Evidencebased criteria for celiac disease diagnosis

1
Evidence-based criteria for celiac disease
diagnosis

• Steffen Husby
• Hans Christian Andersen Childrens Hospital
  Odense University Hospital
• Denmark

2
ESPGHAN Working GroupCeliac Disease Diagnosis

• David Branski
• Carlo Catassi
• Steffen Husby
• Sibylle Koletzko
• Ilma Korbonai-Zsabo
• Markku Maki
• Luisa Mearin

• Carmen Ribes
• Luca Ronfani
• Raanan Shamir
• Riccardo Troncone
• Peter Zimmer
• Alessandro Ventura

3
Outline

• Celiac disease diagnosis
• Definition of celiac disease
• Current practices in Europe
• Evidence-based Medicine, principles
• Already-existing data
• Addition 2004-8
• Literature search

4
Celiac disease as a multiorgan autoimmune disease
CNS Ataxia, seizures
Depression Heart Carditis Skin
mucosa Dermatitis herpetiformis Aphtous
stomatitis Hair loss Reproductive
system Miscarriage Infertility
General Puberty growth delay
Malignancies Anemia GI system
Diarrhea, vomiting Distension, pain
Malnutrition, weight loss Hepatitis,
cholangitis Bone Osteoporosis,
fractures Arthritis Dental
anomalies
Modified from Rewers, Gastroenterology 2005
5
Towards a new definition of Celiac Disease

• A permanent gluten-sensitive enteropathy
• 
  Ferguson, 1995
• Celiac spectrum (disease?) is an immune-mediated
  systemic disorder elicited by gluten and related
• prolamines in genetically (mainly HLA)
  susceptible
• individuals, characterized by anti-tissue
• transglutaminase antibodies and/or gluten
  dependent
• clinical manifestations and/or enteropathy
• Troncone/
• ESPGHAN 2008

6
Celiac disease
7
Histology Marsh criteria
ORIGINAL
MODIFIED

• 0 pre-infiltrative, normal
• I infiltrative
• Normal mucosa and villous architecture, IELs
• II hyperplastic
• enlarged crypts, increased turnover
• III Destructive lesion
• VA, lymphocytre infiltration, hyperplastic crypts
• IV Hypoplastic
• total VA, normal IELs
• Does it exist?

• 0 pre-infiltrative, normal
• I infiltrative
• as original
• II hyperplastic
• as original
• III Destructive lesion
• A. partial VA
• B. sub-total VA
• C. total VA
• IV Hypoplastic
• as original

Marsh Gastro. 1982 102 330
Rostami Am.J.Gastro. 1989 94 888
8
Interlaken ESPGHAN criteria

• 1. biopsy Pathological small intestinal biopsy
  villous atrophy
• Gluten free diet for 1-2 years
• 2. biopsy Normalised
• 3. biopsy Again pathology after re-introduction
  of gluten - villous atrophy

McNeish et al. Arch. Dis. Childh. 1979 54 783
9
Revised ESPGHAN criteria 1990

• 1. biopsy Pathological small intestinal biopsy
  villous atrophy
• Clinical and serological improvement after 2-3
  months
• No further biopsy
• Provided age gt 2 years

Walker-Smith et al. Archs. Dis. Child. 1990 65
99
10
COELIAC DISEASE DIAGNOSIS ESPGHAN 1990
Criteria or need for a change? 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, unpublished 2008
11
Evidence-based criteria for clinical decisions
12
Origin of Clinical Questions

• Diagnosis how to select and interpret diagnostic
  tests
• Prognosis how to anticipate the patients likely
  course
• Therapy how to select treatments that do more
  good
• than harm
• Prevention how to screen and reduce the risk for
  
• disease

13
Steps in EBM

• Formulate an answerable question
• Track down the best evidence
• Critically appraise the evidence for
• Validity
• Impact (size of the benefit)
• Applicability
• Integrate with clinical expertise and patient
  values
• Evaluate our effectiveness and efficiency
• keep a record improve the process

14
Step 1- Framing the Question (Q)

• Clear, unambiguous, structured question
• Questions formulated re PPICO
• Populations of interest
• Prior test(s) (if appropriate)
• Intervention
• Comparisons (if appropriate)
• Outcomes

15
Step 2 Identifying relevant publications (F)

• Wide search of medical/scientific databases
• Medline, EMBASE
• Cochrane Reviews
• Ovid
• Relevance to focused question PPICO
• Population
• Prior test
• Intervention
• Comparator
• Outcome

16
Publication and reporting biases
All studies conducted
All studies published

• Positive Results Bias
• Grey Literature Bias
• Time-Lag Bias
• Language and Country Bias
• Multiple Publication Bias
• Selective Citation Bias
• Database Indexing Bias
• Selective Outcome
• Reporting B.

Grey literature
Studies reviewed
Health Technology Assessment, 2000 4(10)1-115
17
Quality of the evidence

• clinical aspects
• patient characteristics
• comparator
• duration of follow-up
• relevance of endpoints
• (outcomes)
• relevance of effect sizes

• Methodological aspects
• Randomisation
• Concealement of allocation
• Blinding
• intention-to-treat
• subgroup analyses
• .........

