New ESPGHAN guidelines for the diagnosis of Coeliac Disease in Children and Adolescents

Transcription

1 New ESPGHAN guidelines for the diagnosis of Coeliac Disease in Children and Adolescents Steffen Husby Hans Christian Andersen Children s Hospital Odense University Hospital, Denmark

2 Agenda Change in clinical paradigm Definitions of coeliac disease New diagnostic guidelines Algorithms

3 Interlaken ESPGHAN criteria (1979) 1. Small intestinal biopsy: villous atrophy 2. Gluten free diet for 1-2 years 3. Biopsy: normal. 4. Re-introduction of gluten 5. Biopsy: villous atrophy McNeish et al. Arch Dis Childh 1979;54:783

4 Revised ESPGHAN criteria Small intestinal biopsy: villous atrophy 2. Clinical and serological improvement after 2-3 months No further biopsy Provided age > 2 years Walker Smith et al. Arch Dis Child 1990;65:99

5 Celiac disease as a multiorgan autoimmune disease General: Puberty & growth delay Malignancies Anemia GI system: Diarrhea, vomiting Distension, pain Malnutrition, weight loss Hepatitis, cholangitis CNS: Ataxia, seizures Depression Heart: Carditis Skin & mucosa: Dermatitis herpetiformis Aphtous stomatitis Hair loss Bone: Osteoporosis, fractures Arthritis Dental anomalies Reproductive system: Miscarriage Infertility Modified from Rewers, Gastroenterology 2005

6 Patient Type 1 Diabetes Adrenal antibodies Coeliac disease Dermatitis herpetiformis Hansen et al. unpublished Autoimmune hypothyroidism

7 Towards a new definition of coeliac disease Chronic Multi-organ Small intestinal inflammation Transglutaminase-related ESPGHAN working group, 2011

8 Suggestion: New definition an immune-mediated systemic disorder elicited by gluten and related prolamines in genetically (mainly HLA) susceptible individuals characterized by a combination of: gluten dependent clinical manifestations anti-tissue transglutaminase (TG2) antibodies enteropathy Husby et al. JPGN 2012

9 ESPGHAN classification Silent CD: positive CD antibodies and biopsy findings, not sufficient symptoms to warrant clinical suspicion of CD Latent CD: positive CD antibodies, no villous atrophy. The patient has had a glutendependent enteropathy. Patient may/may not have symptoms Potential CD: positive antibodies, but no villous atrophy. Patient may/may not have symptoms. CD may or may not develop

10 The Oslo Definitions Coeliac disease is a chronic small intestinal immune-mediated enteropathy precipitated by exposure to dietary gluten in genetically predisposed individuals. Discourage the use of classical vs. non-classical, typical vs. atypical Discourage the use of the term latent CD Ludvigsson et al. Gut 2012

11 ESGPHAN member Questionnaire 85 % of those who are compliant to the 1990 criteria want them to be changed challenge policy: 100 % HLA should be included for DX 80% C.Ribes et al. JPGN 2012

12 Previous evidence-based guidelines for CD diagnosis AHRQ (USA, 2004) Adults and children NICE guidelines (UK, 2009) Adults and children For GP s and general paediatricians None questioned the biopsy Rostom A, et al.. Celiac Disease. EvidenceReport/ Technology Assessment No AHRQ Publication No. 04-E029-2, 2004 NICE Clinical Guidelines 86. Coeliac Disease: Recognition and assessment of coeliac disease. UK, May 2009

13 Guidelines: AHRQ (USA, 2004) Main issues 1. Sensitivity/specificity of serological tests 2. Prevalence / incidence of CD 3. CD associated lymphoma 4. Consequences of testing for CD 5. Interventions for adherence to a glutenfree diet Conclusions 1. Sensitivity and specificity of EMA and TG2 ab quite high 2. CD common, prevalence in the general population likely close to 1: Education/participation in coeliac societies improves compliance with a GFD Rostom A, et al.. Celiac Disease. EvidenceReport/Technology Assessment No AHRQ Publication No. 04 E029 2, 2004

14 Evidence-based criteria for clinical decisions 1. Formulate an answerable question 2. Track down the best evidence 3. Critically appraise the evidence for Validity Impact (size of the benefit) Applicability 4. Integrate with clinical expertise and patient values 5. Evaluate our effectiveness and efficiency keep a record/improve the process Clinical circumstances Patient preferences and values Evidence-based medicine Devereaux 2004

15 Literature search Search 1: n=1,418 EMBASE, Medline Search 2: n=402 Medline Search 3: n=778 Embase Medline n=2,598 Entering Level 1 screening n=334 Full text Entering Level 2 screening n=87 Entering Level 3 screening n = 16 publications Included in data synthesis n=2, no full text excluded n=247 excluded N = 71 excluded based on E1-8: No biopsy Age Quality etc. Giersiepen et al. 2010

