used for dilation of typical esophageal strictures. During the procedure, the balloon is placed across the LES and inflation results in disruption of the muscles of the sphincter. Short term treatment is effective in 85-90% of patients. However, at 12 months, relief is seen in only 60-70% and repeat dilation is required for those who lose response.8 Complications of pneumatic dilation include chest pain in 10-15% and perforation at the gastroesophageal junction in 2-3% of patients. Perforation is usually managed conservatively with endoscopic closure or stenting.9

Surgery

The standard surgical procedure for achalasia is laparoscopic Heller myotomy (LHM). This procedure creates a three-inch myotomy across the LES on the anterior lower esophageal and upper gastric wall. This myotomy is followed in most patients by a fundoplication to decrease the risk of GERD after the procedure. Multiple long-term studies demonstrate efficacy of LHM in 85-90% in most patients.8

Novel Treatments

The newest endoscopic treatment for achalasia and related esophageal motility disorders is per-oral endoscopic myotomy (POEM). This procedure replicates the myotomy from LHM but without the fundoplication. The four steps with POEM involve: 1) mucosal incision of the esophageal wall; 2) creation of a submucosal tunnel to the upper stomach; 3) myotomy of the circular and/or longitudinal muscle from the distal esophagus to the upper stomach and 4) closure of the mucosal incision used to enter the esophageal wall. Case series have demonstrated relief of dysphagia equal to that of Heller myotomy but with shorter recovery times, lower cost, and decreased cardiopulmonary complications.10GERD is seen more commonly with POEM, however since fundoplication is not performed after myotomy. Randomized trials comparing POEM with Heller myotomy are ongoing.

CONCLUSION

Under normal circumstances, esophageal peristalsis occurs in a coordinated, sequential fashion to propel food into the stomach. Esophageal motility disorders represent a diverse group of conditions that alter this peristalsis either in the esophageal body or lower esophageal sphincter. Symptoms most commonly include dysphagia and chest pain. Differentiation from other common conditions such as coronary artery disease, gastro-esophageal reflux disease and malignancy may be difficult. Standard workup includes upper endoscopy, barium esophagram and high resolution esophageal manometry. Treatment of achalasia focuses on reducing the pressure of the lower esophageal sphincter. Pneumatic dilation and laparoscopic Heller myotomy are the most commonly used treatments. Per oral endoscopic myotomy (POEM) represents the newest endoscopic treatment option and early data suggests efficacy comparable to that of Heller myotomy. Due to the increasing diagnostic and treatment options of EMDs, a multidisciplinary approach is required and referral to gastroenterology or surgery is recommended for further management of these disorders.

FROM THE LITERATURE

Video Capsule Endoscopy and Crohn’s Disease

February 2019 • Volume XLIII, Issue 2

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A prospective, multi-center study was carried out to evaluate small-bowel capsule endoscopy (CE) for the longitudinal assessment of mucosal inflammation in subjects with Crohn’s disease(CD). Clinical evaluation was carried out with ileocolonoscopy and CE at baseline at 6 month followup. Small bowel patency was confirmedbefore CD at both time points. The Simple Endoscopic Score for CD (SES-C), was used for colonoscopy, and the Lewis Score and the CECD Endoscopic Index of Severity (CECDEIS) were used for CE.

Clinical scoring indices included the physician global assessment (PGA), CD activity index (CDAI), and Harbey-Bradshaw Index (HBI). Laboratory markers included CRP, fecal calprotectin, and ESR collected at baseline and followup. Correlation between endoscopic scores and clinical parameters were measured using Spearman test.

A total of 74 subjects were enrolled; 53 (72%) completed endoscopic procedures at baseline and 6-month followup. The SES-CD ileocolonoscopy score correlated with the Lewis Score and CECDEIS capsule score. None of the three endoscopic scores correlated with PGA, CDAI, HBI, CRP, ESR orfecal calprotectin. A total of 85% of subjects had proximal small bowel inflammation identified onCE. There were no CE-related adverse events.

