prediction of type 1 diabetes mellitus
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Prediction of Type 1 Diabetes (T1DM) & related Autoimmune Diseases (AD)
Marco Songini, MD
Diabetes Unit
Azienda Ospedaliera Brotzu Cagliari (Italy)
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
Strategy 1
AIM:
TEST INTERVENTIONSTRATEGIES
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 subgroupBingley, E. Bonifacio & E. Gale;Diabetes, vol. 42, feb. 1993
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)
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
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.
Immunological markers for T1DM
ICAIslet Cell Abs
Indirectimmunofluorescence on human pancreaticcryosections
Risk at 10 yrs FH+>10 JDFU 41%>80 JDFU 80%
IAAInsulin AutoAbs
R.I.A.In Childrenfirst antibodiesto appear
Risk at 5 yrs FH+ 44%
Risk at 10 yrs ICA + IAA 81%
GADAGlutamic Acid Decarboxilase AutoAbs
Immunological markers for T1DM
R.I.A.Morecommon among adults
High sensitivitylow specificity
IA2-AProtein TyrosinPhosphatase AutoAbs
R.I.A.Morecommon among children
High specificitylow sensitivity
Immunological markers for T1DMCombined 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
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
Background
HLA typing
predisposing:HLA DR3-DQ2, DR4-DQ8
protective:HLA DR2-DQ6
Lernmark A Diabetes Metabolism Rev 1998, 14,3-29
Genetic markers for T1DM
Molecular biology of DQ chains of class second
DQ A301, DQ B302, DQ B501 Alleles: 99% of diabetic patients 50% of normal people
DQ B602 is fully protective for T1DM
Lernmark A Diabetes Metabolism Rev 1998, 14,3-29
Gianani R et al. J Autoimmunity 1996, 9; 423-425
HLAGenetic markers for T1DM
6p21 IDDM1 2,6 35 Davies (1994)
15q IDDM3 - - Field (1994)
11q13 IDDM4 1,07 2,5 Hashimoto (1994), Davies (1994)
6q25 IDDM5 1,16 5,5 Davies (1994)
2q31 IDDM7 1,13 4,5 Davies (1994), Copeman (1994),
Owerbach and Gabbay (1995)
6q27 IDDM8 1,42 12,9 Luo (1995), Davies (1996)
18q IDDM6 1,1 3,5 Meriman (unpub.), Davies (1994)
11p21 IDDM2 1,29 9,4 Davies (1994), Bennet (1995)
Locus s % References
Genetic markers for T1DM (1)
Genetic markers for T1DM (2)
1,45
3q21-q25 IDDM9 1,26 8,5Gough and Todd (unpubl.)
10p11.2-q11.2 IDDM10 13,7 Davies, Hashimoto (1994)
Reed and Todd (unpubl.)
14141414 95.595.595.595.5TOT.TOT.TOT.TOT.
s %
7p GCK Rowe (1995)
IDDM12 (CTLA-4)2q33 Nistico (1996)
14q24.3-q31 IDDM11 Field (1996)
2q34 IDDM13 Morahan (1996)6q21 IDDM15 Delepine (1997)
Locus References
Identical Twins 100%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)
Natural History of T1DM
2 yrs
2 yrs
Popul islet-related Abs+ Follow- Risk References
10 yrs
5 yrs
7 yrs
10 yrs
10 yrs
up
Natural history of T1DM
tt
Beta cell mass
50%
25%
75%
Triggers ?Triggers ?
TYPE 1 DIABETES
Auto Abs +
FPIR
OGTT +
Time0
Triggers ?Triggers ?
Triggers ?Triggers ?
GENES (susc)
Screening for pre-T1DM and related AD
Schoolchildren
Newborn
• DAISY (USA)• BABYDIAB (Germany, Australia) • SNI (Sardinia)• DIPP (Finland)• DIABFIN (Italy)
•France • Sweden • Spain • Oxford• Holland • Estonia • SSI • USA• Finland • Germany
Cost of predicting T1DM Cost of insulin
therapies
(per year)
•Conventional Therapy (CT) $1450
•Intensive Therapy (ICT) $ 2 x CT
•CSII $ 3 x CT
Cost of Screening(for each enrolled case)
•DPT-1 $1751
•DIPP (follow up=10 yrs) (newborns) $245 $733
Birth
Genetic+Absscreening
Counselling
Abs follow up
100%
13%
Birth
Abs screening
Abs follow up
100%
100%
Cost of DM (?AD)
Hahl et al. Diabetologia (1998) 41:79-85
•$ 92 billions
Prevention of T1DM and other related AD
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
• 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
• 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?
• 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?
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
• 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
PrimaryCow’s milk avoidance: TRIGR
Gluten free diet: PREVFIN
SecondaryNicotinamide: DENIS, ENDIT, New Zealand
Insulin: DPT-1, EPLL SCIT; Schwabing, Brunetti 1999
TertiaryCyclosporin: GETREM, French and Canadian studies
Linomide : Franco-Swedish trial
Intervention trials: assumptions
Trial N Yr Diabetes RRR % %
ENDIT 530 5 40:26 35
DENIS 130 3 30:6 80
DPT (high) 340 4 84:55 35
DPT (inter) 490 4 24:12 50
Mahon and Dupre,1997
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?
• 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?
FOLLOW-UP, MONTHS
3 6 9 12 18 24 TOTAL
CASEIN 0/83 0/75 1/72 3/71 1/67 1/62 3/84
HYDROLYSATE (3.6%)
p=0.06
CM-BASED 0/87 1/84 6/79 7/78 6/77 7/76 10/89
FORMULA (11.2%)
Emergence of at least one auto-Abby the age of 2 years (n=173)
The Second TRIGR Pilot Study
EURODIAB Sardinia (1989-98)birth seasonality
02468
101214161820
Jan-March Apr-June Jul-Sept Oct-Dec
Seasons of birth
No.
of
bir
ths/
mon
th
N=1928, 0-29yr
P<0.001
Jan-March Apr-June Jul-Sept Oct-Dec
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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