Crohn's Disease

What is Crohn’s? What is Crohn’s Disease?

Crohn’s disease is a chronic inflammatory disease that can affect the entire gastrointestinal tract, that is, all parts of the gastrointestinal tract from the mouth to the anus. It may cause recurrent complaints of abdominal pain and diarrhea due to ulcerations on the surface of the affected areas and thickening and edema in the entire wall. The disease is characterized by periods of exacerbation and remission.

The small intestine may be involved in 30% of the patients, only the large intestine may be involved in 20%, and both are affected in 45%.

It can be seen in children and different ethnic groups.

What is Crohn's?

How Does Crohn Occur?

Crohn’s disease is a chronic inflammatory disease that can affect the entire gastrointestinal tract, that is, all parts of the gastrointestinal tract from the mouth to the anus. It may cause recurrent complaints of abdominal pain and diarrhea due to ulcerations on the surface of the affected areas and thickening and edema in the entire wall. The disease is characterized by periods of exacerbation and remission.

The small intestine may be involved in 30% of the patients, only the large intestine may be involved in 20%, and both are affected in 45%.

It can be seen in children and different ethnic groups.

What are the symptoms, signs and symptoms of Crohn’s Disease?

The complaints and symptoms you may see in the patients are:

General findings

  • low fever,
  • Prolonged diarrhea with abdominal pain
  • Weakening
  • General state of fatigue
  • Constant or cramping right lower quadrant pain or pain around the navel, which may decrease or go away after defecation.
  • Diarrhea is usually bloodless or rarely occurs
  • Joint pains,

  • iron deficiency anemia,

  • Sacroiliitis -low back pain,

intestinal involvement

  • Widespread abdominal pain may be accompanied by blood with mucus and inflammation in the stool.
  • Rushing to the toilet

Small bowel involvement

  • Malabsorption findings
  • Diarrhea
  • Abdominal pain,
  • weight loss
  • Anorexia

Gastroduodenal involvement

  • Anorexia
  • Nausea
  • Vomiting

perianal disease

  • Tiring perirectal pain
  • Tenezm – feeling of tingling, contraction in the anus
  • Foul smelling discharge from fistula
  • Scar tissue in the anal area that is deformed due to disease or previous surgery

Intestinal Obstruction Findings.

  • Bloating after meals
  • Cramping pains (in the lower right quadrant)
  • stomach rumble
  • Constipation
  • feeling of congestion
  • Signs of intestinal obstruction do not benefit from anti-inflammatory drugs.

Fistulas

Enterovesical Fistula

  • Recurrent urinary tract infections
  • Air bubbles in the urine

Enterovaginal fistula

  • Foul-smelling, fecal vaginal discharge

Enterocutaneous Fistula

  • Stool-like discharge, spotting on the skin

Fistulization or Luminal Microperforation to the Mesenteric Region

  • Intra-abdominal or retroperitoneal abscess may develop.

What are the intestinal complications due to Crohn’s Disease?

Major intestinal complications of Crohn’s disease are:

abscesses

Fistulas

  • It is seen in 20-23% of cases.
  • They can be enterovesical, enterocutaneous and rectovaginal.

sinus tracts

bowel obstruction

perforation puncture

  • is rare
  • Peritonitis that develops after perforation can sometimes be masked by high-dose corticosteroid treatment or immunosuppressive treatment.

Colon cancer

  • The risk of colon cancer in Crohn’s disease is 3% in 10-year cases and 8% in 30-year cases.
  • Cancers frequently occur from low-grade dysplasia or dysplasia-associated lesion or mass (DALM) lesions.
  • Sporadic adenomas and
    The risk of accompanying primary sclerosing cholangitis is increased.
  • For Crohn’s disease that has existed for more than 8 years, screening colonoscopy is recommended every 1 or 3 years.
  • Small bowel cancer risk is increased in Crohn’s disease, although it is low

What are the extra intestinal diseases related to Crohn’s Disease?

