Editing Crohn's disease (section)

== '''Management goals''' ==

# Incurable disease - aim for induction and maintenance of clinical remission
# Avoidance of treatment-related toxicity
# Avoidance of corticosteroids
# Improved quality of life
# Prevention of disease complications, including cancer

=== '''Principles''' ===

* Induce remission with a top-down approach
** Start on oral steroids then attempt to wean
** If unable to wean, treat as moderate-severe disease
* Maintain remission with step-up approach
** More traditional
** Aminosalicylates -> steroids -> immunomodulators -> biologics
* Treat-to-target
** Target endoscopic healing - poor association of inflammation with symptoms. Leads to less surgery and less admissions.
** CDAI can guide symptomatic response (under 'classification')
* Tight control
** Therapeutic drug monitoring - use trough levels combined with symptoms to decide whether disease management is optimal
** Use symptoms and biomarkers (CRP and FC) to predict recurrence and step up therapy
* Minimise treatment toxicity
* Monitor for complications

=== '''Lifestyle''' ===

* Dietary
** Low-fibre diet can help diarrhoea and pain during an acute exacerbation
** Frequently need vitamin supplementation - especially vitamin D, B12, folic acid, iron, zinc, calcium, magnesium
** Exclusive Enteral Nutrition (EEN) is used as an alternative to pharmacological induction agents. This consists of exclusive intake of elemental or non-elemental resource drinks during an acute flare. This is first-line induction therapy in children and second-line in adults (when steroids or biologics are contraindicated), for mild flares. The mechanism is not fully known but may be reduced exposure to antigens in food, altered microbiota, and improved nutritional deficiencies.
** Has been research into elemental diets to maintain remission, but not thought to be particularly important
* Smoking
** Clearly affects disease course - increases incidence of relapse and failure of maintenance therapy, and is associated with severity of disease

