View source for Medicine:Statin-associated autoimmune myopathy

{{Infobox medical condition (new)
| name            = Statin-associated Autoimmune Myopathy 
| synonyms        = Anti-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   
| image           = 
| caption         = 
| alt             = 
| field           = [[Medicine:Rheumatology|Rheumatology]]
| symptoms        = Muscle weakness 
| onset           = 
| duration        =
| causes          =
| risks           = 
| diagnosis       =
| differential    = 
| prevention      =
| treatment       = [[Biology:Corticosteroid|Corticosteroid]]s, immunosuppressive medications, withdrawal of the implicated [[Biology:Statin|statin]]
| medication      = 
| prognosis       =
| frequency       = Rare
| deaths          =
}}
<!-- Definition and symptoms -->
'''Statin-associated autoimmune myopathy (SAAM)''', also known as anti-HMGCR myopathy, is a very rare form of muscle damage caused by the [[Biology:Immune system|immune system]] in people who take [[Biology:Statin|statin]] medications.<ref name="Thompson2016">{{cite journal |last1=Thompson |first1=PD |last2=Panza |first2=G |last3=Zaleski |first3=A |last4=Taylor |first4=B |title=Statin-Associated Side Effects |journal=Journal of the American College of Cardiology |date=May 2016 |volume=67 |issue=20 |pages=2395–2410 |doi=10.1016/j.jacc.2016.02.071 |pmid=27199064 |type=Review|doi-access=free }}</ref> 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 [[Chemistry:Red yeast rice|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.<ref name="Ge2015">{{cite journal |last1=Ge |first1=Y |last2=Peng |first2=Q |title= Clinical characteristics of anti-3-hydroxy-3-methylglutaryl coenzyme a reductase antibodies in Chinese patients with idiopathic inflammatory myopathies |journal = PLOS ONE |date= October 2015 |volume= 10 |issue= 10 |pages=e0141616 |doi= 10.1371/journal.pone.0141616 |pmid=26509687 |pmc=4624805 |bibcode=2015PLoSO..1041616G |doi-access= free }}</ref>

The exact cause is unclear. A combination of consistent findings on physical examination, the presence of anti [[Biology:HMG-CoA reductase|HMG-CoA reductase]] [[Biology:Antibodies|antibodies]] in a person with myopathy, evidence of muscle breakdown, and [[Biology:Muscle biopsy|muscle biopsy]] diagnose SAAM.<ref name="Mammen2016"/>

Treatment involves stopping the associated statin medication and taking medication to [[Biology:Immunosuppression|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.<ref name="Mammen2016">{{cite journal |last1=Mammen |first1=AL |title=Statin-Associated Autoimmune Myopathy |journal=New England Journal of Medicine |date=February 2016 |volume=374 |issue=7 |pages=664–9 |doi=10.1056/NEJMra1515161 |pmid=26886523|type=Review}}</ref>

==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 [[Biology:Enzyme|enzyme]] [[Biology:Creatine kinase|creatine kinase]] (CK) being released by broken down  [[Biology:Skeletal muscle|skeletal muscle]], and persistent symptoms and CK elevation despite stopping the offending [[Biology:Statin|statin]] medication are the hallmarks of SAAM.<ref name="Thompson2016"/><ref name="Mammen2016"/>  Other forms of statin associated muscle damage (myopathy) usually resolve after stopping the involved statin.<ref name="Thompson2016"/> Mild [[Medicine:Arthralgia|joint pain]] and rash may be present.<ref name="Mammen2016"/> In people affected by SAAM, the median duration of statin therapy was 38 months before the onset of muscular symptoms.<ref name="Christopher2017"/> SAAM may affect people after long-term statin use even if they had no previous muscular side effects.<ref name="Christopher2017">{{cite journal |last1=Christopher-Stine |first1=L |last2=Basharat |first2=P |title=Statin-associated immune-mediated myopathy: biology and clinical implications. |journal=Current Opinion in Lipidology |date=April 2017 |volume=28 |issue=2 |pages=186–92 |doi=10.1097/MOL.0000000000000399 |pmid=28207435|s2cid=19330288 |type=Review}}</ref>

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.<ref>{{Cite journal|last=Irvine|first=Nathaniel J.|date=2020-09-01|title=Anti-HMGCR Myopathy: A Rare and Serious Side Effect of Statins|url=https://www.jabfm.org/content/33/5/785|journal=The Journal of the American Board of Family Medicine|language=en|volume=33|issue=5|pages=785–788|doi=10.3122/jabfm.2020.05.190450|issn=1557-2625|pmid=32989074|doi-access=free}}</ref>

==Pathogenesis==
It is unclear precisely how statins lead to statin-associated autoimmune myopathy.<ref name="Thompson2016"/> The disorder is positively associated with [[Biology:HLA-DR11|HLA-DR11]] and the DRB1*11:01 [[Biology:Allele|allele]].<ref name="Thompson2016"/> 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.<ref name="Mammen2016"/> Statins inhibit [[Biology:HMG-CoA reductase|HMG-CoA reductase]] activity and consequently lower [[Chemistry:Cholesterol|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.<ref name="Thompson2016"/> 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 [[Biology:Antigen|antigen]]s that the immune system is not tolerant to resulting in the production of antibodies against it.<ref name="Mammen2016"/>

