Inflammatory Bowel Disease

Definition

• Phenotypes

  • penetrating

  • stricturing 

  • ileocolonic

  • perianal

• High risk features 

  • young age of onset

  • initial presentation with significant number of bowel movements

  • perianal or severe rectal disease

  • penetrating or stenosing phenotype

  • ileal or ileocolonic involvement

  • failed lines of therapy

Signs and Symptoms

• Enteroenteric fistula

• Enterovesical vistula

  • frequent UTIs

  • pneumaturia

• Uveitis

  • assess for alarm symptoms, "RSVP" - redness, sensitivity to light, vision changes, pain

  • if present, assess emegently for elevated ocular pressure

• Nephrolithiasis

  • most frequent types of stones in Crohn's disease

    • • calcium oxalate

        • result from hyperoxaluria due to disruption of the enterohepatic circulation and bile acid malabsorption (ex. in distal ileal disease or ileal resection)

        • as more bile acids enter the colon, they competitively bind with calcium, allowing more free oxalate to be absorbed into the circulation and eventually excreted through the kidneys where it binds to calcium and forms calcium oxalate stones

        • altered colonic permeability and GI decolonization of Oxalobacter formigenes have also been implicated 

        • Prevention

          • hydration

          • restrict dietary fat and oxalate

          • increase dietary calcium

          • cholestyramine - can reduce fat malabsorption and enhance oxalate excretion in stool

      • uric acid

        • caused by low urine pH and low urine volume which can develop in the setting of increased stool output, particularly in those with end ileostomy or significant colonic resection

        • Prevention

          • hydration

          • alkalization of the urine - use potassium bicarbonate or potassium citrate

• Hepatosplenic T-cell lymphoma (HSTCL)

  • a very rare neoplasm, accounting for <1% of non-Hodkin's lymphoma

  • ~10-20% of these HSTCL cases are associated with immunosuppression

  • in IBD there is an association with thiopurines + anti-TNF combination therapy with the two

    • not seen in anti-TNF monotherapy or in combination with MTX

  • greater risk in males < 35 yo

• Non-Hodgkin's Lymphoma

  • increased risk in men and patients <30 yo treated with thiopurines

Endoscopic Findings

• Following ileocecal resection

  • ulceration limited to the anastomosis but not involving the neoterminal ileum is not considered endoscopic recurrence

  • frequently reflects ischemia at the site of the anastomosis rather than recurrent disease

• Rutgeerts score

  • assessment after surgery

  • i1 (< 5 ulcers) - low risk for recurrence

    • continue current medication regimen

  • i2 (> 5 ulcers) - high risk for recurrence

    • optimize or augment medication regimen  

Imaging Findings

• MRE

  • should be a part of initial diagnostic work up for CD

Lab Findings

• Elevated fecal calprotectin

  • poor sensitivity for small bowel inflammation

Treatment Agents

• Mesalamine

  • no significant benefit over placebo in Crohn's in induction or maintenance of remission

• Oral steroid

  • Intermittent courses of budesonide

  • can be used for induction, NOT for maintenance

• Anti-TNF inhibitor

  • Treatment failure

• • • Primary non-responder

      • no improvement after completing induction

    • Secondary loss of response with mechanistic failure

      • sufficient drug level, absent antibodies

      • change to another drug in a DIFFERENT class

    • Secondary loss of response with immunogenic failure

      • low drug level, elevated antibodies

      • may change to another drug within the SAME class

• • Contraindications

    • small increased risk of lymphoma

    • anti-TNF treatment linked demyelination disorders (ex. optic neuritis, multiple sclerosis)

      • avoid in patients with personal or family history of demyelination disease

    • all can be used safely in pregnancy

    • avoid initiating in those with latent tuberculosis until completing treatment 

      • but if urgent, may initiate after at least 4 wks of latent TB treatment

    • avoid in moderate to severe heart failure

      • AT-TACH trial assessing anti-TNF therapy for heart failure  showed high rate of death

  • Factors associated with accelerated drug clearance

    • increased BMI leads to increased clearance

    • presence of anti-drug antibodies

    • greater degree of systemic inflammation (evidenced by higher levels of serum CRP or plasma TNF concentration)

    • lower serum albumin concentration leads to increased clearance

    • ulcerative colitis has greater drug clearance than Crohn's disease

    • concomitant therapy with immunosuppressive agents 

    • retrospective data have demonstrated reduction in 3 month colectomy rate with higher dosing of infliximab in those with these risk factors. Further prospective studies are needed to guided dosing

