Statin-associated autoimmune myopathy

Last updated
Statin-associated Autoimmune Myopathy
Other namesAnti-HmG Coenzyme A Reductase Myopathy, Immune-mediated necrotizing myopathy associated with statins, Statin-associated immune-mediated myopathy, Statin-induced autoimmune myositis, Statin-induced necrotizing autoimmune myopathy
Specialty Rheumatology
Symptoms Muscle weakness
Treatment Corticosteroids, immunosuppressive medications, withdrawal of the implicated statin
FrequencyRare

Statin-associated autoimmune myopathy (SAAM), also known as anti-HMGCR myopathy, is a very rare form of muscle damage caused by the immune system in people who take statin medications. [1] However, there are cases of SAAM in patients who have not taken statin medication, and this can be explained by the exposure to natural sources of statin such as red yeast rice, which is statin rich. This theory is supported by the higher prevalence of statin-naive SAAM patients in Asian cohorts, who have statin-rich diets. [2]

Contents

The exact cause is unclear. A combination of consistent findings on physical examination, the presence of anti HMG-CoA reductase antibodies in a person with myopathy, evidence of muscle breakdown, and muscle biopsy diagnose SAAM. [3]

Treatment involves stopping the associated statin medication and taking medication to suppress the immune system.

SAAM is estimated to occur in 2-3 people out of every 100,000 statin-treated individuals. It appears to be more common in people over the age of 50. [3]

Signs and symptoms

Severe weakness of the proximal muscles (shoulders, upper arms, thighs) on both sides of the body, very high blood levels of the enzyme creatine kinase (CK) being released by broken down skeletal muscle, and persistent symptoms and CK elevation despite stopping the offending statin medication are the hallmarks of SAAM. [1] [3] Other forms of statin associated muscle damage (myopathy) usually resolve after stopping the involved statin. [1] Mild joint pain and rash may be present. [3] In people affected by SAAM, the median duration of statin therapy was 38 months before the onset of muscular symptoms. [4] SAAM may affect people after long-term statin use even if they had no previous muscular side effects. [4]

A differentiating feature between this and more benign statin side effects is SAAM typically has a late onset. While muscle pain (myalgia) is seen in 9-20% of patients treated with statins, it typically occurs in the first month of treatment. SAAM has a later onset, occurring years after uncomplicated statin use. In some cases even after statins have been discontinued for several years. [5]

Pathogenesis

It is unclear precisely how statins lead to statin-associated autoimmune myopathy. [1] The disorder is positively associated with HLA-DR11 and the DRB1*11:01 allele. [1] There are likely other unidentified genetic and environmental risk factors associated with SAAM, given the prevalence of the DRB1 allele and the low incidence of autoimmunity in that group. [3] Statins inhibit HMG-CoA reductase activity and consequently lower cholesterol levels in the blood. However, by doing this, they also increase the production of the HMG-CoA reductase protein. SAAM hypothetically triggers this increase in the production of HMG-CoA reductase and associated abnormal processing of this protein in genetically susceptible individuals. This abnormal processing theoretically triggers the generation of antibodies targeting the HMG-CoA reductase protein resulting in SAAM. [1] Another theory postulates that the configuration of the HMG-CoA reductase protein may change when statin medications bind to it causing the protein to expose certain antigens that the immune system is not tolerant to resulting in the production of antibodies against it. [3]

Diagnosis

Diagnostic algorithm for statin-associated myopathy. Algorithm for statin-associated myopathy.jpg
Diagnostic algorithm for statin-associated myopathy.

The development of necrotizing myopathy after statin exposure is insufficient to make the diagnosis. Testing must first exclude other causes of myositis and necrotizing myopathy. [7] A muscle biopsy consistent with SAAM will demonstrate muscle cell death with muscle fiber regeneration and typically has few inflammatory cells. [7] [8] Immunohistochemistry testing may demonstrate additional pathologic features of SAAM. Such findings include the presence of endothelial cell membrane attack complex in non-necrotic muscle fibers and MHC class I expression. [8]

Antibodies against HMG-CoA reductase occur in 94% of affected individuals. [1] These antibodies are known to also occur in people who do not take statin medications. [3] Conversely, these antibodies are absent in people who take statin medications but do not have myopathy. Thus, the presence of anti-HMG CoA reductase antibodies in someone who uses a statin and has myopathy strongly supports the diagnosis. [3] CK levels increase to 10-100 times above normal (2000–20,000 IU/L) in more than 90% of cases. [3] [8] Electromyography (EMG) typically demonstrates a myopathic pattern of findings. [8] Muscle swelling may be seen on MRI imaging. [3]