18
Oxford Centre for Evidence-based Medicine Levels
of Evidence (May 2001)
19
Grading the quality of evidence

• Give the confidence of the recommendation.
• Can the reader be sure that the recommendation
  reflects the evidence
• Is coded into 4 grades
• NOT Strength of recommendation

20
Grades of quality of Evidence
for the Statements

• High Further research is unlikely to change our
  confidence in the estimate of effect
• Moderate Further research is likely to have an
  important impact on our confidence in the
  estimate of effect and may change the estimate
• Low Further research is very likely to have an
  important impact on our confidence in the
  estimate of effect and may change the estimate
• Very low Any estimate of effect is uncertain

GRADE working group BMJ20043281490-4
21
(No Transcript)
22
From evidence to recommendations
Quality of evidence
Strength of recommendation
do / dont do we recommend
1 high
probably do/dont do we suggest
2 - moderate
3 - low
Uncertain can be considered we do not know
4 - very low
considered judgment a group decision
DM-CPG programme method report
(www.versorgungsleitlinien.de/english/methods) Eur
opean Council, Recommendation (2001) 13 GRADE
2004 (www.gradeworkinggroup.org)
23
Step 4 Summarising the Evidence (S)

• Extracting data from trials
• Combining data Meta analysis
• Does it make sense to combine?

Oxford Centre for Evidence-based Medicine, 2001
24
Diagnostic Test Accuracymeasurements

• Sensitivity is the probability of a positive test
  in a diseased person
• Specificity is the probability of a negative test
  in a non-diseased person.

25
Can a test rule-in or rule-out?

• SpPln
• Specific test, Positive rules Ine.g. Rovsing's
  sign, ST elevation gt 2mm
• SnNout
• Sensitive test, Negative rules Oute.g. Erect
  abdominal film for obstruction, Elevated WCC in
  CSF (gt5/mm )

26
organisational framework names and jobs
coordinator, secretary
consensus-panel
steering group
Working Group 1
Working group 2
27
Vote Rules for identifying agreement and dissent
28
Why we need formal methods of consensus
development

• Safety in numbers several people are less
  likely to arrive at a wrong decision than a
  single individual.
• Authority a selected group of individuals is
  more likely to lend some authority of the
  decision produced.
• Rationality decisions are improved by reasoned
  arguments in which assumptions are challenged and
  members forced to justify their views.
• Controlled process by providing a structured
  process formal methods can eliminate negative
  aspects of group decision-making.
• Scientific credibility formal consensus methods
  meet the requirements of scientific methods.

Murphy, Black et al. Consensus development
methods and their use in clinical guideline
development a review. HTA 1998
29
(No Transcript)
30
USA AHRQ report 2004 Main issues

• (1) sensitivity, specificity of serological tests
• (2) prevalence and incidence of CD
• (3) CD associated lymphoma
• (4) consequences of testing for CD
• (5) interventions for adherence to a gluten-
  free diet.

Rostom A, et al.. Celiac Disease.
EvidenceReport/Technology Assessment No. 104.
AHRQ Publication No. 04-E029-2, 2004
31
USA AHRQ report 2004. Conclusions.

• The sensitivity and specificity of EMA and tTG
  are quite high
• CD is a very common disorder with a prevalence in
  the general population that is likely close to
  1100 (1)
• No specific interventions have been identified
  that promote adherence to a GFD, but education
  and participation in local celiac societies has
  been shown to improve compliance.

Rostom A, et al.. Celiac Disease.
EvidenceReport/Technology Assessment No. 104.
AHRQ Publication No. 04-E029-2, 2004
32
NASPGHAN guidelines 2005

• PubMed, DARE, Cochrane
• 317 articles
• Evaluation by two committee members
• Consensus Nominal Group Technique
• Quality of evidence

Hill ID et al. JPGN 2005 40 1-19
33
NASPGHAN 2005 Algorithms for diagnosis
34
ESPGHAN EBM and Celiac disease
35
Celiac disease 2008 ESPGHAN diagnostic
questions

• Clinical presentation
• What are the symptoms of CD?
• What sub-clinical signs are present in CD?
• What are the risks for developing sequelae in
  asymptomatic CD?
• Serology
• What are convincing CD-antibody tests (type,
  level, quality, number)?
• HLA
• How many with pos. EMA/TTG are positive for HLA
  DQ2/DQ8?
• Do we need both HLA and serology in asymptomatic
  risk groups?
• Biopsy
• Does the pathology from intestinal biopsy qualify
  for the gold standard?
• Is intestinal biopsy necessary in patients with
  symptomatic CD and convincing CD-antibodies?

36
Task ESPGHAN criteria for celiac disease
To try to answer our questions update the AHRQ
systematic review (from 2004 to 2008) - update
the literature - select the papers (3 levels
screening) - evaluate the methodological quality
- synthesize the evidence
Rostom A, et al. Celiac disease. Agency for
Healthcare Research and Quality (AHRQ) 2004)
37
3 levels of screening for papers selection

• Level 1 (broad screening).
• Inclusion any article reporting
  sensitivity/specificity of AGA, EMA, tTG, HLA
  DQ2/DQ8, or biopsy. Exclusion clearly unrelated
  citation
• Level 2 (refined screening).
• Inclusion for serology/HLA articles where
  sensitivity and specificity could be extracted
  for biopsy articles where some measure of
  diagnostic utility could be obtained.
• Level 3 (final screening) ? see below

Trieste
Groups
38
2.1 from 2004 to July 15, 2007
39
(No Transcript)
40
(No Transcript)
41
ESPGHAN Working GroupCeliac Disease Diagnosis

• David Branski
• Carlo Catassi
• Steffen Husby
• Sibylle Koletzko
• Ilma Korbonai-Zsabo
• Markku Maki
• Luisa Mearin

• Carmen Ribes
• Luca Ronfani
• Ranaan Shamir
• Riccardo Troncone
• Peter Zimmer
• Alessandro Ventura

42
Thank you!
Hans Christian Andersen