Extra-intestinal findings have prognostic importance in Crohn’s disease

musculoskeletal diseases

arthritis

  • Common: 9-53%
  • seronegative, temporary, leaves no deformation, is asymmetrical, involves large joints in the lower extremities
  • It is more common in adults with active disease.
  • The knee is mostly affected. It is in the type I peripheral arthritis group; < less than 5 joints are involved.

Dermatological diseases

It is seen in 2-34% of cases.

erythema nodosum

  • The most common skin finding is more common in Crohn’s disease than in ulcerative colitis.
  • Arthritis develops in 75% of erythema nodosum cases.
  • Erythema nodosum appears as red, raised, tender nodules usually on the front of the leg.

pyoderma gangrenosum

  • It is rare, but can also be seen in patients in remission.
  • Therefore, dermatologist consultation should be requested.

Other dermatological findings

• Sweet syndrome
• Orofacial granulomatosis
• Angular and aphthous stomatitis
• Acrodermatitis enteropathica
• Alopecia
• Metastatic Crohn disease
• Crohn disease of the vulva and penis
• Psoriasis

oral lesions

aphthous ulcers

  • It is often seen together with skin and joint lesions.
  • It may start without any gastrointestinal complaints.

eye involvement

  • It occurs in 0.5-5% of cases and occurs when the disease is active.
  • The main treatment for eye involvement is aimed at the treatment of Chrone disease.
  • increased intraocular pressure and conjunctivitis
  • It may occur in children due to corticosteroid use.

episcleritis

  • redness, burning, irritation in one or both eyes

anterior uveitis

  • Blurred vision of pain

Urological involvement

nephrolithiasis

  • In malabsorption of fatty acids and bile salts, dietary calcium binds to them. Since the released oxalate is absorbed abundantly, first hyperoxaluria and then oxalate stones form.

hydronephrosis

  • It may occur as a result of inflammation or abscess pressing on the ureters.

other urological findings

  • enterovesical fistula
  • recurrent urinary tract infection
  • pneumoturia

Hepatobiliary involvement

  • If increases in serum aminotransferase levels persist for more than 6 months, further testing should be performed.

Intrahepatic findings

  • Chronic active hepatitis
  • Granulomatous hepatitis
  • amyloidosis
  • fatty liver
  • pericholangitis

Extrahepatic findings

  • Cholelithiasis – occurs due to changes in the bile salt pool due to malabsorption.
  • Choledocholithiasis.

Primary sclerosing cholangitis

  • It causes an increase in the risk of cholangiocarcinoma and colorectal cancer.
  • It has a closer connection with ulcerative colitis.
  • While 5-10 percent of cases with primary sclerosing cholangitis have Crohn’s disease, only 2 percent of Crohn’s patients develop primary sclerosing cholangitis.
  • Primary sclerosing cholangitis does not parallel disease activation.

Thromboembolic diseases

  • There is a predisposition to thromboembolic events due to thrombocytosis, increased plasma fibrinogen, factor 8 and low antithrombin 3 levels seen in Crohn’s disease.
  • Deep vein thrombosis, pulmonary thromboembolism, and neurovascular events are 3 times more common in Crohn’s disease.
  • Other risk factors that increase thromboembolic events, such as immobility, surgery, steroid use, venous catheter use, smoking, antiphospholipid syndrome and hyperhomocystinemia, are also more common in Crohn’s disease.

Other extra intestinal findings

metabolic bone diseases

  • osteopenia and osteoporosis.

Hematologic findings

  • iron deficiency anemia, vitamin B-12 deficiency, folate deficiency anemia, chronic disease anemia, autoimmune hemolytic anemia, thrombocytosis, anemias due to GI bleeding and thrombosis.

