Crohn disease (CD) and ulcerative colitis (UC) are collectively known as inflammatory bowel diseases (IBD). CD is an inflammation of the gastrointestinal tract caused by genetic and environmental factors, which lead to altered gut microbiota resulting in adaptive immune responses.1 Bowel damage and disability can ensue. Early diagnosis and treatment are necessary to improve quality of life. Treatment focuses on prolonged remission, prevention of complications, and slowing disease progression.1 This article will discuss early identification/diagnosis, severity classification, genomics, manifestations, management, and sequelae of CD.
As the population ages, the prevalence of IBD is expected to grow.2 In 2017, the CDC reported 16 hospitalizations for CD/100,000 Medicare recipients, with higher prevalence in urban communities.2 Ananthakrishnan et al. reviewed IBD-related hospitalizations and found that older adults have substantial morbidity and higher mortality.3 Ng et al. found the highest prevalences in Germany (322/100,000) and Canada (319/100,000).4
The etiology of IBD likely involves genetic predisposition and environmental exposures. In most studies, the peak incidence of IBD is in the second to fourth decade of life and has remained so over several decades.5 In some developing countries, increased incidence of CD is partially attributable to improved sanitation and decrease of helminthic infections, which produce type 2 immune (Th2) responses that lend protection against CD.6
Genetic predisposition appears to be the strongest indicator of development with 2.2% to 16.2% of patients having an affected first-degree relative.7 In one review of meta-analyses, smoking, antibiotic exposure, history of appendectomy or tonsillectomy surgeries, oral contraceptive use, urban living, vitamin D deficiency, and intestinal colonization with non-Helicobacter pylori-like enterohepatic Helicobacter species were identified as risk factors.8 Several factors, such as physical activity, breastfeeding, sharing a bed, high levels of folate or vitamin D, and gastric H. pylori infection, have been identified as reducing the risk.8 Counterintuitively, other identified protective factors are associated with lower socioeconomic status, such as lack of tap or hot water, large or poor familial situation, crowded living conditions, and contaminated food consumption—possibly due to increased exposure to environmental antigens building stronger immunity.7,9
ACG, ECCO, and Montreal classifications of CD1,4,20,55
|Age at onset
≤16 years (A1)
17-40 years (A2)
>40 years (A3)
Terminal ileum (L1)
Upper GI (L4) - (modifier that can be added to L1-L3 when concominant upper GI disease is present)
||Not mentioned for CD
Penetrating (B3) (“p” is additional to B1-B3 with concominant perianal disease presence)
||Not addressed for CD
|Response to treatment
||May have response to medical/surgical treatment (excludes patients who require corticosteroids)
||Not addressed for CD
Mild or Mild-Moderate Symptomatology
||Ambulatory; able to tolerate oral alimentation without dehydration, systemic toxicity, abdominal tenderness, painful mass, intestinal obstruction, or weight loss over 10%
||Ambulatory; eating and drinking; weight loss less than 10%; no obstruction, fever, dehydration, abdominal mass, or tenderness; CRP above normal
||Not addressed for CD
|Response to treatment
||Not addressed for CD
Moderate to Moderate-Severe Symptomatology
||Fever, significant weight loss, abdominal pain, intermittent nausea/vomiting, or significant anemia. Does not have obstruction.
||Intermittent vomiting or weight loss >10%; no overt obstruction; CRP above normal
||Not addressed for CD
|Response to treatment
||Ineffective or has tender mass
||Persistent high fever, vomiting, obstruction, peritoneal signs, cachexia, or abscess; high fever, vomiting, obstruction, significant peritoneal signs, cachexia, or abscess
||Persistent symptoms; cachexia, obstruction, or abscess; CRP above normal
|Response to treatment
||Failed: persistent symptoms despite corticosteroids/biologics
||Failed: persistent symptoms despite intensive treatment
Abbreviations: ACG, American College of Gastroenterology; CDAI, Crohn's Disease Activity Index; CRP, C-reactive protein; ECCO, European Crohn's and Colitis Organisation
In a retrospective study, the authors compared resource utilization, lost workdays, and related costs among a cohort of patients with CD versus a cohort without IBD.10 Data revealed a significantly higher mean direct healthcare cost per patient/year in the cohort with CD ($24,500 versus $7,037). In the subgroup who underwent a CD-related surgery, cost per patient/year reached $101,013, likely in part due to procedures such as intestinal resection, colostomies, endoscopic balloon dilation, and stricturoplasty. Fondell et al. found that infusion therapy is a driving cost for newly diagnosed cases, followed by hospitalization and outpatient procedures, oral medications, imaging, and visits.11 In addition to high medical management costs, patients also endure the psychological impacts of the disease on quality of life. Depression and anxiety associated with the condition can perpetuate lower adherence to medical regimens and increased cost of care. Thus, the American College of Gastroenterology (ACG) clinical guidelines support management of stress and depression in the comprehensive plan of care.12
Early identification and diagnosis
Diagnosis of CD is multifactorial, including history and physical exam, labs, and radiologic, endoscopic, and histopathologic findings.13 Patients often experience abdominal pain, diarrhea, rectal bleeding, fever, weight loss, and/or fatigue, consistent with many abdominal disorders, making identification complicated.
