Statinassoziierte Muskelsymptome und Statinmyopathie

Statine sind hocheffizient zur Senkung erhöhter Cholesterolwerte. Allerdings sind statinassoziierte muskuläre Symptome (SAMS) die häufigste Nebenwirkung von Statinen und der Hauptgrund für Non-Adhärenz bzw. Therapieabbruch. Kenntnis der verschiedenen Präsentationen von SAMS und der ätiologischen Einordnung von Muskelbeschwerden unter Statinmedikation sowie Schritte der Diagnostik und Therapie sind daher nicht nur für den Neurologen relevant.

Kernaussagen

• Statinassoziierte Muskelsymptome (SAMS) sind die wichtigste Nebenwirkung von Statinen.

• Die Symptome umfassen Hyper-CK-ämie, Myalgien und unspezifische Myopathie – selten sind lebensbedrohliche Rhabdomyolysen zu verzeichnen.

• Die Statintherapie kann ebenfalls die Entwicklung einer immunmediierten nekrotisierenden Myopathie (IMNM) mit HMGCR-Antikörpern triggern – allerdings kann diese auch ohne vorherige Statinmedikation entstehen.

• Für die Diagnose von SAM ist der kausale Zusammenhang von Beschwerden mit einer Statinmedikation entscheidend: Die genaue Anamnese des zeitlichen Bezugs von Beschwerden zur Statinmedikation ist daher essenziell.

• Zur klinischen Erfassung erfolgen die Bestimmung von CK-Wert, Paresen sowie EMG und Muskel-MRT.

• Eine Statinpause ist für die differenzialdiagnostische Abgrenzung gegenüber unspezifischen Muskelbeschwerden und anderen Myopathien hilfreich.

• Das Risiko für SAMS hängt von der Art und Dosis der Statine sowie der Komedikation und den Begleiterkrankungen ab.

• Therapeutisch ist oft eine Dosisreduktion oder ein Statinwechsel ausreichend, um die Beschwerden zu lindern und die Statinmedikation wieder fortsetzen zu können – nur bei sehr wenigen Patienten ist ein gänzlicher Statinverzicht nötig.

• Der Nachweis von HMGCR-Antikörpern spricht für das Vorliegen einer immunmediierten nekrotisierenden Myopathie (IMNM) mit typischem Bild in der Muskelbiopsie und erfordert therapeutisch eine Immunsuppression.

• Wegen der Tumorassoziation bei der IMNM sollten regelmäßige Screening-Untersuchungen stattfinden.

Schlüsselwörter

statinassoziierte Muskelbeschwerden (SAMS) - HMGCR-assoziierte immunmediierte nekrotisierende Myopathie (INMN) - Nebenwirkungen von Statinmedikation - autoimmune nekrotisierende Myopathie (NAM) - Hyperlipidämie

