Indian Journal of Rheumatology

REVIEW ARTICLE
Year
: 2020  |  Volume : 15  |  Issue : 6  |  Page : 137--144

Statin-associated muscle disorders


Alan Xu1, Vidya Limaye2,  
1 Department of Medicine, University of Adelaide, Adelaide, SA, Australia
2 Department of Rheumatology, Royal Adelaide Hospital; Discipline of Medicine, University of Adelaide, Adelaide, SA, Australia

Correspondence Address:
Asst. Prof Vidya Limaye
Department Rheumatology, Royal Adelaide Hospital, Port Road, 5000, Adelaide, SA; University of Adelaide, North Tce, 5000, Adelaide, SA
Australia

Abstract

Statins are one of the most widely used and reputable medications worldwide, with strong evidence of mitigating cardiovascular complications and with a generally favorable safety profile. Nevertheless, statins have commonly come under scrutiny, owing to their associations with muscle disorders. Statins are known to cause a range of effects on muscles, varying from mild self-limiting symptoms to detrimental muscular necrosis. In particular, there has been emerging evidence of statin-associated necrotizing autoimmune myositis related to the presence of anti-3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) autoantibodies. Patients often demonstrate proximal muscle weakness and hyperCKemia, and treatment guidelines are not robust owing to the rarity of the disease. Nevertheless, literature provides evidence for use of corticosteroids, and there are emerging data supporting the incorporation of immunomodulatory agents such as methotrexate, intravenous immunoglobulin, and rituximab. In performing this review, we searched databases in PubMed and EMBASE written in English and limited to the last two decades. Keywords used included “statin,” “myositis,” “autoimmune myopathy,” “anti-HMGCR,” and “necrotising.” Articles were selected by relevance to the topic, and articles pertaining to antisignal recognition particle myopathy and other forms of myositis were excluded.



How to cite this article:
Xu A, Limaye V. Statin-associated muscle disorders.Indian J Rheumatol 2020;15:137-144


How to cite this URL:
Xu A, Limaye V. Statin-associated muscle disorders. Indian J Rheumatol [serial online] 2020 [cited 2021 Apr 18 ];15:137-144
Available from: https://www.indianjrheumatol.com/text.asp?2020/15/6/137/307135


Full Text



 Introduction



Statins have come to be recognized as one of the leading pharmaceuticals in modern medicine, with significant benefits demonstrated in the control of numerous chronic conditions. The advantages largely center around controlling the risk of cardiovascular disease, with a vast array of trials having demonstrated a reduction in the incidence of myocardial infections, strokes, and death.[1] A meta-analysis published by the Lancet in 2005 reported a 21% reduction in vascular events over a period of 5 years, and another meta-analysis in 2010 also showed that higher doses of statins produced a further 15% reduction in the incidence of vascular events.[2],[3]

Given the well-documented benefits, statins are commonly prescribed. An Australian study published in 2012 reported that 40% of patients over 65 years of age were being prescribed statins.[4] The statins currently available for clinical use in Australia, as approved by the Therapeutic Goods Administration of Australia, are atorvastatin, fluvastatin, pravastatin, rosuvastatin, and simvastatin. The primary mode of action of statins is inhibition of the enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR).[5] HMGCR catalyzes the production of mevalonate, an intermediary in the cholesterol synthesis pathway. The inhibition of cholesterol synthesis also results in increased hepatic low-density lipoprotein (LDL) receptor expression and reduction in serum LDL cholesterol.

There are two broad classes of statins: Class I are the statins which are derived naturally and include simvastatin and mevastatin and Class II are synthetically produced statins and include atorvastatin and rosuvastatin.

Statins are considered to be generally safe, with evidence suggesting little difference in the incidence of adverse events in patient groups taking statins compared to placebo groups.[6] In fact, a systematic review of 35 randomized control trials published in 2006 only identified a minor risk of transaminase elevation associated with statin therapy as statistically significant.[6] Despite this, widespread use of statins continues to remain contentious, with the predominant concerns related to adverse effects on skeletal muscle. Indeed, there are growing reports, suggesting that the impact and incidence of statin-associated muscle diseases are not negligible.[7]

Herein, we provide an up-to-date literature review of statin-related adverse effects on muscle, ranging from myalgia, to myonecrosis and rhabdomyolysis and also explore the newly recognized entity of statin-induced immune-mediated necrotizing myopathy (IMNM).

In performing this review, we searched databases in PubMed and EMBASE written in English and limited to the last two decades. Keywords used for the search included “statin,” “myositis,” “autoimmune myopathy,” “anti-HMGCR,” and “necrotising.” Articles were selected by relevance to the topic, and articles pertaining to antisignal recognition particle myopathy and other forms of myositis were excluded.

