treatment of ibd
DESCRIPTION
TRANSCRIPT
IBD Therapy
August 24,2012
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.
Common pyramid of treatment
Crohn’s Disease Therapy
5-ASAs, Budesonide, Antibiotics
Corticosteroids, Immunomodulator
s
Surgery
Infliximab, Adalimumab, Certilizumab
TysabriSeverity
Mild
Ulcerative Colitis Treatment Pyramid
Infliximab
Severe
Mild
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?
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).
Mechanism Of ActionArachidonic Acid
5-Lipoxygenase Cyclo-oxygenase
Leukotrienes Prostaglandins
Inflammation
SULFASALAZINEMESALAMINE
XX
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
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.
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
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
Adverse effects - sulfapyridine
• Heinz body anaemia; Megaloblastic anaemia• Hypersensitivity reactions• Orbital oedema• Renal reactions• Neurological reactions• Oligoospermia• Orange coloured urine & tears
Blood disorders
• Agranulocytosis; aplastic anaemia; leucopenia; neutropenia; thrombocytopenia; methaemoglobinemia
• Patients should advised to report any unexplained bleeding; bruising; purpura; sore throat; fever or malaise
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)
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)
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
• 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!!
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
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
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.
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
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
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
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
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
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
Metronidazole -Spectrum of activityE. histolytica
Trichomonas vaginalisGiardia lambiaAnaerobes : Gm+ve & Gm-veBacteroides fragilis, other speciesClostridium Fusobacterium Peptococcus Peptostreptococcus EubacteriumHelicobacter
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.
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
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
IMMUNEMODULATORSOTHERS INCLUDE…..•INFLIXIMAB Anti TNF antibody•ADALIZUMAB Anti TNF antibody•GOLIMUMAB•VISILIZUMAB Anti CD3•NATALIZUMAB Anti alpha-4 antigen•FONTOLIZUMAB Anti –INF gamma
How do they differ?• Route of administration
– Infliximab IV– Certilizumab and Adalimumab: SC– Natalizumab iv infusions
• Amount of Mouse protein
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
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
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.
GUIDELINES FOR MANAGEMENT OF IBD IN UNITED KINGDOM
http://www.aafp.org/afp/2003/0815/p707.html
Ulcerative Colitis
Contiguous diseaseMucosal involvementCrypt abscesses/chronicityCultures negative
Treatment of UCCHALLENGES!!•Induction vs. Maintenance•Left-sided vs. pan-colonic•Fulminate disease•Steroid dependent disease•Chemoprevention of colon cancer
What do we know?
• 5-Aminosalicylates• Steroids• Immunomodulators• Anti-TNF• Antibiotics• Probiotics• Nicotine
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
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