It was concluded that there was high correlation between CE and ileocolonoscopy scores for the assessment of mucosal disease activity over time; however, there were no correlations between endoscopic scores and clinical parameters. The use of CE for the assessment of small-bowel CD is feasible and valid.

Melmed, G., Dubinsky, M., Rubin, D., et al. “Utility of Video Capsule Endoscopy for Longitudinal Monitoring of Crohn’s Disease Activity in the Small Bowel: A Prospective Study. Gastrointestinal Endoscopy; Vol. 88, No. 6, 2018, pp. 947-955.

Murray H. Cohen, DO, “From the Literature” Editor, is on the Editorial Board of Practical Gastroenterology.

THE MICROBIOME AND DISEASE, SERIES #7

How Globalization Changes the Microbiome

February 2019 • Volume XLIII, Issue 2
Sabine Hazan,Skylar Steinberg

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The digestive tract’s microbial ecosystem is tailored for specific geographic areas. Here we discuss how the rise of globalization has spurred a mass transition of the European and American microbiome worldwide, altering the unique digestive patterns and processes of other nations. We can partially attribute our global obesity epidemic to the decrease in microbial diversity because of a larger adaptation of a Western diet.

Skylar Steinberg, BS, Health Promotion and Disease Prevention, Research Assistant, Ventura Clinical Trials Sabine Hazan, MD, Gastroenterology/Hepatology/Internal Medicine Physician, CEO, Ventura Clinical Trials, CEO, Malibu Specialty Center, Ventura, CA 

Globalization, which is the fusing of disparate trade agreements, communications, economies, technologies, and cultures,1 has significantly changed humans’ environments, diets, and overall health. The term “globesity” refers to the shift from traditional, localized diets to a Western diet, known as “nutrition transition.”2 Research has shown that increasing globalization by one standard deviation often results in a 23.8% increase in obesity and a 4.3% rise in calorie intake.3 Integrating Western habits alters lifestyles, demographics, and economic conditions in ways that promote obesogenic environments. Global trade agreements facilitate the consumption of highly-processed foods in lieu of traditional fare, such as fruits, vegetables, and raw foods. As a result, communities across the world are eating more high-fat, high-sugar foods, as well as larger quantities of meat than before.4

Historically, the digestive tract’s microbial ecosystem was tailored for a specific geographic area, much as the flora and fauna of an ecosystem are geographically distinct.5However, the rise of globalization has spurred a mass transition of the European and American microbiome worldwide, altering the unique digestive patterns and processes of other nations, which has, arguably, caused a global rise in obesity.6 For example, Western microbiomes consist of 15% to 30% fewer species than non-Western microbiomes7 and research shows that lower gut microbiome diversity is associated with weight gain.8Therefore, it is fair to partially attribute our global obesity epidemic to the decrease in microbial diversity because of a larger adaptation of a Western diet.

The “disappearing microbiome hypothesis” has been used to describe how technological and cultural changes accompanying industrialization has lead to a “disappearing microbiome”.9 Bacteria in the genus Treponema, which appears in the stool of numerous non-Western populations, for example, does not appear in the microbiomes of those in Western civilizations.10

Additionally, Western microbiomes generally bear a greater amount of Bacteroides, while non-Western microbiomes generally contain greater amounts of Firmicutes and Proteobacteria,11 and the ratio of these phyla has been associated with the development of obesity.12

After the age of three, the adult microbiome develops and becomes highly-resistant to changes on a short-term basis. However, long-term dietary shifts can result in significant impacts and can potentially harm future generations. As we age and our health deteriorates, the stability and diversity of the gut microbiota declines, which major changes to diet can exacerbate and accelerate.13

