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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
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
CD is a complex multifactorial disorder
• “Personalised” Coeliac Disease
• Prevention
• New biomarkers
• Advanced therapeutic strategies
The Future of Coeliac Disease
• Symptomatic (typical,
malabsorption)
• Symptomatic (atypical, extraGI)
• Silent
• Potential
Heterogeneity in Coeliac Disease
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
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
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
All have at risk HLA, but still there is a dose-effect (p = 0,04)
Risk factors: HLA doses
DQ8
DQ2
/ DQ2/DQ2
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
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%!!!
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Discepolo V. Barreiro LB Unpublished data
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
• 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
• “Personalised” Coeliac Disease
• Prevention
• New biomarkers
• Advanced therapeutic strategies
The Future of Coeliac Disease
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
Gene expression profile could represent an
early biomarker of the disease
Galatola et al, JPGN 2017
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
• “Personalised” Coeliac Disease
• Prevention
• New biomarkers
• Advanced therapeutic strategies
The Future of Coeliac Disease
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
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
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
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
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
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
• “Personalised” Coeliac Disease
• Prevention
• New biomarkers
• Advanced therapeutic strategies
The Future of Coeliac Disease
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
A vaccine for celiac disease: Nexvax2
Peptide library:
2,922 20mers
90 peptides active
262 patients
Dominant
peptides combopeptide
• 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
Acknowledgments
• Renata Auricchio
• Maria Vittoria Barone
• Valentina Discepolo
• Carmen Gianfrani
• Luigi Greco
• Giuliana Lania
• Maria Maglio
• Merlin Nanayakkara
• Salvatore Auricchio
• Bana Jabri