Immunogenetic and Environmental Risk Factors for Juvenile Myositis - PDF

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					    Immunogenetic and
 Environmental Risk Factors
    for Juvenile Myositis
                    Lisa G. Rider, MD
    Deputy Chief, Environmental Autoimmunity Group
      NIEHS Office of Clinical Research, NIH, DHHS
                  Bethesda, MD. 20892
               Email: riderl@mail.nih.gov




    Juvenile Idiopathic Inflammatory
           Myopathies (JIIM)
• Chronic muscle inflammation
  and weakness of unknown
  etiology
     Diagnosed by clinical, laboratory
     and pathologic features

• Onset age < 18 years
     Dermatomyositis is the most
     common clinical subgroup

• “Characteristic” features of
  JDM include
     Calcinosis
     Ulcerations (“vasculopathy”)
     Lipodystrophy
     Better outcomes




                                                     1
            IIM - Adult and Juvenile -
                  Classifications
   Clinical groups              Serologic groups
      Dermatomyositis             Myositis-specific (MSA)
      Polymyositis                 − Anti-synthetases

      Myositis with other CTD      − Anti-SRP

      Inclusion body               − Anti-Mi-2

      Cancer-associated           Myositis-associated (MAA)
                                   − Anti-p155 (TIF1-g)
      Focal / Nodular
                                   − Anti-U-RNP (U1, U2, U5)
      Ocular / Orbital
                                   − Anti-Ro52
      Eosinophilic
                                   − Anti-PM/Scl
      Granulomatous
                                   − Anti-Ku
                                   − Anti-MJ
                                   − Anti-PMS-1, PMS-2
                                  MSA and MAA negative




     Characteristics of the Myositis-
     Specific Autoantibodies (MSA)                                                JoRo
                                                               PL12
                                           Mi-2




                                                                      myo

                                                                            Nml



   PM: often directed against                                                            Sm
                                                          Ku




cytoplasmic ribonucleoproteins 240
involved in translation              150
   DM: directed against nuclear                    PL12
transcription regulating proteins 95
   Present in all cells, but        HDAC          Ku80
                                       1          Ku70
increased expression in                2
regenerating myoblasts                              Ro
   Inhibit protein target                           Jo
   Antigen-driven: arise months
prior to myositis onset, vary in      34
titer with myositis disease activity
   Tend to be mutually exclusive




                                                                                              2
                             Myositis Serologic Groups Differ
                                in Clinical Presentations
                                  Anti-synthetase                            Anti-SRP                Anti-Mi-2




                             Interstitial lung disease              Acute muscle weakness       Classic dermatomyositis
                                      Arthritis                       Cardiac involvement             V-sign rash
                                Mechanic’s hands                           Myalgias                 Shawl-sign rash
                                       Fever                                                     Cuticular overgrowth




  Anti-p155 Ab is Associated with JDM/DM
      and Cancer-Associated Myositis
                             Juvenile and Adult IIM
                        80                                          75                 • Most common autoantibody
                        70                                                             identified in JDM and cancer
                        60                                                             myositis
P e rc e n t o f P ts




                        50                                                                Also assoc with DM, CTM
                        40      29                       33                               Seen in 1 SLE pt, no other
                        30             21                                                CTD or muscle diseases
                                                               15
                        20                                                             •A distinct protein of 155 kD,
                        10                  0 0                          0
                         0
                                                                                       often with a 140 kD weaker
                                                  anti-p155+                           protein (immunoprecipitation)
       JDM (n=103)                   DM (n=39)        JPM (n=9)      PM (n=48)
       JCTM (n=15)                   CTM (n=13)       CAM (n=8)      Other IIM (n=9)
Targoff et al, Arthritis Rheum, 2006; 54: 3682;
Targoff et al, A&R, 2006; 54S: S518




                                                                                                                          3
Features of Adult Patients with Anti-p155
compared to IIM and Anti-Synthetase Abs
                   100
                    90
                    80
                    70
   % of Patients