• Literatur

• 1 Colantonio LD, Bittner V, Reynolds K. et al. Association of serum lipids and coronary heart disease in contemporary observational studies. Circulation 2016; 133: 256-264
• 2 Robinson JG, Stone NJ. The 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular disease risk: a new paradigm supported by more evidence. Eur Heart J 2015; 36: 2110-2118
• 3 Laufs U, Scharnagl H, Halle M. et al. Treatment options for statin-associated muscle symptoms. Dtsch Arztebl Int 2015; 112: 748-755
• 4 Toth PP, Patti AM, Giglio RV. et al. Management of statin intolerance in 2018: still more questions than answers. Am J Cardiovasc Drugs 2018; 18: 157-173
• 5 Joy TR, Hegele RA. Narrative review: statin-related myopathy. Ann Intern Med 2009; 150: 858-868
• 6 Bitzur R, Cohen H, Kamari Y. et al. Intolerance to statins: mechanisms and management. Diabetes Care 2013; 36 Suppl 2: S325-S330
• 7 Cohen JD, Brinton EA, Ito MK. et al. Understanding statin Use in America and Gaps in Patient Education (USAGE): an internet-based survey of 10,138 current and former statin users. J Clin Lipidol 2012; 6: 208-215
• 8 Bruckert E, Hayem G, Dejager S. et al. Mild to moderate muscular symptoms with high-dosage statin therapy in hyperlipidemic patients – the PRIMO study. Cardiovasc Drugs Ther 2005; 19: 403-414
• 9 Bays H. Statin safety: an overview and assessment of the data-2005. Am J Cardiol 2006; 97: 6C-26C
• 10 Phillips PS, Haas RH, Bannykh S. et al. Statin-associated myopathy with normal creatine kinase levels. Ann Intern Med 2002; 137: 581-585
• 11 Riaz H, Khan AR, Khan MS. et al. Meta-analysis of placebo-controlled randomized controlled trials on the prevalence of statin intolerance. Am J Cardiol 2017; 120: 774-781
• 12 Marcoff L, Thompson PD. The role of coenzyme Q10 in statin-associated myopathy: a systematic review. J Am Coll Cardiol 2007; 49: 2231-2237
• 13 Sirvent P, Mercier J, Lacampagne A. New insights into mechanisms of statin-associated myotoxicity. Curr Opin Pharmacol 2008; 8: 333-338
• 14 Allard NAE, Schirris TJJ, Verheggen RJ. et al. Statins affect skeletal muscle performance: evidence for disturbances in energy metabolism. J Clin Endocrinol Metab 2018; 103: 75-84
• 15 Mancini GB, Baker S, Bergeron J. et al. Diagnosis, prevention, and management of statin adverse effects and intolerance: Canadian Consensus Working Group Update (2016). Can J Cardiol 2016; 32: S35-65
• 16 Armitage J. The safety of statins in clinical practice. Lancet 2007; 370: 1781-1790
• 17 Group SC, Link E, Parish S. et al. SLCO1B1 variants and statin-induced myopathy-a genomewide study. N Engl J Med 2008; 359: 789-799
• 18 Niemi M. Transporter pharmacogenetics and statin toxicity. Clin Pharmacol Ther 2010; 87: 130-133
• 19 Needham M, Mastaglia FL. Statin myotoxicity: a review of genetic susceptibility factors. Neuromuscul Disord 2014; 24: 4-15
• 20 Carr DF, Alfirevic A, Johnson R. et al. GATM gene variants and statin myopathy risk. Nature 2014; 513: E1
• 21 Isackson PJ, Ochs-Balcom HM, Ma C. et al. Association of common variants in the human eyes shut ortholog (EYS) with statin-induced myopathy: evidence for additional functions of EYS. Muscle Nerve 2011; 44: 531-538
• 22 Vladutiu GD, Simmons Z, Isackson PJ. et al. Genetic risk factors associated with lipid-lowering drug-induced myopathies. Muscle Nerve 2006; 34: 153-162
• 23 Rosenson RS, Baker SK, Jacobson TA. et al. An assessment by the Statin Muscle Safety Task Force: 2014 update. J Clin Lipidol 2014; 8: S58-71
• 24 Alfirevic A, Neely D, Armitage J. et al. Phenotype standardization for statin-induced myotoxicity. Clin Pharmacol Ther 2014; 96: 470-476
• 25 Kley RA, Schmidt-Wilcke T, Vorgerd M. Differential diagnosis of hyperCkemia. Neurology International Open 2018; 02: E72-E83
• 26 Taylor BA, Sanchez RJ, Jacobson TA. et al. Application of the statin-associated muscle symptoms-clinical index to a randomized trial on statin myopathy. J Am Coll Cardiol 2017; 70: 1680-1681
• 27 Abdulrazaq M, Hamdan F, Al-Tameemi W. Electrophysiologic and clinico-pathologic characteristics of statin-induced muscle injury. Iran J Basic Med Sci 2015; 18: 737-744
