CROHN’S DISEASE

EPIDEMIOLOGY:

In 1998, the prevalence of Crohn disease in the United States was estimated on the basis of data from Olmstead County, Minnesota, and was approximated at 8 cases per 100,000 populations.⁽¹⁾ A subsequent analysis of a geographically diverse health insurance claims database estimated the prevalence of Crohn disease among US children and adults in 2003-2004 to be closer to 201 cases per 100,000 persons among adults and 43 per 100,000 among children.⁽²⁾

There is paucity of valid epidemiological studies on IBD from Asian countries and the results are variable. The incidence of Crohn’s Disease (CD) ranges from 0.5 to 1.0 per 100000 person-years. There is no epidemiological study from Pakistan.⁽³⁾

PATHOPHYSIOLOGY:

Chronic inflammation from T-cell activation leading to tissue injury is implicated in the pathogenesis of Crohn disease.

After activation by antigen presentation, unrestrained responses of type 1 T helper (Th1) cells predominate in Crohn disease as a consequence of defective regulation. Th1 cytokines such as interleukin (IL)-12 and TNF-α stimulate the inflammatory response. Inflammatory cells recruited by these cytokines release nonspecific inflammatory substances, including arachidonic acid metabolites, proteases, platelet activating factor, and free radicals, which result in direct injury to the intestine.

In a study from 2012, investigators suggested that genetic predispositions for inflammatory bowel disease (IBD) lead to abnormal epithelial barrier integrity and homeostasis, deficits in autophagy, deficiencies in innate pattern recognition receptors, and problems with lymphocyte differentiation, especially in Crohn disease.⁽⁴⁾

Microscopically, the initial lesion starts as a focal inflammatory infiltrate around the crypts, followed by ulceration of superficial mucosa. Later, inflammatory cells invade the deep mucosal layers and, in that process, begin to organize into noncaseating granulomas. The granulomas extend through all layers of the intestinal wall and into the mesentery and the regional lymph nodes.

Neutrophil infiltration into the crypts forms crypt abscesses, leading to destruction of the crypt and atrophy of the colon. Chronic damage may be seen in the form of villous blunting in the small intestine as well. Ulcerations are common and are often seen on a background of normal mucosa. Although granuloma formation is pathognomonic of Crohn disease, its absence does not exclude the diagnosis.⁽⁵⁾

Macroscopically, the initial abnormality consists of hyperemia and edema of the involved mucosa. Later, discrete superficial ulcers form over lymphoid aggregates and are seen as red spots or mucosal depressions. These can become deep, serpiginous ulcers located transversely and longitudinally over an inflamed mucosa, giving the mucosa a cobblestone appearance. The lesions are often segmental, being separated by healthy areas, and are referred to as skip lesions.⁽⁵⁾

Transmural inflammation results in thickening of the bowel wall and narrowing of the lumen. As Crohn disease progresses, it is complicated by obstruction or deep ulceration leading to fistulization by way of the sinus tracts penetrating the serosa, microperforation, abscess formation, adhesions, and malabsorption.⁽⁶⁾

Bowel obstruction is caused initially by significant edema of the mucosa and associated spasm of the bowel. Obstruction is intermittent and can often be reversed by means of conservative measures and anti-inflammatory agents. With further disease progression, the obstruction becomes chronic because of fibrotic scarring, luminal narrowing, and stricture formation.⁽⁶⁾

Fistulae may be enteroenteral, enterovesical, enterovaginal, or enterocutaneous. The inflammation extending through the bowel wall may also involve the mesentery and surrounding lymph nodes. Creeping fat may be seen when the mesentery wraps around the bowel surface. Serosal inflammation causes adhesions; thus, free perforations are less common in Crohn disease than in other inflammatory bowel conditions. ⁽⁶⁾

NATURAL HISTORY:

