Therapeutics of IBD

What is IBD?

Inflammatory disease of the bowel. Idiopathic and chronic. Relapse and remission. Distinct differences between UC and CD. Umbrella term for UC and CD

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Describe the pathology of CD

Can affect any part of the GIT. Patchy, transmural inflammation. Defined by location or by pattern (inflammatory, fistulating or stricturing). Terminal ileum, ileocolon, colon

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Describe the pathology of UC

Diffuse mucosal inflammation, limited to the colon, broadly divided into distal and more extensive disease, not associated with fistulae or fissures. Pancolitis, distal colitis, proctitis

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Describe the management of mild to moderate CD (1)

Induce remission - oral steroids (prednisolone) or budesonide/5-ASA if prednisolone is not tolerated and distal ileal, ileocecal

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Describe the management of mild to moderate CD (2)

Induce remission/add-on therapy - azathioprine/mercaptopurine or methotrexate (if >2 exacerbations in 12 months or steroids cannot be weaned)

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Describe the management of mild to moderate CD (3)

Maintenance - azathioprine/merceptopurine or methotrexate

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Describe the management of moderate to severe CD (1)

Induce remission - glucocorticoids (PO/IV), consider using infliximab, adalimumab, vedolizumab or ustekinumab

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Describe the management of moderate to severe CD (2)

Induce remission/add-on therapy - azathioprine/mercaptopurine or methotrexate

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Describe the management of moderate to severe CD (3)

Maintenance - infliximab, adalimumab, vedolizumab or ustekinumab potientially with azathioprine/mercaptopurine or methotrexate

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Describe the management of fistulating disease for CD (1)

Induce remission - antibiotics (check if anaerobic needed e.g. metronidazole/ciprofloxacin)/drainage, consider infliximab or adalimumab

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Describe the management of fistulating disease for CD (2)

Induce remission/add-on therapy - azathioprine/mercaptopurine or methotrexate

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Describe the management of fistulating disease for CD (3)

Maintenance - infliximab or adalimumab potentially with azathioprine/mercaptopurine or methotrexate

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Describe the management of mild UC (1)

Induce remission - oral 5-ASA (use topical if left sided disease/proctitis either alone or in combination with PO 5-ASA) and/or topical steroid (left sided/proctitis) or PO steroid (beclomethasone, budesonide or prednisolone)

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Describe the management of mild UC (2)

If contraindicated/not tolerated to 5-ASA or no improvements after 4 weeks of 5-ASA therapy

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Describe the management of mild UC (3)

Add in therapy/maintenance - PO 5-ASA (topical if left sided, proctitis, alone or in combination with PO 5-ASA) and oral azathioprine/mercaptopurine if >2 inflammation exacerbations in 12 months requiring systemic corticosteroids

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Describe the management of mild UC (4)

Or if remission not maintained by aminosalicylates

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Describe the management of moderate UC (1)

Induce remission - PO 5-ASA and/or PO beclomethasone/budesonide or prednisolone if cannot tolerate/CI to 5-ASA or no improvements after 4 weeks of 5-ASA therapy and tacrolimus in adequate response to oral prednisolone after 2-4 weeks

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Describe the management of moderate UC (2)

Add in therapy/maintenance - PO 5-ASA (topical if left sided/proctitis, alone/with PO 5-ASA) and PO azathioprine/mercaptopurine if >2 inflammatory exacerbations in 12 months requiring systemic corticosteroids or if remission not maintained by 5-ASA

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Describe the management of severe UC (1)

Induce remission - IV corticosteroids (hydrocortisone), (IV cyclosporin for symptoms which don't improve after 72 hours, not used anymore, toxic). Or infliximab rescue therapy in those who fail steroid therapy

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Describe the management of severe UC (2)

Infliximab, adalimumab, golimumab and vedolizumab can be considered for treatment of moderate-active UC. Or consider surgery in acute severe colitis not responding to steroid treatment

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Describe the management of severe UC (3)

Maintenance - infliximab, adalimumab, golimumab, vedolizumab and tofacitinib can be considered for treatment of moderate-active UC and consider adding PO azathioprine/mercaptopurine for maintenance treatment