  • Side effects

    • anti-TNF induced psoriasis

      • most commonly involves palms of hands, soles of feet, and scalp

      • female gender and smoking increases risk for this

      • can be seen in both UC and Crohn's (though slightly more common in Crohn's)

      • the IBD is often in clinical remission (88.1%) at the onset of psoriasis

      • dermatologic complications associated with higher anti-TNF dosing suggesting a dose dependent effect

      • withdrawal of therapy typically not recommended (though does result in rapid resolution of rash)

        • most improve with topical therapies - corticosteroid, keratolytics, emollients, or UV lights)

        • may consider switching to a different anti-TNF but risk of recurrence is high

        • may consider ustekinumab in severe cases of anti-TNF induced psoriasis

      • Versus: idiopathic plaque psoriasis - affects extensor surfaces of elbows, knees

    • eczema, vitiligo, lichenoid reactions, acneiform eruptions

    • vasculitis

    • erythema nodosum

  • infliximab monotherapy

    • 5 mg/kg at weeks 0, 2, and 6, then every 8 weeks

      • may adjust to every 4-10 wks pending trough levels

    • trough goal >5 mcg/mL

      • patients with fistulizing Crohn's may need higher levels 15 mcg/mL

      • if trough low without antibodies

        • non-immune medicated pharmacokinetic failure

        • optimize the index drug before switching to a different agent

          • increase drug dose

          • decrease drug dosing interval

          • add immunomodulator therapy 

      • moderate to severe disease activity despite adequate trough level and no antibodies

        • suggests mechanism failure and should consider switching drug classes

      • High titer of anti-drug antibodies

        • suggests immune medicated pharmacokinetic failure

        • conisder trying a different TNF-inhibitor

  • adalimumab (Humira) monotherapy

    • 160 mg at wk 0, then 80 mg at wk 2, then 40 mg every 2 wks

    • Goal trough level 10-12

  • certolizumab

    • only approved for use in Crohn's disease, NOT in UC

• Combination therapy

  • adalimumab and azathioprine

    • use when failing infliximab (high antibody level, low drug level)

• Antimetabolite

  • Methotrexate

    • can be used for maintenance in CD, NOT for induction

• Thiopurine

  • Drug characteristics

    • slow onset of action, may take 6-12 wks to achieve full clinical response

    • unlikely to see additional benefit after 12 wks, especially if 6-TGN is already therapeutic 

  • Metabolites

    • 6-TGN level (normal 230-450 pmol/8x108 RBC)

      • ongoing disease activity despite therapeutic level suggests thiopurine therapy failure

        • consider changing to another therapeutic class, such as anti-TNF

        • or add a second therapeutic agent 

    • 6-MMP level (normal less than 5700 pmol/8x108 RBC)

  • Labs to monitor, dose dependent toxicity

    • LFTs - assess for hepatotoxicity

    • WBC - assess for leukopenia

  • Side effects

    • drug-induced pancreatitis - a dose dependent idiosyncratic reaction

      • contraindication for the use of any other thiopurine agent

    • small increased risk of lymphoma

      • Non-Hodgkin's lymphoma in men and patients <30 yo

      • HSTCL in men <35 yo

    • risk of lymphoproliferative disorder

      • highest risk in older patients (>50 yo)

      • if in clinical and endoscopic remission, consider discontinuing 

    • bone marrow suppression

    • increased risk of non-melanoma skin cancer

      • thought to be related to increased photosenstivity

    • increased risk of herpes zoster

  • Azathioprine

    • 2-2.5 mg/kg/d

    • effective of maintenance but NOT for induction of remission 

      • prolonged time to onset of drug activity

  • 6-MP

    • 1.5 mg/kg/d

    • effective of maintenance but NOT for induction of remission 

      • prolonged time to onset of drug activity

• Anti-integrin

  • Vedolizumab

    • approved for induction and maintenance in Crohn's disease

    • a humanized monoclonal antibody that targets α4β7 

      • a4b7 is a cell-surface glycoprotein variably expressed on circulating B and T lymphocytes

      • it interacts with mucosal vascular addressin cell adhesion molecule 1 (MAdCAM-1) on intestinal vasculature

    • selectively blocks gut lymphocyte trafficking without interfering with trafficking to the central nervous system

