Case Report – Anti‐HMGCR‐Associated Immune‐Mediated Necrotizing Myopathy and Interstitial Lung Disease With Long‐Term Use of Ezetimibe and Low‐Dose Atorvastatin

Dear Editor,

Inflammatory myopathies (IM), also known as idiopathic inflammatory myopathies (IIM) and commonly referred to as myositis, form a group of autoimmune diseases that mostly affect striated muscle [1]. Non‐muscular manifestations such as rash, arthritis, interstitial lung disease (ILD) or cardiac disease are common. Five different forms of IM are usually distinguished. These include dermatomyositis, anti‐synthetase syndrome, overlap myositis, sporadic inclusion body myositis, and immune‐mediated necrotizing myopathy (IMNM) [1]. Organ manifestations, response to treatment, and prognosis vary considerably between these subtypes, suggesting different pathophysiologic mechanisms in each subtype [1]. IMs may or may not be associated with myositis‐specific antibodies (MSA) or myositis‐associated antibodies (MAA) [2]. The diagnosis of IMs can be made by various methods, including history, clinical and physical examination, blood tests, electromyography (EMG), magnetic resonance imaging (MRI) or by muscle or skin biopsy. Subgroups defined by MSA/MAA may help to define the underlying pathophysiology and will also be important in future clinical trials for the development of targeted therapies and for identifying biomarkers to inform treatment decisions and monitor treatment response in individual patients [1].

IMNMs are clinically characterized by a predominant proximal weakness and elevated creatine kinase (CK) [3]. They may be associated with autoantibodies (e.g., anti‐3‐hydroxy‐3‐methyl‐glutaryl coenzyme A reductase [HMGCR], anti‐signal recognition peptide [SRP]), triggered by statin use (e.g., anti‐HMGCR‐associated IMNM), associated with cancer or idiopathic [3]. Immunotherapy is required to improve strength and reduce CK levels. However, no therapies for IMNM are currently approved by the Food and Drug Administration (FDA) or the European Medicines Agency (EMA), as the optimal treatment strategy for IMNM is currently unknown. In practice, there is wide variation in the treatment of IMNMs, but certain therapies may be more effective for the different serologic subtypes of IMNMs [3]. Anti‐HMGCR‐associated IMNM often responds well to intravenous immunoglobulin (IVIG), even as monotherapy. SRP and seronegative IMNM usually require combination immunotherapy, usually consisting of an oral immunosuppressant, corticosteroids and IVIG or rituximab (RTX) [3]. Patients often require immunotherapy for years, and relapses frequently occur when immunotherapy is discontinued. To our knowledge, no patient with anti‐HMGCR‐associated IMNM and ILD treated with ezetimibe and low‐dose atorvastatin over a prolonged period has been reported. The patient's verbal consent to the publication of the case was obtained.

The patient is a Caucasian woman in her eighties, who developed gait disturbances and exertional dyspnoea 23 days prior to admission (Table S1). Two weeks later, her internist recorded a CK level of 7900 U/L leading to the suspicion of heart attack. However, coronary angiography revealed only a 50% stenosis of the right coronary artery. Her medical history was positive for arterial hypertension, thrombendarterectomy (TEA) of a 90% stenosis of the right internal carotid artery at the age of 80, polyarthrosis, recurrent moderate renal failure, cataract surgery and hyperlipidemia. The family history was negative for neuromuscular disorders. She had been taking lisinopril (10 mg/day), acetylsalicylic acid (100 mg/day), triazolam (0.25 mg/day) and ezetimibe/atorvastatin (10 mg/20 mg/day) regularly for 2 years. On admission, CK had risen to 10 669 U/L (Table S2). Clinical neurological examination revealed proximal quadriparesis (M5‐), weak anteflexion of the head (M1) and weak retroflexion (M4). The left palpebral fissure was wider than the right due to a previous left eye trauma. Investigation for suspected myositis revealed positive HMGCR‐antibodies. HMGCR‐antibodies were detected using the combination immunoblot from Euroimmun (Euroline autoimmune inflammatory myopathies 16 + 2 Ag (IgG)). An MRI of the thigh muscles with contrast showed high STIR‐signals in the anterior, medial and posterior thigh musculature with surrounding edema compatible with myositis (Figure 1). Anti‐HMGCR‐associated IMNM was diagnosed.

