8. Myositis as an idiosyncratic drug reaction to leflunomide
Authors: Darren Angeline , Levasseur Kirsty , Chandratre Priyanka 
Published: September 2019

Abstract

Introduction
Myositis is a broad diagnosis with a number of potential causes. There are numerous drugs that can lead to myotoxicity. We discuss a case of a patient with known rheumatoid arthritis who developed myositis with no evidence of an additional autoimmune condition and where the most likely cause seems to be leflunomide.

Case description
A 46-year-old Asian lady with a background of seropositive rheumatoid arthritis and overactive bladder developed increasing muscle weakness. Disease activity was well-controlled on leflunomide which had been started four years ago after an initial trial of methotrexate proved ineffective. Other regular medications include tolterodine and rigevidon (combined oral contraceptive pill), paracetamol and co-codamol. She presented to her GP in February with generalised muscle weakness, fatigue, dry mouth, hair loss and occasional shortness of breath on exertion. Blood tests showed elevated CK at 1132 u/l, ALT 57 u/l (AST normal), LDH 302 u/L, CRP 4 mg/l and ESR 25mm/h.
Further tests were subsequently arranged following rheumatology review including ANA and ENA (both negative), an extended myositis panel and HMGCoAR antibodies (also negative). MRI of her lower limbs showed bilateral oedema within the anterior and lateral muscle compartments of her thighs, worse on the left, and in keeping with myositis. Given the possibility of leflunomide being the cause of her symptoms it was stopped. Her CK one month after stopping leflunomide had decreased to 819 u/l and then 389 u/l after four months. The patient reported improvement in her muscle weakness, CK is currently being monitored, and she is awaiting an EMG. A muscle biopsy has been discussed with her previously and although she had refused initially, in view of persistent mild elevation in CK, the biopsy and leflunomide washout will be discussed again with her again. As she is clinically asymptomatic and not keen to try new medications, further immunosuppression has not been started.

Discussion
Myositis is seen in a wide range of conditions with numerous possible causes. It can be drug-induced, secondary to viral infections or caused by autoimmune conditions including overlap conditions and idiopathic inflammatory myopathies. Drug-induced myositis is most commonly associated with statins, but has been seen with many different medications.
Leflunomide is a disease-modifying anti rheumatic drug used particularly in the treatment of inflammatory arthritis but has also been used in treatment resistant dermatomyositis. It inhibits the mitochondrial enzyme, dihydroorotate dehydrogenase to reduce the reproduction of rapidly dividing cells. A rise in CK is considered a common side effect. We have only found one other case report where leflunomide was suspected to have induced polymyositis, also in a patient with rheumatoid arthritis. Both biochemical and clinical improvement following cessation of leflunomide, with no other inventions raises the likelihood of this being a leflunomide-induced myositis.

Key learning points
When faced with a patient with rheumatoid arthritis presenting with symptoms suggestive of myositis, whilst an overlap autoimmune condition is a possibility, it is important to consider potential drug causes. Numerous drugs have been implicated through both direct myotoxicity and immunologically mediated myotoxicity. Importantly for rheumatologists these can include glucocorticoids, antimalarial drugs, colchicine and tumour necrosis factor inhibitors. According to the summary of product characteristics a rise in CK is commonly seen with leflunomide but clinical myositis has only been reported rarely.

Conflicts of interest
The authors have declared no conflicts of interest.