Editing Crohn's disease (section)

=== '''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