Genitourinary findings

  • Nephrolithiasis
  • obstructive uropathy
  • glomerulonephritis
  • amyloidosis

Pulmonary findings

  • granulomatous lung disease
  • fibrosing alveolitis
  • pulmonary vasculitis

Cardiovascular findings

  • pericarditis
  • myocarditis
  • vasculitis

malabsorption

  • protein-calorie malnutrition
  • dehydration
  • bile salt malabsorption and resulting steatorrhea, fat-soluble vitamin deficiencies, cholelithiasis, calcium deficiency, osteomalacia, osteoporosis
  • vitamin B12 deficiency

What are the tests for the diagnosis of Crohn’s Disease, diagnosis, how is the diagnosis made?

The diagnosis of Crohn’s disease is made in the light of clinical, laboratory, pathology and radiological findings. Diagnosis of the disease should be considered primarily in people with abdominal pain and bloody diarrhea.

Endoscopic findings

Colonoscopy

It is the most effective method in diagnosis. Involvement of the ileum and colon is in the area of colonoscopy examination in approximately 60% of cases. It is examined by endoscopy and diagnosed by taking biopsies.

Gastroscopy

Gastroscopy may be performed for other areas of the gastrointestinal tract that are thought to be involved, such as the stomach. Especially in those who have difficulty differentiating Crohn’s disease and ulcerative colitis or have stomach complaints, it would be appropriate to look at the stomach with endoscopy and take a biopsy.

laboratory findings

CRP and sedimentation

It may be high during active periods of the disease, but being normal does not indicate that the disease is not active.

Anemia

Causes of anemia seen in Crohn’s disease include chronic inflammation, iron deficiency, chronic blood loss, vitamin B12 or folic acid deficiency.

thrombocytosis

It is one of the causes of increased thromboembolism in Crohn’s disease.

White blood cell height

It can be seen in cases of chronic active inflammation, steroid use and abscess development.

ASCA IgG, ASCA IgA and p-ANCA

These tests may be useful in distinguishing between Crohn’s disease and colitis. However, it may not always be decisive. If they are p-ANCA positive, both ASCA Ig G and ASCA Ig A negative, this supports ulcerative colitis in the patient. It should also be kept in mind that the p-ANCA test is also positive in Crohn’s disease.

Laboratory tests that vary depending on malabsorption

Hypoalbuminemia, vitamin B12 and vitamin D deficiency, iron deficiency, elevated oxalate in blood and urine, electrolytes, temporary or chronic elevation of liver enzymes

Stool tests

Fecal white blood cells, occult blood test, stool culture, fecal parasite and egg examination, fecal amoeba antigen test, and fecal giardia antigen test should be performed routinely.

Clostridium difficile toxin level should be checked in patients with a history of antibiotic use.

Fecal calprotectin is elevated in both ulcerative colitis and Crohn’s disease. However, it should be kept in mind that this test may be high in other gastrointestinal infections and colorectal cancer.

Lactoferrin in feces increases in parallel with the degree of histological inflammation.

When the patient is in remission and returns to the clinic, stool amoeba antigen test, CRP, and fecal calprotectin levels should be checked again. In those with a positive amoeba antigen test, the Entamoeba histolytica antibody test should also be added to the tests. Because administering steroid treatment while an amoeba is present may cause amoeba dissemination. First, the amoeba must be treated.

Radiological findings

Barium Intestinal X-ray

These are intestinal films taken by administering medicated liquid (barium) to the intestines rectally. Nowadays, it is used less after CT enterography and MR enterography became available.

CT enterography, MR enterography

Both tests are effective diagnostic methods for wall thickness and abscessed fistulas.

MR enterography is superior because it is performed without radiation and provides better images in the pelvic region and perianal region.

enteroclysis

It is more successful in providing small intestine mucosal detail. However, in terms of patient tolerance and since it does not provide extra-luminal information, CT should be preferred in the absence of enterography.

Capsule endoscopy

It is useful in patients who cannot be diagnosed with other methods but are suspected to have Crohn’s disease or another intestinal problem.

Transrectal ultrasound

It may give additional findings in patients with perianal involvement.

What are the differential diagnoses in Crohn’s Disease?

