Management of Crohn's disease

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Management of Crohn's disease
Specialty gastroenterology

Management of Crohn's disease involves first treating the acute symptoms of the disease, then maintaining remission. Since Crohn's disease is an immune system condition, it cannot be cured by medication or surgery. Treatment initially involves the use of medications to eliminate infections (generally antibiotics) and reduce inflammation (generally aminosalicylate anti-inflammatory drugs and corticosteroids). Surgery may be required for complications such as obstructions, fistulae, abscesses, or if the disease does not respond to drugs within a reasonable time. However, surgery cannot cure Crohn's disease. It involves removing the diseased part of the intestine and rejoining the healthy ends, but the disease tends to recur after surgery.

Contents

Once remission is induced, the goal of treatment becomes maintenance of remission: avoiding the return of active disease, or "flares". Because of side effects, the prolonged use of corticosteroids is avoided. Although some people are able to maintain remission spontaneously, many require immunosuppressive drugs. [1]

Aminosalicylates

5-ASA compounds, such as mesalazine and sulfasalazine, have shown to be of very little efficacy in the treatment of Crohn's disease, either for induction or for maintenance of remission. [2] Current guidelines do not advise the use of 5-ASA compounds in Crohn's disease. [3]

Corticosteroids

Steroid enemas can be used for treatment of rectal disease symptoms. Cortifoam.jpg
Steroid enemas can be used for treatment of rectal disease symptoms.

Corticosteroids are a class of anti-inflammatory drugs used to treat moderate to severe flares of Crohn's disease. However, they are used sparingly because they can cause serious side effects, [4] including Cushing's syndrome, mania, insomnia, hypertension, high blood glucose, osteoporosis, and avascular necrosis of long bones. Corticosteroids should not be confused with the anabolic steroids used to enhance athletic performance.

The most commonly prescribed oral steroid is prednisone, which is typically dosed at 0.5 mg/kg for induction of remission in Crohn's disease. [5] Intravenous steroids, administered in a hospital setting, are used when oral steroids do not work or cannot be taken. [4] Because corticosteroids reduce the body's ability to fight infection, care must be taken to ensure that there is no active infection, particularly an intra-abdominal abscess, before the initiation of steroids.[ citation needed ]

Another oral corticosteroid, budesonide (trade name Entocort), has limited absorption and a high level of first-pass metabolism, meaning that lower quantities of the drug enter the bloodstream. It has been shown to be useful in the treatment of mild to moderate Crohn's disease, [6] and in maintaining remission. [7] It is also effective when used in combination with antibiotics to treat active Crohn's disease. [8] Budesonide is released in the ileum and right colon, and therefore has a topical effect against disease in that area. [6]

Steroid enemas can also be used to treat symptoms in the lower colon and rectum. Hydrocortisone and budesonide liquid and foam enemas are marketed for this purpose.[ citation needed ]

Mercaptopurine immunosuppressing drugs

Azathioprine, shown here in tablet form, is a first line steroid-sparing immunosuppressant. Imuran 2.JPG
Azathioprine, shown here in tablet form, is a first line steroid-sparing immunosuppressant.

Azathioprine and 6-mercaptopurine (6-MP) are the most commonly used immunosuppressants for maintenance therapy of Crohn's disease. They are purine anti-metabolites, meaning that they interfere with the synthesis of purines required for inflammatory cells. They have a duration of action of months (slow-acting). [9] Both drugs are dosed at 1.5 to 2.5 mg/kg, with literature supporting the use of higher doses. [10]

A Cochrane systematic review that included 13 randomized controlled trials, concluded that azathioprine and 6-mercaptopurine are not effective for inducing remission when a person has Crohn's disease. [9]

Azathioprine and 6-MP may be useful for the following indications:

Azathioprine treatment may lead to rare but life-threatening side effects. The rare side effects include leukopenia or pancreatitis. [9] There may also be an increased risk of lymphoma that is associated with azathioprine or 6-mercaptopurine treatment. [9]

Azathioprine is listed by the United States FDA as a human carcinogen. [13] However, it confers considerably less morbidity and mortality than corticosteroids.[ citation needed ]