The disorder has a heterogeneous clinical expression and data from tertiary care settings have documented its female predominance, occasional familial nature, and high rate of stricture formation and penetrating disease. It may appear from early childhood to late adulthood, although over 80% are currently diagnosed before age 40 years, usually with terminal ileal and colonic involvement. Several studies have now shown differences in phenotypic clinical expression depending on the initial age at diagnosis, with pediatric-onset disease being more severe and more extensive with more involvement of the upper gastrointestinal tract compared to adult-onset disease. In addition, long-term studies from these tertiary care settings have documented that the disorder may evolve with time into a more complex disease with stricture formation and penetrating disease complications (i.e. fistula and abscess). Although prolonged remission with no evidence of inflammatory disease may occur, discrete periods of symptomatic and active granulomatous inflammatory disease may re-appear over many decades. Long-term studies on the natural history have also suggested that discrete events (or agents) may precipitate this granulomatous inflammatory process.⁽⁷⁾

SIGN AND SYMPTOMS:

The characteristic presentation in Crohn disease is abdominal pain and diarrhea, which may be complicated by intestinal fistulization or obstruction. Unpredictable flares and remissions characterize the long-term course.^{(8.9, 10,)}

Other signs and symptoms of Crohn disease may include the following:

• Rectal bleeding
• Fever
• Weight loss, anorexia
• Nausea, vomiting
• Malnutrition, vitamin deficiencies
• Generalized fatigability
• Bone loss
• Psychosocial issues (e.g. depression, anxiety, and coping difficulty); pediatric patients may also experience psychological issues regarding quality of life and body image^{(11, 12)}
• Growth failure in pediatric patients: May precede gastrointestinal symptoms by years

DIAGNOSTIC TESTS:
Examination for Crohn disease includes the following:

• Vital signs: Normal, but possible presence of tachycardia in anemic or dehydrated patients; possible chronic intermittent fever
• Gastrointestinal: May vary from normal to those of an acute abdomen; assess for rectal sphincter tone, gross rectal mucosal abnormalities, presence of hematochezia
• Genitourinary: May include presence of skin tags, fistulae, ulcers, abscesses, and scarring in the perianal region; nephrolithiasis, hydronephrosis, and enterovesical fistulae
• Musculoskeletal: Possible arthritis and arthralgia, particularly of the large joints⁽¹³⁾
• Dermatologic: May show pallor or jaundice, mucocutaneous or aphthous ulcers, erythema nodosum, and pyoderma gangrenosum
• Ophthalmologic: May reveal episcleritis; possible uveitis
• Growth delay: Decreased growth velocity (e.g. height), pubertal delay
• Hematologic: Hypercoagulable state

LABORATORY TESTS:

Although laboratory results for Crohn disease are nonspecific and are of value principally for facilitating disease management, they may also be used as surrogate markers for inflammation and nutritional status and to screen for deficiencies of vitamins and minerals.

Routine laboratory studies include the following:

• Complete Blood Count (CBC) count
• Chemistry panel
• Liver function tests
• Inflammatory markers
• Stool studies
• Serologic tests

IMAGING STUDIES:

Imaging modalities used for Crohn disease include the following:

• Plain abdominal radiography
• Barium contrast studies (e.g. small bowel follow-through, barium enema, enteroclysis)
• CT scanning of the abdomen
• CT enterography or magnetic resonance enterography: Replacing small bowel follow-through studies
• MRI of the pelvis
• Abdominal and/or endoscopic ultrasonography
• Nuclear imaging (e.g. technetium-99m hexamethyl propylene amine oxime, indium-111)
• Fluorine-18-2-fluoro-2-deoxy-D-glucose scanning combined with positron emission tomography or CT scanning

PROCEDURES:

The following procedures may help in the evaluation of Crohn disease:

• Endoscopic visualization and biopsy (e.g. upper gastrointestinal endoscopy, esophagogastroduodenoscopy, endoscopic retrograde cholangiopancreatography)
• Colonoscopy, ileocolonoscopy
• Small bowel enteroscopy
• Interventional radiology: For percutaneous drainages of abscesses

THERAPY CONSIDERATIONS:

Treatment of Crohn disease has changed over the past few years, reflecting new therapies that can target specific locations in the gastrointestinal (GI) tract and specific cytokines. The development of biologic anti–tumor necrosis factor (anti-TNF) agents (e.g. infliximab, adalimumab, certolizumab pegol, and natalizumab) has significantly advanced the treatment of Crohn disease and improved the induction and maintenance of clinical remission in patients with moderate to severe disease, especially in those who are corticosteroid dependent.