                    60
                    50
                    40
                    30
                    20
                    10
                     0
                         r        s        is     E                 s         n        n
                       ve      d'       rit               IL
                                                            D     nd        ig       ig
                     Fe      au       th        DO              ha        -s      l-s
                           yn       Ar                       's          V
                                                                                aw
                         Ra                                ic                 Sh
                                                        han
                                                      ec
                                                     M
   Anti-p155 Pts (N=16)              All IIM Pts (N=181)   Antisynthetase Pts (N=47)

                    Pc < 0.05 for anti-p155 vs. anti-synthetase Pts
                                                              Targoff et al, Arthritis Rheum, 2006; 54: 3682




   Evidence for a Genetic Role in the
   Etiology of Autoimmune Diseases
  Increased prevalence in families
  Gradients of disease concordance in pedigrees:
  monozygotic twins > dizygotic twins > others
  Animal models with autosomal dominant and other
  inheritance patterns
  Disease associations with specific genes or loci
         Candidate gene approaches using case-control studies have
         identified immunogenetic, pharmacogenetic and other loci as
         risk or protective factors
         Genome-wide linkage studies in families and animal models
         Genome-wide association studies in case-control studies




                                                                                                               4
                  Human Leukocyte Antigens (HLA)
                   and Juvenile Dermatomyositis
HLA molecules are expressed
on cell surfaces and bind
peptides for immune
presentation
HLA genes are the most
polymorphic in the genome
This HLA structural variety
reflects individual differences
in immune responses to
infections, allergens, and
other proteins
Specific HLA genes have
been associated with many
autoimmune and other
conditions




Major Immunogenetic Risk Factors
      for JDM in Caucasians
                  80
                  70
                  60
  % of Patients




                  50
                  40
                  30
                  20
                  10
                   0           1                    13               1                 1
                             30                   TS               30                50
                           *0                   YS               *0                *0
                         B1                   9E               A1                A1
                       DR                B1                  DQ                DQ
                                       DR

                                    JDM (n=142)          Controls (n=797)

                                   DRB1*0301 OR = 3.9; 9EYSTS13 OR = 2.0
                                    DQA1*0301 OR = 2.8; *0501 OR = 2.1
                                                         Mamyrova et al. A&R, 2006; 54: 3979-87




                                                                                                  5
                Major Protective Factors for
                    JDM in Caucasians
                90
                80
                70
% of Patients




                60
                50
                40
                30
                20
                10
                 0                                                                  47
                       01           02           01        25          26         /K
                    *01          *01          *02        1F          1S         WR
                  A1           A1           A1         QA          QA         /A
                DQ          DQ           DQ           D           D        45
                                                                             V
                                                                        A1
                                                                      DQ

                            JDM (n=142)          Controls (n=797)

                      DQA1*0101 OR = 0.38; *0102 0R = 0.51; *0201 OR = 0.37
                     *F25 OR = 0. 26; *S26 OR = 0.45; * 45 (V/A)W(R/K) OR = 0.46
                                                      Mamyrova et al. A&R, 2006; 54: 3979-87




Random Forests Classification Confirms
DRB1*0301 as Major Risk Factor for JDM
                               Allele or Motif                             Relative
                                                                         Importance
                                                                             (%)
                 DRB1*0301                                                       100
                 DQA1*0301                                                        57
                 DQA1*0501                                                        42
                 DQA1 S26 (*01, 02, 04, 06)                                       40
                 DQA1 45(V/A)W(R/K)47 (*01, 02)                                   37
                 DQA1*0201                                                        37
                 DRB1 9EYSTS13 (*03, 11, 13, 14)                                  32
                                                       Mamyrova et al. A&R, 2006, 54: 3979-87