=== '''Drug options:''' ===

* '''Aminosalicylates (a.k.a. 5-aminosalicylate or 5-ASA)'''
** More useful in UC than Crohn's
** Exact mechanism of action unknown, but speculated to decrease prostaglandin and leukotriene synthesis
** Folic acid supplementation required
** More useful in UC than Crohn's
** Can be given orally or rectally
** Formulations:
*** Mesalazine/mesalamine are drugs in the 5-ASA class, along with olsalazine and balsalazide
*** Azulfidine/Salazopyrin - sulfasalazine (mesalazine with sulfapyridine molecule (an obsolete antibiotic) still attached - brand name Azulfidine). Clear benefit for colonic CD, but controversial for purely small bowel disease since 90% of it is released in colon. Can't have this with sulfa allergies.
*** Pentasa - slow release of mesalazine though the small bowel and colon, starting in duodenum.
**** Interstitial nephritis (1%) - need regular UEC
**** Can be for UC or Crohn's
*** Asacol (contains mesalazine) - only begins to be released in TI, then coats entire colon
*** Salofalk/Mesasal/Claversal (mesalazine) - released starting in ileocaecal region. Used for UC.
*** Mesavant - mesalazine released throughout colon and rectum
*** Dipentum (olsalazine) - colon
*** Colazide/Colazal (balsalazide) - colon
* '''Corticosteroids'''
** Inhibit the production of pro-inflammatory mediators
** Fast-acting and effective at inducing remission, but not ideal as maintenance therapy (no more effective than placebo, do not induce mucosal healing, and have long-term adverse effects)
** Budesonide - useful due to high first-pass metabolism, allowing targeted GIT therapy. Used at 9mg/day (controlled release) when active mild-mod disease is confined to ileum or right colon.
** Prednisolone - good for mod-severe disease at 40-60mg daily until resolution of symptoms and resumption of weight gain.
** Parenteral steroids (hydrocortisone) are used in severe disease, as long as there is no abscess, and should be tapered once there is clinical improvement (by 5-10mg per week until 20mg, then 2.5-5mg/week until cessation)
* '''Antibiotics'''
** No more effective than placebo in inducing remission
** Clear role for septic complications
** Beneficial in perianal disease
* '''Immunomodulators/suppressors'''
** 'Steroid-sparing' medications - normally used once patients have been unsuccessful in weaning off steroids once or twice
*** Effective in maintenance therapy and for the treatment of mod/severe CD
*** Slow onset (3-4 months) - steroids are needed in induction until the transition to immunomodulators is complete
*** Side effects of pancreatitis, hepatitis, fever and rash, but considered relatively safe
** Thiopurines: AZT (azathioprine (Imuran))/6-MP (mercaptopurine) - both effective in maintaining steroid-induced remission. Purine analogues which inhibit cell proliferation, and suppress cell-mediated events by inhibiting the activity of cytotoxic T cells and NK cells.
*** TPMT (thiopurine methyltransferase) is the enzyme responsible for metabolising AZT and 6-MP and has significant polymorphisms - need to use it to regulate therapy, as low levels can predict adverse effects such as bone marrow suppression, leucopoenia, pancreatitis, hepatitis, fevers and rashes. Need to test for it before starting therapy.
** MTX (methotrexate) - folic acid antagonist - both induction and maintenance therapy. Can be given IM. Inhibits T cell activation and suppression of intracellular adhesion molecule expression by T cells. Down-regulates B cells. Inhibits methyltransferase, which leads to de-activation of enzyme activity that is important to immune cell function. Leads to hepatotoxicity, ulcerative stomatitis, BM suppression, pneumonitis, pulmonary fibrosis and kidney failure. Teratogenic.
* '''Biologic agents'''
** ''Monoclonal antibodies, which target mediators of the inflammatory response.''
** ''Similar safety profiles''
*** ''Increased risk of TB activation/invasive fungal and other opportunistic infections''
*** ''Demyelinating CNS lesions''
*** ''Activation of latent MS''
*** ''Exacerbation CCF''
*** ''Increased risk of melanoma''
** ''Treatment failure on anti-TNF agents''
*** ''Measure serum drug concentrations and anti-drug antibodies''
*** ''If low concentration, increase dose''
*** ''If anti-drug antibodies, switch agent''
*** ''If both ok, switch to another drug class''
** '''Infliximab''' (Remicade/Inflectra/Renflexis) - chimeric monoclonal antibody to TNF-⍺. 
*** Efficacious and safe as induction and maintenance monotherapy for mod/severe CD. 
*** Highly effective in penetrating and extra-intestinal disease. 
*** Results in perineal fistula closure in 65% of patients. 
*** Not every patient responds
*** Levels can be measured - aim for >5microg/mL
** '''Adalimumab''' (Humira/Amjevita/Cyletzo/Hadlima) - humanised IgG1 monoclonal antibody to TNF-⍺.
*** Maintenance agent that can be self-administered
*** Levels can be measured - aim for >5microg/mL
** '''Certolizumab''' (Cimzia) - humanised antibody fragment to TNF-⍺.
*** Ideal in pregnant and breastfeeding women as it does not cross placenta or get excreted in breast milk
** '''Novel therapies'''
*** '''Natalizumab''' (Tysabri) - recombinant humanised monoclonal antibody against ⍺4 integrin 
**** Refractory CD
*** '''Vedolizumab''' (Entyvio)
**** Anti-integrin therapy - prevents lymphocyte migration into intestinal tissue
**** Induction of remission, but very slow onset of action
**** Used in those with a poor response to anti-TNF or immunosuppressants
*** '''Ustekinumab''' (Stelara) - humanised IgG1 monoclonal antibody targeting IL-12/23
**** Effective in severe CD which is refractory to anti-TNF therapies
**** Also good for psoriasis
*** '''Upadacitinib''' (Rinvoq)
**** JAK-1 inhibitor (second-gen JAK inhibitor, more selective than previous)
**** Only approved by FDA since 2022 for IBD, for patients who do not respond adequately to anti-TNF agents
**** Response speed varies from days to 12 weeks
**** Can be used for both induction and maintenance

=== '''Medical management (based on eTG 2/1/23)''' ===

* Induction
** Mild-mod: Prednisolone/prednisone 40-50mg daily in the morning until clinical response, taper over 6-8 weeks. For ileocaecal disease, consider an enteric-coated preparation of budesonide (Entocort or Budenofalk), particularly for patients with a history of adverse reactions to systemic steroids, or precautions to their use (diabetes) - 9mg PO daily in the morning for 4-8 weeks, then taper over 2-4 weeks in 3mg increments to stop.
*** Antibiotics only if there is a confirmed infection
*** After 3 months, if no response, consider TNF inhibitor eg infliximab
** Severe: hydrocort 100mg q6h IV or methylprednisolone 60mg IV total daily, in single or divided dose
*** Generally give IV for 3-7 days depending on response. Switch to PO corticosteroids when disease activity has subsided.
*** Antibiotics only if confirmed infection
*** Alternatives/refractory disease: biologics - infliximab/updacitinib
* Maintenance
** Most patients need ongoing maintenance therapy
** Biologics can maintain remission if they were successfully used for induction
** Thiopurine therapy: azathioprine 2-2.5mg/kg PO daily OR mercaptopurine 1-1.5mg/kg PO daily
** Methotraxate 10-25mg subcut or IM, once per week OR 10-25mg PO weekly PLUS folic acid 5-10mg PO weekly on a different day
** Luminal or fistulising CD that is refractory to above therapy should be given a biologic
* Perianal Crohns disease:
** Metronidazole 400mg BD OR ciprofloxacin 500mg BD is appropriate for active perianal CD. Therapy may be needed for weeks to months. 
** Complex perianal disease should have a TNF inhibitor
* Ileal malabsorption (bile salt diarrhoea)
** Cholestyramine 2-4g PO daily, with all other drugs taken at least 1 hour prior or 4-6 hours afterwards
** Need B12, iron and fat-soluble vitamin supplementation