If medical therapy for active Crohn disease fails, surgical resection of the inflamed bowel, with restoration of continuity, is indicated. Urgent surgery may be required in rare cases of sustained or recurrent hemorrhage, perforation, abscess, and toxic megacolon. Partial small bowel obstruction or intra-abdominal abscess may sometimes be treated conservatively with intravenous (IV) hydration, nasogastric suction, and parenteral nutrition if there is no evidence of ischemia.

Many patients with an exacerbation of Crohn disease can be treated on an outpatient basis. However, if a serious complication of Crohn disease (e.g. obstruction, perforation, abscess, or hemorrhage) is a concern or if outpatient treatment fails, IV therapy (e.g. corticosteroids, antibiotics, or total parenteral nutrition [TPN]) may be required, and hospitalization is warranted.

Patients should be examined on a regular basis, with the frequency of examination depending on the severity and activity of their disease. Follow-up laboratory workup and diagnostic testing should be performed regularly as needed to monitor the safety and success of therapy.

Therapy for mild Crohn disease is typically administered in a sequential “step-up” approach, in which less aggressive and less toxic treatments are initiated first, followed by more potent medications or procedures if the initial therapy fails. Patients are treated with preparations of 5-aminosalicylic acid (5-ASA), antibiotics, and nutritional therapy. However, the use of 5-ASA for the treatment of Crohn disease is controversial; only a small subset of patients may benefit from this agent.

If no response occurs or if the disease is more severe than initially thought, corticosteroids and inhibitors of DNA synthesis (i.e. immunomodulators) with 6-mercaptopurine (6-MP)/azathioprine or methotrexate are administered. Finally, biologic agents (infliximab, adalimumab, certolizumab pegol, and natalizumab) and surgical therapies can be useful.

For the treatment of moderate to severe Crohn disease, current recommendations include the “top-down” approach, which differs from the conventional step-up approach in that more potent agent are administered initially. Top-down therapies include biologic agents and steroids as needed versus combination therapy with both biologic drugs and immunomodulator agents.

TREATMENT OPTIONS:

PHARMCOLOGICAL:

Mesalamine rectal: Rectal mesalamine is a formulation of mesalamine that specifically releases 5-ASA in the distal colon. This agent elicits an anti-inflammatory effect by an unknown mechanism.

Mesalamine: Products such as mesalamine, which releases 5-ASA in the distal small bowel secondary to pH changes, are more useful in patients with small intestinal Crohn disease. Long-term maintenance with mesalamine may delay clinical relapse. This agent is better tolerated than sulfasalazine and has fewer adverse effects.

Sulfasalazine: Sulfasalazine is useful mainly in colonic disease because the active compound, 5-ASA, is released in the large bowel by bacterial degradation of the parent compound. Sulfasalazine does not alleviate small bowel disease; it acts locally in the colon to reduce the inflammatory response and systemically inhibits prostaglandin synthesis. It has no additive or steroid-sparing effects when used in conjunction with corticosteroids. In contrast to its action in ulcerative colitis, sulfasalazine does not seem to maintain remission in Crohn disease.

Balsalazide: Balsalazide is an active component of sulfasalazine and is metabolized to mesalamine by intestinal flora. It has an anti-inflammatory effect, but its exact mechanism of action is not known. Balsalazide is used to treat ulcerative colitis.

Prednisone: Prednisone exerts anti-inflammatory effects through decreased capillary permeability, impaired neutrophil chemotaxis, release of anti-inflammatory cytokines, decrease of production of eicosanoids, and stabilization of lysosomal membranes. This agent is generally helpful in acute inflammation.

Methylprednisolone: Methylprednisolone exercises anti-inflammatory effects through decreased capillary permeability, impaired neutrophil chemotaxis, release of anti-inflammatory cytokines, decreased production of eicosanoids, and stabilization of the lysosomal membrane.

