Version May 2024
INTRODUCTION — Glucocorticoids are important in the treatment of many inflammatory, allergic, immunologic, and malignant disorders. Toxicity from glucocorticoids is one of the commonest causes of iatrogenic illness associated with the treatment of chronic inflammatory diseases. Recognition of these toxicities, many of which are similar to the manifestations of spontaneous (endogenous) Cushing syndrome, is valuable in their prevention and management. (See "Epidemiology and clinical manifestations of Cushing syndrome".)
The major adverse effects seen with systemic (oral and parenteral) glucocorticoid therapy will be reviewed here. The adverse effects resulting from the use of inhaled, topical, and intraarticular glucocorticoids; adverse effects of glucocorticoids on the immune system; clinical manifestations of endogenous glucocorticoid excess (Cushing syndrome); glucocorticoid withdrawal; and use during pregnancy are discussed in detail separately:
●Adverse effects of inhaled glucocorticoids (see "Major side effects of inhaled glucocorticoids")
●Adverse effects of topical glucocorticoids (see "Topical corticosteroids: Use and adverse effects", section on 'Adverse effects')
●Adverse effects of intraarticular glucocorticoids (see "Joint aspiration or injection in adults: Complications", section on 'Glucocorticoid-associated toxicity')
●Adverse effects of glucocorticoids on the immune system (see "Glucocorticoid effects on the immune system")
●Diagnosis of Cushing syndrome (see "Epidemiology and clinical manifestations of Cushing syndrome")
●Glucocorticoid withdrawal (see "Glucocorticoid withdrawal")
●Glucocorticoid use in pregnancy and lactation (see "Safety of rheumatic disease medication use during pregnancy and lactation", section on 'Glucocorticoids')
This topic focuses on the side effects of systemic prednisone, prednisolone, and methylprednisolone in particular, as there are more data for these medications. More information about various types of steroids and equivalent doses can be found elsewhere. (See "Determinants of glucocorticoid dosing".)
FACTORS RELATED TO GLUCOCORTICOID TOXICITY — Numerous toxicities, or adverse effects, have been attributed to glucocorticoids (table 1). However, other factors may also contribute to the development of adverse effects in a given patient, such as the nature and severity of the underlying disease being treated and the other concurrent medications. Estimates of the frequency and severity of adverse effects, as well as the respective dose and duration of therapy that may result in adverse effects, are also limited by the modest number of prospective studies and the very few randomized controlled trials that address this question with high methodologic rigor.
Mechanisms of adverse effects — Glucocorticoids used in chronic disease (eg, prednisone or prednisolone) do not have significant mineralocorticoid, androgenic, or estrogenic activity; thus, their major adverse effects result from inhibition of hypothalamic-pituitary-adrenal function and the development of iatrogenic Cushing syndrome. (See "Pharmacologic use of glucocorticoids", section on 'Complications of chronic use' and "Epidemiology and clinical manifestations of Cushing syndrome".)
Differences in glucocorticoid bioavailability and receptor activation influence the efficacy and toxicity of different glucocorticoids. Genetic polymorphisms in the glucocorticoid receptor and glucocorticoid metabolism can therefore impact glucocorticoid effects. This variability helps explain the differential resistance to therapy and toxicities among patients [1-4]. Mechanisms involved in the adverse effects of glucocorticoids are described in more detail elsewhere. (See "Determinants of glucocorticoid dosing".)
Prolonged effects of glucocorticoid exposure, such as atrophy of cells in the anterior pituitary and adrenal gland, are caused in part by the nonspecific effects of glucocorticoids on cellular function [5]. Once cell atrophy occurs, full recovery from glucocorticoid effects may take months or even years after stopping the medication.
Glucocorticoid dose and duration — Several retrospective reviews have shown that long-term glucocorticoid use, even in low doses, is a significant independent predictor of numerous adverse effects and that the risk is both dose- and duration-dependent [6-9].
Dose — The daily dose of glucocorticoid is a key factor in toxicity, with higher doses carrying a higher risk of adverse effects [6,7,9]. A study of 112 patients with rheumatoid arthritis (RA) found that the average daily prednisone dose was the strongest predictor of a serious adverse effect potentially attributable to glucocorticoid therapy, even after adjustment for RA disease severity (odds ratio [OR] 4.5 for 5 to 10 mg and 32.3 for 10 to 15 mg) (figure 1) [7]. The preselected adverse effects included in the analysis were fracture, serious infections, gastrointestinal bleed or ulcer, and cataracts.
