Crohn’s Disease: A Clinical Summary Kara Nazminia with Dr. Jaime Hornecker University of Wyoming School of Pharmacy Oral Presentation Honors College Laramie, WY Crohn’s disease (CD) is an immune-mediated chronic intestinal condition that affects nearly 780,000 patients in the United States. Patients with Crohn’s disease often present with various gastrointestinal (GI) symptoms in addition to other, more specific symptoms such as malabsorption and pertinent laboratory derangements (Peppercorn, 2019). For many of these patients, CD not only causes physical barriers to normal life but also presents social and mental barriers. The etiology of this disease is largely unknown currently; infectious, immunologic, and genetic factors are thought to play a role (Boyapati, 2015). Treatment of Crohn’s disease is guideline-driven and focuses on obtaining remission of symptoms and maintaining remission. Many medications can achieve these goals and with the advent of antibody directed therapies, the number of medications with promise in this disease is rapidly growing. Many of the new medications pose a great opportunity for pharmacists to get involved in patient-centered medical care through therapeutic drug monitoring, education, and assistance with symptom remission and control. Crohn’s Disease Kara Nazminia, PharmD Candidate 2020 University of Wyoming School of Pharmacy Reflective Week #1 September 2019 Learning Objectives At the completion of this presentation, participants should be able to… 1. Identify Crohn’s disease (CD) and differentiate the disease from other inflammatory bowel diseases 2. Understand what is standard in the diagnosis of Crohn’s disease 3. Understand the goals of therapy and prognosis of Crohn’s disease 4. Accurately assess medication therapy in the treatment of Crohn’s disease 5. Understand the role of the pharmacist in Crohn’s disease 2 What is Crohn’s Disease (CD)? § An immune-mediated chronic intestinal condition § One of two major types of Inflammatory Bowel Disease (IBD) § Crohn’s disease and ulcerative colitis (UC) § Characterized by diarrhea and abdominal pain § Crohn’s disease can involve any part of the GI tract and cause discontinuous lesions, known as “skip” lesions § Transmural process § UC differs in that it is often confined to the rectum and colon and causes continuous lesions Freidman SA , Harrison’s Principles of Internal Medicine 20th ed. 2018 Hemstreet BA, Pharmacotherapy: A Pathophysiologic Approach 10th ed. 2018 3 Comparison of Inflammatory Bowel Diseases Crohn’s Disease Ulcerative Colitis (UC) § Malaise and Fever § Abdominal cramping § Abdominal Pain § Frequent bowel movements § Frequent Bowel Movements § Hematochezia frequently Signs/Symptoms § Hematochezia § Weight loss § Fistula § Fever/Tachycardia (Severe UC) § Weight loss/Malnutrition § Blurred vision, eye pain, photophobia § Arthritis § Arthritis § Hemorrhoids, fissures or perirectal abscesses Physical § Abdominal mass and tenderness § Iritis, uveitis, episcleritis, or conjunctivitis Examination § Perianal fissure or fistula § Erythema nodosum, pyoderma gangrenosum, or aphthous ulceration § Decreased hematocrit/hemoglobin Laboratory § Increased white blood cell count, eosinophil sedimentation § Increased eosinophil sedimentation rate (ESR) or C- Findings rate (ESR) or C-Reactive Protein (CRP) Reactive Protein (CRP) § (+) anti-Saccharomyces cerevisiae antibodies § Leukocytosis/Hypoalbuminemia (Severe UC) § (+) perinuclear antineutrophil cytoplasmic antibodies Adapted from Hemstreet BA, Pharmacotherapy: A Pathophysiologic Approach 10th ed. 2018 4 Comparison of Inflammatory Bowel Diseases Crohn’s Disease Ulcerative Colitis (UC) § Malaise and Fever § Abdominal cramping § Abdominal Pain § Frequent bowel movements § Frequent Bowel Movements § Hematochezia frequently Signs/Symptoms § Hematochezia § Weight loss § Fistula § Fever/Tachycardia (Severe UC) § Weight loss/Malnutrition § Blurred vision, eye pain, photophobia § Arthritis § Arthritis § Hemorrhoids, fissures or perirectal abscesses Physical § Abdominal mass and tenderness § Iritis, uveitis, episcleritis, or conjunctivitis Examination § Perianal fissure or fistula § Erythema nodosum, pyoderma gangrenosum, or aphthous ulceration § Decreased hematocrit/hemoglobin Laboratory § Increased white blood cell count, eosinophil sedimentation § Increased eosinophil sedimentation rate (ESR) or C- Findings rate (ESR) or C-Reactive Protein (CRP) Reactive Protein (CRP) § (+) anti-Saccharomyces cerevisiae antibodies § Leukocytosis/Hypoalbuminemia (Severe UC) § (+) perinuclear antineutrophil cytoplasmic antibodies Adapted from Hemstreet BA, Pharmacotherapy: A Pathophysiologic Approach 10th ed. 2018 5 Comparison of Inflammatory Bowel Diseases Crohn’s Disease Ulcerative Colitis (UC) § Malaise and Fever § Abdominal cramping § Abdominal Pain § Frequent bowel movements § Frequent Bowel Movements § Hematochezia frequently Signs/Symptoms § Hematochezia § Weight loss § Fistula § Fever/Tachycardia (Severe UC) § Weight loss/Malnutrition § Blurred vision, eye pain, photophobia § Arthritis § Arthritis § Hemorrhoids, fissures or perirectal abscesses Physical § Abdominal mass and tenderness § Iritis, uveitis, episcleritis, or conjunctivitis Examination § Perianal fissure or fistula § Erythema nodosum, pyoderma gangrenosum, or aphthous ulceration § Decreased hematocrit/hemoglobin Laboratory § Increased white blood cell count, eosinophil sedimentation § Increased eosinophil sedimentation rate (ESR) or C- Findings rate (ESR) or C-Reactive Protein (CRP) Reactive Protein (CRP) § (+) anti-Saccharomyces cerevisiae antibodies § Leukocytosis/Hypoalbuminemia (Severe UC) § (+) perinuclear antineutrophil cytoplasmic antibodies Adapted from Hemstreet BA, Pharmacotherapy: A