Riccardo Troncone - fimpnapoli.it FIMP 2018... · La celiachia domani Riccardo Troncone Department...
Transcript of Riccardo Troncone - fimpnapoli.it FIMP 2018... · La celiachia domani Riccardo Troncone Department...
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La celiachia domani
Riccardo Troncone
Department of Medical Translational Sciences &
European Laboratory for the Investigation of Food-
Induced Diseases
University Federico II, Naples, Italy
18° Congresso FIMP Napoli
Ischia, 19 maggio 2018
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Today
any age
systemic manifestations
autoimmune features
spectrum of histological
abnormalities
In the 70s-80s
confined to childhood
gastrointestinal symptoms
malabsorption
villous atrophy
Celiac Disease
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CD is a complex multifactorial disorder
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• “Personalised” Coeliac Disease
• Prevention
• New biomarkers
• Advanced therapeutic strategies
The Future of Coeliac Disease
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• Symptomatic (typical,
malabsorption)
• Symptomatic (atypical, extraGI)
• Silent
• Potential
Heterogeneity in Coeliac Disease
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Potential Celiac Disease
A condition that may preceed overt CD
Our cohort (Naples)
331 pediatric patients
• F>M 67,1%
• Mostly asymptomatic
• 37,1% belong to at-risk groups
50 autoimmune
73 1st degree relatives
• 34,4 % Marsh 0, 61,3% Marsh 1
• Anti-TG2 median: 28,99 U/l (nv<7).
• Diet: normal daily gluten intake
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Will all become coeliac?
42 villous atrophy in all
patients on GCD
51,5% still potential after
median follow up 151
months
Two clusters of events:
24-48 and 96-120 months
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Risk factors for VA: gd infiltration
Major risk to become
celiac depends on
Marsh grade at the
time of the diagnosis
(p= .009) 75% in
Marsh 1
patients
57% in
Marsh 0
gd IEL biopsy at diagnosis
Cases Potential
11,9 6,44
CI 8,3-15,5 5,5-7,3
p 0,05
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All have at risk HLA, but still there is a dose-effect (p = 0,04)
Risk factors: HLA doses
DQ8
DQ2
/ DQ2/DQ2
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Risk factors: age at diagnosis
Children recruited at older ages (above 10 years old) have an
increased risk to become celiac, compared to children enrolled
younger (< 3 years)
This effect is not related to the length of follow up
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Discriminant analysis at time of diagnosis
By this model the outcome of about 80% of cases
might be predicted at time of enrollment.
Add serology at 24 and 36 months of follow-up, we can
improve prediction of developing villous atrophy to 86,8%!!!
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Viral infections
Type-1 IFN induction
IFN-g+
IL21+
anti-gluten T cells
Anti-gluten Ab Anti-TG2 Ab
? IL-15 upregulation IL-15posType-A CD
MXAposType-B CD
Disease subtype Genes and environment
Heterogeneity of CD patients IL-15- IL-15+
Mx1- Mx1+
Mx1 = type-1 interferon inducible gene
% o
f IL
-15
+ c
ell
s
% of Mx1+ cells
Active CD LP IL-
15High
37%
Mx1high 18%
Discepolo V. Barreiro LB Unpublished data
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Adult CD patients clearly segregated into two classes based on colon tissue
gene expression – one that largely resembled the normal colon and one
where certain genes showed expression patterns normally specific to the
ileum.
The treatment-naïve pediatric CD patient cohort could be similarly
subdivided into colon- and ileum-like classes. Finally, expression patterns
within these CD subclasses highlight large-scale differences in the immune
response and aspects of cellular metabolism, and were associated with
multiple clinical phenotypes describing disease behavior, including rectal
disease and need for colectomy.
Weiser M et al Gut 2018;67:36-42
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• Recognition of heterogeneity
• Identification of risk factors
• Definition of the natural history of the
disease
will pave the way to
new strategies for “personalised”
therapy and prevention
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• “Personalised” Coeliac Disease
• Prevention
• New biomarkers
• Advanced therapeutic strategies
The Future of Coeliac Disease
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Up to 30% of infants born in coeliac families who are homozygous
DQ2 (HLA class 1 risk) will develop coeliac disease by age 5
Vriezinga SL et al. NEJM 2014
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Gene expression profile could represent an
early biomarker of the disease
Galatola et al, JPGN 2017
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Lessons from prospective studies:
miRNAs as early biomarkers of the
disease Prevent-CD study
miRNA profiles determined in 253 serial samples of 43
children enrolled: 32 developed CD vs 11 developing
gliadin antibody but not CD
25 miRNA differentially expressed between the time of
gluten introduction and the time of diagnosis
miRNA may display a gradual increase or decrease until
diagnosis and normalize on gluten-free diet
Ineke Tan et al, ESPGHAN 2015
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• “Personalised” Coeliac Disease
• Prevention
• New biomarkers
• Advanced therapeutic strategies
The Future of Coeliac Disease
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Antibodies, the best biomarkers
available
Positive
likelihood ratio
Negative
likelihood ratio
Odds
ratio
EMA /IgA 31.8
(18.6-54.3)
0.067
(0.038-0.118)
553
(218-1402)
Anti-TG2 /IgA 21.8
(12.9-36.8)
0.060
(0.040-0.090)
469
(250-880)
Anti-DGP /IgG 13.6
(8.1-22.8)
0.061
(0.017-0.221)
234
(100-546)
Anti-DGP /IgA 9.4
(6.8-13.1)
0.121
(0.072-0.203)
86.1
(56-132)
AGA /IgA 7.3
(4.5-11.8)
0.186
(0.095-0.362)
40.6
(14-117)
ESPGHAN Evidence Report 2011
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Child / Adolescent with Symptoms suggestive of CD
Anti-TG2 IgA & total IgA*
Anti-TG2
negative
Anti-TG2
positive
OEGD & biopsiesEMA & HLA DQ8/DQ2
EMA pos
HLA pos Marsh 0 -1 Marsh 2 or 3
Transfer to Paediatric GI Paed. Gi discusses with family the 2 diagnostic pathways
and consequences considering patient’s history &
anti-TG2 titers
EMA pos
HLA neg
* Or specific IgG based tests
CD+
GFD
& F/u
Consider
false pos.
