The spectrum of muscle toxicity caused by antimalarial drugs is extensive and in some cases controversial. The presence of the specific ultrastructural findings of antimalarial toxicity in muscle tissue may not always imply a muscle disease but could be a muscular deposit of these drugs or their metabolites. Thus Kumamoto et al18
observed by electron microscopy that experimental chloroquine treated rats developed dense membranous structures (curvilinear bodies) in soleus muscle fibres after the eighth day of daily intraperitoneal injections of chloroquine. In our study we considered that an antimalarial myopathy was present only if the patient had both these specific histological findings and a persistent muscle enzyme disturbance, regardless of their clinical symptoms. On this basis we found a prevalence of antimalarial myopathy of 9.2% and an annual incidence of 1.2%, because four new patients developed the myopathy during the follow up period. This represents an accumulated prevalence of 12.6%. Though 11 patients had antimalarial myopathy at the start of the study, we do not know exactly when these patients developed the myopathy. Most had been taking antimalarial drugs for more than two years, but this complication can be present at a subclinical stage.
Our results seem to suggest a much higher incidence of myopathy than was found in previous small retrospective uncontrolled studies.5,10,11
No report with prospective data on the incidence of antimalarial myopathy has been published to date. Avina‐Zubieta et al11
reported an incidence of 1 in 100 patient‐years of treatment, but their study was retrospective and showed the frequency of clinical myopathy related to the time of treatment and not the true incidence of this complication. Furthermore, the differences between our study and other series5,10,11
could be explained by the screening method used to reach a diagnosis of antimalarial myopathy. While earlier reports based their diagnosis on the patient's clinical symptoms, a persistent disturbance of serum muscle enzymes was used as a starting point in the present study. We chose these biochemical tests because they are simple to perform and sensitive enough to detect muscle injury.
The serum muscle enzyme disturbance observed in most patients with myopathy in our study was mild, and LDH was by far the most sensitive enzyme for detecting muscle damage, as has previously been suggested.12
However, it is well known that LDH is not specific for muscle disease and raised concentrations can be found in other conditions, for example myocardial infarction, chronic liver and pulmonary diseases, haemolysis, renal and intestinal infarction, stroke, pulmonary emboli, pancreatitis, low grade infections, neoplasias, and fractures. Nevertheless, in our patients we were able to exclude these conditions (for example, a patient with a hepatic carcinoma was excluded from the study). That all patients with abnormal LDH from whom antimalarial drugs were withdrawn subsequently showed normalisation of their levels (table 2) reinforces the muscular origin of the LDH in those cases. We have no definite explanation for the poor sensitivity of CK as a screening tool, but low serum CK levels in some rheumatic diseases are a reflection of the inflammatory activity.19,20,21
We did not use clinical manifestations as a starting point in our study as muscle weakness can be difficult to detect clinically. Furthermore, the underlying chronic rheumatism may mask muscle symptoms and can delay the diagnosis. However, we also determined the prevalence of clinical myopathy, investigating how many of the 15 patients with proven antimalarial myopathy had signs or symptoms of muscle weakness. Some degree of weakness was observed in 53% of these patients, which represent a prevalence of clinical myopathy of 6.7% in our study—quite a high figure compared with previous series.5,10,11
These differences can be explained by the high sensitivity of the screening method which we used, which was different from those used in previous studies, which were specifically based on the patient's symptoms. In addition, it is important to emphasise that only two of these patients developed severe clinical disease as a result of muscle weakness. We do not have muscle strength assessments for all 119 patients treated with antimalarial drugs, but in all patients with clinical antimalarial myopathy for whom we had data, muscle strength improved after drug withdrawal (table 2), suggesting that the muscle weakness was caused by the antimalarial agents and not primarily by the underlying rheumatic disease.
It is known that electromyography is useful in the evaluation of any myopathy. However, our study showed that its sensitivity was low for the diagnosis of antimalarial myopathy (53%), and therefore it seems inadvisable to use it as the sole diagnostic screening tool in this context. However, all patients with clinical myopathy also had abnormal electromyography, so the technique may be useful in monitoring patients with antimalarial myopathy to detect the evolution of the disease from a subclinical to a clinical stage.
Confirmation of a suspicious diagnosis of antimalarial myopathy should be made through a histological study of the tissue samples. In our series, a muscle biopsy was carried out in all patients with a persistent muscle enzyme disturbance, regardless of their clinical manifestations or electromyography. In these cases an ultrastructural examination is absolutely mandatory to detect the characteristic tissue deposits that confirm the diagnosis of an antimalarial myopathy, since light microscopy has numerous false negatives (80% in our series). The three patients with vacuolar myopathy in the light microscopy had clinical involvement, with muscle strength impairment and electromyographic changes, which could mean that this technique may only detect the most advanced cases. Cytoplasmic complex lipid bodies (myeloid and curvilinear bodies) constitute the characteristic features of antimalarial myopathy. These findings have not been detected in any other muscle disease except ceroid lipofuccinosis, a rare lipid storage disease.22
Whether these specific findings are seen in patients on antimalarial drugs but with no myopathy is unknown, but all our biopsied patients had muscle impairment as reflected by raised muscle enzymes.
During the follow up, after the discontinuation of the antimalarial treatment in all patients with moderate to severe clinical myopathy, the muscle weakness, muscle enzyme disturbances, and electromyographic changes tended to normalise, as previously reported,9
reinforcing the view that the antimalarial agents caused the myopathy in our patients.
It is thought that hydroxychloroquine has less neuromuscular toxicity than chloroquine. Nevertheless, in the present study, a proven antimalarial myopathy was found in two of the eight patients taking this drug. Although the patient sample is insufficient to draw any firm conclusions about this, a toxic myopathy with hydroxychloroquine may not be as rare as previously thought. More studies are required to establish the prevalence of myopathy during treatment with hydroxychloroquine, using sensitive screening tools.
What clinical importance should be attached to the diagnosing of antimalarial myopathy in asymptomatic patients? Should the antimalarial drug be withdrawn when a subclinical myopathy is detected in well controlled patients? The high prevalence of this adverse effect may, in the future, make it advisable to recommend regular determinations of serum muscle enzymes in patients chronically treated with antimalarials. We opted for discontinuation of antimalarial treatment only in patients with clinical myopathy, while monitoring the remaining patients (with a complete muscle strength test and an electromyographic study). A prospective controlled study to determine the likelihood of progression of a subclinical to a clinical myopathy is needed before definitive recommendations can be made.
Our study suggests that the prevalence of antimalarial myopathy is higher than previously recognised. Regular determination of serum muscle enzymes, mainly LDH, seems to be a good screening tool for myopathy. When a persistent muscle enzyme disturbance is detected, a clinical and electromyographic study should be carried out periodically to establish the development of a clinical myopathy as soon as possible. In cases of clinical myopathy, an anatomical‐pathological tissue study, including an ultrastructural study, is mandatory to confirm the diagnosis, and the withdrawal of antimalarial drugs should be considered.