Anti-3-Hydroxy-3-Methylglutaryl-Coenzyme A Reductase Immune-Mediated Necrotizing Myopathy following mRNA SARS-CoV-2 Vaccination

The new coronavirus (COVID-19) pandemic has resulted in the unprecedented production of vaccines. In this context, the possible adverse effects remain to be identified and reported. In this article, we report the case of a young female patient who developed anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase (anti-HMG-CoA) immune-mediated necrotizing myositis (IMNM) after receiving the Pfizer-BioNTech (BNT162b2) COVID-19 vaccine. The diagnosis of probable post-vaccination IMNM was made due to the absence of other factors that may have led to the development of autoantibodies (medicines; e.g., statins, drugs) and the temporal relationship between exposure and event. This case report is the first to suggest that a COVID-19 vaccine may trigger anti-HMG-CoA reductase necrotizing myopathy.


Introduction
In 2019, the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was identifed as responsible for pneumonia of unknown cause in Chinese patients [1,2]. On March 11, 2020, the World Health Organization classifed the global outbreak of the disease as a pandemic [3]. In this setting, several vaccines have been produced and released to the public at unprecedented speeds and quantities, putting the scientifc community and the world population on alert for possible adverse events [4]. In this paper, we report a case of immune-mediated necrotizing myositis (IMNM) that developed one week after a patient received the frst dose of the COVID-19 vaccine Pfzer-BioNTech (BNT162b2).

Case Presentation
A 22-year-old woman of African ancestry, with no medical history of previous comorbidities or use of any medication, was admitted to our tertiary hospital with symptoms of marked muscle weakness, loss of ambulation, and elevated creatine kinase levels (21,921 U/mL).
She reported the onset of symptoms one week after receiving the frst dose of the Pfzer-BioNTech (BNT162b2) vaccination (applied on August 15, 2021). Te initial symptoms were paresthesia in the shoulder girdle and tightness and pain in the upper limbs, mainly when moving and lifting objects. She worked as a clerk in a supermarket; after seeking medical care, the symptoms were attributed to her profession.
Te symptoms progressed to weakness of the lower limbs, severe girdle weakness, and loss of walking ability. Te patient was admitted to our hospital in December 2021. On admission, her physical examination revealed symmetrical weakness in the neck and extremities, specifcally Medical Research Council grade 3/5 in her neck and proximal upper limbs, grade 4/5 in the distal upper limbs, grade 2/5 in her proximal lower limbs, and grade 3/5 in the distal lower limbs. Tendon refexes of the extremities were normal. No abnormalities were found on cranial nerve testing. No sensory, autonomic, or coordination disturbance was observed.
At admission, her blood count and biochemical examinations did not show any alterations except for creatine kinase (21,921 U/L). Serological tests for HIV, HTLV, brucellosis, Chagas disease, toxoplasmosis, and treponema were all negative. Electroneuromyography of the upper and lower limbs showed sensory conduction velocities, amplitudes, and latencies of sensory action potentials of the median, ulnar, sural, and superfcial peroneal nerves within normal limits; motor conduction velocities, distal latencies, and amplitudes of compound muscle action potentials of the median, ulnar, tibial, and deep peroneal nerves within normal limits; F waves with preserved latencies in the median, ulnar, tibial, and deep peroneal nerves. Electromyography showed increased activity of insertion, fbrillation potentials, and discharge of acute positive waves at rest in the deltoid, triceps, biceps brachii, pronator teres, frst dorsal interosseous, abductor pollicis brevis muscles, trapezius, iliopsoas, quadriceps, tibialis anterior, gastrocnemius medial, and adductor magnus. During the voluntary contraction test, polyphasic action potentials of the motor unit were observed with reduced durations and amplitudes and increased recruitment and interference patterns. Echocardiography and chest and abdominal computed tomography showed no alterations. Magnetic resonance imaging of the shoulder and pelvic girdles was performed, which showed difuse edema of the musculature ( Figure 1).
Te patient received methylprednisolone intravenously (1 g per day for fve days) and additional symptomatic treatment. She showed mild improvement in motor function. Te hypothesis of infammatory myopathy of postvaccination etiology was made, and after 10 days of hospitalization, the patient was discharged with a proposal to continue the investigation on an outpatient basis (discharge creatine kinase: 10,931 U/mL).
After hospital discharge, vaccination campaigns were still in force in our country, and the patient inadvertently received the second dose of the Pfzer-BioNTech (BNT162b2) COVID-19 vaccination on January 7, 2022. One week later, she experienced further marked deterioration in motor strength, losing the ability to walk, and requiring a second cycle of intravenous methylprednisolone (1 g per day for fve days). In addition, her creatine kinase level was elevated (13,519 U/mL). Te patient was then readmitted to the hospital for treatment and was discharged fve days later.
After the second admission for treatment with methylprednisolone, during the outpatient investigation, rheumatological tests (antinuclear factor, rheumatoid factor, and antisynthetase antibodies) were performed and resulted in negative.
After the biopsy, a myositis panel analysis was performed. Anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase (anti-HMG-CoA) was positive at titers almost 10 times above the reference value (result: 193 AU; reference value: <20 AU). Antisignal recognition particle (SRP) tests were negative. A genetic panel was done, and one heterozygous variant of the uncertain signifcance of the dysferlin gene was described as NM_003494.4(DYSF): c.2093C>T (p.Ala698Val). Type 2 girdle muscular dystrophy is a condition of autosomal recessive inheritance, requiring two causative variants in distinct alleles for the complete expression of the clinical picture. Te presence of an isolated variant, as in the case described, is not sufcient for the development of the phenotype. Additionally, we performed western blot to assess dysferlin expression in the muscle, which resulted in the normal presence of calpain and dysferlin bands.
We decided to perform immunosuppressive treatment with methotrexate (15 mg/week) and corticosteroids (80 mg/ day); however, the patient persisted with severe muscle weakness, high levels of creatine kinase, and dependency on a wheelchair for locomotion. A gradual reduction of corticosteroids was attempted, and the patient presented with a recurrence of symptoms and renewed increase in creatine kinase levels. After further review and discussion, we decided to administer intravenous immunoglobulin; however, the patient has not yet undergone treatment due to its unavailability in the public health system.
Because of the results, a new review of the history and chronology of the events was conducted by specialists. Te diagnosis of probable post-vaccination IMNM was made due to the absence of other factors that may have led to the development of autoantibodies (medicines; e.g., statins, drugs) and the temporal relationship between exposure and event. 2 Case Reports in Neurological Medicine

