Polymyositis, Dermatomyositis, and Statins: A Review

Mauro Turrin 1

1 Former Department of Internal Medicine, Ospedali Riuniti Padova Sud, Monselice – Padova, Italy

Abstract

BACKGROUND: Statins are a well-recognized cause of a variety of skeletal myopathic effects, which generally resolve when discontinuing the treatment. Among autoimmune manifestations associated with statins, there are typical polymyositis (PM) and typical dermatomyositis (DM).

OBJECTIVE: To perform a review on published case reports and case series about statin-associated PM and DM.

METHODS: This literature comprehensive search was conducted mainly on PubMed, but also congress abstracts and university websites were considered. Given the paucity of cases, the search was extended to include articles in all languages with English abstract.

RESULTS: Twenty-eight PM and 30 DM cases have been described with prevalence in female (64%) and senile age. The drugs most frequently involved were atorvastatin and simvastatin. The differential diagnosis should be made among the main myositis subtypes: immuno-mediated necrotizing myopathy (IMNM), inclusion body myositis (IBM), and overlap syndrome with myositis (OM), including anti-synthetase syndrome (ASS).

CONCLUSIONS: Even though the onset of polymyositis or dermatomyositis is a rare phenomenon, it is advisable to consider their presence in patients taking statins and with a non-reversible elevation of creatine phosphokinase.

Keywords: Statins; Dermatomyositis; Polymyositis; Autoimmune Myositis

Polimiosite, dermatomiosite e statine: una review

CMI 2018; 12(1): 89-102

https://doi.org/10.7175/cmi.v12i1.1364

Clinical Management

Corresponding author

Dr. Mauro Turrin

Monselice – Padova

Tel.: +39 3289032440

m.turrin@libero.it

Received: 6 June 2018

Accepted: 5 December 2018

Published: 19 December 2018

Introduction

Statins

Due to the wide diffusion of statins, which have the undoubted merit of increasing the survival rate in patients affected by cardiovascular disease, particular attention should be paid to their side effects. The most common ones are toxic myopathies, affecting 2-20% of patients [1], that generally resolve after drug discontinuation. The risk of statin myopathy and creatine phosphokinase (CPK) increase is dose-dependent.

Polymyositis and Dermatomyositis

Polymyositis (PM) and dermatomyositis (DM) are idiopathic inflammatory myopathies (IIMs) that may be related to statins. All forms of IIMs are considered rare diseases. In USA, DM has prevalence of ~1-6 patients per 100,000 persons, while PM has a prevalence ~10 per 100,000 [2].

In this context, some cases of association of statins with polymyositis [3-16] and with dermatomyositis [10-12,15,17-35] have been described.

A rate of exposure to statins up to 48% was found among patients with PM or DM over 50 years of age [10].

The outdated, but still used, diagnostic criteria for PM and DM, according to Bohan and Peter [36,37], are:

• Increase in muscle enzymes;
• Weakness of proximal muscles;
• Electromyographic alterations;
• Bioptic alterations; and
• Characteristic skin rash.

As described in Table I, PM and DM are judged “definite”, “probable”, or “possible” according to the number of criteria met by the patient.

The classification of inflammatory myopathies has undergone several revisions [38-40] since the earliest descriptions by Bohan and Peter.

Five main subtypes of myositis, i.e. dermatomyositis (DM and juvenile DM), necrotizing myopathy (NM), PM, overlap myositis (OM and anti-synthetase syndrome—ASS), and inclusion body myositis (IBM), have been well described in a recent German review [41] (Table II).

In September 2018, Selva-O’Callaghan and colleagues published on Lancet Neurology a new classification of inflammatory myopathies in the adult [42] based on the clinical characteristics of the main clinical and phenotype-specific autoantibody groups, in which they specified also that the diagnosis of PM is a diagnosis of exclusion.

In the same period a further classification was published also based on a targeted clinical-serological approach [43]. In reference to the 708 variables (in particular myositis-specific autoantibodies—MSA) collected in 260 adult patients of the French register on myositis, 4 clusters of patients emerged (IBM, IMNM, DM, ASS), while PM did not more found place.

Besides clinical criteria, magnetic resonance imaging (MRI) [39,44] can be useful to make the right diagnosis. MRI with whole-body technique (WBMRI) is considered particularly useful for identifying the involvement of muscles: parameters such as inflammation, fibrosis, and atrophy can be used to determine the pattern of disease activity even at subclinical level [45-49]. In addition, MRI guides the choice of the site for muscle biopsy.