Ulcerative colitis

Ulcerative colitis (UC) can often be confused with colon involvement of Crohn’s disease (CD) in clinical and pathological examination.

    • Involvement: UC shows continuous involvement, starting from the anus and moving towards the beginning of the large intestine. CH, on the other hand, shows skipping, patchy involvement.
    • Wall thickness: CH covers the entire wall of the intestinal system, affecting the serosa as well. UC only affects the mucosa.
    • In CD, there is a non-caseating granuloma in the pathology. Not available in UC
    • Perianal fistula and abscesses are more common in CD.
    • While bloody diarrhea is more common in UC, diarrhea accompanied by abdominal pain is more common in CD.
    • Obstruction is common in CH.

Intestinal Tuberculosis

In intestinal tuberculosis, the ileocecal valve region is often affected by a mass that causes adhesion and obstruction in this area. Granuloma may be seen in biopsies taken. If caseating granuloma can be seen, the diagnosis of tuberculosis comes to the fore. However, even in tuberculosis, non-scaling granuloma may be seen, which further confuses the picture. Testing tuberculosis PCR in tissue samples taken or serological T-spot test or quantiferon test may help in the differential diagnosis. Sometimes, although we give trial treatment for tuberculosis, sometimes differential diagnosis may be the last option.

Other diseases in differential diagnosis

  • Behςet’s disease
  • Celiac disease
  • Irritable bowel syndrome
  • Nonsteroidal anti-inflammatory drug (NSAID) enteropathy
  • amebiasis
  • Appendicitis
  • Bacterial gastroenteritis
  • Diverticulitis
  • Giardiasis
  • Intestinal Carcinoid tumor
  • ischemia
  • Viral Gastroenteritis

Inflammatory Bowel Diseases

Treatment modalities that can be used in Crohn’s disease

Anti-inflammatory drugs

5-ASA preparations

They can be used in mild to moderate Crohn’s disease, but they are not considered very effective in inducing remission. Their place in maintenance treatment is not accepted. However, it is often used for maintenance in mild cases.

Sulfasalazine

It is generally used in colon disease.
It has no effect on the small intestine
It has no steroid additive or steroid sparing effect.

corticosteroids

prednisolone

It is quite successful in putting the patient into remission in case of acute inflammation of Crohn’s disease in patients without signs of infection.
Before starting treatment, one should make sure that there is no intra-abdominal abscess.

budesonide

It is the first choice in low-risk, mildly active Crohn’s patients with ileum and proximal colon involvement. It has high first pass metabolism from the liver. Its systemic side effects are less than prednisolone.

Budesonide is started at 9 mg, decreased to 3 mg after 4 weeks, and discontinued at 12 weeks.

Immunomodulatory agents

azathioprine

6- merkaptopürin

Methotrexate

When azathioprine and 6-MP cannot be used due to side effects or tolerance, 1 mg folic acid per day can be used alongside methotrexate.

Biological agents

infliximab, adalimumab, certolizumab pegol, natalizumab, vedolizumab, ustekinumab

stem cell therapy

Plazmaferez

Step-up treatment

It refers to giving treatment starting with 5-asa preparations, followed by immunomodulators and then biological treatments as needed.

Step-down treatment (Top-down)

It means starting the treatment with biological agents and decreasing to immunomodulator or 5-wand preparations as the case improves.
Step-down treatment should be preferred in some cases. The poor prognostic features of the group in which step-down treatment should be considered are as follows.

  • Those who were young at diagnosis
  • perianal disease
  • Upper gastrointestinal tract involvement
  • Those with more than one extra intestinal finding
  • smoking
  • fistulizing disease

Medical treatment of diarrhea in Crohn’s disease

The causes of diarrhea in Crohn’s disease may be the following.

  • active disease itself
  • Clostridium difficile infection
  • bacterial overgrowth
  • loss of ileocecal valve integrity
  • short bowel syndrome
  • lactase deficiency
  • Accompanying Celiac disease
  • diarrheal form of irritable bowel syndrome

Anti-diarrheal drugs are not used during the active inflammation period of Crohn’s disease due to the risk of toxic megacolon.

