GENERAL INFORMATION
Gary Gorodokin
Gary Gorodokin was born in Ukraine and left the former Soviet Union with his parents as a teenager. He did his undergraduate studies at and graduated from New York University in 1984, followed by medical school at the State University of New York Downstate Medical Center in Brooklyn, NY. He received my medical degree (M.D.) in 1989. G. Gorodokin was a Resident in Internal Medicine at the Bronx Municipal Hospital Center of the Albert Einstein College of Medicine in the Bronx, NY. followed by a Fellowship in Gastroenterology and Hepatology at the Long Island College Hospital in Brooklyn, NY. He completed his training in 1994 and have been in private practice since. Recently he was asked to Chair the Division of Gastroenterology and Digestive Diseases at the Elena Malysheva Medical Center in Moscow, where he started in 2017, while maintaining a full time private practice in Fair Lawn, New Jersey and in Brooklyn, New York.
Treatment Modalities for Crohn's Disease
Sharing the Experience at International Conference in Moscow, Russia, November 2019
INTRODUCTION
- Increasing incidence and prevalence of the disease
- Increasing therapeutic options
- Describe the clinical features and natural history of Crohn's Disease
- Diagnostics
- Therapeutic intervention
CLINICAL FEATURES
- Abdominal pain
- Diarrhea
- Fatigue
- Weight Loss
- Fever
- Growth Failure
- Anemia
- Recurrent Fistulas
NATURAL HISTORY
Crohn's Disease, in most cases, is a chronic, progressive, destructive disease
The location of Crohn's disease tends to be stable, but can occasionally extend
Most, but not all, patients with Crohn's disease will present with non-penetrating, non-stricturing disease behavior, but up to half of patients would have developed an intestinal complication (i.e.,stricture, abscess, fistula, or phlegmon) within 20 years of diagnosis.
The location of Crohn's disease tends to be stable, but can occasionally extend
Most, but not all, patients with Crohn's disease will present with non-penetrating, non-stricturing disease behavior, but up to half of patients would have developed an intestinal complication (i.e.,stricture, abscess, fistula, or phlegmon) within 20 years of diagnosis.
NATURAL HISTORY
Patients with ileal, ileocolonic, or proximal gastrointestinal ( GI) involvement are significantly more likely than those with isolated colonic disease to progress to an intestinal complication.
Extensive anatomic involvement and deep ulcerations are other risk factors for progression to intestinal complications
Extensive anatomic involvement and deep ulcerations are other risk factors for progression to intestinal complications
ILEOCOLONOSCOPY
NATURAL HISTORY
- Over long periods of observation, only 20–30% of patients with Crohn's disease will have a non-progressive or indolent course. Therefore, the majority of patients will require active effort to identify therapies that achieve adequate control of bowel inflammation
- Features that are associated with a high risk for progressive disease burden include
- Young age at diagnosis
- Initial extensive bowel involvement
- Ileal/ileocolonic involvement
- Perianal/severe rectal disease
- Penetrating or stenosing disease phenotype.
- Visceral adiposity may be a marker for increased risk of penetrating disease.
- Symptoms of Crohn's disease do not correlate well with the presence of active inflammation, and therefore should not be the sole guide for therapy. Objective evaluation by endoscopic or cross-sectional imaging should be undertaken periodically to avoid errors of under- or overtreatment
- Perianal fistulizing Crohn's disease occurs in up to one-quarter of patients
- Symptoms of Crohn's disease occur in most cases as a chronic, intermittent course; only a minority of patients will have continuously active symptomatic disease or prolonged symptomatic remission
- In the absence of immunomodulator or biologic treatment, steroid dependency and/or resistance occurs in up to half of patients
- Up to 80% of patients with Crohn's disease require hospitalization at some point during their clinical course, but the annual hospitalization rate decreases in later years after diagnosis
- The 10-year cumulative risk of major abdominal surgery in Crohn's disease is 40% to 55%, although recent studies performed in the biologic era suggest that the 10-year risk may have decreased to 30%.
