Ibd treatment options: Medication Options for Crohn’s Disease

11.06.197814.11.2021 by alexxlab

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Medication Options for Crohn’s Disease

Successful medical treatment allows your intestinal tissue to heal and it helps relieve symptoms such as fever, diarrhea, and abdominal pain.

There are several groups of drugs used to treat Crohn’s disease. Some of these options are used to get your symptoms under control, which is known as inducing remission. Medical therapy, also called maintaining remission or maintenance, is used to decrease the frequency of Crohn’s flares.

You and your health care provider are partners in your health. This list of common Crohn’s medications can help you begin an informed discussion with your doctor.

Aminosalicylates (5-ASA)

These include medications that contain 5-aminosalicylic acid (5-ASA). These drugs are not specifically approved by the Food and Drug Administration (FDA) for use in Crohn’s, yet they can work to decrease inflammation in the lining of the GI tract.

Aminosalicylates are thought to be effective in treating mild-to-moderate episodes of Crohn’s disease and useful as a maintenance treatment in preventing relapses of the disease. They work best in the colon and are not particularly effective if the disease is limited to the small intestine.

Examples

Sulfasalazine
Mesalamine
Olsalazine
Balsalazide

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00:01:04

Aminosalicylates
Aminosalicylates are compounds that contain 5-aminosalicylic acid (5-ASA) and reduce inflammation in the lining of the intestine. Watch this video to learn more!

Corticosteroids

Corticosteroids suppress the immune system and are used to treat moderate to severely active Crohn’s disease. These drugs work non-specifically, meaning that they suppress the entire immune response, rather than targeting specific parts of the immune system that cause inflammation.

Corticosteroids have significant short- and long-term side effects and should not be used as a maintenance medication. If you cannot come off steroids without suffering a relapse of your symptoms, your doctor may need to prescribe other medications to help manage your disease.

Examples

These medications are available orally and rectally.

Prednisone
Methylprednisolone

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00:01:13

Corticosteroids for IBD
Corticosteroids are powerful and fast-acting anti-inflammatory drugs that have been frequently used in the treatment of acute flare-ups of IBD. Watch this video to learn more.

Immunomodulators

This class of medications modulates or suppresses the body’s immune system response so it cannot cause ongoing inflammation. Immunomodulators, which may take several months to begin working, are generally are used when aminosalicylates and corticosteroids haven’t been effective, or have been only partially effective.

These medications may be useful in reducing or eliminating the need for corticosteroids, and in maintaining remission in people who haven’t responded to other medications given for this purpose.

Examples

Azathioprine
6-mercaptopurine
Cyclosporine
Tacrolimus

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Immunomodulators for IBD
Immunomodulators weaken or modulate the activity of the immune system. And are medications often used to treat people with IBD. Watch this video to learn more.

Antibiotics

Antibiotics may be to treat bacterial infections in the GI tract. Infections in Crohn’s disease can include abscesses and fistulas around the anal canal and vagina.

Examples

Metronidazole
Ampicillin
Ciprofloxacin

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00:01:21

Antibiotics for IBD
Antibiotics are frequently used as a primary treatment approach primarily in Crohn’s disease and with particular complications in IBD. Watch this video to learn more.

Biologic/Biosimilar Therapies

These medications are the latest class of therapy for people with Crohn’s disease who have not responded well to conventional therapy. Biologics are antibodies grown in the laboratory that stop certain proteins in the body from causing inflammation.

Examples

Adalimumab
Certolizumab pegol
Infliximab
Natalizumab
Ustekinumab
Vedolizumab

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Biologics for IBD
Biologics are antibodies grown in the laboratory that stop specific proteins in the body from causing inflammation. Their mechanisms of action are more precisely targeted to the factors responsible for IBD.

Biosimilars are nearly identical copies of other already approved biologic therapies. They have the same effectiveness and safety as the originally approved biological therapy, in the target patient population. Learn about recently approved biosimilars.

Examples

Infliximab-abda
Infliximab-dyyb
Infliximab-qbtx
Adalimumab-fkjp
Adalimumab-bwwd
Adalimumab-afzb

Have you been affected by step therapy? Step therapy is a health insurance practice that may require you to try and fail on a medication before providing coverage for your originally prescribed treatment. Learn more about step therapy and what you can do to advocate for your health.

Surgery for Crohn’s Disease | Crohn’s & Colitis Foundation

Crohn’s Disease Complications Requiring Surgery

Medication alone may not adequately control symptoms for everyone with Crohn’s disease. Complications can develop that need more aggressive treatment, including surgery. Seek immediate medical attention if you believe you may have one or more of these complications.

Intestinal obstruction or blockage

Chronic inflammation in the intestines can cause the walls of your digestive organs to thicken or form scar tissue. This can narrow a section of intestine, called a stricture, which may lead to an intestinal blockage. Symptoms of a blockage include crampy abdominal pain, inability to have a bowel movement or pass gas, nausea and vomiting, and constipation.

Excessive bleeding in the intestine

This is a rare complication of Crohn’s disease. Surgery is performed only if the bleeding cannot be controlled with other treatments.

Perforation of the bowel

Chronic inflammation may weaken the wall of the intestine and cause a hole called a perforation. This can also happen if a portion of the bowel expands and weakens near a stricture. Once the intestinal wall has been perforated, the contents of the intestine can spill into the abdomen and cause a serious infection called peritonitis.

Fistula

Inflammation can cause sores, or ulcers, to form in the inside wall of the intestines or other organs. Sometimes, these ulcers can extend through the entire thickness of the bowel wall and form a connection or tunnel, called a fistula. Fistulas often occur between two parts of the intestine, between the intestine and another organ such as the bladder or vagina, or break through to the skin surface.

Fistulas can also form around the anal area, which may cause drainage of mucus or stool from an area adjacent to the anus.

Abscess

An abscess, or a collection of pus, can develop in the abdomen, pelvis, or around the anal area. Symptoms include severe pain in the abdomen, fever, painful bowel movements, discharge of pus from the anus, or a lump at the edge of the anus that is swollen, red, and tender. An abscess requires both antibiotics and surgical drainage of the pus cavity.

Toxic megacolon

Severe inflammation in the colon can lead to toxic megacolon. Symptoms include pain, distention/swelling of the abdomen, fever, rapid heart rate, constipation, and dehydration. This is a potentially life-threatening complication that requires immediate treatment and surgery.

Elective Crohn’s Surgery

Doctors and patients will often consider surgery if a person’s quality of life has been severely impacted despite medical treatment, or if they experience significant side effects from their medication.

Some people find they are no longer responding to their medication. Others decide they are no longer able to cope with severe side effects from their medication.

Colorectal cancer

Patients with Crohn’s disease and ulcerative colitis have a higher risk for colorectal cancer (CRC) than the general population, so elective surgery may be recommended to eliminate that risk.

Colorectal cancer risk factors

The risk of CRC increases after living with IBD for 8 to 10 years
The risk increases the longer a person lives with IBD
The greatest risk is for people with IBD affecting their colon

In most cases, colorectal cancer begins as a polyp, or a small lump growing from the wall of the intestine. Polyps typically start out benign, or not cancerous, but become cancerous over time. In patients with IBD, abnormal and potentially precancerous tissue, called dysplasia, may lay flat against the wall of the intestine and can even be found in areas of the intestinal wall that appear normal during a colonoscopy.

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00:03:00

Minimizing your Colorectal Cancer Risk – How IBD patients can take control
IBD patients can minimize their colorectal cancer risk. Listen to learn more!

Colorectal Cancer Screening

If you’ve had IBD symptoms for 8 to 10 years or longer, you should have surveillance colonoscopies every one to two years depending on your other risk factors, such as a family history of colorectal cancer.
A standard colonoscopy is usually accompanied by a series of biopsies, which are small tissue samples taken for microscopic examination.
If dysplasia is found, even if it’s not cancerous, surgery to remove the colon and rectum is usually recommended to eliminate the risk of developing cancer.

Choosing Your Healthcare Team

If you have been recommended for surgery, you and your doctor should consult with a colorectal surgeon who specializes in surgery of the gastrointestinal tract. Your regular gastroenterologist will continue to treat you before and after your surgery.

If surgery is elective, take time to research a surgeon and a hospital that fits your needs.
Your surgeon should be board certified in general surgery or colon and rectal surgery, and should have significant experience performing the surgical procedure that has been recommended for you. Ask your surgeon about his or her experience. Do not be afraid to seek a second or third opinion.
You can ask your your gastroenterologist or other healthcare provider to recommend surgeons. You can also use our resources to help find a specialist, or check with the American Society of Colon and Rectal Surgeons or the American College of Surgeons for more information.
Ask your surgeon for help in connecting with other people who have had the same procedure. You can also connect with other patients through the Foundation’s Power of Two program.
Talk with your surgeon and your other healthcare providers about what preparations you may need before surgery, what to expect after surgery, and any medical supplies you might need once you return home.
Check to see if your state health departments publish data about the outcomes of certain procedures at specific hospitals.

Thank you to Bonnie & Andrew Stern for supporting the development of educational images and resources on surgery options. Additional support is provided through the Crohn’s & Colitis Foundation’s annual giving program and donors.

Inflammatory Bowel Disease (IBD) Diagnosis and Treatment Options

Inflammatory bowel disease (IBD) is the overarching name for two chronic diseases which cause swelling of the intestines or the colon: Crohn’s disease and ulcerative colitis. Ulcerative colitis only affects the colon, but Crohn’s disease may affect any area of the gastrointestinal tract, most commonly the end of the small intestine (the ileum) and the colon.

What causes inflammatory bowel disease (IBD)?

Although there are a number of theories involving genetic and environmental factors, the cause of inflammatory bowel disease ultimately remains unknown.

Common genetic variations in over 100 genes have been identified as increasing the risk of IBD. Having a relative with IBD increases the risk several fold. People of Jewish ancestry have a greater risk of developing inflammatory bowel disease, although the disease occurs in all ethnic and racial groups.

Environmental risk factors include living in a Western industrialized country, particularly in urban and higher latitude environments, and for Crohn’s disease smoking and for ulcerative colitis not-smoking. Numerous other factors have been proposed including infectious triggers.

What are the symptoms of inflammatory bowel disease (IBD)?