Pathophysiologic Approach 10th ed. 2018 6 Comparison of Inflammatory Bowel Diseases Crohn’s Disease Ulcerative Colitis (UC) § Malaise and Fever § Abdominal cramping § Abdominal Pain § Frequent bowel movements § Frequent Bowel Movements § Hematochezia frequently Signs/Symptoms § Hematochezia § Weight loss § Fistula § Fever/Tachycardia (Severe UC) § Weight loss/Malnutrition § Blurred vision, eye pain, photophobia § Arthritis § Arthritis § Hemorrhoids, fissures or perirectal abscesses Physical § Abdominal mass and tenderness § Iritis, uveitis, episcleritis, or conjunctivitis Examination § Perianal fissure or fistula § Erythema nodosum, pyoderma gangrenosum, or aphthous ulceration § Decreased hematocrit/hemoglobin Laboratory § Increased white blood cell count, eosinophil sedimentation § Increased eosinophil sedimentation rate (ESR) or C- Findings rate (ESR) or C-Reactive Protein (CRP) Reactive Protein (CRP) § (+) anti-Saccharomyces cerevisiae antibodies § Leukocytosis/Hypoalbuminemia (Severe UC) § (+) perinuclear antineutrophil cytoplasmic antibodies Adapted from Hemstreet BA, Pharmacotherapy: A Pathophysiologic Approach 10th ed. 2018 7 Epidemiology Highest rates in North America, Northern Europe, Great Britain Centers for Disease Control and Prevention. Epidemiology of the IBD. Centers for Disease Control and Prevention Website 8 Epidemiology 201 cases per 100,000 Adults Highest rates in North America, Increasing in More prevalent in Northern Europe, incidence those with white- Great Britain collar occupations Centers for Disease Control and Prevention. Epidemiology of the IBD. Centers for Disease Control and Prevention Website 9 Epidemiology 201 cases per 100,000 Adults Highest rates in North America, Increasing in More prevalent in Northern Europe, incidence those with white- Great Britain collar occupations Centers for Disease Control and Prevention. Epidemiology of the IBD. Centers for Disease Control and Prevention Website 10 Epidemiology 201 cases per More common in 100,000 Adults Females Highest rates in North America, Increasing in More prevalent in Northern Europe, incidence those with white- Great Britain collar occupations Centers for Disease Control and Prevention. Epidemiology of the IBD. Centers for Disease Control and Prevention Website 11 Epidemiology 201 cases per More common in 100,000 Adults Females Highest rates in North America, Increasing in More prevalent in Northern Europe, incidence those with white- Great Britain collar occupations Centers for Disease Control and Prevention. Epidemiology of the IBD. Centers for Disease Control and Prevention Website 12 Etiology § Exact etiology is unknown § Very complex § Immune mediated condition in genetically susceptible individuals whose onset is triggered by environmental factors that: § Perturb the mucosal barrier of the intestines § Alter healthy balance of gut microbiota § Abnormally stimulate gut immune responses § Infectious processes may also play a part in Crohn’s disease as well § One theory involves abnormal NOD-2 function which leads to a possible sustained inflammatory and immune response against gut microbiota Boyapati R, Satsangi J, Ho GT. Pathogenesis of Crohn’s Disease. F1000Prime Report 13 NOD-2’s Effect on Intestinal Function § NOD-2 § Pattern recognition receptor that controls immunity against intracellular bacteria § Activates nuclear factor-kappa-B (NF-κB) § NF-κB activation results in: § Production of mucin § Provides barrier protection against bacteria § Anti-microbial peptide that kills any bacteria that gets too close to the mucous membrane § Also plays a role in the release of pro-inflammatory cytokines such as IL-1β, IL-6, and IL-23 § Any loss of function mutation in NOD-2 disrupts From: Philpott DJ. NOD Proteins: Regulators of Inflammation in Health and Disease. intestinal homeostasis Nature Reviews Immunology, 2014; Volume 14 Issue 1 Boyapati R, Satsangi J, Ho GT. Pathogenesis of Crohn’s Disease. F1000Prime Report 14 NOD-2’s Effect on Intestinal Function § NOD-2 § Pattern recognition receptor that controls immunity against intracellular bacteria § Activates nuclear factor-kappa-B (NF-κB) § NF-κB activation results in: § Production of mucin § Provides barrier protection against bacteria § Anti-microbial peptide that kills any bacteria that gets too close to the mucous membrane § Also plays a role in the release of pro-inflammatory cytokines such as IL-1β, IL-6, and IL-23 § Any loss of function mutation in NOD-2 disrupts From: Philpott DJ. NOD Proteins: Regulators of Inflammation in Health and Disease. intestinal homeostasis Nature Reviews Immunology, 2014; Volume 14 Issue 1 Boyapati R, Satsangi J, Ho GT. Pathogenesis of Crohn’s Disease. F1000Prime Report 15 Infectious Factors § Shift toward proinflammatory bacteria (also known as dysbiosis) § Increased numbers of mucus, Microorganisms Thought to be Involved with mucosal, and intraepithelial bacteria Crohn’s Disease Pathology § Saccharomyces cerevisiae Mycobacterium paratuberculosis antibodies Mycobacterium avium § Demonstrates immunologic Ruminococcus gnavus response to intestinal Ruminococcus torques microorganisms Listeria monocytogenes § Bacterial gene products may: Chlamydia trachomatis Escherichia coli § Promote alteration of intestinal barrier § Propagate inflammatory response Hemstreet BA, Pharmacotherapy: A Pathophysiologic Approach 10th ed. 2018 16 Clinical Presentation and Differential Diagnosis Clinical Presentation of Crohn’s Disease Abdominal Pain Diarrhea Hematochezia (less frequent than in UC) Fistulas Differential Diagnosis Malabsorption Perianal Disease (skin tags, perirectal abscesses, etc.) Irritable Bowel Syndrome Phlegmon Lactose Intolerance Aphthous Ulcers Infectious Colitis Odynophagia Ulcerative Colitis Dysphagia