INFLAMMATORY BOWEL DISEASETREATMENT AND PREGNANCY

Dr Theodora DemetriouMBChB MSc MRCP (UK)

Gastroenterologist / HepatologistPaphos General Hospital Cyprus

ECCO Rep. CyprusAliathon Paphos

21th March 2015

Incidence of Ulcerative colitis and Crohn’s Symptoms Diagnostic tests Prognosis Current therapy and side effects Emerging therapies Survailance endoscopy guidelines ECCO pregnancy guidelines

Contents

Ulcerative colitis 150-200/ 100,000 ( 7-22 new cases per year)

Crohn’s 50-100/ 100,000 (4-11 new cases per year) UK 240.000 IBD patients Europe 2 million IBD patients Hospital population 300,000: 40- 50 new cases each year Incidence is higher in Northern Europe but recently

increasing in Southern Europe 30% onset before age 18 years old Disease activity in children more pronounced and extensive

Incidence of IBD

Colon Anatomy

Classification of UC

Involves the mucosa of colon only Proctitis- only rectum Distal colitis- rectum and sigmoid Left sided- descending Extensive - transverse Pan colitis/ subtotal- right colon Adults 80% distal, 42% subtotal Children 3% distal, 76% subtotal

90% bloody diarrhoea Fatigue, anaemia Earlier diagnosis than Crohn’s disease Appendicectomy reduction of risk 70% 3x increase risk in ex-smokers 29% extra intestinal symptoms that may

present before UC (i.e. Arthritis, Erythema nodosum, Sclerosing cholangitis, pyoderma gangrenosum, Uveitis)

Symptoms of UC

Extra-intestinal symptoms

Chronic transmural inflammation Stricturing Fistulating Any part of GI tract (stomach, small bowel,

colon) Ileocaecal valve/ terminal ileum common site Not continuous

Classification of Crohn’s disease

stool: normal, diarrhoea, occult blood weight loss obstruction (distention, vomiting,

constipation) abdominal pain abdominal mass fever growth failure and puberty delay perianal disease (anal fissure, fistula,

abscess fatigue anaemia

Symptoms of Crohn’s disease

Blood tests; full blood count, ferritin, CRP, ESR, liver enzymes Stool test: Faecal occult blood test, culture (clostridium

difficile, E.coli, salmonella, campylobacter, CMV) Clinical examination of the abdomen Anal exam Flexible sigmoidoscopy and biopsy Colonoscopy- not in acute phase (danger of perforation) and

no preparation CT enterography MRI small bowel and Pelvis Capsule endoscopy

Diagnostic Tests

Ulcerative colitis

Crohn’s disease

Capsule endoscopy

MRI ENTEROGRAPHY

IPSEN Cohort Norway 1990-1994 843 IBD (519; UC) patients followed up 1, 5 and 10

years from diagnosis 423 UC completed follow up No increase in mortality compared to general population At 10 years 9.8% colectomy (high risk if ESR>30,

Extensive) 83% relapsing disease 48% relapse free after 5 years 20% proctitis progressed to extensive colitis

Prognosis

IBD Prognosis IPSEN

55%

1%

6%

37%

Mesalazine/ 5-ASA Sulphasalazine Azathioprine Methotrexate Steroids Cyclosporine Biologics /anti-TNF: REMICADE (infliximab), HUMIRA

(adalimumab) Inflectra, Remsima (CT-P13 biosimilar to REMICADE) Vedolizumab (anti a4b7) Nutritional therapy with semi-elemental diet

(MODULEN)

IBD Therapy

MESALAZINE: ASACOL 400 mg tds, SALOFALK 500mg tds, PENTASA500 mg tds, MEZAVANT1.2g OD

Sulphasalazine 1gbd In acute phase increase 4.5g/day Continue long term as reduction in colon cancer risk Do not work in small bowel crohn’s Mild- moderate UC No difference if all take once a day (poor compliance 40%) Can use as suppositories and enema proctitis/ sigmoid Side effects: nephrotoxic (check renal blood test every 6-

