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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