Treatment

SAAM is treated by stopping the offending statin medication and taking immunosuppressive medications. [7] In rare cases, affected people spontaneously improve after just stopping the implicated statin. [3] However, most cases mandate the use of immunosuppressive medication. [8]

Corticosteroids are considered first-line treatment. Prednisone dosed at 1 milligram/kilogram of body weight daily is generally recommended. [3] Corticosteroid therapy alone may be reasonable in cases of mild muscular weakness. More severe cases require the use of combined methotrexate, azathioprine, or mycophenolate with corticosteroids. [3] Severe cases of SAAM may fail to respond to 8–12 weeks of combination therapy. Rituximab or intravenous immunoglobulin are recommended as add-on therapy in such cases. [3] Intravenous immunoglobulin is an appropriate first-line therapy in select individuals. Suitable candidates for first-line intravenous immunoglobulin include people who have diabetes mellitus or who wish to avoid corticosteroid therapy. [3]

Prognosis

Proper treatment of SAAM often results in full recovery. [3] Recovery can occur even with persistently elevated creatine kinase (CK) levels. [3] Conversely, some people with SAAM do not regain full muscle strength despite the normalization of their CK levels. [3] Longitudinal analysis of a patient cohort revealed that the majority of patients (85%) over 60 years old recovered full strength within four years, compared to less than half of patients below 52 years old, indicating that age during disease onset may be an important prognostic determinant. [9] Once strength recovers, immunosuppressive medications should be tapered. [3] Relapse remains possible during tapering efforts, and some people require long-term immunosuppression. [3] An affected person is more likely to experience permanent muscle damage if they do not receive adequate treatment for a long time. Muscle weakness occurs due to the replacement of some muscle with fatty tissue. [3]

Related Research Articles

Inclusion body myositis (IBM) is the most common inflammatory muscle disease in older adults. The disease is characterized by slowly progressive weakness and wasting of both proximal muscles and distal muscles, most apparent in the finger flexors and knee extensors. IBM is often confused with an entirely different class of diseases, called hereditary inclusion body myopathies (hIBM). The "M" in hIBM is an abbreviation for "myopathy" while the "M" in IBM is for "myositis". In IBM, two processes appear to occur in the muscles in parallel, one autoimmune and the other degenerative. Inflammation is evident from the invasion of muscle fibers by immune cells. Degeneration is characterized by the appearance of holes, deposits of abnormal proteins, and filamentous inclusions in the muscle fibers. sIBM is a rare disease, with a prevalence ranging from 1 to 71 individuals per million.

<span class="mw-page-title-main">Myasthenia gravis</span> Autoimmune disease resulting in skeletal muscle weakness

Myasthenia gravis (MG) is a long-term neuromuscular junction disease that leads to varying degrees of skeletal muscle weakness. The most commonly affected muscles are those of the eyes, face, and swallowing. It can result in double vision, drooping eyelids, and difficulties in talking and walking. Onset can be sudden. Those affected often have a large thymus or develop a thymoma.

<span class="mw-page-title-main">Myalgia</span> Muscle pain

Myalgia is the medical term for muscle pain. Myalgia is a symptom of many diseases. The most common cause of acute myalgia is the overuse of a muscle or group of muscles; another likely cause is viral infection, especially when there has been no trauma.

<span class="mw-page-title-main">Statin</span> Class of drugs used to lower cholesterol levels

Statins are a class of medications that reduce illness and mortality in people who are at high risk of cardiovascular disease. They are the most commonly prescribed cholesterol-lowering drugs, and are also known as HMG-CoA reductase inhibitors.

<span class="mw-page-title-main">Cramp</span> Pathological, often painful, involuntary muscle contraction

A cramp is a sudden, involuntary, painful skeletal muscle contraction or overshortening associated with electrical activity; while generally temporary and non-damaging, they can cause significant pain and a paralysis-like immobility of the affected muscle. A cramp usually goes away on its own over a period of several seconds or (sometimes) minutes. Cramps are common and tend to occur at rest, usually at night. They are also often associated with pregnancy, physical exercise or overexertion, age, in such cases, cramps are called idiopathic, because there is no underlying pathology. In addition to those benign conditions cramps are also associated with many pathological conditions.

<span class="mw-page-title-main">Atorvastatin</span> Cholesterol-lowering medication

Atorvastatin is a statin medication used to prevent cardiovascular disease in those at high risk and to treat abnormal lipid levels. For the prevention of cardiovascular disease, statins are a first-line treatment. It is taken by mouth.

<span class="mw-page-title-main">Simvastatin</span> Lipid-lowering medication

Simvastatin, sold under the brand name Zocor among others, is a statin, a type of lipid-lowering medication. It is used along with exercise, diet, and weight loss to decrease elevated lipid levels. It is also used to decrease the risk of heart problems in those at high risk. It is taken by mouth.