Discussion
Idiopathic infammatory myopathies or myositis comprises a cluster of heterogeneous autoimmune diseases characterized by muscle infammation and distinct symptoms, including muscle weakness, myalgia, and elevated muscle enzymes [5]. Te treatment relies mostly on immunosuppression, and the clinical course and treatment are variable [5]. IMNMs are distinct diseases inside this group and present with severe proximal muscle weakness, elevated muscle enzyme concentrations, myopathic fndings in electroneuromyography, and necrosis in muscle biopsies [6]. Patients can be classifed according to the autoantibody identifed as anti-SRP, anti-HMG-CoA, or autoantibody negative [6]. Anti-HMG-CoA is the second most identifed antibody associated with immune-mediated necrotizing myopathy [7]. Patients usually present subacute or chronic progressive proximal bilateral and symmetrical weakness, myalgia, dysphagia, and elevated serum creatine kinase levels [8]. It is most related to exposure to statins [9] but is also reported following infections [10][11][12], malignancies [13], other risk factors, and no known risk factors [8].
Vaccination is a major public health advancement but can also dysregulate autoimmune responses [14]. Te COVID-19 mRNA vaccine is a lipid nanoparticleencapsulated protein that encodes the SARS-CoV-2 spike glycoprotein [15]. Tis vaccine works by inducing the T-cell immune response and has been reported to induce a strong type I interferon response [16]. Recently, a review showed that most patients who develop infammatory myopathies had received the Pfzer-BioNTech (BNT162b2) vaccine and reported symptoms just after the frst dose [17].
To the best of our knowledge, this is the frst case report suggesting the COVID-19 vaccine as a possible trigger for anti-HMG-CoA necrotizing myopathy. An extensive search in PubMed using the MeSH terms "myositis" and "coronavirus" and "vaccination" returned 134 results. Of these, only two reported IMNM after SARS-CoV-2 vaccination, using CoronaVac and Pfzer-BioNTech BNT162b2. Another study reported IMNM after yellow fever, tetanus/diphtheria, and hepatitis B. Te studies mentioned above suggested the presence of anti-SRP antibodies, but none described the presence of anti-HMG-CoA autoantibodies (Table 1) [18][19][20].