                                                                                                6
 Juvenile and Adult DM Share HLA Risk Factors,
   but JDM has Additional Protective Factors


           Juvenile DM                                       Adult DM
                                        DRB1*0301
                                        DQA1*0501
         DQA1*0201                      DQA1*0301
         DQA1*0101                      DRB1 9EYSTS13
         DQA1*0102
         DQA1 S26                          DQA1 F25
         DQA1 45 (V/A)W(R/K)47




                                                             Mamyrova et al. A&R, 2006, 54: 3979-87




 Clinical Phenotypes                   Genotypes                          Autoantibodies

         All IIM*                8.1 ancestral haplotype
                                  A1,B8, Cw7, DRB1*0301, DQA1*0501
        Caucasian                                                         anti-synthetase
                                                A*68                            anti-PL-7
             PM
                                                B*50
                                                                                anti-SRP
                                              C*0304
  JDM        DM                                                                anti-PM/Scl
                                                C*14

                                             DRB1*11                             anti-Ro
            IBM
                                          DRB1*15/*16                            anti-Mi-2

            CTM                            DQA1*0104                              anti-Ku
                                           DQA1*0201                            anti-p155
O’Hanlon et al, Medicine, 2006; 2005
                                           DQA1*0301




                                                                                                      7
   JDM and DM Share HLA Risk and
Protective Factors in African Americans
                            40
    Patient Frequency (%)



                            30

                            20

                            10

                            0
                                             01                       01                *1
                                                                                          4                 01
                                          03                       06                                    01
                                       1*                       1*                    B1              1*
                                      B                        A                 DR                  A
                                 DR                       DQ                                    DQ

                                                   JDM/DM (n=87)             Controls (n=311)
                                                  DRB1*0301 OR = 3.9; DQA1*0601 OR = 12.5
                                                     DRB1*14 OR 0.2; DQA1*0101 OR 0.5
                                                                              O’Hanlon et al. A&R, 2006; 54: 3670 - 3681




        Cytokines in Pathogenesis of
         Inflammatory Myopathies
 TNF-α expression is increased in
 mononuclear cell infiltrates and
 on muscle fibers of myositis
 biopsies

 IL-1α,IL-1β, and IL-1R expression
 are increased in mononuclear cell
 infiltrates, muscle fibers, and
 muscle capillary endothelial cells
 of myositis biopsies                                                             IL-1α expressed on endothelial cells
                                                                                  of capillaries and larger vessels in
                                                                                  muscle tissue

                                                                     Lundberg et al, Rheum Dis Clinic N Am, 2002;28: 799




                                                                                                                           8
TNF-α and IL-1 Cytokine Polymorphisms
     are on Chromosome 6 and 2
                                TNF-α




                                 IL-1
                       +4845




 Cytokine Polymorphisms are Risk
  Factors for JDM in Caucasians

Chrom       Allele             Odds Ratio                Functional
                                                        Significance
  6      TNFα-308 AG                 3.6                  ↑ TNF α
  2     IL-1RN VNTR A1               2.5                    ↓ IL1Ra




                 Pachman et al, Arthritis and Rheumatism, 2000; 43: 2368-77
                 Rider et al, Clin Exp Immunol, 2000, 121: 47 – 52.




                                                                              9
Evidence for Environmental Influences in the
   Pathogenesis of Autoimmune Diseases
  < 50% disease concordance in monozygotic twins
  Dechallenge = disease improvement after agent removal
  Rechallenge = disease recurrence after re-exposure
  Geographic clustering in disease incidence
  Changes in incidence of disease over time
  Seasonality of disease onset and birth dates
  Biologic plausibility from animal models
  Epidemiologic associations between particular exposures
  and certain diseases
                                                 Miller 2006 The Autoimmune Diseases




   Environmental Agents Associated
           with Juvenile IIM
Infectious Agents
  Coxsackie B virus: elevated antibody titers;
  + PCR from some muscle biopsies;
  negative case control study                                           100                                                    Guatemala
                                                                         90                                                    Mexico city