●Very low doses – There are some data that suggest that very low doses of glucocorticoids (eg, prednisone <5 mg/day) are associated with fewer adverse effects [10,11]. While randomized trial data are limited, a double-blind placebo-controlled trial randomized patients over age 65 years with RA to an add-on of 5 mg/day of prednisolone for a two-year period [12]. At least one adverse effect was noted in 60 percent of patients on prednisone versus 49 percent of patients on placebo, giving an increased adjusted relative risk of 1.24 (95% CI 1.04). The largest difference between groups was in mild to moderate infections requiring treatment, and other glucocorticoid-specific adverse effects were rare. However, other studies have suggested adverse effects even at low doses, including suppression of the hypothalamic-pituitary-adrenal (HPA) axis in patients who were on under 5 mg/day of prednisone for less than four weeks and development of cataracts [6,13].
●Linear and threshold patterns of adverse effects – Different patterns dose-related adverse glucocorticoid effects have been described, including a "linear" relationship (increasing frequency with increasing dose) and a "threshold" effect (effect more common above a certain dose). A large retrospective analysis, which included data from 1066 patients with RA on glucocorticoids for more than six months, observed a linear pattern for Cushingoid phenotype, ecchymosis, leg edema, fungal infections, parchment-like skin, shortness of breath, and sleep disturbance [6,14]. A threshold pattern was seen for glaucoma, depression, and elevated blood pressure at doses of prednisone greater than 7.5 mg/day and for weight gain and epistaxis at doses of prednisone greater than 5 mg/day.
●High "pulse" dose – Glucocorticoids are sometimes given as high-dose "pulse" infusions (eg, 1 g/day of intravenous methylprednisolone for multiple days) in an attempt to rapidly control severe manifestations of autoimmune or other rheumatic diseases. Such dosing may cause more prominent adverse effects including increased appetite and weight gain, gastritis, insomnia, and mood changes. It can also cause bradycardia and rarely other serious cardiovascular toxicities [15]. (See 'Cardiovascular effects' below.)
Duration — Longer duration of glucocorticoid therapy and therefore higher cumulative doses are associated with adverse effects [6-9]. However, shorter-term glucocorticoid use may also be associated with serious adverse effects, particularly with higher doses.
It is unclear if there is a threshold for duration of glucocorticoid therapy at which adverse effects become more prominent. For example, patients may experience iatrogenic adrenal insufficiency regardless of the duration of therapy, although it is more common with longer courses [16]. In our opinion, taking a week of prednisone, even at higher doses, is unlikely to suppress the HPA axis; however, this is based on limited data. A study of a short course of moderate-dose prednisone (40 mg/day, tapering off over seven days) did not show HPA axis suppression [17].
Several studies describe a potential link between serious adverse effects and relatively short-term glucocorticoid use. These studies used nationwide datasets of private insurance claims, meaning important limitations include potential misclassification of diagnoses in large databases, lack of accounting for comorbidities and concomitant medications, and inability to control for other time-varying factors that could have been differentially distributed between the risk and baseline periods.
●A retrospective cohort study and self-controlled case series using a nationwide dataset of private insurance claims in the United States assessed the risk of three adverse effects (sepsis, venous thromboembolism [VTE], and fracture) in 327,452 adults younger than 65 years of age who received at least one short-term (<30 days) outpatient prescription over a three-year period [18]. The glucocorticoid dose varied, with prepackaged methylprednisolone accounting for almost half of prescriptions (equivalent to 105 mg of prednisone over six days) and doses equivalent to <17.5 mg/day of prednisone accounting for only 6.3 percent of prescriptions. Within 30 days of drug initiation, there were increases in the rates of sepsis (incidence rate ratio [IRR] 5.30, 95% CI 3.80-7.41), VTE (IRR 3.33, 95% CI 2.78-3.00), and fracture (IRR 1.887, 95% CI 1.69-2.07), which then decreased over the subsequent 31 to 90 days. The absolute risks of each of the adverse effects was low.
