Alopecia Areata Registry Model
Transcript of Alopecia Areata Registry Model
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National Alopecia Areata Registry
• Madeleine Duvic, MD
• Professor of Medicine & Dermatology
• MD Anderson Cancer Center
• Houston, Texas
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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
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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.
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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.
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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
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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.
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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.
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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
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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
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AlopeciaAreataRegistry.orgAlopeciaAreataRegistry.org
REGISTRATION on WEB or
Print-out, Fill-out, & Mail or Fax in.
Brochures available
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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
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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.
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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
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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%)
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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
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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
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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
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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
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• 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
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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
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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
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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.
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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
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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
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The registry is one room with five desks and lots of filing cabinets
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Our laboratory Team is standing by waiting for your samples!!
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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.
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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