Maneuvering Clinical Pathways for Crohn's Disease
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Current Gastroenterology Reports (2019) 21: 20 https://doi.org/10.1007/s11894-019-0687-4 INFLAMMATORY BOWEL DISEASE (S HANANAUER, SECTION EDITOR) Maneuvering Clinical Pathways for Crohn’s Disease Thomas X. Lu1 & Russell D. Cohen1 Published online: 23 April 2019 # Springer Science+Business Media, LLC, part of Springer Nature 2019 Abstract Purpose of Review Crohn’s disease management has changed significantly with increasing use of biologics. We review the recent literature on the clinical management of Crohn’s disease and new approaches in selecting and optimizing therapy. Recent Findings Recent studies have addressed the efficacy of proactive anti-TNFα trough level monitoring, the efficacy of biosimilars, and the efficacy and immunogenicity of newer biologics including anti-integrin therapy and anti-IL12/23 therapy. Optimizing anti-TNFα therapy according to trough concentrations correlates with improved remission rates. Patients can be switched from the reference drug to a biosimilar, or vice versa, without a measurable change in efficacy, safety, or immunoge- nicity. Immunomodulators are effective in decreasing immunogenicity and boosting anti-TNFα drug level. The anti-integrin and anti-IL12/23 therapies are effective as induction and maintenance therapy with low immunogenicity and excellent safety profiles. Patients at high risk for post-operative recurrence should be started on a biologic therapy within 4 weeks post-op. Summary Multiple biologic therapies are currently available for treatment of Crohn’s disease including anti-TNFα therapy, anti- integrin therapy, and anti-IL12/23 therapy. The choice of first-line therapy should be based on individual risk-benefit analysis, route of administration, and patient preference. Patient with inadequate response should have their trough level checked and therapy optimized. Therapeutic prophylaxis for post-operative recurrence should be based on patient’sriskfactorsforrecurrence. Keywords Crohn’s disease inflammatory bowel disease . Anti-TNFα . Anti-integrin . Anti-IL12/23 . Infliximab . Adalimumab . Certolizumab pegol . Natalizumab . Vedolizumab . Ustekinumab Introduction likelihood of success and the safety of the various classes of therapies have raised the possibility of personalized medicine, The management of Crohn’s disease has evolved significantly with possible beneficial economic consequences. In this re- over the last decade [1••, 2–4]. While the anti-TNFα agents view, we will discuss recent data on the optimal use of the accounted for virtually all biologic use prior to 2014, new biological therapies, updates in treatment and monitoring with biologic agents including vedolizumab and ustekinumab have the anti-TNFα agents, when and how to use the newer bio- been approved and are rapidly gaining market share. A new logic agents, and how to integrate immunomodulators and paradigm of optimizing biological drug dosing according to steroids in the clinical pathways for management of Crohn’s serum drug levels, and/or co-administration of immunosup- disease. pressants to boost drug levels and lower immunogenicity has emerged, with the goal of improving the clinical efficacy of the monoclonal antibodies. Evolving studies looking at the presence of biological markersinpatientstopredictthe Disease Severity and Risk Factors This article is part of the Topical Collection on Inflammatory Bowel The optimal therapeutic regimen is individualized based on Disease each patient’s disease severity and risk factors [1••]. Individuals with mild disease are ambulatory, able to tolerate * Russell D. Cohen oral intake, and has minimal to no weight loss, no complica- [email protected] tions such as intestinal obstruction or development of abscess, and no systemic toxicity such as high fevers. Endoscopically, 1 Section of Gastroenterology, Hepatology and Nutrition, these individuals may have isolated erosions or very shallow Inflammatory Bowel Disease Center, University of Chicago Medicine, Chicago, IL 60637, USA ulcerations but do not have extensive or deep large ulcers. 