ACCME/Disclosure Dr. Russo has nothing to disclose

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1 USCAP 2016 EVENING SPECIALTY CONFERENCE Pierre Russo, MD ACCME/Disclosure Dr. Russo has nothing to disclose A 2 month old girl with fevers and intractable enterocolitis Clinical History The patient presented at 2 months of age with listlessness in the setting of fever of unknown origin, vomiting and diarrhea with hypovolemic shock. Prior to this presentation, she was seen in the ER for bronchiolitis and ear infection Full term infant. Family history significant for SLE and RA in paternal grandmother and great-grandmother. The severity of her symptoms, in addition to severe dehydration prompted a PICU admission. The patient was placed NPO and was not able to tolerate oral feeds. Physical exam was notable for mild hepatomegaly and splenomegaly Her laboratory studies were notable for significantly elevated inflammatory markers (CRP), elevated AST, LDH, ferritin, triglycerides, hypoalbuminemia, anemia and lymphocytosis Extensive infectious workup (blood and stools) negative Newborn screen Negative for SCID BMT panel (T, B and NK cells) normal. IgG and IgA levels normal; elevated IgE and IgM She underwent upper endoscopy and flex sigmoidoscopy 1

2 Upper Endoscopy Stomach Stomach: diffuse erythema Duodenum: edema and purulent white plaques Duodenum Sigmoidoscopy Diffuse erythema and white plaques 2

3 Sigmoid Differential diagnosis Infection All cultures and viral PCR s negative Primary Immunodeficiency T, B and NK cells normal; newborn screen for SCID normal; IgA and IgG levels normal Hyper IgM syndrome Most common forms X linked AR forms usually feature low IgA and IgG; no CD40 mutation detected Autoimmune enteropathy Most common form, IPEX (FOX P3 gene) is X linked; CD 25 and STAT1 mutations can cause IPEX like disease in girls (no mutations identified in this case) Absence of anti enterocyte antibodies Absence of response to immunosuppression Hemophagocytic Lymphohistiocytosis Normal perforin and granzyme Analysis of a panel of HLH associated genes (14) by NGS did not identify any mutations Cryopyrin Associated Periodic Syndrome (CAPS) Severe enterocolitis with hypertryglyceridemia, hyperferritinemia, splenomegaly do not favor CAPS Very early onset IBD Very Early Onset IBD (VEO IBD) 20% 25% IBD patients diagnosed < 18 years of age North Am. Pediatric IBD consortium (2005) 37% diagnosed yrs of age 48% diagnosed 6 12 yrs of age 15% diagnosed < 6 yrs of age Very early onset IBD (VEO IBD) 6% < 3 years of age 1% diagnosed during 1 st year VEO IBD is characterized by an aggressive disease phenotype with poor response to conventional IBD therapy 3

4 Features of Very Early Onset (VEO) and older onset inflammatory bowel disease Genome wide association studies (GWAS) in IBD 163 IBD loci identified in IBD (adults and adolescents) 110 associated with both diseases 30 CD specific; 23 UC specific 66 loci associated with other autoimmune disorders Marked enrichment of genes associated with primary immunodeficiencies and susceptibility to mycobacterial infections From Kelsen et al, Cell Mol Gastroenterol Hepatol, 2015 From Jostins et al, Nature 2012;491:119 Monogenic disorders associated with VEO IBD VEO IBD Pathways A spectrum of rare monogenic disorders confers increased susceptibility to IBD like disease Most monogenic disorders have onset of colitis in early childhood (VEO colitis) There are few common genes between those that cluster within the 163 IBD loci and monogenic disorders with IBD phenotype Many better characterized primary immunodeficiencies (CGD, CVID) have IBD like features Epithelial Barrier ADAM17, IKBKG, COL7A1, FEMT1, TTC7A, GUCY2 Phagocyte Defects NADPH Complex IL10, IL10RA, IL10RB, FOXP3, CTLA T & B Cell Defects RAG1/2, IL7R, PTEN, WASP Immunoregulation Hyperinflammatory XIAP, STXBP2, LYST, RAGB27a VEO-IBD Courtesy of Judith Kelsen, CHOP 4

5 Monogenic disorders associated with IBD like pathology Epithelial barrier defects Dystrophic EB Kindler syndrome X linked ectodermal dysplasia ADAM 17 deficiency Familial diarrhea Neutropenia and phagocyte defects CGD GSD type I Congenital Neutropenia Leukocyte adhesion deficiency Hyper and autoinflammatory disorders Mevalonate kinase deficiency Phospholipase C2 defects Familial Mediterranean fever Familial macrophage activation syndrome X linked lymphoproliferative syndromes Hermansky Pudlak syndrome Complex defects in T and B cell function (WAS, CVID, SCID) Defects in regulatory T cells and IL 10 signaling 9 yo female with immunodeficiency, liver disease, severe failure to thrive and chronic diarrhea for many years DOCK 8 deficiency (dedicator of cytokinesis 8 protein) Combined T and B cell immunodeficiency recurrent cutaneous viral infections susceptibility to cancer and elevated serum levels of IgE Cryptosporidium Apoptosis Male, onset of disease 3 4 months Numerous GI biopsies Total colectomy at age 10 Segmental ileal resection age 14 X linked inhibitor of apoptosis (XIAP) deficiency X linked lymphoproliferative disease type 2, Severe Crohn s like disease Colectomy for colonic strictures Segmental ileal resection Clues for suspecting monogenic IBD Very early age of onset and severe or early onset perianal disease Family history Atypical endoscopic or histologic features Resistance to conventional therapy Skin, nail or hair abnormalities Macrophage activation syndrome Associated autoimmunity Early development of tumors Adapted from Uhlig et al, Gastroenterol 2014;147:990 5