Long-term diet studies have shown that humans can alter the ratio of Bacteroidetes and Firmicutes by consistently consuming different foods abnormal to our environments.14Additionally, evidence shows that our diet shapes the relative abundance of dominant phyla in our systems and the composition of macronutrients that we consume influence specific bacterial groups.15

This Western dietary shift can significantly impact developing nations, which are more susceptible to obesity and other diseases. Low-cost, easily-accessible packaged food also decreases the need for physical activity and as these populations start eating differently, it can significantly harm their gut biome and lead to other health complications.16

While more research is needed to better assess how globalization causes the microbiome to shift, it’s evident that people in developing areas lack the necessary resources and education to inform them how consuming these processed, high-fat, and high-sugar Westernized foods can compromise their overall health.

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Frontiers In Endoscopy, Series #49

Transluminal ERCP using a Lumen Apposing Metal Stent in a Patient with Roux-En-Y Gastric Bypass Anatomy: The EDGE Procedure

February 2019 • Volume XLIII, Issue 2
Douglas G. Adler,Jay Dubroff

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In this article we discuss the EDGE procedure, which provides the endoscopist another potential modality for accomplishing ERCP in the technically challenging RYGB anatomy.

Case Report

A57 year old man with a history of a Roux-en-Y gastric bypass developed symptomatic cholelithiasis. The patient underwent laparoscopic cholecystectomy with an intraoperative cholangiogram. The cholangiogram showed filling defects in the distal CBD. A common bile duct exploration was not performed and the patient was referred for endoscopic treatment. Given his anatomy, a transluminal approach was selected for access to his biliary tree. Using a linear EUS scope, when viewing from the gastric pouch the remnant stomach was identified. A 19g EUS FNA needle was used to access the gastric remnant and fill it with saline mixed with water. (Figure 1) A 0.035″ guidewire was passed through the needle and coiled in the gastric remenant. (Figure 2). A 20mm Hot Axios lumen apposing metal stent (LAMS) (Boston Scientific, Natick MA) was passed over the wire and, using an electrocautery enhanced catheter, deployed transluminally between the pouch and the gastric remnant (Figure 3). Several days later, the patient returned to the endoscopy suite and the LAMS was widely patent. (Figure 4) The duodenoscope was passed through the LAMS and ERCP was performed in a standard manner with biliary sphincterotomy and stone extraction. (Figure 5). Afterwards, the LAMS was removed with a rat-tooth forcep. The gastro-gastro fistula was mature appearing. The fistula was closed using an over the scope clip, with contrast injection into the pouch confirming closure. The patient tolerated all endoscopic procedures well. 

ERCP in patients with Roux-en-Y Gastric Bypass

Patients who have undergone Roux-en-Y gastric bypass surgery (RYGB) present a distinctive challenge for the endoscopist seeking to perform endoscopic retrograde cholangiopancreatography (ERCP). Patients with RYBG anatomy are often at greater risk of requiring ERCP as both rapid weight loss,1 obesity,2 increased abdominal and visceral adipose3 predispose patients to augmented risk of gallstone formation. The altered anatomy resulting from RYGB precludes a standard duodenoscope from accessing the second portion of the duodenum through the stomach given the creation of the gastric pouch and a distal jejunal limb. 

Endoscopic Options

For ERCP to be performed via oral endoscopy insertion in this setting would require the endoscope to pass through the gastric pouch, Roux limb, jejunojejunostomy and finally up the pancreatobiliary limb to access to the ampulla in a retrograde approach as is typically encountered in patients with Billroth II anatomy. Generally, oral approaches utilize single balloon enteroscopy (SBE), spiral balloon enteroscopy (SE) or double balloon enteroscopy (DBE), which all rely upon an overtube to provide anchoring to facilitate deeper advancement of the enteroscope.4,5 All of these endoscopes have limited maneuverability, lack an elevator and have limited accessories, making ERCP difficult even if the ampulla is reached.4,5 Indeed, balloon enteroscopy guided ERCP have less than optimal reported success rates with one multicenter study indicating 60% success rate for SBE, 63% for DBE and 65% for SE.4 A more recent large, international study found a similar success rate for SBE and DBE, 63% and 37%, respectively.6 Despite the technical disadvantages of balloon enteroscopy guided ERCP, this approach is common given the alternatives.6,7