<span class="mw-page-title-main">Cerivastatin</span> Chemical compound

Cerivastatin is a synthetic member of the class of statins used to lower cholesterol and prevent cardiovascular disease. It was marketed by the pharmaceutical company Bayer A.G. in the late 1990s, competing with Pfizer's highly successful atorvastatin (Lipitor). Cerivastatin was voluntarily withdrawn from the market worldwide in 2001, due to reports of fatal rhabdomyolysis.

<span class="mw-page-title-main">HMG-CoA reductase</span> Mammalian protein found in Homo sapiens

HMG-CoA reductase is the rate-controlling enzyme of the mevalonate pathway, the metabolic pathway that produces cholesterol and other isoprenoids. HMGCR catalyzes the conversion of HMG-CoA to mevalonic acid, a necessary step in the biosynthesis of cholesterol. Normally in mammalian cells this enzyme is competitively suppressed so that its effect is controlled. This enzyme is the target of the widely available cholesterol-lowering drugs known collectively as the statins, which help treat dyslipidemia.

<span class="mw-page-title-main">Dermatomyositis</span> Medical condition

Dermatomyositis (DM) is a long-term inflammatory disorder which affects the skin and the muscles. Its symptoms are generally a skin rash and worsening muscle weakness over time. These may occur suddenly or develop over months. Other symptoms may include weight loss, fever, lung inflammation, or light sensitivity. Complications may include calcium deposits in muscles or skin.

In medicine, myopathy is a disease of the muscle in which the muscle fibers do not function properly. Myopathy means muscle disease. This meaning implies that the primary defect is within the muscle, as opposed to the nerves or elsewhere.

<span class="mw-page-title-main">Polymyositis</span> Medical condition

Polymyositis (PM) is a type of chronic inflammation of the muscles related to dermatomyositis and inclusion body myositis. Its name means 'inflammation of many muscles'. The inflammation of polymyositis is mainly found in the endomysial layer of skeletal muscle, whereas dermatomyositis is characterized primarily by inflammation of the perimysial layer of skeletal muscles.

Microscopic polyangiitis is an autoimmune disease characterized by a systemic, pauci-immune, necrotizing, small-vessel vasculitis without clinical or pathological evidence of granulomatous inflammation.

<span class="mw-page-title-main">Myositis</span> Medical condition

Myositis is a rarely-encountered medical condition characterized by inflammation affecting the muscles. The manifestations of this condition may include skin issues, muscle weakness, and the potential involvement of other organs. Additionally, systemic symptoms like weight loss, fatigue, and low-grade fever can manifest in individuals with myositis.

Mixed connective tissue disease, commonly abbreviated as MCTD, is an autoimmune disease characterized by the presence of elevated blood levels of a specific autoantibody, now called anti-U1 ribonucleoprotein (RNP) together with a mix of symptoms of systemic lupus erythematosus (SLE), scleroderma, and polymyositis. The idea behind the "mixed" disease is that this specific autoantibody is also present in other autoimmune diseases such as systemic lupus erythematosus, polymyositis, scleroderma, etc. MCTD was characterized as an individual disease in 1972 by Sharp et al., and the term was introduced by Leroy in 1980.

<span class="mw-page-title-main">Drug-induced lupus erythematosus</span> Medical condition

Drug-induced lupus erythematosus is an autoimmune disorder caused by chronic use of certain drugs. These drugs cause an autoimmune response producing symptoms similar to those of systemic lupus erythematosus (SLE). There are 38 known medications to cause DIL but there are three that report the highest number of cases: hydralazine, procainamide, and quinidine. While the criteria for diagnosing DIL has not been thoroughly established, symptoms of DIL typically present as muscle pain and joint pain. Generally, the symptoms recede after discontinuing use of the drugs.

Scleromyositis, is an autoimmune disease. People with scleromyositis have symptoms of both systemic scleroderma and either polymyositis or dermatomyositis, and is therefore considered an overlap syndrome. Although it is a rare disease, it is one of the more common overlap syndromes seen in scleroderma patients, together with MCTD and Antisynthetase syndrome. Autoantibodies often found in these patients are the anti-PM/Scl (anti-exosome) antibodies.

<span class="mw-page-title-main">Inflammatory myopathy</span> Medical condition

Inflammatory myopathy, also known as idiopathic inflammatory myopathy (IIM), is disease featuring muscle weakness, inflammation of muscles (myositis), and in some types, muscle pain. The cause of much inflammatory myopathy is unknown (idiopathic), and such cases are classified according to their symptoms and signs, electromyography, MRI, and laboratory findings. It can also be associated with underlying cancer. The main classes of idiopathic inflammatory myopathy are polymyositis (PM), dermatomyositis (DM), inclusion-body myositis (IBM), immune-mediated necrotising myopathy (IMNM), and focal autoimmune myositis.