  Group A Streptococcal and influenza:                                   80                                                    Guadalajara
                                                    % Dermatomyositis




                                                                                                                               New Delhi
                                                                         70
  increased antibody titers in juvenile DM                               60
                                                                                                                               Santiago
                                                                                                                               Tokyo

  compared to controls                                                   50
                                                                         40
                                                                                                                               Seoul
                                                                                                                               Bethesda


  Parvovirus B19, echovirus, hepatitis, HIV
                                                                                                                               Barcelona
                                                                         30
                                                                                                                               Warsaw
                                                                         20                                                    Aachen
    -Case reports and series of temporal                                 10         N = 919, R 2 = 0.9, P < 0.0000001          Nijmgen
                                                                          0                                                    Stockholm
      association of infection with onset JIIM                                0   1000        2000         3000         4000   Glasgow

                                                                                                                 2

Non-infectious Agents
                                                                                  UV Exposure (Joules/ m )



  Ultraviolet light
  Medications (reports)                                                  Okada et al, A&R, 2003; 48: 2285
    -Caine anesthetics, penicillamine,
      growth hormone
  Vaccines – Hepatitis B, influenza (reports)




                                                                                                                                             10
 Parvovirus B19 Detection Methods
Vary in their Sensitivity and Timelines
                        Method          Sensitivity      Timeline of Positive
                                                               Result
                      IgM (ELISA)          85%           + 2- 3 days following
                                                                viremia,
                                                         Remains + for 2 – 3
                                                                months
                      IgG (ELISA)         100%         + 2 – 3 weeks following
                                                       viremia, + result for life

                       DNA direct      > 106 genome     + at viremia, + for 2 - 4
                      hybridization    equivalents/u          days only in
                          (dot blot)         L            immunocompetent
                                                               individuals
                          DNA           > 1 genome       + ≥ 3 months following
                       amplification   equivalent/uL   infection; can remain + at
                      (nested PCR)                       same level for several
                                                                  years




         Parvovirus is Not Associated
              with Onset of JDM
                                                         PCR          PCR
              IgM (%)         IgG (%)      Dotblot
                                                        Serum        Muscle
JDM
(n=62)            0          26 (42%)          0            2           1/4

Controls
                  1          36 (58%)          0            2           0/4
(n = 62)




           Mamyrova et al, 2005, JAMA, 294: 2170




                                                                                    11
      Seasonality in Myositis and
      Other Autoimmune Diseases
Seasonality in adult DM and PM onset of weakness
   Anti-synthetase: peak onset in March-April (spring)
   MSA negative: peak onset in June-July (summer)
                     Sarkar et al, Arthritis and Rheumatism, 2005; 52: 2433-38

Seasonality in birth distribution in a number of autoimmune
diseases
   Type I diabetes
   Multiple sclerosis
   Celiac disease
   Crohn’s disease
Hypothesis: There are seasonal patterns of birth dates for
subgroups of JIIM patients that differ from those of other
JIIM patients or of healthy individuals




Hispanic JIIM Patients Differ in Birth
Distribution from Hispanic Controls
Distribution of Birth Dates for                     Distribution of Birth Dates for
Hispanic JIIM Patients (n = 42)                     Hispanic Controls (n = 283)




                                                                Dec. 9
           Sept 30




             Seasonal                                                          Uniform


     Rank-Based Comparison of the Two Distributions, p = 0.002
                                             Vegosen L et al, Arthritis Rheum. 2007; In press




                                                                                                12
  P-155 Autoantibody Positive JIIM Patients Differ in
  Birth Distribution from Antibody Negative Patients
Distribution of Birth Dates for p-155 Ab   Distribution of Birth Dates for p-155 Ab
Positive Juvenile IIM Patients (n = 32)    Negative Juvenile IIM patients (n = 38)