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What is the management strategy for IBD? (1)

Top-down treatment. Aggressive therapy for acute attack/relapse. Supportive/symptomatic during remission for - dehydration (seen as medical emergency/hypovolemic shock, most water absorbed in colon, frequent urination), malabsorption (need nutrition)

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What is the management strategy for IBD? (2)

Anaemia (need to stop bleed), infection (give antibiotics). Want to achieve remission - absence of inflammatory symptoms (rectal bleeding/diarrhoea), evidence of mucosal healing (absence of ulceration/granularity/friability on biopsy)

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What is the management strategy for IBD? (3)

Prophylaxis/maintenance medications. Want to stop inflammation and avoid surgery if possible

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What does the choice of therapy depend on? (1)

Diagnosis, disease severity (mild, moderate, severe). Severity based on - stool frequency (particularly nocturnal), passage of blood, abdominal pain, sense of wellbeing (systemic toxicity). Disease extent and location. Response to treatment

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What does the choice of therapy depend on? (2)

Patient preference. Empower patients to become centre on their own disease management (as in other chronic diseases)

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Describe the role of corticosteroids (1)

Used only to induce remission for acute flares in IBD. No role in maintenance of disease (ADRs, associated with use >12 weeks). Induce remission, start with 40 mg prednisolone then reduce gradually over 8 weeks to avoid relapse

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Describe the role of corticosteroids (2)

(Bad side effects of prednisolone e.g steroid induced diabetes)

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When is the therapy escalated beyond corticosteroids?

When there is no response to corticosteroids. >2 steroid courses in 12 months (4 months of steroids with a break in between). Relapse if dose weaned. Relapse within 6 weeks of stopping steroids

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What are the formulations for corticosteroids? (1)

IV - hydrocortisone, methylprednisolone, for 3-5 days in severe acute attack and then switch to oral prednisolone. Oral - prednisolone, budesonide, beclomethasone

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What are the formulations for corticosteroids? (2)

Rectal - prednisolone, hydrocortisone, budesonide (for local effect on terminal colon/rectum only, reduces ADRs, formulation depends on extent of disease)

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Describe features of budesonide (Entocort/Budenofalk) (1)

Alternative to prednisolone. Used mainly in CD affecting terminal ileum, ileo caecal and ascending colon. Extensive first pass metabolism (90%). Less adrenal suppression and adverse effects compared to prednisolone but less effective and expensive

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Describe features of budesonide (Entocort/Budenofalk) (2)

Budenofalk, 3 mg TDS, released in terminal ileum and caecum. Entocort CR, 9 mg OD for up to 8 weeks, released in ileum and ascending colon

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Which brand of budesonide if used in UC only?

Budesonide MMX (Cortiment) - timed release preparation specific to colon

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Describe features of aminosalicylates (5-ASA) - 1

Mainstay treatment of UC. For acute attacks (high doses) in mild-moderate UC and CD. Maintenance in UC. Maintenance therapy may reduce risk of colorectal cancer by 75%. Role for maintaining remission for CD less clear (sulphasalazine)

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Describe features of aminosalicylates (5-ASA) - 2

Choice of 5-ASA influenced by tolerability, dose schedule, site of action and cost

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Describe features of sulphasalazine

(5-ASA + sulfapyridine). Less favoured due to adverse effects of sulfapyridine (agranular cytosis, nausea) . Cheap, still well tolerated by 70% of patients (large tablets, multiple dosing). Still used in patients with UC and rheumatoid symptoms

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Describe features of other aminosalicylates

Topically acting rather than systemic action. Mesalazine (no sulphonamide), coated 5-ASA designed to be delivered in the colon. Olsalazine and balsalazide, 5-ASA linked to an inert carrier

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Mesalazine is available in which formulations?

Suppositories, foam enemas, liquid enemas

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Topical preparations are good for which cases?

Disease located in sigmoid colon, descending colon and rectum. Long term proctitis. (Oral - different formulations not necessarily interchangeable). Brand/drug/formulation depends on site of delivery (table) and pH of site

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What are the adverse effects of aminosalicylates?

