treatment of ibd

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IBD Therapy August 24,2012

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Page 1: Treatment of ibd

IBD Therapy

August 24,2012

Page 2: Treatment of ibd

What is CD AND UC????? CD is a condition of chronic CD is a condition of chronic

inflammation potentially involving inflammation potentially involving any location of the GIT from mouth any location of the GIT from mouth to anus.to anus.

UC is an inflammatory disorder that UC is an inflammatory disorder that affects the rectum and extends affects the rectum and extends proximally to affect variable extent proximally to affect variable extent of the colon.of the colon.

Page 3: Treatment of ibd

Common pyramid of treatment

Page 4: Treatment of ibd

Crohn’s Disease Therapy

5-ASAs, Budesonide, Antibiotics

Corticosteroids, Immunomodulator

s

Surgery

Infliximab, Adalimumab, Certilizumab

TysabriSeverity

Mild

Page 5: Treatment of ibd

Ulcerative Colitis Treatment Pyramid

Infliximab

Severe

Mild

Page 6: Treatment of ibd

Therapy Goals of therapy

– Induce and maintain remission.– Ameliorate symptoms– Improve patient’s quality of life– Adequate nutrition– Prevent complication of both the disease and medication

PRACTICAL CHALLENGES IN DRUG TREATMENT•How sick is the patient?•What is the disease distribution?•Are there complications abscess, fistula, obstuction•Has the patient had prior surgery for Crohn’s disease?

Page 7: Treatment of ibd
Page 8: Treatment of ibd

5-AminosalicylatesWhat are the drugs?

• Sulfasalazine Tab 0.5-4g• Mesalamine

– Pentasa 2 -4g QID (mesalamine DR tab)– Asacol 1.6-2.4g tid (mesalamine DR tab)– Rowasa – 4 g enema qd (mesalmine rectal enema)– Canasa – 1 gram supp QD (mesalamine rectal supp)– Lialda – 1.2 gram tablet QD (Mesalamine DR tab)

• Balsalazide 6.75g Caps• Osalazine 1g Caps

What are the issues?

• Differ in release characteristics• Evidence based medicine

greater role in UC than CD• Sulfasalazine have efficacy in

colonic CD• Use in mild disease• Adverse events: worsening of

disease activity, increased serum creatinine, pancreatitis, allergic reaction (rash).

Page 9: Treatment of ibd

Mechanism Of ActionArachidonic Acid

5-Lipoxygenase Cyclo-oxygenase

Leukotrienes Prostaglandins

Inflammation

SULFASALAZINEMESALAMINE

XX

Page 10: Treatment of ibd

5-amino salicylic acid(5-ASA)

The mainstay treatment of mild to moderately active UC and CD (induction).

5-ASA may act by blocking the production of prostaglandins and

leukotrienes, inhibiting bacterial peptide–induced neutrophil

chemotaxis and adenosine-induced secretion, scavenging reactive oxygen metabolites

Page 11: Treatment of ibd

5-amino salicylic acid For patients with distal colonic disease, a

suppository or enema form will be most appropriate.

Maintenance treatment with a 5-aminosalicylic acid can be effective for sustaining remission in ulcerative colitis but is of questionable value in Crohn's disease.

Page 12: Treatment of ibd

Location of Oral Mesalamine Release

Stomach Jejunum Ileum Colon

Sulfasalazine

Dipentum®

(olsalazine)

Asacol® (mesalamine)delayed-release tablets

Pentasa® (mesalamine) controlled-release capsules

Colazal ®

(balsalazide)

Lialda® (mesalamine)Mesalamine delayed release tab

Page 13: Treatment of ibd

Adverse effects - 5-ASA

• Dose-related (10-45%) - headache, nausea, epigastric pain, diarrhoea*• Idiosyncratic (rare) - acute pancreatitis; hepatitis; myocarditis; pericarditis;

eosinophilia; fibrosing alveolitis; interstitial nephritis; nephrotic syndrome

- peripheral neuropathy - blood disorders - skin reactions – lupus like syndrome; Stevens-Johnson

syndrome; alopecia

Page 14: Treatment of ibd

Adverse effects - sulfapyridine

• Heinz body anaemia; Megaloblastic anaemia• Hypersensitivity reactions• Orbital oedema• Renal reactions• Neurological reactions• Oligoospermia• Orange coloured urine & tears

Page 15: Treatment of ibd

Blood disorders

• Agranulocytosis; aplastic anaemia; leucopenia; neutropenia; thrombocytopenia; methaemoglobinemia

• Patients should advised to report any unexplained bleeding; bruising; purpura; sore throat; fever or malaise

Page 16: Treatment of ibd

Contraindications/cautions

• 5-ASA - Salicylate hypersensitivity• Sulfapyridine + 5-ASA = Sulfasalazine(cleaved in

colon by colonic bacteria) - G6PD deficiency (haemolysis) - Slow acetylator status ( risk of hepatic and blood

disorders)

Page 17: Treatment of ibd

Steroids The National Cooperative Crohn’s Disease

Study and The European Co-operative Crohn’s Disease Study demonstrated that steroids are

efficacious-inducing remission ineffective- maintaining remissionDRUGS: Prednisolone oral/ enema Hydrocortisone iv Budesonide (poorly absorbed – used for

iliocaecal CD/ UC)