anti-TG2
Consider
false neg.
HLA test,
Consider
biopsies
Not CD
Consider further diagnostic
testing if:
IgA deficiency
Age: < 2 years
History: - low gluten intake
- drug pretreatment
- severe symptoms
- associated diseases
CD+
GFD
& F/u
Unclear caseConsider:
false positive serology
false negative biopsy
or potential CD
Extended evaluation of
HLA/;serology/biopsies
EMA neg
HLA pos
Anti-TG2 <10 x normalAnti-TG2 >10 x normal
EMA neg
HLA neg
Not
available
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HLA DQ2 / DQ8 (+/- TG2)
HLA positive
DQ2 and/or DQ8
HLA negative
DQ2 and DQ8
OEGD & Biopsiesfrom Bulbus & 4 x pars descendens,
proper histological work up
Marsh 0 or 1
EMA
EMA negativeEMA positive
TG2 & total IgA*
No CD,
no riks for CD
Not CD
Marsh 2 or 3
TG2 NegativeTiter < 3 x normalTiter > 3 x normal
* Or specific IgG based tests
Consider retesting in
intervals or if symptomatic
CD+
GFD & F/u
x
x
Consider:
False negative results,
exclude IgA deficiency
and history of low gluten
intake or drugs
Consider:
Transient / false positive Anti-TG2
F/u on normal diet with further
serological testing
Unclear caseF/u on normal diet Consider:
false pos serology, false neg
biopsy or potential CD
Asymptomatic person at genetic risk for CDexplain implication of positive test result(s) and get consent for testing
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Werkstetter et al, Gastroenterology 2017;153:924-935
Criteria
for non-biopsy
approach using
local TGA / EMA
and central HLA
Final cohort (N=707) inconclusive
cases considered as “no CD”
Sensitivity analysis (N=691)
excluding 16 inconclusive cases
PPV [95% CI]
False
positives
[n]
PPV [95% CI]
False
positives
[n]
TGA-IgA ≥10xULN 99.13 [97.80;99.76] 4 99.78 [98.80;99.99] 1
+EMA-IgA positivity 99.56 [98.40;99.95] 2 100.0 [99.18;100.0] 0
+ EMA-IgA
+ HLA positivity 99.56 [98.40;99.95] 2 100.0 [99.18;100.0] 0
+ EMA, HLA
+ any symptom(s) 99.75 [98.61;99.99] 1 100.0 [99.08;100.0] 0
+ EMA, HLA
+ symptom(s) of
malabsorption
100.0 [98.68;100.0] 0 100.0 [98.68;100.0] 0
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Towards a revision of the ESPGHAN
diagnostic criteria
Really needed a separate algorythm for asymptomatic
subjects?
HLA typing not necessary to avoid biopsy
Which antibody tests are the first choice tests?
Critical interpretation of antibody results: the 10x threshold
works, but necessary the referral to pediatric
gastroenterologist
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From antibodies to T cells
T cells specific for immuno-dominant gluten
peptides express a highly biased TCR repertoire
as result of a strong selective process
The presence of such TCR indicating the
appearance of gliadin-specific T cells could
represent a very early marker of disease
Petersen et al, Nat Struct Mol Biol 2014; 21: 480-8
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• “Personalised” Coeliac Disease
• Prevention
• New biomarkers
• Advanced therapeutic strategies
The Future of Coeliac Disease
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Future therapeutic strategies
Reduction of gluten load
• Selection/production of varieties without biologically relevant sequences
• Detoxification
• Use of glutenase
• Reduced gluten entrance
Immune modulation
• HLA blockers
• TG2 inhibitors
(dihydroisoxazole, KCC009)
• Peptide-based vaccines
• Anti-IL15
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A vaccine for celiac disease: Nexvax2
Peptide library:
2,922 20mers
90 peptides active
262 patients
Dominant
peptides combopeptide
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• The concept of CD is evolving: from an enteropathy to a
systemic genetic-immunological disease.
• Sub-phenotyping CD and personalized diagnosis will
help in defining the most appropriate targets for therapy
and prevention
• New disease biomarkers: histology is not anymore the
gold standard for diagnosis (at least in Peds); antibodies
are the best biomarker available, but others are coming…
• New therapeutic strategies: many different attempts
Conclusions
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Acknowledgments
• Renata Auricchio
• Maria Vittoria Barone
• Valentina Discepolo
• Carmen Gianfrani
• Luigi Greco
• Giuliana Lania
• Maria Maglio
• Merlin Nanayakkara
• Salvatore Auricchio
• Bana Jabri