Clinical relevance of autoantibodies in MDs clinical practice

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1 4 rd Congress of the European Academy of Neurology Lisbon, Portugal, June 16-19, 2018 Teaching Course 2 How to proceed with a suspected myopathy? - Level 2 Clinical relevance of autoantibodies in MDs clinical practice Benedikt Schoser Munich, Germany bschoser@med.uni-muenchen.de

2 Clinical relevance of autoantibodies in MDs clinical practice Benedikt Schoser Friedrich Baur Institut Neurologische Klinik Ludwig Maximilians Universität München Conflicts of interest Scientific Research support grants: Speaker honoraria: Alexion Pharmaceuticals Member of advisory boards: CLS Behring, Lupin Pharmaceuticals 1

3 hereditary neuropathies HMSN, HINT1 NEUROLOGISCHE primary KLINIK channelopathies neuromyotonia (VGKC, CASPR2, LGI1, contactin 2) motoneuron disease ALS, SMA, SBMA, Polio, HSP neurogenic toxic/ endocrine/ metabolic diabetes, alcohol, etc. Neuromuscular hypoactivity/ hyperactivity ENG/ EMG, Ultrasound secondary primary inflammatory/ autoimmune myasthenic syndromes hereditary myopathies CIDP, CIP, paranodopathies, paraproteinaemia NF 155, contactin, Caspr, GM1, MAG MG, LEMS AChR, MUSK, LRP4, agrin, cortactin, titin, VGCCs, SOX1 Myotonic dystrophies, glycogenoses mitochondrial myopathies limb girdle myopathies Rippling muscle disease myopathic channelopathies myotonia (CLCN1; SCN4A) Brody (SERCA1) secondary endocrine/ metabolic/ toxic statin myopathy hyper /hypothyreosis, hyperparathyreoidism alcohol, drugs inflammatory / autoimmune Stiff person GAD / amphiphysin myositis Focused agenda Autoantibodies in 1) immune mediated myopathies 2) in endplate disorders 2

4 Autoantibodies in immune mediated myopathies Advances in serological diagnostics of inflammatory myopathies. Benveniste O, Stenzel W, Allenbach Y. Curr Opin Neurol ;29(5): Immune mediated necrotizing NEUROLOGISCHE myopathy KLINIK (IMNM) Clinical phenotype Acute to subakute severe proximal tetraparesis neck flexior weakness dysphagia marked myalgia massive rapid muscle atrophy CK U/L SRP autoantibodies HMGCR autoantibodies 3

5 1250 INM patients and 656 other disease Anti-HMGCR abs linked to statin intake: classic INM These patients were older and muscle fiber necrosis was prominent in biopsies. 4

6 A synopsis of autoantibodies in immune mediated myopathies High CK Muscle weakness and atrophy Clinical Muscle features weakness Morphology autoantobod ies Dermatitis Muscle pain Weakness CK elevation Fiber necrosis SRP HMGCR liquid biopsy Perifascicular atrophy Mi 2, MDA5, TiF c, NXP2, SAE IMNM Lung Dermatitis involvement Perifascicular atrophy Jo 1 et al. Dermatomyositis Overlap myositis IBM with cn1a / Mup44 autoantibodies First description Larman et al and Pluk et al antibodies against the muscle specific cytosolic 5 nucleotidase 1A DNA repair and RNA metabolism rarely found in other immunogenic myopathies about 60% of sibm patients positive 5

7 cn1a/mup44 autoantibodies in sibm Kramp et al. Auto Immun Highlights Dec;7(1):16. (23) Aquired neuromuscular endplate diseases Myasthenia gravis Prevalence in Incidence 4 12 in Heldal AT et al., 2009 Andersen JB et al Gilhus&Verschuuren 2015 Posey & Spiller Fatigue (Ptosis) in a patient with MG 1904 Lambert Eaton syndrome Prevalence 2 in Incidence 0.5 in Wirtz PW et al., 2003 Gilhus NE

8 Antigenes in myasthenia gravis Cortactin Modif. from Evoli A, Lindstrom J, Neurology 2011 Subtypes of myasthenic syndromes Gilhus&Verschuuren Lancet Neurol