Budesonid: Budesonide alters levels of inflammation in tissues by inhibiting multiple types of inflammatory cells and decreasing the production of cytokines and other mediators involved in inflammatory reactions.

Hydrocortisone: Adrenocortical steroids act as potent inhibitors of inflammation. They may cause profound and varied metabolic effects, particularly in relation to salt, water, and glucose tolerance, in addition to their modification of the immune response of the body.

Prednisolone: Prednisolone may decrease inflammation by reversing increased capillary permeability and suppressing polymorphonuclear leukocyte (PMN) activity. It is a commonly used oral agent. Prednisolone is used for an oral taper of steroids, which may reduce the emotional effects of steroid withdrawal and the risk of the development of adrenocortical insufficiency. However, these risks are not very high after only 3 days of treatment with high-dose steroids, and most neurologists do not use a prednisone taper.

Mercaptopurine: 6-MP and its prodrug azathioprine are purine analogues; they interfere with protein synthesis and nucleic acid metabolism and have cytotoxic effect on lymphoid cells. If steroid withdrawal proves difficult, immunosuppressants such as 6-MP may be considered.

Methotrexate: Methotrexate is used for the treatment of moderate-to-severe Crohn disease and maintenance of remission. It is effective in inducing and maintaining remission in chronic Crohn disease in adults and has been shown to be effective and well tolerated for maintenance of remission in children. Methotrexate is a structural analogue of folic acid that inhibits binding of dihydrofolic acid to the enzyme dihydrofolate reductase. It impairs DNA synthesis, induces apoptosis, and reduces interleukin (IL)-1 production.

Tacrolimus: Tacrolimus is an immunomodulator produced by the bacteria Streptomyces tsukubaensis. Its mechanism of action is similar to that of cyclosporine. Tacrolimus may be effective in treating Crohn disease.

Infliximab: Infliximab is a chimeric mouse-human monoclonal antibody against tumor necrosis factor (TNF)-α which shows promise in the treatment of Crohn disease. This agent blocks TNF-α in the serum and at the cell surface, leading to the lysis of TNF-producing macrophages and T cells. Infliximab has been approved for the treatment of pediatric Crohn disease.

Adalimumab: Adalimumab is indicated for the induction and remission of moderate-to-severe active inflammatory Crohn disease. This agent is a recombinant human immunoglobulin (Ig) G1 monoclonal antibody specific for human TNF. It binds specifically to TNF-α and blocks interaction with p55 and p75 cell-surface TNF receptors. This interferes with the cytokine driven inflammatory processes. Adalimumab also lyses surface TNF-expressing cells in vitro in the presence of complement, but it does not bind to TNF-β (lymphotoxin).

Certolizumab pegol: Certolizumab pegol is indicated for moderate-to-severe Crohn disease in individuals whose condition has not responded to conventional therapies. It is a pegylated anti–TNF-α blocker, and its action results in disruption of the inflammatory process.

Natalizumab: Natalizumab is indicated for moderate-to-severe Crohn disease in patients who have had inadequate responses to other therapies. It is a monoclonal antibody that binds α4β7 and α4β1 those results in inhibition of leukocyte adhesion and migration to areas of inflammation.

Vedolizumab: Vedolizumab is a recombinant humanized monoclonal antibody that binds specifically to α4β7 integrin. It blocks the interaction of α4β7 integrin with mucosal addressin cell adhesion molecule-1 (MAdCAM-1) and inhibits the migration of memory T-lymphocytes across the endothelium into inflamed gastrointestinal parenchymal tissue. It is indicated for both ulcerative colitis and Crohn disease.

Metronidazole: Metronidazole is an imidazole ring–based antibiotic that is active against various anaerobic bacteria and protozoa. It is sometimes used in combination with other antimicrobial agents (except for Clostridium difficile enterocolitis). Metronidazole also possesses immunosuppressive and anti-inflammatory properties.

