IBD Flashcards
Why are treatments useful in IBD
Medications are used:
- to induce remission if there is active inflammation
- maintain remission when the inflammation is controlled.
Describe treatment modalities for UC
- 5- Aminosalicylates (5-ASA)
- Steroid (prednisone, prednisolone, budesonide)
- immunosuppression (azathioprine/methotrexate)
- cyclosporin
- Anti-TNF (infliximab) or other biological agents including vedolizumab
Describe treatment modalities for Crohn’s
- steroid (prednisone, prednisolone, budesonide) together with
- immunosuppression (azathioprine/6-mercaptopurine /methotrexate)
- Anti-TNF (infliximab) or other biological agentsincluding vedolizumab and ustekinumab
- 5-ASAhas a limited role
Describe 5ASA
MoA
5-ASA is an agonist for peroxisome proliferator activated receptor gene-γ (PPARγ) ->stimulation of PPARγ decreasesinflammation in the bowel mucosa.
Indications
The mainstay of maintaining remission in UC (can also be used to induce remission in mild disease).
The active agent, 5-ASA, is delivered to the site of action in various formulations:
- Sulfasalazine (5-ASAconjugated to sulfapyridine)
- mesalazine (5-ASA)
- olsalazine (5-ASA dimer linked by a bond that is hydrolysed by colonic bacteria)
- balsalazide (pro-drug of 5-ASA and released following hydrolysis)
A combination of oral and topical 5-ASA compounds brings patients into remission more quickly than oral therapy alone
Adverse effects
- headache, nausea, epigastric pain, skin rashes, interstitial nephritis, blood dyscrasias and hepatitis.
- reversible male infertility (sulfasalazine)
Administration
- 5-ASA is absorbed when administered orally so various formulations are used to deliver the active drug (to prevent absorption) to the colonic mucosa topically so that it can reach the site of action. This can be done a few different ways eg:
- combining 5-ASA with a carrier molecule (e.g. sulfapyridine to form sulfasalazine)
- creating a dimer (eg olsalazine) to prevent its absorption in the small intestine.
- These combination molecules are linked by a diazo ( -N=N- ) bond which is broken down by colonic bacteria to release 5-ASA.
- using formulations which release 5-ASA in the distal small bowel and colon by a pH-dependent mechanism (e.g. mesalazine).
- The choice of formulation for rectal administration of 5-ASA depends on the extent of active disease involvement:
- suppositories can be used for limited proctitis;
- foam preparations for disease extending to the sigmoid colon;
- enemas for disease extending to the descending colon and splenic flexure.
Describe corticosteroids
MoA
Corticosteroids are used for anti-inflammatory properties. They regulate gene expression, which results in:
- glucocorticoid effects, e.g. gluconeogenesis, proteolysis, lipolysis, suppression of inflammation and immune responses
- mineralocorticoid effects, e.g. hypertension, sodium and water retention, potassium loss.
Rapid suppression of inflammation and symptoms usually within days(weighed against the significant side effect profile)
Steroids can also be given topically: the formulation (suppository, foam or enema) depends on the extent of active disease as for 5-ASA.
Indications
Patients with acute flares who are either too sick for or don’t respond/tolerate 5-ASA therapy oral steroids are considered.
Used for moderate to severe UC
NOT effective for maintenance therapy
Crohn’s
For ileocaecal disease, oralbudesonide, particularly for patients with a history of adverse reactions to systemic corticosteroids may be used.
For mild to moderate disease oral therapy is usually adequate, however induction for severe disease may require intravenous therapy for a period.
Adverse effects
Side effects: MANY! Less with topical compared with systematic steroids.
- psychological effects
- sleep disturbance
- weight gain and fat redistribution
- skin atrophy
- immunosuppresssion
- metabolic effects
- osteoporosis
- GI effects
- myopathy
- HPA suppression
- hypertension
- sodium retention
Contraindications
Other information
Budesonide is more active topically in the bowel (compared to it’s systemic effect) when given orally and may offer benefit over other corticosteroids.
Therapy usually requiresstep-down and tapering.
List the immods used in IBD
- corticosteroids
- thiopurines (azathioprine, 6-mercaptopurine)
- methotrexate
- calcineurin inhibitors (eg ciclosporin) - reserved for severe UC (discussed in Block 6 - not here)
- Biologics
- tumour necrosis factor (TNF)inhibitors (e.g. adalimumab, infliximab, golimumab)
- anti-integrin antibodies (e.g. vedolizumab)
- anti-cytokine antibodies (e.g. ustekinumab [anti-IL-23 and IL-12])
All these agents areassociated with an increased risk of infection and requirepre-treatment screeningand, if appropriate, vaccination. Ongoing monitoring is required to minimise the risk of infection and adverse effects.
Immunomodulators are required to maintain disease remission and prevent steroid dependence.