Surgical Options

Laparoscopic-assisted ERCP (LA-ERCP) provides another means of performing ERCP in RYGB altered anatomy by creating access via a surgically placed trocar into the remnant stomach, allowing access to the pylorus and the duodenum via the normal route, through which ERCP can be easily performed. Compared to balloon enteroscopy ERCP, LA-ERCP is a superior technique with nearly 100% of cases achieving successful papilla cannulation, or approximately 28% higher than either SBE or DBE.7,8 However, this technique is markedly resource intensive and carries higher associated costs, hospital stays and rates of adverse events.8,9,10 Relative to balloon enteroscopy, LA-ERCP has been noted to carry an 11% increased risk of adverse events.8 One study found that even in cases of failed balloon enteroscopy ERCP with subsequent rescue LA-ERCP procedures still incurred a total cost savings of $1015 compared to LA-ERCP alone.7 This cost savings was diminished if the jejunojejunal limb length was greater than 150cm as this resulted in increased time undergoing balloon enteroscopy ERCP.7 Additionally, LA-ERCP requires the coordination of endoscopic, anesthesia and surgical teams, which raises potential institution specific challenges for both resource allocation and creates difficulties with arranging physician availability.

EDGE Procedure

The endoscopic ultrasound-directed transgastric ERCP (EDGE) procedure provides an innovative solution to this technically challenging anatomy by deploying a lumen apposing metal stent (LAMS) between the remnant stomach and either the gastric pouch or the proximal jejunal Roux limb.11,12 The LAMS, placed under EUS guidance, effectively creates a connection to the remnant stomach through which a standard duodenoscope can be passed, allowing ERCP to be performed in the standard direction and manner, and without the need for any special accessories once the remnant stomach has been reached. First described in 2014,13 the EDGE procedure is typically performed in two stages; after EUS guided placement of the LAMS to create temporary access via the remnant stomach the stent is typically allowed to mature for several days or even weeks before the second stage and transluminal ERCP are performed.12 While the initial feasibility study excluded patients with indications for acute biliary intervention,12 more recently, EDGE procedures have been successfully performed in a single stage for acute indications, such as acute cholangitis.14 This approach is usually reserved for acute cases in need of urgent biliary intervention. After ERCP is performed, and ampullary access is no longer indicated the LAMS is usually removed with a snare or grasping forceps. The remaining fistula can be closed with endoscopic clips (usually over the scope clips), endoscopic suturing, or a combination thereof. Argon plasma coagulation (APC) has also been proposed as a potential means to support fistula closure by promoting granulation tissue formation, as has been used to close fistulas in other contexts.15 In some patients, the fistula can be left to close secondarily. 

