Final Diagnosis

Hydroxychloroquine Myopathy

Patient Follow-up

Hydroxychloroquine was discontinued. The patient underwent physical therapy. She reported marked improvement of her weakness and endurance 2 months later when she returned for follow-up. She could walk a mile without feeling fatigue or shortness of breath. Examination showed minimal weakness in the bilateral deltoid and iliopsoas muscles (5−/5). Weakness in the biceps and quadriceps muscles resolved. She was able to get up from a chair without her hands to push.

Discussion

Hydroxychloroquine and its predecessor chloroquine were first introduced as antimalarial drugs. They were subsequently found to also have anti-inflammatory properties and have been widely used for treating connective tissue diseases, including SLE, rheumatoid arthritis, and Sjogren’s syndrome, among others [1–4]. They are 4-aminoquinolones and amphiphilic cationic drugs with a high affinity for the lipid-rich membranes of lysosomes. Once the drugs enter lysosomes, they tend to accumulate, where they neutralize lysosomal contents and raise intra-lysosomal pH. This in turn inhibits lysosomal enzyme activities and affects lysosomal protein, phospholipid, and glycogen degradation [5]. The toxicity mainly affects muscle, nerve, myocardium and retina. Hydroxychloroquine is less toxic than chloroquine [6–9].

Hydroxychloroquine myopathy is considered to be rare, but it is probably underrecognized and underreported. The risk factors include Caucasian race, renal dysfunction, and concomitant use of other myotoxic drugs. The occurrence of hydroxychloroquine myopathy does not appear to be dose-dependent [10, 11]. The disease may predominantly affect proximal limb muscles or in severe cases may affect both proximal and distal limb muscles as well as respiratory muscles with resultant respiratory failure [12–14]. Therefore, it is important to make an early diagnosis to avoid mortality and morbidity.

As hydroxychloroquine is often used along with corticosteroids to treat connective tissue diseases, a myopathy that develops in this clinical setting may represent hydroxychloroquine myopathy, steroid myopathy, and/or an inflammatory myopathy associated with connective tissue diseases. Serum CK and EMG findings can sometimes be helpful in differentiating these conditions. Serum CK is usually normal in steroid myopathy while it is usually elevated in inflammatory myopathies. CK can be normal or mildly elevated in hydroxychloroquine myopathy. EMG often shows an irritable myopathy in hydroxychloroquine myopathy and inflammatory myopathy but a non-irritable myopathy or no myopathic findings in steroid myopathy. Diffuse myotonic discharges, if present, can help indicate hydroxychloroquine myotoxicity [12]. A muscle biopsy is necessary for a definitive diagnosis.

Muscle biopsies in hydroxychloroquine myopathy, steroid myopathy, and inflammatory myopathy have very different and distinctive features. The muscle biopsy in hydroxychloroquine myopathy is characterized by the presence of a vacuolar myopathy with autophagic rimmed vacuoles and, at an ultrastructural level, the accumulation of myeloid profiles and curvilinear bodies due to the enzymatic degradation of lysosomal membranes. The muscle fibers with vacuolar changes are often severely atrophic and basophilic [12, 13]. These vacuoles are red rimmed in GT stain as they contain membranous debris. Unlike lysosomal glycogen storage diseases such as late-onset Pompe disease, sarcoplasmic vacuoles in hydroxychloroquine myopathy do not contain excessive glycogen accumulation. EM study shows distinctive curvilinear bodies, a characteristic finding only seen in chloroquine/hydroxychloroquine and other amphiphilic cationic myopathies and some variants of neuronal ceroid lipofuscinosis [11, 15]. Steroid myopathy is characterized by type 2b myofiber atrophy, a non-specific finding which can also be seen in disuse, cachexia, alcohol abuse, connective tissue diseases, and a number of endocrinopathies. Inflammatory myopathy is characterized by primary endomysial and/or perimysial inflammation, morphological evidence of myofiber injury and either diffuse of selective perifascicular MHC1 upregulation. Although inclusion body myositis (IBM) also shows red rimmed vacuoles, these vacuoles contain tubulofilamentous inclusions but not curvilinear bodies. In addition, biopsies from patients with IBM often have many cytochrome c oxidase (COX)-deficient fibers . Clinically, IBM tends to affect men above 50 years of age with predominant involvement of finger flexors and knee extensors. Therefore, the clinical presentation and muscle biopsy findings in our patient are consistent with hydroxychloroquine myopathy.

The management of hydroxychloroquine myopathy is simple, and the disease can be reversible by discontinuing hydroxychloroquine. Patients may show significant improvement over several months if diagnosed and managed early as seen in our case [10, 13]. However, the disease can also be severe and life-threatening due to the respiratory muscle involvement [12, 14]. It is thus important to make an early diagnosis by a muscle biopsy.

Pearls