Gallstones Fatigue Vitamin B12 Deficiency Peppercorn MA. Clinical manifestations, diagnosis, and prognosis of Crohn’s Disease; UpToDate, 2019 17 Laboratory Values and Diagnosis § Diagnosis made based on a combination of: Laboratory Tests for Assessing Crohn’s Disease § Clinical presentation Complete Blood Count § Endoscopic findings Blood Chemistry (Electrolytes, Renal Function, Liver § Ileocolonoscopy with biopsy should Function Tests) be performed in patients with Eosinophil Sedimentation Rate ↑ suspected Crohn’s disease C-Reactive Protein ↑ § Radiologic findings Serum Iron ↓ § Histologic findings Serum Vitamin B12 ↓ § Pathologic findings Fecal Calprotectin ↑ § Lab testing is complementary and helps Fecal Lactoferrin ↑ determine: Stool Testing (to rule out C. difficile) § Disease severity § Complications of Crohn’s disease Peppercorn MA. Clinical manifestations, diagnosis, and prognosis of Crohn’s Disease; UpToDate, 2019 Lichenstein, GR. ACG Clinical Guideline: Management of Crohn’s Disease in Adults. Am J Gastroenterol. 2018;113(4) 18 Sequalae of Crohn’s Disease Increased Risk § Risk Factors § Long-duration of disease Non- Hodgkin’s Myelodysplastic § Extensive disease Lymphoma Syndromes § Bypassed colon segments § Colon strictures § Primary sclerosing cholangitis Leukemia § Family history of colon cancer § Up to 2.2% of patients at 25 years with Crohn’s may develop carcinoma Freidman SA , Harrison’s Principles of Internal Medicine 20th ed. 2018 19 Determining and Monitoring Disease Activity Methods in Determining Disease Activity § Fecal calprotectin Categories of Disease Activity § Levels > 100 mcg/g indicate recurrence § Remission § Fecal lactoferrin § Mild (ambulatory, eating/drinking normally, § CRP <10% weight loss, no complications) § Levels >15 mg/L at baseline may § Moderate predicate primary nonresponse to § Severe (cachectic with significant weight loss, therapy complications, symptoms despite therapy) § Crohn’s Disease Activity Index (CDAI) § Fulminant § Harvey Bradshaw Index Lichenstein, GR. ACG Clinical Guideline: Management of Crohn’s Disease in Adults. Am J Gastroenterol. 2018;113(4) 20 Determining and Monitoring Disease Activity Crohn’s Disease Activity Index Item (Daily Sum per Week) Weighting Factor Number of liquid or very soft stools 2 Abdominal pain score in 1 week (rating 0-3) 5 General well-being (rating 1-4) 7 § CDAI and Harvey Bradshaw index are very similar and evaluate the Sum of physical findings per week: § Arthritis/Arthralgia same measures § Mucocutaneous Lesions § Scores from these indices § Iritis/Uveitis 20 § Anal disease (fissure/fistula, etc.) correlate with severity of current § Fever over 37.8°C disease Antidiarrheal Use 30 Abdominal Mass (no = 0; equivocal = 2; yes = 5) 10 Males <47 hematocrit; Females <42 hematocrit 6 1-x(body weight divided by standard weight) 1 Freeman HJ. Use of the Crohn’s Disease Activity Index in Clinical Trials of Biological Agents. World J Gastroenerol. 2008:14(26) 21 Goals of Therapy in Crohn’s Disease Inducing Maintaining Mucosal Remission Quality of Life Healing Maintaining Reducing Remission Complications Hemstreet BA, Pharmacotherapy: A Pathophysiologic Approach 10th ed. 2018 22 Approach to Therapy Agents used to Severity of disease relieve will determine Surgery if inflammation and which agent will be unmanaged with induce remission most effective medication Hemstreet BA, Pharmacotherapy: A Pathophysiologic Approach 10th ed. 2018 23 Non-Pharmacologic Therapy Nutritional Support Surgery § Exclusion diets generally not supported § Many patients will require surgery even with § Avoidance of dairy may improve diarrheal symptoms if expanding pharmacologic options patient has lactase deficiency § Often involves resection of segments of Patients with small bowel strictures should avoid nuts to intestine that are affected, drainage of § prevent obstruction abscesses, or correction of fistulas Probiotic Administration § Usually reserved for patients with complications (fissures, strictures, etc.) § Has been explored and is thought to: despite medical management § Re-establish normal bacterial flora § High rate of recurrence even with resection § Reduce bacterial adhesion § Compete for nutrients with pathogenic bacteria § Produce antibacterial substances § Not recommended due to lack of evidence Hemstreet BA, Pharmacotherapy: A Pathophysiologic Approach 10th ed. 2018 24 Medications used in treatment of Crohn’s Disease Infliximab (Remicade®) Adalimumab (Humira®) Biologics Certolizumab pegol (Cimzia ®) Vedolizumab (Entyvio®) Natalizumab (Tysabri®) Ustekinumab (Stelara®) Corticosteroids Budesonide (Entocort EC ®, Uceris®) Prednisone (Deltasone®, predniSONE®) ® ® ® ® ® ® ® 5-Aminosalicylates Mesalamine (Asacol HD , Lialda , Canasa , Delzicol , Apriso , Rowasa , Pentasa ) Sulfasalazine (Azulfidine®) Azathioprine Immunomodulators 6-Mercaptopurine Methotrexate Lichenstein, GR. ACG Clinical Guideline: Management of Crohn’s Disease in Adults. Am J Gastroenterol. 2018;113(4) 25 Commonly Used Medications in Crohn’s Disease Drug Mechanism of Action Dose Route of Administration Budesonide (Entocort EC®) Corticosteroid Induction: 9 mg once daily for up to 8 weeks Oral Sulfasalazine (Azulfidine®) 5-Aminosalacylic Acid 3 to 6 g daily Oral Azathioprine (Azasan®, Imuran®) Purine Synthesis Inhibitor 50 mg PO daily (1.5-2.5 mg/kg/day) Intravenous 6-Mercaptopurine (Purixan®) Purine Antagonist 50 mg PO daily (0.75-1.5 mg/kg/day) Oral Methotrexate (Otrexup®, Rasuvo®) Dihydrofolate Reductase 25 mg SQ or IM once SubcutaneousInhibitor weekly Intramuscular Lexi-Drugs Online™. Lexi-Comp Online™. Hudson (OH): Lexi-Comp, Inc.; 2019 Veauthier B. Crohn’s Disease and Management. Am Fam Physician. 