In a cross-sectional study of 201 participants, Danese et al. developed an eight-item tool designed to identify signs and symptoms suggestive of CD, the Red Flags Index for Suspected Crohn's Disease.14 The red flag findings are (in order of strength of correlation): perianal fistula/abscess, first degree relative with IBD, 3-month weight loss of over 5% of usual body weight, abdominal pain lasting longer than 3 months, nocturnal diarrhea, mild fever within 3 months, no abdominal pain 30 to 45 minutes after meals, and no rectal urgency. Although absence of pain after meals and rectal urgency are mentioned with a lower strength of correlation, the ACG guidelines indicate hallmark or cardinal symptoms including abdominal pain, diarrhea, weight loss, fatigue, anemia, fistulas, growth failure, and/or extraintestinal features.12 One source indicates further testing may include a comprehensive metabolic panel (CMP), complete blood count (CBC) with differential, erythrocyte sedimentation rate (ESR), transferrin, ferritin, vitamin B12, folic acid, urinalysis, C-reactive protein (CRP), fecal calprotectin, and possibly a stool study for Clostridium difficile.13 The ACG guidelines indicate that stool studies for C. difficile and other fecal pathogens do impact diagnosis and management.12 Markers such as fecal calprotectin serve to not only differentiate IBD from irritable bowel syndrome but also help monitor patient response to therapy.12
While radiologic exams are necessary, the gold standard for diagnosis is endoscopy.15 Small bowel capsule endoscopy visualizes mucosal inflammatory changes.16 According to Goran et al., capsule exam enables early diagnosis and a very good stratification of prognosis, helping direct the treatment strategy.17 Based on history and physical exam, computed tomography and magnetic resonance enterography or enteroclysis scanning may be useful for assessment of CD signs and symptoms.12 In addition, it is common practice to utilize barium contrast studies of the small bowel for diagnosis of small bowel CD.
Disease severity classification
In 1976, the National Cooperative Crohn's Disease Study group developed the Crohn's Disease Activity Index (CDAI) to classify the severity of the disease. This calculation integrates weight, gender, hematocrit, number of loose stools, degree of pain, general well-being, use of antidiarrheal medications, presence of abdominal mass, and other extraintestinal findings/complications.18 Index values greater than 150 indicate active disease, with values exceeding 450 indicating the most severe forms.
Common genetic and epigenetic abnormalities associated with CD29,56-59
||Effect on CD
||p.Leu1007fs, p.Arg702Trp, p.Gly908Arg
||Innate mucosal defense, oxidative stress, immune tolerance
||Alteration of alpha-defensin expression and TLR downregulation, impairing mucosal immunity and increasing inflammatory response to microbiota
||Autophagy and inflammatory signaling
||Promotion of CD pathogenesis by causing reduced autophagy, increased inflammatory cytokine responses, impaired response to beneficial bacteria (that is, Bacteroides fragilis)
||Autophagy, involved in innate immunity against intracellular pathogens
||Altered binding site of miRNA-196 that downregulates IRGM and is overexpressed in CD, reducing autophagy efficiency
||Synthesis of Forssman glycolipid, forming attachment sites for pathogens
||Cell adhesion and cell surface mediated signaling involved in the immune response
||Mediator of bcr-abl signaling
||More frequent than controls
||Involved in T-cell antigen-presenting cell interactions and adhesion of activated T cells to endothelial cells
||Axon projection and neuronal migration
||Associated with increased endoscopic and histologic activity
Abbreviations: TLR, toll-like receptors
In 1998, the World Congresses of Gastroenterology developed the Vienna classification (VC). The VC has three main categories: age at onset (A), disease location (L), and disease behavior (B).19,20 In 2005, the Montreal classification, a revision of the VC, was presented by the Working Party of the Montreal World Congress of Gastroenterology and new subcategories were added. Subcategory A1 allows for the classification of earlier onset and subcategories A2 and A3 stratify age groups. The European Crohn's and Colitis Organization (ECCO) also provides updates and guidelines on aspects of IBD care (see ACG, ECCO, and Montreal classifications of CD).20
Systemic manifestations can be intestinal and extraintestinal. Intestinal effects may include strictures, fissures/fistulas/abscesses (potentiating loss of intestinal function), or bowel obstruction with a high likelihood of requiring surgical resection.12 According to Veauthier et al., other manifestations may include:
- Inflammatory arthropathies (10%-35%)
- Osteoporosis (2%-30%)
- Pyoderma gangrenosum (0.5%-2%)
- Erythema nodosum (2%-20%)
- Uveitis (17%)
- Scleritis (18%)/episcleritis (29%)
- Anemia (9%-74%)
- Venous thromboembolism (10%-30%)
- Cholelithiasis (13%-34%)
- Nephrolithiasis (8%-19%)
- Aphthous stomatitis (4%-20%)21
Patients with CD are at increased risk for developing colorectal cancer. Risk increases with longer duration, extensive colonic involvement, primary sclerosing cholangitis, positive family history (colon cancer), and a higher degree of inflammation.12 Additionally, patients may be at increased risk for developing small bowel adenocarcinoma due to chronic inflammation.
