Overview of Diagnostic Autoantibodies in Inflammatory Myopathy

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1 Overview of Diagnostic Autoantibodies in Inflammatory Myopathy Minoru Satoh, M.D., Ph.D. Research Associate Professor of Medicine Division of Rheumatology and Clinical Immunology University of Florida

2 Disclosure none

3 Evidence-based Medicine (EBM) Anti-p155/140 (TIF1γ/α) 1. Targoff IN, Mamyrova G, Trieu EP, Perurena O, Koneru B, O'Hanlon TP, et al. A novel autoantibody to a 155-kd protein is associated with dermatomyositis. Arthritis Rheum. 2006;54: Anti-MDA5/CADM Sato S, Hoshino K, Satoh T, Fujita T, Kawakami Y, Kuwana M. RNA helicase encoded by melanoma differentiation-associated gene 5 is a major autoantigen in patients with clinically amyopathic dermatomyositis: Association with rapidly progressive interstitial lung disease. Arthritis Rheum. 2009;60: Review on autoantibodies in inflammatory myopathy 3. Nakashima R, Mimori T. Clinical and pathophysiological significance of myositis-specific and myositis-associated autoantibodies. Int J Clin Rheumatol. 2010;5:

4 Clinical subsets of polymyositis/dermatomyositis (PM/DM) and autoantibodies (2004) Severe, Tx resistant myopathy Anti-synthetase antibody syndrome ILD Raynaud s Arthritis Good response to Tx

5 Clinical subsets of polymyositis/dermatomyositis (PM/DM) and autoantibodies (2012) Rapidly progressive ILD Amyopathic DM malignancy Calcinosis malignancy Satoh 2012

6 Anti-p155/140 (Transcription intermediary factor-1γ/α, TIF-1γ/α tripartite motif-containing, TRIM33/24)

7 Anti-p155/140 (Transcription intermediary factor-1γ/α, TIF-1γ/α, tripartite motif-containing, TRIM33/24)

8 Prevalence of anti-p155/140 (TIF-1γ/α, TRIM33/24) Category Clinical group Prevalence N = adult DM 21% 39 PM 0% 48 Overlap with other CTD 15% 13 Cancer-associated myositis 75% 8 Other 0% 9 Juvenile DM 29% 103 PM 0% 9 Overlap with other CTD 33% 15 all Non-PM/DM 0.7% 138 Targoff IN et al., Arthritis Rheum 2006, 54: 3682

9 Clinical features of anti-p155/140 (TIF-1γ/α) vs antisynthetase antibody positive PM/DM Feature Anti-p155/140 Anti-synthetase P value N = Fever 44% 87% Raynaud s phenomenon 19% 62% Arthritis 31% 94% Interstitial lung disease 0% 89% Mechanic s hands 25% 71% V-sign rash 75% 15% Shawl-sign rash 56% 7% Malignancy 38% (0%) Targoff IN et al., Arthritis Rheum 2006, 54: 3682

10 Anti-p155/140 (transcription intermediary factor, TIF-1γ/α, tripartite motif-containing, TRIM33/24) p155/140(tif-1γ/α) and β interact and function as a tumor suppressor. Found in ~20-30% of DM but ~0% in PM or other diseases Found in % of cancer-associated DM % of anti-p155/140 (+) DM have cancer Negative association with fever, lung disease, arthritis, Raynaud s phenomenon, Very similar clinical association in 8 studies from 5 countries

11 Anti-p155/140 (TIF-1γ/α) - Meta analysis Trallero-Araguas E et al., Arthritis Rheum. 2012;64(2):523-32

12 Anti-TIF-1β (transcription intermediary factor-1β, TRIM28) Satoh M et al., Arthritis Res Ther. 2012;14(2):R79 Fujimoto M et al., Arthritis Rheum. 2012;64(2):513-22

13 Anti-TIF1β (transcription intermediary factor-1β) Satoh M et al., Arthritis Res Ther. 2012;14(2):R79 Fujimoto M et al., Arthritis Rheum. 2012;64(2): Associated with mild DM May coexist with anti-tif-1γ/α (Japanese study) Association with malignancy is not as strong as anti-tif1γ/α (p155/p140)

14 Anti-CADM140 (clinically amyopathic dermatomyositis140) MDA5 (melanoma differentiation associated gene 5) IFIH1 (interferon induced with helicasec domain 1)

15 Anti-CADM140 (clinically amyopathic dermatomyositis)/ MDA5 (melanoma differentiation associated gene 5) ~140kD single protein ANA weak cytoplasmic staining or negative MDA5 is a cytoplasmic innate immune receptor for viral RNA Stimulation of MDA5 induces type I interferon Levels of anti-mda5 goes down after Tx Patients with high levels of anti-mda5 are resistant to Tx (Gono T, et al., Rheumatology 2012, Sato S et al., Mod Rheuma 2012)