==Diagnosis==
[[File:Algorithm for statin-associated myopathy.jpg|thumb|Diagnostic algorithm for statin-associated myopathy.<ref>{{cite journal| author=Selva-O'Callaghan A, Alvarado-Cardenas M, Pinal-Fernández I, Trallero-Araguás E, Milisenda JC, Martínez MÁ | display-authors=0| title=Statin-induced myalgia and myositis: an update on pathogenesis and clinical recommendations. | journal=Expert Rev Clin Immunol | year= 2018 | volume= 14 | issue= 3 | pages= 215–224 | pmid=29473763 | doi=10.1080/1744666X.2018.1440206 | pmc=6019601 }}</ref>]]
The development of necrotizing myopathy after statin exposure is insufficient to make the diagnosis. Testing must first exclude other causes of [[Medicine:Myositis|myositis]] and necrotizing myopathy.<ref name="Hamann2013"/> A [[Biology:Muscle biopsy|muscle biopsy]] consistent with SAAM will demonstrate [[Biology:Necrosis|muscle cell death]] with muscle fiber regeneration and typically has few inflammatory cells.<ref name="Hamann2013">{{cite journal |last1=Hamann |first1=PD |last2=Cooper |first2=RG |last3=McHugh |first3=NJ |last4=Chinoy |first4=H |title=Statin-induced necrotizing myositis - a discrete autoimmune entity within the "statin-induced myopathy spectrum". |journal=Autoimmunity Reviews |date=October 2013 |volume=12 |issue=12 |pages=1177–71 |doi=10.1016/j.autrev.2013.07.001 |pmid=23851103 |pmc=4589155 |type=Review}}</ref><ref name="Selva2018"/> 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 [[Biology:MHC class I|MHC class I]] expression.<ref name="Selva2018"/>

[[Biology:Antibodies|Antibodies]] against HMG-CoA reductase occur in 94% of affected individuals.<ref name="Thompson2016"/> These antibodies are known to also occur in people who do not take statin medications.<ref name="Mammen2016"/> 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.<ref name="Mammen2016"/> CK levels increase to 10-100 times above normal (2000–20,000 IU/L) in more than 90% of cases.<ref name="Mammen2016"/><ref name="Selva2018">{{cite journal |last1=Selva-O'Callaghan |first1=A |last2=Alvarado-Cardenas |first2=M |last3=Pinal-Fernández |first3=I |last4=Trallero-Araguás |first4=E |last5=Milisenda |first5=JC |last6=Martínez |first6=MA |last7=Marín |first7=A |last8=Labrador-Horrillo |first8=M |last9=Juárez |first9=C |last10=Grau-Junyent |first10=JM |title=Statin-induced myalgia and myositis: an update on pathogenesis and clinical recommendations. |journal=Expert Review of Clinical Immunology |date=March 2018 |volume=14 |issue=3 |pages=215–24 |doi=10.1080/1744666X.2018.1440206 |pmid=29473763|pmc=6019601|type=Review}}</ref> [[Biology:Electromyography|Electromyography]] (EMG) typically demonstrates a myopathic pattern of findings.<ref name="Selva2018"/> Muscle [[Medicine:Edema|swelling]] may be seen on [[Physics:Magnetic resonance imaging|MRI imaging]].<ref name="Mammen2016"/>

==Treatment==
SAAM is treated by stopping the offending statin medication and taking [[Biology:Immunosuppression|immunosuppressive medication]]s.<ref name="Hamann2013"/> In rare cases, affected people spontaneously improve after just stopping the implicated statin.<ref name="Mammen2016"/> However, most cases mandate the use of immunosuppressive medication.<ref name="Selva2018"/>

[[Biology:Corticosteroid|Corticosteroid]]s are considered first-line treatment. [[Chemistry:Prednisone|Prednisone]] dosed at 1 milligram/kilogram of body weight daily is generally recommended.<ref name="Mammen2016"/> Corticosteroid therapy alone may be reasonable in cases of mild muscular weakness. More severe cases require the use of combined [[Chemistry:Methotrexate|methotrexate]], [[Chemistry:Azathioprine|azathioprine]], or mycophenolate with corticosteroids.<ref name="Mammen2016"/> Severe cases of SAAM may fail to respond to 8–12 weeks of combination therapy. [[Chemistry:Rituximab|Rituximab]] or intravenous immunoglobulin are recommended as add-on therapy in such cases.<ref name="Mammen2016"/> Intravenous immunoglobulin is an appropriate first-line therapy in select individuals. Suitable candidates for first-line intravenous immunoglobulin include people who have [[Medicine:Diabetes mellitus|diabetes mellitus]] or who wish to avoid corticosteroid therapy.<ref name="Mammen2016"/>

==Prognosis==
Proper treatment of SAAM often results in full recovery.<ref name="Mammen2016"/> Recovery can occur even with persistently elevated [[Biology:Creatine kinase|creatine kinase]] (CK) levels.<ref name="Mammen2016"/> Conversely, some people with SAAM do not regain full muscle strength despite the normalization of their CK levels.<ref name="Mammen2016"/> 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.<ref name="Tiniakou2017">{{ cite journal |last1=Tiniakou |first1=E |last2= Pinal-Fernandez |first2=I |last3=Lloyd |first3=TE |title= More severe disease and slower recovery in younger patients with anti-3-hydroxy-3-methylglu- taryl-coenzyme A reductase-associated autoimmune myopathy. |journal= Rheumatology |date=January 2017 |volume=56 |issue=5 |pages=787–794 |doi=10.1093/rheumatology/kew470 |pmid=28096458|pmc=5850825 |doi-access=free }}</ref> Once strength recovers, immunosuppressive medications should be tapered.<ref name="Mammen2016"/> Relapse remains possible during tapering efforts, and some people require long-term immunosuppression.<ref name="Mammen2016"/> 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.<ref name="Mammen2016"/>

==References==
{{reflist}}

[[Category:Rheumatology]]
[[Category:Statins]]

{{Sourceattribution|Statin-associated autoimmune myopathy}}