Crohn’s disease and ulcerative colitis share many of the same symptoms, including:

Abscesses
Abdominal pain
Arthritis
Diarrhea
Eye inflammation
Fistulas
Incontinence
Rectal bleeding
Skin inflammation
Weight loss

How is inflammatory bowel disease treated?

Treatment options vary depending on the severity of each patient’s case. These treatments are designed to help control symptoms, reduce inflammation, and relieve abdominal pain, diarrhea, and rectal bleeding.

At the Johns Hopkins Inflammatory Bowel Disease Center, our team of gastroenterologists and gastric surgeons specialize in providing treatment for the simple to the most complex and complicated cases. Treatment for Crohn’s and ulcerative colitis may include:

Topical anti-inflammatory medications – These medications are usually very well tolerated, have minimal systemic risks, and are especially useful for mild-to-moderate cases of IBD.
Antibiotics – Certain antibiotics are helpful for mild-to-moderate Crohn’s disease cases, and for abscess and anal fistula treatment.
Immunomodulator and biological immunosuppressive medications – These medications are used to suppress the immune system’s attack on the intestine, and are recommended for moderate to severe cases.
Steroids – In combination with other anti-inflammatory drugs, steroids can greatly improve symptoms in patients, and are typically used for short-term treatment and to treat inflammation flareups.
Dietary changes – Occasionally, dietary therapy can have similar effects to drug therapy, but are often used in conjunction with medication.
Surgery – When medications no longer control symptoms, or an intestinal blockage occurs, surgery may be necessary. Often, surgical treatment involves the removal of the diseased portion of the bowel, but occasionally a complete removal of the colon or rectum is considered.

Request an Appointment

If you or a loved one suffers from inflammatory bowel disease, our specialists can help – request an appointment today.

Emerging treatments for inflammatory bowel disease

Ther Adv Chronic Dis. 2020; 11: 2040622319899297.

Karl Hazel

Department of Gastroenterology, Tallaght University Hospital, Belgard Road, Tallaght, Dublin D24NR0A, Ireland

Anthony O’Connor

Centre for Inflammatory Bowel Disease, Tallaght University Hospital, Dublin, Ireland University of Dublin, Trinity College, Dublin, Ireland

Karl Hazel, Department of Gastroenterology, Tallaght University Hospital, Belgard Road, Tallaght, Dublin D24NR0A, Ireland;

Received 2019 Feb 11; Accepted 2019 Dec 6.

This article has been cited by other articles in PMC.

Abstract

Inflammatory bowel disease (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC), is characterized by chronic inflammation, a relapsing and remitting clinical course, requirement for lifelong medication and often, significant morbidity. While multiple effective therapeutic options exist for the treatment of IBD, a proportion of patients will either fail to respond or lose response to therapy. Advances in therapeutics, such as the gut-specific anti-integrins, now offer patients an alternative option to systemic immunosuppression. Anti-interleukin 12 (anti-IL-12)/IL-23 agents offer new and effective treatment options for CD, while the oral small molecules now offer an oral alternative for the treatment of moderate-to-severe disease, previously requiring subcutaneous injection or intravenous infusion. Alternatives to pharmacological treatment such as stem-cell transplant and faecal microbiota transplant are also showing some promise in the treatment of both CD and UC.

Keywords: Crohn’s disease, inflammatory bowel disease, ulcerative colitis

Introduction

Inflammatory bowel disease (IBD) comprises two major disorders: Crohn’s disease (CD) and ulcerative colitis (UC). Both conditions are characterized by histologic chronic inflammation, periods of clinical relapse and remission, use of medication and risk of surgery, and impaired quality of life.

While a universal, validated definition of ‘remission’ is lacking for IBD, the concept of ‘deep remission’, encompassing clinical remission, biochemical remission and mucosal healing, has become established in the literature as the optimum therapeutic target for optimizing quality of life and preventing disease progression. It is to this standard that we must assess all new therapies.

Historically, the mainstay of treatment for UC has been aminosalicylates, with short courses of steroids for severe flares, and escalation to immunomodulators and anti-tumour necrosis factor alpha (anti-TNFα) inhibitors should remission not be maintained. Aminosalicylates appear ineffective in CD, where remission may be induced using enteric-coated budesonide in patients with distal ileal, ileocaecal or right-sided colonic disease, or prednisolone in patients with more severe or extensive disease. Should remission not be maintained, immunomodulators and anti-TNFα inhibitors may be used either in combination or as monotherapy with clinical factors used to predict those who may benefit from a ‘top-down’ approach with early aggressive therapy.

In spite of the tremendous advances made in recent years in IBD therapeutics, approximately 30% of patients are primarily unresponsive to anti-TNFα and even among responders, up to 10% will lose their response to the drug every year. In addition, current IBD medications are associated with significant infectious and neoplastic side effects. It is therefore clear that the development and implementation of highly effective drugs or drug combinations with favourable side-effect profiles for patients is an important, unmet need. The pathogenesis of IBD remains unclear but is thought to be multifactorial, including genetic and environmental components, and it is in understanding these factors and the inflammatory cascade they induce that therapeutic targets emerge and progress will be made (). This review examines a number of newly approved and upcoming therapeutic options for IBD, including newer anti-TNFα agents, S1P-receptor modulators, antiadhesion agents, IL-12/IL-23 inhibitors, transforming growth-factor beta (TGFβ) inhibitors, Janus kinase (JAK)/STAT inhibitors, stem-cell transplant and faecal microbiota transplant (FMT), all of which shall be discussed below.

The inflammatory cascade in inflammatory bowel disease.¹

IFNγ, interferon gamma; IL, interleukin; Th, T-helper cell; TLR, toll-like receptor; TNF, tumour necrosis factor.

New anti-TNFs

AVX-470

AVX-470 is an orally administered polyclonal immunoglobulin purified from the colostrum of cows immunized with recombinant human TNF. These large molecules are poorly absorbed from the gastrointestinal tract into the systemic circulation and are therefore suitable for oral delivery. Estimated concentrations of TNF-specific antibodies are shown to be 1000-fold less than levels seen in systemic anti-TNF agents and therefore, the risks of systemic immunosuppression and complications of this are lower. In the study by Harris and colleagues, the greatest effects of AVX-470 were seen in the 3.5 g/day dosing group, with a greater percentage of patients achieving clinical response and both clinical and endoscopic remission when compared with placebo at week 4.² While further trials are required, AVX-470 may offer an alternative to both subcutaneous and intravenous infusions of traditional anti-TNFs in UC, with lower immunogenicity and systemic side effects.

Anti-adhesion biologics

The first anti-adhesion biologic to establish an evidence base in IBD was natalizumab, which causes nonspecific inhibition of both α4β7- and α4β1-integrins, and was used as second-line or rescue therapy for the treatment of IBD, mainly in North America. However, there is a substantial risk of developing progressive multifocal leukoencephalopathy (PML), a devastating and fatal neurological disorder, caused by the reactivation of the JC virus. Studies of natalizumab use in multiple sclerosis showed a PML incidence of 1 per 1000.³ Because of this, gut-specific anti-integrin therapy is favoured.

α4β7-integrin is an adhesion molecule expressed on the surface of gut-specific lymphocytes and is a target for the drug vedolizumab, discussed below. They bind to mucosal vascular addressin cell adhesion molecule 1 (MAdCAM-1), which exists on intestinal vasculature and mediates leukocyte trafficking to the gut.⁴ Like vedolizumab, etrolizumab selectively binds the β7 subunit of α4β7, but also αεβ7 integrin heterodimers. This gives a double-headed treatment approach, antagonizing the egress of lymphocytes by blocking the interaction between α4β7 and MAdCAM-1 at the vascular level, and also blocking the interaction between αεβ7 and E-cadherin, potentially avoiding the retention of αεβ7+ cells in the intraepithelial compartment.⁵ The concomitant blockade of αεβ7-E-cadherin avoids the adhesion of intraepithelial T cells to the epithelial cells.⁶ Around 1–2% of circulating lymphocytes express αεβ7, while it is present in over 90% of intraepithelial lymphocytes and intestinal dendritic cells.^7,8 Etrolizumab may block immunological pathways that trigger and maintain chronic inflammation directly at the mucosal level, with no systemic effects.⁹

A systematic review and meta-analysis by Luthra and coworkers showed that there is no significant increase in either the rate of opportunistic infection or malignancies with non-gut-specific (natalizumab) or gut-specific anti-integrin antibodies (vedolizumab, etrolizumab) compared with placebo.¹⁰

Vedolizumab

Vedolizumab is an anti-α4β7-integrin monoclonal antibody approved for use in both UC and CD.¹¹ The GEMINI 1 trial provided significant safety and efficacy data for the use of vedolizumab in UC.¹² The results of this study showed superiority of vedolizumab versus placebo in all primary and secondary outcomes. A subsequent Cochrane meta-analysis showed that vedolizumab is superior to placebo in UC for achieving clinical response, clinical remission and endoscopic remission.¹³ The 2015 Toronto consensus guidelines for nonhospitalized UC recommend the use of vedolizumab in patients with moderate-to-severe UC who have failed corticosteroid, immunomodulator or anti-TNF therapy,¹⁴ while the European Crohn’s and Colitis organization guidelines recommend vedolizumab as either first-line therapy to induce remission or after anti-TNF failure.¹⁵

The GEMINI 2 and 3 trials examined the use of vedolizumab in CD.^16,17 These studies showed less favourable outcomes with regard to clinical remission at 6 weeks when compared with the UC cohort. No mucosal healing data were collected in GEMINI 3. It was proposed that the mechanism of action of vedolizumab may require a longer duration of treatment in CD when compared with UC in order to induce and maintain remission. At 10 weeks, vedolizumab is superior to placebo in inducing remission.¹⁷ GEMINI 2 showed superiority of vedolizumab to placebo in achieving both clinical- and steroid-free remission at 52 weeks. A further meta-analysis showed that vedolizumab is superior to placebo for inducing and maintaining clinical remission in Crohn’s but inferior to adalimumab in maintaining remission.¹⁸ Several retrospective cohorts, however, with long duration of follow up, including those by Shelton, Baumgart and Amiot, have shown that vedolizumab is effective at inducing and maintaining remission at week 14, both in anti-TNFα-naïve and -treated patients.