Dry skin, headaches, decreased renal function, hypersensitivity and rashes, blood dycrasias (report any unexplained bleeding, bruising, sore throat, fever, malaise), reversible male fertility, hepatitis

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Steroid sparing is considered for which patients?

Patient needing 2 or more steroid course a year. Those with disease relapsing as dose of steroid reduced <15 mg OD. If relapse within 6 weeks of stopping steroids

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Describe features of azathioprine (AZA) - 1

Effective for both active disease and maintaining remission in UC/CD. Used in steroid dependent/resistant patients. Main agent for maintenance therapy for CD. Slow onset - cover with steroids for 8-12 weeks (or infliximab)

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Describe features of azathioprine (AZA) - 2

Good maintenance of fistulating CD. Can lead to mucosal healing. (Cochrane Reviews)

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Which agents are used in Crohn's Disease?

Azathioprine, 6-mercaptopurine (6MP), tioguanine and methotrexate (cyclosporin and tacrolimus not used)

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Describe features of thiopurines (AZA, 6MP) - 1

Effective for active disease and maintain remission. Slow onset of action 2-3 months (not suitable as monotherapy in active disease). Dampen down the overactive immune system (inhibits ribonucleotide synthesis, inhibits T cell apoptosis, target TNFa)

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Describe features of thiopurines (AZA, 6MP) - 2

Can lead to mucosal healing. AZA is a prodrug for mercaptopurine (imidazole ring increases bioavailability, increases side effects, 80% of AZA converted to 6MP

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Describe features of thiopurines (AZA, 6MP) - 3

Metabolised to active thioguanine nucleotides (fake nucleotide, prevent RNA replication, breaks down rapidly dividing cells). Tioguanine - active drug, hospital only, consultant advice, not prescribed by GP. Unlicensed for IBD (allopurinol)

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Why are immunosuppressants used in combination with a biologic (e.g. infliximab)?

Biologic contains monoclonal antibodies. The body can develop antibodies to the immunosuppressant drug and reduce the effectiveness of the drug. Use of a biologic prevents antibodies forming against immunosuppressant drug

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Which test needs to be carried out before azathioprine/6-MP dosing? (1)

TPMT level should be taken (Thiopurine methyltransferase). High activity (26-50), AZA dose of 2-2.5 mg/kg/day or 6MP dose of 1-1.5 mg/kg. Intermediate activity (10-25), AZA dosing of 1mg/kg, 6MP dosing of 0.5mg/kg

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Which test needs to be carried out before azathioprine/6-MP dosing? (2)

Low activity (<10), AZA dosing - avoid 5-10 mg/day, 6MP dosing - avoid or 2.5-5mg/day. (Dosing for AZA and 6MP is a 2:1 ratio, 6MP is half the mwt of AZA)

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What are the adverse affects of azathioprine? (1)

Flu-like symptoms occur 2-3 weeks later and cease rapidly when drug is withdrawn. Joint pains, fatigue, nausea, bone marrow suppression - risk increased after using drug for 5 years (FBC). Risk of bowel cancer if IBD not controlled

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What are the adverse affects of azathioprine? (2)

Liver toxicity, idiosyncratic pancreatitis (2%), increased risk of skin cancer and non-Hodgkins lymphoma

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What is the monitoring for azathioprine (or 6MP)?

Dose based on TPMT. Monitor FBC, LFT, CRP, TGN, MMP levels regularly for first 3 months then at 3 monthly intervals. PE - try to take drug at night to prevent nausea/vomiting, or change AZA to 6MP if S/E not tolerated

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Describe features of methotrexate (1)

Immunosuppressant. PO or SC once weekly. Evidence for use in CD (not UC). 2nd line for inducing remission/preventing relapse in CD. Successful in steroid and AZA-unresponsive CD

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Describe features of methotrexate (2)

Dose to achieve remission - 25 mg OW for 16/52. Dose to maintain remission - 15 mg OW for 40/52. Measure MTX polyglutamate levels, takes 8 weeks to reach steady state (monitoring booklet). One strength of MTX provided (e.g. 2.5 mg tablets)

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What are the adverse effects of methotrexate? (1)

Nausea, vomiting (co-prescribe with 5 mg folic acid, take weekly but not on the same day as MTX). Mouth ulcers. Rash. Bone marrow suppression (bruising, bleeding, sore throat, increased risk of infection, avoid live vaccines

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What are the adverse effects of methotrexate? (2)

Lung disease (unexplained SOB, severe abdominal pain, jaundice). Teratogenic (not suitable to patients who wish to start a family, need to stop 3-6 months in advance for family planning)

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What needs to be monitored for MTX?