A familial predisposition has been demonstrated for over 70 years, with the prevalence of CD or UC about 2% to 15% higher among first-degree relatives than in the general population and a relative risk 3 to 20 times higher.22 Familial link is one of the best indicators and strongest known risk factor for the development of CD.22 Sharing the same genetic background is not always sufficient to determine an identical phenotype: differences in type of IBD and course of the disease have been described even among monozygotic twins, often due to environmental and other influences.23-25 Genetic studies identified variants in several genes involved in pathways related to immune response: from autophagy to antigen presentation, oxidative stress to T-cell regulation, and immune cell recruitment.26 While most loci are associated with a more generic predisposition, variants in certain genes may be linked to CD alone or have a direct correlation with the number of mutant alleles. Homozygosity for the nucleotide-binding oligomerization domain containing 2 (NOD2) variant rs2066847 (p.Leu1007fs) has been attributed to a 20- to 40-fold increased risk of developing CD, with a less dramatic 2- to 4-fold elevation estimated for heterozygous carriers of the variant.21 The disruptive effects of genetic variants on the immune interaction with intestinal flora have been validated as a main pathogenic mechanism in mouse models.27
Numerous variants have been associated with a predisposition to the disease and some have combined effects when occurring in the same individual. For example, NOD2 controls the polyubiquitination of the IRGM gene and enhances its association with autophagy regulators ULK1 and Beclin 1, by forming a polypeptidic complex. However, IRGM variants limit the capacity of NOD2 to bind IRGM and initiate the complex, disrupting the autophagic process.28
Interest in epigenetic regulation of human genes has revealed increased/decreased methylation levels of regulatory regions of numerous genes in subjects with CD.29 Genes involved in immune pathways are highly represented among those that are affected by these epigenetic abnormalities and functional studies are beginning to reveal correlations with clinical presentation (see Common genetic and epigenetic abnormalities associated with CD).29 Increasing knowledge of genetic/epigenetic factors involving pathogenesis is helping counseling and managing patients and developing targeted drugs, but is not sufficient to develop personalized medicine guidelines.
Medical management for CD is multifactorial and includes education on medications, disease progression, preventive measures to minimize complications and flares, as well as importance of routine follow-up to monitor the condition and lab values. Other management includes tobacco cessation and correction of nutritional deficiencies. Elemental and semielemental diets have shown some benefit in reducing inflammation but should be adjuncts to other therapies.12 Shorter-acting agents, such as antitumor necrosis factor agents or steroids may help with quicker relief of symptoms. Adding thiopurines or methotrexate helps balance long-term adverse reactions and complications. Although primary care providers can comanage stable cases, providers should consider a consultation with a gastrointestinal advanced practice provider or gastroenterologist for closer monitoring as dictated by the stability of the disease state. While initial lab evaluation includes review of inflammation, anemia, or dehydration potential, routine monitoring includes a CBC to assess for infection or other blood dyscrasias and ESR to assess disease progression.7,12 Other treatment options require CMPs to assess for adequate renal and hepatic drug metabolism.