Vedolizumab appears to have a favourable safety profile. The most common adverse events, all occurring ⩽ 6% are: headache, nasopharyngitis, nausea, arthralgia, upper respiratory tract infection and fatigue.¹⁹ Among all participants of the GEMINI 1, 2 and 3 trials, no cases of PML were observed. Vedolizumab should be considered as primary therapy in those patients with infection-related concerns, most notably, the elderly IBD cohort.²⁰ There has been conflicting evidence surrounding the perioperative use of vedolizumab and the risk of postoperative infections following intestinal surgery. Lightner and coworkers have shown that 26% of CD patients who received vedolizumab within 12 weeks prior to major abdominal surgery experienced a 30-day postoperative surgical site infection; significantly higher than those receiving neither anti-TNFα or biologic therapy.²¹ A recent study showed that the use of vedolizumab in patients undergoing non-intestinal surgery conferred no increased risk of postoperative infections, readmission or reoperation when compared with control, and therefore, no washout period is required.²² There is an increased risk for gastroenteritis when compared with placebo with vedolizumab therapy, but serious Clostridium difficile infections occur at a rate ⩽ 0.6%.²³ Although drug and anti-drug antibody levels are not yet commercially available for vedolizumab, the GEMINI trials showed a positive correlation between vedolizumab levels and clinical efficacy. Anti-vedolizumab antibodies, are present in 1–4.1% of patients, with no patients having consistently positive results in GEMINI 3.

Data presented at UEGW 2018 from the VISIBLE1 trial showed that subcutaneous vedolizumab, 108 mg administered every 2 weeks, was safe, efficacious and well tolerated as maintenance therapy in UC patients following induction with intravenous (IV) vedolizumab 300 mg. It showed a safety and efficacy profile similar to that of IV vedolizumab. Subcutaneous vedolizumab was significantly superior to placebo in mucosal healing and durable clinical response. Clinical remission was significantly higher in both anti-TNFα-inhibitor-naïve and -failure patients.²⁴

Etrolizumab

Etrolizumab represents the next generation of anti-adhesion molecules.²⁵ Phase I and II trials have been conducted on the safety and efficacy of etrolizumab in UC.^26,27 Etrolizumab may offer an alternative, not only to anti-TNFs, but also vedolizumab in the treatment of UC due to its different mechanism of action, giving an additional blockade and layer in the control of intestinal inflammation when compared with vedolizumab.

Data from phase I and II trials show that etrolizumab is superior to placebo in inducing both clinical remission and endoscopic healing at week 10. Patients taking steroids, not taking immunomodulators and who were anti-TNF naïve, were more likely to reach clinical remission at week 10. There was a greater reduction in those achieving remission at week 10 in addition to a significant increase in the expression of E-cadherin. There was no decrease in aE+ cells in the lamina propria, showing the high selectivity of the molecule at the mucosal level.⁸

Serious adverse events were reported as 12% overall between etrolizumab and placebo.²⁸ Higher rates of influenza-like illness, arthralgia and rash were observed in those receiving etrolizumab 100 mg when compared with the 300 mg or placebo cohorts. The severity of all events was deemed to be mild or moderate.^7,8 There was no association between antibody formation and pharmacokinetic parameters of the drug.⁷

The phase III BERGAMOT induction trial examined the use of etrolizumab in patients with moderate-to-severe CD who were refractory or intolerant to anti-TNF agents, immunosuppressants or corticosteroids. Patients were assigned 2:2:1 to the 105 mg subcutaneous 4-weekly, 210 mg at week 0, 2, 4, 8 and 12 or placebo groups during a 14-week induction period. Endpoints included clinical remission defined as a Crohn’s Disease Activity Index (CDAI) < 150, CDAI-100 and -70 responses, PRO2 remission, symptomatic remission and endoscopic improvement defined as >50% reduction from baseline Simple Endoscopic Score for Crohn’s Disease (SES-CD) at week 14. A sum of 300 patients were included in the trial, with 73% being anti-TNF exposed. Symptomatic remission was observed in a greater proportion of patients receiving etrolizumab 105 mg and 210 mg compared with placebo at weeks 6, 10 and 14. More patients achieved endoscopic improvement with etrolizumab therapy when compared with placebo at week 14. CDAI remission was greater in the etrolizumab group at week 14 (23.3%, 28.9% and 16.9%, respectively). Enrolment into induction cohorts and maintenance phase is ongoing.²⁹

While phase III trials are ongoing, etrolizumab is emerging as a potential therapeutic agent in the treatment of UC and CD. It offers an alternative to anti-TNF therapy in those who have shown primary nonresponse, secondary loss of response or those not suitable for anti-TNF therapy, as mentioned above. It may also offer an alternative to vedolizumab.

Abrilumab

Abrilumab is a monoclonal antibody that selectively blocks α4β7 and can be administered subcutaneously, with high bioavailability and a long half-life.^30,31 A recently published randomized, phase IIb study showed that treatment with abrilumab significantly improved 8-week remission rates (13.5%) when compared with placebo (4.4%) in patients with moderate-to-severe UC who had failed conventional therapies. Clinical response was seen in almost half of all patients and mucosal healing in one third of patients treated with a dose of either 70 mg or 210 mg, compared with 26% and 16.8% who received placebo, respectively.³² Induction of response, along with increases in clinical remission and mucosal healing at week 6, show similar results to that of vedolizumab in the GEMINI trials.¹¹ PML was not observed in trial patients.

PF-00547659

PF-00547659 is a subcutaneously administered monoclonal antibody that inhibits binding of α4β7-integrin to MAdCAM with high affinity and selectivity.³³ Two phase II, randomized, double-blind, placebo-controlled trials have been conducted on this agent. The TURANDOT trial examined safety and efficacy of PF-00547659 in moderate-to-severe UC.⁹ At 12 weeks of treatment, 23.6% in the treatment arm compared with 5.5% in the placebo arm were in endoscopic remission, with the highest rates of remission observed in anti-TNF-naïve patients. Although a limited, 12-week study, the safety profile seemed similar to placebo.⁹

The OPERA study looked at the clinical response to PF-00547659 in moderate-to-severe CD.³⁴ Response was measured using the CDAI score at 8 and 12 weeks. There was no statistically significant reduction in CDAI scores when compared with placebo, with 27% of the highest-dose group of PF-00547659 versus 48% of the placebo cohort exhibiting a response, rendering the trial a failure.

IL-12/IL-23 inhibitors

Interleukin 12 (IL-12) is produced by phagocytic and dendritic cells in response to microbial stimulation, driving cell-mediated immunity by inducing lymphokine-activated killer cells and activation of natural killer (NK) cells and T lymphocytes.³⁵ IL-12 is a key inducer of T-helper 1 (Th2) cells, promoting cell-mediated immunity to intracellular pathogens, delayed-type hypersensitivity and macrophage activation.³⁶ IL-23 is critical for Th27 differentiation,³⁷ which produce several pro-inflammatory cytokines, including IL-17A and F, TNFα, IL-22, IL-26 and interferon gamma.³⁸ By preventing IL-12 and IL-23 from binding to the IL-12Rβ1 receptor chain of IL-12 and IL-23 receptor complexes on the surface of NK and T cells, neutralizing IL-12 and IL-23-mediated responses, these drugs prevent IL-17 and IL-22 cytokine production.³⁹ Dysregulation of the Th2/Th27 pathways has been strongly linked to CD, rheumatoid arthritis, psoriasis and multiple sclerosis, all of which may be treated with selective interleukin inhibitors.

Ustekinumab

Ustekinumab is a monoclonal antibody to the p40 subunit of IL-12 and IL-23 that has been approved for the treatment of moderate-to-severe CD. Clinical efficacy and safety data were collected via the UNITI-1, UNITI-2 and IM-UNITI trials. All studies examined patients who had failed anti-TNF therapy or conventional therapies. Ustekinumab showed benefit over placebo, irrespective of previous exposure to anti-TNF.⁴⁰ In UNITI-1, the patient cohort had severe CD of long duration, were primary or secondary nonresponders or had adverse side effects to at least one anti-TNF agent. In UNITI-2, most patients were anti-TNF naïve. At week 8, 20.9% of patients in UNITI-1, receiving 6 mg/kg dosing were in remission when compared with placebo. UNITI-2 showed higher absolute rates of remission against placebo, attributable to the treatment naïve, and less severe nature of disease. Decline and normalization of C-reactive protein (CRP) and faecal calprotectin (FCP) levels were seen with ustekinumab therapy, both at week 8 and week 44. Among all three trials (UNITI-1, -2 and IM-UNITI), the rate of serious adverse event was 9.9%, 12.1% and 15%, respectively. Thirteen patients experienced serious infection.