 Etiopathogenesis



The pathogenic mechanisms of underlying statin-induced muscle symptoms have not been fully elucidated to date and a number of factors have been implicated. Considerable evidence suggests that deficiency of certain intermediaries in the cholesterol synthesis pathway leads to mitochondrial dysfunction, and this is implicated as a key mechanism in skeletal muscle injury [Figure 1]. Inhibition of HMGCR by statins inhibits other intermediaries in the cholesterol synthesis pathway, in particular, ubiquinone, also known as coenzyme Q10 (CoQ10). Ubiquinone is a critical component of the mitochondrial respiratory chain, necessary for generating energy within myofibers, and depletion of this leads to inhibition of mitochondrial respiratory chain complexes and oxidative damage with resultant skeletal muscle injury.[8] Rundek et al. demonstrated a 50% reduction in CoQ10 levels within 30 days of atorvastatin therapy at a dose of 80 mg daily, and another study concluded similar results with high-dose simvastatin.[9],[10],[11]{Figure 1}

The inhibition of mevalonate and isoprenoids including farnesyl pyrophosphate and geranylgeranyl pyrophosphate has also been implicated. The reduction of these isoprenoids are hypothesized to inactivate the action of GTPases, increasing cytosolic calcium and subsequently altering cellular function, increasing apoptosis, and ultimately leading to myotoxicity.[12]

Evidence also suggests that Vitamin D deficiency may predispose to statin-induced muscle injury. A meta-analysis of seven studies conducted in 2015, with 2420 patients treated with statins, established a correlation between lower Vitamin D levels and higher incidence of statin-induced symptoms.[13] Suggested mechanisms include reduced activation of Vitamin D receptors and the preferential metabolism of Vitamin D by CYP3A4 resulting in reduced statin metabolism and increased serum levels of statins. Clarifying a role for Vitamin D in this regard is critical, as correction of deficiency may be a simple therapeutic strategy in preventing or treating statin-induced muscle damage.

 Statin Properties



Not all statins appear to have the same risk for developing muscle symptomatology and select statins, such as simvastatin and atorvastatin especially at higher doses have been associated with a higher incidence of symptoms.[14],[15],[16] Part of the risk has been attributed to whether the statin is more or less hydrophilic; rosuvastatin is chemically more hydrophilic and is thought to have a lower risk of penetrating muscle cells.

In addition to the relative hydrophilic properties of the individual statin, the mode of metabolism is also known to confer risk. Many statins, such as simvastatin and lovastatin (and atorvastatin to a lesser extent), are metabolized by the CYP450 3A4 cytochrome pathway. The use of concomitant medications which are metabolized by the same pathway may inhibit the metabolism of statins, thus increasing the serum statin concentration and increasing the likelihood for toxicity.[17] Such medications include cyclosporine, fibrates, macrolide antibiotics, fungal medications, antivirals, and calcium channel blockers. Grapefruit juice also contains compounds that may cause similar inhibitory effects. Rosuvastatin, fluvastatin, and pravastatin are notable exceptions and are metabolized via alternative pathways. This, however, does not preclude them from statin-induced muscle symptoms. Fluvastatin is metabolized via the CYP450 2C9 pathway and must be used with caution in conjunction with medications such as warfarin.

 Genetic Risk Factors



There has been an interest in identifying the risk factors associated with an increased incidence of statin-associated myalgia and myopathy. Patient characteristics, including female sex, older age, certain ethnic groups, and presence of certain neuromuscular comorbidities, have all been postulated to increase risk.[18],[19],[20] Genetic studies have, in recent years, advanced the understanding of genetic risk factors for risk.

SLCO1B1 is a gene which encodes OATP1B1 – an organic anion transporter that promotes hepatic cell uptake of drugs, including statins. Carriers of certain alleles of the gene, including the rs4149056 gene variant, have been linked with increased incidence of muscle symptoms. These links have been shown to be strong with simvastatin, especially in high doses, but have not been confirmed with other statins including rosuvastatin and atorvastatin.[21],[22],[23],[24] At this point in time, there are no clear guidelines regarding the clinical utility of identifying polymorphisms in this gene, though it could be proposed that a nonsimvastatin statin could be preferred in patients with the particular gene variant.

Preexisting genetic metabolic disease may be linked with a higher incidence of statin-associated muscle disorders. A cross-sectional study in 2006 showed higher rates of underlying metabolic disorders in patients with drug-induced myopathies compared with a control group. Out of 136 patients in the study group, 110 were tested for a number of genetic mutations, and 10% were identified to have an underlying metabolic disease, including McArdle's disease and carnitine palmitoyltransferase II deficiency.[25] This suggests that patients with statin-associated muscle disorders have a higher incidence of genetic metabolic disease and raises the possibility that statins may unmask an underlying undiagnosed metabolic disease.