- The 10-year risk of a second resection after the first is 35%, although again more recent studies suggest that this may have dropped to closer to 30%
- In Crohn's disease, the 5-year rate of symptomatic post-operative recurrence is ∼50%
- Overall mortality in Crohn's disease is slightly increased, with a standardized mortality ratio of 1.4 times that of the general population.
- Causes of excess mortality include GI disease, GI cancer, lung disease, and lung cancer
INTESTINAL MALIGNANCY
*Patients with colonic involvement are at increased risk of colorectal cancer, and risk factors include duration of disease, extent of colonic involvement, primary sclerosing cholangitis, family history of colorectal cancer, and severity of ongoing colonic inflammation
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*Patients with small bowel involvement are at increased risk of small bowel adenocarcinoma that can be difficult to diagnose preoperatively
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*Patients with small bowel involvement are at increased risk of small bowel adenocarcinoma that can be difficult to diagnose preoperatively
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DIAGNOSIS
Routine laboratory investigation
- Initial laboratory investigation should include evaluation for inflammation, anemia, dehydration, and malnutrition
- In patients who have symptoms of active Crohn's disease, stool testing should be performed to include fecal pathogens, Clostridium difficile testing, and may include studies that identify gut inflammation such as a fecal calprotectin
- Genetic testing is not indicated to establish the diagnosis of Crohn's disease
- Serologic markers of IBD
- Routine use of serologic markers of IBD to establish the diagnosis of Crohn's disease is not indicated
- Ileocolonoscopy with biopsies should be performed in the assessment of patients with suspected Crohn's disease
- Disease distribution and severity should be documented at the time of diagnosis. Biopsies of uninvolved mucosa are recommended to identify extent of histologic disease
- Upper endoscopy should only be performed in patients with upper GI signs and symptoms
- Video capsule endoscopy is a useful adjunct in the diagnosis of patients with small bowel Crohn's disease in patients in whom there is a high index of suspicion of disease
- Deep enteroscopy is not part of routine diagnostic testing in patients with suspected Crohn's disease, but may provide additional information in patients who require biopsy/sampling of small bowel tissue to make a diagnosis
DIAGNOSIS - Imaging Studies
- Small bowel imaging should be performed as part of the initial diagnostic workup for patients with suspected Crohn's disease
- Computed tomography enterography (CTE) is sensitive for the detection of small bowel disease in patients with Crohn's disease and is comparable to magnetic resonance enterography (MRE)
CT Enterography
DIAGNOSIS - Imaging Studies
- Computed tomography enterography (CTE) is sensitive for the detection of small bowel disease in patients with Crohn's disease and is comparable to magnetic resonance enterography (MRE)
- Because of the absence of any radiation exposure, MRE should be used preferentially in young patients (<35 years) and in patients in whom it is likely that serial exams will need to be performed
- The decision for which small bowel imaging study to use is in part related to the expertise of the institution and the clinical presentation of the patient
- Cross-sectional imaging with MRI of the pelvis and/or endoscopic ultrasound may be used to further characterize perianal Crohn's disease and perirectal abscesses
- If an intra-abdominal abscess is suspected, cross-sectional imaging of the abdomen and pelvis should be performed
- Monitoring disease activity
- Fecal calprotectin and fecal lactoferrin measurements may have an adjunctive role in monitoring disease activity
- Serum CRP is relatively nonspecific for the inflammation of Crohn's disease, but in select patients serial measurements may have a role in monitoring disease activity and response to therapy
- Periodic cross-sectional imaging (CTE, MRE) may be considered in monitoring response to therapy in certain patients with small bowel Crohn's disease