<span class="mw-page-title-main">Acquired non-inflammatory myopathy</span> Medical condition

Acquired non-inflammatory myopathy (ANIM) is a neuromuscular disorder primarily affecting skeletal muscle, most commonly in the limbs of humans, resulting in a weakness or dysfunction in the muscle. A myopathy refers to a problem or abnormality with the myofibrils, which compose muscle tissue. In general, non-inflammatory myopathies are a grouping of muscular diseases not induced by an autoimmune-mediated inflammatory pathway. These muscular diseases usually arise from a pathology within the muscle tissue itself rather than the nerves innervating that tissue. ANIM has a wide spectrum of causes which include drugs and toxins, nutritional imbalances, acquired metabolic dysfunctions such as an acquired defect in protein structure, and infections.

<span class="mw-page-title-main">Antisynthetase syndrome</span> Medical condition

Antisynthetase syndrome (ASS) is a multisystematic autoimmune disease associated with inflammatory myositis, interstitial lung disease, and antibodies directed against various synthetases of aminoacyl-transfer RNA. Other common symptoms include mechanic's hands, Raynaud's phenomenon, arthritis, and fever.

References

  1. 1 2 3 4 5 6 7 Thompson, PD; Panza, G; Zaleski, A; Taylor, B (May 2016). "Statin-Associated Side Effects". Journal of the American College of Cardiology (Review). 67 (20): 2395–2410. doi: 10.1016/j.jacc.2016.02.071 . PMID   27199064.
  2. ↑ Ge, Y; Peng, Q (October 2015). "Clinical characteristics of anti-3-hydroxy-3-methylglutaryl coenzyme a reductase antibodies in Chinese patients with idiopathic inflammatory myopathies". PLOS ONE. 10 (10): e0141616. Bibcode:2015PLoSO..1041616G. doi: 10.1371/journal.pone.0141616 . PMC   4624805 . PMID   26509687.
  3. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 Mammen, AL (February 2016). "Statin-Associated Autoimmune Myopathy". New England Journal of Medicine (Review). 374 (7): 664–9. doi:10.1056/NEJMra1515161. PMID   26886523.
  4. 1 2 Christopher-Stine, L; Basharat, P (April 2017). "Statin-associated immune-mediated myopathy: biology and clinical implications". Current Opinion in Lipidology (Review). 28 (2): 186–92. doi:10.1097/MOL.0000000000000399. PMID   28207435. S2CID   19330288.
  5. ↑ Irvine, Nathaniel J. (2020-09-01). "Anti-HMGCR Myopathy: A Rare and Serious Side Effect of Statins". The Journal of the American Board of Family Medicine. 33 (5): 785–788. doi: 10.3122/jabfm.2020.05.190450 . ISSN   1557-2625. PMID   32989074.
  6. ↑ Selva-O'Callaghan A, Alvarado-Cardenas M, Pinal-Fernández I, Trallero-Araguás E, Milisenda JC, Martínez MÁ; et al. (2018). "Statin-induced myalgia and myositis: an update on pathogenesis and clinical recommendations". Expert Rev Clin Immunol. 14 (3): 215–224. doi:10.1080/1744666X.2018.1440206. PMC   6019601 . PMID   29473763.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  7. 1 2 3 Hamann, PD; Cooper, RG; McHugh, NJ; Chinoy, H (October 2013). "Statin-induced necrotizing myositis - a discrete autoimmune entity within the "statin-induced myopathy spectrum"". Autoimmunity Reviews (Review). 12 (12): 1177–71. doi:10.1016/j.autrev.2013.07.001. PMC   4589155 . PMID   23851103.
  8. 1 2 3 4 5 Selva-O'Callaghan, A; Alvarado-Cardenas, M; Pinal-Fernández, I; Trallero-Araguás, E; Milisenda, JC; Martínez, MA; Marín, A; Labrador-Horrillo, M; Juárez, C; Grau-Junyent, JM (March 2018). "Statin-induced myalgia and myositis: an update on pathogenesis and clinical recommendations". Expert Review of Clinical Immunology (Review). 14 (3): 215–24. doi:10.1080/1744666X.2018.1440206. PMC   6019601 . PMID   29473763.
  9. ↑ Tiniakou, E; Pinal-Fernandez, I; Lloyd, TE (January 2017). "More severe disease and slower recovery in younger patients with anti-3-hydroxy-3-methylglu- taryl-coenzyme A reductase-associated autoimmune myopathy". Rheumatology. 56 (5): 787–794. doi: 10.1093/rheumatology/kew470 . PMC   5850825 . PMID   28096458.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.