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Original Articles

Statin-Associated Autoimmune Myopathy

A Systematic Review of 100 Cases

Nazir, Salik MD*; Lohani, Saroj MD*; Tachamo, Niranjan MD*; Poudel, Dilliram MD*; Donato, Anthony MD, MHPE

Author Information
JCR: Journal of Clinical Rheumatology: April 2017 - Volume 23 - Issue 3 - p 149-154
doi: 10.1097/RHU.0000000000000497

Abstract

Statins are a group of drugs that reduce the levels of triglycerides and cholesterol in blood by inhibiting HMG-CoA reductase, an enzyme involved in rate limiting step in cholesterol synthesis. Nearly one-quarter (23.2%) of US adults over 40 years reported use of statin in 2012.1 Statins are known to decrease cardiovascular disease mortality.2 While generally well tolerated, 2–20% of patients develop significant muscle symptoms or laboratory evidence of muscle injury while on therapy, believed to be a toxic myopathy, which resolves soon after discontinuation of statin.3 More recently, case reports and case series have described an immune mediated necrotizing myopathy associated with statin use.4 This disorder is characterized by progressive symmetric muscle weakness despite discontinuation of statin, evidence of necrosis on muscle biopsy and autoantibodies to HMG-CoA reductase. We aim to synthesize the current literature to better understand the clinical features and response to treatment of this potentially morbid medication side effect.

MATERIALS AND METHODS

Search Strategy

We searched major databases PubMed, EMBASE, ClinicalTrials.gov and the Cochrane library for case reports, case series and systematic reviews on statin-associated autoimmune myopathy from inception until March 19, 2016. The search was performed for English-language articles using three broad search themes: autoimmune, statin and myositis (Supplementary File 1, http://links.lww.com/RHU/A61). These themes were combined using boolean operator “AND”. We also performed a hand search of references from included articles to identify additional publications.

Eligibility Criteria

  1. Reports in English language delineating patient exposure to statins.
  2. Positive anti HMG-CoA reductase antibody and/or necrotizing myopathy on biopsy.

Data Collection and Analysis

Two authors (SN and NT) screened articles for eligibility. Discrepancies among screeners were resolved by third author (DRP). Screening, inclusion and elimination of articles was performed as per PRISMA guidelines (Supplementary File 2, http://links.lww.com/RHU/A62). Authors SN, SL and NT extracted data from the included articles. Data extracted included demographic variables, clinical presentation, investigations, treatment and outcomes (Table 1). The data analysis was performed by DRP. Statistical analysis was carried out using Microsoft Excel 2010 (Microsoft Corporation, Redmond, VA) and Stata 13.1 (Stata Corporation, College Station, TX).

TABLE 1
TABLE 1:
Demographic Features, Clinical Features, Laboratory Parameters, Management and Outcomes of Statin Induced Autoimmune Myopathy Cases

RESULTS

A total of 16 articles were included in the final analysis, which reviewed 100 cases with statin-associated autoimmune myopathy (Table 1). There was no statistical difference between incidence in males (54.44%) and females (45.56%). The mean age of patients was 64.72 years. The mean duration of statin use prior to myopathy symptom onset was 40.48 months. All of the studied patients described proximal weakness on presentation. Most (83.33%) reported the weakness to be symmetrical. Symptoms were bilateral in 92.85% of cases. One patient presented with bulbar weakness.7 Mean creatine kinase (CK) upon initial presentation was 6853 IU/l. Anti-HMG-CoA reductase antibody was positive in all cases where it was checked (n = 57/57, 100%). In patients with no anti-HMG-CoA antibody results, diagnosis was established by findings of necrotizing myopathy on biopsy. Among the 83 cases where muscle biopsy information was available, 81.48% had necrosis, while 18.51% had combination of necrosis and inflammation. Inflammatory infiltrates composed of macrophages in majority of cases (55.55%) with small number of cases reporting lymphocytic infiltrates (33.33%). In 11.12% cases, patients had both macrophagic and lymphocytic infiltrates. There was resolution of myopathic symptoms with discontinuation of statins and no other therapy was used in two cases.5,11 Steroids were used alone to induce remission in 6 out of 68 cases only (8.82%). Two cases out of 68 required only azathioprine.11 Intravenous immunoglobulin (IVIG) was used as a single agent in three cases.20 Fifty-seven cases out of 68 (83.82%) required two or more immunosuppressants. Plasmapheresis was used in addition to immunosuppressants in two cases.8 Ninety-one percent (61/67) of patients had resolution of symptoms after treatment. Clinical status was unchanged in two patients. Two patients were lost to follow-up and had no reported outcomes. In two patients, the muscle strength (according to Medical Research Council scale for muscle strength) decreased from 5 to 4+ and 4 to 4− on follow up.12