●Another large case-controlled case series using a nationwide dataset of private insurance claims included 2,623,327 persons aged 20 to 64 years who had received a single prednisone burst for 14 days or fewer [19]. Within the 5 to 30 days after glucocorticoid initiation, rates of gastrointestinal bleeding (IRR 1.80, 95% CI 1.75-1.84), sepsis (IRR 1.99, 95% CI 1.70-2.32), and heart failure (IRR 2.37, 95% CI 2.13-2.63) increased, but then the risk attenuated during the subsequent 31 to 90 days.
ORGAN-BASED TOXICITY OF SYSTEMIC GLUCOCORTICOIDS
Delayed presentation — Some adverse effects, such as accelerated reductions in bone mineral density or early cataracts, may be largely asymptomatic until later manifestations develop that require medical attention (eg, acute vertebral collapse, cataract requiring surgical extraction).
Reversibility — Many glucocorticoid toxicities are at least partially reversible over time with glucocorticoid discontinuation, with the exception of cataracts, a potential acceleration in atherosclerotic vascular disease, bone effects (osteoporosis and osteonecrosis), and possible long-term effects on linear growth in children. (See 'General treatment considerations and monitoring' below.)
Specific systems — Glucocorticoids have numerous and variable toxicities (table 1). These adverse effects range from those that are temporary but challenging for patients (eg, insomnia) to those that are life threatening (eg, serious infections).
Metabolic and endocrine effects
●Hypothalamic-pituitary-adrenal axis suppression – Administration of exogenous glucocorticoids, particularly when given in divided doses, can suppress the hypothalamic-pituitary-adrenal (HPA) axis. Abrupt cessation or rapid withdrawal of glucocorticoids in such patients may cause symptoms of adrenal insufficiency. The approach to withdrawal of glucocorticoids, HPA axis suppression, and the clinical manifestations of adrenal insufficiency are presented separately [20]. (See "Glucocorticoid withdrawal" and "Clinical manifestations of adrenal insufficiency in adults".)
●Hyperglycemia – The mechanism by which glucocorticoids cause hyperglycemia is multifactorial, including augmentation of hepatic gluconeogenesis, inhibition of glucose uptake in adipose tissue, and alteration of receptor and post-receptor functions [1,21-23]. It is also possible that some underlying disorders for which glucocorticoids are used, such as rheumatoid arthritis (RA), may independently predispose to a higher rate of glucose intolerance [24]. Monitoring for hyperglycemia is discussed below. (See 'Monitoring and treatment of adverse effects' below.)
•Patients without preexisting diabetes mellitus – Patients who do not have preexisting diabetes may develop hyperglycemia and/or diabetes mellitus while taking glucocorticoids. A meta-analysis of studies involving glucocorticoids indicated that hyperglycemia and diabetes were discovered in 23 and 19 percent of patients respectively [25]. Glucocorticoid-induced hyperglycemia improves with reduction in the dose of glucocorticoid and usually reverses when the medication is stopped, although some patients develop persistent diabetes [26,27]. New-onset hyperglycemia or, rarely, a nonketotic hyperosmolar state or diabetic ketoacidosis can develop without warning in patients with early subclinical diabetes or glucose intolerance [28-30].
More commonly, systemic glucocorticoids can cause a dose-dependent, usually mild, increase in fasting glucose levels and a greater increase in postprandial glucose levels in patients without preexisting diabetes mellitus. In a case-control study of Medicaid recipients, the relative risk of developing hyperglycemia requiring glucose-lowering therapy increased progressively with increasing glucocorticoid dose [30]. The relative risk increased from 1.8 in patients treated with the equivalent of less than 10 mg/day of prednisone to 10.3 in those with the equivalent of more than 30 mg/day of prednisone [30]. Risk factors for new-onset hyperglycemia during glucocorticoid therapy are thought to be the same as those for other patients, including a family history of diabetes, increased age, obesity, and a history of gestational diabetes [31]. (See "Comorbidities that impact management of osteoarthritis", section on 'Diabetes mellitus'.)
•Patients with preexisting diabetes mellitus – Patients with preexisting diabetes mellitus or glucose intolerance exhibit higher blood glucose levels while taking glucocorticoids, leading to increased difficulty with glycemic control.
