Anti-HMGCR myopathy presenting with acute systolic heart failure

Abstract

Necrotising autoimmune myopathy (NAM) is an immune-mediated myopathy that may be associated with statin use, malignancy or an autoimmune connective tissue disease, but it can also be idiopathic. Anti-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) myopathy is an extremely rare side effect of statin use, occurring in approximately 2–3 out of every 100 000 patients who use statins. Patients typically present with subacute proximal muscle weakness and creatine kinase levels >10 times the upper limit of normal. The diagnosis is suggested by muscle biopsy showing necrotic fibres with minimal inflammation along with positive anti-HMGCR antibodies. Treatment nearly always requires multiple immunosuppressive agents, the earlier use of which is associated with improved outcomes. Reports of statin-induced NAM leading to heart failure are limited. We present the case of a 69-year-old woman with statin-induced NAM who presented with acute systolic heart failure. Early initiation of high-dose corticosteroids and IVIG resulted in significant improvement in her symptoms.

Background

Necrotising autoimmune myopathy (NAM) is a rare but increasingly recognised side effect of statin use.¹ Multiple recent case reports describe cases of anti-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) myopathy induced by statins, although none of them describes significant cardiac involvement.^2–6 It is being increasingly shown that early recognition and treatment with immunosuppression improves outcomes in NAM.⁷ We describe a patient diagnosed with anti-HMGCR myopathy who presented with acute systolic heart failure and had significant clinical improvement after initiation of corticosteroids and IVIG. We present this case for two reasons. First, we hope to add to the limited literature concerning cardiac involvement in NAM. Second, we hope to illustrate that with early recognition and prompt initiation of immunosuppression, it is possible to achieve a positive clinical outcome despite a severe initial presentation.

Case presentation

A 69-year-old woman presented to her primary care provider with a 1-month history of progressive, severe proximal muscle weakness involving her thighs and neck. Her weakness was so severe that she was unable to walk, get out of bed or rise from a chair without assistance. She denied any myalgias, Raynaud’s phenomenon, rashes, dysphagia, chest pain, shortness of breath, orthopnoea, paroxysmal nocturnal dyspnoea, lower extremity oedema, vision changes, rash, numbness or tingling. Her medical history was significant for mucosal-associated lymphoid tissue lymphoma of the bilateral orbits and left lung treated with radiation and rituximab; she also had essential hypertension, hypothyroidism, hyperlipidaemia, type II diabetes and non-ischaemic cardiomyopathy secondary to inducible ventricular arrhythmias treated with ICD placement. Her echocardiogram 1 year prior to her current presentation showed a preserved ejection fraction of 57%. In addition to lisinopril, metoprolol tartrate, hydrochlorothiazide and metformin, she also was taking 40 mg of atorvastatin, a dose she had taken for the previous 2 years without side effects. She denied any significant tobacco or alcohol use, and she had no family history of cardiac or rheumatologic disease. She was up to date on all cancer screening and had no evidence of active lymphoma in the prior 12 years. She was found to have a creatine kinase (CK) of 11 062 U/L (26–192 U/L), lactate dehydrogenase (LDH) of 1116 U/L (122–222 U/L) and thyroid-stimulating hormone (TSH) of 6.3 mIU/L (0.3–4.2 mIU/L), so she was subsequently admitted to the hospital on the same day for further workup and management.

On admission, she was unable to lift her head or neck against gravity and she had 3/5 strength of her shoulders and hip flexors. She had 5/5 strength in distal muscle groups. She had no rash, skin tightening or joint swelling. Additional pertinent labs on admission included an aspartate aminotransferase (AST) of 525 U/L (8–43 U/L), alanine aminotransferase (ALT) of 661 U/L (7–45 U/L), aldolase of 128.8 U/L (<7.7 U/L) and creatinine of 0.86 mg/dL (0.59–1.04 mg/dL). Her TSH was re-checked and found to be normal at 4.2 mIU/L. Despite discontinuation of atorvastatin and aggressive intravenous fluid resuscitation, her CK remained significantly elevated, and she began to develop worsening dyspnoea and lower extremity oedema without significant chest pain.