                                                                   July 1
                Feb. 16



     Uniform                                             Seasonal




        Rank-Based Comparison of the Two Distributions, p = 0.010
                                           Vegosen L et al, Arthritis Rheum. 2007; In press




     JIIM Genetic and Environmental
         Risk Factors - Summary
     A new autoantibody to a transcription factor is the most
     common autoantibody identified in JDM to date.
     Primary genetic risk factors are HLA DRB1*0301 and
     DQA1*0301 in Caucasians
        Primary risk factor is DRB1*0301 in African Americans
        A number risk factors shared with adult DM and some unique protective
        factors, suggest similarities and differences in pathogenesis
        Cytokine polymorphisms of TNF-α and IL-1 are also important risk and
        severity factors
        Likely a number of other non-HLA genes involved in basic cellular
        metabolism are risk factors for myositis or its subsets
     Anecdotal and epidemiologic data suggest a possible role for
     environmental factors in JIIM
        Controlled study suggests Parvovirus B19 not associated with JDM
        onset
        Seasonal patterns of birth distributions suggest peri-natal or neonatal
        factors important in onset of subgroups of JIIM




                                                                                              13
          Acknowledgements
EAG, NIEHS          Collaborators
Gulnara Mamyrova    Ira Targoff, OMRF
Terrance O’Hanlon   Janardan Pandey, MUSC
Leora Vegosen       Kevin Brown, NHLBI
Fred Miller




                                            14
Childhood Myositis Heterogeneity
   Collaborative Study Group
L Abramson, B Adams, E Adams, P Alepa, K Amoroso, E Arioglu, E Arthur, B Athreya,
A Baer, I Balboni, S Ballinger, K Barron, A Bingham, W Blocker, J Bohn, J Bohnsack,
G Boire, M Borzy, G Botstein, S Bowyer, R Brackett, E Brooks, C Brunet, L Campbell,
V Cartwright, G Cawkwell, C Chao, D Crisp, R Cron, R Culp, J Daigh, L David,
F Delafield, A Eichenfield, J Eggert, M Elder, J Ellsworth, C Etheridge, S Evans,
K Fearn, T Finkel, R Fuhlbrigge, V Garwood, A Gedalia, N Gehringer, S George,
H Gewanter, E Goldmuntz, E Goldsmith, G Gordon, L Greenbaum, K Gross, H Haftel,
M Hawkins-Holt, C Hendrics, M Henrickson, G Higgins, R Hollister, R Hopp, E Huh,
N Ilowite, L Imundo, J Jacobs, R Jerath, C Johnson, M Jones, O Jones, L Jung,
L Kagen, S Kahn, T Kantor, I Katona, G Keenan, E Keystone, Y Kimura, D Kingsbury,
S Klein, M Knee, J Koenig, B Lang, A Lasky, A Lawton, J Levine, C Lindsley,
R Lipnick,,S Lourie, E Love, M Lundberg, K Madson, P Malleson, D Maneice,
A Mariano, H Marks, A Martin, F Matthew, J Miller, R Mitchell, H J Moallem, C
Morishima, F Murphy, H Nathan, A Neumeyer, J Olson, K Onel, B Ostrov, L Pachman,
R Pappu, M Passo, M Perez, D Person, K Peterson, P Plotz, L Punaro, C Radis, L Ray,
A Reed, R Rennebohm, R Rivas-Chacon, A Rosenberg, P Reuman, R Rivas-Chacon,
A Rosenberg, D Rothman, P Schlesinger, K Schuberth, D Scott, D Seamon, B Shaham,
R Sheets, D Sherry, S Sinal, F Stafford, H Stang, R Sundel, I Szer, I Targoff, S Taylor,
E Taylor-Albert, D Thomas, R Vehe, M Villalba, S Vogelgesang, L Vogler, E Von
Scheven, S Wahl, C Wallace, H Wander, A Weinstein, J Wells, P White, G Wright, J Yee,
C Young, L Zemel




                                                                                           15