• 28 Cziraky MJ, Willey VJ, McKenney JM. et al. Risk of hospitalized rhabdomyolysis associated with lipid-lowering drugs in a real-world clinical setting. J Clin Lipidol 2013; 7: 102-108
• 29 Thompson PD, Panza G, Zaleski A. et al. Statin-associated side effects. J Am Coll Cardiol 2016; 67: 2395-2410
• 30 Catapano AL, Graham I, De Backer G. et al. 2016 ESC/EAS Guidelines for the management of dyslipidaemias. Rev Esp Cardiol (Engl Ed) 2017; 70: 115
• 31 Banach M, Stulc T, Dent R. et al. Statin non-adherence and residual cardiovascular risk: There is need for substantial improvement. Int J Cardiol 2016; 225: 184-196
• 32 Serban MC, Colantonio LD, Manthripragada AD. et al. Statin intolerance and risk of coronary heart events and all-cause mortality following myocardial infarction. J Am Coll Cardiol 2017; 69: 1386-1395
• 33 Stroes ES, Thompson PD, Corsini A. et al. Statin-associated muscle symptoms: impact on statin therapy-European Atherosclerosis Society Consensus Panel Statement on Assessment, Aetiology and Management. Eur Heart J 2015; 36: 1012-1022
• 34 Laufs U, Filipiak KJ, Gouni-Berthold I. et al. Practical aspects in the management of statin-associated muscle symptoms (SAMS). Atherosclerosis Supp 2017; 26: 45-55
• 35 Rosenson RS, Baker S, Banach M. et al. Optimizing cholesterol treatment in patients with muscle complaints. J Am Coll Cardiol 2017; 70: 1290-1301
• 36 Palamaner Subash Shantha G, Ramos J, Thomas-Hemak L. et al. Association of vitamin D and incident statin induced myalgia-a retrospective cohort study. PLoS One 2014; 9: e88877
• 37 Khayznikov M, Hemachrandra K, Pandit R. et al. Statin intolerance because of myalgia, myositis, myopathy, or myonecrosis can in most cases be safely resolved by vitamin D supplementation. N Am J Med Sci 2015; 7: 86-93
• 38 Taylor BA, Lorson L, White CM. et al. A randomized trial of coenzyme Q10 in patients with confirmed statin myopathy. Atherosclerosis 2015; 238: 329-335
• 39 Mortensen SA, Rosenfeldt F, Kumar A. et al. The effect of coenzyme Q10 on morbidity and mortality in chronic heart failure: results from Q-SYMBIO: a randomized double-blind trial. JACC Heart Fail 2014; 2: 641-649
• 40 Dadu RT, Ballantyne CM. Lipid lowering with PCSK9 inhibitors. Nat Rev Cardiol 2014; 11: 563-575
• 41 Heber D, Yip I, Ashley JM. et al. Cholesterol-lowering effects of a proprietary Chinese red-yeast-rice dietary supplement. Am J Clin Nutr 1999; 69: 231-236
• 42 Sahebkar A, Saboni N, Pirro M. et al. Curcumin: An effective adjunct in patients with statin-associated muscle symptoms?. J Cachexia Sarcopenia Muscle 2017; 8: 19-24
• 43 Christopher-Stine L, Casciola-Rosen LA, Hong G. et al. A novel autoantibody recognizing 200-kd and 100-kd proteins is associated with an immune-mediated necrotizing myopathy. Arthritis Rheum 2010; 62: 2757-2766
• 44 Schmidt J. Current Classification and management of inflammatory myopathies. J Neuromuscul Dis 2018; 5: 109-129
• 45 Pinal-Fernandez I, Casal-Dominguez M, Mammen AL. Immune-mediated necrotizing myopathy. Curr Rheumatol Rep 2018; 20: 21
• 46 Ge Y, Lu X, Peng Q. et al. Clinical characteristics of Anti-3-Hydroxy-3-Methylglutaryl Coenzyme A reductase antibodies in Chinese patients with idiopathic inflammatory myopathies. PLoS One 2015; 10: e0141616
• 47 Watanabe Y, Uruha A, Suzuki S. et al. Clinical features and prognosis in anti-SRP and anti-HMGCR necrotising myopathy. J Neurol Neurosurg Psychiatry 2016; 87: 1038-1044
• 48 Musset L, Allenbach Y, Benveniste O. et al. Anti-HMGCR antibodies as a biomarker for immune-mediated necrotizing myopathies: A history of statins and experience from a large international multi-center study. Autoimmun Rev 2016; 15: 983-993
• 49 Allenbach Y, Drouot L, Rigolet A. et al. Anti-HMGCR autoantibodies in European patients with autoimmune necrotizing myopathies: inconstant exposure to statin. Medicine (Baltimore) 2014; 93: 150-157
• 50 Tansley SL, Betteridge ZE, Simou S. et al. Anti-HMGCR autoantibodies in juvenile idiopathic inflammatory myopathies identify a rare but clinically important subset of patients. J Rheumatol 2017; 44: 488-492
• 51 Mammen AL, Chung T, Christopher-Stine L. et al. Autoantibodies against 3-hydroxy-3-methylglutaryl-coenzyme A reductase in patients with statin-associated autoimmune myopathy. Arthritis Rheum 2011; 63: 713-721