FBC, renal and liver function tests, lung function before and during therapy. Adjust dose after 3 months

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Describe features of cyclosporin (for acute UC only) - no longer used due to toxicity (1)

Used in acute steroid resistant severe UC (toxic megacolon). Used infrequently and for short periods (3-6 months). Last measure before surgery. IV infusion (if successful, PO form substituted before bridging to AZA/6-MP)

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Describe features of cyclosporin (for acute UC only) - no longer used due to toxicity (2)

If used with steroids and AZA/6MP give cover against infection (co-trimoxazole). Regular measurement of BP, FBC, LFT, Mg and renal function (tacrolimus - alternative)

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Describe features of tacrolimus (1)

Last resort after trying immunosuppressants/biologics, toxic, need to carry out ECG. Recommended by NICE in moderate-severe UC. PO preparation (Adoport). Monitor trough levels, renal function, LFTs, Mg, cholesterol, BP, signs of neuropathy

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Describe features of tacrolimus (2)

Not well tolerated, hospital only medication

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Describe features of infliximab (1)

Genetically engineered murine-human chimeric monoclonal antibody. 5 mg/kg at week 0,1,6 then 8 weekly. Review after 2nd/3rd dose. Infusion over 2 hours. Risk of ADRs (infusion reaction). Dose escalate if stop responding/switch to adalimumab

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Describe features of infliximab (2)

Could get sensitivity reactions. Need LD due to long t 1/2, ensure there is enough drug in the body for an effect. Check infliximab levels, adjust dose after month 4, check effectiveness. Max of 10 mg/kg (depends on cost)

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Describe features of infliximab (3)

Consider alternative treatment if there is a flare after second dose. Pre-meds - paracetamol, adrenaline, hydrocortisone (for hypersensitivity reaction)

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What is infliximab licensed for? (1)

Treatment of severe active CD (no response/CI of corticosteroids and immunosuppressants). Treatment of fistulising CD (no response to conventional treatments - antibiotics, drainage, immunosuppressive therapy). Maintenance of CD

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What is infliximab licensed for? (2)

Treatment of severe acute UC (for patients where cyclosporin is inappropriate). Maintenance of remission in UC patients. Neutralisation anti-TNFa activity

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How is infliximab administered?

Given every 8 weeks. Most patients lose response over years (aim to give immunosuppressant alongside where possible). Limitation - IV administration, cost, long-term, consequences

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What are the ADRs for infliximab?

Derived from murine (mouse) protein. Reactivation of latent infections e.g. TB, infusion reactions, neuropathy, demyelination, dermatitis, psoriasis

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Describe features of adalimumab (Humira) - 1

Fully humanised anti-TNF monoclonal antibody - less associated reactions. Neutralisation anti-TNFa activity. 160 mg week 0, 80 mg week 2, 40 mg every 2 weeks. Can increase to 40 mg weekly. Can be self-administered at home (SC)

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Describe features of adalimumab (Humira) - 2

Evidence that can switch to Humira when infliximab fails. Immunosuppressive therapy should be given alongside if possible

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Describe features of golimumab

Alternative to adalimumab in moderate UC only. Neutralisation anti-TNFa activity. SC injection, self-administered, 4 weekly, dose depends on weight (>80 kg, 100 mg per week, <80 kg, 50 mg per week)

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Describe features of vedolizumab (1)

For moderate-severe active UC where previous therapies were ineffective/poorly tolerated. Binds to a4b7 integrin on surface of gut homing circulating lymphocytes. Inhibits interaction between leukocytes and intestinal vasculature

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Describe features of vedolizumab (2)

Blocks recruitment of inflammatory cells into intestine. Used in CD and UC, 8 weekly infusion, less S/E than anti-TNF (gut specific), dose of 300 mg (no change in dosing), expensive