Weight Gain Following EDGE

Weight gain following EDGE procedures has been a concern as creation of a temporary fistula could potentially work against RYGB anatomy and its original indication. Most studies have found that patients undergoing EDGE procedures experience, on average, a net negative weight loss of approximately 1 to 3 kg.6,16,17 However, one small retrospective study including nineteen patients showed a mean weight gain of 1.7 kg.15The weight loss may be due to the biliary issues needing attention in the first place. Similar to LA-ERCP, the EDGE procedure carries a high technical success rate that approaches 100%, which is 40% greater compared to enteroscopy guided ERCP.14 Unlike LA-ERCP, the EDGE procedure has fewer reported adverse events, which have been described as similar to enteroscopy guided approaches; 6.7% versus 10%, respectively.14This low adverse event rate may be secondary to the nature of the procedure itself or may be underrepresented given the novelty of the procedure. Previously described adverse events associated with EDGE approaches include localized PEG site infections,12intraprocedure bleeding, fistula persistence and previously described adverse events associated with conventional ERCP.14 Reports in the literature of fistula persistence following stent removal are rare, and are usually managed endoscopically without surgical intervention.6,16 Compared to previously employed modalities for achieving ERCP in RYGB anatomy, the EDGE procedure has emerged as a promising, new technique. Although the EDGE procedure is novel, it seemingly combines the high technical success rate of LA-ERCP with the safety profile of oral balloon enteroscopy approaches. EDGE procedures also result in significantly shorter procedure times as well as length of hospital stays when compared to LA-ERCP.17 Accordingly, there is a small amount of initial evidence that EDGE, as an initial approach, may be less costly than either LA-ERCP or balloon enteroscopy guided ERCP.18 While preliminary published evidence of the EDGE procedure is encouraging, future longitudinal studies are needed to further validate the technique’s success rate, safety, effect on weight and cost over time.

CONCLUSION

The EDGE procedure provides the endoscopist another potential modality for accomplishing ERCP in the technically challenging RYGB anatomy. No single technique will accommodate all patients and the choice of technique in this context, should be carefully weighed against multiple considerations including clinical circumstances, urgency, need for future repeat ERCP as well as institutional resources and expertise.

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NUTRITION ISSUES IN GASTROENTEROLOGY, SERIES #138

Hydrating Adult Patient with Short Bowel Syndrome

February 2015 • Volume XXXIX, Issue 2
Carol Rees Parrish,John K. DiBaise

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Fluid and electrolyte abnormalities are a major cause of morbidity in short bowel syndrome. Part three of this five-part series on short bowel syndrome is dedicated to the challenges involved in keeping the patient with short bowel syndrome hydrated. Strategies to improve hydration to prevent morbidity and enhance quality of life are presented.

INTRODUCTION

Achieving adequate hydration status (euvolemia) can be very difficult for patients with ileostomies.1,2 It is even more challenging for those with short bowel syndrome (SBS). Identifying dehydration is often straightforward in patients who have high output ostomies, as the clinician can estimate the volume of stool output by the number of times the patient empties their ostomy appliance in a 24 hour period (Clinical pearl: it is important to ask patients, “In a 24 hour period,” or “during the day, and then, what about at night?”—As clinicians may only get half the story otherwise). In contrast, recognizing dehydration in a patient without an ostomy can be difficult, as the clinician cannot rely on the number of bowel movements per day to accurately quantitate the volume of output.

About 4 liters of fluid (0.5L saliva, 2L gastric acid and 1.5L pancreaticobiliary secretions) are normally secreted into the intestinal lumen each day in response to food and drink. Because of regional gut differences in water and sodium handling, SBS patients without a colon may be ‘net secretors’ (they lose more water and sodium from their stoma than they take in by mouth). In patients who have < 100cm of residual jejunum, daily jejunostomy output can be more than four liters per day.

Electrolyte disturbances are a major cause of morbidity in patients with SBS. In particular, those with an end-jejunostomy lose large amounts of sodium in the stool, often resulting in chronic sodium depletion and dehydration. It is imperative that clinicians teach SBS patients not only what to expect in terms of stool/ostomy output (see Table 1), but also the basic symptoms and risks of dehydration (see Table 2).

Fluid and electrolyte disorders predominate the early clinical course following massive intestinal resection. These issues may continue long term, particularly in patients without a colon who can suffer from substantial enteric volume loss resulting in severe dehydration, nephrolithiasis, renal insufficiency/failure,3,4 persistent metabolic acidosis, hypokalemia, hypomagnesemia, and hypocalcemia.

