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Immunogenetic and Environmental Risk Factors for Juvenile Myositis

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Immunogenetic and Environmental Risk Factors for Juvenile Myositis Powered By Docstoc
					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

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IIM - Adult and Juvenile Classifications
Clinical groups
Dermatomyositis Polymyositis Myositis with other CTD

Serologic groups
Myositis-specific (MSA) − Anti-synthetases − Anti-SRP − Anti-Mi-2 Myositis-associated (MAA) − Anti-p155 (TIF1-g) − Anti-U-RNP (U1, U2, U5) − Anti-Ro52 − Anti-PM/Scl − Anti-Ku − Anti-MJ − Anti-PMS-1, PMS-2 MSA and MAA negative

Inclusion body Cancer-associated Focal / Nodular Ocular / Orbital Eosinophilic Granulomatous

Characteristics of the MyositisSpecific Autoantibodies (MSA)
PM: often directed against cytoplasmic ribonucleoproteins 240 involved in translation 150 DM: directed against nuclear transcription regulating proteins 95 HDAC Present in all cells, but 1 increased expression in 2 regenerating myoblasts Inhibit protein target Antigen-driven: arise months prior to myositis onset, vary in 34 titer with myositis disease activity Tend to be mutually exclusive
JoRo PL12 Mi-2 myo Nml Sm Ku

PL12 Ku80 Ku70 Ro Jo

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

Interstitial lung disease Arthritis Mechanic’s hands Fever

Acute muscle weakness Cardiac involvement Myalgias

Classic dermatomyositis V-sign rash Shawl-sign rash Cuticular overgrowth

Anti-p155 Ab is Associated with JDM/DM and Cancer-Associated Myositis
Juvenile and Adult IIM
80 70 60 50 40 30 20 10 0
75

• Most common autoantibody

P e rc e n t o f P ts

identified in JDM and cancer myositis
Also assoc with DM, CTM Seen in 1 SLE pt, no other CTD or muscle diseases
0

29 21 0 0

33
15

anti-p155+ DM (n=39) CTM (n=13) JPM (n=9) CAM (n=8) PM (n=48) Other IIM (n=9)

•A distinct protein of 155 kD, often with a 140 kD weaker protein (immunoprecipitation)

JDM (n=103) JCTM (n=15)

Targoff et al, Arthritis Rheum, 2006; 54: 3682; Targoff et al, A&R, 2006; 54S: S518

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Features of Adult Patients with Anti-p155 compared to IIM and Anti-Synthetase Abs
100 90 80 70 60 50 40 30 20 10 0
% of Patients

s r is d' ve rit au th Fe yn Ar Ra

E DO

s D nd IL ha 's ic an h ec M

n n ig ig -s l-s V aw Sh

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

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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 50 40 30 20 10 0
% of Patients

1 30 *0 B1 DR

B1 DR

13 TS YS 9E

1 30 *0 A1 DQ

1 50 *0 A1 DQ

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

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Major Protective Factors for JDM in Caucasians
90 80 70 60 50 40 30 20 10 0
% of Patients

01 *01 A1 DQ

02 *01 A1 DQ

01 *02 A1 DQ

25 1F QA D

47 26 /K 1S WR /A QA V D 45 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
DRB1*0301 DQA1*0301 DQA1*0501 DQA1 S26 (*01, 02, 04, 06) DQA1 45(V/A)W(R/K)47 (*01, 02) DQA1*0201 DRB1 9EYSTS13 (*03, 11, 13, 14)

Relative Importance (%)
100 57 42 40 37 37 32

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

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

Juvenile DM
DQA1*0201 DQA1*0101 DQA1*0102 DQA1 S26 DQA1 45 (V/A)W(R/K)47

Adult DM
DRB1*0301 DQA1*0501 DQA1*0301 DRB1 9EYSTS13 DQA1 F25

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

Clinical Phenotypes

Genotypes 8.1 ancestral haplotype
A1,B8, Cw7, DRB1*0301, DQA1*0501

Autoantibodies

All IIM*
Caucasian PM DM IBM CTM

anti-synthetase anti-PL-7 anti-SRP anti-PM/Scl anti-Ro anti-Mi-2 anti-Ku anti-p155

A*68 B*50 C*0304 JDM C*14 DRB1*11 DRB1*15/*16 DQA1*0104 DQA1*0201
O’Hanlon et al, Medicine, 2006; 2005

DQA1*0301

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

40 30 20 10 0
DR

01 03 1* B

DQ

01 06 1* A

DR

4 *1 B1 DQ

01 01 1* A

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

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

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

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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 Group A Streptococcal and influenza: increased antibody titers in juvenile DM compared to controls Parvovirus B19, echovirus, hepatitis, HIV
-Case reports and series of temporal association of infection with onset JIIM
100 90 80 70 60 50 40 30 20 10 0 0
N = 919, R 2 = 0.9, P < 0.0000001

Guatemala Mexico city Guadalajara New Delhi Santiago Tokyo Seoul Bethesda Barcelona Warsaw Aachen Nijmgen Stockholm

% Dermatomyositis

1000

2000

3000
2

4000

Glasgow

Non-infectious Agents
Ultraviolet light Medications (reports)
-Caine anesthetics, penicillamine, growth hormone

UV Exposure (Joules/ m )

Okada et al, A&R, 2003; 48: 2285

Vaccines – Hepatitis B, influenza (reports)

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Parvovirus B19 Detection Methods Vary in their Sensitivity and Timelines
Method IgM (ELISA) Sensitivity 85% Timeline of Positive Result + 2- 3 days following viremia, Remains + for 2 – 3 months + 2 – 3 weeks following viremia, + result for life + at viremia, + for 2 - 4 days only in immunocompetent individuals + ≥ 3 months following infection; can remain + at same level for several years

IgG (ELISA) DNA direct hybridization (dot blot) DNA amplification (nested PCR)

100% > 106 genome equivalents/u L > 1 genome equivalent/uL

Parvovirus is Not Associated with Onset of JDM
IgM (%) JDM (n=62) Controls (n = 62) 0 1 IgG (%) 26 (42%) 36 (58%) Dotblot 0 0 PCR Serum 2 2 PCR Muscle 1/4 0/4

Mamyrova et al, 2005, JAMA, 294: 2170

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

Sept 30

Dec. 9

Seasonal

Uniform

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

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

Feb. 16

July 1

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

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

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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

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