Biologic therapies

Infliximab

Infliximab (trade name Remicade, among others) is a mouse-human chimeric antibody that targets tumor necrosis factor alpha (TNFα), a cytokine in the inflammatory response. It is a monoclonal antibody that inhibits the pro-inflammatory cytokine TNFα. It is administered intravenously and dosed per weight starting at 5 mg/kg and increasing according to character of disease.[ citation needed ]

Infliximab has found utility as follows:

Side effects of infliximab, like other immunosuppressants of the TNF class, can be serious and potentially fatal, and infliximab carries an FDA black-box warning on the label. Listed side effects include hypersensitivity and allergic reactions, risk of re-activation of tuberculosis, serum sickness, and risk of multiple sclerosis. [16] Serious side effect also include lymphoma and severe infections. [17]

Adalimumab

Adalimumab, like infliximab, is an antibody that targets tumor necrosis factor. [18] It has been shown to reduce the signs and symptoms of, and is approved for treatment of, moderate to severe Crohn's disease in adults who have not responded well to conventional treatments and who have lost response to or are unable to tolerate infliximab. [19]

Adalimumab also has a number of serious, potentially fatal, safety concerns characteristic of the anti-TNFα drugs. It, too, has a black-box warning on its FDA label. Listed potential side effects include serious and sometimes fatal blood disorders; serious infections including tuberculosis and infections caused by viruses, fungi, or bacteria; rare reports of lymphoma and solid tissue cancers; rare reports of serious liver injury; and rare reports of demyelinating central nervous system disorders; and rare reports of cardiac failure.[ citation needed ]

Natalizumab

Natalizumab is an anti-integrin monoclonal antibody that has shown utility as induction and maintenance treatment for moderate to severe Crohn's disease. [20] Natalizumab may be appropriate in patients who do not respond to medications that block tumor necrosis factor-alpha, such as infliximab. [21]

In January 2008, the FDA approved natalizumab for both induction of remission and maintenance of remission for moderate to severe Crohn's disease. [22]

A total of 3 large randomized controlled trials have demonstrated that natalizumab is effective in increasing rates of remission [23] and maintaining symptom-free status [24] in patients with Crohn's disease.

Natalizumab has also been linked to PML (though only when used in combination with interferon beta-1a). [25] [26] The label also recommends monitoring of liver enzymes due to concerns over possible damage or failure. [27]

Also associated with a rare but serious risk of multifocal leukoencephalopathy (brain infection leading to death or severe disability). Therefore, a specific program exists in which prescribers must be enrolled, CD-TOUCH (Crohn's Disease-Tysabri Outreach Unified Commitment to Health) Prescribing Program.[ citation needed ]

Ustekinumab

Ustekinumab (CNTO 1275) is a monoclonal antibody that suppresses cytokines IL-12 and IL-23. Originally designed to treat psoriasis, ustekinumab was approved by the FDA for the treatment of Crohn's disease in 2016. [28] Evidence from four quality randomized control trials suggest that ustekinumab is effective for induction of clinical remission and clinical improvement in patients with moderate to severe Crohn's disease. [29] Based on these studies, ustekinumab appears to be safe, but the implications of longer-term drug administration needs to be studied.

Vedolizumab

Vedolizumab is a gut-selective, Alpha-4 Beta-7 anti-integrin, monoclonal antibody that was approved by the U.S. Food and Drug Administration (FDA) to treat Crohn's disease in 2014. It is indicated for management of moderate-to-severe, active Crohn's disease patients and it works by inhibiting the trafficking of pro-inflammatory immune cells to the site of inflammation. Evidence from three randomized control trials, including an international, multi-center, randomized, parallel-group, double-blind clinical trial, GEMINI 2 (NCT00783692), demonstrated that Vedolizumab is effective for induction and maintenance of remission in patients with active Crohn's disease.