Assessment of Hydration Status

The initial evaluation of all SBS patients should include a history of weight change, medication usage, signs/ symptoms of electrolyte deficiencies, gastrointestinal or other symptoms that may affect oral intake or fluid loss (nausea, vomiting, bloating, distension, etc.). The physical examination should also assess for malnutrition and signs of dehydration and nutrient deficiencies. Serial weight measurements are useful to track trends and serve as a warning of nutritional and/ or hydrational compromise. It is imperative that SBS patients are instructed to measure and record their daily fluid intake and urine/stool output to help to guide fluid needs. Adequate hydration is considered to be present when urine output is > 1 L/day and urinary sodium concentration is > 20 mEq/L.4-6

The usual laboratory parameters to assess hydration such as serum sodium, creatinine, and blood urea nitrogen are unreliable in SBS as they become abnormal only after severe dehydration occurs. This is due to the normal homeostatic mechanisms including elevation of plasma renin and secondary hyperaldosteronism that occur in response to a subtle decrease in serum sodium or blood volume. Sodium, and hence water, are avidly conserved by the kidney, so a rise in BUN to creatinine ratio is a late response and only occurs after the patient is significantly dehydrated.7

Management of Dehydration

Patients (and some health care providers) often believe that large quantities of water should be ingested to make up for stool losses in the setting of SBS. This misconception, however, generally leads to increased ostomy outputs and creates a vicious cycle that further exacerbates fluid and electrolyte disturbances. Patients are often surprised to find that stool/ostomy output is significantly reduced following a twenty-four hour trial where they ingest only appropriate solids and NO oral fluids (IV fluids may be needed during the trial to prevent dehydration).

In SBS patients with excessive thirst due to dehydration, oral fluids should be restricted to < 1500mL/day and supplemental intravenous hydration provided to maintain euvolemia.8 SBS patients may benefit from substituting regular beverages/fluids with glucose-electrolyte oral rehydration solution (ORS) to enhance intestinal absorption and reduce secretion (see ORS section below).

The ability to maintain euvolemia while ingesting common oral liquids is often dependent upon the presence or absence of a colon. Most SBS patients with a colon can tolerate ingesting hypotonic fluids. They can usually maintain adequate hydration and sodium balance without excessive fluid loss.9 Patients without a colon often require additional sodium (~ 90mEq or ~ 2 g sodium (7/8 teaspoon of table salt) per liter of stool lost—in enterally fed patients, the sodium content of the formula should be brought up to ~ 90-100mEq/liter7 (1/4 teaspoon table salt = 600mg/26mEq of sodium) if no other sodium source is available.10

Special Considerations
Hypomagnesemia

Like chronic sodium depletion, hypomagnesemia can also be problematic in SBS. It occurs as a consequence of multiple factors including malabsorption of magnesium that is exacerbated by the binding of magnesium by unabsorbed fatty acids and increased renal excretion due to sodium/water depletion (and the hyperaldosteronism that follows). The major clinical manifestations include tetany, tremor, weakness, apathy, convulsions, coma, and electrocardiographic abnormalities. Hypomagnesemia may contribute to hypocalcemia as a result of impaired parathyroid hormone (PTH) release.11 Hypokalemia occurs in nearly half of those with chronic hypomagnesemia. The correction of sodium depletion is critical in treating hypomagnesemia. Measurement of urinary sodium may assist in the assessment of sodium balance in some patients; a random urinary sodium concentration of < 20 mEq/L is generally a good indicator of sodium depletion.

Oral magnesium salts can be administered in doses of 12-24 mEq/day and do not appear to increase stomal output, particularly when taken at night when intestinal transit is at its slowest. Higher doses are frequently needed, however, and may be difficult to use due to the laxative effects of oral magnesium causing a worsening of diarrhea. Magnesium heptogluconate is available as a liquid that may be added to an ORS (see section below) at a dose of 30 mEq/L. The oral administration of 1a-hydroxycholecalciferol may also be useful as it can increase both intestinal absorption and renal absorption of magnesium.12 If moderate to severe hypomagnesemia (< 1 mg/dL) persists, parenteral magnesium sulfate may be necessary. Intravenous magnesium replacement should be given over 8-12 hours (rather than the usual IV piggy back bolus over 1-4 hours) to prevent significant renal excretion when the renal threshold is exceeded.13

