Significance of antibody testing in idiopathic inflammatory myopathies
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1 2/0/20 Significance of antibody testing in idiopathic inflammatory myopathies Jiří Vencovský Institute of Rheumatology, Prague Diagnosis Polymyositis Juvenile DM (JPM) Paraneoplastic Myositis in overlap IBM Necrotizing myopathy Antisynthetase syndrome Amyopathic DM DM without dermatitis Nonspecific myositis Myositis is a heterogeneous disease Autoantibody Negative Jo- or ARS SRP Mi-2 PM-Scl U-RNP TIF-g MDA NXP2 HMGCR cn-a FHL- Organ involvement Muscle Skin Lung Heart Oesophagus Joints Calcinosis Frequency is variable 0-90% Usually only autoantibody/ patient Almost each year a new antibody discovered Autoantibodies in myositis According to Gunawardena H. Clinic Rev Allerg Immunol 207;2: 7. Autoantibodies in myositis Autoantibodies are associated with disease characteristics Diagnostic tool Define clinically similar situations Correlation with disease activity Mediate disease pathogenesis? Disease manifestation Disease course Prognosis Response to treatment Extramuscular manifestations Complications
2 2/0/20 Myositis specific antibodies (MSA) Antisynthetase syndrome and ARS autoantibodies ARS ILD Jo- Histidyl-tRNA synthetase -0% PL-7 Threonyl-tRNA synthetase < % PL-2 Alanyl-tRNA synthetase < % EJ Glycyl-tRNA synthetase < % Myositis OJ Isoleucyl-tRNA synthetase < % KS (AsnRS) Asparaginyl-tRNA synthetase Rare Zo Phenylalanyl-tRNA synthetase Rare Jo- YRS Zo EJ PL-7 KS OJ PL-2 YRS (Ha) Tyrosyl-tRNA synthetase Rare RIM study - subanalysis SRP antibodies severe weakness, marked disability, dysphagia myalgia, highly elevated CK necrotizing myopathy with capillary abnormalities poor response to treatment shorter survival onset in the fall (anti-7sl RNA) cardiac involvement (?) ILD in 2% somewhat better prognosis response to rituximab? Aggarwal R, et al. Arthritis Rheumatol 20;():70-9. Mi-2 antibodies skin manifestations relatively mild disease treatment response - fair latitudinal gradient (UV intensity) tendency for antibodies to NTfragment of the Mi-2β antigen to have a higher risk for malignancy Hengstman GJD et al. Ann Rheum Dis 200;:22-. Love LA et al. Arthritis Rheum 2009;0:
3 2/0/20 p/0 antibody kd, 0 kd (K2). Nuclear speckled., 2, 0% of myositis patients Heliotrope rash, Gottron s papules, ulceration (in JDM), flagellate erythema In 2, 29% JDM In 7%, (7% vs. %), (0% vs. %) of cancer associated DM No ILD DQA*00 association Transcriptional intermediary factor g TIF-g in European patients with IIMs. Targoff IN et al. Arthritis Rheum 200;:2-9. Kaji K et al. Rheumatology 2007;:2-. Gunawardena H et al. Rheumatology (Oxford). 200 ;7:2-. Chinoy H et al. Ann Rheum Dis 2007;:-9. Mann H et al. ACR 20. NXP-2, anti-p0 (anti-mj), Autoantibodies associated with calcinosis 0 kda protein (nuclear matrix protein NXP-2) Weak or no immunofluorescence, sometimes dots in ANA test 2% JDM Association with calcinosis in JDM, but also adult DM HLA DRB*0 Recently - most frequent antibody in Italian cohort (7%) Younger age at onset, no ILD. Association with malignancy Gunawardena H. et al. Arthritis Rheum 2009; 0:07-. Ceribelli A. et al. Arthritis Res Ther 202+:R97. Fredi M, et al. Clin Exp Rheumatol 207;(2):0-0. Rogers A, et al. Arthritis Care Res (Hoboken). 207;9(2): Albayda J, et al. Arthritis Care Res (Hoboken) 207; 9(): CADM-0 (MDA) autoantibody First described in Japan (9 - % DM and - 7% CADM), recently US 0 patients with DM (%) Strongly associated with CADM and interstitial lung disease Poor prognosis (% died within months) Ulcerations, palmar papules, vasculopathy Drop in anti-mda antibody <00 U/ml after treatment - improvement, whereas anti-mda antibody >00 U/ml are resistant to treatment and die of respiratory failure in a short period. Anti Melanoma Differentiation Associated Gene Is Associated With Rapidly Progressive Lung Disease and Poor Survival in US Patients With Amyopathic and Myopathic Satoh S. et al. Arthritis Rheum 200;2: 7 7 Moghadam-Kia S, et al. Arthritis Care Res (Hoboken). 20 May;():9-9.