Surgery

Resected ileum for Crohn's disease ResectedIleum.jpg
Resected ileum for Crohn's disease

Surgery is normally reserved for complications of Crohn's disease or when disease that resists treatment with drugs is confined to one location that can be removed. [30] Surgery is often used to manage complications of Crohn's disease, including fistulae, small bowel obstruction, colon cancer, small intestine cancer and fibrostenotic strictures, when strictureplasty (expansion of the stricture) is sometimes performed. Otherwise, and for other complications, resection and anastomosis – the removal of the affected section of intestine and the rejoining of the healthy sections – is the surgery usually performed for Crohn's disease (e.g., ileocolonic resection). None of these surgeries cure or eliminate Crohn's disease, as the disease eventually comes back in healthy segments of the intestine, although when Crohn's disease recurs after surgery, it usually comes back at the site of the surgery. [31]

Small intestine transplants are becoming less experimental, but are still mainly performed in response to short bowel syndrome due to a high rate of transplant rejection. [32]

Diet and lifestyle

Many diets have been proposed for the management of Crohn's disease, and many do improve symptoms, but none have been proven to cure the disease. [33] The specific carbohydrate diet usually requires adjustments by patients; if a patient finds that certain foods increase or decrease symptoms, they may adjust their diet accordingly. A food diary is recommended to see what positive or negative effects particular foods have. A low residue diet may be used to reduce the volume of stools excreted daily. People with lactose intolerance due to small bowel disease may benefit from avoiding lactose-containing foods. Patients who cannot eat may be given total parenteral nutrition (TPN), a source of vitamins and nutrients.

Fish oil may be effective in reducing the chance of relapse in less severe cases. [34]

Because the terminal ileum is the most common site of involvement and is the site for vitamin B12 absorption, people with Crohn's disease are at risk for B12 deficiency and may need supplementation. In cases with extensive small intestine involvement, the fat-soluble vitamins A, D, E and K may be deficient. Folate deficiency is a risk for patients treated with methotrexate who do not simultaneously receive folate supplementation.

Stress can influence the course of Crohn's disease. Smoking has also been associated with the disease, and smokers with Crohn's are encouraged to explore smoking cessation programs. Smoking can not only make Crohn's disease worse in people who do it, but also increase the risk of recurrence after surgery. If a Crohn's disease patient who undergoes surgery does not quit smoking, the disease is likely to recur more aggressively.

Microbiome Modification

The use of oral probiotic supplements to modify the composition and behaviour of the gastrointestinal microbiome has been researched recently to understand whether it may help to improve remission rate in people with Crohn's disease. However only 2 controlled trials were available in 2020, with no clear overall evidence of higher remission nor lower adverse effects, in people with Crohn's disease receiving probiotic supplementation. [35]

Helminthic therapy

In an experimental idea called helminthic therapy, moderate hookworm infections have been demonstrated to have beneficial effects on hosts who have diseases linked to overactive immune systems. This may be explained by the hygiene hypothesis. [36] Hookworm therapy is currently in the trial stage at the University of Nottingham. Due to the unconventional nature of this therapy, it is not widely used.

Alternative medicine

More than half of people with Crohn's disease have tried complementary or alternative therapy. [37] These include diets, probiotics, fish oil and other herbal and nutritional supplements. The benefit, if any, and risks of these therapies is uncertain.

Acupuncture

Acupuncture is used to treat inflammatory bowel disease in China, and is being used more frequently in Western society. [38] Evidence has been put forth suggesting that acupuncture can have benefits beyond the placebo effect, improving quality of life, general well-being and a small decrease in blood-bound inflammatory markers. [38] This study however had a very small test set and did not reach the threshold for benefit.

Herbal

Other medications

Non-steroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen and naproxen, can cause flares of inflammatory bowel disease in approximately 25% of patients. [46] These flares tend to occur within one week after starting regular use of the NSAID. In contrast, acetaminophen (paracetamol) and aspirin appear to be safe. [46] Celecoxib (Celebrex), a cox-2 inhibitor, also appears to be safe, at least in short-term studies of patients in remission and on medication for their Crohn's disease. [46]

Research

Egg of Trichuris spp. whipworm. Trichuris suis or pig whipworm has been investigated for treatment of Crohn's disease. Trichuris trichiura egg (01).tif
Egg of Trichuris spp. whipworm. Trichuris suis or pig whipworm has been investigated for treatment of Crohn's disease.