16 Grading Evidence Type of study: Diagnosis Study Quality Level 1: Good quality patient-oriented evidence Level 2: Limited quality patientoriented evidence Level 3: Other evidence Validated clinical decision rule Systematic Review(SR)/metaanalysis of high quality studies High quality diagnostic cohort study Unvalidated clinical decision rule SR/meta-analysis of lower quality studies or studies Lower quality diagnostic cohort study or diagnostic case control study Consensus guidelines, extrapolations from bench research, usual practice, opinion, disease-oriented evidence, case series etc. Ebell MH et al. JABFP 2004

17 Example statement: Increased prevalence of CD in children with Type 1 diabetes 2 12 Down s syndrome 5-12 Autoimmune thyroid disease up to 7 Turner syndrome 2-5 Williams syndrome up to 9 IgA deficiency 2-8 Autoimmune liver disease First degree relatives with CD %

18 Recommendation: ( ) offer testing for CD of children and adolescents with the following conditions: Type 1 diabetes Down s syndrome Autoimmune thyroid disease Turner syndrome Williams syndrome IgA deficiency Autoimmune liver disease 1st degree relatives with CD

19 Coeliac Antibodies IgA Anti-TG2 antibody IgA Endomysial antibody (EMA) IgA and IgG Deamidated Gliadin Peptide (DPG) antibody NOT: IgA and IgG anti-gliadin antibodies

20 DISEASE PREDICTION BY ANTIBODIES (pooled estimates with 95% confidence values; indicates high hetereog neity) Positive likelihood ratio EMA /IgA 31.8 ( ) Anti-TG2 /IgA 21.8 ( ) Anti-DGP /IgG 13.6 ( ) Anti-DGP /IgA 9.4 ( ) AGA /IgA 7.3 ( ) Negative likelihood ratio ( ) ( ) ( ) ( ) Odd s ratio 553 ( ) 469 ( ) 234 ( ) 86.1 (56-132) ( ) (14-117) Giersiepen, Evidence report, JPGN 2012

21 Development of symptomatic coeliac disease in EMA positive subjects Diagnosed celiac: % :99 Mäki, N Engl J Med 2003

22 Predictive values for TG2 antibody Positive predict. value Toftedal et al. JCLM 2010

23 AU Median ELISA values in 14 commercial anti-tg2 assays AU in Varelisa [Celikey] (data kindly provided by UK NEQAS) Aesku Binding Site BMD Luminex 43 DiaSorin 57 High sample xuln Euroimmun Eurospital* Generic Assays Genesis Immco Inova* Orgentec Phadia ELIA Phadia ImmunoCAP Phadia Varelisa *logarithmic assays

24 Child / Adolescent with Symptoms suggestive of CD Anti-TG2 IgA & total IgA * Anti-TG2 positive Anti-TG2 negative Not CD Transfer to Paediatric GI Paed. GI discusses with family the 2 diagnostic pathways and consequences considering patient s history & anti-tg2 titers Anti-TG2 > 10 x normal Anti-TG2 < 10 x normal Consider further diagnostic testing if: IgA deficiency Age: < 2 years History: - low gluten intake - drug pretreatment - severe symptoms - associated diseases EMA & HLA DQ8/DQ2 Not available OEGD & biopsies EMA pos. HLA pos. EMA pos. HLA neg. EMA neg. HLA neg. EMA neg. HLA pos. Marsh 0-1 Marsh 2 or 3 CD+ Consider false neg. HLA test. Consider biopsies Consider false pos. anti-tg2 Unclear case Consider: false pos. serology false neg. biopsy or potential CD CD+

25 Child / Adolescent with Symptoms suggestive of CD Anti-TG2 IgA & total IgA * Anti-TG2 positive Anti-TG2 negative Not CD Transfer to Paediatric GI Paed. GI discusses with family the 2 diagnostic pathways and consequences considering patient s history & anti-tg2 titers Anti-TG2 > 10 x normal Anti-TG2 < 10 x normal Consider further diagnostic testing if: IgA deficiency Age: < 2 years History: - low gluten intake - drug pretreatment - severe symptoms - associated diseases EMA & HLA DQ8/DQ2 Not available OEGD & biopsies EMA pos. HLA pos. EMA pos. HLA neg. EMA neg. HLA neg. EMA neg. HLA pos. Marsh 0-1 Marsh 2 or 3 CD+ GFD & F/u Consider false neg. HLA test. Consider biopsies Consider false pos. anti-tg2 Unclear case Consider: false pos. serology false neg. biopsy or potential CD Extended evaluation of HLA/serology/biopsies CD+ GFD & F/u

