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Prediction of Type 1 Diabetes (T1DM) & related Autoimmune Diseases (AD). Marco Songini, MD Diabetes Unit Azienda Ospedaliera Brotzu Cagliari (Italy).

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Prediction of Type 1 Diabetes (T1DM) & related Autoimmune Diseases (AD)

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Prediction of type 1 diabetes t1dm related autoimmune diseases ad

Prediction of Type 1 Diabetes (T1DM) & related Autoimmune Diseases (AD)

Marco Songini, MD

Diabetes Unit

Azienda Ospedaliera Brotzu Cagliari (Italy)


Prediction of type 1 diabetes t1dm related autoimmune diseases ad

Type 1 diabetes develops from the interaction between susceptibility genes and enviromental determinants. The major genetic susceptibility to type 1 diabetes is conferred by markers from HLA locus, but other genes are involved. The non genetic contribution to the disease (i.e. nutritional factors and infective agents) is even less wll-defined. This may imply aetiological heterogeneity in patients so that particular combinations of genetic susceptibility factors require exposure to specific non-genetic factors in order to initiate the disease developing process in type 1 diabetes. It is well known that immune markers (ICA, GADA, IA2, IAA) appear many years before clinical onset of type 1 diabetes. These “windows” offers the chance to pinpoint subjects at risk eventually suitable to preventive therapies. At present, intervention trials are recommended in the small subset of the population at high risk identified by genetic and immune markers.


Complementary strategies in the prediction of t1dm

Complementary strategies in the prediction of T1DM

Strategy 1

AIM:

TEST INTERVENTION

STRATEGIES

High specificity/

low sensitivity

families

immune markers

high risk subgroup

Strategy 2

AIM:

REDUCE INCIDENCE

OF IDDM

Low specificity/

high sensitivity

general population

genetic + immune markers

moderate risk subgroup

Bingley, E. Bonifacio & E. Gale;Diabetes, vol. 42, feb. 1993


Preventive strategies for t1dm 1

Preventive strategies for T1DM (1)

Selective immunosuppression, using depleting or nondepleting monoclonal antibodies to lymphocyte cell surface molecules such as CD3, CD4, CD8, T cell receptor and major histocompatibility complex (MHC) antigens, or blocking peptides to T cell receptors

Immunostimulation by viruses, cytokines, calcitriol, concanavalin A, bacille Calmette-Guèrin (BCG), Freund’s adjuvant or tranfusion of deficient lymphocyte subsets B-Cell rest by suppressive therapy with insulin

E. Bosi & G.F. Bottazzo; Clin. Immunother. 3 (2) 1995


Preventive strategies for t1dm 2

Preventive strategies for T1DM (2)

Protection from oxygen radical-mediated and nitric oxide-mediated damage by nicotinamide, deferoxamine (desferrioxamine) and aminoguanidine

Environmental intervention by manipulation of temperature, diet (gluten free) and hormonal milieu

Induction of tolerance to B-cells by bone marrow transplantation, lymphocyte transfusion, intrathymic islet transplantation, neonatal B-cell stimulation and administration (intravenous, intrathymic, intraperitoneal or oral) of putative B-cell autoantigens such as insulin or glutamic acid decarboxylase

E. Bosi & G.F. Bottazzo; Clin. Immunother. 3 (2) 1995


Prediction of type 1 diabetes t1dm related autoimmune diseases ad

Tests to predict T1 DM & AD

Autoantibodies: ICA, GADA, IA2-A, IAA, AD-Abs

HLA-phenotype:DR3/DR4 (DQ2/DQ8), AD phenos

HLA-genotype:Eterodimers 57Non Asp/53Arg

DQ beta/DQ Alfa, AD genos

? Cell mediated markers: Alteration of lymphocyte

subsets CD4/CD8, etc.


Prediction of type 1 diabetes t1dm related autoimmune diseases ad

Immunological markers for T1DM

ICA

Islet Cell Abs

Indirect

immunofluorescence on human pancreatic

cryosections

Risk at 10 yrs FH+

>10 JDFU 41%

>80 JDFU 80%

Risk at 5 yrs

FH+ 44%

IAA

Insulin AutoAbs

In Children

first antibodies

to appear

R.I.A.

Risk at 10 yrs

ICA + IAA 81%


Prediction of type 1 diabetes t1dm related autoimmune diseases ad

Immunological markers for T1DM

IA2-A

Protein Tyrosin

Phosphatase AutoAbs

More

common

among

children

High specificity

low sensitivity

R.I.A.

GADA

Glutamic Acid Decarboxilase AutoAbs

High sensitivity

low specificity

More

common

among

adults

R.I.A.