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Describe features of ustekinumab (1)

Human IgG1k MAB binds. First dose given as IV infusion (based on weight) then SC administration after. Second SC dose of 90 mg at week 8. Review at week 14 to decide frequency. Maintenance either 8 weekly or 12 weekly. Only for CD (currently)

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Describe features of ustekinumab (2)

First IV dose given over 1 hr. Next doses SC, expensive

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What needs to be considered when using biologics? (1)

CI (active infection, moderate-severe HF, known hypersensitivity to drug). Pre-screening (FBC, CRP, LFT, renal profile, Hep B serology, Hep C, HIV, in absence of clear PMH of chickenpox, varicella zoster virus, active/latent TB, active malignancy)

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What needs to be considered when using biologics? (2)

Monitoring (FBC, LFTs, renal profile, HBI and markers of disease, weight, infliximab patients). Reassess patient every 3 months then every 12 months (and check disease activity scores)

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Describe features of tofacitinib (1)

Treatment of adult patients with moderate-severe active UC with inadequate response, loss of response or intolerance to either conventional therapy or biological agent. Potent JAK inhibitor

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Describe features of tofacitinib (2)

10 mg PO BD for induction for 8 weeks then 5 mg BD for maintenance (reduced dose if patient improves). Given PO with/without food. Pre-checks - RF, liver, pregnancy/breastfeeding, stop CIM/biologics, serology, TB

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Which biologics are used in moderate-severe active CD?

Infliximab, adalimumab, ustekinumab and vedolizumab

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Which biologics are used in moderate-severe active UC?

Infliximab, adalimumab, golimumab, vedolizumab and tofacitinib

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Which antibiotics are used in IBD? (1)

Metronidazole (prevent relapse after surgery including pouchitis - 6 months, perianal Crohn's fistulating disease, bacterial overgrowth symptoms, not used regularly, peripheral neuropathy)

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Which antibiotics are used in IBD? (2)

Ciprofloxacin and rifampicin/rifazimin (bacterial overgrowth, anti-AMP/triple therapy). Ciprofloxacin - long term, low dose if chronic pouchitis

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What are the adjunctive treatments? (1)

Smoking cessation (CD, smoking can worsen symptoms). Diet (elemental, low FODMAP - removal of sugars to improve symptoms). Antimotility and antispasmodic drugs e.g. codeine, loperamide (limited use - short term symptomatic use in mild exacerbations)

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What are the adjunctive treatments? (2)

May induce toxic megacolon in UC. Diarrhoea, cholestyramine if due to bile salt malabsorption, especially after small bowel surgery. Iron and vitamins, stress management

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Describe features of surgery and IBD

Indications. UC - unresponsive to medical therapy, toxic megacolon, colorectal cancer. CD - unresponsive to medical therapy, disease is treatable by surgery, severe perianal infection, cancer, obstruction, fistula, abscess, strictures

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What are the complications of surgery?

Pouchitis, faecal incontinence, prolapse, anastomotic stricture/leak, stoma, short bowel syndrome. Anastomosis - 2 ends of cut bowel are joined together

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Describe features of surgery and UC (1)

Colectomy (total or partial). Ileal pouch-anal anastomosis as an alternative to stoma. Allows patient to maintain anal function and continence. Pouchitis, long term problem in 30-35% of patients (antibiotics)

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Describe features of surgery and UC (2)

UC is a surgically curable disease if entire colorectal mucosa is removed. Partial colectomy - diseased colon removed, healthy bowel tissue stitched to abdomen, colostomy (bag). Less colon removed, more normal stools. May not need prevention meds

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Describe features of surgery and CD

Avoided as far as possible as relapse is common. Abscess, strictures, perforation, Total colectomy, ileostomy. Segmental resection with re-anastomosis. Recurrence at anastomotic sit (50% relapse). Post-op recurrence prevention - AZA/6MP/MTX

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What are the roles for pharmacists?

Monitoring drugs treatment. Patient counselling. Facilitating actions required by NPSA alert on MTX. Gaining funding for new expensive drugs. Guidelines on drug use. During hospital admissions for surgery

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Therapeutics of IBD

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