They are not ideal for induction of remission due to their slow onset of action (months)
Recall- axathioprine
MoA
see immsupp deck
Indications
Adverse effects
Contraindications
Other information
AZA- XOI eg allopurinol reduce azathioprine metabolism, increasing the risk of severe bone marrow toxicity. Avoid combination or reduce azathioprine dose to one quarter to one third of normal and monitor CBC closely.
Adverse effects of thiopurines can limit tolerability and adherence. This can be due to shunting, where thiopurines are preferentially metabolised to 6-MMP in preference to 6-tioguanine nucleotides or 6-TGN, resulting in adverse effects eg hepatitis, nausea, and decreased efficacy. This can be confirmed by measuring thiopurine metabolites. Shunting can be reversed by co-administration of allopurinol, reduce the dose of azathioprine, or mercaptopurine to one-third of the patient’s current dose.
AZA- TMPT deficiency must be measured to determine phenotype i.e. enzyme activity, or genotype before starting treatment. People who have low or no detectable TPMT activity are at risk of severe myelosuppression. Avoid use or reduce dose to 1/10th of normal or less
Describe use of thiopuriens eg AZA or mtx FOR IBD
Note for thiopurines or MTX
- Much more evidence for the use of thiopurines and are therefore the class of choice.
- Started when disease is severe at onset
- steroid-dependent
- a second course of steroid for relapse is required within 12 months
- patient has important reason to avoid steroids.
When are biologics used and provide some examples
- Where standard medical therapy has been insufficient
-
TNF-alpha inhibitors (infliximab and adalimumab)
- Effective and approved for both CD and UC
-
Anti-integrin (vedolizumab)
- approved for both CD and UC
- gut-specific target
- longer onset of action than anti-TNF
- IL-12 and IL-23 (ustekinumab)
Describe TNFai
MoA
TNF-alpha antagonists (infliximab, adalimumab and golimumab).
Appear to be effective with 60-70% improvement.
Indications
Effective and approved for both CD and UC
Adverse effects
Contraindications
Other information
Precautions
- _Infection:_Contraindicated in serious or untreated infection, e.g. sepsis, abscess, hepatitisB, active TB (before completing TB treatment). May reactivate inactive hepatitisB and latent TB (begin TB treatment before starting a TNF-alpha antagonist).
- Demyelinating disorders: e.g. MS — contraindicated; TNF-alpha antagonists may increase disease activity.
- Psoriasis and other skin reactions: up to 20% of patients on anti-TNF agents develop skin reactions including psoriasis and eczema.
- _Heart failure:_contraindicated in moderate or severe heart failure (NYHA classIII–IV) and left ventricular ejection fraction <50%; use cautiously in mild disease as TNF-alpha antagonists may worsen heart failure.
- _Treatment with other immunosuppressants:_increases risk of infection;
- _History of blood dyscrasias:_rare cases of serious blood dyscrasias (some fatal) have been reported; monitor complete blood count regularly.
- _Respiratory disease:_may be at increased risk of interstitial lung disease with TNF-alpha antagonists
- _Antibodies against double-stranded DNA (eg lupus):_TNF-alpha antagonists are associated with the formation of autoantibodies to ds-DNA. These mayworsen or induce a lupus-like syndrome.
- Malignancy:Contraindicated if there is a history of lymphoproliferative disease within the last 5years. TNF-alpha affects cellular immune response and its inhibition may affect development of malignancies.
- _Surgery_: Consider the risk of infection.
Describe anti-integrin
eg vedolizumab
MoA
- Gut-specific, recombinant, humanised IgG1 monoclonal antibody against alpha4-beta7-integrin present on the surface of leucocytes, including Tlymphocytes.
- Inhibits adhesion of Tlymphocytes to mucosal addressin-cell adhesion molecule‑1 (MAdCAM‑1) expressed in the GIT and prevents lymphocyte migration into intestinal tissue.
- Slower onset of action compared with anti-TNF
Indications
Approved for both UD and DC, gut-specific targeted. Longer onset of action than anti-TNF
Adverse effects
- Favourable due to GIT selectivity
- Arthralgia, headache, cough, infections, hypersensitivity reactions (may be significant)
Contraindications
Other information
Describe anti-cytokine antibodies
eg *Ustekinumab (IL-12 and IL-23 inhibition)**
MoA
Recombinant human immunoglobulin monoclonal antibody that targets the p40 subunit on IL-12 and IL-23 inhibiting their activity.
Indications
Indicated for moderate to severe CD; well tolerated
Adverse effects
Similar Adverse effects as the other biological classes (listed above)
Contraindications
Other information
When are calcineurin inhibitors used?
- reserved for “medical rescue” when severe disease is non-responsive to high-dose intravenous corticosteroids
- Not discussed here - covered in block 6 as used for other indications