    • 300 mg at weeks 0, 2, 6, and then every 8 wks

  • Natalizumab

    • inhibits a4b7 and a4b1 integrins

    • monoclonal antibody with efficacy in multiple sclerosis and Crohn's disease

    • associated with primary multi-focal leukoencephalopathy (PML)

• IL12/IL23 inhibitor 

  • ustekinumab

    • used for induction and maintenance for Crohn's disease

    • induction dose based on weight, then 90 mg SQ every 8 wks

    • blocks P40, a common subunit of IL12/IL23

    • approved for treatment of psoriasis and Crohn's 

• Treatment with IL17 inhibitor (secukinumab) is NOT used

  • currently used to treat psoriasis and ankylosing spondylitis

  • shown to cause aggravation of Crohn's

  • IL17 (product of T helper 18, Th17)  is a potent proinflammatory cytokine that facilitates T cell activation leading to production of inflammatory cytokines/chemokines

  • But blocking IL17 did not result in improved colitis in experimental mice

Treatment by Indication

• Moderate to severe ileocolonic CD

  • Induction: infliximab with a thiopurine is superior to either therapy alone

• Moderate to severe distl ileal disease

  • Induction: short term ileal release budesonide

• Ileocecal resection

  • In ileal resection <100 cm where the ileum is connected to an intact colon

    • associated with bile acid wasting

    • leads to secretory diarrhea (choleretic enteropathy)

      • results from the reduction in bile acid absorption at the terminal ileum

      • more bile acids reach the colon irritating the mucosa and causing secretory diarrhea

      • can be treated with bile acid binding agents (ex. cholestyramine)

      • may consider SIBO if the patient doesn't respond to cholestyramine

  • In ileal resection >100 cm

    • leads to insufficient bile acid concentrations, fat malabsorption, fat soluble vitamin deficiency

    • cholestyramine may worsen the malabsorption

• In the case of high risk features for recurrence following surgical resection

  • early prophylaxis recommended over endoscopy guided therapy

  • First line: anti-TNF therapy and/or thiopurine

  • Second line: antibiotics (nitroimidazoles)

  • AGA recommends against mesalamine, budesonide, and probiotics

  • Repeat colonoscopy at 6-12 mo after surgical resection to evaluate for disease recurrence

• Abdominal pain and IBS like symptoms in the absence of active disease

  • nortriptyline

• Diarrhea in absence of active disease with intact anatomy and gallbladder

  • eluxadoline

• Perianal fistula with abscess

  • exam under anesthesia with drainage

• Perianal fistula without abscess

  • ustekinumab - may be beneficial for fistula closure and maintaining closure

  • short course of antibiotics in combination with anti-TNF

  • if severe or refractory consider diverting colostomy

Treatment in Pregnancy

• ongoing disease activity carries the highest risk in pregnancy outcome

  • preterm birth

  • low birth weight

  • stillbirth 

  • miscarriages or abortions

• majority of IBD therapies have been showing to be safe during pregnancy, including...

  • TNF-inhibitors

  • thiopurines

  • most 5-ASA compounds

  • Vedolizumab - appear safe, but safety data are limited

  • Ustekinumab - appear safe, but safety data are limited

  • Tofacitinib - appear safe, but safety data are limited

• Teratogenic medications

  • methotrexate

  • metronidazole - may be associated with cleft lip and palate (avoid in 1st trimester)

  • ciprofloxacin - risk of skeletal deformities in fetus

  • steroids - can be used to control flares but avoid in 1st trimester, linked to cleft lip/palate and premature rupture of membranes

• C-section delivery recommended for those with active perianal disease

  • A few studies have shows worsening perianal disease after vaginal delivery

  • Active perianal disease is associated with increased risk of 4th degree laceration with vaginal delivery

• Children born to mothers who have received infliximab, adalimumab, or golimumab (in UC) 

  • should not get any live vaccines during the first 6 mo of life (ex. rotavirus vaccine)

  • these newborns are immunosuppressed because anti-TNF agents cross the placenta

  • newborns have an immature reticuloendothelial system and are unable to clear antibodies

  • these children do NOT have a reduced response to inactivated vaccines (PIANO study)

  • no clear guidelines about when to hold anti-TNF therapy in pregnant patients

Vaccinations

• in general, live vaccines should be avoided for at least 4 wks prior to initiation and during treatment with biologic therapy

• live attenuated vaccines are contraindicated in patients on immunosuppressive therapies, avoid the following vaccines

  • MMR, varicella, herpes zoster live-attenuated (Zostavax), yellow fever

• inactivated zoster vaccine (Shingrix) can be given, also has superior efficacy and durability

• Ensure vaccination for... 