Dermatologic effects and appearance — Many clinically relevant adverse effects of glucocorticoids on the skin and appearance have been observed even at lower doses, including Cushingoid features, weight gain, skin thinning, striae, ecchymoses, acne, mild hirsutism, and facial erythema.
●Cushingoid features – The development of Cushingoid features (redistribution of body fat with truncal obesity, buffalo hump, and moon face) and weight gain are dose- and duration-dependent and can develop within the first two months of therapy (picture 1 and picture 2 and picture 3). A Cushingoid appearance is uncommon at doses below the physiologic glucocorticoid-replacement range but can develop even with low-dose therapy. Cushingoid features showed a linear increase in frequency with dose rather than a threshold effect. In an observational study of 779 patients RA who received <5, 5 to 7.5, and >7.5 mg/day of prednisone or equivalent, Cushingoid features were observed in 4.3, 15.8, and 24.6 percent of patients, respectively [6]. (See "Epidemiology and clinical manifestations of Cushing syndrome", section on 'Progressive obesity'.)
●Weight gain – Weight gain is commonly reported among patients taking glucocorticoids, and was the most common self-reported adverse effect (70 percent of patients) in a survey of 2167 patients taking long-term glucocorticoids (mean prednisone equivalent dose ± standard deviation [SD] of 16±14 mg/day for ≥60 days) [9]. Studies have noted weight gain is more common among patients with RA taking 5 mg of prednisone or more daily [6]. The amount of weight gained can vary, but in an analysis of four prospective trials of glucocorticoids in patients with RA, the use of 5 to 10 mg/day of prednisone or equivalent over two years was associated with an increase of mean body weight of 4 to 8 percent [10]. Factors that may contribute to increased weight include an increased appetite, which is a common side effect of glucocorticoid therapy, and an increase in food intake for symptomatic relief in patients with gastropathy or peptic ulcer disease [32].
●Skin thinning, striae, and ecchymoses – Among the most common toxicities attributable to glucocorticoids are skin thinning, striae, and ecchymoses, which can occur even at low doses and are similar to those noted in Cushing syndrome (picture 4 and picture 5) [10,33]. A large observational study with patient-reported data from patients with RA on glucocorticoids for at least six months reported rates of parchment-like skin and ecchymoses in 10 and 17 percent, respectively [6]. The prevalence of these effects also increased with higher doses of prednisone. In a prospective study with 80 patients, skin changes were observed in 46 percent of patients treated for three months with prednisone at doses greater than 20 mg/day [33]. The ecchymoses or purpura associated with glucocorticoid use often affects the sun-exposed areas of the dorsum of the hand and forearm and is not accompanied by palpable swelling (see "Photoaging", section on 'Photoaging in individuals with phototypes I to IV'). Striae develop often due to a combination of skin thinning and weight gain.
While evidence is limited to support any intervention to prevent skin manifestations, patients may benefit from photoprotective measures (eg, use of sunscreen with sun protection factor [SPF]) and keeping the skin moisturized. Although there is some reported success for various creams, lasers, and microabrasion, no large well-conducted studies have been done and no specific recommendations can be made to prevent or treat striae associated with glucocorticoid use [34].
●Other – Other side effects such as acne (occurring in 2 to 19 percent of patients), hirsutism (occurring in 5 to 8 percent of patients), and facial swelling may occur but are reversible when the glucocorticoids are stopped. The treatment of these conditions is the same as for people who are not taking glucocorticoids. (See "Acne vulgaris: Overview of management" and "Removal of unwanted hair".)
Cardiovascular effects — Glucocorticoid use has been associated with a variety of adverse cardiovascular effects including fluid retention, hypertension, premature atherosclerotic disease, and arrhythmias. Cardiovascular disease risk is dose-dependent and may be low or absent in patients on low-dose glucocorticoid therapy [35].
●Fluid retention – Higher-dose glucocorticoids may promote fluid retention, which is of particular concern to patients with underlying heart or kidney disease. This is not a problem in patients without those comorbidities because of the phenomenon of mineralocorticoid escape that prevents progressive fluid overload. (See "Pathophysiology and clinical features of primary aldosteronism".)
