Statin-induced autoimmune myopathy: a case report

Abstract

Statins are widely used in the treatment of hypercholesterolemia. Muscle weakness and elevated creatine kinase (CK) are frequent side effects of statins with an incidence of about 15%. Statin-associated myopathy is more common in people who receive multiple drugs, the elderly or women but the mechanism underlying it is still unclear. These symptoms generally improve after drug discontinuation. However, there is a type of autoimmune mediated myopathy characterised by the persistence of muscle weakness and CK elevation after stopping statins. Herein, we discuss a case of autoimmune myopathy associated with statin exposure and responsive to immunossupresive drugs. The increased use of statins in recent years raises the importance of acquaintance with this disease in clinical practice.

BACKGROUND

Statins are used in the treatment of hypercholesterolemia by specifically inhibiting hydroxy-methylglutaryl-coenzyme A reductase (HMGCR), the key enzyme in the cholesterol biosynthetic pathway. Moreover, they can reduce cardiovascular risk in both primary and secondary prevention. Thus, they are among the most commonly prescribed medications.¹

One of the side effects of treatment with statins is the appearance of myalgia in 5%–10% of patients or myopathy with creatine kinase (CK) elevation in one in 10 000 patients.² In the great majority of the cases, statin-induced myopathic events are self-limited, with complete recovery in the weeks or months after statin withdrawal.³ However, in some cases, patients who developed an autoimmune myopathy following statin exposure, this adverse effect did not improve after drug discontinuation.⁴

Immune-mediated necrotising myopathy (IMNM) associated with statin use is a rare process characterised by an acute (days to weeks) or sub-acute (<6 months) onset of mild to moderate symmetrical muscle weakness and high CK values.¹ Its aetiology is not known in detail, but it seems to respond to an autoimmune process that is sometimes triggered after exposure to drugs (for example, statin consumption), connective tissue diseases, cancer and viral infections. The susceptibility to develop myopathy is higher in elderly, diabetic patients, liver or kidney failure, and hypothyroidism.⁵

Herein, we present the case of a man who developed a probable case of anti-HMGCR antibody-mediated IMNM associated with statin use. The muscle biopsy and serology (positive anti-HMGCR antibodies) confirmed the anti-HMGCR antibody-mediated IMNM. The episode was solved after atorvastatin withdrawal and treatment with inmunosuppressants (corticosteroids and azathioprine).

Consequently, we consider it relevant to describe this case to highlight that this rare effect might be a severe adverse event related to statins' use that should be studied.

Case presentation

A 49-year-old man was admitted due to developing progressive fatigue and muscle weakness, and pain in both legs and arms for 2 months. He had a history of hypertension, hyperlipidemia, hyperparathyroidism and stage 3 chronic kidney failure secondary to nephrectomy due to renal carcinoma. His usual treatment included pantoprazole 40 mg/day, atorvastatin 20 mg/day and ramipril 5 mg/day.

The patient had been taking atorvastatin 20 mg daily for the last 8 years. There was no history of auto-immune disease, and no family history of neuromuscular disorders.

Laboratory workup showed an elevated CK (23 171 U/L, reference value <170 U/L), aspartate aminotransferase (AST) (3851 U/L, ref. <32 U/L), alanine aminotransferase (ALT) (594 U/L, ref. <31 U/L), and gamma-glutamyl transferase and bilirubin were normal. He had stage 3 chronic kidney disease with a creatinine level of 2.13 mg/dL, blood urea of 74 mg/dL and glomerular filtration rate of 36 mL/min/1.73 m². Abdominal ultrasound and chest X-ray showed no abnormalities.

Investigations

On admission, atorvastatin was discontinued and fluid therapy was given for the prevention of rhabdomyolysis (crystaloids and sodium bicarbonate) for the first days. Consequently, muscle pain improved and CK value (8308 U/L), (176 U/L) and (594 U/L) decreased during the following days. At that moment, an IMNM was suspected and a muscle biopsy was performed showing mild infiltration with necrotic muscle fibres. Slight structural alterations of muscle fibres were seen, consisting of a slight increase in central nuclei and isolated nuclear clusters. The presence of focal perimysial inflammatory infiltrate composed of macrophages, without acute inflammatory activity, deposits or vacuoles was apparent. The expression of MHC I on the non-necrotic myocyte’s membrane was not performed. Muscle MRI showed adductor muscle oedema and symmetric involvement of the dorsal muscle groups of both the calves, compatible with inflammatory myopathy. Electromyography showed abnormal spontaneous muscle activity with active denervation in all examined muscles suggestive for an inflammatory myopathy. All myositis-specific auto-immune serology was negative (anti-Mi2, MDA5, TIF1, anti-striated muscle antibodies, antisynthetase antibodies and anti-signal recognition particle), except for anti-HMGCR antibodies, which were positive. The diagnosis of HMGCR antibody-mediated IMNM associated with statin use was reached with the global findings in the imaging tests, histological tests, autoimmunity and the patient's response to statin suppression. No further immunohistochemical studies were conducted

In addition, this adverse event was evaluated according to the Naranjo et al⁶ (table 1) adverse drug reaction probability scale. The causal relationship between atorvastatin and HMGCR antibody-mediated IMNM was classified as 'probable'.

Table 1.