2018 26 Adverse Effects and Monitoring of Commonly Used Medications in Crohn’s Disease Drug Adverse Reactions Monitoring Diarrhea, nausea, arthralgias, § Signs and symptoms (S/S) Budesonide (Entocort EC®) headache, respiratory tract infection, of hyperadrenocorticism sinusitis § S/S of adrenal suppression with long term therapy § Complete blood count Skin rash, dyspepsia, anorexia, (CBC) with differential Sulfasalazine (Azulfidine®) oligospermia, leukopenia, abnormal § Liver function tests hepatic function (LFTs) § Serum creatinine Lexi-Drugs Online™. Lexi-Comp Online™. Hudson (OH): Lexi-Comp, Inc.; 2019 Veauthier B. Crohn’s Disease and Management. Am Fam Physician. 2018 27 Adverse Effects and Monitoring of Commonly Used Medications in Crohn’s Disease Drug Adverse Reactions Monitoring § CBC with differential and Gastritis, nausea, vomiting, lymphoma, platelets fever § Weekly x 1 month Azathioprine (Azasan®, Imuran®) § Every other week x 2 May cause pancreatitis, leukopenia, months anemia, thrombocytopenia § Monthly thereafter § Liver function tests (LFTs) § Serum creatinine Myelosupression, hepatotoxicity, § CBC with differential weekly 6-Mercaptopurine (Purixan®) immunosuppression, hepatic during inductionencephalopathy, pancreatitis, rash, § LFTs weekly during induction hyperpigmentation, lymphoma, fever § Serum Creatinine Alopecia, photosensitivity, rash, diarrhea, anorexia, nausea, vomiting, stomatitis, § CXR at baseline leukopenia, pneumonitis § CBC with differential and platelets at baseline then Methotrexate (Otrexup®, Rasuvo®) May also cause hyperuricemia, monthly gastrointestinal hemorrhage, § Blood Urea Nitrogen (BUN), myelosuppression, hepatotoxicity, lung serum creatinine, and LFTs fibrosis, renal failure baseline then every 4-8 weeks Lexi-Drugs Online™. Lexi-Comp Online™. Hudson (OH): Lexi-Comp, Inc.; 2019 Veauthier B. Crohn’s Disease and Management. Am Fam Physician. 2018 28 Biologics Used in the Treatment of Crohn’s Disease Drug Dose Route of Administration Mechanism of Action Adalimumab Induction: 160 mg then 80 mg two weeks later (Humira®) SubcutaneousMaintenance: 40 mg every other week Certolizumab Induction: 400 mg at weeks 0, 2, and 4 (Cimzia®) Subcutaneous Anti-TNFαMaintenance: 400 mg every four weeks Infliximab Induction: 5 mg/kg at weeks 0, 2, and 6 (Remicade®) IntravenousMaintenance: 5-10 mg/kg every 8 weeks Natalizumab Induction: 300 mg at weeks 0, 4, and 8 (Tysabri®) IntravenousMaintenance: 300 mg every four weeks Integrin Receptor Vedolizumab Induction: 300 mg at weeks 0, 2, and 6 Antagonist (Entyvio®) IntravenousMaintenance: 300 mg every eight weeks ≤55 kg: 260 mg Induction 56 to 85 kg: 390 mg Intravenous Ustekinumab Interleukin-12/23 (Stelara®) >85 kg: 520 mg Inhibitor Maintenance: 90 mg every eight weeks starting eight weeks after induction Subcutaneous Adapted From: Biologics for Crohn’s Disease. Pharmacist’s Letter/Prescriber’s Letter. 2018;25(7) 29 Adverse Effects and Monitoring of Biologics Used in the Treatment of Crohn’s Disease Drug Adverse Reactions Monitoring Adalimumab Injection site reactions, infection, tuberculosis (TB), (Humira®) malignancies, autoantibodies/lupus-like syndrome § Purified protein derivative Certolizumab Injection site reactions, upper respiratory tract test at baseline (Cimzia®) infection, headache, hypertension, rash, infections, § Chest x-ray (CXR) at autoantibodies/lupus-like syndrome baseline § S/S of tuberculosis and Acute or delayed infusion reactions (arthralgia, active hepatitis B (in myalgia, fever, malaise, hives, angioedema, hepatitis B carriers) Infliximab lymphadenopathy, itching), infections, pneumonia, § CBC (Remicade®) cellulitis, abscess, skin ulceration, sepsis, bacterial § BUN, serum creatinine, infection, lymphoma, autoantibodies/lupus-like LFTs syndrome Adapted From: Veauthier B. Crohn’s Disease and Management. Am Fam Physician. 2018 30 Adverse Effects and Monitoring of Biologics Used in the Treatment of Crohn’s Disease Drug Adverse Reactions Monitoring § LFTs Headache, fatigue, respiratory tract and other infections, § Hypersensitivity reactions Natalizumab nausea, arthralgia, depression, progressive multifocal § S/S acute retinal necrosis (Tysabri®) leukencephalopathy (in patients that have Anti-John § Anti-JCV antibody Cunnigham virus (JCV) antibodies), positivity § S/S of PML Vedolizumab Nasopharyngitis, headache, arthralgias, nausea, pyrexia, § LFTs upper respiratory tract and other infections, § TB screening(Entyvio®) hypersensitivity reactions, anaphylaxis, lupus-like syndrome § New onset or worsening neurologic s/s § Purified protein derivative test at baseline § CXR at baseline Ustekinumab Vomiting, nasopharyngitis, injection site erythema, § CBC (Stelara®) infections, pruritus § S/S of infection or reversible posterior leukoencephalopathy syndrome Adapted From: Veauthier B. Crohn’s Disease and Management. Am Fam Physician. 2018 31 Ustekinumab as Induction and Maintenance Therapy for Crohn’s Disease General Inclusion Criteria § At least 18 years old § Randomized, controlled double-blind trials § Crohn’s Disease for at least 3 months § Two 8-week induction trials § Score of 220 to 450 points on the CDAI § One 44-week maintenance trial § Objective evidence of active Crohn’s Disease § CRP >3.0 mg/dL § Fecal calprotectin >250 mg/kg § Endoscopic ulcerations Feegan BG. Ustekinumab as Induction and Maintenance Therapy for Crohn’s Disease. N Engl J Med. 2016;375 32 Ustekinumab as Induction and Maintenance Therapy for Crohn’s Disease Exclusion Criteria Induction Trial Inclusion Criteria § History of treatment with IL-12 or IL-23 § Therapy with one or more Anti-TNFα agent antagonists § Primary non-response or secondary § Treatment with IV glucocorticoids, Anti-TNFα non-response agents or natalizumab during wash-out period § Treatment failure