Investigations

Given her increased dyspnoea, a cardiac workup was pursued. Her troponin T was 607 ng/L (<10 ng/L, fifth generation assay) with subsequent values of 525 ng/L and 418 ng/L 2 and 6 hours later, respectively. An ECG showed normal sinus rhythm with occasional premature ventricular complexes and a right bundle branch block, all of which was unchanged from ECGs prior to admission. An echocardiogram showed global hypokinesis with an ejection fraction of 15%–20%. Rheumatologic workup revealed a strongly positive ANA of 1:640 in a homogenous pattern (<1:80) along with a weakly positive anti-SCL70 antibody of 3.6 U (<1.0 U) and MDA-5 antibody of 20 U (<20 U). Antibodies against rheumatoid factor, CCP, SS-A/B, centromere, Jo1, dsDNA, RNA polymerase III, PL-7, PL-12, EJ, OJ, signal recognition particle (SRP), MI-2, TIF 1 gamma, NXP-2, PM/SCL, fibrillarin U3, U2 SN RNP, U1 RNP, KU and SSA 52 KD were negative. A CT of the chest, abdomen, and pelvis did not reveal any evidence of recurrent lymphoma. Electromyogram revealed frequent waning myotonic-like discharges and fibrillation potentials. Activation of most muscles showed rapid recruitment of short duration low-amplitude motor unit potentials, most pronounced in the proximal muscles. Due to evidence of an active myopathy without a specific diagnosis, a left biceps biopsy was obtained, which showed several necrotic fibres, some of which were replaced by macrophages (figure 1A). There were minimal mononuclear cells with increased acid phosphatase activity at rare endomysial sites adjacent to the necrotic fibres (figure 1B). These biopsy findings were consistent with NAM. Subsequent testing via ELISA revealed a strongly positive anti-HMGCR antibody level of >200 (<20).

Figure 1.

Frozen sections of left biceps muscle show (A) numerous necrotic muscle fibres on H&E (arrows), some of which are invaded by macrophages. (B) Acid phosphatase stained section shows increased enzyme reactivity in macrophages invading necrotic fibres (arrows).

Differential diagnosis

The patient presented with rhabdomyolysis of unclear aetiology. On admission, initial differential diagnosis included statin-associated rhabdomyolysis, connective tissue disease-associated myopathy, hypothyroidism and inflammatory myopathy, such as dermatomyositis or polymyositis. We were also concerned about recurrent lymphoma given the elevated LDH. However, the lack of constitutional symptoms and negative imaging made lymphoma less likely. Although she had a slightly positive anti-SCL70 antibody, she had no skin tightening to suggest scleroderma. Additionally, connective tissue disease-associated myopathy typically does not present with such profound weakness and CK elevation. Hypothyroidism was also less likely given the modest TSH elevation that subsequently normalised. Persistent elevation of CK despite statin discontinuation and hydration led us to believe that an immune-mediated myopathy was the likely cause. This hypothesis was strengthened when we discovered her acute systolic heart failure, as we knew of the existing literature describing cardiac involvement in dermatomyositis and polymyositis.^8–10 However, the largely negative serologic workup prompted a muscle biopsy for confirmation. The finding of necrotic fibres with a paucity of inflammatory cells pointed toward a diagnosis of NAM, as dermatomyositis and polymyositis typically show inflammatory lymphocytic cells invading non-necrotising muscle fibres on biopsy.⁷ Subsequent detection of anti-HMGCR antibodies allowed us to confirm the diagnosis of anti-HMGCR myopathy.

Treatment

Beginning on hospital day 2, she received 1 g of methylprednisolone daily for 3 days and had a reduction in her CK with subjective improvement in her weakness. She was then transitioned to 60 mg of prednisone daily. She required brief diuresis, but quickly became euvolemic. Repeat echocardiogram 1 week after initiation of steroids showed significant improvement in her ejection fraction to 42%. She was subsequently discharged from the hospital with cardiology and rheumatology follow-up.

Outcome and follow-up

She was seen in the rheumatology clinic 1 month after initial presentation. Despite reduction in her CK to 1664 U/L, she still had a significant objective weakness, primarily in her neck. She was initiated on IVIG, 1 mg/kg monthly for 4 months. She continued 60 mg of prednisone for 1 month and then tapered by 10 mg every 2 weeks thereafter. Following her 4 months of IVIG, she was initiated on methotrexate 10 mg weekly. She had an excellent response to this with a reduction in her CK to 49 U/L, aldolase to 4.2 U/L, AST to 29 U/L and ALT to 25 U/L. Her most recent echocardiogram performed 4 months after initial presentation showed continued improvement in her ejection fraction to 47%. She is currently being treated with 10 mg of prednisone daily and 20 mg of methotrexate weekly. She completed a course of physical therapy and is now able to do the majority of activities and hobbies she enjoyed prior to presentation.