Ciprofloxacin: A fluoroquinolone, ciprofloxacin has activity against pseudomonads, streptococci, methicillin-resistant Staphylococcus aureus (MRSA), Staphylococcus epidermidis, and most gram-negative organisms, but it has no activity against anaerobes. Ciprofloxacin inhibits bacterial DNA synthesis and, consequently, growth.

Loperamide: Loperamide, which is available over the counter, acts on intestinal muscles to inhibit peristalsis and to slow intestinal motility. It prolongs the movement of electrolytes and fluid through the bowel and increases the viscosity and loss of fluids and electrolytes. Loperamide improves stool frequency and consistency, reduces abdominal pain and fecal urgency, and may exacerbate constipation.

Diphenoxylate-atropine: The combination of diphenoxylate with atropine consists of 2.5 mg of diphenoxylate, which is a constipating meperidine congener, and 0.025 mg of atropine to discourage abuse. The preparation inhibits excessive gastrointestinal (GI) propulsion and motility, but it may exacerbate constipation.

Cholestyramine: Cholestyramine is used for diarrhea associated with Crohn disease. It binds bile acids, thereby reducing damage to the intestinal mucosa. Cholestyramine also reduces the induction of colonic fluid secretion. It forms a nonabsorbable complex with bile acids in the intestine, thereby, in turn, inhibiting enterohepatic reuptake of intestinal bile salts.

Colestipol: Colestipol forms a soluble complex after binding to bile acid, increasing fecal loss of bile acid–bound low-density lipoprotein cholesterol.

Dicyclomine: Dicyclomine treats GI motility disturbances. It blocks the action of acetylcholine at parasympathetic sites in secretory glands, smooth muscle, and the central nervous system (CNS). Adverse effects are dose-dependent.

Hyoscyamine: Hyoscyamine blocks the action of acetylcholine at parasympathetic sites in smooth muscle, secretory glands, and the CNS, thereby exerting antispasmodic effects. This agent decreases fecal urgency and pain.

Propantheline: Propantheline is a quaternary ammonium antimuscarinic agent with peripheral effects that are similar to those of atropine. It inhibits GI motility and decreases gastric acid secretion.

SURGERY:

Unlike ulcerative colitis, Crohn disease has no surgical cure. Most patients with Crohn disease require surgical intervention during their lifetime.

Surgical management of the terminal ileum, ileocolon, and/or upper gastrointestinal tract may include the following:⁽¹⁴⁾

• Resection of the affected bowel
• Ileocolostomy or proximal loop ileostomy
• Drainage of any septic foci with later definitive resection
• Strictureplasty
• Bypass
• Endoscopic dilatation of symptomatic, accessible strictures

Surgical management of the colon may include the following: ⁽¹⁴⁾

• Subtotal or total colectomy with end ileostomy (laparoscopic or open approach)
• Segmental or total colectomy with or without primary anastomosis
• Total proctocolectomy or proctectomy with stoma creation

GOALS OF THERAPY: 

The general goals of treatment for Crohn disease are as follows:

• To achieve the best possible clinical, laboratory, and histologic control of the inflammatory disease with the least adverse effects from medication
• To permit the patient to function as normally as possible
• In children, to promote growth with adequate nutrition.

GUIDELINES: 

Treatment of crohn’s disease is based on guidelines from prestigious societies such as American College of Gastroenterology (ACG) and NICE guidelines

To review the ACG guidelines, click on the link below.

http://gi.org/guideline/management-of-crohn%E2%80%99s-disease-in-adults/

To review the NICE   guidelines, click on the link below:

https://www.nice.org.uk/guidance/cg152

LONG TERM MONITORING 

The response to therapy is based upon the clinician's evaluation of clinical disease activity and supporting laboratory data, assessed during clinical visits approximately every three to four months.⁽¹⁵⁾

CONSULTATION AND COUNSELING:

Crohn disease is a chronic disease that requires treatment by a team of experts consisting of primary care providers, gastroenterologists, psychologists, nutritionists, social workers, and nurses. A multidisciplinary approach involving the participation of specialists such as surgeons, dermatologists, rheumatologists, endocrinologists, and obstetricians is often necessary to manage complications of the disease, as well as potential side effects of therapy, if these occur unexpectedly.

