paediatric messages for grown-ups: biological therapy holm ... · oxford inflammatory bowel disease...

Oxford Inflammatory Bowel Disease MasterClass

Paediatric messages for grown-ups: biological therapy

Holm Uhlig

Translational Gastroenterology Unit and Children’s Hospital Oxford

Paediatric messages for grown-‐ups: biological therapy

Petritsch et al JCC 2012

Oxford Inflammatory Bowel Disease MasterClass Efficacy results of main prospec@ve trials on biologic therapy in paediatric Crohn’s disease

Aloi, M. et al. (2013) Advances in the medical management of paediatric IBD Nat. Rev. Gastroenterol. Hepatol. doi:10.1038/nrgastro.2013.158

Oxford Inflammatory Bowel Disease MasterClass Efficacy results of main prospec@ve trials on biologic therapy in paediatric Crohn’s disease


message similar to adult IBD an@-‐TNF-‐a works to induce remission and maintenance therapy safe

Biologic therapy in paediatric IBD

Paediatric IBD oSen presents with a more severe phenotype and course than the adult-‐onset disease Current therapeu@c goals for paediatric IBD have evolved from symptoma@c control towards the achievement of mucosal healing and deep remission Widely agreed data indicate that biologic agents in paediatric IBD facilitate mucosal healing and improve growth and quality of life by achieving steroid-‐sparing remission.


Study informa@on

Safety concerns (Toxicity) liability/insurance smaller study popula@on parental consent heterogenous paediatric popula@on



-‐ use of biologics during pregnancy -‐ biologics in very early onset of IBD

•  462 women with IBD exposed to an@-‐TNF agents during pregnancy (17 case reports, 13 case series, 2 uncontrolled cohort studies and 2 controlled cohort)  prevalence of pregnancy complica@ons, including preterm delivery, s@llbirth, low birth weight, miscarriages, or congenital malforma@ons in children exposed to IFX throughout pregnancy is likely similar to controls  infec@ons observed in infants exposed to immunomodulators plus an@-‐TNF drugs in utero > lethal mycobacteria infec9ons •  an@-‐TNF drugs should be stopped during the second trimester only if in remission -‐ alterna@ve Certolizumab i.e. Fab fragment Gisbert JP et al.. Am J Gastroenterol. 2013 Mahadevan et al. : Am J Gastroenterol 2011, 106:214–223. Cheent K, J Crohns Coli@s. 2010 Nielsen BMC Medicine 2013

Exposure of anti-TNF-a during pregnancy

•  462 women with IBD exposed to an@-‐TNF agents during pregnancy (17 case reports, 13 case series, 2 uncontrolled cohort studies and 2 controlled cohort)  prevalence of pregnancy complica@ons, including preterm delivery, s@llbirth, low birth weight, miscarriages, or congenitalmalforma@ons in children exposed to IFX throughout pregnancy is limited   infec@ons observed in infants exposed to immunomodulators plus an@-‐TNF drugs in utero > lethal mycobacteria infec9ons •  an@-‐TNF drugs should be stopped during the second trimester only if in remission -‐ alterna@ve Certolizumab i.e. Fab fragment Gisbert JP et al.. Am J Gastroenterol. 2013 Mahadevan et al. : Am J Gastroenterol 2011, 106:214–223. Cheent K, J Crohns Coli@s. 2010 Nielsen BMC Medicine 2013


•  World Congress of Gastroenterology consensus statement on vaccina@ons in infants exposed to biologic therapy in utero recommend delay of all live-‐virus vaccines un@l aSer biologic molecules are no longer detectable in the child’s blood [62].