Metabolic Acidosis

Bicarbonate

Metabolic acidosis may arise from excessive gastrointestinal bicarbonate loss. The acidosis may be further compounded by impaired renal homeostasis caused by profound salt and water depletion. Relevant to the SBS patient, chronic acidosis can lead to bone resorption and osteopenia, aggravation of secondary hyperparathyroidism, increased protein catabolism, reduced respiratory reserve and malaise.14,15 Metabolic acidosis can be detected on laboratory testing by the finding of low serum bicarbonate (or CO2). SBS patients can have either a normal anion gap or hyperchloremic metabolic acidosis. In patients with metabolic acidosis, alkali therapy (usually with oral sodium bicarbonate) is used to maintain the serum bicarbonate concentration in the normal range. A bicarbonate solution such as bicitra may prove beneficial over sodium bicarbonate tablets due to the sheer number of tablets needed for the equivalent amount of bicarbonate in bicitra.15 Occasionally, parenteral alkali therapy may be needed.

D-lactic acidosis

D-lactic acidosis is a rare neurological syndrome associated with SBS that is characterized by altered mental status ranging from confusion to coma, slurred speech, seizures and ataxia. D-lactic acidosis results from bacterial fermentation of unabsorbed carbohydrates seen in SBS patients, particularly children, with a remaining colon.16 Development of this syndrome requires carbohydrate malabsorption with increased delivery of nutrients to the colon, ingestion of a large amount of carbohydrate (usually concentrated sweets), microbes that produce D-lactate and impaired D-lactate metabolism. Excessive production of D-lactate occurs when abnormal gut microbes overwhelm the normal metabolism of D-lactate and results in the accumulation of this substance in the blood.17 Because measurement of D-lactate requires a special laboratory request (unlike L-lactate), a high level of suspicion is needed. This condition should be considered when an anion-gap metabolic acidosis with normal lactate (L-lactate) level is present in the SBS patient with a colon-in-continuity and typical clinical manifestation. Although the optimal treatment of this condition is unclear, options include a carbohydrate (sugar)-restricted diet and the use of antibiotics to reduce the production of D-lactate producing gut microbes.

Fluid Options for Those with SBS

SBS patients can lose large volumes of fluids and electrolytes due to diarrhea/high ostomy output and, occasionally, from the presence of decompressive gastric/enterostomy tubes. Fluids should be given to cover all losses and maintain a urine output of at least 1 L/d. The sodium and glucose content of the fluid are important considerations, as inappropriate fluids will exacerbate fluid losses in SBS. Hyperosmolar fluids (e.g., regular soda and fruit juices) are concentrated and induce secretion from enterocytes in an attempt to dilute the concentration of the luminal contents, which then contributes to increased diarrhea. In contrast, hypo-osmolar fluids (e.g., water) do not contain the sodium or glucose necessary to optimally facilitate absorption in an end-jejunostomy patient and may lead to dehydration if consumed in large amounts as they pull sodium (and hence water) into the lumen. In the normal subject, when water or other solutions with a sodium concentration < 60-90mEq are consumed, sodium (and hence water— as water follows sodium) is secreted into the intestinal lumen during passage through the duodenum and jejunum in an effort to equilibrate the concentration gradient differences. The sodium is normally reabsorbed in the distal small bowel; however, in those with an end jejunostomy, both sodium and fluid are lost in the stool.18 See Table 3 for examples of both hypertonic and hypotonic fluids.

