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Research Letter |

Myopathy Induced by Antimalarial Agents: The Relevance of Screening Muscle Enzyme Levels FREE

Andrew H. Kalajian, MD; Jeffrey P. Callen, MD
Arch Dermatol. 2009;145(5):597-600. doi:10.1001/archdermatol.2009.60.
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Published online

Myopathy induced by antimalarial agents (AMM) is presumably clinically rare, and little is known about its pathogenesis. Defined as clinical muscle weakness in a patient receiving antimalarial therapy, AMM has a reported incidence of 2 to 10 cases in 1000 patient-years and a prevalence of less than 2%.1,2

Recently, Casado et al3 performed the first prospective study of AMM. Screening their patients' muscle enzyme levels, including creatine kinase, lactate dehydrogenase, and aldolase, the authors further evaluated those having persistently elevated levels of muscle enzymes with physical examination, electromyography, and muscle biopsy. Of 119 patients screened, 22 (18.5%) had persistently elevated muscle enzyme levels, and excluding 7 patients lost to follow-up, the remaining 15 patients (12.6%) all demonstrated characteristic curvilinear and/or myeloid bodies on skeletal muscle electron microscopy (defined as AMM). However, only 8 of these patients (6.7%) manifested clinical muscle weakness (defined as clinical AMM), which improved in all patients on cessation of antimalarial therapy. Casado et al3 report the prevalence of AMM (12.6%) and clinical AMM (6.7%) as higher than that previously reported (<2%), and they suggest screening patients without clinical symptoms by measuring muscle enzymes on a repeated basis.

One of us (J.P.C.) has used antimalarial agents extensively in the treatment of cutaneous disease over the past 30 years and has not identified a relationship between elevated muscle enzyme levels and underlying clinical AMM or clinical benefit of routine determination of muscle enzyme levels. Casado et al3 identified 22 of 119 patients receiving long-term treatment with antimalarial agents as having persistent muscle enzyme level elevation (18.5%). The clinical significance of this elevation is not clear because only 6.7% were ultimately determined to have clinical AMM, and all patients improved on cessation of antimalarial therapy. Thus, we designed this prospective study to evaluate the clinical relevance of screening muscle enzyme levels in our dermatologic patients treated with AMM.

The study was approved by the institutional review board at the University of Louisville, Louisville, Kentucky. We prospectively enrolled study participants who met inclusion criteria during routine follow-up visits. Patients were eligible for inclusion if they had been undergoing antimalarial therapy for at least 3 months at a minimum oral dose of 200 mg of hydroxychloroquine sulfate every other day or 250 mg of chloroquine hydrochloride daily. Patients were excluded if they had any medical condition potentially affecting neuromuscular function or muscle enzyme levels.

After giving written informed consent, patients completed a comprehensive questionnaire targeting symptoms of muscle weakness and/or pain or any coexisting confounding medical condition. A focused neuromuscular examination was performed on each patient, evaluating proximal muscle strength, vibratory sensation, and deep-tendon reflex status. Creatine kinase, lactate dehydrogenase, and aldolase levels were measured. Results of muscle enzyme testing were considered abnormal if 1 (or more) of the 3 tested muscle enzyme levels was elevated.

Over a 10-month study period, we prospectively enrolled 21 patients (20 women and 1 man), mean age, 51.7 years (age range, 35-76 years). Eight patients were treated with chloroquine and 13 patients with hydroxychloroquine. The most common underlying disease was cutaneous lupus erythematosus. Seven patients (33%) had either symptoms of muscle weakness or abnormal results of neuromuscular examination; 4 of these 7 patients exhibited both weakness and abnormal examination results.

Laboratory evaluation detected abnormal muscle enzyme levels in 4 patients (19%). However, there was no correlation between abnormal muscle enzyme levels and the presence of either muscle symptoms or abnormal neuromuscular examination results. Our patient population and study results are summarized in the Table. The trend showing higher prevalence of muscle enzyme level elevation in chloroquine-treated patients (38%) than in hydroxychloroquine-treated patients (8%) is not statistically significant (P = .25 using the Fisher exact test).

