Immune mediated enteropathies. Aurora Tatu Bern 26/07/2017

Transcription

1 Immune mediated enteropathies Aurora Tatu Bern 26/07/2017

2 Definition/classification Systemic disease, mediated by antibodies, caracterised by histological changes of the small bowel Coeliac and noncoeliac

3 Coeliac disease elicited by gluten and related prolamines: wheat, rye, barley in genetically predisposed individuals characterized by the presence of a variable combination of gluten-dependent clinical manifestations CD-specific antibodies, HLA-DQ2 or HLA-DQ8 haplotypes a characteristic histomorphological picture of the proximal small intestinal mucosa (inflammatory infiltrate, crypt hyperplasia, villous atrophy) remission of clinical and serologic findings on keeping a gluten-free diet

4 Pathogenesis

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6 Diarrhea Abd pain Malabsorption Dermatitis Anemia Osteoporosis/penia Diabetes Neurological Reproductive IBS Autoimmune disorders Hepatic Lymphoma

7 Coeliac disease-testing whom Symptoms signs and laboratory of malabs Postive fam anamn + /- symptoms Hepatic cytolysis without other ethiology Assoc diseases: diab type I+sympt

8 ttg IgA EMA IgA Coeliac disease-testing how

9 Coeliac disease-testing how ttg IgA EMA IgA (cave IgA deficiency) IgG deaminated gliadin/ttg

10 Coeliac disease-testing how ttg IgA EMA IgA (cave IgA deficiency) IgG deaminated gliadin/ttg Intestinal Biopsies 4duodenum 2bulbus

11 Coeliac disease-testing how ttg IgA EMA IgA (cave IgA deficiency) IgG deaminated gliadin/ttg Intestinal Biopsies 4duodenum 2bulbus Avoiding diet

12 Coeliac disease-testing how (Ab) Children + symptoms + 10fold ttg IgA+HLADQ2 = no biopsy needed

13 Coeliac disease-testing how (B)

14 Positive diagnosis Serology ttg IgA At least 6 biopsies : scalloping/flaten folds, nodularity If there is a disagreement between serology and biopsy then HLA DQ2 and DQ8 genotyping Consider selective IgA deficiency Other reasons for villous atrophy

15 Other reasons for villous atrophy

16 Spectrum of the disease

17 If Gluten free diet

18 Management GFD for life Summary of the FDA Gluten Free Label Rules enacted August 2013 A food label gluten free must: Be inherently gluten free (raw vegetables, water, 100% juice) Does not contain an ingredient that is a gluten containing grain such as wheat, rye, barley Does not contain an ingredient derived from a gluten containing grain that has not been processed to remove gluten May contain an ingredient derived from a gluten containing grain that has been processed to remove gluten (wheat starch) as long as the food does not contain more that 20 ppm gluten The food product contains less than 20 parts per million gluten 2 mg/100 gm (<0.002%) Any unavoidable presence of gluten in the food is less than 20 ppm gluten 1 slice of Bread mg of gluten = 125,000 ppm gluten Interindividual variability Dietetician Search for micronutrient deficiencies +/- osteodensitometry

19 Phase II/III Studies

20 Follow up Other causes: In a meta-analysis of patients with biopsy-confirmed celiac disease undergoing follow-up biopsy on a gluten-free diet, we found that tests for serum ttg IgA and EMA IgA levels had low sensitivity (below 50%) in detection of persistent villous atrophy. Gastroenterology 05/2017 Silvester et al Gluten intake Bacterial overgrowth Microscopic colitis Exokrine pancreas insufficiency Fructose / Lactose intolerance Refractory coeliac disease Autoimmune enteropathy

21 Refractory coeliac disease Villous atrophy unresponsive to gluten-free diet (GFD) 6-12 month

22 Therapy RCD type 1+2 : Prednisone (0.5 1 mg/kg/day), budesonide (9 mg/day) Prednisone + azathioprine (2 mg/kg/day) - caution myelosuppression, infections, and lymphomagenesis Steroid dependence is observed in most patients Steroidrefractory: oral cyclosporine (5 mg/kg/day), infliximab (5 mg/kg/day), alemtuzumab (30 mg twice a week per 12 weeks). Lymphomagenesis is of special concern in patients Clinical response to steroids is observed in the majority (~75%) of patients with RCD type 2, however mucosal recovery is infrequent and progression to EATL is not prevented. RCD type 2 -higher risk of EATL if monoclonality persist after treatment with azathioprine Intravenous cladribine (0.1 mg/kg/day for 5 days) can induce clinical improvement (36%), histological improvement (59%), and significant decrease in the number of clonal intraepithelial lymphocytes (35%).Up to 41% developed EATL and died despite therapy. Caution: accelerated lymphomagenesis Case reports : alemtuzumab (anti-cd52 monoclonal antibody) or a combination of pentostatin (4 mg/m2 every two weeks per 24 weeks) and budesonide EATL may still occur over time in patients with RCD type 2 even after the T-cell clone was not further detected in the intestinal tissue by conventional ASCT disappointing for patients with overt EATL interleukin-15 blockade Rubio Tapia et al Gut April ; 59(4):

23 Autoimmune entropathy - Autoantigen is known Autoimmune enteropathy with nephropathy - Mutation of immunoregulatory gene Immune dysregulation, polyendocrinopathy, enteropathy, Xlinked: (IPEX) syndrome Autoimmune Polyendocrinopathy Candidiasis Ectodermal Dystrophy: (APCED) Syndrome - T lymphocyte activation deficiencies (CD3gamma mutation) - Unclassified

24 Autoantigen Autoimmune Enteropathy and Nephropathy Severe Relative paucity of intraepithelial lymphocytes 75kD autoantigen identified as the intestinal isoform of harmonin^a molecule that regulates tight junctions and intestinal paracellular permeability

25 Mutation of immunoregulatory gene

26 Diagnosis -Ab IgG, IgA or IgM antibody directed against the enterocyte, globlet cells Is this specific for this disease? Is the presence of an anti enterocyte antibody related to the mechanism of intestinal injury? Does the titer of the anti enterocyte antibody correlate with the severity of epithelial injury?

27 Diagnosis -Biopsy marked villous blunting Intense lymphocytic (CD3+ T cells) lamina propria infiltrate Injured surface epithelial cells Crypt number may be decreased in AIE Intraepithelial lymphocytes NOT increased in AIE May see non specific changes in the colon

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29 Differential diagnosis Infection: viral, cryptosporidium, parasites Cow s milk/protein enteropathy (?RAST testing) CIVD Quantitative immunoglobulins (G, A, M, E) IgG subclasses Anti PRP and anti tetanus antibody Neuroendocrine: VIP, gastrin, urine vanillylmandelic acid (VMA) Medicaments: Olmesartan, AZA, Micofenolate

30 Therapy TPN Long term immunosuppression: steroids, 6MP, AZA, cyclosporine Tacrolimus (serum level adapted)+/- IFX