  • influenza (inactivated vaccine)

  • pneumococcal (PPSV-23 and PCV-23)

  • zoster (Shingrix)

  • HPV (recommended for men and women 11-45 yo)

• Malaria prophylaxis (doxycycline, mefloquine, primaquine, chloroquine, hydroxychloroquine, and atovaquone-proguanil) are safe in IBD or those on TNF inhibitors

Screening

• Screening colonoscopy 

  • First 8-10 y after diagnosis of UC or CD that involves >1/3 of the colon

  • subsequent intervals at 1-3 years

• Monitor for post-operative recurrence

  • colonoscopy 6-12 mo after surgery

• Screening for osteoporosis

  • prevalence of osteoporosis in IBD patients is ~15% and is strongly affected by age

  • in IBD patients, men and women are at equal risk

  • strongest risk factor for osteoporosis in IBD patients is steroid use

  • screen if oral steroids used for >3 consecutive mo at ≥7.5 mg of prednisone 

  • no specific age recommendation for screening in IBD patients

• women with UC and Crohn's have an increased risk of cervical dysplasia 

  • in UC there is an increased risk of low and high grade squamous intraepithelial lesions

  • in Crohn's there is an increased risk of cervical cancer

  • age appropriate screening with annual pap smears recommended regardless of treatment type

Fish Oil

• benefit thought to be driven by it's main component, omega-3 polyunsaturated fatty acids (implicated in a favorable shift of gut microbiota)

• no convincing evidence of benefit

  • Crohn's

    • Two large RCTs - EPIC 1 and EPIC 2 - no better than placebo in preventing relapses

  • Ulcerative colitis

    • Some potential impact on fecal inflammatory markers and steroid requirements

    • no impact on reducing relapses

 Curcumin

• major ingredient in the spice, turmeric

• has anti-inflammatory and antioxidative properties on lymphocytes and gut epithelial cells

• Ulcerative colitis

  • Hanai et al - RCT showed potential efficacy in maintaining remission, less likely to relapse

  • Lang et al - RCT showed potential role in inducing remission, more likely to achieve clinical and endoscopic remission

Cannabis

• Few small studies - 3 RCTs in IBD patients

  • improves quality of life and general health perception

  • no impact on rates of remission, disease activity scores, or inflammatory markers

VSL #3

• probiotic, with role most established in patients with ileal pouch-anal anastamosis (IPAA)

• superior to placebo in reducing risk of first episode of pouchitis and reducing rates of recurrence after an episode of pouchitis 

• Crohn's 

  • meta-analysis - no clear role in inducing remission or preventing relapse

• Mild to moderate UC

  • meta-analysis - VSL #3 as an addon to conventional therapy is safe and more effective than conventional therapy alone in achieving clinical response in remission

Low dose naltrexone

• Crohn's

  • Cochrane review - current evidence is insufficient to allow firm conclusions on efficacy and safety in patients with active Crohn's disease

Definition

• ileal pouch anal anastamosis  (IPAA)

  • following total proctocolectomy for refractory ulcerative colitis

• ~50% of patients will have no symptoms of pouchitis after total proctocolectomy and IPAA

• ~50% experience pouchitis

  • 11% have 1-2 episodes per year

  • 24% have occasional symptoms

  • 10% have constant symptoms

  • 4% have refractory symptoms

Risk Factors

• NSAID use may be a trigger

  • may also cause ileal inflammation proximal to the pouch

Signs and Symptoms

• increased stool frequency 

• urgency

• lower abdominal pain

Endoscopic Findings

• pre-pouch ileitis limited to the distal 10 cm of the pre-pouch ileum in the setting of diffuse pouchitis

  • more likely an equivalent to backwash ileitis seen in patients with pancolitis rather than Crohn's disease of the small bowel

• rectal cuff mucosa appears normal

Treatment

• ciprofloxacin and metronidazole

• oral budesonide

  • for those who do not response to antibiotics

• discontinue NSAIDs

• VSL-3 

  • a probiotic that has been shown to prevent recurrence of pouchitis after treatment with antibiotics

Endoscopic Findings

• Pouchoscopy

  • normal neo-termianl ileum

  • normal pouch

  • ulceration and erythema in the area of the cuff

Treatment

• mesalaine suppositories

Treatment

• If unresponsive to steroids treat with infliximab