Drugs that can be used in the treatment of chronic diarrhea that exists even though there is no active inflammation are as follows.

  • Loperamide
  • In diarrhea due to bile acid (Bile acid binders, cholestyramine or colestipol)
  • Diphenoxylate plus atropine
  • Tincture of opium
  • For developing steatorrhea in people with long-segment bowel resection (low-fat diet, medium-chain fatty acids)
  • mesalamine

Diet therapy in active Crohn’s disease

Dietary changes that rest the intestines are included in the treatment of active Crohn’s disease.

Parenteral and Enteral Nutrition are effective.

Elemental Enteral feeding

  • It has been shown to be as effective as corticosteroids in inducing remission of Crohn’s disease. It was also found to be more successful in mucosal healing.
  • However, when normal treatment is started, relapse often occurs.
  • Enteral nutrition is thought to benefit by changing the intestinal flora, reducing antigen load, and reducing inflammatory cytokines levels.
  • Dietary fiber supplementation should be involved in colonic retention as it converts into short-chain fatty acids, which in turn fuel the healing of the colon mucosa.
  • In patients with obstructive symptoms, low fiber is preferred.
  • Milk and dairy products should be restricted in patients with small intestine involvement, as they may have lactose intolerance.
  • Osteoporosis is observed in Crohn’s disease not only due to calcium absorption, but also due to bone resorption due to the activation of osteoclasts by cytokines during steroid use.
  • Enteral nutrition is continued for 6-8 weeks, and the majority of centers use polymeric formulas.
  • A low-fat diet and medium-chain fatty acids should be used in patients with extensive ileum resection.

Total parenteral nutrition

  • Total parenteral nutrition (TPN) can be used. It can be used for a short time in active patients before surgery, in those with abscess or fistula, and in cases with severe malnutrition.
  • In cases with clinically developed short bowel syndrome and long segment ileum resection, long-term TPN may have to be used.

OK Crohn’s Disease Biological treatments

Anti-TNF agent therapy

Who benefits?

  • Crohn’s patients with moderate and severe complaints
  • Patients with active inflammation
  • In patients who are dependent on corticosteroids and cannot reduce Alo

For whom is anti-TNF monotherapy recommended?

  • Those over 60 years of age
  • In young patients who do not want to use thiopurine drugs
  • In those without a history of Epstein Barr virus
  • people at increased risk of infection or malignancy

Before administering any anti-TNF agent therapy

  • The patient should be screened for Mycobacterium tuberculosis.
  • Other points to consider
    • hepatitis B virus carrier
    • Risk of Legionella and Listeria infection,
    • hepatosplenic T-cell lymphoma. It may rarely occur in adolescents and young adults when 6-MP or azathioprine and TNF-α inhibitors are used together.

There is no difference in clinical response between anti-TNF Mono therapy and treatments given by giving anti-TNF agents together with immunomodulatory drugs such as azathioprine.

More major and minor side effects are observed in Anti-TNF monotherapy than when Anti-TNF drugs and Immunomodulator drugs are used together. Therefore, combination treatment should be preferred.

İnfiliximab ( Remicade)

It is a chimeric IgG 1 monoclonal antibody against tumor necrosis factor (TNF)-alpha.
It can be used during remission induction and maintenance. It is preferred in peri-anal fistula diseases along with immunomodulatory drugs. Antibodies may develop against this agent during use. This may cause the effectiveness of the drug to decrease or disappear. It is more recommended to use it together with azothiopurine or 6-to reduce antibody development.

Dosage: 5 mg/kg IV given initially, in the second week, and in the sixth week. Thereafter, it continues to be given intravenously every 8 weeks.

Side effects: Lupus like syndrome, multiple sclerosis, psoriasiform rash, and opportunistic or fungal infections (eg, Pneumocystis jiroveci pneumonia or histoplasmosis).