FIGURE 1.

Magnetic resonance imaging of thighs bilaterally showing high short tau inversion recovery (STIR) signals in the anterior, medial, and posterior thigh musculature with surrounding edema compatible with myositis. Axial STIR images (panel A), coronal STIR images (panel B). On T1 with contrast, the muscles were enhanced (panel C). On coronal T1 images without contrast, the muscles appear isointense (panel D).

Investigation for malignancy, including thoracic and abdominal CT, gastroscopy, colonoscopy, gynecologic examination, and whole‐body fluorodeoxy‐glucose positron emission tomography (FDG‐PET), revealed only diverticulosis but no malignancy. High‐resolution chest‐CT showed reticular densities and ground‐glass areas posterolaterally in both upper and lower lobes, being interpreted as early ILD (Figure 2). Pulmonary function testing revealed a restrictive ventilatory disorder (TLC 4.0 L, FVC 1.7 L). The diffusion capacity of the lung for carbon monoxide was 46%. Video cinematography of the swallowing act showed marked vallecular and piriform sinus retention with postdeglutitive aspiration. However, MRI of the neck and pharyngeal muscles showed no signs of myositis. The cardiologic examination was unremarkable.

FIGURE 2.

High‐resolution chest computed tomography showing reticular densities and ground‐glass areas posterolaterally in both upper and lower lobes, being interpreted as early interstitial lung disease (ILD) (panels A–D).

From the first day of hospitalization, the patient was treated with prednisolone, which led to a rapid reduction in CK and transaminases, but CRP and leukocytes remained elevated (Table S2). The patient also benefited from the steroids in terms of quadriparesis, gait disturbance, and exertional dyspnea. To further enhance the therapeutic effect, she received 2 g/kg body weight of IVIG (30 g each on 4 consecutive days [120 g in total]). To avoid long‐term steroid use, it was decided to also administer RTX because of the ILD and dysphagia (Table S1). She was given calcium, vitamin‐D, and zoledronic acid to prevent osteoporosis. On hospital day 39, the patient was discharged on a regimen of lisinopril (10 mg/day), prednisolone (12.5 mg/day), amlodipine (10 mg/day), furosemide/spironolactone (20/50 mg/day), acetylsalicylic acid (100 mg/day), and pantoprazole (40 mg/day). Fourteen days after discharge, she received a second IVIG cycle (25 g each on 4 consecutive days [100 g in total]). As a result of these therapies, the patient regained her pre‐illness condition and reported that she was no longer restricted in her daily life. Six months after discharge, the patient received the third dose of RTX. One month later, the patient was readmitted due to right heart failure.

The patient presented is interesting for several reasons. First, the patient had anti‐HMGCR‐associated IMNM that responded to prednisolone, IVIGs and RTX. Previously reported patients with anti‐HMGCR‐associated IMNM [4, 5] presented with proximal predominant muscle weakness, myalgia, elevated CK, and myofiber necrosis with minimal inflammatory infiltrates on muscle biopsy [6]. There are also patients, like the index patient, who do not complain of myalgia. Some patients, but not the index patient, also have cardiac involvement, which may manifest as acute systolic dysfunction. In rare cases, HMGCR‐associated IMNM may resemble facioscapulohumeral dystrophy [7]. Some patients also present with atypical skin lesions, such as rashes with ash‐like scales or non‐scaly red patches and nodules [8]. The prevalence of anti‐HMGCR‐associated IMNM is estimated at 2–3/100 000 [9]. If IMNM is refractory to glucocorticoids, IVIG, plasmapheresis, and RTX may be beneficial [10]. There is also a case of anti‐HMGCR‐associated IMNM that responded favorably to efgartigimod [11].