20 Page 2 of 9 Curr Gastroenterol Rep (2019) 21: 20 Individuals with moderate to severe disease have significant of both clinical and endoscopic remission. Clinical response weight loss, anemia, intolerance to oral intake, fever, and/or should be evaluated within the first few weeks of therapy, abdominal pain. Endoscopically, these individuals may have although that timing may vary depending upon the treatment diffuse or large deep ulcers affecting more than one segment regimen and disease severity of the patient. Updated treatment of colon and/or small bowel. Individuals with fulminant dis- recommendations suggest evaluating patients endoscopically ease are those with systemic toxicity such as high fever, intes- or with an objective measure of inflammation such as fecal tinal obstruction, persistent nausea/vomiting, severe malnutri- calprotectin or C-reactive protein within 6 months after initi- tion, development of an abscess, and/or persistent symptoms ating therapy and adjusting the medication doses and/or despite corticosteroid or biologic therapy. Non-modifiable risk choices if endoscopic healing is not reached [1••]. For patients factors for severe and progressive disease over time include with Crohn’s disease that is not accessible by endoscopic eval- young age at diagnosis, penetrating/stenosing disease, ileal uation, radiographic monitoring for outcomes may be appro- disease location, extensive bowel involvement, and severe priate. Non-invasive measures such as measuring serum C- perianal disease. Modifiable risk factors include smoking reactive protein, fecal calprotectin, or fecal lactoferrin moni- and NSAID use [5, 6]. In addition, biomarkers can be helpful toring may be helpful if the patient has elevated levels with for risk stratification. The rate of complicated Crohn’sdisease their bowel inflammation [15]. has been shown to increase as the number and magnitude of We will discuss treatment options below based on patient’s reactivity to microbial antigens increases [7, 8]. disease severity and risk factors. General Principles of Treatment Mild Disease With No Risk Factors Current therapeutic approaches are focused on inducing re- The modern biological agents to date have not been formally mission then maintaining remission. There are several differ- tested as induction therapies for mild to moderately active ent targets of treatment including clinical remission, Crohn’s disease. As a result, the data on therapies targeting endoscopic/radiologic remission, and histologic remission this patient population is rather weak. Currently, only con- [9]. While clinical trials in Crohn’s disease often define clin- trolled ileal release budesonide 9 mg daily is FDA-approved ical remission by a compilation score composed of disease- for remission induction in this population. Systemic cortico- specific as well as generalized systemic issues, such as the steroids, mesalamine, sulfasalazine, various antibiotics, and Crohn’s Disease Activity Index (CDAI) [10], in “real life,” a probiotics have either been inadequately studied or have failed patient is often considered as in clinical remission when that to convincingly show an induction benefit [1••]. Meta- person has no subjective symptoms of their disease. However, analyses have shown a modest benefit of mesalamine at best. researchers and more recent clinical trials have shown that Mesalamine use should be limited to those patients with mild patients who meet the criteria for clinical remission may con- disease who respond objectively to therapy [4]. tinue to have endoscopic and/or histological inflammation in For maintenance of therapy, there is currently no FDA- the bowel, despite having no symptoms [11, 12•]. An individ- approved therapy in this population. The best data exists for ual is in endoscopic and/or radiologic remission when there the thiopurines (azathioprine and 6-mercaptopurine; limited are no endoscopic lesions detected on ileocolonoscopy and/or data on thioguanine) and methotrexate. Unfortunately, oral the bowel appears normal on radiologic imaging. Evolution of budesonide, mesalamine, sulfasalazine, antibiotics, and clinical trial endpoints in the last decade has moved from probiotics have failed to show convincing evidence of a main- simple clinical remission to a composite of clinical and endo- tenance benefit, and systemic corticosteroids are toxic and scopic endpoints to meet the criteria of remission [1••]. An ineffective as well [16]. The biological agents are increasingly individual is in histologic remission when segmental biopsies being used in this patient group, or in those who fail to main- taken during ileocolonoscopy showed no evidence of active tain remission with the immunosuppressants, due to their ef- inflammation under the microscope. Studies and clinical trial ficacy and safety profiles. data have shown that Crohn’s disease patients who achieve endoscopic remission are less likely to be hospitalized, started on corticosteroids, or have surgery within 1 year [13]. Deep Moderate to Severe Disease or Patients With remission is a new term in the nomenclature and is considered Risk Factors achieved when an individual is in clinical, endoscopic, radio- logic, and histologic remission [14]. At the current time, the For patients with moderate to severe disease at presentation or requirement for histological remission has not been a primary patients with risk factors for severe progressive disease, induc- endpoint in clinical trials.