National Alopecia Areata Registry

1
National Alopecia Areata Registry

• Madeleine Duvic, MD
• Professor of Medicine Dermatology
• MD Anderson Cancer Center
• Houston, Texas

2
Making the Diagnosis of AA

• Characteristic patches of hairloss with broken
  off hairs - exclammation points
• Scale, redness may or may not be present. Biopsy
  is diagnostic.
• Must rule out tinea capitus, lupus, MF, scarring
  alopecias, syphillis, etc.
• Onset before 6 mos, suggests papular atricia with
  mutation in hairless gene chrom 8.

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What causes AA?

• Immune reaction by T-cells that are white blood
  cells called lymphocytes.
• They surround hair follicles, causing breakage of
  growing hairs and bald spots.
• What are they reacting to? Hair? Infection?
• Virus? Melanocytes? unknown

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HYPOTHESIS Alopecia Areata is

• Host determined
• HLA restricted
• Organ specific
• Reaction directed to the hair follicle
• Triggered by an external event, infection
• Mediated by cytokines neuropeptides locally.

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Is AA caused by genes?

• T cells talk to messenger cells (interleukins)
  divide, and release of mediators (cytokines,
  chemokines) that start, intensify, and stop
  inflammation.
• These mediators are turned on by genes and made
  by genes.
• What the immune system reacts to is also caused
  by genes.

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HLA - histocompatibility

• Proteins that tell your cells that you are you
  are called HLA or histocompatibility antigens.
• Must be matched in case of transplants
• Bind to and show foreign proteins to T cells.
• They control what gets seen by T cells

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The Trimolecular Complex

• T cells recognize Antigen when presented by HLA
  chains on APC

Antigen Presenting Cell
T cell
Costimulatory
CD4 or CD8
HLA Class 2 (CD4)
T cell receptor
8
HF presents Antigen to T cells

• CD4 T cells help Bs make Antibodies

B
CD4
APC
HF
Y Y
Kerat
Y
Y
Interferon Gamma
HAIR Follicle
Y
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The Hair Follicle is Attacked !

• Cytotoxic CD8 T cells could initiate AA

CD4
APC
B
CD8
HF
Y Y
Helper
Kerat
Y
Interferon Gamma
Cytotoxic
Y
HAIR Follicle
Y
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The Hair Follicle is Innocent !

• A Viral or other trigger initiates the CD8 or the
  CD4 Response - Molecular Mimicry

CD4
APC
CD8
Kerat
HF
Helper
Interferon Gamma
Y
Cytotoxic
Y
HAIR Follicle
Y
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Class II HLA Associations

• CLASS II MHC (DR,DQ,DP) ASSOCIATIONS
• HLA-DR4, DR5 (Italian, Danish, English)
  HLA-DR7 (Russians)
• HLA-DR5 allele DR-1104-patchy early onset
• 80 of AA have HLA-DQB103 alleles
• Welsh/Duvic JID 103 758,1994
• Colombe/Price JAAD 33757, 1995

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How many genes cause AA?

• Not one!! Or else half of the children would
  inherit it
• Not two!! One fourth of the children would
  inherit.
• Multiple genes in autoimmune diseases start
  it,keep it going, amplifiy, stop it.
• Often genes from both parents contribute.
• Chances of having another offspring are small.

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AA in Identical Twins

• 55 concordancy in monozygotic twins.
• More severe in first affected, MF.
• All had HLA-DQ 0302
• Stress was precipitating factor
• No association with CMV
• Jackow Duvic, JAAD 1998.

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Inheritance of AA

• Identical twins only half are both affected
• Environmental trigger ???
• Or low penetrance
• Hard to find families with more than three
  members affected with AA multiplex family.
  These are ideal for studying the genes causing AA.

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Purpose of the AA Registry

• 1. To find and collect samples from multiplex
  families, siblings, and individuals with alopecia
  areata.
• 2. To encourage research using the data and
  samples from the registry.
• 3. By understanding AA to find effective
  treatments or cures.

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Who Funds the Registry?

• You do! Tax dollars
• National Institutes of Health Institute for
  Arthritis, Musculoskeletal, and Skin (NIAMS)
• Competition for Registry contract
• Awarded in 2001 to consortium of five centers to
  establish and maintain.

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AlopeciaAreataRegistry.org REGISTRATION on WEB
or Print-out, Fill-out, Mail or Fax in
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Registration is Two Steps

• Step One General Registration of AA patients
  using short input form.
• (Web, Doctor or patient initiated)
• AlopeciaAreataRegistry.org
• Step Two patient must visit one of five sites
  or derm for exam, questionnaire, and sample
  collection.

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Registration Sites

• Minneapolis, Minn. Maria Hordinsky
• New York City Columbia Angela Christiano
• Denver, Colorado David Norris
• Houston, Texas Madeleine Duvic
• San Francisco, Calif Vera Price

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Informed consent

• Must have a signed consent to participate in step
  2 of the registry. Document describing the
  research study.
• Disclosure of pros and cons.
• Place for patient and witness and doctor to sign
  if patient agrees to participate. Children can
  give their assess, parents their consent.

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Who Can Register in First Tier?

• United States Resident
• Alopecia Areata patchy loss
• Alopecia Totalis all scalp hair
• Alopecia Universalis scalp/body
• Diagnosis is confirmed by a Dermatologist.

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Progress Report

• Registration to date 4,984
• 3,380 women
• 1,604 men
• Race Caucasians 3901
• African Am 189
• Asian 189
• Hispanic 267

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Breakdown of AA

• Alopecia Universalis 1102
• Alopecia Totalis 462
• Patchy persistant AA 1040
• Transient AA 980
• Unconfirmed AA 50
• All AA 3122
• Controls 1369

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After registering what next?

• Information is completed by email or paper.
• Patient invited for exam at center.
• Signs consent and has brief exam
• Donate blood for DNA, Cell lines, and serum
  banking.
• Solicits family members and controls to help.

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Selection of the Second Tier?

• Multiplex Families three or more affected
  persons with AA/AT/AU
• Affected Sib-pairs/twins and parents

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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 regrowth
• Unrelated Normal controls are just as important
  as AA subjects.

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Optional Components

• Collection of Biopsies by sites
• Digital photography
• Quality of Life questionnaires

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Progress Report

• Multiplex Families 145
• Sib pairs 54
• Simplex family 167
• Singles 559
• Unaffected controls 254
• Unrelated controls 271
• TOTAL 1,451

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Type of AA in Registry

• Persistent patchy AA 277
• Transient AA 209
• Alopecia Totalis (scalp) 104
• Alopecia Universalis 335
• Controls unrelated 271
• All AAs 925
• Goals 500 of each

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Progress in AA Research

• Confirmed the HLA associations in Registry AA
• Studies of cytokine profiles in AA with or
  without atopy.
• Incidence of autoimmunity in AA
• Quality of life in adolescents with AA
• Linkage studies identified four regions where
  alopecia areata genes are present.

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Enlisting Dermatology

• Please tell every AA patient about the registry,
  distribute the brochures.
• Take an AA family history - identify multiplex
  families/ sib-pairs.
• Draw samples on multiplex families, sib-pairs who
  cannot travel to one of five sites.

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Goals for this conference

• To help anyone who wants to register do it.
• To get all families with 3 or more AA cases, all
  twins, all sib pairs for linkage studies.
• To go above 5000 registrations today
• To go above 1000 AA second step registrations
  this meeting.
• To answer your questions!!!