Page 18: Treatment of ibd

Budesonide in Crohn’s Disease

Budesonide - Entocort• 3 mg capsules P/O BD• 9mg capsules P/O qd• Ileal release based on pH

dependent mechanism• Steroid with rapid 1st pass

metabolism less systemic effects

Budesonide vs. Mesalamine

Pati

en

ts i

n r

em

issi

on

Thomsen et al 339 (6): 370

Page 19: Treatment of ibd

• Indicated in mild to moderate ileal Crohn’s disease• Prescribing information for 9 week course of

therapy – 3 weeks at each dose 9 mg, 6 mg, 3 mg• Can be used as a long term drug therapy in some

patients• bone density- needs a check!!

Page 20: Treatment of ibd

Steroids and IBDRole

• important role in the management of acute disease

• No maintenance role in either UC or CD

• Oral prednisone or prednisolone is used for moderately severe UC or CD, in doses ranging up to 60 mg per day.

• For acute disease 40 mg/day x 3 weeks then start taper at 5 mg q 1-2 weeks

• IV steroids for hospitalized, severely ill patient.

Side effects• Osteoporosis• Cataracts• Poor tissue healing• Increased complications• Infections

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Page 22: Treatment of ibd

IMMUNOSUPPRESSIVES• These agents are generally appropriate for patients in whom

the dose of corticosteroids cannot be tapered or discontinued.

• Azathioprine & 6-MP – The most extensively used immunosuppressive agents.– The mechanisms of action unknown but may include

• suppressing the generation of a specific subgroup of T cells.

– The onset of benefit takes several weeks up to six months.– Dose-related BM suppression is uniformly observed

Page 23: Treatment of ibd

CONTD..• Methotrexate

– Effective in steroid-dependent active CD and in maintaining remission.

• Cyclosporine – Severe UC not responding to IV steroid &need

urgent proctocolectomy.– 50% of the responders will need surgery within a

year.

Page 24: Treatment of ibd

Azathioprine/6MP in IBD

Efficacy/Issues• Effective in 50 – 70% of

patients with IBD• 30% failure due to

intolerance (15%) or no response (15%)

• Metabolism issues TPMT• Uses

– Steroid sparing– Post operative

prophylaxis

Intolerance/Risks• Bone marrow suppression• Pancreatitis• Hepatotoxicity• Nausea• Myalgias – flu like

symptoms• Other Risks

– Lymphoma – 4 fold– Infection

Page 25: Treatment of ibd

AZA 6-MP HPRT

TPMT

6-TImP

DNADNARNARNA

PurinePurinesynthesissynthesis

6-MMP

6-TU

XO

TPMT

Circulation Intracellular

AZA/6MP Metabolism

6-MMP6-MMPribonucleotidesribonucleotides

6-TG6-TGnucleotidesnucleotides

Page 26: Treatment of ibd

Adverse effects• Flu-like symptoms (20%) - occur at 2-3 weeks; cease on withdrawal• Hepatotoxicity; pancreatitis (<5%)• Leucopenia (3%) – myelotoxicity - determined by TPMT activity - weekly FBC x 8 weeks - 3 monthly thereafter - warn patients reg: sore throat/fever

Page 27: Treatment of ibd

Ciclosporin• Indicated in Severe UC • No value in CD• MOA:inhibitor of calcineurin preventing clonal

expansion of T cells• S/E dose dependent

nephrotoxicityhepatotoxicity;hypertension; hypertrichosis; gingival hypertrophy etc.

• Need to monitor BP; FBC/ RF and levels

Page 28: Treatment of ibd

Methotrexate• Inducing remission/preventing relapse in CD

(Unlicensed indication) • Refractory to or intolerant of Azathioprine• MOA: inhibitor of dihyrofolate reductase; anti-

inflammatory• S/E: myelosupression*;mucositis;GI; hepatotoxicity;

pneumonitis• Co-administration of folinic acid reduces

myelosupression;mucositis

Page 29: Treatment of ibd

Methotrexate

• Immunomodulatory vs. Immunosuppressant• Active both in induction and maintenance of remission• 25 mg sc/week x 16 weeks then dosage reduce to 15 mg

sc/week• Refractory to or intolerant of Azathioprine• MOA: inhibitor of dihyrofolate reductase; anti-inflammatory• S/E: myelosupression*;mucositis;hepatotoxicity;

pneumonitis• Co-administration of folinic acid reduces

myelosupression;mucositis• Monitor LFTs, CBC

Page 30: Treatment of ibd

Metronidazole -Spectrum of activityE. histolytica

Trichomonas vaginalisGiardia lambiaAnaerobes : Gm+ve & Gm-veBacteroides fragilis, other speciesClostridium Fusobacterium Peptococcus Peptostreptococcus EubacteriumHelicobacter

Page 31: Treatment of ibd

Metronidazole -Mechanism of action

It is a prodrug activated by the susceptible microorganisms to a highly reactive nitro radical anion that target the DNA and other molecules.