=== '''Surgery''' ===

* 70% of patients will require bowel resection within 15 years of diagnosis
** Pre-op
*** Medical optimisation - correct anaemia, treat malnutrition (TPN), literature says can operate on infliximab
** Post-op
*** Clinical monitoring
*** Endoscopic surveillance 6-12 months for recurrence
* Minimise surgery, and extent of surgery
** Operative treatment of a complication should treat only that complication - don't attempt to resect more bowel, even if disease is grossly apparent
* General indications:
** Neoplastic and pre-neoplastic lesions
*** Total proctocolectomy is preferable to segmental resection if this occurs in colon
** Obstructing stenoses
** Suppurative complications
*** Fistula (rarely requires operation unless the fistula involves bladder, vagina or skin)
*** Abscess not amenable to conservative management
** Medically intractable disease, including growth retardation
** Haemorrhage
** Free perforation
** Steroid dependence
* '''General tips for operating'''
** Suture ligate mesenteric pedicles rather than simply tying - risk of haematoma/bleeding due to thick, stiff and vascular mesentery
** Low threshold for giving a stoma, if patient is nutritionally depleted. Mostly do a double-barrelled stoma.
* Common situations/general advice
** Operating for RIF pain - acute ileitis found with normal appendix
*** Resect appendix if caecum and appendix appear normal - remove potential cause of pain in the future
*** Do not resect ileum
** Known CD and concomitant appendicitis
*** If base is healthy, resect as normal
*** If base/caecum are unhealthy, consider either treating with antibiotics or performing an ileocaecectomy 
** Stricturing disease causing obstruction
*** See below under 'obstruction'
** Initial resection of short segment of diseased TI
*** Also resect caecum unless there are >6 inches of uninvolved TI distal to diseased segment, as there is highly likely to be a recurrence in this segment
** Bypass procedure
*** Indications:
**** Severe gastroduodenal disease not amenable to stricturoplasty
**** Older poor-risk patients
**** Patients who have had several prior resections and cannot afford to lose any more bowel
**** Resection would necessitate entering an abscess or endangering a normal structure
** Penetrating disease
*** Enteroenteral fistula - not itself an indication for surgery in the absence of sepsis. Medical management with anti-TNF drugs is best.
*** Enterocutaneous fistula - rarely spontaneous, most likely after bowel resection or drainage of an intra-abdominal abscess. May close spontaneously. Follow usual ECF protocol. If conservative management fails, excise the fistula tract and perform a primary anastomosis.
*** Fistula between bowel and other viscera - excise the diseased segment of bowel and the fistula tract, and close the defect in the viscera primarily.
*** Ileosigmoid fistula - only excise the sigmoid if it is also diseased, which is rarely the case.
** Perianal disease
*** Aim for non-operative treatment unless an abscess or complex fistula develops - trial one month metronidazole (or ciprofloxacin), another month antibiotics, then consider seton
*** Don't excise haemorrhoids or large anal skin tags
**** Differentiate between oedematous skin tags vs loose/soft skin tags - the latter can reflect less active disease and may be more ok to excise
*** Non-suppurative, chronic fistulisation or perianal fissuring is treated with antibiotics, immunosuppressive agents and infliximab (results in much improved rates of fistula closure)
**** Can often start medical management with infliximab (targeted to degree of persistent luminal disease/other disease activity/drug levels), then consider removing seton once treatment is established - work closely with gastroenterologists
**** If disease control is unable to be established, keep going with setons
**** If disease is well-controlled, consider definitive fistula treatment
*** Operate carefully, with as small of an intervention as possible
*** Liberal placement of drainage catheters and non-cutting setons
*** Superficial, low trans-sphincteric and low inter-sphincteric fistulas - fistulotomy
*** High trans-sphincteric, supra-sphincteric and extra-sphincteric fistulas - non-cutting setons
*** Fissures are usually lateral, relatively painless, large and indolent and often respond to conservative management
*** Drain abscesses without large excisions of tissue
**** Two weeks post-op metronidazole
*** Proctectomy is sometimes required for patients who have persistent and unremitting symptoms despite conservative medical and surgical therapy
** Duodenal disease
*** Occurs in <5%, most commonly in the duodenal bulb
*** Primary indication for surgery is duodenal obstruction not responding to medical therapy
**** Endoscopic balloon dilation
**** Gastrojejunostomy to bypass
**** Consider stricturoplasty if possible


=== '''Endoscopic surveillance''' ===

* CD: those with extensive or left-sided colitis should be screened at diagnosis and then every 1-2 years until they have 2 consecutive negative exams, at which point stretch out to 3-yearly. After 20 years of disease, should screen 1-2 yearly again.