Figure 1, coming from a personal case report [50], highlights the typical MRI elements, which are suggestive for DM/PM.

IIMs can be treated with glucocorticoids (initial and basic treatment) and with immunosuppressants (methotrexate, azathioprine, mycophenolate mofetil). An additional or alternative therapy may be undertaken with cyclosporin A (or tacrolimus) or intravenous immunoglobulin, with therapy escalation to rituximab or cyclophosphamide.

Treatment with repository corticotropin injection (RCI) in a recent open label clinical trial [51] was effective, safe and tolerable, and led to a steroid dose reduction in adult patients with myositis refractory to glucocorticoid and traditional immunosuppressive drugs.

In this article, the possible implications of statins in autoimmunity have been thoroughly considered with the support of a literature search.

Literature Search Strategy

In this review, the literature search was conducted mainly on PubMed, but also congress abstracts and universities websites were considered. The search terms used were: “myositis”, “myopathy”, “statins”, “muscular manifestations”, “dermatomyositis”, “polymyositis”, “statin-induced autoimmune myopathy”, “creatine (phospho) kinase”, “myoglobin”, and “troponin”. The keywords were combined with the Boolean operators “AND” and “OR”. Given the paucity of cases, we extended the search to include articles in all languages with English abstract. The selection of the descriptors was carried out in November 2018. No time limit was set in the search.

Results

Tables III and IV describe the main characteristics of case reports, related to the exposure to statins in 28 adult patients with polymyositis [3-10,12-14,16] and in 30 adult patients with dermatomyositis [10,12,17-35].

On the basis of the results shown in Tables III and IV, these diseases were more frequent in women (66%) and in senile age (the median age at the time of diagnosis was 68 years). The drugs most frequently associated with the disease were atorvastatin and simvastatin in PM and DM, respectively.

The exposure period was very variable: in the PM there was a minimum of two days, in a case concerning an African American patients with CPK peak very high [12], while the maximum exposure time was of 25 years in an elderly woman. In DM, the exposure duration was shorter (median = 6 months; range = 6 days-10 years).

The CPK peak was higher in PM (median = 2802 U/l; range = 355-126,000) than in DM (median = 1574 U/l; range = 207-20,424), but the difference was not statistically significant.

In one case of dermatomyositis (55 years, F, atorvastatin 80 mg) [34], a normal value of CPK was found associated with increased aldolase. In three further cases, the CPK was lower than 300 U/l.

The determination of ANAs refers only to 33 patients: they were positive in 76% of patients, i.e. 23 cases (14/18 DM and 9/15 PM).

Anti-HMGCR antibodies were dosed in a total of 9 patients: those described in the Brazilian series published in 2018 [12] and the recent case published in October 2018 [34]. All were negative. These antibodies, discovered in 2010 [52,53], are currently being measured in a few specialized centers. Even the anti-signal recognition particle autoantibodies (anti-SRPs), mentioned in the same series, were negative.

In PM, anti-Jo antibodies were negative in 10 out of 14 assays performed. Among the 4 positive patients, one had antisynthetase syndrome. In DM, 12 patients were tested, but none was positive.

We found also a case of polymyositis during therapy with atorvastatin diagnosed after an episode of rhabdomyolysis (CPK = 14.611 U/l with myoglobinuria) from cerivastatin, with subsequent detection of positive anti-Jo-1 [16].

Discussion

According to the literature [11,54-57], statins are involved also in other autoimmune diseases, such as interstitial lung disease, myasthenia gravis, systemic lupus erythematosus, cutaneous lupus, vasculitis, autoimmune hepatitis, lichen planus pemphigoides, and pemphigus erythematosus.

Even more cases appeared in recent years in literature concerning necrotizing myopathies associated with statins and with the coexistence of autoimmune phenomena [11,55].

From 1992 to November 2018 at least 58 defined cases of DM (n. 30) and PM (n. 28), with histological confirmation, associated with exposure to statins were described.

It should be noticed that in the analysis of the South Australian Myositis database including 221 patients with histologically confirmed idiopathic inflammatory myositis, 68 patients (30.8% of cases) were found exposed to statins, at the time of diagnosis: 27/89 PM, 4/23 DM, 12/24 necrotizing myopathy, 20/66 inclusion body myositis, and 5/19 nonspecific chronic inflammatory myositis patients. Exposure to statins was found in 30.3% of PM and in 17.4% of DM, thereby highlighting an almost 2-fold increased likelihood compared with controls. However, details on the type of statin, dosage, or duration of statin exposure was not available in this study [58].