 Myalgia, Myopathy, and Myonecrosis



Classification of statin-associated muscle symptomatology and pathology is varied, with inconsistency between definitions in the literature. The National Lipid Association of America provided clear definitions of the spectrum of phenomena, which include myalgia, myopathy, myonecrosis, rhabdomyolysis, and myositis [Figure 2].[18],[26]{Figure 2}

Approximately 10%–20% of patients taking statins report myalgia, often described as muscle discomfort and ache, and likened to influenza-like symptoms.[1],[14],[27] There is usually a temporal association with the onset of these symptoms after statin use – they are often first reported approximately 1 month after treatment initiation, but can present at any time within the first few months.[14],[24],[28]

The recognition of statin-associated myalgia can be difficult due to multiple reasons. The nonspecific and subjective nature of these symptoms renders systematic recording difficult. Recognition may be confounded by the presence of preexisting medical conditions (including neuromuscular disease) and concurrent consumption of other medications that may cause similar symptoms, thus making it tricky to establish statins as the true culprit.[26] Furthermore, there is large variability in defining statin-associated myalgias and also a lack of definitive clinical markers for diagnosis.

Some patients with myalgia also experience muscle weakness, otherwise known as myopathy, with statin use. Reported muscle weakness may be subjective, as a study published in 2012 did not show any significant change in muscle strength measurements.[24] Some patients with myopathy may also have elevations in serum creatine kinase (CK) levels, implicating enhanced leakage of this enzyme from muscle into serum and reflecting muscle breakdown, or myonecrosis. The incidence of this is reported to be very low (<0.1%).[29]

For the vast majority of patients, the myalgia, myopathy, and myonecrosis are reversible with statin cessation. The mean time to resolution of symptoms after statin cessation was found to be approximately 2 months in a group of 45 patients, published in 2005.[28] A 2013 study that followed 69 patients up to 18 months after withdrawal of statin demonstrated complete resolution of symptoms in 72.5% of patients and an improvement in 13% of patients. In the same study, 75% of the patients showed an elevated CK level at the start of the study, and 20% of these patients returned to a normal CK level after 18 months.[30]

 Rhabdomyolysis



Rhabdomyolysis is a syndrome of more florid myonecrosis often above ten times the upper limit of normal and clinically manifests as rapid onset of weakness together with severe hyperCKemia, myoglobinuria, and acute renal failure. Severe cases can also lead to death.

Rhabdomyolysis is rare – a meta-analysis of 24 studies reported 15 cases out of 49,691 patients treated with statins over 1990–2012, equating to < 0.03% of patients.[31] The risk of developing rhabdomyolysis significantly increases with concurrent drugs that are metabolized by the cytochrome P450 pathway. The simultaneous use of cerivastatin and gemfibrozil has historically caused high rates of fatal rhabdomyolysis, leading to its withdrawal from the market approximately two decades ago.[32]

Patients with rhabdomyolysis require inpatient treatment in hospital with supportive therapy. This includes intravenous fluids, urine alkalinization, and statin cessation.[12],[33]

 Statin-associated Inflammatory Myopathy



Numerous case reports to date have featured cases of statin-induced inflammatory myopathies including polymyositis and dermatomyositis. An Australian study conducted in 2018 studied a group of 221 patients with histologically confirmed inflammatory myopathy and showed that patients with inflammatory myopathy had an increased likelihood of prior statin exposure (with an odds ratio of 1.6).[34] Importantly, this statistical association remained significant even when the group of patients with necrotizing myopathy were excluded from the analysis, suggesting that all subtypes of inflammatory myopathies are potentially associated with statin exposure.

 Statin-induced Immune-mediated Necrotizing Myopathy



In a small proportion of patients exposed to statins, progressive muscle weakness and hyperCKemia continues despite statin cessation, suggesting that immunological mechanisms are involved in sustaining the ongoing process.