Many clinical trials have been recently completed or are ongoing for new therapies for Crohn's disease. They include the following:

See also

Related Research Articles

<span class="mw-page-title-main">Crohn's disease</span> Type of inflammatory bowel disease

Crohn's disease is a type of inflammatory bowel disease (IBD) that may affect any segment of the gastrointestinal tract. Symptoms often include abdominal pain, diarrhea, fever, abdominal distension, and weight loss. Complications outside of the gastrointestinal tract may include anemia, skin rashes, arthritis, inflammation of the eye, and fatigue. The skin rashes may be due to infections as well as pyoderma gangrenosum or erythema nodosum. Bowel obstruction may occur as a complication of chronic inflammation, and those with the disease are at greater risk of colon cancer and small bowel cancer.

<span class="mw-page-title-main">Ulcerative colitis</span> Inflammatory bowel disease that causes ulcers in the colon

Ulcerative colitis (UC) is one of the two types of inflammatory bowel disease (IBD), with the other type being Crohn's disease. It is a long-term condition that results in inflammation and ulcers of the colon and rectum. The primary symptoms of active disease are abdominal pain and diarrhea mixed with blood (hematochezia). Weight loss, fever, and anemia may also occur. Often, symptoms come on slowly and can range from mild to severe. Symptoms typically occur intermittently with periods of no symptoms between flares. Complications may include abnormal dilation of the colon (megacolon), inflammation of the eye, joints, or liver, and colon cancer.

<span class="mw-page-title-main">Immunosuppressive drug</span> Drug that inhibits activity of immune system

Immunosuppressive drugs, also known as immunosuppressive agents, immunosuppressants and antirejection medications, are drugs that inhibit or prevent the activity of the immune system.

<span class="mw-page-title-main">Infliximab</span> Biopharmaceutical drug for autommune disorders

Infliximab, a chimeric monoclonal antibody, sold under the brand name Remicade among others, is a medication used to treat a number of autoimmune diseases. This includes Crohn's disease, ulcerative colitis, rheumatoid arthritis, ankylosing spondylitis, psoriasis, psoriatic arthritis, and Behçet's disease. It is given by slow injection into a vein, typically at six- to eight-week intervals.

<span class="mw-page-title-main">Azathioprine</span> Immunosuppressive medication

Azathioprine, sold under the brand name Imuran, among others, is an immunosuppressive medication. It is used for the treatment of rheumatoid arthritis, granulomatosis with polyangiitis, Crohn's disease, ulcerative colitis, and systemic lupus erythematosus; and in kidney transplants to prevent rejection. It is listed by the International Agency for Research on Cancer as a group 1 human carcinogen. It is taken by mouth or injected into a vein.

<span class="mw-page-title-main">Enteritis</span> Intestinal inflammatory disease

Enteritis is inflammation of the small intestine. It is most commonly caused by food or drink contaminated with pathogenic microbes, such as Serratia, but may have other causes such as NSAIDs, radiation therapy as well as autoimmune conditions like coeliac disease. Symptoms include abdominal pain, cramping, diarrhoea, dehydration, and fever. Related diseases of the gastrointestinal system involve inflammation of the stomach and large intestine.

<span class="mw-page-title-main">Inflammatory bowel disease</span> Medical condition

Inflammatory bowel disease (IBD) is a group of inflammatory conditions of the colon and small intestine, with Crohn's disease and ulcerative colitis (UC) being the principal types. Crohn's disease affects the small intestine and large intestine, as well as the mouth, esophagus, stomach and the anus, whereas UC primarily affects the colon and the rectum.

<span class="mw-page-title-main">Colitis</span> Inflammation of the colon (large intestine)

Colitis is swelling or inflammation of the large intestine (colon). Colitis may be acute and self-limited or long-term. It broadly fits into the category of digestive diseases.

<span class="mw-page-title-main">Natalizumab</span> Medication used to treat multiple sclerosis and Crohns disease

Natalizumab, sold under the brand name Tysabri among others, is a medication used to treat multiple sclerosis and Crohn's disease. It is a humanized monoclonal antibody against the cell adhesion molecule α4-integrin. It is given by intravenous infusion. The drug is believed to work by reducing the ability of inflammatory immune cells to attach to and pass through the cell layers lining the intestines and blood–brain barrier.

