42‐YEAR‐OLD MAN WITH DISCOID LUPUS AND PROGRESSIVE WEAKNESS

CLINICAL HISTORY

A 42‐year‐old man presented with three months of progressive proximal weakness, a thirty pound weight loss, and worsening dysphagia for solids. He had been hospitalized two months earlier for respiratory failure requiring intubation and five days of mechanical ventilation. Arterial blood gas on admission revealed a pH of 7.26; pCO₂ 58.8 torr; bicarbonate 26.2; and pO₂ of 57.1 torr. A primary pulmonary etiology was not found, and he improved. During that hospitalization, an electromyogram of the upper extremities was normal. There were chronic neurogenic changes in the lower extremities. Low amplitude, short duration motor unit potentials suggestive of myopathy were noted in the cervical and thoracic paraspinal muscles.

His past medical history was significant for chronic low back pain, multiple lumbar surgeries, hypertension, glaucoma, and discoid lupus. He had been maintained on hydroxychloroquine 1000 mg/day for 15–20 years for discoid lupus. Neurologic examination revealed Medical Research Council grade 4/5 strength in neck flexor and proximal upper and lower extremity muscles. Distal muscles were strong. Tendon reflexes were diminished. There was mild distal loss of sensation from the toes to the ankles bilaterally. He was unable to rise from a chair without using his hands. Laboratory studies, including complete blood count, erythrocyte sedimentation rate, thyroid functions, and electrolytes were normal. Total creatine kinase was elevated at 509 IU/L (normal < 200). A repeat limited electromyogram immediately prior to deltoid needle muscle biopsy revealed mild fibrillation potential and positive wave activity along with short duration motor unit potentials in a proximal arm muscle.

PATHOLOGY

Hematoxylin and eosin stained frozen sections of the left deltoid muscle revealed an abnormal variation in myofiber size with a mild increase in internalized nuclei. Rare degenerating and occasional regenerating fibers were noted. Inflammatory infiltrates were not seen. Most fibers showed multiple vacuoles containing granular amphophilic material (1, 2; size marker in figures 1–8 equals 40 microns). With the Gomori trichrome stain, purplish material was highlighted within the vacuoles and in the sarcoplasm (Figure 3). Oil red‐O demonstrated lipid in some of vacuoles. The material in the vacuoles was strongly reactive for acid phosphatase (4, 5) and esterase (Figure 6). NADH‐ tetrazolium reductase reacted sections revealed a few small hyperreactive fibers and targetoid fibers. PAS stained sections contained no abnormal accumulations of glycogen. Examination of thioflavin‐T and Congo red stains under fluorescence revealed no abnormal accumulations. ATPase reacted sections revealed loss of normal checkerboard pattern, mild myofiber atrophy of both type 1 and 2 fibers and vacuoles in both type 1 and 2 fibers (Figure 7; pH 9.4). Paraffin sections showed strong nonspecific immunoreactivity for ubiquitin in many vacuoles (Figure 8). Electron microscopy revealed curvilinear inclusions in vacuoles (9, 10) and myeloid bodies with lysosomal degradation products within membrane bound vacuoles (11, 12).

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DIAGNOSIS

Hydroxychloroquine myopathy.

DISCUSSION

Hydroxychloroquine (HCQ), a commonly used drug for various autoimmune conditions, is widely distributed into cardiac and skeletal muscle tissue. It is a large amphiphilic molecule that can cause both myofiber necrosis and vacuolar myopathy. It can permeate lysosomes and accumulate, leading to impaired lysosomal protein degradation and accumulation of vacuoles containing membrane phospholipids and glycogen (4). These changes are visualized on electron microscopy as curvilinear bodies and lamellar structures called myeloid bodies. Curvilinear bodies are only seen in two conditions: neuronal ceroid lipofuscinosis and myopathy secondary to HCQ or chloroquine.

Large secondary lysosomes may also be present. The hydrophobic region of the HCQ molecule interacts with membrane phospholipids causing neutralization of phosphate groups and displacement of calcium. This leads to myofiber necrosis through alterations in the plasmalemma (1). The findings of vacuolar myopathy, myofiber necrosis, myeloid bodies, and curvilinear bodies in isolation can be seen in other conditions and are not specific for antimalarial toxicity. These features in combination, and in the correct clinical scenario, may be specific for this diagnosis.

Neuromyotoxicity due to HCQ is thought to be rare. It was first reported in 1965. One prospective study estimated the incidence of HCQ myopathy to be 1.9 per 1000 patient years (5). Toxicity may be more likely in patients with renal or hepatic disease, advanced age, or on chronic drug therapy. Hydroxychloroquine myopathy presents with proximal muscle weakness and normal to mildly elevated creatine kinase levels. There are very few reported cases of ventilatory failure due to HCQ myopathy 2, 3.

This patient was on HCQ therapy for discoid lupus for up to twenty years. With discontinuation of the medication, he had noticeable improvement in strength four weeks later. Muscle strength was Medical Research Council grade 5‐/ 5 in the proximal muscles. Hydroxychloroquine myopathy may be more common than previously reported and should be considered in patients on long term therapy presenting with weakness or ventilatory failure. In these cases, muscle biopsy should be performed, as the characteristic pathologic findings may confirm the diagnosis.

ABSTRACT

A 42‐year‐old man presented with three months of progressive proximal weakness, a thirty pound weight loss, and dysphagia. He was hospitalized two months earlier for ventilatory failure requiring five days of mechanical ventilation. His history also included long‐term hydroxychloroquine therapy for discoid lupus and a recently elevated total creatine kinase. An electromyogram revealed evidence of an irritable myopathy. Microscopic examination of a muscle biopsy specimen revealed vacuolar myopathy with lysosomal activation. Electron microscopy demonstrated curvilinear inclusions that, given his history, were diagnostic of hydroxychloroquine (HCQ) myopathy. Although HCQ myopathy typically presents with proximal muscle weakness and normal‐to‐mildly‐elevated creatine kinase levels, this is one of the few reported cases of ventilatory failure due to HCQ myopathy. Hydroxychloroquine myopathy may be more common than previously reported and should be considered in patients on long term therapy presenting with weakness or ventilatory failure. In these cases, muscle biopsy should be performed to confirm the diagnosis.