DISCUSSION

Statin-associated autoimmune myopathy is a very rare side effect of use of HMG-CoA reductase inhibitor. The incidence of statin-associated autoimmune myopathy has been estimated to be 2 cases per million per year.10 This is in contrast to toxic myopathy associated with statins, which is more common and occurs in 2–20% of patients treated with statins.3 The pathogenesis of statin-associated autoimmune myopathy has not yet been clearly elucidated. The current proposed mechanism involves damage to muscle cells by autoantibodies directed against HMG-CoA reductase, an enzyme present in muscle cells to which statins are directed.4 HMG-CoA reductase is increased in muscle cells exposed to statins.21 The antibody associated with immune mediated necrotizing myopathy frequently associated with prior statin use was first described by Christopher-Stine et al. and was named as anti-200/100 antibody.22 Anti-200/100 antibody was later recognized to be anti-HMG-CoA reductase antibodies by Mammen et al.10 It has also been proposed that statin-associated autoimmune myopathy occurs in genetically susceptible patients. This is supported by increased frequency of DRB1*11:01 in patients with positive anti HMG-CoA reductase antibody.23

Demographic Variables

Our review identified older patients (average 64.72 years) without a sex predominance. This finding was similar to other reviews published on statin-associated autoimmune myopathy.4,24 Most patients had taken statin therapy for years (average: 40 months) before they developed any symptoms suggestive of autoimmune myopathy, in contrast to patients with typical toxic myopathies who develop their symptoms soon after medicine initiation.25

Clinical Presentation

The most common clinical presentation in our review was bilateral proximal symmetric weakness. Apart from two cases,5,11 symptoms persisted despite discontinuation of statins and additional immunosuppressive treatment was administered. One patient had dysphagia on presentation.7

Laboratory Investigations

In our review, the mean CK was about 45 times the upper limit of normal (150 IU/l). This is in contrast with most cases of toxic myopathy associated with statins, CK levels are mildly elevated (i.e. about three times the upper limit of normal).26 Only in rare cases of self-limited toxic myopathy is the CK severely elevated (more than 10 times upper limit of normal).26 Our review revealed necrosis reported in muscle biopsy specimen of 100% patients, with inflammation reported in 19% of biopsy specimens. The muscle biopsy findings support the hypothesis that muscle damage in statin-associated autoimmune myopathy is antibody-mediated.4

Treatment and Prognosis

The mainstay of treatment was immunosuppressants, including corticosteroids, along with cessation of statins. The majority (83.82%) required two or more immunosuppressants. Ninety percent responded to treatment with improvement in muscle strength and decline in CK levels. In two patients, the muscle strength was reported to be decreased from 5 to 4+ and 4 to 4− despite decline in CK levels. Five patients underwent rechallenge with statin.5,8,12 Two patients underwent rechallenge with same statin,5,12 two underwent rechallenge with different statin5,12 while in one patient the details were not available.8 In all cases, the rechallenge was unsuccessful with worsening of symptoms. In contrast, 70–90% patients with statin-induced toxic myopathy are able to tolerate rechallenge with statins.26

Study Limitations

The quality of the synthesis of the data for this study was dependent on each study uniformly reporting study parameters and outcomes, and was therefore limited by missing and incomplete data. Doses and types of statins were unreported in most cases. The description of biopsy was based on the written pathology reports and could not be independently verified. Our review was limited to English-language articles, so there may be a substantial population whose literature we have not included. Possible patients with positive anti-HMG-CoA reductase antibodies and muscle biopsy with fiber necrotizing, but not previous exposure to statins, and vice versa (patients with exposure to statins and clinical features of myopathy but with negative antibodies and biopsy) could not be included in the analysis. Many of the patients were not tested for anti-HMG-CoA reductase antibodies but were included in the study because of evidence of necrosis and the association with statin use. Since this is a fairly newly recognized antibody, we assumed that testing would not be widely available and hence included these cases in our study. Statin-associated autoimmune myopathy is a relatively newly identified disorder, with first case reports published in the last 5 years, and autoantibodies were only recently identified10,22 despite almost three decades of use, leading us to believe the disorder may be underdiagnosed.27

CONCLUSION

Statins are a group of drugs that reduce the levels of triglycerides and cholesterol in blood by inhibiting HMG-CoA reductase, an enzyme involved in rate limiting step in cholesterol synthesis. Statin-associated necrotizing myopathy is a symmetric proximal weakness associated with extreme elevations of CK and usually requires discontinuation and immune suppression for resolution. Patients should not be rechallenged with statins until this strategy is proven safe. As this is a newly identified disorder, next steps may be the creation of a registry of patients for data synthesis and potential future treatment trials.

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      Keywords:

      statin; anti-HMGCR antibody; idiopathic inflammatory myopathy; necrotizing; autoimmune myopathy

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