Indeed, there have been emerging links between statin use and necrotizing autoimmune myopathy (NAM), which is part of a wider group of diseases known as IMNM.[35] IMNM encompasses a broad range of conditions which histologically feature dominant muscle necrosis with little or no inflammation, and may be due to a variety of causes, including but not limited to statin use, malignancy, and other autoantibodies.[36] Features that may be present on a biopsy include but are not limited to myofiber necrosis, the presence of CD4+, CD8+, and plasmacytoid dendritic cells, the upregulation of major histocompatibility complex Class I antigen, and the deposition of membrane attack complex.[37]

Much of the literature spanning the last decade has established clear links between the presence of autoantibodies and IMNM, the first of which was reported in 2010.[38] In the same study, 63% of patients who had displayed autoantibodies were also found to have been taking a statin prior to disease onset. These autoantibodies were further characterized and found to target 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) – the pharmacological target of statins.[39] Since the publication of this research, a number of international studies have reinforced the relationship between the use of statins, the expression of autoantibodies against HMGCR, and the development of IMNM, with a study in 2019 demonstrating that 78% of patients with seropositivity of these autoantibodies also having had previous statin exposure.[40],[41],[42],[43] A body of evidence has demonstrated the presence of these autoantibodies in a number of patients presenting with IMNM. Although conclusively associated with statin-induced IMNM, our own South Australian study has in fact detected anti-HMGCR in all subtypes of inflammatory myopathies.[41] In this study, anti-HMGCR autoantibodies were detected in 19 out of 207 patients with IIM, with no difference in their prevalence between the subsets of disease. This suggests that anti-HMGCR may be associated with inflammatory muscle disease per se, and the association may extend beyond IMNM.

There have been interesting genetic links established for patients with anti-HMGCR IMNM. Most notably, a study published in 2012 demonstrated a significantly increased prevalence of a combination of antigens, namely, HLA-DR11, DQA5, and DQB7 in Caucasian patients with anti-HMGCR compared with control groups.[44] In our own Australian study, we confirmed that anti-HMGCR autoantibodies were strongly associated with HLA-DR11, with an extremely high odds ratio of 50 and P < 0.0001.[41] The role of genetic typing prior to statin prescription remains undefined at present, but as personalized medicine becomes more developed, this could certainly be a foreseeable avenue of practice.

The workup of a patient who presents with persistent muscle weakness and hyperCKemia despite statin cessation should include a muscle biopsy and serological testing for anti-HMGCR autoantibodies, which are considered disease specific.[45] Indeed, the prevalence of anti-HMGCR is negligible in the general population and similarly in patients with self-limiting statin-related adverse effects. In addition to their disease specificity, anti-HMGCR titers also correlate with disease activity and serial monitoring of titers can be useful to gauge response to treatment.[46]

In our own case series of patients with statin-induced NAM, anti-HMGCR titers became undetectable following treatment in four of seven patients, which paralleled the clinical response of disease improvement.[47] Conversely, two of the three patients with persistent anti-HMGCR had disease relapse. Temporal seronegativity of anti-HMGCR autoantibodies may signify clinical remission.

 Management



Management of statin-induced myalgia

The management of statin-associated myalgia, myopathy, or myonecrosis primarily involves statin cessation and monitoring for improvement of symptoms. In the vast majority of these patients, withdrawing, reducing the dose, or substituting the offending statin will lead to symptom resolution. Statins may be rechallenged at a later date if the indications for therapy remain strong.[27],[48] A large retrospective cohort study in 2013 showed favorable results of rechallenge, with over 90% of patients who had ceased statin therapy successfully tolerating a statin 12 months later.[49] Concomitant medications should be rationalized, to avoid the risk of drug interactions with agents that are metabolized via the same pathways.

There have been a number of trials investigating the role of CoQ10 supplementation in treating statin-induced muscular symptoms. A double-blind trial of 38 patients with statin-induced myalgia suggested a benefit in 40% of patients receiving CoQ10 at 100 mg per day by 1 month.[50] A meta-analysis of 12 randomized controlled trials was consistent with this.[51] However, there is conflicting evidence for its benefit and larger-scale trials are needed.[52] Vitamin D supplementation for those with deficiency has also been recommended by some; however, larger trials and further study in this area are needed.

Management of statin-induced immune-mediated necrotizing myopathy

The evidence surrounding treatment for IMNM, and other forms of myositis, remains limited, with a paucity of large-scale randomized clinical trials.[53] This largely reflects the rarity of these conditions and, in turn, supports the pressing need for large-scale multinational collaborative efforts. As such, the recommendations for treatment to date have been based on small-scale, often nonrandomized trials and also clinician expertise. Although clear criteria for clinical remission do not currently exist, reduced CK levels and return of muscle strength are the primary outcomes for most clinicians. The 224th European Neuromuscular Workshop published a report in 2018 outlining some general strategies for managing this disease.[54]

Induction therapy largely centers around immunosuppression, and the first-line treatment generally involves the use of corticosteroids – whether it be oral prednisolone at a dose of 1 mg/kg/day, or pulsed intravenous methylprednisolone at a dose of 0.5–1 g/day for those with more severe symptoms or systemic disease.[55] Oral prednisolone is often prescribed at high doses for several weeks, with close monitoring of response to treatment and the development of adverse effects.[56]