Discussion

NAM is an immune-mediated myopathy characterised by subacute proximal muscle weakness, elevated CK levels and histology revealing muscle fibre necrosis with regeneration and a paucity of inflammatory cells.⁷ This is in stark contrast to the idiopathic inflammatory myopathies (dermatomyositis, polymyositis and inclusion body myositis), which often show an inflammatory infiltrate on muscle biopsy.⁷ While it is often idiopathic, NAM can be subdivided based on the presence of known risk factors including statins, malignancy and connective tissue disease.⁷ NAM has been associated with multiple autoantibodies, including anti-HMGCR, anti-SRP and antisynthetase antibodies.¹¹ Anti-HMCGR myopathy is a form of NAM and is a rare side effect of statin use, which is estimated to occur in 2–3 out of every 100 000 statin users.¹ Multiple recent case reports, including the aforementioned case, describe atorvastatin-induced NAM, although pravastatin, rosuvastatin and simvastatin have also been implicated.^{2–7 12} However, no studies have been done investigating the relative risk of developing NAM with different statins (such as hydrophobic vs hydrophilic statins), and the preponderance of atorvastatin-induced cases likely represents prescribing practices as opposed to a specific drug effect.¹³ Additionally, patients often have a long period of prior statin exposure prior to developing NAM, with one case series reporting an average of 3 years of statin usage prior to the development of NAM.¹²

Suspected cases of anti-HMGCR myopathy can be confirmed through the detection of anti-HMGCR antibodies.¹¹ This is a fairly specific test for anti-HMGCR myopathy, as anti-HMGCR antibodies are typically not seen in non-statin exposed patients, statin users with mild myalgias or no side effects and patients with other immune-mediated myopathies, including other subsets of NAM.^{7 11} The role of anti-HMGCR antibodies in the pathogenesis of anti-HMGCR myopathy is still being debated and elucidated.^{14 15} While no randomised controlled trials exist, multiple reviews and case series demonstrate improvement in symptoms and CK levels with the use of a variety of immunosuppressive medications including corticosteroids, IVIG, rituximab, mycophenolate, methotrexate and azathioprine, with most patients requiring more than one medication.1 7 11 12 Positive prognostic factors include the use of two or more immunosuppressants in the first 3 months and the use of IVIG, which appears to be the most effective treatment available.^{7 14}

Cardiac involvement, including systolic dysfunction, has been reported previously as a presenting sign and cause of death in the idiopathic inflammatory myopathies, including dermatomyositis and polymyositis.^8–10 However, documentation of cardiac involvement in anti-HMGCR myopathy is less robust. A recent retrospective review found echocardiographic abnormalities in 25 of 41 patients with NAM, the most common of which was diastolic dysfunction.⁷ Two patients had abnormal left ventricular wall motion with no prior history of coronary artery disease.⁷ However, these findings were not stratified according to the specific NAM subtype.⁷ Multiple recent case reports of anti-HMGCR myopathy do not describe significant cardiac involvement.^2–6 A recent case report does describe the rapid progression of heart failure in a patient with pre-existing idiopathic inflammatory myopathy, but does not further specify a specific diagnosis.¹⁶ Thus, more investigation is needed to determine the true prevalence of cardiac dysfunction in NAM, specifically anti-HMGCR myopathy. A low threshold for cardiac investigation, including echocardiography, should be maintained to detect clinical or subclinical cardiac dysfunction that could be mitigated with early aggressive immunosuppression.

In summary, we described the case of a patient who presented with weakness and acute systolic heart failure who was diagnosed with anti-HMGCR myopathy and had a positive outcome with early initiation of corticosteroids and IVIG. This highlights the need to keep a high index of suspicion for NAM when weakness and CK elevation persist despite discontinuation of statins. Additionally, further investigation is needed to better elucidate the prevalence of cardiac involvement in anti-HMGCR myopathy.

Patient’s perspective.

Concerned that my muscles seemed to be weakening, I made an appointment with my primary care doctor, where my blood levels showed very elevated results. This led to a trip to the emergency room where I was admitted and started a 9-day hospital stay. Many tests began to find the cause of the weakness.

On discharge, I was still extremely weak. Medications were started to help to jump-start rebuilding my muscle strength. Walking with a cane helped me with balance, but it was still difficult getting up from a chair and I was not able to lift my head up from my pillow or raise my legs off the bed. It took almost a month before I slowly noticed my mobility improving. After going through physical therapy with continued daily home exercise, I feel I have regained at least 75% of my muscle strength.

Even though my life was extremely challenged by what was attacking my body, my medical team gave me continued hope that if this was drug-induced then there was a great chance that it could be reversed. I reminded myself daily of these words. Now, going into the eighth month of my journey, I am so blessed that my strength continues to improve.

Learning points.

• Necrotising autoimmune myopathy (NAM) is a rare but important side effect of statin use.

• Persistently elevated creatine kinase despite discontinuation of statins should increase suspicion for NAM and prompt consideration of checking anti-hydroxy-3-methylglutaryl-coenzyme A reductase antibodies.

• Treatment of NAM often requires immunosuppressive agents in addition to discontinuation of statins.

• Early recognition of NAM is important, as earlier use of immunosuppressive agents leads to improved outcomes.

• Cardiac involvement is increasingly recognised as a manifestation of immune-mediated myopathies, necessitating a low threshold for cardiac evaluation in this population.