or unacceptable side effects with immunomodulators or § Patients with GI conditions that might require corticosteroids surgery or preclude use of CDAI Maintenance Trial Inclusion Criteria § Active infections § Completion of induction trial § History of cancer Feegan BG. Ustekinumab as Induction and Maintenance Therapy for Crohn’s Disease. N Engl J Med. 2016;375 33 Ustekinumab as Induction and Maintenance Therapy for Crohn’s Disease IV ustekinumab SQ ustekinumab 130 mg 90 mg q 8 weeks Randomized to receive… IV ustekinumab Responders at week Placebo 6 mg/kg 8 randomized to… Week 0 Placebo SQ ustekinumab 90 mg q 12 weeks Feegan BG. Ustekinumab as Induction and Maintenance Therapy for Crohn’s Disease. N Engl J Med. 2016;375 34 Ustekinumab as Induction Therapy for Crohn’s Disease Primary Endpoint for Induction Trials § Clinical response at week 6 § Decrease from baseline CDAI of at least 100 points or a total CDAI <150 Secondary Endpoints for Induction Trials § Clinical remission at week 8 (CDAI <150) § Clinical response at week 8 § Decrease in baseline CDAI of at least 70 points at week 8 § Change in CDAI score § Change in CRP level/normalization of CRP level (<3.0 mg/L) at weeks 3, 6, and 8 § Change in fecal calprotectin level/normalization of level (<250 mg or <100 mg/kg) at week 6 Feegan BG. Ustekinumab as Induction and Maintenance Therapy for Crohn’s Disease. N Engl J Med. 2016;375 35 Ustekinumab as Induction Therapy for Crohn’s Disease Results Primary Endpoint— Clinical Response at week 6 IV ustekinumab 130 mg: 34.3% (P≤0.003) IV ustekinumab 6 mg/kg: 33.7% (P≤0.003) Placebo: 21.5% (P<0.001) Secondary Endpoints (Clinical remission 6 and 8 weeks) Favored ustekinumab 6 mg/kg over ustekinumab 130 mg and placebo for all secondary endpoints Feegan BG. Ustekinumab as Induction and Maintenance Therapy for Crohn’s Disease. N Engl J Med. 2016;375 36 Ustekinumab as Maintenance Therapy for Crohn’s Disease Primary Endpoint— Clinical Remission at week 44 Primary Endpoint for Maintenance SQ ustekinumab every 8 weeks: 53.1% (P=0.005) Trial SQ ustekinumab every 12 weeks: 48.8% (P=0.04) § Clinical remission at week 44 Placebo: 35.9% (P=0.005, P=0.04) § Total CDAI <150 Secondary Endpoint— Clinical Response at week 44 Secondary Endpoints for SQ ustekinumab every 8 weeks: 44.3% (P=0.02) Maintenance Trial SQ ustekinumab every 12 weeks: 58.1% (P=0.03) § Clinical response at week 44 Placebo: 59.4% (P=0.02, P=0.03) § Maintenance of remission among Secondary Endpoint— Maintenance of Remission patients in remission at week 0 of Higher in 8-week (66.7%, P=0.007) and 12-week (56.4%, IM-UNITI P=0.19) groups compared to placebo (45.6%) Feegan BG. Ustekinumab as Induction and Maintenance Therapy for Crohn’s Disease. N Engl J Med. 2016;375 37 Autoantibody Development § With all biologics used to treat Crohn’s disease, there is a risk for production of anti-drug antibodies (ADA) § More likely with chimeric monoclonal antibodies such as infliximab than humanized monoclonal antibodies such as adalimumab § In biologic-naïve patients, serum ADA is: § Detectable within 2-6 months of initiation of therapy § Undetectable after 12 months of therapy § Clinical effects of ADA development include: § Increased risk for hypersensitivity reactions § Diminished efficacy (which is generally seen with increasing doses to achieve similar clinical control) § Reduced cost-effectiveness § Co-treatment with an immunomodulator such as methotrexate or azathioprine is associated with decreased levels of serum ADA Strand V. Immunogenicity of Biologics in Chronic Diseases: A Systematic Review. BioDrugs. 2017 38 Therapeutic Drug Monitoring of Biologics in CD § Various drug threshold Goal Drug Concentrations for Anti-TNF⍺ Agents concentrations based on: Infliximab Trough at week 14 >3 mcg/mL; >7 mcg/mL Disease phenotype (increased mucosal healing)§ Trough at week 4 >5 mcg/mL; >7 mcg/mL § Desired therapeutic outcome Adalimumab (increased mucosal healing) § Importance of therapeutic drug Maintenance trough >5 mcg/mL concentrations Trough at week 6 >32 mcg/mLCertolizumab pegol Maintenance trough >15 mcg/mL § If a patient has adequate trough concentrations, ADA are unlikely Goal Drug Concentrations for other Biologics to be relevant clinically Vedolizumab Lacking evidence for specific goals; can be used to confirm detectable drug § May be more cost effective than Ustekinumab Lacking evidence for specific goals; can be empiric dose escalation used to confirm detectable drug Papamichael K. Appropriate Therapeutic Drug Monitoring of Biologic Agents for Patients with Inflammatory Bowel Diseases. Clin Gastroenterol Hepatol. 2019 39 Therapeutic Drug Monitoring of Biologics in CD § Anti-TNF⍺ Therapy § Ustekinumab and Vedolizumab § Recommendation to order § Recommendation to order drug/antibody drug/antibody concentration testing: concentration testing: 1. In responders and primary non- 1. In non-responders at the end of responders at the end of induction induction 2. In patients with confirmed secondary 2. At least once during loss of response maintenance for all patients 3. For all anti-TNF ⍺ agents in patients with a confirmed secondary loss of response Papamichael K. Appropriate Therapeutic Drug Monitoring of Biologic Agents for Patients with Inflammatory Bowel Diseases. Clin Gastroenterol Hepatol. 2019 40 American College of Gastroenterology’s Approach in Mild-Moderate Disease Induction Therapy Maintenance Therapy § Budesonide (Entocort EC®) 9 mg once § Sulfasalazine (Azulfidine®) 3 to 6 g/day daily in the morning for up to 8 weeks for treatment of symptoms for up to 16 § Budesonide should be tapered by 3 mg weeks increments every 2 to 4 weeks § Has not been shown to be more effective than placebo in achieving mucosal healing § Preferred over prednisone due to a lower rate of systemic side effects § No maintenance treatment in patients with mild disease is recommended provided they are asymptomatic Lichenstein, GR. ACG Clinical Guideline: Management of Crohn’s Disease in Adults. Am J Gastroenterol. 