26 Child / Adolescent with Symptoms Suggestive of CD Anti TG2 & total IgA* Anti TG2 positive Anti TG2 negative Not CD Transfer to Paediatric Gastroenterologist Paed. GI discusses with family the 2 diagnostic pathways and consequences considering patient s history & anti TG2 - titers Positive Anti TG2 > 10 x normal Positive Anti TG2 <10 xnormal Consider further diagnostic testing if: IgA deficient Age: < 2 years History: low gluten intake drug pretreatment severe symptoms associated diseases EMA & HLA testing for DQ2/DQ8 Not available OEGD & biopsies EMA pos. HLA pos. EMA pos. HLA neg. EMA neg. HLA neg. EMA neg. HLA pos. Marsh 0 1 Marsh 2 or 3 CD+ GFD & F/u Consider false neg. HLA test Consider biopsies Consider false pos. Anti TG2 Unclear case Consider: false pos. serology false neg. biopsy or potential CD Extended evaluation of HLA/serology/biopsies CD+ GFD & F/u *or specific IgG based tests *

27 Rationale for omitting biopsies in selected cases Serological tests improved over last years Histology not as perfect as thought 20 yrs ago (lower sensitivity and specificity than serology) Risk-benefit ratio has changed: risk and cost of invasive procedure (OEGD, histological work-up) versus risk of false positive diagnosis

28 Asymptomatic person at genetic risk for CD Explain implication of positive test result(s) and get consent for testning HLA DQ2 / DQ8 (+/- TG2) HLA positive DQ2 and/or DQ8 HLA negative DQ2 and/or DQ8 No CD, no risk for CD TG2 & total IgA * Consider retesting in intervals or if symptomatic Titer > 3 x normal Titer < 3 x normal TG2 negative Not CD OEGD & biopsies From bulbus & 4 pars descendens, proper histological work up EMA EMA positive EMA negative Consider: False neg. Results, exclude IgA deficiency and history of low gluten intake or drugs Marsh 2 or 3 Marsh 0-1 CD+ GFD & F/u Unclear case F/u on normal diet. Consider: False pos. serology, false neg. biopsy or potential CD Consider: Transient/false pos. anti- TG2 F/u on normal diet with further serological testing * Or specific IgG based tests

29 Asymptomatic person at genetic risk for CD Explain implication of positive test result(s) and get consent for testning HLA DQ2 / DQ8 (+/- TG2) HLA positive DQ2 and/or DQ8 HLA negative DQ2 and/or DQ8 Not CD, no risk for CD TG2 & total IgA * Consider retesting in intervals or if symptomatic Titer > 3 x normal Titer < 3 x normal TG2 negative Not CD OEGD & biopsies From bulbus & 4 pars descendens, proper histological work up EMA EMA positive EMA negative Consider: False neg. Results, exclude IgA deficiency and history of low gluten intake or drugs Marsh 2 or 3 Marsh 0-1 CD+ GFD & F/u Unclear case F/u on normal diet. Consider: False pos. serology, false neg. biopsy or potential CD Consider: Transient/false pos. anti-tg2 F/u on normal diet with further serological testing * Or specific IgG based tests

30 Asymptomatic Person at Genetic Risk for CD Explain implication of positive test result(s) and get consent for testing HLA DQ testing (+/ Anti TG2) HLA positive for DQ2 and/or DQ8 HLA negative for DQ2 and/or DQ8 Not CD, no risk for CD Anti TG2 & total IgA* Consider retesting in intervals or if symptomatic Positive Anti TG2 >3x normal Positive Anti TG2 < 3x normal Anti TG2 negative Not CD OEGD & biopsies: 1 x bulbus & 4 x pars descendens, proper histological work up EMA EMA positive EMA negative Consider: age, false neg. results, exclude IgA deficiency and history of low gluten intake or drugs Marsh 2 or 3 Marsh CD+ GFD & F/u Unclear case F/u on normal diet Consider: false pos. serology, false neg. biopsy or potential CD Consider: Transient / false pos. anti TG2 F/u on normal diet with further serological testing *or specific IgG based tests *

31 Why different algorithms for symptomatic and asymptomatic (at risk) patients? 1. False positive or transient TG2 antibody levels more frequent in genetically at risk persons than symptomatic cases 2. TG2 titres with normal histology (Marsh 0) are often of low titre (<3 x upper limit of normal) 3. In asymptomatic patients with low antibody levels there no urgency to perform biopsies compared to symptomatic patients with the same low levels.

32 Conclusions 1. The new guidelines will offer the option of omitting biopsies in selected cases with symptoms suggestive of CD without increasing the risk of misclassification. 2. Preconditions are high quality serology including EMA taking quantitative antibody levels into account HLA typing full information to parents/patient on consequences

33 ESPGHAN Working Group on Celiac Disease Diagnosis David Branski Carlo Catassi Steffen Husby Sibylle Koletzko Ilma Korbonay-Szabo Luisa Mearin Markku Maki Alan Phillips Carmen Ribes Luca Ronfani Raanan Shamir Riccardo Troncone Alessandro Ventura Klaus Peter Zimmer Tunde Koltai Klaus Giersiepen Monika Lelgemann Hans Christian Andersen