●Hypertension – Hypertension is a known adverse effect of glucocorticoids and has been observed in up to 20 percent of patients with iatrogenic Cushing syndrome [36]. It is a dose-related adverse effect and is unlikely in patients receiving low doses of glucocorticoids (eg, 10 mg/day of prednisone) [6,28,37-39]. Based on pooled data from trials involving patients with RA, blood pressure was not significantly higher among patients who were randomized to receive low-dose glucocorticoids (equivalent to 7.5 mg/day or less of prednisone) for two years compared with those receiving placebo [40]. In patients taking low doses, significant hypertension may be better explained by age and initial blood pressure than by the glucocorticoids themselves [41]. The mechanism by which glucocorticoid therapy can raise the blood pressure is not well understood [42,43]. (See "Epidemiology and clinical manifestations of Cushing syndrome", section on 'Hypertension'.)
●Premature atherosclerotic disease – Glucocorticoid use has been associated with increased rates of myocardial infarction, stroke, heart failure, and all-cause mortality, at least at doses greater than 5 to 7.5 mg/day [35,44]. However, rheumatic disease may be an independent risk factor for premature atherosclerotic disease, and it is unclear to what extent this may confound current studies. The association between glucocorticoid use and atherosclerotic disease is less clear when studies are limited to populations receiving glucocorticoid for inflammatory disorders [39,45-47]. In a large longitudinal cohort study of over 12,000 patients with rheumatoid arthritis, the relationship between glucocorticoid exposure and incident major adverse cardiovascular events (MACE) was assessed over a mean follow-up time of 8.7 years [48]. Patients taking >5 mg/day of prednisolone had a higher risk of MACE compared with patients not taking glucocorticoids (adjusted hazard ratio [HR] 2.20 [95% CI, 1.87-2.37]), and the risk increased with intermediate-term (up to 180 days) and long-term (>180 days) use. The risk of MACE was not significantly different for patients taking under 5 mg of prednisolone compared with patients not taking glucocorticoids.
●Arrhythmias – An association of glucocorticoid use with risk of atrial fibrillation and flutter has been reported in several studies [49-51]. In a population-based case-control study, current glucocorticoid use was more common among 20,221 patients with atrial fibrillation or flutter compared with the 202,130 population controls (6.4 versus 2.6 percent) [51]. Currently using glucocorticoids was associated with a significant increased risk of atrial fibrillation or flutter, compared with never having used glucocorticoids (adjusted odds ratio [OR] 1.9). Risk was increased for new users and long-term users but not for former users (ORs 3.6, 1.7, and 1.0, respectively) and was unrelated to whether or not pulmonary or cardiovascular disease was present. Sinus bradycardia has also been reported with glucocorticoids, especially with higher "pulse" dosing [52].
Serious adverse cardiovascular toxicities, including sudden death, have been reported in occasional patients who have been given pulse infusions of glucocorticoids (eg, 1 g/day of methylprednisolone for multiple infusions) [15]. In many of these cases, however, it was difficult to determine whether this adverse effect was more likely attributable to glucocorticoids or to the underlying disorder necessitating the therapy. Thus, cardiac monitoring is indicated in patients with significant cardiac disease who are treated with pulse glucocorticoid therapy, especially those on diuretics, the use of which may also be associated with electrolyte disturbances such as hypokalemia.
●Pulmonary emboli and venous thrombotic events – Limited observational data suggest that glucocorticoids may be associated with an increased risk of pulmonary emboli and venous thromboembolism (VTE).
•In a retrospective study in the Netherlands that compared 648 patients using chronic glucocorticoids for asthma with the general population, both severe asthma and oral glucocorticoids appeared to be independent risk factors for pulmonary emboli (HR 3.33, 95% CI 1.16-9.93 and 2.82, 95% CI 1.09-7.30, respectively) [53].
•Two large retrospective studies using national databases in the United States identified increased risk of VTE. A cohort study and self-controlled case series using private insurance claims and assessed the risk of VTE in 27,452 adults using short-term (ie, less than 30 days) glucocorticoid use over three years. Within 30 days of glucocorticoid use, there was an increased rate of VTE (incidence rate ratio [IRR] 3.33, 95% CI 2.78-3.00), which then decreased over the subsequent 31 to 90 days [18]. Another analysis of 94,620 neurosurgical patients found that glucocorticoids were associated with an increased risk of pulmonary emboli (OR 1.47, 1.13-1.90) and deep vein thrombosis (OR 1.55, 1.28-1.87) within 30 days of surgery [54].
