IBD Part 2

In IBD, what are the updated guidelines for treatment?

• Separate disease activity from disease severity

• Include prognosis when deciding on induction and maintenance therapy

• Focus on mucosal healing and objective evidence of disease control, including fecal calprotectin

• All biologics are appropriate 1st line for pts whose severity warrants it

What is the window of opportunity?

• Intervention early in the disease is better to put a biologic vs drugs that may not work

• Another intervention point is surgery which is last line

What are sulfasalazine S/E? What are comments with sulfasalazine?

• Sulfasalazine’s Sulfapyradine groups causes a lot of ADRs vs Mesalamine

  • N/V/H

  • Rash, anemia, pneumonitis

  • Hepatotoxicity, nephritis

  • Thrombocytopenia, lymphoma

  • Hypersensitivity rxns more likely than with mesalamine

  • CI: salicylate, sulfa allergy

• DR tablets less GI intolerance

• May cause urine/skin to turn yellow-orange color

• Take folate 1 mg/day

• Caution in pts with G6PD deficiency

• Reduce sperm count and fertility in males, reversible (oligospermia)

What are the 5-ASA?

• Mesalamine

• Balsalazine (prodrug to be mesalamine)

• Olsalazine (prodrug to be mesalamine)

What is the CI of 5-ASA?

• Salicylate allergy

What are comments in mesalamine?

• Better tolerated than sulfasalazine

What are the different formulations of Mesalamine?

• Mesalamine suppository → rectum

• Mesalamine enema or steroid enema → rectum, distal colon

• Apriso, balsalazide, lialda, olsalazine, deltzicol → rectum, distal colon, proximal colon

• Asacol HD → rectum, distal colon, proximal colon, terminal ileum

• Pentasa → rectum, distal colon, proximal colon, terminal ileum, ileum, jejunum

Where do aminosalicylates fit in for IBD?

• ASAs not as effective in CD as in UC

• Mesalamines have minimal efficacy in CD

  • Despite this mesalamine are often tried as initial therapy in CD

  • Usually pentasa is used as its release reaches small intrestine

How are corticosteroids used in IBD?

• Suppress acute inflammation

• No role in maintenance of IBD

• Route depend on severity of dz

  • IV (methylprednisolone, hydrocortisone)

  • Oral (prednisone prednisolone, budesonide, dexamethasone)

  • Rectal (enema, foam prep, suppository)

Why do we use corticosteroids only short term?

• Cushing syndrome

• Osteoporosis

• Retardation of growth

• Thinning of skin

• Immunosuppression

• Cataracts/glaumcoma

• Edema

• Suppression of of pituitary

• Teratogenic

• Emotion disturbance

• Hypertension

• Obesity

• Increase body hair growth

• Diabetes

• Striae

How is Budesonide used?

• Entocort EC for CD

• Uceris for UC

• Used as bridge therapy, newer CS → minimal systemic absorption, swallow whole

• ADRs less than prednisolone

• Separate 2 hours from antacids

What is immunomodulator therapy can how/when can it be used?

• Azathioprine, mercaptopurine → PO

• Can be used long term for both UC and CD

  • Reserved for pts who fail ASA therapy

  • Refractory to or dependent on CS

  • Can be alone or adjunct to mesalamine, CS, TNF-alpha antagonist for maintenance

  • NOT used alone for induction of remission

• Few wks to 1 year before benefits are observed

AZA and 6-MP have what AE? What is known about it?

• AE: bone marrow suppression, pancreatitis

• Monitor, kidney fxn, LFT, CBC

• Comments: check TPMT activity (if lower TPMT → increase myelosuppression risk)

  • BBW: malignancy (lymphoma), NO LIVE VACCINES

AZA gets converted to 6-MP which leads to what?

• TPMT convert 6-MP to → 6methyl mercaptopurine (hepatotoxic)

  • Poor TPMT means more other pathways

• XO can convert 6-MP → 6 thiouric acid (inactive moiety)

• 6-thioinisoinc acid convert 6-MP to → 6-thioguanine nucleotides (myelosuppression)

What are XO inhibitors which interact with AZA and 6-MP

• Allopurinol and Febuxostat

Dose of what should be reduced by at least 25% when used with allopurinol?

• 6-MP/AZA

What is CI with AZA and 6-MP?

• Uloric (Febuxostat)

What is another immunomodulator and what is it used for?

• Methotrexate for CD only (IM, SQ, PO)

• Maintenance of remission CD (Not 1st line)

• Use for induction of remission only if no other options

MTX is CI where? What are some AE and comments?

• Pregnancy and breastfeeding

• AE: bone marrow suppression, pancreatitis

• BBW: death, fetal death, lymphoma, bone marrow toxicity

• NSAID, phenytoin, ciprofloxacin, penciillin, probenecid, amiodarone, PPI → MTX toxicity, inhibit renal excretion of MTX

• NO LIVE VACCINES

How is Cyclosporine used?

• IV for UC only

• 20 weeks to see response

• Short term benefit for tx of acute, severe UC to avoid surgery

Cyclosporine has DDI, CI with what? What should you monitor? What are the S/E?

• DDI with all statins

• CI with simvastatin, pitavastatin

• NTW 10 mg atorvastatin, 5 mg rosuvastatin

• NO LIVE VACCINES

• Monitor cyclosporine levels (300-400)

• S/E: neurotoxicity, nephrotoxicity

QUIZ

• What is oligospermia? → reduce sperm count, med is sulfasalazine

• Which labs are markers of inflammation? → CRP, ESR (nonspecific)

• Uceris is what? → Budesonide

• Urine turn yellow/orange? → Sulfasalazine

  • NO SASLICAYLATE ALLERGY

• Mesalamine can be taken in sulfur but not salicylate allergy

• Chrons nutritional deficiency → B12 and Vitamin A, B, C, D, B12, folate, iron

• S/E in Chrons is terminal ilium

• Pts with actie inflammatory bowel disease → FIBER IS FALSE NO FIBER

• Not to be used in maintenenace of remission? → STEROIDS

• Prior to initiating azothiaprine → TMPT enzyme activity b/c low can cause myelosuppression

• Greater risk of colorectal cancer → UC patients not CD

When do you use antimicorbial therapy? What are they?