- Mucosal healing as determined by endoscopy is a goal of therapy
MANAGEMENT OF DISEASE
General principles
- Treat "acute disease" or "induce clinical remission" and then "to maintain remission"
- Remission – CDAI < 150
- Mild-to-Moderate Disease – CDAI 150-220
- Severe Disease – CDAI 220-450
- Patient reported outcomes (PRO)
- Symptom assessment
- Rule out other causes (check stool culture, C. Diff, Calprotectin, CRP, SIBO, lactose intolerance, medications, food intolerances, IBS et al)
MEDICAL THERAPY
MILD-TO-MODERATE DISEASE / LOW RISK
- YES
Sulfasalazine
CIR Budesonide
AntiDiarrheals
Diet modification - NO
Oral Mesalamine
Metronidazole
Ciprofloxacin
Moderate-to-Severe Disease/Moderate-to Severe Risk
- Oral corticosteroids are effective for short term use
- Conventional steroids do not consistently achieve mucosal healing and should be used sparingly
- Azathioprine (at doses of 1.5–2.5 mg/kg/day) and 6-mercaptopurine (at doses of 0.75–1.5 mg/kg day) are not more eff ective than placebo to induce short-term symptomatic remission and should not be used in this manner
- Thiopurines (azathioprine, 6-mercaptopurine) are effective and should be considered for use for steroid-sparing in Crohn's disease
- Azathioprine and 6-mercaptourine are effective therapies and should be considered for treatment of patients with Crohn's disease for maintenance of remission
- Thiopurine methyltransferase (TPMT) testing should be considered before initial use of azathioprine or 6-mercaptopurine to treat patients with Crohn's disease
- Methotrexate (up to 25 mg once weekly IM or SC) is effective and should be considered for use in alleviating signs and symptoms in patients with steroid-dependent Crohn's disease and for maintaining remission
- Anti-TNF agents (infl iximab, adalimumab, certolizumab pegol) should be used to treat Crohn's disease that is resistant to treatment with corticosteroids
- Anti-TNF agents should be given for Crohn's disease refractory to thiopurines or methotrexate
- Combination therapy of infliximab with immunomodulators (thiopurines) is more effective than treatment with either immunomodulators alone or infliximab alone in patients who are naive to those agents
- Biosimilar infliximab and biosimilar adalimumab are effective treatments for patients with moderate-to-severe Crohn's disease and can be used for de novo induction and maintenance therapy
- For patients with moderately to severely active CD and objective evidence of active disease, anti-integrin therapy (with vedolizumab) with or without an immunomodulator is more effective than placebo and should be considered to be used for induction of symptomatic remission in patients with Crohn's disease
- Natalizumab is more effective than placebo and should be considered to be used for induction of symptomatic response and remission in patients with active Crohn's disease
- Natalizumab should be used for maintenance of natalizumab-induced remission of Crohn's disease only if serum antibody to John Cunningham (JC) virus is negative. Testing for anti-JC virus antibody should be repeated every 6 months and treatment stopped if the result is positive
- Ustekinumab should be given for moderate-to-severe Crohn's disease patients who have failed previous treatment with corticosteroids, thiopurines, methotrexate, or anti-TNF inhibitors, or who have had no prior exposure to anti-TNF inhibitors
- Cyclosporine, mycophenolate mofetil, and tacrolimus should not be used for Crohn's disease
FISTULIZING CROHN'S DISEASE
Perianal/fistulizing disease
- The presence of a perianal abscess in CD should prompt surgical drainage
- Infliximab is effective and should be considered in treating perianal fistulas in Crohn's disease
- Infliximab may be effective and should be considered in treating enterocutaneous and rectovaginal fistulas in Crohn's disease
- Adalimumab and certolizumab pegol may be effective and should be considered in treating perianal fistulas in Crohn's disease
- Thiopurines (azathioprine, 6-mercaptopurine) may be effective and should be considered in treating fistulizing Crohn's disease
- Tacrolimus can be administered for short-term treatment of perianal and cutaneous fistulas in Crohn's disease