A TNF inhibitor is a pharmaceutical drug that suppresses the physiologic response to tumor necrosis factor (TNF), which is part of the inflammatory response. TNF is involved in autoimmune and immune-mediated disorders such as rheumatoid arthritis, ankylosing spondylitis, inflammatory bowel disease, psoriasis, hidradenitis suppurativa and refractory asthma, so TNF inhibitors may be used in their treatment. The important side effects of TNF inhibitors include lymphomas, infections, congestive heart failure, demyelinating disease, a lupus-like syndrome, induction of auto-antibodies, injection site reactions, and systemic side effects.

Management of ulcerative colitis involves first treating the acute symptoms of the disease, then maintaining remission. Ulcerative colitis is a form of colitis, a disease of the intestine, specifically the large intestine or colon, that includes characteristic ulcers, or open sores, in the colon. The main symptom of active disease is usually diarrhea mixed with blood, of gradual onset which often leads to anaemia. Ulcerative colitis is, however, a systemic disease that affects many parts of the body outside the intestine.

<span class="mw-page-title-main">Certolizumab pegol</span> Pharmaceutical drug

Certolizumab pegol, sold under the brand name Cimzia, is a biopharmaceutical medication for the treatment of Crohn's disease, rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis. It is a fragment of a monoclonal antibody specific to tumor necrosis factor alpha (TNF-α) and is manufactured by UCB.

<span class="mw-page-title-main">Biological therapy for inflammatory bowel disease</span>

Biological therapy, the use of medications called biopharmaceuticals or biologics that are tailored to specifically target an immune or genetic mediator of disease, plays a major role in the treatment of inflammatory bowel disease. Even for diseases of unknown cause, molecules that are involved in the disease process have been identified, and can be targeted for biological therapy. Many of these molecules, which are mainly cytokines, are directly involved in the immune system. Biological therapy has found a niche in the management of cancer, autoimmune diseases, and diseases of unknown cause that result in symptoms due to immune related mechanisms.

The Crohn's Disease Activity Index or CDAI is a research tool used to quantify the symptoms of patients with Crohn's disease. This is of useful importance in research studies done on medications used to treat Crohn's disease; most major studies on newer medications use the CDAI in order to define response or remission of disease. As Crohn's disease is a disease with a variety of symptoms that affect quality of life, the quantification of symptoms may be of secondary importance to a quantitative assessment of the effect on quality of life. This has been addressed by the Inflammatory Bowel Disease Questionnaire (IBDQ) and other indices of quality of life for patients with Crohn's disease.

Vedolizumab, sold under the brand name Entyvio, is a monoclonal antibody medication developed by Millennium Pharmaceuticals, Inc. for the treatment of ulcerative colitis and Crohn's disease. It binds to integrin α4β7, blocking the α4β7 integrin results in gut-selective anti-inflammatory activity.

<span class="mw-page-title-main">Budesonide</span> Type of corticosteroid medication

Budesonide, sold under the brand name Pulmicort, among others, is a steroid medication. It is available as an inhaler, nebulization solution, pill, nasal spray, and rectal forms. The inhaled form is used in the long-term management of asthma and chronic obstructive pulmonary disease (COPD). The nasal spray is used for allergic rhinitis and nasal polyps. Modified-release pills or capsules and rectal forms may be used for inflammatory bowel disease including Crohn's disease, ulcerative colitis, and microscopic colitis.

<span class="mw-page-title-main">Enteropathic arthropathy</span> Medical condition

Enteropathic arthropathy commonly referred to as enteropathic arthritis, is a type of arthritis linked to Crohn's disease, ulcerative colitis, and chronic inflammatory bowel diseases.

<span class="mw-page-title-main">Alicaforsen</span> Chemical compound

Alicaforsen is an antisense oligonucleotide therapeutic that targets the messenger RNA for the production of human ICAM-1 receptor and is being developed for the treatment of acute disease flares in moderate to severe Inflammatory Bowel Disease (IBD).

Darvadstrocel, sold under the brand name Alofisel, is a medication used to treat complex perianal fistulas in adults with non-active/mildly active luminal Crohn's disease when fistulas have shown an inadequate response to at least one conventional or biologic therapy. It contains mesenchymal stem cells from fat tissue of adult donors.

Shomron Ben-Horin is an Israeli physician, a co-founder & Chief Medical Officer of Evinature, and professor of medicine at the Tel-Aviv University.

References

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