Oral Rehydration Solution (ORS)

The rationale to include sodium in oral rehydration solutions is to replace sodium losses and to promote water absorption. Water movement in response to a water gradient is about nine-times greater in the upper small bowel than in the distal small bowel.19

As the jejunum is more permeable to small molecules, osmolality makes a difference in fluid flux in this area and is the basis for use of ORS. Intestinal luminal sodium and glucose play important roles in promoting fluid absorption.20,21 Glucose in the gut lumen stimulates sodium absorption across the small intestine, which is followed by anions and water. For each cycle of this transport, two sodium ions and one molecule of glucose/galactose are transported together across the cell membrane and hundreds of water molecules move into the epithelial cell. Absorption of sodium occurs by 3 different mechanisms across the GI tract epithelium:

  1. Passive absorption; probably through the intercellular junctions of the mucosal cells,
  2. Active absorption of sodium, mediated by the sodium-potassium pump, and
  3. Glucose-coupled transport of sodium (most active in the jejunum).

Oral rehydration solutions are efficacious because they utilize the glucose-coupled transport system. Use of an ORS has been shown to enhance water and sodium absorption in patients with SBS,10,19.22-24 and it has allowed some patients to discontinue supplemental parenteral fluid support. The optimal sodium concentration of ORS to promote jejunal absorption has been demonstrated to be 90-120 mEq Na+/L25 (with optimum carbohydrate: sodium ratio of 1:1).9

While ORS therapy has been extremely successful in the treatment of diarrheal illnesses worldwide, it is not a panacea, and in some SBS patients, it too can increase stool output.22 Furthermore, some patients may find it unpalatable. To hydrate some patients, 2-3 liters per day may be required, however, would start with the goal of 500-1000 mL per day. If the patient will sip ORS over the course of a day and is willing to maintain this regimen day after day, the volume can be titrated as needed. To improve palatability, ORS can be made into ice cubes or popsicles. Both homemade recipes and commercial preparations are available (see Tables 4 & 5). If better hydration is achieved with use of an ORS, then it can be continued indefinitely; however, if output is increased without net gain of increased urine output, then it should be stopped. ORS has also been administered via a gastrostomy tube as a nocturnal infusion with success.24 ORS should not be substituted with commercial sports drinks as sports drinks contain considerably higher carbohydrate and lower sodium content than ORS. Potassium and magnesium may be added to the ORS as gluconate (12mmol/L of ORS) and heptogluconate (30 mmol/L of ORS) salts, respectively, where available. Realistically, despite our best efforts, there are some patients who just will not drink ORS. In those cases, it is best to at least give suggestions for better options (or the least “bad” options), rather than those that will definitely aggravate stool/ostomy output (see Table 6).

Parenteral Fluid

In some SBS patients following the acute stage, parenteral fluids without macronutrients may be needed for those who require the fluid, but not the calories. If a patient cannot maintain a urine output of > 1 liter daily, then supplemental parenteral fluids may be needed. Intravenous fluid is commonly provided as a liter of normal saline infused over 2 to 4 hours once daily as needed. Although the content of the fluid may include only sodium chloride, occasionally dextrose, other electrolytes, vitamins and bicarbonate may be added. Parenteral fluids will be necessary if the stool output consistently exceeds fluid intake (‘net secretors’), a situation most commonly seen in the SBS patient with an end-jejunostomy who has < 100cm of jejunum and an output of > 2 liters/day. As mentioned earlier, ORS may be administered via a gastrostomy tube as a nocturnal infusion.18 During the hot summer months, patients receiving parenteral nutrition overnight may require additional parenteral hydration during the day to prevent dehydration and reduce potential injury to the kidneys. Parenteral fluids may also be needed in the SBS patients who have successfully weaned from PN but still require occasional parenteral fluid support.

CONCLUSION

Maintaining hydration status is a central component in the care of the patient with SBS. Failure to do so can result in dehydration, rapid weight loss and fatigue. If chronic and untreated, it can also lead to nephrolithiasis and jeopardize renal function. Educating patients to identify signs of dehydration as well as to properly instruct them on measures to protect against it should be a high priority to clinicians taking care of these patients.

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