Adalimumab (Humira)

It is a recombinant IgG 1 monoclonal antibody against tumor necrosis factor (TNF)-alpha. It is used as subcutaneous injection. It is less immunogenic than infliximab.

Dosage: The loading dose is 160 mg subcutaneously initially, 80 mg in the second week, and then 40 mg every 2 weeks.

Certolizumab pegol( Cimzia)

PEGylated humanized monoclonal antibody Fab fragment, neutralizes TNF alpha. PEG prolongs the half-life of the drug and is thought to reduce the immunogenic effect.

Although it is thought to be useful in remission induction, it is generally used as a second-line drug when the effect disappears in patients using infliximab and adalilumab.

Dosage:

Vedolizumab (Entyvio)

It is an anti-integrin agent. It is approved for ulcerative colitis and Crohn’s disease. Its specific substance is α4β7 integrin.

Unlike natalizumab, it is not an antibody against integrin in the brain. Therefore, the side effect of progressive multifocal leukoencephalopathy (PML) due to JC virus, which can be seen with natalizumab, is not expected.

dosage : 300 mg IV at week 0 and 2

Ustekinumab (Stelara)

This medication is an anti-interleukin 12/23 antibody. It was approved by the FDA for ulcerative colitis in 2019. It can be used in naive patients as well as in cases where other medications have been tried and have not been beneficial. In induction, the initial dose can be given subcutaneously at 6 mg/kg. The maintenance dose is 90 milligrams subcutaneous application every 8 weeks.

Treatment of perianal and other fistulas in Crohn’s Disease

  • Ileoileal, ileocecal, ileosigmoid, enterovesical, rectovaginal, enterocutaneous, cologastric, and colloduodenal fistulas may be seen in Crohn’s disease.
  • In the treatment of fistulas, medications, surgical methods and sometimes follow-up treatment can be performed.
  • You can see the following relatives in patients with fistula.
      • unexplained diarrhea
      • Abdominal pain,
      • Abscess development
  • In general, systemic sepsis is not observed in fistula patients. Ancak apse gelişimi eşlik ediyor ise bu durumda geniş spektrumlu antibiyotikler ve drenaj ile tedavisi yapılmalıdır. However, if it is accompanied by abscess development, it should be treated with broad-spectrum antibiotics and drainage.

Medication

  • Oral metronidazole and ciprofloxacin can be used. In addition to antibiotics, anti-TNF-alpha agents and or azathioprine/6-MP are used.
  • Endoscopic ultrasound, magnetic resonance imaging (MRI), or both are tests used in the anatomical identification of fistulas, especially perianal fistulas, and in the monitoring of treatment.

Are ulcerative colitis patients stranded in conceptive pregnancy?

Ulcerative colitis is considered to be due to the activity of the course at the time of pregnancy. If activation occurs when pregnancy occurs, the disease will continue actively. If the disease is in remission, it will continue to be calm throughout pregnancy. Therefore, if the pregnancy is planned, it would be appropriate to try to ensure that the disease is in remission during the period of pregnancy.

Ulcerative colitis and medications used in pregnancy

Many of the ulcerative colitis drugs can be used safely during pregnancy and lactation. Medications that can be used safely or continue to be used:

  • metronidazol – Category B
  • 5-ASA preparations – Asacol is not recommended due to the additive in it but there is no problem with other drugs with the same content
  • azathioprin
  • Cyclosporine
  • biological agents – some drugs should pay attention to the postpartum below.
  • corticosteroids- It is recommended to use without exceeding a certain dose, if possible, after 12 weeks

Insecure:

  • Methotrexate
  • rifaximin

You can read the detailed description of drug treatment in pregnant patients with ulcerative colitis, pregnancy planners and lactating in our article “Use of ulcerative colitis drugs pregnancy and lactation “.

remission

remission of active disease

relapse

relapse of the disease after it has subsided

remission induction

Efforts to achieve initial soothing of the disease

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