Another serious muscle complication associated with statin use has recently been described: autoimmune necrotizing myopathy (IMNM: immune-mediated necrotizing myopathy). It is associated with anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase antibodies (anti-HMGCR) [59].

According to some Authors, most patients affected by necrotizing myopathy with a history of statins, before the discovery of anti-HMGCR were classified as polymyositis. Statin-triggered IMNM and polymyositis would therefore not be two distinct entities, but part of the same pathophysiological spectrum also because they respond well to immunosuppressive treatment [5,60].

Pathognomonic clinical manifestations for dermatomyositis and polymyositis have been reported in three adult patients with autoimmune necrotizing myopathy positive for anti-HMGCR [61-63].

In the IMNM, magnetic resonance detects a characteristic pattern of muscular abnormalities involving mainly hip rotators and glutei: IMNM have significantly more widespread muscle edema, atrophy, and fatty replacement compared with those with polymyositis and dermatomyositis, unlike the fascial edema is more common and widespread in dermatomyositis [44].

In 2013, a Canadian Working Group Consensus defined the main predisposing conditions that promote intolerance or side effects of statins [64]:

• Hypothyroidism;
• Hypovitaminosis D;
• Low body mass index;
• Low CoQ10 enzyme level;
• Excessive use of alcohol;
• Excessive use of cranberry or grapefruit juice;
• Illicit drugs (amphetamine, cocaine, heroin);
• Drug-statin interaction;
• Renal failure;
• Liver failure;
• Diabetes mellitus;
• Biliary obstruction;
• History of pre-existing asymptomatic increase in CPK.

However, a more recent meta-analysis conducted by Nguyen in 2018 found that the significant risk factors for myopathy and/or rhabdomyolysis associated with statins were [65]:

• Age > 65 years;
• Female gender;
• Diabetes mellitus;
• Renal insufficiency;
• Cardiovascular disease;
• Drug-drug interactions (clarithromycin, erythromycin, cyclosporin, mibefradil, verapamil, diltiazem, nefazodone, itraconazole, fibrates, gemfibrozil, amiodarone, and protease inhibitors);
• Statin dose;
• Genetic factors (SLCO1B1 gene mutation).

It is useful to dose CPK before starting statin therapy to discover a subclinical myopathy and to exclude, even if very rare, the presence of macro-creatinekinase [66].

Subsequent CPK checks should be done in the third, sixth, and twelfth months because most statin myopathies occur within the first six months of therapy.

Concerning the case with high aldolase [50], it should be pointed out that aldolase dosage is useful because its isolated increase reflects preferential immune-mediated damage affecting early regenerating cells [67].

Regarding the therapy of hypercholesterolemia to be implemented after clinical recovery in patients with IIMs, to my knowledge specific indications do not exist in the literature. Drugs with no side effects on the muscle should be used. In primary prevention, the range of therapy extends from nutraceuticals to ezetimibe. As for nutraceuticals, monacolin K should not be prescribed because it is chemically identical to lovastatin.

Berberine does not modify CPK [68], while for ezetimibe the incidence of myopathy/rhabdomyolysis was identical (0.2%) to that found in placebo patients. PCSK9 inhibitors may be used in myopathic patients at high cardiovascular risk. These fully human monoclonal antibodies (e.g. evolucumab, alirocumab), which act against the proprotein convertase subtilisin/kexyn type 9, could be an alternative to statin therapy in severe cases of drug toxicity, such as rhabdomyolysis [1]. Clinical studies comparing statins versus statins + anti-PCSK9 found no differences in muscle and CPK side effects between the two groups [69,70]. For patients with idiopathic inflammatory myositis and with coexistent dyslipidemia, anti-cholesterol therapy should be implemented, obviously, with defined drugs without toxic effects on the muscle.

Conclusions

The present literature review identified 28 cases of polymyositis and 30 cases of dermatomyositis related to exposure to statins.

To my knowledge, this is currently the widest research about these two rare statin-triggered pathologies.

Funding

This article has been published without the support of sponsors.

Conflicts of interests

The Author declares that he has no conflicts of financial interest regarding the topics covered in this article.

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