9 Subtypes of myasthenic syndromes Sex F > M F >> M M=F M=F M>F Onset early and late variable variable variable late HLA DR3 B8 A1 DR14,DR16,DQ5? Thymus hyperplasia normal normal? mostly normal Modified form Gilhus&Verschuuren Lancet Neurol 2015 Immunodiagnostics associated autoimmune diseases hyper or hypothyreosis (TSH, T3, T4, TPO abs) polyarthritis (RF, ANA, CRP) pernicious anaemia (parietalcell abs) Sjögren syndrom (SSA) SLE (ANA, ds DNS abs) sarcoidosis (X ray of the lung) Rippling muscle syndrom 8

10 Acetylcholine receptor antibodies Anti AChR antibody testing is in 80% of the patients with generalized myasthenia gravis positiv Titin antibodies 20 40% of all AChR+MG patients have anti titin abs. age dependent (< 40 yrs. under 6%; > 40 yrs %) titin antibodies have a positive association with HLA DR7. about 70% of MG patients have thymus hyperplasia about 20% have a thymoma (=malignant thymus tumor) titin and ryandoidine receptor abs are in thymoma patients under age 50 positive. => indicative for a more severe MG disease course thymoma? 9

11 Titin antibodies in triple seronegative MG 13.4% (50/372) of the triple seronegative MG patients were titin antibody positive. C. Stergiou et al. / Journal of Neuroimmunology 292 (2016) MuSK MG about 4 6% of MGs are MuSK abs. positive 85% female 60% above age 40 acutetosubacuteptosisand double vision bulbo facial weakness (cardinal symptom ) paresisof neckflexors 10

12 MuSK Abs pos. MG Single fiber EMG most sensitive about30% have a normal tensilon test Thymus pathology: no lymphofollicular hyperplasia, nogerme cell centers Patientsdo not profit from thymectomy Plasmapheresis in 93%, ivig in 61% with improvement Improvement to AChE inhibitors mostly insufficient Guptill JT, Sanders DB, Evoli A. Anti MuSK antibody myasthenia gravis; clinical findings and response to treatment in two large cohorts. Muscle Nerve 2011; 44: Double sero negative Myasthenia gravis About 10 % with generalized Myasthenia gravis have neither antibodies against AChR nor MuSK Vincent et al Start and progression seems identical to AChR or MuSK seropositive MG Leite et al Romi et al Vincent et al Gilhus&Verschuuren Lancet Neurol

13 9 of 300 MG LRP4 abs positive 3 of 28 MUSK with additional LRP4 abs 1 of 100 LEMS with additional LRP4 abs 12

14 Low-density lipoprotein Receptor-like Protein 4 (LRP4 ) associated Myasthenia gravis LRP4 antibodies in sero negativen Myasthenia gravis patients 13

15 AGRIN abs associated MG Anti Agrin autoantibodies in Myasthenia gravis Gasperi C, Melms A, Schoser B, Zhang Y, Meltoranta J, Risson V, Schaeffer L, Schalke B, Kröger S Neurology 2014; 82(22): sera of double seronegative generalized MG 30 sera seronegative of anti AChR or MuSK 15 sera anti MuSK positive 9 sera anti AChR positive Solid phase ELISA with purified mini agrin protein 5 sera anti Agrin antibody positive 4 of 5 agrin positive sera positive for anti MuSK 1 Agrin positive in the anti AChR cohort 2 Agrin positive in the anti LRP4 cohort Multiple antigenes in doublesero negative MG! Cortactin antibody associated MG JAMA Neurol. doi: /jamaneurol Published online July 5, In this cross sectional study of 250 patients, cortactin antibodies were identified in 9 of 38 patients with dsnmg (23.7%). These patients had an ocular or mild generalized phenotype of myasthenia gravis. 14

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16 Thanks for you attention! Many thanks to Federica Montagnese, Stephan Wenninger 15

The many faces of myositis. Marianne de Visser Academic Medical Centre Dept of Neurology Amsterdam The Netherlands

The many faces of myositis. Marianne de Visser Academic Medical Centre Dept of Neurology Amsterdam The Netherlands The many faces of myositis Marianne de Visser Academic Medical Centre Dept of Neurology Amsterdam The Netherlands Outline of the presentation Classification Diagnosis Therapy Prognosis Diagnostic criteria