- Antibiotics (imidazoles) may be effective and should be considered in treating simple perianal fistulas
- The addition of antibiotics to infliximab is more effective than infliximab alone and should be considered in treating perianal fistulas
- Drainage of abscesses (surgically or percutaneously) should be undertaken before treatment of fistulizing Crohn's disease with anti-TNF agents
MAINTENANCE THERAPY OF LUMINAL CROHN'S DISEASE
- No maintenance treatment is a treatment option for some patients with asymptomatic (silent), mild Crohn's disease
- Surgery may be considered for patients with symptomatic Crohn's disease localized to a short segment of bowel
- Once remission is induced with corticosteroids, a thiopurine or methotrexate should be considered
- Patients who are steroid dependent should be started on thiopurines or methotrexate with or without anti-TNF therapy
- Oral 5-aminosalicylic acid has not been demonstrated to be effective for maintenance of medically induced remission in patients with Crohn's disease, and is not recommended for long-term treatment
- Data are lacking demonstrating the eff ectiveness of sulfasalazine or of olsalazine for the maintenance of medically induced remission in patients with Crohn's disease and these agents are not recommended for long-term treatment
- Corticosteroids are not effective for maintenance of medically induced remission in Crohn's disease and should not be used for long-term treatmen
- Budesonide should not be used to maintain remission of Crohn's disease beyond 4 months
- Anti-TNF therapy, specifically infliximab, adalimumab, and certolizumab pegol, should be used to maintain remission of anti-TNF-induced remission
- Anti-TNF monotherapy is effective at maintaining anti-TNF-induced remission, but because of the potential for immunogenicity and loss of response, combination with azathioprine/6-mercaptopurine or methotrexate should be considered
- Ustekinumab should be used for maintenance of remission of ustekinumab-induced response of Crohn's disease
POSTOPERATIVE CROHN'S DISEASE: MAINTENANCE, PREVENTION, AND TREATMENT
- Prophylactic treatment is recommended after small intestinal resection in patients with risk factors for recurrence
- Risk factors for postoperative Crohn's disease recurrence should be taken into account when deciding on treatment
- All patients who have Crohn's disease should quit smoking
- Mesalamine is of limited benefit in preventing postoperative Crohn's disease, but in addition to no treatment is an option for patients with an isolated ileal resection and no risk factors for recurrence
- Imidazole antibiotics (metronidazole and ornidazole) at doses between 1 and 2 g/day can be used after small intestinal resection in Crohn's disease patients to prevent recurrence
- Thiopurines may be used to prevent clinical and endoscopic recurrence and are more effective than mesalamine or placebo. However, they are not effective at preventing severe endoscopic recurrence
- In high-risk patients, anti-TNF agents should be started within 4 weeks of surgery in order to prevent postoperative Crohn's disease recurrence
- Surgery is required to treat enteric complications of Crohn's disease
- A resection of a segment of diseased intestine is the most common surgery for a Crohn's disease
- Crohn's disease patients who develop an abdominal abscess should undergo a surgical resection. However, some may respond to medical therapy after radiologically guided drainage
FUTURE DIRECTIVES
Precision Medicine
- More selective use of biologic therapy based on individual risk/benefit assessment (specific tissue signatures and reliable biomarkers)
- Etrolizumab (dual action anti-integrin that inhibits both α 4β 7 and α Eβ 7)
- Ozanimod (a potent sphingosine-1-phosphate receptor modulator that inhibits the egress of lymphocytes from lymph nodes)
- Risankizumab and brazikumab (anti-IL-23 agents)
- Filgotinib and upadacitinib (formerly ABT-494, selective Janus kinase-1 inhibitors)
- Other treatment modalities, some of which will be discussed here by other speakers
References:
Gary Gorodokin
Gastroenterology Consultants of North Jersey, New Jersey, USA
Gastroenterology Consultants of North Jersey, New Jersey, USA