Crohn’s disease

An incurable chronic inflammatory disease of the GI tract.

Can affect any part of the G.I. tract from mouth to anus.

Crohn’s disease is characterized by involvement of the gastrointestinal tract from mouth to anus in a discontinuous fashion, with the development of strictures, abscesses, or fistulas that can penetrate into neighboring organs or the peri anal skin.

Pathophysiology is related to interaction of various causes and current theory suggests that genetics and environmental aspects play a significant role in this regulation of the immune system.

Genetics, the microbiome, environmental factors, such as smoking, medications, and diet contribute to the pathogenesis of CD.
Smoking is associated with an increased risk of CD, CD flare, and need for surgery.
Smokers compared to non-smokers have increased need for steroids, immunosuppressive medications, and anti-tumor necrosis factor biologic therapies.
Smoking cessation is advised for all patients with CD.
More than 100 genetic markers have been associated with CD.  highlighting the polygenic nature of the disease.
Implicated genes indicate that immunoteactivity to gut bacteria is a critical component of the risk of the development of CD.

Gene and environmental interactions may facilitate the pathogenesis of the disease by damaging the lining of the intestine or perturbation of immune defenses, increasing exposure of the primed immune system to intestinal bacteria.

Crohn’s disease can affect any part of the digestive tract, often in a noncontiguous manner.

Crohn’s disease  is characterized by transmural inflammation, which can lead to complications such as fibrotic strictures, fistulas, and abscesses.

Incidence and prevalence is increasing worldwide.

Approximately a half million people in United States have Crohn’s disease.

Incidence 6.3 and 23.8 cases and a prevalence of 96.3 and 318 cases per hundred thousand persons per year.

The prevalence of Crohn disease varies significantly between populations: In North America, the incidence of Crohn disease can be as high as 20.2 cases per 100,000 population.

Previously considered a disease of Western nations, the incidence is rising in Asia.

The incidence of Crohn disease is higher at northern latitudes than at southern latitudes.

Estimated cost is $18,000 per patient per year in the US.

The peak age of onset is between 15 and 40 years.

There is a well-documental bimodal age distribution associated with the onset of Crohn disease: the peak incidence occurs in the second and third decades of life, with a second, smaller peak in the sixth and seventh decades.

Genetics have also been implicated in the development of the disease as certain populations ( Ashkenazi Jewish populations) have a much higher risk for the development of the disease.

Crohn disease?associated genetic loci have been identified.

About 25% of patients develop symptoms in childhood, and these patients generally have a more severe disease than those with adult onset cases.

The incidence is increasing globally in the prevalence is particularly elevated in North America and Europe.

Incidence increasing in countries with increasing industrialization, air pollution, and western diets.

Majority of cases involve the small bowel and may follow an unrelenting course characterized by alternating periods of remission and exacerbation.

Primarily affects the terminal ileum and right: colon.

Characterized by transmural, granulomatous inflammation occurring in a discontinuous pattern and a tendency to form fistulae.

Disease associated inflammation is segmental and transmural leading to tissue damage.

Radiographic findings include stratified mural enhancement and luminal narrowing.
Imaging can also detect intra-abdominal abscesses and fistulaw.
In patients with disease in the small bowel out of the reach of standard colonoscopy they may need a capsule endoscopy to identify alterations, followed by balloon enteroscopu to obtain biopsies.
Histologic of evidence is required for Crohn’s disease diagnosis given its costs and risk of biologic therapy.
Tissue histology is the cornerstone of diagnosis with findings of transmural Inflammation and architectural distortion, lymphoid infiltrates and or granulomas.

At onset most patients have inflammatory lesions which become predominantly strictures or penetrating lesions over time.

Fecal Calprotectin is useful for diagnosingCrohn’s disease among patients in whom both inflammatory bowel disease and irritable bowel syndrome are being considered.

Any part of the gastrointestinal tract from mouth to anus may be involved.

Most frequently the terminal ileum, ileocecal region, colon and perianal areas are involved.

Related to genetic predisposition, environmental triggers and mucosal immunity.

Associated with an overly aggressive immune response to commensal bacteria in genetically predisposed individuals.

Activated lymphocytes and overexpression of inflammatory cytokines lead to chronic inflammation.

Persistent recruitment of leukocytes into gut tissue with secondary inflammation.

Antibodies to Saccharinyces cerevisiae present in 50-70% of patients.

10-25% of patients have pANCA antibodies.

Gene encoding capsase activating recruitment domain 15 (CARD15) also known as nucleotide oligomerisation domain 2 (NOD2) important in pathogenesis.

NOD2/CARD15 gene associated with CD and encodes a protein that acts as an intracellular pattern recognition receptor for bacterial muramyl dipeptides contributing to abnormal immune response to luminal bacteria.

Preclinical studies have implicated IL-12 and IL-23 in its pathophysiology.

Overexpression of interleukin-12 p35 and interleukin-12/23 p40 subunits.