2018;113(4) 41 American College of Gastroenterology’s Approach in Moderate-Severe Disease Induction Therapy § Oral corticosteroids can be used short term to alleviate symptoms of moderate to severely active Crohn’s Disease § Prednisone equivalent doses of 40 to 60 mg/day maintained for 1-2 weeks § Taper 5 mg weekly until 20 mg/day then 2.5-5 mg weekly § 1 in 5 patients will be steroid refractory § 1 in 3 patients will become steroid dependent and unable to taper due to symptoms § Vedolizumab (Entyvio®) and Natalizumab (Tysabri®) can also be used for induction of remission Lichenstein, GR. ACG Clinical Guideline: Management of Crohn’s Disease in Adults. Am J Gastroenterol. 2018;113(4) 42 American College of Gastroenterology’s Approach in Moderate-Severe Disease Maintenance § Immunomodulators such as azathioprine, 6-mercaptopurine, or methotrexate may be used when a patient is steroid-refractory § Anti-TNFα agents can be used in patients are steroid-refractory and immunomodulator-refractory with or without immunomodulator therapy § Infliximab (Remicade®), Adalimumab (Humira®), or Certolizumab pegol (Cimzia®) § Ustekinumab (Stelara®) can be given to patients who have failed corticosteroids, immunomodulators or anti-TNFα agents or those who have had no prior anti-TNFα exposure Lichenstein, GR. ACG Clinical Guideline: Management of Crohn’s Disease in Adults. Am J Gastroenterol. 2018;113(4) 43 American College of Gastroenterology’s Approach in Severe-Fulminant Disease Induction and Maintenance Therapy § Intravenous corticosteroids § Parenteral methylprednisolone 40-60 mg/day § Anti-TNFα agents (infliximab, adalimumab, certolizumab pegol) § Infliximab for fulminant Crohn’s Disease § Adalimumab and certolizumab have not shown as clear of efficacy in fulminant disease § Thought to be because of infliximab’s weight-based dosing as patients can receive more medication Lichenstein, GR. ACG Clinical Guideline: Management of Crohn’s Disease in Adults. Am J Gastroenterol. 2018;113(4) 44 American Gastroenterological Association’s Crohn’s Disease Recommendations Induction Therapy in Moderate-Severe Maintenance Therapy in Moderate-Severe Disease Disease Steroid Induced Anti-TNFα + § In patients whose symptomology persists Immunomodulator Induced despite steroid, immunomodulator, or 5-ASA Immunomodulator Anti-TNFα Induced therapy: § Anti-TNFα therapy Anti-TNFα +/-Immunomodulator OR § Anti-TNFα therapy + immunomodulator Anti-TNFα +/- therapy Immunomodulator Anti-TNFα +/- Immunomodulator Terdiman JP. American Gastroenterological Association Institute Guideline on the Use of Thiopurines, Methotrexate, and Anti–TNF-a Biologic Drugs for the Induction and Maintenance of Remission in Inflammatory Crohn’s Disease. Gastroenterology. 2013;145(6) 45 American Gastroenterological Association’s Crohn’s Disease Recommendations Induction Therapy in Moderate-Severe Maintenance Therapy in Moderate-Severe Disease Disease Steroid Induced Anti-TNFα + § In patients whose symptomology persists Immunomodulator Induced despite steroid, immunomodulator, or 5-ASA Immunomodulator Anti-TNFα Induced therapy: § Anti-TNFα therapy Anti-TNFα +/-Immunomodulator OR § Anti-TNFα therapy + immunomodulator Anti-TNFα +/- therapy Immunomodulator Anti-TNFα +/- Immunomodulator Terdiman JP. American Gastroenterological Association Institute Guideline on the Use of Thiopurines, Methotrexate, and Anti–TNF-a Biologic Drugs for the Induction and Maintenance of Remission in Inflammatory Crohn’s Disease. Gastroenterology. 2013;145(6) 46 The Study of Biologic and Immunomodulator Naïve Patients in Crohn’s Disease (SONIC) Trial Inclusion Criteria § At least 21 years old § Randomized, double-blind, 30-week trial § Crohn’s Disease for at least 6 weeks § 20-week extension in which blinding was maintained § Score of 220 to 450 points on the CDAI § Conducted at 92 centers from March § Corticosteroid dependent 2005 to March 2008 § Being considered for a second course of systemic § 508 patients steroids within 12 months § No response to at least 4 weeks of mesalamine or budesonide Colombel JF. Infliximab, Azathioprine, or Combination Therapy for Crohn's Disease. N Engl J Med. 2010:362(15) 47 The Study of Biologic and Immunomodulator Naïve Patients in Crohn’s Disease (SONIC) Trial Exclusion Criteria § No previous treatment with azathioprine, 6-mercaptopurine, methotrexate or an Anti-TNFα agent § History of short bowel syndrome, ostomy, symptomatic stricture, abscess § Abdominal surgery within previous 6 months § History of tuberculosis or other granulomatous infection § History of opportunistic infection within previous 6 months § Active infection with Hepatitis B or C § Infection with Human Immunodeficiency Virus § Multiple Sclerosis § Cancer § Homozygous mutant or heterozygous methyltransferase phenotype Colombel JF. Infliximab, Azathioprine, or Combination Therapy for Crohn's Disease. N Engl J Med. 2010:362(15) 48 The Study of Biologic and Immunomodulator Naïve Patients in Crohn’s Disease (SONIC) Trial § Randomized based on stratification Groups Randomized to Receive according to duration of Crohn’s 1. IV infliximab 5mg/kg + daily oral placebo capsules Disease and status with respect to corticosteroid dose 2. Oral azathioprine 2.5 mg/kg daily + placebo infusions § Infusions at 0, 2, 6, and then every 8 3. IV infliximab 5mg/kg + oral azathioprine 2.5 mg/kg weeks daily Colombel JF. Infliximab, Azathioprine, or Combination Therapy for Crohn's Disease. N Engl J Med. 2010:362(15) 49 The Study