Background/Purpose: Elevated muscle enzymes in the course of systemic lupus erythematosus (SLE) usually represent active myositis or drug-related toxicity. Lipid-lowering agents and, less frequently, antimalarials (chloroquine, CQ and hydroxychloroquine, HCQ) have been implicated. Aim of this observational cohort study was to delineate the possible role of antimalarials in inducing myotoxicity.

Methods: Patients with SLE have been followed prospectively s according to a standard protocol at 2-6 month interval. From this cohort we identified 325 patients who had elevated muscle enzymes, defined as abnormal creatine phosphokinase (CPK) measurements in at least two consecutive visits. Fifty-four patients on statins/fibrates and/or myositis were excluded. The final cohort of 271 patients (cases) were compared to 1453 patients who never had elevated CPK levels during their follow-up (controls) with regard to epidemiological variables and antimalarial treatment. Statistical software SAS (version 9.3) was used for analysis; p<0.05 was considered significant.

Results: Cases and controls did not differ with regard to gender, age at disease diagnosis and disease duration. Controls were characterised by higher disease activity and cumulative damage. Black patients were more commonly had elevated CPK levels (57/271, 21% vs. 143/1453, 9.8%, p<0.001). Antimalarial use was more frequent in cases (216/271, 79.7% vs 821/1453, 56.5%, p<0.001). Total frequency of elevated CPK in antimalarial users was 216/1322, 16.3%. Duration of antimalarial use was longer in patients with elevated CPK levels (4.33±4.96 years vs. 3.84±5.47 years, p<0.001). Cox multiple regression analysis showed antimalarials to be strong predictors for CPK elevation [HR=8.6 (CI=5.7-13) for CQ, p<0.001 and HR=7.4 (CI=5.2-10.4) for HCQ, p<0.001]. The cumulative CQ dose before the first abnormal CPK measurement was 148±324g in 2.0±4.4 years; for HCQ that was 307±426g in 2.6±3.6 years. In all patients CPK levels did not exceed 2-4x the upper limit of normal regardless of the duration of therapy. Over 7.3±5.6 years of follow-up, 18 patients (8.3%) developed clinical myopathy with proximal muscle weakness of the lower limbs. Of 203/216 patients who had more than 2 subsequent clinic visits after the second visit with elevated CPK and continued taking antimalarials, 101 (49.8%) patients had persistent enzyme elevation, 30 (14.8%) had intermittent elevation whereas in 72 (35.4%) CPK normalised immediately or shortly after that visit. Of note, one patient developed HCQ-induced cardiomyopathy after 13 years and a cumulative dose of 1623g.

Conclusion: Chronic antimalarial use is a risk factor for muscle enzyme elevation in SLE patients. In the vast majority of patients, CPK elevation remains a biochemical abnormality as it evolves to clinical myopathy in less than 10%; however, it persists in almost two thirds of the patients with continuous antimalarial treatment. Further studies are needed to assess abnormal CPK value in predicting serious outcomes, such as cardiomyopathy.      

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/is-there-a-relationship-between-antimalarial-treatment-and-elevated-muscle-enzymes-in-systemic-lupus-erythematosus/