Corticosteroids are often paired with a second-line immunomodulatory agent, such as methotrexate or azathioprine, if there has been an inadequate response or a relapse of symptoms. In some cases, second line agents are started from the outset with corticosteroids, or alone in lieu of corticosteroids if there are contraindications to use of corticosteroids, such as severe osteoporosis, psychiatric illness, diabetes, or if a prolonged course of treatment is expected based on disease severity. Although the literature is incomplete, patients with IMNM have shown poorer outcomes with corticosteroid monotherapy and require a second agent to be added [Table 1].[57],[58] However, as mentioned, no strict guidelines exist and there may be great variability between patients and clinicians. Each of these agents has their own safety profile and risks, with close monitoring for cytopenias and disturbances in liver function.{Table 1}

For patients who do not respond to the above treatments, various third-line treatments, including intravenous immunoglobulin (IVIG), rituximab, mycophenolate, and cyclosporin, have been trialed. The evidence surrounding the use of IVIG is, at this stage, scarce but certainly appears promising. There have been a number of reports which seem to have displayed some reduction in severity of muscle symptoms and CK levels in patients who have received IVIG.[58],[59] Based on these emerging reports, the guidelines set by the European Neuromuscular International Workshop in 2018 suggested the potential of using IVIG as first-line treatment in some cases, at a dose of 2 g/kg/month, over 3–6 cycles.[54] Indeed, IVIG has been used together with corticosteroids as first-line combination therapy, or in the place of corticosteroids, in patients with statin-induced IMNM.[56],[57]

Rituximab has also shown promising results. A 2016 Australian retrospective cohort study studied a group of 20 patients with IMNM.[60] Twelve of these patients were seropositive for anti-HMGCR and had been previously exposed to a statin. Three patients required IVIG and two patients also received rituximab due to relapses in disease activity after steroid tapering. The same study also reported on two statin-naïve, anti-HMGCR seropositive patients, who both required IVIG and rituximab for control of their disease. Many other smaller scale cohort studies have also used rituximab as rescue therapy or as part of a multiagent regimen.[58] The reports published thus far do show benefit in the use of rituximab, especially in refractory disease and for the prevention of relapse.

A recent Canadian study published in 2020 following a cohort of 55 patients also demonstrated interesting findings.[61] In this paper, 14 of 55 patients who underwent induction without corticosteroids successfully achieved clinical remission, thus evading harmful corticosteroid-induced adverse effects. A large number of patients who underwent triple induction with corticosteroids, steroid-sparing agents, and IVIG also showed promising results, with 82% achieving remission. Interestingly, 100% of the group that were not induced with corticosteroids did not require maintenance steroids during remission, compared with 73% of the group that was induced with corticosteroids, suggesting that corticosteroids may not be absolutely necessary for sustained clinical remission.

The evidence for maintenance therapy is not robust. In general, corticosteroids are to be tapered as early as is practical once there is an improvement in symptoms and reduction in CK levels – this varies between patients and disease severity. Immunomodulatory treatment is generally continued and tapered slowly.[54] Patients often require multiple adjustments to therapy and occasionally bouts of rescue therapy, with partial response to treatment.[58] Relapses in disease activity may occur after the withdrawal or tapering of immunomodulatory treatment, and therefore long-term immunosuppression may be required in some cases.[40],[62],[63]

The prognosis for those with IMNM has been poor, with patients displaying ongoing hyperCKemia and positive autoantibodies even after treatment, which may imply an element of irreversibility to the condition.[59] A mere 44% of patients included in a study published in 2017 reported recovery with immunosuppression, and furthermore, many patients continued to display hyperCKemia and persistent symptoms.[63]

It is clear, despite the challenges in achieving clear treatment guidelines, that early identification and diagnosis of the condition and using combination therapy may improve outcomes and increase the chance of remission. There remains much to be known, including the dosage and duration of maintenance corticosteroid therapy, how early to introduce agents such as rituximab, and the use of IVIG whilst in remission.

 Conclusions



Statin-associated muscle disorders remain an area that is rapidly evolving. Despite the above review, statins remain one of the most efficacious and safest pharmaceuticals available today. With careful monitoring and early recognition of adverse effects, they may continue to be able to be used widely in medical practice. The management of statin-associated muscle disorders is patient dependent and there is still much more to be uncovered.

The rare statin-induced necrotizing autoimmune myositis is still a relatively novel syndrome that also requires ongoing research, particularly its management.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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