The UNIFI trial examined the efficacy of ustekinumab as induction and maintenance therapy in patients with UC. The drug was evaluated as 8-week induction and 44-week maintenance therapy in moderate-to-severe UC. A total of 961 patients were randomized to receive an IV induction dose of 130 mg, a weight-based dose of 6 mg/kg, or placebo. Patients with response to induction therapy after 8 weeks of administration were randomized to receive 90 mg of ustekinumab either 8 weekly or 12 weekly. The primary endpoint in the induction and maintenance trials was clinical remission (total Mayo score < 2 and no subscore > 1 on any of the four Mayo scale components). The percentage of patients achieving clinical remission at week 8 who had received a dose of 130 mg (15.6%) or 6 mg/kg (15.5%) was significantly higher than those who received placebo (5.3%; p < 0.001 for both comparisons). The percentage of patients with clinical remission at week 44 was significantly higher among those assigned to 90 mg every 12 weeks (38.4%) or every 8 weeks (43.8%) than those assigned to placebo (24.0%; p = 0.002 and p < 0.001), respectively. The incidence of serious adverse events with ustekinumab therapy was similar to that with placebo. Ustekinumab was shown to be more effective than placebo for inducing and maintaining remission in patients with moderate-to-severe UC.⁴¹

Risankizumab

Risankizumab is a humanized monoclonal antibody to the p19 subunit of IL-23.⁴² Risankizumab offers a more selective downregulation than ustekinumab, not affecting IL-12-dependent T-cell pathways which are important for infection and cancer immunity.⁴³ A recent randomized, double-blind, placebo-controlled phase II study examined the efficacy of IV risankizumab for the induction of remission in moderate-to-severe CD, with a primary outcome of clinical remission (CDAI < 150) at week 12.⁴⁴ A total of 69% of patients had been exposed to at least two anti-TNFs, indicating a highly treatment-refractory population. At week 12, 31% of patients achieved clinical remission compared with 15% of the placebo group. A total of 20.99% of those treated with the 600 mg dosing regimen achieved clinical remission when compared with placebo. Larger decreases in CRP and FCP were seen at week 12, when compared with placebo. The most common side effect observed was a worsening of underlying CD. The results thus far suggest that specific blockade of IL-23 via inhibition of p19 may be a viable therapeutic approach in Crohn’s and warrants further investigation.⁴⁴

Small-molecule drugs

Small-molecule drugs (SMDs) have a molecular weight < 1 kDa,⁴⁵ and most are organic compounds composed of oxygen, carbon and nitrogen.⁴⁶ Their low molecular weight allows SMDs to diffuse readily through cell membranes, when compared with large macromolecules such as the anti-TNFαs,⁴⁷ which may weigh up to 144 kDa, as in the case of infliximab. A wide variation in the size and structure of biologics significantly affects the administration route, target site, pharmacokinetics, antigenicity and drug–drug interactions.⁴⁸ A significant advantage of SMDs over biologic therapy is the ability to take the medication orally, which may be preferential to the patient; removing the need for hospital attendance, self-injection and repeated cannulation. SMDs tend to have a short serum half-life and may offer an advantage over biologics in cases where rapid elimination of the drug is required.⁴⁶ SMDs also offer advantage over biologics due to their lack of immunogenicity. They do, however, require once- or twice-daily dosing, which may affect compliance and therefore, disease control.

JAK inhibitors

Tofacitinib is a recently licensed, oral JAK inhibitor that inhibits JAK1, JAK2, JAK 3 and TYK2.⁴⁹ Cytokines activate intracellular JAKs, which causes phosphorylation and activation of STAT proteins, regulating the expression of target genes.⁵⁰ The JAK–STAT pathway is shown to be involved in the pathogenesis of IBD, and because JAKs are activated in pairs and in various combinations of cytokine receptors, JAK inhibition has the potential to block several inflammatory pathways concomitantly.^45,51

The clinical efficacy and safety of tofacitinib for the treatment of moderate-to-severe UC were examined in the OCTAVE trials.⁵² The primary endpoint of clinical remission at week 8, was met by a significantly higher number of patients in the tofacitinib group in both trials when compared with placebo (18.5% versus 8.2%). Mucosal healing, with a Mayo subscore ⩽ 1, was more common in the tofacitinib group. Both anti-TNF-naïve and previously exposed patients had equal benefit when treated with tofacitinib in induction studies; however, OCTAVE Sustain data showed less stable remission in TNF-failure patients where 10 mg twice-daily dosing seems to be more important than in TNF-naïve patients. Data for the use of tofacitinib in CD have not been promising to date.⁵³

In the OCTAVE trials, tofacitinib was well tolerated but there was an increased risk for herpes zoster infection, anal abscess, cellulitis, C. difficile infection, pneumonia and venous thromboembolism.⁵⁴ An increased risk of lung cancer, breast cancer, lymphoma (and gastric cancer in Japan only) was observed when compared with placebo in rheumatoid arthritis studies.⁵⁵

Sphingosine-1-phosphate receptor modulators

Sphingosine-1-phosphate (S1P) binds specifically to five widely expressed subtypes of the G-protein-coupled receptor S1P_1–5.⁵⁶ The S1P receptors have been shown to mediate angiogenesis, vascular tone and permeability, and the trafficking of lymphocytes, both to the lymphoid organs and their migration into the circulation.⁵⁷ S1P modulators bind to the S1P receptor and induce its internalization and degradation, trapping lymphocytes within lymphoid tissue.⁵⁸ This results in a reduction in the levels of circulating effector T cells and causes selective immunosuppression, without downregulating overall immune function.⁵⁹

Ozanimod is an orally administered S1P receptor modulator; selectively modulating S1P₁ and S1P₅ receptors. It is currently under investigation in the treatment of IBD as part of the phase II clinical trial: the TOUCHSTONE study evaluated the efficacy of ozanimod in the induction and maintenance therapy in patients with moderate-to-severe UC.⁶⁰ Significant differences were seen at week 32 with respect to clinical remission, clinical response and mucosal healing, with slight difference only noted at week 8. Greater histological remission, however, was noted at weeks 8 and 32.⁶⁰ It seems that ozanimod is a well-tolerated medication, but the TOUCHSTONE trial was underpowered from a safety perspective. Fingolimod, a similar agent used for multiple sclerosis has been associated with adverse events such as bradycardia and atrioventricular block and macular oedema. Serious infections, such as disseminated varicella zoster and herpes simplex infections are rare but have been observed.⁶¹ There is also some concern with regard to the development of PML in natalizumab-naïve patients, and it is likely that all patients taking S1P receptor modulators will need full PML assessment for JC virus prior to, and during therapy.⁶²

Phosphodiesterase 4 inhibitors

Phosphodiesterase 4 (PDE4) is an enzyme that controls the concentration of circulating cyclic adenosine monophosphate (cAMP). cAMP has been shown to affect NF-κ-B signaling in macrophages and T cells, therefore, giving it potential anti-inflammatory and immunosuppressive properties.⁶³ PDE4 inhibition also leads to reduced TNFα messenger ribonucleic acid expression via transcriptional modulation of NF-κ-B and increased synthesis of IL-10, an anti-inflammatory cytokine, via activation of protein kinase A (PKA).⁶⁴ PDE4 inhibitors have shown beneficial effects in murine studies of colitis.

Apremilast, which specifically targets PDE4, has been approved as an oral therapy for psoriatic arthritis (PsA), and as PsA shares several pathogenic mechanisms with IBD, has been proposed as a potential therapeutic agent. A recent phase II, randomized, double-blind, placebo-controlled trial by Danese and colleagues examined the efficacy of apremilast in active UC. Patients treated with apremilast 30 mg twice daily showed superior clinical disease indices, mucosal healing, CRP and FCP reduction when compared with placebo.⁶⁵ The drug is no longer being developed in IBD, and phase III trials will not be undertaken due to commercial decisions of the company, not a lack of phase II trial efficacy data.

Stem-cell transplant

There is emerging evidence that stem-cell therapy may be used as an alternative method to treating tissue damage caused by chronic inflammation in IBD through alteration of the mucosal immune response.⁶⁶ Results from ongoing clinical trials using both haematopoietic stem cells (HSCs) and mesenchymal stem cells (MSCs) continue to be inconsistent. HSCs are multipotent cells isolated from bone marrow, umbilical cord or peripheral blood and have the ability to differentiate into blood and immune cells.⁶⁷ By migrating to damaged tissue, they may differentiate to epithelial or immune-modulatory cells to restore normal mucosal tissue and integrity.⁶⁸ MSCs are multipotent cells found in bone marrow, umbilical cord and adipose tissues. MSCs have immunomodulatory capability for downregulating mucosal immune reactivity by promoting regulatory T-cell formation,⁶⁹ including the inhibition of proliferation and function of Th2 and Th27 cells, promoting tissue healing.⁷⁰

Current studies are focusing on autologous haematopoietic stem-cell transplant (HSCT). A Spanish trial showed drug-free clinical remission at 6 months in 70% of patients (n = 29).⁷¹ A total of 15% of patients remained in drug-free remission at 5 years and of those who relapsed, 80% responded to subsequent medical therapy. The largest trial to date, the ASTIC study, showed 3-month steroid-free clinical remission was seen in 38% of patients, half of whom achieved complete endoscopic healing. Best results were seen in patients with short disease duration and low baseline CDAI; however, there was a very high burden of adverse events, mainly infection in 23 of 40 participants and a single death.⁷² The study failed to meet its primary endpoint.

The major advantage of using MSCs over HSCT are their low immunogenicity profile, and lack of requirement for whole-body irradiation or chemotherapy following transplant. The use of MSC therapy (MSCT) has been evaluated in the treatment of IBD in two ways. The first involves injection of MSCs directly into perianal fistulas to promote repair and second, IV administration to treat luminal UC and CD. Local injection at fistula sites of both autologous and allogenic MSCs have shown positive results in multiple case series and randomized controlled trials when compared with placebo.⁷² A further phase I trial has shown an 83% rate of complete clinical healing and radiological evidence of response in complicated Crohn’s fistulae treated with autologous MSCT directly to the fistula site.⁷³ IV autologous MSCT for luminal CD did not show sustained clinical remission, with worsening of symptoms in some patients.^74,75 However, a single trial of seven patients (four CD, three UC), treated with IV allogenic MSCs while on concomitant steroid or immunomodulatory therapy reported a significant reduction in clinical activity of disease in all patients, and full clinical remission in five out of seven (two CD, three UC), with significant endoscopic healing also being observed.⁷⁶

The ADMIRE CD study was a double-blind study performed at 49 hospitals in Europe and Israel including 212 patients with CD and treatment-refractory, draining, complex perianal fistulas. As part of the phase III trial, patients were randomized 1:1 to groups given a local injection of 120 million Cx601 cells or placebo, in addition to conventional therapies. Efficacy endpoints at week 52 included combined remission classified as closure of all treated external fistulae draining at baseline, with an absence of collections > 2 cm confirmed by magnetic resonance imaging and clinical remission which was classified by an absence of draining fistulae. At week 24, combined remission was observed in 51.5% of patients given Cx601 compared with 35.6% in the placebo group (p = 0.021). At week 52, 56.3% of patients achieved combined remission versus 38.6% of the placebo group (p = 0.010), while 59.2% achieved clinical remission compared with 41.6% receiving placebo (p = 0.013). Adverse events occurred in 76.7% of patients in the treatment arm, compared with 72.5% of the placebo group. The phase III trial showed Cx601 to be a safe and effective treatment option for closing externally draining fistulae after 1 year.⁷⁷ Despite the findings of the above studies, the National Institute for Health and Care Excellence guidelines do not currently recommend the use of stem-cell transplant in the treatment of complex perianal fistulae in CD due to uncertainties surrounding the long-term benefits and cost effectiveness of the therapy.