12 months) Sulphasalazine; nausea, abdominal pain, oligospermia-

reversible

5-ASA

Prednisolone 40mg po/ Medrol po/ Hydrocortisone (iv)

Budesonide 9mg/d only in mild to moderate disease distal ileum/ ascending colon- less side effects

ECCO guidance: only allow 2 courses of steroids in one year

calcium/vit D and omeprazole/ Dexa scan for chronic steroid users

Topical steroid less effective than asacol/salofalk

Steroids

Osteoporosis Glaucoma/ cataracts Cushingoid features Acne Hypertension Gastritis/duodenitis Emotional/psychiatric disturbance Growth/puberty delay Infections/ poor wound healing

Steroid side effects

Slow onset of action (3-6 months) Metabolite 6-mercaptopurine (6-MP) Remission in 2/3 patients Reduction in colectomy and hospitalisation Reduction in colorectal cancer risk

Azathioprine

SIDE EFFECTS: 0.3% population no TPMT leads to more active metabolite BONE MARROW SUPPRESSION

2-17% hepatitis 2% pancreatitis Vomiting/nausea (6-MP better) Increased risk of Lymphoma (young males

also on Biologics) Increase in non-melanoma skin cancers-

annual dermatology review

Azathioprine side effects

Moderate to severe Crohn’s disease Not effective in UC (METEOR study 2015) 25mg IM once a week/ Folic acid 5mg for 4

months then PO 15mg/wk po Effective after 3 months (65% maintain

remission) Side effects:1. Contraindicated in pregnancy2. Hepatotoxicity/ liver fibrosis3. Bone marrow suppression

Methotrexate

Acute severe colitis No difference between infliximab (similar response

and colectomy rates) Side effects many so not commonly used any

more 1. hypertension 2. seizures 3. Hirsutism 4. gingival hyperplasia 5. renal impairment

Cyclosporine

REMICADE/ Infliximab (IV every 2 months for 2hs) Adalimumab (sc injection every 2 weeks) Moderate to severe ulcerative colitis not responding to

steroids/ steroid dependent/ not responding to AZA Reduction in colectomy rate and hospitalisation in

moderate UC (75% 1 yr, 50% 2-3 ys) Crohn’s disease with fistulating disease or poor

prognosis (stricturing, deep ulcers, smokers, young age, family history)

Remission in 60% and at one year 50% Mucosal healing proven to decrease surgery and

hospitalisations Better results if given with AZA/ MTX in first 2 years

BIOLOGICS/ ANTI-TNF

Anaphylaxis Infusion reactions Infections Psoriasiform rash Exacerbation of MS/ optic neuritis Worsening of congestive heart failure Increase in non-melanoma skin cancers Latent TB reactivation Lymphoma risk if given with AZA in young males Hepatotoxicity Not allowed if untreated TB, hepatitis, malignancy in last

5 years

Side effects of Anti-TNF drugs

Chest x-ray Mantoux test Hepatitis A,B,C CMV/EBV Vaccines upto date (annual influenza, 5ys

pneumococcus) Varicella/ chicken pox

Before starting anti-TNF

New anti-TNF for UC Injection SC once a month Fast response at week 6: 52% 43% mucosal healing

GOLIMUMAB

Antibody to a4b7 Effective in ulcerative colitis 47% Mucosal healing 40% Not effective in crohn’s disease

VEDOLIZUMAB

Similar but not identical to original biological medicine already authorized

Biological and physiological comparable INFLECTRA/ REMSIMA (CT-P13) Given like REMICADE 5mg/kg iv every 2 months Clinical trials PLANETAS in Ankylosing spondylitis and