Development of resistance limited.

Page 32: Treatment of ibd
Page 33: Treatment of ibd

Adverse effects of Methotrexate

Serious Adverse Events

• Hepatotoxicity• Hypersensitivity

pneumonitis• Myelosuppression• Birth defects in offspring

Common Adverse Events

• Nausea and vomiting (42%)• Diarrhea(7%)• Headache (17%)• Abdominal pain (18%)• Joint pain (16%)• Elevated AST, ALT• Stomatitis

Page 34: Treatment of ibd

Anti-TNF Antibodies

Chimeric monoclonal

antibody

Human recombinant

antibody

Humanized Fab’

fragment

Infliximab Adalimumab Certolizumab

pegol

PEG

PEG

VHVL

CH1No Fc

IgG1 IgG1

Mouse

Human

PEG = Polyethylene glycol

Page 35: Treatment of ibd

IMMUNEMODULATORSOTHERS INCLUDE…..•INFLIXIMAB Anti TNF antibody•ADALIZUMAB Anti TNF antibody•GOLIMUMAB•VISILIZUMAB Anti CD3•NATALIZUMAB Anti alpha-4 antigen•FONTOLIZUMAB Anti –INF gamma

Page 36: Treatment of ibd

How do they differ?• Route of administration

– Infliximab IV– Certilizumab and Adalimumab: SC– Natalizumab iv infusions

• Amount of Mouse protein

Page 37: Treatment of ibd

INFLIXIMAB• Potent anti-inflammatory• Indicated active and fistulating CD - in severe CD refractory or intolerant of steroids & immunosupressants - for whom surgery is inappropriate

• MOA: anti-TNF monoclonal antibody• S/E: infusion reactions/anaphylaxis- COMMON• infection (TB reactivation; overwhelming sepsis) ????

malignancy

Page 38: Treatment of ibd

Anti-TNF therapy• Infliximab (infusion)

▫ Induction 5mg/kg IV at weeks 0, 2 and 6▫ Maintenance 5mg/k IV at 8 weeks

• Cetolizumab pegol ( SC , nurse administered)▫ Loading dose 400 mg sc at weeks 0, 2 and 4▫ Maintenance 400 mg sc at 4 weeks

• Adalimumab ( SC, prefilled syringe)▫ Loading dose 160 mg at week 0, 80 mg at week 2▫ Maintenance 40 mg sc EOW or weekly

Page 39: Treatment of ibd

According to AAFP Guidelines:• patients with Crohn's disease need vitamin and mineral

supplementation.• vitamin B12, folic acid, fat soluable vitamins, and calcium

should be considered, and periodic checks may be necessary.

• Osteopenia and osteoporosis are potential complications of Crohn's disease, often aggravated by chronic steroid use.

• Despite expanding evidence of the carcinogenic potential of longstanding Crohn's disease. Colonoscopic monitoring 10 years after the onset of disease is recommended, the frequency of which depends on the extent of colonic disease.

• Research suggests that supplemental folate may have a protective effect against colon cancer.

Page 40: Treatment of ibd

GUIDELINES FOR MANAGEMENT OF IBD IN UNITED KINGDOM

Page 41: Treatment of ibd

http://www.aafp.org/afp/2003/0815/p707.html

Page 42: Treatment of ibd

Ulcerative Colitis

Contiguous diseaseMucosal involvementCrypt abscesses/chronicityCultures negative

Page 43: Treatment of ibd

Treatment of UCCHALLENGES!!•Induction vs. Maintenance•Left-sided vs. pan-colonic•Fulminate disease•Steroid dependent disease•Chemoprevention of colon cancer

Page 44: Treatment of ibd

What do we know?

• 5-Aminosalicylates• Steroids• Immunomodulators• Anti-TNF• Antibiotics• Probiotics• Nicotine

Page 45: Treatment of ibd
Page 46: Treatment of ibd
Page 47: Treatment of ibd

Surgical TherapyThere are four surgical options in patients with UC: 1)Total proctocolectomy and ileostomy

2) total procto-colectomy with continent ileostomy (Koch pouch)

3) total procto-colectomy with ileal pouch-anal anastomosis (IPAA)

4) colectomy with ileorectal anastomosis

THE SOCIETY FOR SURGERY OF ALIMENTARYT TRACT

Page 48: Treatment of ibd

REFERENCES• http://www.gastro.theclinics.com/article/S0889-8553(12)00005-2/pdf• Management of Crohn’s disease-A practical Approach; American Family Physician; volume

68; Number 4; August 15,2003• Ulcerative Colitis- Diagnosis and Treatment; AAFP 2007 Annual Clinical Focus On

Management Of Chronic illness; pg 1331• British Society Of Paediatric and Gastroenterology and Hepatology And Nutrition• GUT, 2002 october, 51(4):616• Journal Of Clinical Gastroenterology ,August 22,2012• En.wikipedia/wiki/crohns disease.html• En.wikipedia/wiki/ulcerative colitis.html• Gastroenterology clinics, elsevier • Disease Of Colon And Rectum; Wolter & Kluwers• CMDT; 2010

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Page 50: Treatment of ibd