●Possible hyperlipidemia – The effect of glucocorticoids on atherosclerotic vascular disease is thought to be mediated in part by elevated nonfunctional lipoprotein levels [55]. However, studies analyzing the impact of glucocorticoids on hyperlipidemia have had mixed results and interpretation is complicated by the difficulty of distinguishing effects due to disease activity from effects directly related to the medications themselves [56]. One large observational study concluded that glucocorticoid use was associated with a more favorable lipid profile in older adults (≥60 years) [57]. In another report, moderate- to low-dose prednisone (20 mg/day tapered to 5 mg/day over three months) had no significant adverse effect on lipoprotein levels if other risk factors were taken into account [58]. Studies in patients with systemic lupus erythematosus (SLE) have indicated that the adverse effects of glucocorticoids on lipid profiles are dose-dependent, occurring only at prednisone doses greater than 10 mg/day [59-61].
Gastrointestinal effects
●Upper gastrointestinal tract complications – Glucocorticoids increase the risk for adverse gastrointestinal effects, such as gastritis, ulcer formation, and gastrointestinal bleeding. The estimated relative risks of glucocorticoids alone for gastrointestinal adverse effects vary from 1.1 (not significant) to 1.5 (marginally significant) [62,63]. However, the combination of glucocorticoids and nonsteroidal antiinflammatory drugs (NSAIDs) results in a synergistic increase in the incidence of gastrointestinal events as shown by the following findings from two meta-analyses:
•Glucocorticoid use is associated with a nearly twofold increased risk of a gastrointestinal adverse effect among patients also taking NSAIDs when compared with those who use NSAIDs alone [64,65].
•The use of NSAIDs and glucocorticoids is associated with a fourfold increased risk of a gastrointestinal adverse effect compared with nonuse of either drug [63].
Whether substitution of a selective cyclooxygenase (COX) 2 inhibitor for a nonselective NSAID would lower this risk is unclear.
●Lower gastrointestinal tract complications – Potential complications of glucocorticoid use include visceral perforation [66-68]. Glucocorticoids may also mask the symptoms of serious gastrointestinal disease, an effect that may partially account for the increased risk of perforated sigmoid diverticular abscess associated with their use [68].
Given the apparent association of tocilizumab and tofacitinib with lower gastrointestinal tract perforations, the question has been raised as to whether the concomitant use of glucocorticoids can further increase this risk. In one study using registry data of patients on biologic agents for RA, the risk of lower intestinal perforation increased by 1.28 (95% CI 1.18-1.38) for each 5 mg/day increase in prednisone dose when added to tocilizumab [65]. In another cohort study that included 167,113 patients with RA, the use of tocilizumab, and possibly tofacitinib, was associated with an increased risk of gastrointestinal perforation [69]. The risk of gastrointestinal perforation appeared to be further increased with prednisone use of more than 7.5 mg/day (HR 2.29, 95% CI 1.39-3.78).
●Hepatic steatosis – Glucocorticoid use has been associated with hepatic steatosis (fatty liver) that can rarely lead to cirrhosis [70-73]. This is more common when the patient is obese.
●Pancreatitis – Although glucocorticoids have also been implicated in causing acute pancreatitis [74-76], their role remains uncertain. In a study including 6161 patients with acute pancreatitis each matched with 10 controls, the multivariable-adjusted risk of acute pancreatitis was increased among current glucocorticoid users compared with nonusers (OR 1.53, 95% CI 1.27-1.84) [76]. Other studies, particularly in patients with SLE, have shown that pancreatitis is caused by the disease rather than the drugs and that glucocorticoids may be beneficial therapeutically [77,78]. (See "Etiology of acute pancreatitis".)
Bone and muscle effects
●Osteoporosis – Osteoporosis is a well-known and exceptionally common adverse effect of glucocorticoid use and is discussed in detail elsewhere. (See "Clinical features and evaluation of glucocorticoid-induced osteoporosis" and "Prevention and treatment of glucocorticoid-induced osteoporosis".)
