Muscle Injury from Hydroxychloroquine: What muscles exactly?

‘Antimalarial Myopathy’ Includes an Array of Muscles

The ‘antimalarial’ drugs like chloroquine (CQ) and hydroxychloroquine (HCQ) have been reported to be associated with a rare chance of muscle injury. A study from 2006 suggested that clinically apparent myopathy in the proximal skeletal muscles muscles was apparent in approximately 7 % of users of antimalarial drugs.

Retrospective Study Identifies 13 Patients with Myopathy

A new retrospective study from 2021 set out to evaluate the clinical phenotype, laboratory features, and treatment outcomes of antimalarial myopathy, as well as the safety profile of these drugs. The authors identified 13 patients seen between 2000 and 2019, with a median age at presentation of 66 years (range 53-89); 10 were using hydroxychloroquine. 2 were using chloroquine and 1 was using both.

11 of the 13 patients were female. Patients were using hydroxychloroquine and chloroquine for a range of disorders including lupus (n=5), morphea (n=1), overlapping connective tissue disease (n=2), seronegative arthritis (n=2), Sjogren’s syndrome (n=1), scleroderma (n=1) and undifferentiated connective tissue disease (n=1)

At onset of symptoms, patients were on either of these two antimalarial drugs for a minimum of 6 months but some had been on the drug up to 21 years. Diagnosis was often delayed by a median of 6 months (range 3-48). At presentation, 13 patients reported limb weakness with five patients requiring assistance in walking. Ten patients reported dysphagia (trouble swallowing). The dysphagia was often severe and resulted in marked weight loss or aspiration pneumonia. Nine reported respiratory symptoms, which were multifactorial in four, and four reported severe neck weakness.

Myopathy clinical phenotype showed predominant involvement of one or more of the following: proximal limb muscle weakness (12 patients), dysphagia (9), axial weakness (4), and respiratory failure (5). Eleven patients had a cardiac evaluation. ECG showed a prolonged QT interval in 10 patients and CQ/HCQ cardiomyopathy (CMP) in four.

Ten out of 12 patients markedly improved after discontinuing the medication, but most were left with some residual weakness.

Nine had elevated creatine kinase (CK) levels up to 1,199 U/L. Aldolase was elevated in 2 of 8 patients. Twelve patients had an electromyography (EMG), which showed myopathic motor unit potentials with fibrillation potentials in 11 and myotonic discharges in 3. There seemed to be a cumulative dose effect with higher cumulative dose and longer exposure duration being associated with more severe disability and more common heart and swallow involvement.

Conclusion

The authors concluded that long-term exposure to chloroquine and hydroxychloroquine may result in a myopathy with a wide spectrum of clinical presentation and particular predilection for the swallowing, respiratory, and cardiac muscles. Affected patients may have significant associated morbidity. Once accurately diagnosed and the drug is discontinued, patients usually improve but unfortunately many affected patients do not return back perfectly to baseline.

I think this study is important as it reminds us that concerns related to muscle-related side effects need attention.

Whether risks of myopathy are different in different populations is unclear. For example, it is certainly possible that the risks of myopathy in the setting of rheumatoid arthritis is different than the risk in the setting of scarring alopecia. Patient characteristics are different, prior and concurrent medications are different, and risk factors are different. However, studies that evaluate the risks of myopathy in patients with scarring alopecia who use hydroxychloroquine have not been done.

It is probably important for us to consider ordering baseline CK, LDH prior to starting hydroxychloroquine and screen for dysphagia, skeletal muscle weakness, respiratory symptoms and neck weakness at baseline as well. These can be re-assessed at follow up visits. Patients with elevated muscle enzymes or muscle related symptoms (swallowing, neck weakness, skeletal muscle weakness, respiratory muscle issues) will likely require dose adjustment (or stopping) and may require further EMG and muscle biopsy studies. Patients on hydroxychloroquine for more 3-4 years might benefit from ECG studies to better assess the QT interval, but good studies to guide these kind of recommendations have not been done. It is likely that a muscle biopsy will be strongly considered for patients with clinical manifestations of myopathy combined with chronically elevated muscle enzyme disturbances, such as aldolase (ALD), creatine phosphokinase (CK or CPK) and lactate dehydrogenase (LDH).

REFERENCE

Naddaf E et al. Chloroquine and Hydroxychloroquine Myopathy: Clinical Spectrum and Treatment Outcomes. Front Neurol. 2021 Feb 2;11:61607