# Immune-mediated myopathy related to anti 3-hydroxy-3-methylglutaryl-coenzyme A reductase antibodies as an emerging cause of necrotizing myopathy induced by statins

Clément Lahaye, Anne Marie Beaufrére, Olivier Boyer, Laurent Drouot, Martin Soubrier, Anne Tournadre

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Clément Lahaye, Anne Marie Beaufrére, Olivier Boyer, Laurent Drouot, Martin Soubrier, et al. Immune-mediated myopathy related to anti 3-hydroxy-3-methylglutaryl-coenzyme A reductase antibodies as an emerging cause of necrotizing myopathy induced by statins. Joint Bone Spine, 2014, 81 (1), pp.79-82. 10.1016/j.jbspin.2013.06.008. hal-05484794

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# Brief Report : Immune-mediated myopathy related to anti 3-hydroxy-3-methylglutaryl-coenzyme A reductase antibodies as an emerging cause of necrotizing myopathy induced by statin.

C. Lahaye¹, A. Tournadre¹, O. Boyer², A.M. Beaufrére³, M. Soubrier.¹

1 Service de rhumatologie CHU Gabriel Montpied 63003 Clermont-Ferrand

2 Anatomie et cytologie pathologique CHU Estaing 63003 Clermont-Ferrand

3 Laboratoire d'immunopathologie clinique et expérimentale CHU Charles Nicolle 76183 Rouen

Today, the diagnosis and treatment of recent adult myopathy still remains a challenge. Distinguishing differential diagnosis that include inflammatory myopathies, toxic myopathies, and muscular dystrophies is crucial for appropriate treatment [1]. The classification of inflammatory myopathies improved with the development of histopathological approaches and the discovery of myositis-specific and myositis-associated antibodies that led to the characterization of new entities. In addition to polymyositis (PM) and adult and juvenile dermatomyositis (DM), novel classifications distinguish inclusion-body myositis (IBM), immune-mediated necrotizing myopathy (IMNM), overlap myositis, and cancer-associated myositis [2,3]. However, this classification is limited by clinical, histological and serological overlap that may be responsible for diagnosis difficulties. In addition, the management of these rare diseases is still poorly codified.

Characterization of necrotizing myopathy in the setting of statin treatment led to the identification of a new type of myositis-specific autoantibody against the 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR), the pharmacological target of statins [4,5,6]. Recently described and emerging, this new entity raises the questions of distinct clinical phenotypes and treatment strategy [7].

We report a new case of immune-mediated necrotizing myopathy associated with statin exposure and anti-HMGCR antibody.
Case report :

A 65-year-old man had myalgia with elevated CK levels appeared 6 months after statin's initiation.
Preventive treatment by rosuvastatine 20 mg per day was introduced 2 years ago. He was also
treated for arterial hypertension and diabetes mellitus with ramipril and glimepiride. No intercurrent
drug intake was noted. He had no familial medical history, no excessive use of alcohol and did not
smoke. He did not report any travel outside the metropolitan for 3 years. Although statine was
discontinued, symptoms worsened and he was admitted with proximal muscle weakness. Diffuse
amyotrophy without fasciculations was noted with predominant involvement of quadriceps.
Proximal lower and upper extremity strength was MRC grade 4. The neck extensors were MRC
grade 4. He could only get up from stool 8 times in 30 seconds. Neither dyspnoea or swallowing
disorders were noted. Muscle-stretch reflexes were normal and symmetric. The findings on tests of
sensory-nerve and cranial nerve function were normal. Skin examination was normal.