Faecal microbiota transplant

Following the successful treatment of C. difficile infection with faecal microbiota transplant (FMT), attention was turned to its potential use in the treatment of IBD. Over the past 20 years, multiple studies have shown the pivotal role gut microbiota play in the pathogenesis of IBD.⁷⁸ Faecal bacterial of IBD patients has been shown to be different to healthy individuals, with a higher ratio of pathogenic bacteria, (Escherichia coli, Campylobacter spp., Mycobacterium avium) to commensal flora (Bacteroides and Firmicutes phyla) and a decreased bacterial load in areas of active inflammation.⁷⁹ Bacterial invasion of the mucosa has been demonstrated in IBD patients, while rarely found in healthy subjects.⁸⁰ A systematic review of 18 studies that used FMT as primary therapy in IBD showed that of 122 patients who underwent FMT, there was an overall remission rate of 45%.⁸¹ Subgroup analysis indicated that CD patients were more likely to show response to FMT than UC, with 61% of patients achieving clinical remission, compared with 22% in UC. The most interesting study showed a benefit of FMT in UC-delivered FMT over FMT performed via nasoduodenal tube delivery, but also that donor effect may be extremely important with patients treated from a particular donor being most likely to respond. This suggests that there may be a role in the identification and transplantation of specific microbial species to restore intestinal homeostasis.⁸² Reported adverse events associated with FMT include transient fever, and vomiting postduodenal infusions.⁸¹ Serious events are rare but flares of IBD and infection have been reported.^83,84 It is important to realize, however, that all successful studies involved more than a single FMT administration, resulting in an increased burden both on the patient who will require multiple endoscopies and the costs associated with this to the healthcare provider.

Conclusion

While the mainstay of treatment for IBD to date has included aminosalicylates, corticosteroids, immunomodulators and anti-TNFα inhibitors, a significant proportion of patients will fail to respond or lose response to these conventional therapies. As such, alternatives are need for those patients with refractory, and often severe disease. Anti-integrin therapy, IL-12/IL-23 inhibitors and SMDs show significant promise. Stem-cell transplant, particularly in fistulating CD, has been particularly promising. FMT needs more studies but it is clear that questions exist regarding standardized protocols, microbe selection or the best mode of delivery. It is clear that there is a need for drugs or drug combinations with good safety profiles that work in all patients.

Acknowledgments

KH and AOC conceived and drafted the manuscript. Both authors commented on drafts of the manuscript. Both authors have approved the final draft of the manuscript.

Footnotes

Funding: The authors received no financial support for the research, authorship, and/or publication of this article.

Conflict of interest statement: AOC has received speaker and advisory board fees from MSD Human Health, Abbvie, Takeda and Janssen Pharmaceuticals.

ORCID iD: Karl Hazel https://orcid.org/0000-0002-3508-9696

Contributor Information

Karl Hazel, Department of Gastroenterology, Tallaght University Hospital, Belgard Road, Tallaght, Dublin D24NR0A, Ireland.

Anthony O’Connor, Centre for Inflammatory Bowel Disease, Tallaght University Hospital, Dublin, Ireland University of Dublin, Trinity College, Dublin, Ireland.

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Emerging treatments for inflammatory bowel disease

Ther Adv Chronic Dis. 2020; 11: 2040622319899297.

Karl Hazel

Department of Gastroenterology, Tallaght University Hospital, Belgard Road, Tallaght, Dublin D24NR0A, Ireland

Anthony O’Connor

Centre for Inflammatory Bowel Disease, Tallaght University Hospital, Dublin, Ireland University of Dublin, Trinity College, Dublin, Ireland

Karl Hazel, Department of Gastroenterology, Tallaght University Hospital, Belgard Road, Tallaght, Dublin D24NR0A, Ireland;

Received 2019 Feb 11; Accepted 2019 Dec 6.

This article has been cited by other articles in PMC.

Abstract

Keywords: Crohn’s disease, inflammatory bowel disease, ulcerative colitis

Introduction

The inflammatory cascade in inflammatory bowel disease.¹

IFNγ, interferon gamma; IL, interleukin; Th, T-helper cell; TLR, toll-like receptor; TNF, tumour necrosis factor.

New anti-TNFs

AVX-470

Anti-adhesion biologics

Vedolizumab

Etrolizumab

Abrilumab

PF-00547659

IL-12/IL-23 inhibitors

Ustekinumab

Risankizumab

Small-molecule drugs

JAK inhibitors

Sphingosine-1-phosphate receptor modulators

Phosphodiesterase 4 inhibitors

Stem-cell transplant

Faecal microbiota transplant

Conclusion

Acknowledgments

KH and AOC conceived and drafted the manuscript. Both authors commented on drafts of the manuscript. Both authors have approved the final draft of the manuscript.

Footnotes

Funding: The authors received no financial support for the research, authorship, and/or publication of this article.

Conflict of interest statement: AOC has received speaker and advisory board fees from MSD Human Health, Abbvie, Takeda and Janssen Pharmaceuticals.

ORCID iD: Karl Hazel https://orcid.org/0000-0002-3508-9696

Contributor Information

Karl Hazel, Department of Gastroenterology, Tallaght University Hospital, Belgard Road, Tallaght, Dublin D24NR0A, Ireland.

Anthony O’Connor, Centre for Inflammatory Bowel Disease, Tallaght University Hospital, Dublin, Ireland University of Dublin, Trinity College, Dublin, Ireland.

References

Emerging treatments for inflammatory bowel disease

Ther Adv Chronic Dis. 2020; 11: 2040622319899297.

Karl Hazel

Department of Gastroenterology, Tallaght University Hospital, Belgard Road, Tallaght, Dublin D24NR0A, Ireland

Anthony O’Connor

Centre for Inflammatory Bowel Disease, Tallaght University Hospital, Dublin, Ireland University of Dublin, Trinity College, Dublin, Ireland

Karl Hazel, Department of Gastroenterology, Tallaght University Hospital, Belgard Road, Tallaght, Dublin D24NR0A, Ireland;

Received 2019 Feb 11; Accepted 2019 Dec 6.

This article has been cited by other articles in PMC.

Abstract

Keywords: Crohn’s disease, inflammatory bowel disease, ulcerative colitis

Introduction

The inflammatory cascade in inflammatory bowel disease.¹

IFNγ, interferon gamma; IL, interleukin; Th, T-helper cell; TLR, toll-like receptor; TNF, tumour necrosis factor.

New anti-TNFs

AVX-470

Anti-adhesion biologics

Vedolizumab

Etrolizumab

Abrilumab

PF-00547659

IL-12/IL-23 inhibitors

Ustekinumab

Risankizumab

Small-molecule drugs

JAK inhibitors

Sphingosine-1-phosphate receptor modulators

Phosphodiesterase 4 inhibitors

Stem-cell transplant

Faecal microbiota transplant

Conclusion

Acknowledgments

KH and AOC conceived and drafted the manuscript. Both authors commented on drafts of the manuscript. Both authors have approved the final draft of the manuscript.

Footnotes

Funding: The authors received no financial support for the research, authorship, and/or publication of this article.

Conflict of interest statement: AOC has received speaker and advisory board fees from MSD Human Health, Abbvie, Takeda and Janssen Pharmaceuticals.

ORCID iD: Karl Hazel https://orcid.org/0000-0002-3508-9696

Contributor Information

Karl Hazel, Department of Gastroenterology, Tallaght University Hospital, Belgard Road, Tallaght, Dublin D24NR0A, Ireland.

Anthony O’Connor, Centre for Inflammatory Bowel Disease, Tallaght University Hospital, Dublin, Ireland University of Dublin, Trinity College, Dublin, Ireland.

References

Emerging treatments for inflammatory bowel disease

Ther Adv Chronic Dis. 2020; 11: 2040622319899297.

Karl Hazel

Department of Gastroenterology, Tallaght University Hospital, Belgard Road, Tallaght, Dublin D24NR0A, Ireland

Anthony O’Connor

Centre for Inflammatory Bowel Disease, Tallaght University Hospital, Dublin, Ireland University of Dublin, Trinity College, Dublin, Ireland

Karl Hazel, Department of Gastroenterology, Tallaght University Hospital, Belgard Road, Tallaght, Dublin D24NR0A, Ireland;

Received 2019 Feb 11; Accepted 2019 Dec 6.

This article has been cited by other articles in PMC.

Abstract

Keywords: Crohn’s disease, inflammatory bowel disease, ulcerative colitis

Introduction

The inflammatory cascade in inflammatory bowel disease.¹

IFNγ, interferon gamma; IL, interleukin; Th, T-helper cell; TLR, toll-like receptor; TNF, tumour necrosis factor.

New anti-TNFs

AVX-470

Anti-adhesion biologics

Vedolizumab

Etrolizumab

Abrilumab

PF-00547659

IL-12/IL-23 inhibitors

Ustekinumab

Risankizumab

Small-molecule drugs

JAK inhibitors

Sphingosine-1-phosphate receptor modulators

Phosphodiesterase 4 inhibitors

Stem-cell transplant

Faecal microbiota transplant

Conclusion

Acknowledgments

KH and AOC conceived and drafted the manuscript. Both authors commented on drafts of the manuscript. Both authors have approved the final draft of the manuscript.

Footnotes

Funding: The authors received no financial support for the research, authorship, and/or publication of this article.

Conflict of interest statement: AOC has received speaker and advisory board fees from MSD Human Health, Abbvie, Takeda and Janssen Pharmaceuticals.

ORCID iD: Karl Hazel https://orcid.org/0000-0002-3508-9696

Contributor Information

Karl Hazel, Department of Gastroenterology, Tallaght University Hospital, Belgard Road, Tallaght, Dublin D24NR0A, Ireland.

Anthony O’Connor, Centre for Inflammatory Bowel Disease, Tallaght University Hospital, Dublin, Ireland University of Dublin, Trinity College, Dublin, Ireland.

References

What is the purpose of this review?