Autography-related genes ATG16L1 and IRGM are associated with CD and promote degradation and antigen processing of intracellular pathogens.

Associated with at least 30 mutant gene loci.

Linked with cellular autography (Cadwell).

Hallmark of autography is the formation of double-membrane cytosolic vesicles, autophagosomes, that sequester cytoplasm and deliver it to lysosomes for degradation.

The most common symptoms are abdominal pain, diarrhea, blood in the stool, weight-loss, low-grade fever, and fatigue.

Extraintestinal symptoms include arthritis, anemia, growth failure, perianal lesions including fistula and abscesses.

Extraintestinal manifestations ofCrohn’s disease can include arthritis of the knees, hips and shoulders with the prevalence of 10-20%, sacroiliitis with the prevalence of 13-50%, ankylosing spondylitis with a prevalence  1-10%, pyoderma gangrenosum prevalence 2%, erythema nodosum prevalence 6%, uveitis prevalence 1-17%, episcleritis prevalence up to 29%, scleritis president up to 18%, primary sclerosing cholangitis prevalence 1%, and mouth ulcers prevalence 10%.
Many patients have signs of anemia, irondeficiency, low vitamin D levels, elevated inflammatory markers: C reactive protein, erythrocyte sedimentation rate, and fecal Calprotectin.

Fecal calprotectin is the most sensitive screening test for IBD with the specificity of 0.67%.

Most patients will require an operation within 10 years of diagnosis and are subject to yearly surgical recurrence rate of 8-10%.

In the first 10 years following the diagnosis the cumulative surgery rate is 40-55%.

May involve any or all parts of the entire GI tract from mouth to perianal area.

Characterized by skip lesions.

Resistance or intolerance to therapy is common among children, with up to 18% of cases requiring surgery within five use from disease onset.

Complications in children include growth failure, osteoporosis, delayed sexual development, psychological disorders, failure to achieve education and career potential.

Prior to biologic therapies the rate of hospitalizations and the need for surgery was 194 admissions for 1000 patient years in a cohort of Crohn’s disease patients.

Likelihood of multiple bowel resections, placing patients with Crohn’s disease at a small risk of developing short bowel syndrome.

Bowel sparing surgery to promote remission may be preferable to extensive surgical resections to avoid short bowel syndrome.

Tumor necrosis factor-alpha concentration is increased in serum, intestinal tissue, and stool.

Transmural inflammation often leads to fibrosis, causing intestinal obstruction.

Inflammation can also result in sinus tracts that burrow through and penetrate the serosa, thereafter giving rise to perforations and fistulas.

Gross bleeding unusual, occurring in only 4-10% of patients.

Patients at increased risk of adenocarcinoma of the colon and the small intestine.

Cancers are likely to develop in areas affected by Crohn’s disease and the risk of cancer of the small intestine is 5-25 times higher than that of patients unaffected by Crohn’s disease.

Incidence of colon cancer increased in patients with chronic disease with a relative risk of 3.4.

Symptomatic disease requiring therapy occurs in 30-40% of patients with Crohn’s disease.

Symptoms vary but include diarrhea, abdominal pain, bloody stools, stools with mucous, perinea pain, weight loss, perianal discharge and irritation from fistula.

Patients often have symptoms for several years before diagnosis: the cardinal symptoms include fatigue, fever, abdominal pain, diarrhea, and weight loss, rectal bleeding is less common, but can occur with distal colon involvement.
Symptoms can fluctuate in the misdiagnosis of irritable bowel syndrome is common.

The average median diagnostic delay is 9-18 months from the onset of symptoms, and longer delays are associated with more intestinal obstruction and surgery.

Isolated small bowel disease may manifest with protean constitutional symptoms, and up to 20% of patients can initially present with complications ofCrohn’s disease, including intestinal strictures , abscesses, or fistulas.

Extraintestinal manifestations include: arthritis, uveitis and skin rash.Highest reported risk for colon cancer appears to be in patients diagnosed prior to age 25 and who have extensive disease.

A family history of inflammatory bowel disease associated with a 3 to 20 times risk to develop Crohn’s disease.

Colonoscopy for cancer surveillance should begin 8-10 years after diagnosis and be repeated every 1 to 2 years.

Early in life is associated with a decreased serum concentration of vitamin D.

About 30% of older patients have hypovitaminosis D.

Among patients with Crohn’s disease who have had small bowel resections 60% have hypovitaminosis D which contributes to osteopenia and osteoporosis of Crohn’s disease.

Patients are more likely to have lowered bone mineral density than patients with ulcerative colitis and involve malabsorption, corticosteroid usage, inflammatory mediator agents, and hypogonadism.

About 60% of adolescents have ileocolonic disease and 15 to 20% have perianal disease.

Linear ulcerations may be seen in the colon of patients with Crohn’s disease.

Hallmark findings are discontinuous areas of information characterized by ulceration, erythema, mucosal  edema and/or a luminal narrowing.