Naranjo adverse drug reaction probability scale

Question	YES	NO	Do not know	Score
Are there previous conclusive reports on this reaction?	+1	0	0	1
Did the adverse event appear after the suspected drug was administered?	+2	−1	0	2
Did the adverse reaction improve when the drug was discontinued or a specific antagonist was administered?	+1	0	0	1
Did the adverse event reappear when the drug was re-administered?	+2	−1	0	0
Are there alternative causes (other than the drug) that could have caused the reaction?	−1	+2	0	2
Did the reaction reappear when a placebo was given?	−1	+1	0	0
Was the drug detected in blood (or other fluids) in concentrations known to be toxic?	+1	0	0	0
Was the reaction more severe when the dose was increased or less severe when the dose was decreased?	+1	0	0	0
Did the patient have a similar reaction to the same or similar drugs in any previous exposure?	+1	0	0	0
Was the adverse event confirmed by any objective evidence?	+1	0	0	0
TOTAL SCORE				6

Scoring: Definite: > 9; Probable: 5–8; Possible: 1–4; Doubtful: 0.

Treatment

He was subsequently discharged from hospital and should have been controlled in an ambulatory care setting, but 4 weeks' later he presented with severe progressive muscle weakness again. CK value was increased to 22659 U/L. He was re-admitted and treated with intravenous steroids (methylprednisolone 125 mg/day for 3 days) and after that, continued with oral prednisone 30 mg daily for 6 months. In addition, azathioprine 50 mg twice- daily was prescribed after the determination of thiopurine methyltransferase activity. The dose was adjusted to renal function.

He was released from the hospital as a result of an improvement in muscle pain.

Outcome and follow-up

CK value decreased 3 months after presentation (4340 U/L) but laboratory workup showed neutropenia (0.1*10^-9/L, ref. 2.5–7.5*10^-9/L) and leucopenia (0.9*10^-9/L, ref. 4.5–11.5*10^-9/L). Therefore, he was prescribed filgastrim 480 UI/day during 4 days and leucocyte and neutrophil values were normalised. Moreover, he developed cutaneous toxicity. These adverse events were associated with the use of azathioprine, so this drug was discontinued.

In this case, the treatment with methotrexate was not indicated because the patient had a history of stage 3 chronic kidney failure secondary to nephrectomy.

The options considered after azathioprine’s withdrawal were rituximab or intravenous immunoglobulins. Initially, doctors planned to wait for corticosteroids' tapering (doses<20 mg daily) and start one of these options, but the patient had refused to start any of the proposed treatments. Consequently, he continued his treatment with prednisone.

Currently (1 year and 3 months after this episode), he continued treatment with oral prednisone 15 mg daily (slow tapering). CK values decreased (CK 563 U/L) but the patient continued symptomatic. His functional mobility slowly improved, however, muscle weakness persisted. So, he finally accepted to receive immunosuppressive therapy and he has just started the first pulse of immunoglobulin. The treatment consists on the first 5-day pulse of immunoglobulin at a dose of 0.4 g/Kg/day for 6 months and it will help to decrease the prednisone dosage.

This adverse event was reported to the regional pharmacovigilance centre.

DISCUSSION

Statin-associated adverse muscle events are classified in the categories of myalgia, myopathy, myositis, myonecrosis, clinical rhabdomyolysis and HMGCR antibody-mediated IMNM.⁷ Myopathy is defined as muscle weakness (not due to pain), and not necessarily associated with elevated CK.⁸

IMNM is an uncommon condition that may occur in patients on statins' treatment. Affected patients show progressive proximal muscle weakness involving both limb girdles, CK values between 10 and 100 times the upper limit, myophatic electromyography findings and muscle biopsy usually showing necrosis.⁹

Positive anti-HMGCR antibodies-mediated IMNM are strongly associated with statin use because these drugs up-regulate HMGCR expression on muscle cells and may be the trigger for autoimmune response.⁵ So, in addition to the clinical symptoms, positive serology (anti-HMGCR) is the key in the diagnosis.¹⁰

The onset of muscle symptoms is usually within weeks to months after the beginning of statin therapy but it also may occur at any time during treatment. Regarding serum CK levels, it is useful to obtain a baseline CK level for reference purposes prior to starting statin therapy but the routinely monitoring serum CK levels is not recommended on statin therapy.¹¹ One differential characteristic of IMNM is that statin withdrawal does not usually improve the patient’s symptoms and inmunosuppressive treatment is required to obtain a clinical response.⁹

Therapeutic guidelines based on evidence-based medicine are lacking for the management of IMNM and treatment is based on expert opinion and data from case series. A first line of treatment remains oral high-doses corticosteroids or pulsed intravenous methylprednisolone.³ However, some experts recommend intravenous immunoglobulins as a first-line treatment, especially in anti-HMGCR myopathy, pregnant and young patients.¹² Depending on the severity and response to initial treatment, it may be necessary for the addition of another agent at the same time or within 1 month. Among the options, azathioprine or methotrexate are the preferred agents. Cyclosporine, mycophenolate mofetil or rituximab can be considered.¹³

In conclusion, based on available clinical data, the literature review and the application of causality analysis, a causal relationship between the administration of atorvastatin and the development or worsening of HMGCR antibody-mediated IMNM was probable. Knowledge of the possible appearance of HMGCR antibody-mediated IMNM associated with this treatment allows early recognition of the causality and subsequent management of patients. In this context, it is appropriate to advise doctors to monitor patients closely when muscle weakness and CK do not stabilise after the discontinuation of statins.

Learning points.

• Immune-mediated necrotising myopathy (IMNM) associated with statin use is a rare process whose main characteristic is that patients' symptoms do not usually improve after statin withdrawal.

• Immunossupresive therapy is the recommended treatment of IMNM. First-line treatment remains corticosteroids.

• In this case, the association between atorvastatin and HMGCR antibody-mediated IMNM was classified as probable by the Naranjo adverse drug reaction probability scale.