• Used as adjunct if you think infection

• Metronidazole and Ciprofloxacin

  • LIMITED efficacy

  • Decrease bacterial concentration in lumen

  • Usually used if presence of abscess, fistulas, first line in pouchitis

• Rifamycin

  • Some efficacy in UC and CD

• NOT long term use → resistance, ADRs

What are the TNF-a inhibitors?

• Infliximab (Remicade) → UC and CD

  • Premeditate with antihistamines, APAP, and CS may be considered to minimize risk for infusion reaction

• Adalimumab (Humira) → UC and CD

  • Good at RT 14 days

• Golimumab (Simponi) → UC

• Certolizumab (Cimzia) → CD

What is known about the TNF-a inhibitors?

• For induction of remission and maintenance therapy (OFTEN 1st line)

• Moderate and severe IBD

• Vaccine before tx

What are monitoring parameters for TNF-a inhibitors?

• BP/HR during infusion every 2-10 min until normal (infliximab)

• Antidrug antibodies

• Warning: active infx, etc

• Test TB and HepB before

What is known about antibody formation in TNF-a inhibitors

• ATA (antibodies to the antibody) may increase chance of getting injection rxns or delayed infusion

• More likely in pts given episodic anti TNF vs regular scheduled injections

• Prevalence highest with adalimumab and infliximab

What is the BBW with TNF-a inhibitors?

• Increased infx risk which can lead to hospitalization or death

What is known about the risk of HSTCL?

• More common in young men <35 yrs old

• Risk for all pts on thioourine (1:45000)

• Risk In men <35 on thiopurine (1:7500)
  Risk in men <35 on tnf-a and thiopurine (1:3500)

What is risk of malignancy with TNF-a inhibitors?

• Risk of non melanoma skin cancer increased

• Encourage screen in skin cancer patients

What are recommendations for TNF therapy?

• Patients >60 yrs

  • TNF-alpha monotherapy for induction therapy preferred

  • TNF-alpha plus thiopurine - higher risk for infection and malignancy

  • If severe disease may use combo therapy for induction but then d/c the thiopurine after 12-24 months of therapy

• Young male pts

  • TNF-alpha plus MTX may be preferred for induction of remission

  • May use TNF-alpha plus thiopurine for induction of remission with plans to d/c the thiopurine in 12-24 months

• Prior to withdrawing thiopurine therapy

  • Perform ileocolonoscopy to confirm mucosal healing + obtain anti-TNF drug trough to confirm its working

How to know if loss of response to TNF-alpha?

• Pts with low drug levels and positive anti-drug antibodies

  • Immunogenicity failure

  • Low/absent drug trough levels in the presence of anti-drug antibodies

  • Switched to an alternative anti-TNF agent

• Pts with low drug levels and negative anti-drug antibodies

  • PK failures

  • Low/absent trough levels, no anti-drug antibodies

  • Dose optimization by either dose escalation or shortening dosage interval

• Pts with normal drug level and negative drug anti-drug antibodies

  • PD failures

  • Adequate drug levels with absent anti-drug antibodues

  • Switch outside anti-TNF class to another agent (ex: anti-integrin antibody)

If loss of response to Anti-TNF monotherapy what can you do?

• DOse optimization

• Switch to another anti-TNF alpha

• Swap biologic with different MOA

• Addition of an IM

What are other biologics (anti-integrins) to try if TNF-a failed? (1st line other biologics)

• Vedolizumab (Entyvio) → Mod to severe CD or UC (Can be 1st line)

  • GUT selective

  • Check TB prior to start

• Natalizumab (Tysabri) → Mod to serve CD (NOT 1st line)

  • Risk for progressive multifocal leukoencephalopathy, 1 case with Entyvio, more cases with Tysabri

  • Must have negative John Cunningham virus antibody, checked every 6 months

What are other biologics (interleukin inhibitors) to try if TNF-a failed? (NOT 1st line other biologics)

• Ustekinumab (Stelara) → mod to severe CD/UC

  • Reversible posterior leukoenecphalopathy syndrome (RARE)

• Guselkumab (Temfya) → mod to severe UC

  • Reversible posterior leukoenecphalopathy syndrome (RARE)

• Risankizumab (Skyrizi) → mod to severe CD/UC

• Mirikizumab (Omvoh) → mod to severe CD/UC

• **THESE ARE NOT 1st line, TB test prior to start, no live vaccines

What are other JAK inhibitors to try if TNF-a failed? (NOT 1st line other biologics)

• Tofacitnib (Xeljanz) → mod to severe UC

  • Do not initiate if ___ (PO MED)

• Upadacitnib (Rinvoq) → mod to severe CD or UC

  • Do not initiate if ___ (PO MED)

• **Monitor skin exam, Hep and TB screen prior to tx, Lipids, CBC/LFT

What are other sphingosine 1-phosphate receptor modulator (S1P) to try if TNF failed?

• Ozanimod (Zeposia)

• Etrasimod (Velsepity)

• Mod to severe UC (NOT 1st line)

• CI: pace maker, MAOI use, untreated sleep apnea, prior CV events, HF

For treatment of CD and UC, what is recommended?

• Step up approach if mild disease

• Step down approach for moderate to severe disease