16 Anti-CADM140/MDA5 antibodies are highly specific for C-ADM (clinically amyopathic DM) Sato S et al., Arthritis Rheum. 2009;60(7):

17 Anti-CADM140 (clinically amyopathic dermatomyositis140) /MDA5 (melanoma differentiation associated gene 5) Dermatomyositis Strong association with clinically amyopathic dermatomyositis (CADM) ~10% in DM 38-70% in CADM % of anti-cadm140 positive have CADM Associated with rapidly progressive interstitial lung disease and poor prognosis. Reports are mainly from Japan US study DM with severe skin disease

18 Two subsets of ILD in myositis defined by autoantibodies Prevalence of autoantibodies Anti-synthetase Anti-MDA5 ~30% in PM/DM ~10% in DM ~40-70% in C-ADM Prevalence of ILD 70-95% 50-90% Type of ILD Chronic or subacute Acute progressive pathology Mostly NSIP UIP, OP prognosis Fair but recurrent poor Response to treatment fair poor NSIP? (early) DAD (late) DAD, diffuse alveolar damage; NSIP, nonspecific interstitialpneumonia; OP, organizing pneumonia; UIP, usual interstitial pneumonia; Modified from Mimori T, Nakashima R, Hosono Y. Curr Rheumatol Rep. 2012;14(3):264-74

19 Anti-MJ/NXP-2 NXP-2 (nuclear matrix protein 2) MORC-3 (microchidia family CW-type zinc finger protein 3)

20 Anti-MJ (NXP-2, MORC3) antibodies Ceribelli A et al., Arthritis Res Ther. 2012;14(2):R97 Ichimura Y et al., Ann Rheum Dis. 2012;71(5):710-3

21 Anti-MJ (NXP-2, MORC3) antibodies Target protein (MJ antigen) was identified as: NXP-2 (nuclear matrix protein 2) MORC-3 (microchidia family CW-type zinc finger protein 3) Diffuse nuclear distribution but accumulated in nuclear dots structure (promyelocytic leukemia body, PML body).

22 Anti-MJ (NXP-2, MORC3) antibodies are common in juvenile DM 1997 Oddis CV et al., abstract, Arthritis Rheum. 40(9 suupl):s Espada G et al., J Rheumatol 36: Gunawardena H et al., Arthritis Rheum. 2009;60 (6): USA, Argentina and UK 20-30% of juvenile DM had anti-mj associated with severe refractory DM, arthritis, calcinosis, gastrointestinal vasculitis

23 Anti-MJ (NXP-2, MORC3) in adult PM/DM Ceribelli A et al., Arthritis Res Ther. 2012;14(2):R97 58 (27DM, 25PM, 6 overlap) Italian 30% in DM and 8% in PM 6/10 male associated with young onset, calcinosis (3/10) and lack of heart and lung disease (0/10) Ichimura Y et al., Ann Rheum Dis. 2012;71(5): (445DM, 62PM) Japanese 1.6% of DM (6 cases) and 1.6% of PM (1 case) 7/8male No calcinosis 0/8 No ILD 0/8 Associated with malignancy 4/8 (6/8 age >50)

24 A difference in prevalence of myositis autoantibodies (dermatomyositis, DM) Caucasian American (n = 17) Italian (n = 27) Mexican (n = 56) Jo-1 18% 0 4% EJ 0% 4% 0 OJ PL Any synthetase 18% 4% 4% MJ (NXP-2) 6% 30% 4% p155/140 12% 8% 16% Mi-2 6% 4% 43% SRP 0% 0 2% Satoh M, Ceribelli A, Vazquez del-marcado M, unpublished

25 Autoantibodies that recognize UsnRNPs D-E-F-G but not other components???

26 Antibodies that immunoprecipitate D-E-F-G recognize SMN (survival of motor neuron) complex Satoh M, et al. Arthritis Rheum (In Press) 2011

27 Spinal muscular atrophy (SMA) Autosomal recessive neurodegenerative disorder caused by mutation or deletion of SMN (survival of motor neuron) gene Mutation/deletion of SMN induces: degeneration of spinal cord motor neurons atrophy of skeletal muscles generalized weakness

28 Autoimmune sera that immunoprecipitate D-E-F-G proteins stain Cajal body in immunofluorescence Human anti-sm mouse mab Cajal body Human anti-defg #1 h- anti-defg #2 h-anti-defg #3 Normal control Satoh M, et al. Arthritis Rheum (In Press) 2011

29 SMN (survival of motor neuron) complex plays a critical role in assembly of snrnps in Cajal body Matera et al. Nature Reviews Molecular Cell Biology 8, (March 2007)

30 Summary Several new autoantibody specificities that have distinct clinical significance have been described, mainly in DM. -- Anti-p155/p DM with malignancy -- Anti-MDA5/CADM140 ADM with rapidly progressive ILD Further studies will be necessary to confirm the and understand the differences in different race/countries. Immunoassays for clinically useful autoantibodies should become widely available to clinicians.

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