The aim of this Cochrane Review was to identify which drugs are most effective in maintaining remission in people with Crohn’s disease who have undergone surgery to achieve remission. To answer this question, we collected and analyzed all relevant studies. We examined these studies using a technique known as network meta-analysis (NMA) to compare and rank all treatment options in terms of clinical recurrence, endoscopic recurrence, and safety.

What was learned in this survey?

Crohn’s disease is a chronic bowel disease. It is known for alternating periods when people experience flare-ups (relapse) and periods of well-being (remission). Symptoms include abdominal pain, diarrhea, and weight loss. People with Crohn’s disease can undergo surgery to remove the affected intestinal tract and achieve remission. However, after a while, their symptoms return. Various medications can be prescribed to keep people with Crohn’s disease in remission for as long as possible.These medications include mesalazine, antibiotics, corticosteroids, adalimumab, and others. Although these medications are known to reduce inflammation (pain and swelling) in the intestines, side effects can occur when using them. We tried to find out which treatment options are the safest and most effective for maintaining remission in people with Crohn’s disease after surgery.

How relevant is this review?

We searched for studies published up to June 15, 2019.

What are the main findings of this review?

We have included 35 relevant tests that were published between 1976 and 2018. These studies included 3249 participants, mostly adults. Our network meta-analysis included 26 studies (2581 participants) and compared nine treatment groups such as 5-aminosalicic acid, adalimumab, antibiotics, budesonide, infliximab, probiotics, purine analogs, sulfasalazine, and the combination of sulfasalazine and prednisolone used to prevent relapse after surgery in people with Crohn’s disease.Adalimumab appears to reduce the likelihood of clinical relapse compared to placebo (sham treatment). 5-aminosalicic acid appears to reduce the risk of clinical relapse compared to placebo. Budesonide may not be effective in preventing clinical relapse. All evidence is of low certainty due to the small number of participants included in the studies and the high risk of bias (bias). This means that there is limited confidence in these results.Research to understand the effect of treatment on endoscopic recurrence and safety was limited, however, cases of pancreatitis and leukopenia were reported in participants treated with purine analogs.

Key information

We are not sure which treatment options are most effective in preventing postoperative recurrence in Crohn’s disease. Despite limited research on the harm (side effects) of these treatment options, there have been reports of cases of pancreatitis and leukopenia in participants who received purine analogues.

operations on the colon and rectum, | Mount Sinai

The Mount Sinai Department of Colon and Rectal Surgery is renowned nationally and internationally for treating patients with a wide range of gastrointestinal disorders at an impeccable level. The department offers progressive innovations in the treatment of diseases of the colon and rectum, both benign, such as hemorrhoids, fecal incontinence and inflammatory bowel disease (IBD), and cancer.Our team of surgeons work with Mount Sinai experts in other areas to ensure the best possible treatment.

The Department of Colon and Rectum Surgery is actively involved in research programs and multicenter studies dedicated to various proctological diseases. This gives our patients the opportunity to use the most modern methods of treating diseases of this profile.

Modern methods of treating diseases of the rectum and colon
There are a number of benign diseases that affect the quality of life and which are usually not discussed or treated due to embarrassment.There is now a wide range of possibilities that many patients are unaware of. The following are some of the most common conditions we treat.

Fecal Incontinence Our Fecal Incontinence Program focuses on a common but rarely discussed problem. The program is being implemented at the initiative of Alex Ky, MD, who pioneered the use of the sacral nerve stimulator InterStim in a New York practice. Patients who previously required diapers are now able to wear normal underwear and go for walks again.This is a tremendous change in the patient’s quality of life.
Fistulas Dr. Key has published three articles on anal fistulas and their treatment. She is also involved in various multicenter studies to improve therapies for this common condition.
Hemorrhoids This disease affects and distresses many patients. Many patients have heard stories that the surgical treatment of this disease is painful and excruciating. However, many are unaware that there are less painful therapeutic options.Our surgeons have performed more than a thousand painless procedures for the treatment of hemorrhoids in their center. And even surgical treatment in our country is less painful than traditional operations.
Inflammatory Bowel Disease Randolph M. Steinhagen M.D. and Sergey Khaitov M.D. and others in the department are experts in the treatment of inflammatory bowel disease using minimally invasive techniques.

New technologies and laparoscopic operations

The goal of the Department of Colon and Rectal Surgery is to provide the highest quality treatment using the latest capabilities and technologies to ensure the best possible outcome. We work with referring physicians to ensure that patient care is well coordinated.

Below are some of the types of innovative treatments we offer.

Transanal Endoscopic Microsurgery (TEM) Sanghyun Alexander Kim, MD, and Dr. Key have jointly performed hundreds of TEM procedures to treat benign and malignant polyps. TEM helps avoid unnecessary abdominal surgery when treating polyps in the upper rectum.
Robotic Surgery Mount Sinai has three Da Vinci robots that provide clearer imaging and enhanced functionality for our surgeons when working in confined spaces.This allows to preserve the nerves and sphincters of patients with cancer, while in another situation they would have to place a permanent stoma.
Laparoscopic Surgery Mount Sinai Hospital is one of the few healthcare facilities that offers a complete one-stage laparoscopic ileoanal reservoir retraction proctocolectomy. This is especially important for young patients who are hindered by the presence of a stoma.

Serving our foreign clients

The Department of Colon and Rectum Surgery employs doctors who are fluent in Russian, Spanish and Chinese (including Mandarin and Cantonese).In addition, our staff also speaks multiple languages to ensure the perfect treatment experience and maximize patient stress relief.

We strive to provide the best possible comfort and convenience by offering premium patient floor accommodation, Eleven West, with a welcoming and sophisticated atmosphere that fosters privacy and recovery. Mount Sinai has also partnered with a number of nearby hotels for the convenience of patients and families.

90,000 Idiopathic inflammatory bowel disease in cats.Choice of rational therapy

IBD is a common diagnosis in cats with chronic gastrointestinal symptoms. This guideline represents clinical change not least because rational therapy relies on differential diagnosis, and current understanding of the underlying pathogenesis has hitherto stalled the development and development of specific therapies.Diet manipulation and immunosuppressive therapy remain the mainstays of treatment, but treatment failure is not common. The clinical approach is logical and there are a number of alternative and complementary treatment regimens that can be helpful in refractory cases.

This article draws on data from human clinical trials, in vivo trials, possible and retrospective studies in cats with naturally occurring IBD, and clinical experience to discuss research and treatment choices for cats with idiopathic IBD.

IBD occurs in young, adult and old cats of both sexes. It is generally accepted that the pathogenesis of IBD is based on the loss of mucosal tolerance to intestinal antigens, such as commensal bacteria and food components.

Diagnosis IBD

IBD is a common diagnosis in adult cats and has recently been specifically defined by the WSAVA GI standardization group. It is believed that the pathogenesis is based on a disorder of the immunity of the gastrointestinal mucosa (GI) with the loss of its tolerance to intestinal antigens, such as commensal bacteria and food components.In addition to this hypothesis, there is evidence that large molecules of a class 2 tissue compatibility complex, which are antigens to the immune system, are activated in enterocytes of cats with IBD. In addition, the number of bacteria that adhere to the intestinal mucosa of cats with IBD correlates with several pathological features – abnormal duodenal architecture, macrophage and T-lymphocyte infiltration, activation of inflammatory cytokines such as interleukin-8, to the same extent as and clinical symptoms in sick cats.Thus, the goal of IBD therapy is to reduce antigenic stimulation of the intestine and modulate its local immune response.

The first step in the rational management of IBD is to obtain a differential diagnosis.

WSAVA GI standardization group defines IBD GI symptoms lasting more than 3 weeks, incomplete response to trial diet and anthelmintic therapy, histological changes characteristic of mucosal inflammation on biopsy, and clinical response to immunomodulatory therapy.

Gastrointestinal biopsy

Mucosal biopsy obtained from the stomach or duodenum 12 during endoscopy is a relatively inexpensive and minimally invasive method than laparotomy or laparoscopy. Unfortunately, mucosal biopsies can skip lymphoma in cats, especially if only the intestine is involved, not the stomach. In addition, standard GI endoscopy does not allow examination of the jejunum and ileocecal junction. A full-thickness biopsy is obtained at diagnostic laparotomy or laparoscopy, ideal for diagnosing IBD and excluding lymphoma.However, the added cost, hospitalization time, and the risk of potential complications can be inhibitory factors for many pet owners.

Ultrasound data

Abdominal ultrasound may be helpful in biopsy selection. A thickened wall or lymphadenopathy of mesenteric lymph nodes may not be a reliable sign of the most likely IBD and lymphoma, but an aspiration biopsy of an enlarged or thickened bowel may be done to exclude lymphoma. (The absence of a cytological picture of lymphoma does not exclude its presence) Loss of normal lamination of the intestinal wall indicates neoplasia, the formation should be removed as soon as possible, or a biopsy taken through the entire layer if the owners prefer chemotherapy.Lymphoma of the stomach may have a normal ultrasound picture, but if the wall of the stomach or duodenum 12 looks thickened or infiltrated, further gastroscopy may be required to clarify the diagnosis. Adenocarcinoma of the intestine in cats presents a picture of local thickening of the intestinal wall with mixed echogenicity, and should be recommended for removal.

The picture shows an ultrasound image of the abdominal cavity of a 12 year old domestic cat with complaints of chronic vomiting progressing to hematemesis.The picture shows a locally thickened duodenum 12. Subsequent gastroscopy confirmed the diagnosis of T-cell lymphoma.

Concentration of serum folate and cobalamin

Serum folate and cobalamin concentrations are often useful for biopsy planning. Low folate levels are associated with malabsorption in the proximal small intestine. This feature alone, along with a thickened duodenal wall 12 on ultrasound, indicates that endoscopy of this area may be sufficient to obtain a biopstat.A decrease in serum cobalamin concentration indicates malabsorption of cobalamin in the ileum due to either intestinal infiltration or exocrine pancreatic insufficiency.

fTLI and fPLI

Pancreatic insufficiency is rare in cats, but if polyphagia is present in euthyroid and nondiabetic cats and weight loss, trypsin immunoreactivity is recommended. If the indicator is normal, pancreatic insufficiency is excluded, in cats with low cobalamin levels, it is recommended to conduct a biopsy through all 12 layers of the duodenum, ileum and jejunum.Because pancreatitis can compete with IBD, cats with chronic GI symptoms should also screen for pancreatic lipase immunoreactivity, especially if the pancreas appears patchy on ultrasound or physical examination reveals abdominal discomfort.

