National Alopecia Areata Registry

• Madeleine Duvic, MD

• Professor of Medicine & Dermatology

• MD Anderson Cancer Center

• Houston, Texas

Investigators

• Angela Christiano – Columbia, NYC

• Maria Hordinsky – Univ of Minnesota

• David Norris – Univ of Colorado

• Vera Price – Univ of California, SF

• Madeleine Duvic – Univ Texas

– Chris Amos - Bioinformatics

Purpose of the AA Registry

• 1. To find and collect samples from multiplex families, siblings, and individuals with alopecia areata of all severities.

• 2. To encourage research using the data and samples from the registry.

• 3. Information used to understand disease, find effective treatment, and cure.

HYPOTHESIS: Alopecia Areata is

• Genetic - Host determined, HLA restricted • Organ specific T-cell mediated directed to

the hair follicle• AND Environmental - Triggered by an

external event, a viral infection or vaccine or stress??

• Mediated by cytokines & neuropeptides locally.

Class II HLA Genes in AAClass II HLA Genes in AA• CLASS II MHC (DR,DQ,DP) ASSOCIATIONSCLASS II MHC (DR,DQ,DP) ASSOCIATIONS

– HLA-DR4, DR5 (Italian, Danish, & English); HLA-DR7 (Russians)

– The HLA-DR5 allele *1104-patchy early onset

– 80% of AA have HLA-DQB1*03 alleles associated with HLA- DR5

MICA alleles assoc with AA – NK receptor

– Welsh/Duvic JID 103: 758,1994– Colombe/Price JAAD 33:757, 1995

AA in Identical Twins

• 55% concordancy in monozygotic twins.

• More severe in first affected, M>>F.

• All had HLA-DQ 0*302

• Stress was precipitating factor

• No association with CMV

–Jackow & Duvic, JAAD 1998.

Alopecia Areata Registry

• Funded by NIAMS, September 23, 2000

• Self registration for Alopecia Areata via web or paper-based questionnaire/database

and

• Blood samples (DNA, serum, LB lines) from examined confirmed AA patients and multiplex families.

Structure of AA Registry

Patients

San Francisco, CalifDr. Vera Price

Patients

Denver, ColoradoDr. David Norris, CoPI

Patients

Patients

M inneapolis, M inn.Dr. M . Hordinsky

Patients

Colum bia Univ, NYCA. Christiano

Houston-M DACCCentral S ite

Dr. M . Duvic, PI

W ebsite EntryQuestionnaire

Patient entry

REFERBy local

Dermatologist

Registration is Two Steps

• Step One: US AA patients confirmed by dermatologist asked to fill out short form. (Web, Doctor or patient initiated)

• Step Two: patient invited to visit one of 5 sites (or outside derm) to do questionnaire, exam and sample collection

• DNA, LB, sera• Optional photos, quality of life

AlopeciaAreataRegistry.orgAlopeciaAreataRegistry.org

REGISTRATION on WEB or

Print-out, Fill-out, & Mail or Fax in.

Brochures available

Informed consent & confidentiality

• Patients sign 3 written consents to participate in step 2 of the registry.

• Description, pros and cons.

• Children can give assent

• Info is confidential –deidentified personnal code & a family code are given

• Relational databases – Microsoft sequel server – Short, long, laboratory, QOL

Selection for the Second Step

• Single patients examined at site. • AT/AU for > 1 year• Patchy persistent AA for > 1 year• Transient AA for < 6 or < 12 mos. with

complete regrowth• Unrelated Normal controls are just as

important as AA subjects.

Real time report: First Tier Registration 10-14-08

• Total individuals registered - 6,469Females 4,399 vs Males 2,070

• Racial Breakdown: - White 4978; AA 283; hispanic 365, asian 233– Am Indian/Alaska 25; pacific 16; – mixed 293, unknown 192; other 120

Second Tier Report 10-14-08

• Total Registrants - 2397 (37% of 1st tier)Females – 1642 (37%)

Males - 750 (36%)

White - 1791 (36%)

Afr Am - 88 (31%)

Hispanic - 159 (43%)

Asian - 125 (54%)

Second Tier Registrantsby Phenotype Severity

Phenotype

• Transient AA (AAT) 306

• Persistent Patchy AA (AAP) 485

• Alopecia Totalis (AT) 183

• Alopecia Universalis (AU) 676

• Controls related 386

• Controls - unrelated 348

• Total 2,383

AA Registry Goals

• 1000 AU and AT (859)

• 500 AAP (persistent) (485)

• 250 AAT (transient) (183)

• ANOVA, Generalized Linear models –GLM used to look at age of onset, gender and severity

0

1

2

3

4

5

6

7

8

0 10 20 30 40 50 60 70 80

Age of Onset (years)

Per

cent

age

of In

divi

dual

s A

ffec

ted

(%)

AU

AT

AAP

AAT1&2

AGE OF ONSET vs % AA INDIVIDUALS AFFECTED

Age of Onset – AA Registry

• There are two peaks between 1-12 yrs

and 25-35yrs

• Speculation: – First peak genetically influenced

– Second peak environmentally induced

• 57% acquire AA before age 20

• Males develop AA 2.5 yrs earlier than Females

• AU and AT age of onset earlier compared to AAP and AAT groups (p<0.0001)

• AT develops 5 years earlier than AU– Possibly because AT can progress to AU

• AU patients develop disease 4 years earlier than those with AAT assuming other factors are held constant

AA Research Progress

• Confirmed the HLA associations • Studies of cytokine profiles in AA with or

without atopy.• Case Control Study - Incidence of

autoimmunity in AA patients• EBV trigger for AA in adolescents• Treatment Practices in AA• Quality of life in adolescents with AA• Linkage studies

Multiplex FamilyNo AA: 1,2,3,6 and Yes: 4, 5

44,55

1,1,55

AU

AA

44,,55

44,55

AA

AU

1,2

1,4 5,63,4

1,3

3,6 2,4

2,3 4,6

Genome - Families

• 20 families -102 affected, 118 unaffected

• US and Israel families

• Susceptibility found on Chromosomes

• 6 –ASP LOD >2.00 several incl MHC

• 16 –\ASP/LOD 3.11 – Ps locus

• 18 - LOD 3.93 – Ps Locus

Am J Hum Genet. 2007 Feb;80(2):316-28. Epub 2007 Jan 5.

Genome Wide Search

• First: screen of SNPs associated with other autoimmune disease genes.

• Second: Assessment of genetic background of AA patients to match controls (n = 2000).

• Third: full genome SNP search 1000 AU/AT severe patients, Alumina chip

• Angela Christiano and Peter Griegerson

Other Planned Studies

• Case Control Study– associations with asthma, autoimmune disease

• Second study in identical twins

• Validation and study of Quality of Life assessments administered to patients.

• Epidemiology evaluation

• Investigator initiated studies

The registry is one room with five desks and lots of filing cabinets

Our laboratory Team is standing by waiting for your samples!!

Conclusions

• AAR is a prototype of a web-based, patient friendly patient REGISTRY at five cooperating institutions (and IRBs).

• Physician exam required to certify AA.

• Epidemiology, autoimmunity, treatment and quality of life data.

• Samples collected prospectively – DNA, sera and LB lines.

Acknowledgements

• NIAMS & NAAF for support• Steering committee and sites: Drs.

Hordinsky, Price, Norris, Christiano• Advisors: Alan Moshell, Vickie Kalabokas,

Jorge Oxenberg, Kurt Stenn, Lowell Goldsmith.

• All of the families, individuals, med students who have participated to make this a success.

AlopeciaAreataRegistry.org

mduvic@mdanderson.org