Table Graphic Jump LocationTable Summary of Patient Details and Study Findings

Our study identified a 19% prevalence of abnormal muscle enzyme levels in dermatologic patients treated with long-term antimalarial regimens, similar to that determined by Casado et al3 (18.5%). However, in contrast to the 36% correlation between elevated enzyme levels and clinical AMM identified by Casado et al, none of our patients with abnormal muscle enzyme levels experienced clinical myopathy. Thus, our study findings do not support the clinical relevance of muscle enzyme level determination for the identification of clinical AMM. The significance of the observed muscle enzyme level elevations observed in our patients is unknown; they may be incidental findings or may represent subclinical AMM; however, neither invasive testing nor empirical discontinuation of otherwise successful therapy based solely on asymptomatic muscle enzyme level elevations seems warranted.

Of the 5 patients with abnormal physical findings, 1 patient had a history of stroke, thus explaining her unilateral weakness. Three other patients experienced subtle proximal muscle weakness that could potentially be related to antimalarial therapy along with numerous other possible causes. The last patient experienced markedly diminished bilateral patellar deep tendon reflexes that predated antimalarial therapy. While it is difficult to interpret the significance of muscle symptoms and abnormal neuromuscular examinations experienced by some of our patients, we are reassured by the lack of correlation with elevated muscle enzyme levels.

While this prospective study is limited by a small sample size, our findings, combined with prior large retrospective studies failing to identify any correlation between abnormal muscle enzyme levels and clinical AMM, call into question the suitability of using muscle enzyme testing in screening for clinical AMM.1,2,4 As AMM is typically reversible on discontinuation of antimalarial therapy, routine muscle enzyme level determination and potential subsequent electromyography and/or muscle biopsy do not seem warranted. For these reasons, empirical discontinuation of antimalarial therapy may be the most prudent action for the small percentage of patients who develop clinical AMM. Accordingly, we believe screening for AMM via a thorough review of systems and physical neuromuscular examination is most appropriate.

ARTICLE INFORMATION

Correspondence: Dr Kalajian, 310 E Broadway, Floor 2A, Louisville, KY 40202 (akalajian@yahoo.com).

Author Contributions: Drs. Kalajian and Callen had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Kalajian and Callen. Acquisition of data: Kalajian and Callen. Analysis and interpretation of data: Kalajian and Callen. Drafting of the manuscript: Kalajian. Critical revision of the manuscript for important intellectual content: Kalajian and Callen. Administrative, technical, or material support: Kalajian. Study supervision: Callen.

Financial Disclosure: Dr Callen has received honoraria from Amgen, Abbott Immunology, Genentech, Centocor, Electrical Optical Sciences, Medicis, and Steifel. He serves on a safety monitoring committee for Genmab. None of these financial relationships are relevant to this manuscript.

Additional Contributions: Andrea Booth-Kalajian provided assistance with study design and data analysis.

Disclaimer: Dr Callen is associate editor of the Archives of Dermatology, but he was not involved in any of the decisions regarding review of the manuscript or its acceptance.

Avina-Zubieta  JAJohnson  ESSuarez-Almazor  MERussell  AS Incidence of myopathy in patients treated with antimalarials: a report of three cases and a review of the literature. Br J Rheumatol 1995;34166- 170
Link to Article
Wang  CFortin  PRLi  YPanaritis  TGans  MEsdaile  JM Discontinuation of antimalarial drugs in systemic lupus erythematosus. J Rheumatol 1999;26 (4) 808- 815
PubMed
Casado  EGratacos  JTolosa  C Antimalarial myopathy: an underdiagnosed complication? prospective longitudinal study of 119 patients. Ann Rheum Dis 2006;65 (3) 385- 390
PubMed Link to Article
Stein  MBell  MJAng  L Hydroxychloroquine neuromyotoxicity. J Rheumatol 2000;27 (12) 2927- 2931
PubMed

Figures

Tables

Table Graphic Jump LocationTable Summary of Patient Details and Study Findings

References

Avina-Zubieta  JAJohnson  ESSuarez-Almazor  MERussell  AS Incidence of myopathy in patients treated with antimalarials: a report of three cases and a review of the literature. Br J Rheumatol 1995;34166- 170
Link to Article
Wang  CFortin  PRLi  YPanaritis  TGans  MEsdaile  JM Discontinuation of antimalarial drugs in systemic lupus erythematosus. J Rheumatol 1999;26 (4) 808- 815
PubMed
Casado  EGratacos  JTolosa  C Antimalarial myopathy: an underdiagnosed complication? prospective longitudinal study of 119 patients. Ann Rheum Dis 2006;65 (3) 385- 390
PubMed Link to Article
Stein  MBell  MJAng  L Hydroxychloroquine neuromyotoxicity. J Rheumatol 2000;27 (12) 2927- 2931
PubMed

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