A critical factor in the successful management of Crohn disease is the willingness of the patient to participate and cooperate with the team. Adherence to therapy and the management plan is essential in improving outcomes. Patients and parents must be educated and receive support to treat this disorder effectively.

PRECAUTIONS:

Patient should be instructed on following precautions:

• Try eating small, frequent meals, instead of a few big ones.
• When patient enjoy a great restaurant meal without irritation or side effects, jot down which items he/she ordered.
• Manage symptoms of Crohn's disease: enjoy a balanced diet and properportion control
• Smokingcan make Crohn's disease symptoms worse. Now is a good time to quit!
• Regularexercise, a healthy diet, and enough sleep.
• If taking antibiotics for Crohn's disease symptoms, then avoid alcohol, which can worsen some side effects.

REFERENCES: 

• Loftus EV Jr, Silverstein MD, Sandborn WJ, Tremaine WJ, Harmsen WS, Zinsmeister AR. Crohn's disease in Olmsted County, Minnesota, 1940-1993: incidence, prevalence, and survival.Gastroenterology. 1998 Jun. 114(6):1161-8.
• Kappelman MD, Rifas-Shiman SL, Kleinman K, Ollendorf D, Bousvaros A, Grand RJ, et al. The prevalence and geographic distribution of Crohn's disease and ulcerative colitis in the United States.Clin Gastroenterol Hepatol. 2007 Dec. 5(12):1424-9.
• http://www.jpma.org.pk/PdfDownload/7649.pdf
• Tsianos EV, Katsanos KH, Tsianos VE. Role of genetics in the diagnosis and prognosis of Crohn's disease.World J Gastroenterol. 2012 Jan 14. 18(2):105-18.
• Thoreson R, Cullen JJ. Pathophysiology of inflammatory bowel disease: an overview.Surg Clin North Am. Jun 2007. 87(3):575-85.
• Kornbluth A, Sachar DB, Salomon P. Crohn's disease. Feldman M, Scharschmidt BF, Sleisenger MH, eds.Sleisenger & Fordtran's Gastrointestinal and Liver Disease: Pathophysiology, Diagnosis, and Management. 6th. Philadelphia, Pa: WB Saunders Co; 1998. Vol 2: 1708-34.
• http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2658833/
• Kornbluth A, Sachar DB, Salomon P. Crohn's disease. Feldman M, Scharschmidt BF, Sleisenger MH, eds.Sleisenger & Fordtran's Gastrointestinal and Liver Disease: Pathophysiology, Diagnosis, and Management. 6th. Philadelphia, Pa: WB Saunders Co; 1998. Vol 2: 1708-34.
• Panes J, Gomollon F, Taxonera C, et al. Crohn's disease: a review of current treatment with a focus on biologics. Drugs. 2007. 67(17):2511-37.
• Tierney LM. Crohn's disease. Tierney LM, McPhee SJ, Papadakis MA, eds.Current Medical Diagnosis and Treatment. 40th ed. New York, NY: McGraw-Hill Professional Publishing; 2001. 638-42.
• Mackner LM, Bickmeier RM, Crandall WV. Academic achievement, attendance, and school-related quality of life in pediatric inflammatory bowel disease.J Dev Behav Pediatr. 2012 Feb. 33(2):106-11. [Medline].
• Rabbett H, Elbadri A, Thwaites R, Northover H, Dady I, Firth D, et al. Quality of life in children with Crohn's disease.J Pediatr Gastroenterol Nutr. 1996 Dec. 23(5):528-33.
• Nikolaus S, Schreiber S. Diagnostics of inflammatory bowel disease.Gastroenterology. Nov 2007. 133(5):1670-89.
• Strong SA, Koltun WA, Hyman NH, Buie WD. Practice parameters for the surgical management of Crohn's disease.Dis Colon Rectum. 2007 Nov. 50(11):1735-46.
• Rufo PA, Denson LA, Sylvester FA, et al. Health supervision in the management of children and adolescents with IBD: NASPGHAN recommendations. J Pediatr Gastroenterol Nutr 2012; 55:93.