Serum CK level was highly increased to 8690 UI/L (Normal 39-308). Leukocyte count was normal
without hypereosinophilia. Serum creatinin level was 46.4 µmol/L and CRP level 5.3 mg/L.
Antinuclear, antisynthetase (anti-JO1, anti-PL7, anti-PL12, anti-EJ, anti-OJ), anti-SRP, anti-Mi2,
anti-PM-Scl 75 and 100, anti-Ku, anti-CCP antibodies and rheumatoid factor were negative.
Serologies for hepatitis B and C virus, and HIV were negative. Comprehensive malignancy
screening including computed tomography of the chest, abdomen and pelvis,
18FFluorodeoxyglucose positron emission computerised tomography , digestive endoscopy were
unremarkable. Muscle biopsy showed necrotic and regenerating muscle fibers without significant
inflammatory infiltrates in endomysium or perimysium area (Photo de lame Beaufrere).
Immunohistochemistry revealed macrophage infiltration, rare and scattered CD4- and CD8-positive
T lymphocytes. MHC class I expression was only detected in necrotizing muscle fibers. Membrane
attack complex C5-B9 deposition was expressed on necrotic fibers and "normal à préciser" on
capillaries. Muscle protein analysis by western blot showed normal dystrophin 1,2 and 3, alpha-
dystroglycan, alpha-, beta-, gamma- and delta- sarcoglycan, caveolin, merosin and dysferlin. Polymyositis was initially suspected. Steroid therapy was started in a daily dosage of 1 mg/kg in combination with subcutaneous methotrexate (20 mg weekly). Six weeks later, CK levels decreased to 3425 UI/L but the muscle strength did not improve. Monthly intravenous immunoglobulin (IVIG) therapy (1 g/kg for two consecutive days) was associated. By the second treatment dose, strength and physical endurance gradually improved and steroids were tapered. After 4 doses, the patient could get up from stool 15 times in 30 seconds and CK levels normalized. One year later, he was taking methotrexate (20 mg weekly) and 8 mg daily of prednisone. IVIG therapy could have been stopped. A second analysis of the muscular biopsy was highly suggestive of necrotizing myositis associated with anti-SRP or anti-HMGCR antibodies. The dosage of anti-HMGCR antibody, not initially available, was performed on patient sera (Luminex technology, Pr O.BOYER, laboratory of immunology, C.H.U. Rouen, France). Detection of high anti-HMGCR antibody level, confirmed the diagnosis of statin-associated autoimmune necrotizing myopathy.

Discussion

Immune-mediated necrotizing myopathy (IMNM) were first described in association with anti-SRP antibodies, in patients with severe symmetrical proximal weakness, heart and lung involvement and corticoresistance [8,9]. Necrosis and regeneration are the prominent histological characteristics of IMNM, without significant inflammatory cell infiltrates [2]. In addition to anti-SRP antibodies, IMNM have also been reported in the presence of cancer [10]. However, most of IMNM without neoplasm or myositis-specific antibodies remained « unclassified ». The recent identification of anti-HMGCR antibodies in statin-exposed patients with immune-mediated myopathy appears to be helpful both for differential diagnosis and for treatment strategy. Although statin users frequently experienced mild and transient myalgia, rare myopathy can occur, usually self-limiting myopathies resolving within weeks to months of discontinuing the medication [11,12]. However, severe necrotizing myopathies associated with statin treatment that worsened despite drug withdrawal were identified [6]. Those statin- induced myopathy improved following treatment with
immunosuppressive therapy suggesting an immune-mediated myopathy. Recent identification of myositis-specific antibodies against HMGCR in the setting of necrotizing myopathy support an immune mechanism and raises the question of the direct pathogenic effect of statin medication [5]. Statin use seems to represent the environment trigger of this immune-mediated myopathy by up-regulating the expression of HMGCR. Once initiated, muscle damage is sustained by over expression of HMGCR in regenerating muscle, even after statins are discontinued [5,13]. However, the exact role and pathogenesis of anti-HMGCR remains unclear. Anti-HMGCR antibodies were not found in the majority of patients using statin medication and 33 % of patients with necrotizing myopathy associated with anti-HMGCR antibodies have not been exposed to statins [5,14]. Moreover, statin-exposed and statin-unexposed anti-HMGCR subjects may have different phenotypes. In particular statin-exposed subjects may be more responsive to immunosuppressive therapy than statin-unexposed subjects [14]. Most patients with IMNM and anti-HMGCR antibodies had partial response to steroids and required combination immunosuppressive therapy such as azathioprine or methotrexate. In addition, rituximab and IVIG appeared to be effective when other immunosuppressive treatments are insufficient. [4,6,14].

In conclusion, statin use can lead to a necrotizing myopathy despite discontinuation of the offending drug. In patients who did not improve within a few weeks of discontinuation of the statin, a muscle biopsy should be performed as well as test for anti-HMGCR antibodies. Patients with this disorder require aggressive immunosuppressive treatment.

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