of Biologic and Immunomodulator Naïve Patients in Crohn’s Disease (SONIC) Trial § Primary Efficacy Endpoint: § Rate of corticosteroid-free remission at week 26 § Secondary Efficacy Endpoints: Corticosteroid (CS)-Free Remission § Rates of corticosteroid-free Clinical Remission remission at other time points Clinical remission in Patients with CDAI patients who have not § Proportion of patients with mucosal <150 received systemic CS at 3 healing at week 26 among those weeks with mucosal ulcerations at baseline § Change in CRP level from baseline to week 26 Colombel JF. Infliximab, Azathioprine, or Combination Therapy for Crohn's Disease. N Engl J Med. 2010:362(15) 50 The Study of Biologic and Immunomodulator Naïve Patients in Crohn’s Disease (SONIC) Trial Results Primary Endpoint— Corticosteroid-Free Remission IV infliximab + oral azathioprine daily: 56.8% (P=0.02) IV infliximab + daily oral placebo capsules: 44.4% (P=0.02) Oral azathioprine daily + placebo infusions: 30.0% (P <0.001; P=0.006) Secondary Endpoint— Corticosteroid-Free Remission, Mucosal Healing and Change in CRP Level : Favored combination therapy and infliximab monotherapy over azathioprine monotherapy Colombel JF. Infliximab, Azathioprine, or Combination Therapy for Crohn's Disease. N Engl J Med. 2010:362(15) 51 Counseling Points § All patients should be counseled to avoid non-steroidal anti-inflammatory drugs as they may exacerbate Crohn’s disease § All patients should be counseled on using proper contraception while on immunomodulator therapy § Patients receiving corticosteroids should be counseled about importance of tapering therapy and the dangers of stopping their corticosteroid suddenly or taking their corticosteroid long term § All patients should be counseled about their increased risk for infections which should include methods and techniques that can be used to prevent infection § Good hand hygiene § Avoidance of sick contacts 52 Role of the Pharmacist in Crohn’s Disease § As many medications used in the treatment of Drug Cost/Dose Average Crohn’s disease have life-modifying adverse Cost/Year effects Adalimumab § Proper counseling (Humira ®) $2,565 $30,780 Certolizumab § Helping patients with symptom relief (Cimzia®) $4,293 $51,516 § As pharmacists are often able to see patients Infliximab more than physicians (Remicade®) $5,790 $34,740 § Symptom control Ustekinumab (Stelara®) $21,769 $130,614 § Therapeutic drug monitoring as needed Vedolizumab (Entyvio®) $6,413 $38,478§ Cost of therapy Cost data from goodrx.com 53 What questions do you have? 54 Kara Nazminia Crohn’s Disease PharmD Candidate 2020University of Wyoming School of Pharmacy September 2019 What is Crohn’s Disease? Immune-mediated chronical intestinal condition One of two types of Inflammatory Bowel Disease Can involve any part of the gastrointestinal tract Causes discontinuous lesions that are known as "skip" lesions Epidemiology More 201 cases per Increasing in prevalent in More common 100,000 Adults incidence white collar in Females occupations Diagnosis and Pertinent Laboratory Values Laboratory Tests for Assessing Crohn’s § Diagnosis made based on a combination of: Disease § Clinical presentation Complete Blood Count § Endoscopic findings Blood Chemistry § Radiologic findings Eosinophil Sedimentation Rate ↑ C-Reactive Protein ↑ § Histologic findings Serum Iron ↓ § Pathologic findings Serum Vitamin B12 ↓ § Lab testing is complementary and helps determine: Fecal Calprotectin ↑ § Disease severity Fecal Lactoferrin ↑ Stool Testing (to rule out C. difficile) § Complications of Crohn’s disease Approach to Therapy Agents used to Severity of disease relieve will determine Surgery if inflammation and which agent will be unmanaged with induce remission most effective medication Goals of Therapy in Crohn’s Disease Crohn’s Disease Activity Index (CDAI) American College of Gastroenterology’s Approach in Mild-Moderate Crohn’s Disease Induction Therapy Maintenance Therapy § Budesonide (Entocort EC®) 9 mg once daily in § Sulfasalazine (Azulfidine®) 3 to 6 g/day for the morning for up to 8 weeks treatment of symptoms for up to 16 weeks § Budesonide should be tapered by 3 mg § Has not been shown to be more increments every 2 to 4 weeks effective than placebo in achieving mucosal healing § No maintenance treatment in patients with § Preferred over prednisone due to a lower rate mild disease is recommended provided they of systemic side effects are asymptomatic American College of Gastroenterology’s Approach in Moderate-Severe Crohn’s Disease Induction Therapy Maintenance Therapy § Oral corticosteroids can be used short term to alleviate symptoms of § Anti-TNFα agents moderate to severely active Crohn’s Disease ® Induction/Maintenance in Fulminant Disease§ Vedolizumab (Entyvio ) and Natalizumab (Tysabri®) can also be used for induction of remission § Intravenous corticosteroids § Immunomodulators when patient is steroid-refractory § Parenteral methylprednisolone § Anti-TNFα agents when patient is § Infliximab steroid-refractory or immunomodulator-refractory § Ustekinumab (Stelara®) given last line when patient is also Anti-TNFα therapy-refractory American Gastroenterological Association’s Approach in Moderate-Severe Crohn’s Disease Maintenance Therapy Induction Therapy § In patients whose symptomology persists despite steroid, immunomodulator, or 5-ASA therapy: § Anti-TNFα therapy OR § Anti-TNFα therapy + immunomodulator therapy Cost of Biologic Therapy Drug Cost/Dose Average Cost/Year Adalimumab (Humira®) $2,565 $30,780 Certolizumab (Cimzia®) $4,293 $51,516 Infliximab (Remicade®) $5,790 $34,740 Ustekinumab (Stelara®) $21,769 $130,614 Vedolizumab (Entyvio®) $6,413 $38,478 References 1. Biologics for Crohn’s Disease. Pharmacist’s Letter/Prescriber’s Letter. 