PLANETRA in Rheumatoid arthritis. Extrapolation of clinical efficiency in IBD by EMA- No

clinical trial exists in IBD Small study in Portugal 34 patients 56% responded

33%remission, 9% infusion reactions EMA states that country members decide on

interchangeability ( i.e. change REMICADE to Inflectra) but this decision should be taken by the doctor

BIOSIMILARS

Effective in recurrent C. diff diarrhoea No randomised control trial in IBD- only case

studies Clinical improvement in small study 21 patients

(57%) remission in 14% Only for mild UC, no benefit for Crohn’s disease No benefit for pouchitis Healthy donor faeces given via nasogastric tube

or enema for 3 days Safety issues: HIV, Hepatitis A,B,C, Norovirus,

CMV, EBV, Strongyloides, syphilis, parasites

Faecal microbiota transplantation

Increased risk of CRC in IBD if microscopic inflammation over time

Mucosal healing in IBD is associated with lower risk of CRC as well as clinical relapse, hospitalisation and colectomy.

No increased risk for proctitis 2.8x risk increase in left sided colitis and Crohn’s

colitis Family history of CRC and IBD and Primary sclerosing

cholangitis 2-4 x risk increase BUT GOOD NEWS: Measalazine long term 50% reduction in CRC/ dysplasiaAzathioprine decreases risk of CRC in IBD

Colorectal cancer surveillance

Early postoperative recurrence is associated with higher symptomatic and surgical recurrence rates

Ileocolonoscopy recommended 6-12 months after surgery

Start colonoscopy surveillance 8 years from diagnosis

Start as soon as PSC diagnosed HIGH RISK every year; PSC, Family history

CRC<50 or stricture/dysplasia in last 5 years INTERMEDIATE RISK 2-3 years; extensive

colitis, inflammatory polyps, FHCRC >50 LOW RISK 5 years

ECCO Endoscopy guidelines

FERTILITY: normal in females with IBD (only reduced slightly if open surgery; colectomy, pouch, ileostomy)

Laparoscopic pouch/ anal anastomosis lower infertility

Acute Crohn’s disease temporary amenorrhea but associated with weight loss

Male IBD normal fertility (if pouch abscess/ fistula disturbance in erection/ejaculation)

Sulphasalazine temporary infertility 80% - Change to mesalazine

Methotrexate contraindicated in men and female IBD patients trying to conceive

ECCO PREGNANCY GUIDELINES

if conception occurs at time of remission the risk of relapse during pregnancy is low but high if conception during active disease

At second/ third pregnancies less active disease/surgery risk

C-section if active perianal disease or active rectal involvement or Pouch/ Ileo-rectal anastomosis

After delivery no increased risk of flare if remain on medication

Parents with IBD; higher risk of having children with IBD, Higher if both parent have Crohn’s, transmission more from mother, female children higher risk

ECCO PREGNANCY GUIDELINES

C- section more common Higher risk of low birth weight/ preterm birth

– this is associated with disease activity during pregnancy

No increase in congenital abnormalities Normal APGAR scores No increase in ITU admission No increase in seizures or death

Pregnancy and Fetal outcomes

DRUG PREGNANCY BREASTFEEDING

Mesalazine Low risk Low risk

Sulphasalazine Low risk Low risk

Steroids Low risk Low- delay 4hs before

Azathioprine Low risk Low risk

Anti- TNF ( REMICADE/ HUMIRA)

Low risk- STOP AT 24 WEEKS

Limited data/low risk

Methotrexate NOT ALLOWED NOT ALLOWED

Thalidomide NOT ALLOWED NOT ALLOWED

Metronidazole AVOID 1ST TRIMESTER

AVOID

Ciprofloxacin AVOID 1ST TRIMESTER

AVOID

IBD medication during pregnancy

DO NOT ignore your symptoms Acceptance of disease Emotional support Medication management Disclosure of disease (work/ family/ friends) Incontinence Fistula care Travel Support in employment/ university Multidisciplinary management (nurse specialist, dietician,

psychologist/ other specialties- rheumatologist)

Promoting self care