Prediction of type 1 diabetes t1dm related autoimmune diseases ad

Immunological markers for T1DM

Combined markers in FH+

Positivity for 3 or 4 antibodies yelds a risk of

88-100% to become diabetic in 10 years

The best association of autoantibodies is:

GADA + IA2-A

GADA + IA2-A + IAA in young children

Pastore MR et al Diabetes Care 1998, 9; 1445-50

We are able to assay GADA + IA2-A

on blood spots

E. Bosi, E. Bonifacio et al . Diabetes Care - March 1999


Prediction of type 1 diabetes t1dm related autoimmune diseases ad

Background

The preclinical stage of type 1 diabetes and related AD can last even many years

These “windows” offers the chance to pinpoint subjects at risk eventually suitable to preventive therapies


Prediction of type 1 diabetes t1dm related autoimmune diseases ad

Genetic markers for T1DM

HLA typing

predisposing:

HLA DR3-DQ2, DR4-DQ8

protective:

HLA DR2-DQ6

Lernmark A Diabetes Metabolism Rev 1998, 14,3-29


Prediction of type 1 diabetes t1dm related autoimmune diseases ad

Genetic markers for T1DM

HLA

Molecular biology of DQ chains of class second

DQ A301, DQ B302, DQ B501 Alleles:

99% of diabetic patients

50% of normal people

Lernmark A Diabetes Metabolism Rev 1998, 14,3-29

DQ B602 is fully protective for T1DM

Gianani R et al. J Autoimmunity 1996, 9; 423-425


Prediction of type 1 diabetes t1dm related autoimmune diseases ad

Genetic markers for T1DM (1)

References

l

Locus

s

%

IDDM1

2,6

35

Davies (1994)

6p21

11p21

IDDM2

1,29

9,4

Davies (1994), Bennet (1995)

-

-

IDDM3

15q

Field (1994)

IDDM4

1,07

2,5

11q13

Hashimoto (1994), Davies (1994)

Davies (1994)

IDDM5

1,16

5,5

6q25

3,5

1,1

Meriman (unpub.), Davies (1994)

IDDM6

18q

Owerbach and Gabbay (1995)

IDDM7

1,13

4,5

2q31

Davies (1994), Copeman (1994),

1,42

IDDM8

6q27

12,9

Luo (1995), Davies (1996)


Prediction of type 1 diabetes t1dm related autoimmune diseases ad

Genetic markers for T1DM (2)

l

References

Locus

%

s

3q21-q25

1,26

IDDM9

8,5

Reed and Todd (unpubl.)

Gough and Todd (unpubl.)

1,45

13,7

IDDM10

10p11.2-q11.2

Davies, Hashimoto (1994)

95.5

TOT.

14

GCK

Rowe (1995)

7p

Field (1996)

14q24.3-q31

IDDM11

2q33

IDDM12 (CTLA-4)

Nistico (1996)

2q34

IDDM13

Morahan (1996)

6q21

IDDM15

Delepine (1997)


Prediction of type 1 diabetes t1dm related autoimmune diseases ad

Natural History of T1DM

Popul islet-related Abs+ Follow- Risk References

up

Identical Twins100%Tun RY, BMJ 1994

1st degree relatives (FH+)70%ICARUS Group Study

Polyendocrinopathy (FH-)25%Bosi E, Diabetes 1991

Polyendocrinopathy (FH+)70%Bosi E, Diabetes 1991

High risk newborns (FH+)50%BABYDIAB (Germany)

High risk newborns (gene+)50%DIPP Project (Finland)

Sardinian school children (gen) 24%SSI Study (Sardinia)

10 yrs

5 yrs

10 yrs

10 yrs

2 yrs

2 yrs

7 yrs


Natural history of t1dm

Natural history of T1DM

tt

Triggers ?

Triggers ?

Auto Abs +

75%

FPIR

50%

OGTT +

Triggers ?