6 Treatment for monogenic IBD like disorders Conventional IBD treatment often ineffective Therapeutic options Anti-TNFα and anti-il-1β used for CGD and diseases with autoinflammatory component Bone marrow/hematopoietic stem cell transplantation used for IPEX, CGD, XIAP and others Gene therapy has been applied to treat Wiskott-Aldrich associated immunodeficiency and colitis Blocking agents targeting specific cytokines Back to our patient. Further studies also revealed markedly elevated (elevated to the point that they could not be quantified) IL 1 and IL 18 Due to persistent fevers, large volume diarrhea requiring NPO and TPN, and laboratory studies consistent with an autoinflammatory and macrophage activation syndrome (MAS), she was initially started on Anakinra (an IL 1 inhibitor) in addition to numerous courses of IV antibiotics She was also started on methylprednisolone, cyclosporine, as well as IVIG and, in addition, treated with infliximab, at doses of 20mg/kg at 2 3 day intervals. The infliximab had to be discontinued because of an allergic reaction Whole Exome Sequence Analysis revealed a mutation p.val341ala in exon 4 of the NLRC4 gene NLRC4 belongs to a group of proteins called Inflammasomes Multimeric protein complexes that orchestrate host defense against pathogens and are typically composed of: Sensor protein Adaptor protein apoptosis associated speck like protein (ASC) Caspase 1 Found in cells of the innate immune system (macrophages, neutrophils), adaptive immune system (T cells) and epithelial cells Triggered by infection or cellular stress Result in activation of caspase 1, production of pro inflammatory cytokines (Il 1, IL 18) and inflammatory cell death to blunt intracellular pathogen replication 6

7 Inflammasomes A key component of inflammasomes are Pattern recognition receptors (PRRs) which act as scaffolds to activate caspase and release inflammatory cytokines Consist of several families of proteins (NLR, pyrin, HIN200) The best known are the Nucleotide oligomerization domain (NOD) like receptors (NLRs) which include NOD1, NOD2, NLRP3, NLRC4, NLRP6 Loss of function mutations in NOD2 confer increased risk of Crohn s disease Mutations in the nucleotide binding domain of NOD2 cause Pediatric Granulomatous Arthritis (Blau syndrome) and early onset sarcoidosis Mutations in NLRP3 result in the Cryopyrin Associated Periodic Syndromes Muckle Wells Chronic infantile neurological cutaneous and articular syndrome (CINCA) Neonatal onset multisystem inflammatory disease (NOMID) From Man and Kanneganti, Immunol Rev 2015;265:6 21 Clinical Course Required steroids (20X normal dose), vedolizumab (monoclonal ab which blocks α4 β7, used in IBD), infliximab (monoclonal ab against TNF α,used in IBD and autoimmune diseases), cyclosporine, and canakinumab (binds to IL 1) to stabilize Approved for compassionate treatment with IL 18BP (tadekinig alfa, clinical trial for Still s disease) resulting in immediate improvement IL 18 dynamics after recombinant IL 18BP IL 18 response in NLRC4 MAS Total IL-18 and IL-18BP (pg/ml) Free IL-18 Total IL-18 IL-18BP Ferritin Time (days) Above Upper Limit of Detection Free IL-18 (pg/ml) Dramatic and rapid resolution of ferritin, CRP, enterocolitis, and fevers Patient is now completely on oral, full feeds; gaining weight, meeting developmental milestones Unclear whether response can be maintained with monotherapy or continued IL 1 blockade is still needed 7

8 Conclusions Very early onset IBD is characterized by aggressive disease in young patients clearly different from later onset IBD Many are likely associated with rare monogenic variants that are identified by modern genetic analysis pointing to unique defects in epithelial barrier function, stress response and control of the inflammatory response Identifying and understanding these disorders provides targeted treatment options for these patients (personalized medicine) but also add to our understanding of the immune response and pathogenesis of IBD Key references Heyman, M.B., et al., Children with early onset inflammatory bowel disease (IBD): analysis of a pediatric IBD consortium registry. J Pediatr, (1): p Kelsen, J.R., et al., Maintaining intestinal health: the genetics and immunology of very early onset inflammatory bowel disease. Cell Mol Gastroenterol Hepatol, (5): p Uhlig, H.H., Monogenic diseases associated with intestinal inflammation: implications for the understanding of inflammatory bowel disease. Gut, (12): p Uhlig, H.H., et al., The diagnostic approach to monogenic very early onset inflammatory bowel disease. Gastroenterology, (5): p Opipari, A. and L. Franchi, Role of inflammasomes in intestinal inflammation and Crohn's disease. Inflamm Bowel Dis, (1): p Canna, S.W., et al., An activating NLRC4 inflammasome mutation causes autoinflammation with recurrent macrophage activation syndrome. Nat Genet, (10): p Romberg, N., et al., Mutation of NLRC4 causes a syndrome of enterocolitis and autoinflammation. Nat Genet, (10): p