• 52 Klein M, Mann H, Plestilova L. et al. Increasing incidence of immune-mediated necrotizing myopathy: single-centre experience. Rheumatology (Oxford) 2015; 54: 2010-2014
• 53 Troyanov Y, Landon-Cardinal O, Fritzler MJ. et al. Atorvastatin-induced necrotizing autoimmune myositis: An emerging dominant entity in patients with autoimmune myositis presenting with a pure polymyositis phenotype. Medicine (Baltimore) 2017; 96: e5694
• 54 Alarcon J, Aguila S, Arancibia-Avila P. et al. Production and purification of statins from Pleurotus ostreatus (Basidiomycetes) strains. Z Naturforsch C 2003; 58: 62-64
• 55 Barbacki A, Fallavollita SA, Karamchandani J. et al. Immune-mediated necrotizing myopathy and dietary sources of statins. Ann Intern Med 2018; 168: 893-904
• 56 Sulaiman S, Khamis M, Nir S. et al. Stability and removal of atorvastatin, rosuvastatin and simvastatin from wastewater. Environ Technol 2015; 36: 3232-3242
• 57 Mammen AL, Gaudet D, Brisson D. et al. Increased frequency of DRB1*11 : 01 in anti-hydroxymethylglutaryl-coenzyme A reductase-associated autoimmune myopathy. Arthritis Care Research 2012; 64: 1233-1237
• 58 Mammen AL. Statin-associated autoimmune myopathy. N Engl J Med 2016; 374: 664-669
• 59 Chushi L, Wei W, Kangkang X. et al. HMGCR is up-regulated in gastric cancer and promotes the growth and migration of the cancer cells. Gene 2016; 587: 42-47
• 60 Allenbach Y, Mammen AL, Benveniste O. et al. 224th ENMC International Workshop:: Clinico-sero-pathological classification of immune-mediated necrotizing myopathies Zandvoort, The Netherlands, 14–16 October 2016. Neuromuscul Disord 2018; 28: 87-99
• 61 Kassardjian CD, Lennon VA, Alfugham NB. et al. Clinical features and treatment outcomes of necrotizing autoimmune myopathy. JAMA Neurol 2015; 72: 996-1003
• 62 Pinal-Fernandez I, Mammen AL. Spectrum of immune-mediated necrotizing myopathies and their treatments. Curr Opin Rheumatol 2016; 28: 619-624
• 63 Allenbach Y, Keraen J, Bouvier AM. et al. High risk of cancer in autoimmune necrotizing myopathies: usefulness of myositis specific antibody. Brain 2016; 139: 2131-2135
• 64 Kipfer S, Frigerio S, Hench J. et al. Immune-mediated necrotising myopathy linked to statin use. Lancet 2015; 386: e26
• 65 Hoogendijk JE, Amato AA, Lecky BR. et al. 119th ENMC international workshop: trial design in adult idiopathic inflammatory myopathies, with the exception of inclusion body myositis, 10–12 October 2003, Naarden, The Netherlands. Neuromuscul Disord 2004; 14: 337-345
• 66 Chung T, Christopher-Stine L, Paik JJ. et al. The composition of cellular infiltrates in anti-HMG-CoA reductase-associated myopathy. Muscle Nerve 2015; 52: 189-195
• 67 Ladislau L, Arouche-Delaperche L, Allenbach Y. et al. Potential pathogenic role of anti-signal recognition protein and anti-3-hydroxy-3-methylglutaryl-CoA reductase antibodies in immune-mediated necrotizing myopathies. Curr Rheumatol Rep 2018; 20: 56
• 68 Mammen AL, Pak K, Williams EK. et al. Rarity of anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase antibodies in statin users, including those with self-limited musculoskeletal side effects. Arthritis Care Res (Hoboken) 2012; 64: 269-272
• 69 Alvarado-Cardenas M, Marin-Sanchez A, Martinez MA. et al. Statin-associated autoimmune myopathy: A distinct new IFL pattern can increase the rate of HMGCR antibody detection by clinical laboratories. Autoimmun Rev 2016; 15: 1161-1166
• 70 Suzuki S, Nishikawa A, Kuwana M. et al. Inflammatory myopathy with anti-signal recognition particle antibodies: case series of 100 patients. Orphanet J Rare Dis 2015; 10: 61
• 71 Tiniakou E, Pinal-Fernandez I, Lloyd TE. et al. More severe disease and slower recovery in younger patients with anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase-associated autoimmune myopathy. Rheumatology 2017; 56: 787-794
• 72 Mammen AL, Tiniakou E. Intravenous immune globulin for statin-triggered autoimmune myopathy. N Engl J Med 2015; 373: 1680-1682
• 73 Valiyil R, Casciola-Rosen L, Hong G. et al. Rituximab therapy for myopathy associated with anti-signal recognition particle antibodies: a case series. Arthritis Care Res (Hoboken) 2010; 62: 1328-1334