Inactivated vaccinations should be current as immunosuppression from treatment could lead to complications. Vaccinations to consider include influenza; pneumococcal pneumonia; hepatitis A and B; meningococcal; human papillomavirus; and tetanus, diphtheria, and pertussis, as well as certain live vaccinations such as herpes zoster and varicella zoster dependent on status of immunosuppression therapy.30
With IBD, the thought is the immune system attacks its own gastrointestinal tract after an external trigger. After inflammation begins, the immune system does not turn off. Persistent states of inflammation lead to damage in the digestive tract and onset of CD symptoms.31 The manifestations have multifocal distributions, with “jumping” or “skip” lesions; portions of the affected wall are separated by unaffected areas.32 CD is often a relapsing condition. Exacerbations occur randomly and often unpredictably.33 No clinical or biological marker appears to predict recurrences, but fecal markers (fecal calprotectin) show promise.34 Chronic inflammation serves as a negative influence on physical and/or psychological well-being, which may ultimately impact work and social activities.35 One major goal of therapy is working toward remission while avoiding disease progression. Unfortunately, the chance of a relapse is about 20% at 1 year and 76% at 10 years.36
Treatment consists of specific drug therapy, while surgery is used only when necessary. Drug selection is based on disease state and severity, and presence of penetrating phenotypes.37 More than 50% of patients undergo at least one surgery after diagnosis.38 Surgery is generally reserved for those unresponsive to drug therapy or in acute or life-threatening states (for example, bowel obstruction or fistulas with abscesses).39
Upon remission, maintenance therapy is used to support longevity. Factors impacting therapy choices include severity, extraintestinal manifestations, disease location, and patient characteristics (for example, age and concomitant diseases).40 An individual approach is required to recognize possible risks, and for optimization and monitoring of treatment.41 Tailoring treatment strategies may involve multiple drugs and various timings for follow-ups.42
In 1998, CD therapy (steroids and immunosuppressants) underwent a dramatic improvement with the advent of anti-TNF antibodies.43 Treatments with humanized anti-TNF antibodies have allowed for reduction in various types of reactions. Infliximab, adalimumab, and certolizumab pegol are anti-TNFs approved for CD. Anti-TNF antibodies are the most effective for inducing and maintaining remission.44 Medications such as these and other injectable treatments are generally only prescribed by providers with advanced gastroenterological backgrounds and not by primary care providers due to the requirement for careful medication monitoring. These agents are generally administered subcutaneously or I.V. with about 30% to 50% of recipients achieving target remission and mucosal healing. Injections occur at intervals of 2 to 8 weeks. Injection-site redness, infection, and increased risk for tuberculosis and certain malignancies are possible.21 Remission rates without steroid use are still quite low (20% to 30%).45
Ustekinumab, an interleukin-12 and -23 inhibitor, is a human IgG1 monoclonal antibody approved for moderate to severe CD. Ustekinumab data show both efficacy and safety in drug-naive patients as well as those previously exposed to other similar agents.46 This medication is delivered in an I.V. infusion every 8 weeks. Potential adverse reactions include vomiting, nasopharyngitis, injection-site erythema, and pruritus.21 Data demonstrate that ustekinumab has a low immunogenic profile, or low ability to produce an immune response, and is safe, although there is a risk of infectious and malignant complications.47,48 Biologic agents are intended to block leukocyte trafficking in the inflamed gut by targeting adhesions and integrins.49
Another effective agent, vedolizumab, is a monoclonal antibody that specifically targets the α 4 β 7 integrin.49 This agent may help reduce inflammation by blocking the recruitment of T cells and intestinal dendritic cells. It is administered I.V. at intervals leading up to every 8-week maintenance dosing, and adverse reactions can include nasopharyngitis, sinusitis, hypersensitivity, and/or lupus-like syndrome.21 Some studies suggest a role for this agent in programming innate and acquired immune cells.50 Due to limited efficacy of available therapies, research and development of molecules that block new inflammatory pathways and new molecules are under investigation.51
Tofacitinib, approved for UC, is also being studied for induction and maintenance therapy, but is considered investigational for CD.52 It reduces the activation and proliferation of lymphocytes through the inhibition of Janus kinases (JAKs) 1, 2, and 3, promoted by the binding of inflammatory cytokines to their receptors.53 Biological drugs have radically changed the management of patients with CD; however, doubts remain regarding their safety and optimization of use.54 Determining the best treatments by priority of greatest response is essential for remission and quality of life.
The management of CD can be challenging. Primary care providers should be screening, vaccinating, and promptly referring patients to gastroenterology. Further nursing research in properly screening and identifying all types of IBD can increase early detection and referral, improving quality of life for patients.
IBD, particularly CD, can be debilitating for patients and a challenge for providers to treat. Environmental and genetic factors play a role in disease severity and treatment plans. A collaborative approach and regular follow-up can lead to improved quality of life. Newer treatment options can help maintain remission and avoid long-term or repeated steroid use. Education from PCPs as well as gastroenterology providers needs to focus on the importance of proper medical follow-up to assess medications and potential sequelae of the disease process. Overall goals are to manage the condition with the least impact on quality of life while minimizing hospitalizations and surgery.
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