When examining a biopsy specimen, the pathologist should be asked to follow the standards set by the WSAVA GI Standardization Group, which include the assessment of cell infiltration, crypt distortion, dull and fusion of villi, and fibrosis.

Treatment without biopsy

In IBD, differential diagnosis is not possible without an intestinal biopsy. In some situations, however, biopsy may not be possible, such as when the owner is financially limited, or when the cat has contraindications to anesthesia, such as cardiomyopathy or weakness. Unfortunately, long-term clinical symptoms (more than 1 year) do not exclude lymphoma. If a prior diagnosis of IBD is being treated, care must be taken to ensure that owners do not opt for chemotherapy for lymphoma if confirmed, and understand that the diagnosis has not been confirmed.Even if a biopsy is not possible, it is still recommended to perform an ultrasound of the abdominal cavity, measuring the levels of immunoreactivity of pancreatic lipase, folate and coalamin.

Elimination Diet Therapy

Choosing a diet is a critical first step in managing a cat with IBD. Although idiopathic IBD is partly due to an incomplete response to trial diet therapy, some cats, even with severe inflammatory histological changes, may respond to diet alone.The new protein (elimination) diet aims to eliminate the release of proteins to which the immune system of the intestinal mucosa may have previously been sensitized. Most commercial elimination diets contain new sources of protein, no milk, no wheat, and no corn, are highly digestible with moderate amounts of soluble fiber.

An elimination diet should always be conceived as the first line of treatment for chronic gastrointestinal disease in cats, as it is associated with a high response rate.

Diet alone has been shown to be fairly effective in treating chronic GI disease in cats, and avoids the side effects associated with immunosuppressive therapy. In fact, over 50% of cats with idiopathic GI symptoms responded very well to the elimination diet, homemade foods with a new protein source or one of the many commercial diets (venison and rice) can be used.

A trial diet treatment in the first 4 to 6 weeks is recommended first, which may surprise some doctors and owners.However, in the aforementioned study on elimination diets, all sensitive cats responded in the first 2 to 3 days, so a shorter application of the diet is possible, as long as the symptoms do not go away and the owners can follow it (after 1 week it can be changed).

Alternative to the elimination diet – hydrolyzed feed. The goal of such diets (zd or DR) is to minimize the antigenicity of intact food proteins. A hydrolyzed diet may be ideal as a “sacrificial diet” during the initial period of therapy, while glucocorticoids are used to avoid sensitization to any new protein sources not previously used.They can also be used as monotherapy in the treatment of IBD. Diarrhea or not eating this diet can be a problem for some cats and is more expensive than other elimination diets. There are still no studies comparing the efficacy of hydrolyzed diets versus new protein source diets.

This image shows a colonoscopy of a cat with chronic colonic diarrhea and peripheral eosinophilia. The photo shows superficial ulcers and thickening.Mucosal histology showed severe ulcerative lymphocytic-plasmacytic colitis, the cat responded well to prednisolone in combination with a course of fonbendazole.

Response rates to diet therapy

Competitive dermatologic symptoms with chronic GI symptoms may indicate food allergy and increase the likelihood of responding to an elimination diet.
Eosinophilia is an unreliable indicator of a response only to an elimination diet, since it does not take into account the degree and type of mucosal lesion on the biopsy.
Food allergen immunoglobulin E assay is not indicative of response to an elimination diet and should not be used. They are often false positive / negative and in most cats IBD is not igE-mediated.

In cats with chronic GI symptoms, atopic dermatitis, as in this pruritus cat, is more likely to improve GI symptoms with the elimination diet alone.

Immunosuppressive therapy

In cats with a histological diagnosis of inflammatory GI disease that do not respond to dietary changes, immunosuppressive therapy is the therapy of choice, although it is hoped that these drugs will be replaced with more specific drugs when the pathogenesis of IBD is better understood.

Prednisolone

Prednisolone is indicated for patients with severe or severe symptoms and a histological picture of lymphocytic-plasmacytic or eosinophilic inflammation. Prednisone is a precursor that converts to the active form, prednisolone, after administration. This conversion (or possibly absorption of prednisone itself) is low in cats, so the plasma prednisone concentration after prednisone administration is comparatively lower than with oral prednisone. Therefore, prednisone is preferred for cats requiring glucocorticoid therapy, especially if they respond poorly to prednisone.

The initial recommended dose of prednisolone is from anti-inflammatory to immunosuppressive (1-3 mg / kg / day). The dose is changed every 3 to 4 weeks to the minimum effective. Glucocorticoid therapy should be combined with a highly digestible diet, ideally new or hydrolyzed protein sources if possible. In cats with severe malabsorption symptoms, treatment with subcutaneous injections of glucocorticoids early in therapy may improve response. This can be achieved by using dexamethasone, which is prescribed in 1/7 of the doses of prednisolone, which increases the effectiveness of dexamethasone.Dexamethasone has advantages in the treatment of cats with IBD, which often have underlying heart conditions, as it does not cause bicarbonate (soda) retention.

Budesonide

Budesonide is an oral glucocorticoid approved for use in people with Crohn’s disease. This drug undergoes intense hepatic clearance (rapidly excreted) in humans, resulting in a lower systemic drug concentration and a lower incidence of side effects. The drug has been studied in dogs, in which it causes polyuria and an increase in serum acid phosphatase, like prednisone.However, it can still be absorbed at a concentration capable of suppressing adrenal cortex function in dogs.

In our experience budesonide is effective in some cats with IBD. The drug is supplied as enteric 3 mg capsules and must be repackaged to achieve the recommended empiric dose of 0.5 – 0.75 mg / kg / animal per day. Since the extent of intestinal absorption of the drug in cats has not yet been studied, patients should be monitored for the side effects of glucocorticoids, such as urinary tract infections and glucosuria.

Chloralbucil

Chloralbucil is an alkylating agent that binds DNA, but less effective than cyclophosphamide. It is effective in combination with prednisolone in small cell alimentary lymphoma in cats and in refractory IBD. Chloralbucil can be used as an adjunct in cats with IBD that respond poorly to diet and glucocorticoids, or in severe lymphocytic GI disease that is histologically very difficult to differentiate from small cell lymphoma.Doses – 2 mg / animal every 48 to 72 hours or 20 mg / m2 as a single dose every 14 days.

Chloralbucil is well tolerated by most cats. It does not cause hemorrhagic cystitis, and although leukopenia is possible, it is rare. It is necessary to carry out a complete blood count with the introduction of the first three doses, when a dosage of 20 mg / m2 is used, and periodically thereafter (once every 2-3 months). One, rather rare, side effect of the drug – reversible myoclonus, was observed in cats if the frequency of administration of the drug was not observed.

Cyclosporine

Cyclosporin is an effective immunosuppressive agent that suppresses the function of T cells, namely the production of IL-2. The drug has been tested in dogs with IBD and has been shown to be effective in patients with symptoms resistant to glucocorticoid therapy. Cyclosporine is often effective in cats with refractory IBD at doses of 5 mg / kg once or twice daily. Lack of appetite and vomiting are common side effects, but they resolve when the dose is reduced by 50%. Rarer side effects such as gum lesions and secondary fungal infections occur in dogs and have not been reported in cats, but activation of subclinical latent infections such as toxoplasmosis and herpesvirus is possible.

The comparative efficacy of cyclosporine versus chloralbucil as a second-line therapy in cats with IBD has not been investigated.

Probiotics

Probiotics are defined as live microorganisms that aim to maintain microbial balance and have a positive effect on overall health. These are non-pathogenic microorganisms, usually bacteria and sometimes yeast, which can adhere and colonize the intestinal mucosa, and must be resistant to gastric juices and bile if administered orally.Examples are lactobacillus, bifidobacterium, enterococcus.

Possible beneficial effects of probiotics are the normalization of the intestinal flora, inhibition of the growth of pathogenic bacteria, preventing the penetration of bacteria through the intestinal wall. These effects can be due to a decrease in pH in the intestinal lumen (lactic and butyric acid) or the release of bactericides. The substances secreted by these bacteria can also have anti-inflammatory effects.

There is some evidence of the efficacy of probiotics in the treatment of people with IBD, although the effect is multiplicity and dose dependent.Probiotics may reduce the incidence of antibiotic-dependent diarrhea in humans, and may have some effectiveness in maintaining remission in cases of ulcerative colitis. In dogs, they reduce the concentration of Clostridia. Under the action of Lactobacillus, the production of IL-10 and anti-inflammatory cytokines increases. However, in a study of 21 dogs with IBD, no benefit was found with a probiotic cocktail over a hypoallergenic diet, more research needs to be done.

In a study on healthy cats, administration of lactobacilli reduced the number of clostridia and the concentration of endotoxins in plasma for a short period.A commercial probiotic from Purina that has been shown to cause diarrhea in some cats.

If IBD is indeed caused in part by a decrease in the tolerance of the mucous layer to bacterial flora, then parobiotics may have some benefit. Some commercial veterinary probiotics do not contain viable organisms as indicated, or do not live up to description and contain low amounts of live organisms, studies show. It is important to use preparations containing live bacteria that have been shown to colonize the intestines of cats.

Prebiotics

Prebiotics are indigestible food ingredients that promote the growth of beneficial bacteria in the intestines. These components are often selectively fermentable short chain hydrocarbons such as beet cellulose and plantain. Prebiotics are broken down into short chains of fatty acids, such as butyric, food for colonies, which can often reduce the release of proinflammatory cytokines. Butyric acid, which can also be administered orally, produces marked improvements in Crohn’s disease at colonoscopy, histologically, and in mucosal cytokine levels in some patients.

Cats have evidence of drug ineffectiveness.

Cobalamin

Low serum cobalamin levels are often seen in cats with GI symptoms, especially those with a low body condition index, although one study from England suggests a low incidence of this phenomenon. Low cobalamin interferes with normal enterocytic function, which contributes to the maladsorption already present in sick cats. It can be caused by malabsorption in the ileum or pancreatic dysfunction (pancreatitis or exocrine insufficiency – the release of bicarbonate is disrupted in 12 p.to., which connects cobalamin with a binding factor, with which it is absorbed in to-ke).