Increased incidence of lymphoma.

Decreased recurrence associated with blood transfusions (Williams JG).

First line treatment to induce remission of acute illness is corticosteroids.

For Crohn’s disease sulfasalazine was only modestly effective for induction of remission and mesalamine was not significantly more effective then placebo for induction for maintenance of remission.

Azathioprine and mercaptopurine are effective in inducing remissions and healing fistulae.

Azathioprine and mercaptopurine are frequently used when first-line therapies fail.

Approximately 40% of patients treated with azathioprine remain remitted at 1 year (Pearson DC).

Aminosalicylates mesalazine and sulfasalazine may reduce disease activity.

Cyclosporine, oral corticosteroids, or aminosalicylates alone are not likely to be beneficial in maintaining remission.

The benefits of corticosteroids frequently negated by side effects of prolonged exposure.

Corticosteroids and budesonide are not effective for maintenance treatment.

Anti-TNF agents have efficacy in inducing and maintaining remissions, but are utilized after conventional regimens fail.

Biologic therapy with anti-TNF medications, alone or in combination with other immunomodulating drugs is currently the most effective treatment for the induction and maintenance of remission.

Reported response rates with thalidomide in Crohn’s disease associated with remission rates ranging from 40-70%.

In children and adolescents with refractory Crohn’s disease thalidomide compare with placebo results in improved clinical remission at eight weeks.

In a randomized control study of infliximab monotherapy, azathioprine monotherapy and the combination of the two drugs in 508 patients with moderate to severe Crohn’s disease: patients treated with infliximab plus azathioprine, or onfliximab monotherapy were more likely to have a corticosteroid free clinical remission than those receiving azathioprine mootherapy (Study of biologic and Immunomodulator Naive Patients in Crohn’s Disease (SONIC) Study Group).

Mild to moderate disease treated with mesalamine, budesonide or corticosteroids.

Benefits of corticosteroids may be offset by side effects of prolonged exposure to such agents (Faubion WA Jr.).

Corticosteroids and budenoside are not useful for maintenance therapy.

Azathioprine and 6-mercaptopurine frequently used when first line therapies fail.

Approximately 40% of patients treated with azathioprine remain in remission at 1 year (Pearson DC).

Infliximab and other monoclonal antibodies that target TNF are efficacious in inducing and maintaining remission.

In general, antiTNF agents reserved for patients that fail conventional treatments.

In a study of 508 patients in a randomized trial evaluateting the efficacy of infliximab monotherapy, azathioprine monotherapy and a combination of the two drugs in moderate to severe Crohn’s disease in untreated patients: patients treated with infliximab plus azathioprine, or infliximab monotherapy were more likely to have a corticosteroid free clinical remission than those receiving azathioprine monotherapy (Colombrel JF).

One third patients do not have a response to tumor necrosis factor antagonists, and one third have a transient response and required dose escalation or a change in therapy.

Patients who fail TNF antagonists primarily, are unlikely to respond to another similar agent.

Ustekinumab, a fully human IgG monoclonal antibody that blocks biological activity of interleukin-12 and interleukin-23 through common p40 subunit by inhibiting receptors for these 2cytokines on T cells, natural killer cells, and antigen presenting cells.

Ustekinumab in moderate to severe disease resistant to TNF antagonists has increased response rate, as compared to placebo (Sandborn WJ et al).

Crohn’s rectal fistula recur after the first treatment with anal surgery in about 50% of cases and 40% eventually require a proctectomy.

Anti-tumor necrosis factor alpha achieves complete healing rates of 55% of Crohn’s fistula and clinical response of up to 68% ( Presen DH et al).

Crohn’s fistula combined medical and surgical treatment better than either treatment alone.

Crohn’s fistula relapse rate 16% at 1 year, 31%at 3 years, and 40% at 5 years (Bouguen G et al).

American College of Gastroenterology 2018 guidelines for the management of Crohn�s disease in adults:

Oral mesalamine should not be used to treat patients with active Crohn’s disease.

And tumor necrosis factor agents should be used to treat Crohn’s disease that is resistant to treatment with corticosteroids or requires ongoing steroid therapy.

Combination therapy of infliximab with immunomodulators, thiopurines, is more effective in treating with either immunomodulators alone or infliximab alone in patients who have not received these agents in the past.

For patients with moderately to severe active Crohn’s disease and objective evidence of active disease, anti–integrin therapy with vedolizumab with or without an immunomodulator should be considered to induce remission.

In patients with moderate to severe luminal Crohn’s disease, extra intestinal manifestations, and complex perianal fistulas anti-TNF alpha monoclonal antibodies have been considered first line biologics in combination with ciprofloxacin and placement of a silicone string, within the fistula tract.
Upadacitinib, an oral selective Janus kinase inhibitor (JAK) used in induction and maintenance treatment is superior to placebo in patients with moderate to severe Crohn’s disease.

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