Glucocorticoid effects on skeletal muscle: benefit and risk in patients with autoimmune inflammatory rheumatoid diseases

Keywords::

• glucocorticoid
• muscle
• myopathy
• steroid

Glucocorticoids have broad-spectrum immunosuppressive and anti-inflammatory properties that have therapeutic effects for a variety of rheumatologic conditions, such as rheumatoid arthritis, vasculitidies, idiopathic inflammatory myopathies (IIMs) and other connective tissue diseases. It has been estimated that approximately 1% of the general adult population take oral glucocorticoids at any given time, and that in older adults this rate may be as high as 2.5% [1]. In prescribing glucocorticoids to patients, clinicians are cognizant of the myriad adverse effects associated with these medications, but more effective therapeutic alternatives devoid of substantial deleterious effects are lacking.

Individual patient susceptibility to adverse effects depends on glucocorticoid dose, duration of therapy, glucocorticoid receptor saturation levels and glucocorticoid receptor gene polymorphisms [2]. Common adverse effects associated with dose-dependent and cumulative glucocorticoid use include osteoporosis, cataracts, lipodystrophy, weight gain, systemic arterial hypertension, metabolic syndrome and adrenal suppression [3,4]. Osteoporosis is a particularly serious complication of long-term glucocorticoid therapy that is associated with a high personal and economic burden. In the USA alone, care of incident osteoporotic fractures was estimated to total close to US$17 billion in 2005 [5]. A landmark study demonstrated patients taking at least 7.5 mg daily of prednisolone or equivalent had significantly increased risks of vertebral, hip and nonvertebral fractures compared with patients using oral glucocorticoids at lower doses (<2.5 mg daily), where the median duration of glucocorticoid therapy was 28 days overall [6]. Still, according to van Staa et al., older patients and patients with arthritis are more likely to be on prolonged oral corticosteroid treatment for over 2 years compared with younger patients or those with chronic obstructive pulmonary disease, respectively [1]. Therefore, the burden of glucocorticoid therapy is especially high in a typical outpatient rheumatology clinic, where the mean age of patients referred from general practice is approximately 45 years, 18% of patients are 60 or older, and approximately half of all referrals are diagnosed with inflammatory rheumatic diseases that typically require glucocorticoid therapy [7].

Similar to bone, skeletal muscle homeostasis is disrupted by glucocorticoids. Glucocorticoids not only decrease muscle anabolism by inhibiting amino acid transport into muscle [8], but also increase muscle catabolism by altering three major pathways: the myostatin signaling pathway, the IGF-1–PI3K–Akt pathway and the NF-κB pathway [2]. The result is a shift in net skeletal muscle protein balance towards proteolysis. There is also emerging evidence that glucocorticoids inhibit muscle regeneration by interfering with myogenic differentiation [9] and/or immune responses that detect injury and trigger repair [2]. Finally, Schakman et al. recently demonstrated that glucocorticoids, but not IGF-I or TNF-α–NF-κB, play a key role in inducing proteolysis in acute inflammatory states via the autophagy and the ubiquitin–proteasome pathways [10].

In our view, it is plausible, if not likely, that long-term glucocorticoid use could affect skeletal muscle to a similar extent as bone. Certainly, the effect of these important drugs on skeletal muscle should be an area for investigation in patients with rheumatic diseases requiring glucocorticoids. Patients at risk include elderly patients, those with poor nutritional intake, and those not participating in exercise that could counterbalance the negative metabolic effects of glucocorticoids. We speculate that glucocorticoid therapy could contribute to the etiopathogenesis of rheumatoid cachexia, as well as to persistent muscle weakness and loss of endurance in patients with IIM. Rheumatoid cachexia is a well-characterized muscle-wasting condition that affects nearly two-thirds of all rheumatoid arthritis patients, and is thought to be an important contributor to comorbid conditions and decreased life expectancy [11]. Several potential mechanisms of rheumatoid cachexia have been proposed, and include elevated resting energy expenditure, low physical activity, reduced peripheral insulin action, decreased serum IGF-I and excessive production of sarcoactive inflammatory cytokines, such as TNF-α and IL-1β [12]. In our view, glucocorticoid therapy may be a direct contributor to rheumatoid cachexia. Similarly in IIM, while it is true that glucocorticoid therapy may be beneficial acutely, a substantial number of patients persist with decreased muscle strength and endurance [13], even in the absence of significant muscle inflammation, atrophy, fibrosis, fatty infiltration or atrophy [14]. At this time, it is unclear to what extent glucocorticoid therapy plays a role in this adverse outcome.

Finally, it is worth mentioning that glucocorticoids are associated with glucocorticoid-induced myopathy and critical illness myopathy (CIM). Glucocorticoid-induced myopathy is typically associated with the use of glucocorticoids in high doses and fluorinated glucocorticoid preparations. Patients develop insidious pain-free proximal muscle weakness that primarily affects the lower extremities several weeks or years into glucocorticoid therapy. Throughout its course, serum muscle enzyme levels generally remain in the normal range or mildly elevated [15]. On histopathology, glucocorticoid-induced myopathy is characterized by preferential loss and atrophy of type II muscle fibers [16]. Muscle weakness usually begins to ameliorate within 3–4 weeks after glucocorticoid cessation, but may last for up to 6 weeks. CIM, on the other hand, has been linked to treatment with high doses of glucocorticoids and neuromuscular blocking agents. Other risk factors such as renal failure, hyperglycemia and increased severity of the underlying disease are also important [17]. It has been estimated that at least a third of intensive care unit patients treated for status asthmaticus develop CIM [18]. Patients typically present with acute-onset, diffuse, flaccid muscle weakness that generally affects all limb muscles, neck flexors, and often the diaphragm and facial muscles [17]. Serum creatinine kinase levels generally increase ten- to 100-fold higher than normal, peaking at day 3–4 and normalizing after 10 days [19]. The diagnosis is made on the basis of distinctive electrophysiological activity and muscle/nerve biopsies analyses. Electrodiagnostic testing reveals low amplitude, short duration and polyphasic motor unit potentials, low amplitude compound action potentials, fibrillation and sharp wave potentials [20]. On histopathology, CIM is characterized by varying degrees of muscle fiber necrosis and regeneration, no lymphocytic inflammation, preferential atrophy of type II fibers and loss of thick myosin filaments [21].

In conclusion, we propose that glucocorticoid therapy may inadvertently impair skeletal muscle homeostasis and normal skeletal muscle repair processes. Our knowledge of the consequences of long-term glucocorticoid use on skeletal muscle mass, strength and endurance require further studies. A better understanding of the response of skeletal muscle to glucocorticoids, and the processes within muscle that enable some patients to maintain normal function while others suffer from severe impairment, will improve clinical practice and treatment outcomes.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.