Second, the putative trigger of anti‐HMGCR‐associated IMNM in the index patient was low‐dose (20 mg/day) atorvastatin. Although statins are considered the most common trigger of anti‐HMGCR‐associated IMNM, there are rarely other causes or no obvious cause for the disease. In a 47‐year‐old woman who was not taking statins, the trigger of anti‐HMGCR‐associated IMNM was a viral respiratory infection followed by dengue fever [6]. There is also evidence that statin‐naïve anti‐HMGCR‐associated IMNM in particular is associated with certain HLA types, such as HLA‐DRB1*11.01 [12]. There is also a case of hereditary anti‐HMGCR‐associated IMNM [8]. Anti‐HMGCR‐associated IMNM can also be a complication of malignant diseases, especially lymphoma, lung cancer, or breast cancer [12]. Most likely, atorvastatin triggered the myositis in the index patient. There was no evidence of a viral or bacterial infection prior to the onset of the first myositis symptoms.

Thirdly, the patient had early ILD in addition to myositis. ILD describes a group of conditions that cause inflammation and scarring of the lungs [13]. The symptoms commonly reported in ILD include difficulty in breathing and a hacking cough. ILD can be associated with radiation therapy, connective tissue diseases, inhaling toxic substances, or side effects of certain medications. Lung damage caused by ILD is often irreversible [14]. ILD is classified as major (idiopathic pulmonary fibrosis, idiopathic nonspecific interstitial pneumonia, respiratory bronchiolitis‐interstitial lung disease, desquamative interstitial pneumonia, cryptogenic organizing pneumonia, acute interstitial pneumonia), rare (idiopathic lymphoid interstitial pneumonia, idiopathic pleuroparenchymal fibroelastosis) and unclassified [15]. Idiopathic pulmonary fibrosis is the most lethal among the ILDs and presents high heterogeneity in clinical behavior [15]. Since some of the ILDs respond to steroids, IVIGs, and RTX, it is likely that the index patient's ILD also responded to immunosuppressive treatment for myositis.

Fourth, the patient developed delayed right heart failure 7 months after discharge. Since left heart failure has been occasionally reported as a complication of anti‐HMGCR‐associated IMNM [16]. It is conceivable that the right heart failure in the index patient was also a complication of myositis. However, right heart failure has not yet been described in anti‐HMGCR‐associated IMNM. The long latency period between the diagnosis of myositis and the occurrence of heart failure also argues against a causal relationship. Alternatively, the right heart failure could also have been caused by ILD. ILD patients are known to have an increased risk of pulmonary hypertension and thus heart failure, as was found in the index patient. It should also not be neglected that heart failure in the index patient could be a side effect of RTX, as has been repeatedly reported in the literature. The treatment of ILD includes antifibrotic therapy or lung transplantation.

In summary, this case shows that anti‐HMGCR‐associated IMNM can occur together with ILD, that it can occur without muscle pain, that it can occur together with the combination of ezetimibe and low‐dose atorvastatin, and that anti‐HMGCR‐associated IMNM responds favorably to steroids, IVIGs, and RTX. Patients with quadriparesis, rhabdomyolysis and under long‐term treatment with ezetimibe/atorvastatin should be screened for anti‐HMGCR‐associated IMNM and concomitant lung involvement.

Author Contributions

J.F. was responsible for the design and conception, discussed available data with coauthors, wrote the first draft, and gave final approval. J.F.: contributed to literature search, discussion, correction, and final approval.

Funding

The author has nothing to report.

Ethics Statement

The study was approved by the Institutional Review Board.

Consent

Consent was obtained from the patient for participation and the publication of this case report.

Conflicts of Interest

The author declares no conflicts of interest.

Supporting information

Table S1: Disease course before, during and after hospitalization.

Table S2: Results of blood work before, during, and after hospitalization.

Data Availability Statement

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.