Nielsen et al. BMC Medicine 2013, 11:174 Page 7 of 13 Gisbert JP et al.. Am J Gastroenterol. 2013 Mahadevan et al. : Am J Gastroenterol 2011, 106:214–223. Cheent K, J Crohns Coli@s. 2010 Nielsen BMC Medicine 2013


Routine rotavirus infection in the UK

From 1 July 2013, the rou@ne childhood immunisa@on schedule will include a vaccine to protect babies against rotavirus infec@on From today (1 July) around 850,000 babies a year in UKwill be offered a new vaccina@on to protect them against rotavirus (Rotarix)

The rotavirus vaccine is given as two doses for babies aged 2 months and 3 months alongside their other rou@ne childhood vaccina@ons. >> so delay vaccina@on but vaccina@on should be completed by 24 weeks of life

Functional pathways of monogenic diseases with IBD-like phenotype

40 monogenic defects associated with IBD-‐like immunopathology very early onset mul@ple mechanisms high failure rate of conven@onal and biologic treatments

Functional pathways of monogenic diseases with IBD-like phenotype – anti-TNF-alpha treatment

effec@ve

not effec@ve

not effec@ve

effec@ve

not effec@ve

?

effec@ve

effec@ve

Functional pathways of monogenic diseases - IL10 receptor signalling

not effec@ve

Glocker et al. NEJM

Haematopoie@c stem cell transplanta@on

Functional pathways of monogenic diseases - chronic granulomatous disease

effec@ve but...

NADPH oxidase complex gp91phox, p22phox, p40phox, p47phox, p67phox

Effective treatment of chronic granulomatous disease with anti-TNF-a ... but

NADPH oxidase complex gp91phox, p22phox, p40phox, p47phox, p67phox   bacterial handling defect

up to 50% of CGD patients intestinal inflammation, anal fissures, perirectal abscesses, fistulae, Colitis more common in the x-linked than in autosomal recessive

Staphylococcus aureus, Serra9a marcescens, Burkholderia cepacia Nocardia spp Aspergillus spp

•  R. Marsh BMJ

CGD - increased mortality under anti-TNF-a therapy

Staphylococcus aureus, Serra9a marcescens, Burkholderia cepacia Nocardia spp Aspergillus spp

NADPH oxidase complex gp91phox, p22phox, p40phox, p47phox, p67phox   bacterial handling defect exacerbated by anti-TNF-a

Functional pathways of monogenic diseases - mevalonate kinase deficiency

MEVK

Mevalonate kinase deficiency

a)maculopapular rash, b) periorbital erythema c) cervical lymphadenopathy d) bilateral pneumonia, e) transverse nail f) arthri@s of both knees, g) acute intes@nal obstruc@on >>> coli@s .

van der Burgh et al. Mevalonate kinase deficiency, a metabolic autoinflammatory disease Clinical Immunology 2012

van der Burgh et al. Mevalonate kinase deficiency, a metabolic autoinflammatory disease Clinical Immunology 2012

Mevalonate kinase deficiency

Levy et al. Severe Early-‐Onset Coli@s Revealing Mevalonate Kinase Deficiency Pediatrics 2013

1 months bloody diarrhea and pancoli@s, fistula Intravenous methylprednisolone (1 mg/kg per day for 3 weeks) no effect. infliximab infusions and tacrolimus treatment -‐ s@ll coli@s Anakinra (2 mg/kg per day) treatment resulted in clinical remission

before aSer IL1 blockade

IL1b blockade prevents colitis in innate and adaptive mouse models

Interleukin-‐1 signalling in IBD ?

Lin et al. Failure of anakinra treatment of pyoderma gangrenosum in an IBD pa@ent and relevance to the PSTPIP1 gene. Inflamm Bowel Dis. 2011 Dinarello Interleukin-‐1 in the pathogenesis and treatment of inflammatory diseases. Blood 2011 Cominelli F, Pizarro TT. Interleukin-‐1 and interleukin-‐1 receptor antagonist in inflammatory bowel disease. Aliment Pharmacol Ther. 1996

interleukin-‐1 may play an important role in the ini@a@on and amplifica@on of the inflammatory response IL-‐1 has been implicated as a target for therapeu@c interven@on > is there any func@onal role for IL1b blockade in subsets of pa@ents with IBD

paediatric messages for grown-ups: biological therapy holm ... · oxford inflammatory bowel disease...

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