Macrocytosis is an unreliable indicator of cobalamin deficiency in cats, but has been described. Serum cobalamin should be measured in all cats with confirmed IBD and small bowel diarrhea. Assign in a dose of 250 mcg 1 time per week. Treatment leads to weight gain, increased appetite, cessation of vomiting and / or diarrhea in sick cats. Treatment is carried out for 6 weeks until the cause of maladsorption is eliminated.

Metronidazole

Metranidazole is a drug with good antiprotozoal and excellent anti-anaerobic activity, which is surprisingly effective even alone or in combination with glucocorticoids in the treatment of IBD in cats.It may also have immunomodulatory effects, although this is not described for therapeutic dosages.

In cats with IBD, metronidazole is dosed empirically at 15 mg / kg / day. High doses (more than 58 mg / kg / day) are associated with neurotoxicity in cats, with symptoms ranging from dullness of pain sensitivity to necrosis of the brainstem. Metronidazole is tasteless and often causes a decrease in appetite in cats. Metronidazole benzoate is better tolerated by cats, which may be due to both a more pleasant taste and lower plasma concentrations of the drug in humans.Since metronidazole benzoate contains about 60% metronidazole by weight, it should be dosed at 25 mg / kg / day, this dosage is only valid for GI symptoms. Neurotoxicity occurs at a dose of 200 mg / kg / day. In any case, if the cat does not tolerate metronidazole, benzoate is the drug of choice.

Omega-3-polyunsaturated fatty acids

Another option for additional therapy. It increases the production of leukotrienes, which mediate neutrophil recruitment and pro-inflammatory responses.Some of them can prevent cytokine-mediated disturbances in the permeability of the intestinal wall. Effective for prolonging remission in Crohn’s disease.

Starting doses as in humans. Available in FIZOL preparation. Doses are selected individually and titrated, since these acids are tasteless and often provoke diarrhea.

Failed Therapy – Checklist

Dietary aspects

the diet should be selected individually for each cat, home diets are preferable for the period of diagnosis, balanced diets are better for long-term use;
Sometimes you have to try several diets;

The

week diet should be adequately based on clinical response data in cats with IBD.

Glucocorticoids

It is better to use prednisone than prednisone;
use budesonite if you are concerned about side effects;
titrate the dose to the desired effect so as not to induce glucosuria;
whether prednisolone will be absorbed – it is worth considering the use of subcutaneous dexamethasone in cases of severe malabsorption.

Concomitant diseases of the gastrointestinal tract

Are there any concomitant gastrointestinal diseases – cobalamin deficiency, parasites, undiagnosed lymphoma

Diabetes

Long-term weight loss is associated with recent onset diabetes – diabetes can occur with prolonged glucocorticoid use, ask owners to occasionally test glucosuria with test strips.

Hyperthyroidism

Is long-term weight loss related to newly diagnosed hyperthyroidism?

Pancreatitis

often accompanies IBD in cats;
diagnosed with ultrasound and IPL;

90,045 cats with no appetite are treated with SC fluids and analgesics.

Cholangeohepatitis

often accompanies IBD in cats;
is diagnosed using a test for alkaline psfatase, ultrasound of the abdomen and liver biopsy;
bile culture, infection treatment;
start treatment with ursodiol

Highlights

Idiopathic IBD is defined by the wsava classification as: duration of symptoms more than 3 weeks, incomplete response to dietary and anthelmintic tests, histological acrtin of mucosal inflammation and response to immunomodulatory therapy.

Abdominal ultrasound, fPLT, folate and cobalamin are useful additional tests in cats with chronic GI symptoms. Determination of serum Ig-E to food proteins does not affect the response to the elimination diet and has not been shown.

Superficial endoscopy can miss lymphoma

Diet selection and glucocorticoids are the mainstay of IBD therapy, but chloralbucil, metronidazole, probiotics, soluble fiber, omega-3 fatty acids may be helpful in adjunctive or alternative therapy.

Transfer
E.N. Nazarova

90,000 Janssen announces registration of new indications for Stelara in Russia – News Vidal

The Ministry of Health of the Russian Federation approved new indications for the use of Stelara ^® (ustekinumab) for the treatment of moderate to severe active ulcerative colitis.

Janssen, a pharmaceutical division of Johnson & Johnson LLC, announces that the Ministry of Health of the Russian Federation has approved the expansion of indications for the use of ustekinumab in the treatment of moderate to severe active ulcerative colitis in adult patients with an inadequate response, loss of response or intolerance to standard or biological therapy, or with medical contraindications to such treatment.¹ Ustekinumab is the first genetically engineered biological drug available that targets the interleukins IL-12 and IL-23, which play a key role in the inflammatory and immune responses of the body seen in immune-mediated diseases such as ulcerative colitis and Crohn’s disease. ²

“We are taking an important step in the fight against ulcerative colitis,” notes Katerina Pogodina, General Director of Johnson & Johnson LLC, Managing Director of Janssen in Russia and the CIS.- We are pleased that our innovative therapy can support patients in the fight against inflammatory bowel diseases – Crohn’s disease, for the treatment of which ustekinumab was registered in Russia in 2019, and now with ulcerative colitis . Unfortunately, the severity of this disease is often underestimated. Ulcerative colitis most often occurs in young people who are still receiving education or taking their first steps in their careers, and the disease can become a serious obstacle to self-realization. “

Ulcerative colitis is a serious chronic immune-mediated inflammatory disease of the colon. ³ Symptoms may vary, but usually include tenesmus, diarrhea, blood in stools, weight loss (weight loss). These symptoms can be prolonged and debilitating, causing patients to feel embarrassed and uncomfortable. ^4.5 The disease is chronic, progressive, with the development of complications such as intestinal bleeding, toxic dilation and perforation of the colon, as well as colorectal cancer.⁶ For two out of three patients with ulcerative colitis, the available treatments are not fully effective. ^7,8,9,10

“Several genetically engineered biologicals and small molecules are currently registered for the treatment of inflammatory bowel diseases. Despite a fairly large arsenal of remedies, none of the drugs can achieve the desired results in changing the nature of the course of the disease. Each new treatment option gives patients an additional chance to achieve deep long-term remission and improve their quality of life.Registration of the drug ustekinumab for a new indication for the treatment of ulcerative colitis gives Russian patients these new hopes and opportunities, ”- comments MD, Professor Elena Aleksandrovna Belousova, President of the All-Russian Society for the Study of Inflammatory Bowel Diseases.

In patients with ulcerative colitis, as a result of therapy with Stelara ^®, the achievement and maintenance of steroidal remission, the achievement of histo-endoscopic remission (healing of the intestinal mucosa), a significant decrease in the levels of inflammatory markers, including C-reactive protein and fecal calprotectin, were noted. improving the quality of life of patients.¹¹ In patients who received the drug for 44 weeks, compared with the placebo group, a decrease in serum concentrations of TNF-a and IL-17A, which are pro-inflammatory cytokines regulated by IL-12 and IL-23, was achieved and maintained. ¹

The most common (> 5%) side effects observed in controlled periods of clinical trials of Stelara ^® were nasopharyngitis and headache. Most of the cases were considered mild and did not require discontinuation of therapy.¹

Sources:

¹ Instructions for the medical use of the medicinal product Stelara. Ministry of Health of the Russian Federation LSR-006465 / 09-23.04.2020, LP-005728-24.05.2020. URL .: https://grls.rosminzdrav.ru/ Date of treatment 05/26/2020

² Toussirot E. The IL23 / Th27 pathway as a therapeutic target in chronic inflammatory diseases. Inflamm Allergy Drug Targets 2012; 11: 159-68.

³ Ng SC, et al. Worldwide incidence and prevalence of inflammatory bowel disease in the 21st century: a systematic review of population-based studies. Lancet 2017; 390: 2769–78.

⁴ Crohn’s & Colitis Foundation. ‘Living with Ulcerative Colitis’ leaflet. Available at: https://www.crohnscolitisfoundation.org/sites/default/files/legacy/assets/pdfs/living-with-ulcerative.pdf (Accessed August 2019).

⁵ Crohn’s & Colitis UK.What is Ulcerative Colitis? Available at: https://www.crohnsandcolitis.org.uk/about-inflammatory-bowel-disease/ulcerative-colitis (Accessed August 2019).

⁶ Belousova E.A., Abdulganieva D.I., Alekseeva O.A., Achkasov S.I., Valuiskikh E.Yu., Vardanyan A.V., Veselov A.V., Veselov V.V. ., Golovenko O.V., Gubonina I.V., Zhigalova T.N., Kashnikov V.N., Knyazev O.V., Makarchuk P.A., Moskalev A.I., Nanaeva B.A., Nizov A.A., Nikitina N.V., Nikolaeva N.N., Pavlenko V.V., Poluektova E.A., Svetlova I.O., Tarasova L.V., Tkachev A.V., Frolov S.A., Khlynova O.V., Chashkova E.Yu., Shapina M.V., Sheptulin A.A. , Shifrin O.S., Shchukina O.B. DRAFT CLINICAL RECOMMENDATIONS FOR THE DIAGNOSTICS AND TREATMENT OF ULCERIC COLLITIS. Coloproctology. 2019; 18 (4): 7-36. https://doi.org/10.33878/2073-7556-2019-18-4-7-36

⁷ Lopez-Sanroman A, et al . Perceived emotional and psychological impact of ulcerative colitis on outpatients in Spain: UC-LIFE survey. Dig Dis Sci 2017; 62: 207-216.

⁸ Rubin D, et al . The impact of ulcerative colitis on patients ’lives compared to other chronic diseases: A patient survey. Dig Dis Sci 2010; 55: 1044-1052.

⁹ Devlen J, et al . The burden of inflammatory bowel disease: A patient-reported qualitative analysis and development of a conceptual model. Inflamm Bowel Dis 2014; 20: 545-552.

¹⁰ Lonnfors S, et al .IBD and health-related quality of life – Discovering the true impact. J Crohn’s Colitis 2014; 8: 1281-1286.

¹¹ Sands BE et al. N Engl J Med. 2020 Jan 2; 382 (1): 91. doi: 10.1056 / NEJMc1915042