Beta cell mass

25%

GENES (susc)

TYPE 1 DIABETES

0

Time


Screening for pre t1dm and related ad

Screening for pre-T1DM and related AD

•France• Sweden • Spain • Oxford

• Holland • Estonia

• SSI• USA

• Finland• Germany

Schoolchildren

• DAISY (USA)

• BABYDIAB (Germany, Australia)

• SNI (Sardinia)

• DIPP (Finland)

• DIABFIN (Italy)

Newborn


Cost of predicting t1dm

Cost of predicting T1DM

  • Conventional Therapy (CT) $1450

  • Intensive Therapy (ICT) $ 2 x CT

  • CSII $ 3 x CT

Cost of insulin

therapies

(per year)

Cost of Screening

(for each enrolled

case)

  • DPT-1 $1751

  • DIPP (follow up=10 yrs)

  • (newborns) $245 $733

Birth

Birth

Hahl et al. Diabetologia (1998) 41:79-85

100%

100%

Genetic+Abs

screening

Abs screening

100%

13%

Abs follow up

Counselling

Cost of DM (?AD)

  • $ 92 billions

Abs follow up


Prevention of t1dm and other related ad

Prevention of T1DM and other related AD


T1dm ad are theoretically preventable

T1DM&AD are theoretically preventable

  • Because there are environmental causes

  • Because we are beginning to understand the genetic and immune basis

  • Because they develops very slowly

  • Because we have good predictive tests

  • Because we can stop them in animals

  • Because we can run clinical trials


T1dm ad are suitable diseases for preclinical screening and intervention

T1DM & AD are suitable diseases for preclinical screening and intervention

  • Serious consequences (in USA 50 deaths yearly from DKA)

  • Treatment following diagnosis expensive, demanding, limited effect on complications

  • Identifiable preclinical phase also for AD

  • Identifiable subjects “not at risk” also for AD

  • ...but as yet no preventive therapy of proved efficacy (no penicillin for prediabetes!)


Assigning risk

Assigning risk

  • Primary prevention: must be based on family history or high risk HLA - and will miss a lot of cases!

  • Secondary prevention: immune-markers relatively stable after age 5; almost inevitable progression with multiple antibodies; excellent screening efficiency (islet imaging)


Setting up an intervention in whom

Setting up an intervention: in whom?

  • Primary: Neonates with family history or high risk HLA

  • Secondary:

    • Infants: HLA DR3/4 with antibodies

    • Children/young adults with multiple Abs (T1DM&AD)

    • Older adults with LADA


Setting up an intervention with what

Setting up an intervention: with what?

Should work:

  • In animal models

  • In newly diagnosed type 1

  • In pilot trials (assessed how?)

    Must have:

  • An acceptable safety profile

  • Ease of administration


Setting up an intervention conclusions

Setting up an intervention: conclusions

  • At present trials must be large, structured, costly and long term

  • Will depend on international collaboration

  • We need a disciplined consensus process for evaluating and prioritizing new therapies

  • Role of pharmaceutical industry? clinicians should have a say


T1dm prevention trials

T1DM prevention trials

Primary

Cow’s milk avoidance: TRIGR

Gluten free diet: PREVFIN

Secondary

Nicotinamide: DENIS, ENDIT, New Zealand

Insulin: DPT-1, EPLL SCIT; Schwabing, Brunetti 1999

Tertiary

Cyclosporin: GETREM, French and Canadian studies

Linomide : Franco-Swedish trial


Intervention trials assumptions

Intervention trials: assumptions

TrialNYr Diabetes RRR % %

ENDIT5305 40:26 35

DENIS1303 30:6 80

DPT (high)3404 84:55 35

DPT (inter)4904 24:12 50

Mahon and Dupre,1997


Cyclosporin before onset of t1dm

Cyclosporin before onset of T1DM

  • 6 relatives vs 9 historical controls

  • All controls developed diabetes in 12 months

  • 4/6 cyclosporin treated patients developed diabetes within 4 years (5, 24, 24 and 47 months)

Carel et al., 1996


Intervention in early infancy

Intervention in early infancy?

  • Level of risk?

  • Safety of intervention? Long term data?

  • Acceptability/compliance?

  • Efficacy demonstrated in other AD?

  • Can the intervention be tested effectively in this category of patient?


Prediction of type 1 diabetes t1dm related autoimmune diseases ad

Emergence of at least one auto-Ab

by the age of 2 years (n=173)

FOLLOW-UP, MONTHS

3 6 9 12 18 24TOTAL

CASEIN 0/830/751/723/711/671/62 3/84

HYDROLYSATE (3.6%)

p=0.06

CM-BASED0/871/846/797/786/777/76 10/89

FORMULA (11.2%)

The Second TRIGR Pilot Study


Eurodiab sardinia 1989 98 birth seasonality

EURODIAB Sardinia (1989-98)birth seasonality

P<0.001

Jan-March

Apr-June

Jul-Sept

Oct-Dec

N=1928, 0-29yr


Future directions

Future Directions?

  • Surrogate end-points

  • Safety and acceptability need to be balanced against efficacy

  • Early “one-off” therapy would be ideal

  • Explicit standards for performance of trials

  • Fewer, better quality studies based on international consensus

  • Lessons from other human autoimmune disease?


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