2018;25(7):340706. 2. Boyapati R, Satsangi J, Ho GT. Pathogenesis of Crohn’s Disease. F1000Prime Rep. 2015;7:44 3. Centers for Disease Control and Prevention. Epidemiology of the IBD. Centers for Disease Control and Prevention Website. Available from: https://www.cdc.gov/ibd/IBD-epidemiology.htm. Accessed July 10, 2019 4. Colombel JF, Sanborn WJ, Reinisch W, et al. Infliximab, Azathioprine, or Combination Therapy for Crohn's Disease. N Engl J Med. 2010:362(15);1383-1395. 5. Feagan BG, Sandborn WJ, Gasink C, et al. Ustekinumab as Induction and Maintenance Therapy for Crohn’s Disease. N Engl J Med. 2016;375:1946-1960. 6. Freeman HJ. Use of the Crohn’s Disease Activity Index in Clinical Trials of Biological Agents. World J Gastroenerol. 2008:14(26);4127-4130. 7. Freidman S, Blumberg RS. Inflammatory Bowel Disease. In: Jameson J, Fauci AS, Kasper DL, Hauser SL, Longo DL, Loscalzo J, editors. Harrison’s Principles of Internal Medicine. 20th edition. online. New York(NY): McGraw-Hill; 2018. Available from http://accesspharmacy.com. Accessed July 20, 2019. 8. Hemstreet BA. Inflammatory Bowel Disease. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L, editors. Pharmacotherapy: A Pathophysiologic Approach. 10th ed. online. New York (NY): McGraw-Hill; 2018. Available from http://www.accesspharmacy.com. Accessed: July 20, 2019 9. Lexi-Drugs Online™. Lexi-Comp Online™. Hudson (OH): Lexi-Comp, Inc.; 2019. Available from: http://online.lexi.com. Accessed: July 30, 2019. 10. Lichtenstein GR, Loftus EV, Issacs KL, Regueiro MD, Gerson LB, Sands BE. ACG Clinical Guideline: Management of Crohn’s Disease in Adults. Am J Gastroenterol. 2018;113(4):481-517. 11. Papamichael K, Cheifetz AS, Melme GY, et al. Appropriate Therapeutic Drug Monitoring of Biologic Agents for Patients with Inflammatory Bowel Diseases. Clin Gastroenterol Hepatol. 2019;17(9):1655-1668. 12. Peppercorn MA, Kane SV. Clinical manifestations, diagnosis and prognosis of Crohn Disease in adults. In: Rutgeerts P (editor). UpToDate Online. Waltham (MA):UpToDate;2019. Available from http://www.uptodate.com. Accessed July 17, 2019 13. Philpott DJ, Sorbara MT, Robertson SJ, Croitoru K, Girardin SE. NOD proteins: regulators of inflammation in health and disease. Nat Rev Immunol. 2014:14(1):9-23. 14. Strand V, Balsa A, Al-Saleh J, et al. Immunogenicity of Biologics in Chronic Diseases: A Systematic Review. BioDrugs. 2017;31(4):299-316. 15. Terdiman JP, Gruss CB, Heidelbaugh JJ, Sultan S, Falck-Ytter YT. American Gastroenterological Association Institute Guideline on the Use of Thiopurines, Methotrexate, and Anti–TNF-a Biologic Drugs for the Induction and Maintenance of Remission in Inflammatory Crohn’s Disease. Gastroenterology. 2013;145(6):1459-1463. 16. Veauthier B, Hornecker JR. Crohn’s Disease and Management. Am Fam Physician. 2018;98(11):661-669. References 1. Biologics for Crohn’s Disease. Pharmacist’s Letter/Prescriber’s Letter. 2018;25(7):340706. 2. Boyapati R, Satsangi J, Ho GT. Pathogenesis of Crohn’s Disease. F1000Prime Rep. 2015;7:44 3. Centers for Disease Control and Prevention. Epidemiology of the IBD. Centers for Disease Control and Prevention Website. Available from: https://www.cdc.gov/ibd/IBD-epidemiology.htm. Accessed July 10, 2019 4. Colombel JF, Sanborn WJ, Reinisch W, et al. Infliximab, Azathioprine, or Combination Therapy for Crohn's Disease. N Engl J Med. 2010:362(15);1383-1395. 5. Feagan BG, Sandborn WJ, Gasink C, et al. Ustekinumab as Induction and Maintenance Therapy for Crohn’s Disease. N Engl J Med. 2016;375:1946-1960. 6. Freeman HJ. Use of the Crohn’s Disease Activity Index in Clinical Trials of Biological Agents. World J Gastroenerol. 2008:14(26);4127-4130. 7. Freidman S, Blumberg RS. Inflammatory Bowel Disease. In: Jameson J, Fauci AS, Kasper DL, Hauser SL, Longo DL, Loscalzo J, editors. Harrison’s Principles of Internal Medicine. 20th edition. online. New York(NY): McGraw-Hill; 2018. Available from http://accesspharmacy.com. Accessed July 20, 2019. 8. Hemstreet BA. Inflammatory Bowel Disease. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L, editors. Pharmacotherapy: A Pathophysiologic Approach. 10th ed. online. New York (NY): McGraw-Hill; 2018. Available from http://www.accesspharmacy.com. Accessed: July 20, 2019 9. Lexi-Drugs Online™. Lexi-Comp Online™. Hudson (OH): Lexi-Comp, Inc.; 2019. Available from: http://online.lexi.com. Accessed: July 30, 2019. 10. Lichtenstein GR, Loftus EV, Issacs KL, Regueiro MD, Gerson LB, Sands BE. ACG Clinical Guideline: Management of Crohn’s Disease in Adults. Am J Gastroenterol. 2018;113(4):481-517. 11. Papamichael K, Cheifetz AS, Melme GY, et al. Appropriate Therapeutic Drug Monitoring of Biologic Agents for Patients with Inflammatory Bowel Diseases. Clin Gastroenterol Hepatol. 2019;17(9):1655-1668. 12. Peppercorn MA, Kane SV. Clinical manifestations, diagnosis and prognosis of Crohn Disease in adults. In: Rutgeerts P (editor). UpToDate Online. Waltham (MA):UpToDate;2019. Available from http://www.uptodate.com. Accessed July 17, 2019 13. Philpott DJ, Sorbara MT, Robertson SJ, Croitoru K, Girardin SE. NOD proteins: regulators of inflammation in health and disease. Nat Rev Immunol. 2014:14(1):9-23. 14. Strand V, Balsa A, Al-Saleh J, et al. Immunogenicity of Biologics in Chronic Diseases: A Systematic Review. BioDrugs. 2017;31(4):299-316. 15. Terdiman JP, Gruss CB, Heidelbaugh JJ, Sultan S, Falck-Ytter YT. American Gastroenterological Association Institute Guideline on the Use of Thiopurines, Methotrexate, and Anti–TNF-a Biologic Drugs for the Induction and Maintenance of Remission in Inflammatory Crohn’s Disease. Gastroenterology. 2013;145(6):1459-1463. 16. Veauthier B, Hornecker JR. Crohn’s Disease and Management. Am Fam Physician. 2018;98(11):661-669.