4 2/0/20 SAE autoantibody % myositis (% of DM) Severe classical skin Mild myositis Periunugual changes HLA-DRB*0-DQA*0-DQB*0 OR=. P < % Systemic features dysphagia No or mild ILD Rare cancer HLA DRB*0/* is more frequent in anti-fhl+ patients. Betteridge ZE et al. Arthritis Rheum 2007, Betteridge ZE et al. Ann Rheum Dis 2009 IIMs J Clin Invest. 20;2(2):2 2. FHL autoantibodies are associated with severe muscle pathology Phenotype based statin related myotoxicity (SRM) classification Class Phenotype Incidence Definition SRM 0 CK < x ULN.-2% No muscle SxS SRM Myalgia, tolerable 0.-% SxS with normal CK SRM 2 Myalgia, intolerable % SxS, CK< x ULN, complete resolution on Dc SRM Myopathy 0.00%? CK >x ULN < 0x ULN±SxS, complete resolution on Dc SRM Severe myopathy 0.%? CK >0x ULN< 0x, muscle SxS, complete resolution on Dc SRM Rhabdomyolysis % CK >0x ULN, renal impairment + SxS or CK>0x ULN SRM IMNM %?? anti-hmgcr+, HMGCR expression in Bx, incomplete resolution on Dc Albrecht I et al. J Clin Invest. 20;2(2):2 2. Alfirevic A, et al. Clin Pharmacol Ther 20 ;9():70-. Acetyl-CoA + HMG-CoA Mevalonate Isopentyl PP Farnesyl PP Acetoacetyl-CoA HMG CoA reductase Statin HMGCR antibodies IMNM with anti-hmgcr antibodies First described as anti-200/00 kda antibodies in 200 High proportion of statin users among positive patients Directed against -hydroxy--methylglutaryl-coenzyme A reductase Increased HMGCR expression in muscles Heme A Geranylgeranyl PP Squalene Cholesterol Altered myocyte membranes? Isoprenylated proteins Dolichol Ubiquinone Depletion activates apoptotic pathways? Reduced CoQ0 disrupts mitochondrial function? According to Lisa Christopher-Stine, ACR 20 Christopher-Stine L, et al. Arthritis Rheum 200;2(9):277-.
5 2/0/20 IMNM associated with anti-hmgcr Muscle biopsy results (+new cases of IIM) 2% of anti HMGCR-positive patients require a wheelchair Disease improves by immunosuppressive treatment. It frequently relapses after treatment discontinuation. Some patients respond only to IVIGs. Disease is very rare incidence 9/00000 statin users Christopher-Stine L, et al. Arthritis Rheum 200;2(9):277-. Mohassel P et al. Muscle Nerve % 90% 0% 70% 0% 0% 0% 0% 20% 0% 0% * About 0% of IMNM are anti-hmgcr+. All of them have statin exposure in the history vs χ 2 (df)=2,20; p<0.000 normal NC N-SM IBM DM PM IMNM Klein M, et al. Rheumatology (Oxford). 20 ;():200-. The prevalence of statin exposure in anti- HMGCR-associated myopathy worldwide HMGCR+ IMNM without statins Johns Hopkins = 0/ (7%) French cohort = 20/ (%) Czech cohort = 22/2 (9%) Australian cohort = /7 (9%) Chinese cohort = /20 (%) Pleurotus ostreatus, the oyster mushroom, naturally contains up to 2.% lovastatin on a dry weight basis. Capsules 00 mg Wikipedie. Mammen A, ACR 20 Fungus Monascus purpureus - produces a family of monacolin compounds, including monacolin K, which is identical to lovastatin An example how autoimmune disease starts? Enzyme (HMGCR) inhibited by statins Increased HMGCR expression in muscle Loss of tolerance HLA (HLA-DR*:0 7% vs. %), binding of statin to enzyme? Autoantibody development Activity related to Ab levels probably pathogenic effect? Improvement after immunosuppressive treatment
6 2/0/20 Autoantibodies to Cytosolic - Nucleotidase A in Inclusion Body Myositis Disease specificity of autoantibodies to cytosolic - nucleotidase A in sporadic inclusion body myositis versus known autoimmune diseases 7% % 0% % % 20% 2% 2% % % Initially detected in 2%, % and % with very high specificity for IBM Salajegheh M, et al. PLoS One 20;():e202. Pluk H, et al. Ann Neurol 20;7(): Larman HB, et al. Ann Neurol 20;7():0-. Herbert MK, et al. Ann Rheum Dis 20;7:9 70. Polymyositis Skin AnticNA TIF-b SAE Mi-2 Calcinosis NXP2 Malignancy TIF-a TIF-g Juvenile DM MDA ILD Antisynthetase syndrome PL-2 KS OJ PL-7 EJ Zo YRS Jo- EIF FHL Muscle weakness Muscle necrosis IBM IMNM SRP HMGCR
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