●Osteonecrosis – Osteonecrosis (avascular or ischemic necrosis of bone) has also been associated with glucocorticoid use, particularly with high doses of glucocorticoids. Glucocorticoid-induced osteonecrosis is discussed separately. (See "Clinical manifestations and diagnosis of osteonecrosis (avascular necrosis of bone)".)
●Myopathy – Myopathy is an infrequent complication of glucocorticoid therapy and is typical seen at higher doses. It presents as painless proximal motor weakness in both the upper and lower extremities. Glucocorticoid-induced myopathy is discussed in detail separately. (See "Glucocorticoid-induced myopathy".)
More acute and severe weakness noted in critically ill patients has been attributed at least in part to the use of glucocorticoids. Variously referred to as critical illness myopathy and acute quadriplegic myopathy, it has also been suspected to be due to an interaction between glucocorticoids and neuromuscular blocking agents. This is discussed in more detail elsewhere. (See "Neuromuscular weakness related to critical illness", section on 'Critical illness myopathy'.)
Neuropsychiatric effects — Glucocorticoids induce a range of psychiatric and cognitive symptoms, which depend upon dose and duration of therapy [33,79]. In most patients, these symptoms are mild and reversible, but emotional lability, hypomania, mania, depression, psychosis, delirium, confusion, or disorientation (which are more common in older patients), insomnia, motor restlessness, and cognitive changes including memory deficits may occur [80,81]. Older patients may be at higher risk for depression, mania, delirium, confusion, or disorientation [81]. The risk of developing a given neuropsychiatric effects following glucocorticoid therapy may be increased among patients with a past history of neuropsychiatric disorders [81]. We describe several conditions in more depth below:
●Sleep disturbances – Patients commonly report sleep disturbances [82]. Cortisol excretion is lowest between 4 and 8 PM, so logic dictates that using glucocorticoids during that time has the highest probability of disrupting the diurnal rhythm [83]. Sleep disturbances can often be minimized by taking a daily dose on awakening in the morning and avoiding split daily dosing when possible.
●Mood disorders – Patients receiving glucocorticoids often experience an improved sense of wellbeing within several days of starting the medications; mild euphoria or anxiety may also be seen [80,84,85]. Hypomanic reactions and activated states are more common early in therapy than is depression, but the prevalence of depression is greater in patients on more longstanding therapy, even on low to moderate doses [80,84,86]. Patients with a family history of depression or alcoholism are at increased risk for affective diseases when given glucocorticoids [87]. An increased risk of panic disorder may be present [81].
More severe mood disorder symptoms can occur within a few days in patients receiving high doses of glucocorticoids. As an example, in one prospective but uncontrolled study of 50 patients receiving 75 to 100 mg of prednisone or equivalent for greater than a week for various ophthalmologic indications, hypomanic and depressive symptoms were induced in approximately 30 and 10 percent of patients respectively by the end of one week [88]. No patient developed dementia or became delirious or overtly psychotic.
There may be an increased risk of suicidal behavior in patients taking glucocorticoid use, especially among younger patients. In a retrospective analysis involving 372,696 adult patients in general practices in the United Kingdom, there was a five- to sevenfold increased risk of completed or attempted suicide among patients receiving glucocorticoids, compared with patients with the same diagnoses who were not receiving such medications; however, the absolute risk was extremely low, approximating 0.1 cases per 100 patient-years of therapy [81]. The observational nature of the study and potential for unknown confounding variables limit study interpretation.
●Psychosis – Psychosis can occur but does so almost exclusively at doses of prednisone above 20 mg/day given for a prolonged period [10,89,90]. Approximately 10 percent of patients have persistent symptoms that may require treatment despite reduction of glucocorticoid dose [91]. Response to antipsychotic drug treatment is typically complete and occurs within two weeks of initiation of neuroleptics.
Hypoalbuminemia may be a risk factor for glucocorticoid-induced psychosis in patients with SLE [92]. Patients with SLE who are on higher glucocorticoid doses present a particular problem since it is often difficult to differentiate psychosis due to prednisone from neuropsychiatric lupus, which may require high-dose glucocorticoid treatment. (See "Neurologic and neuropsychiatric manifestations of systemic lupus erythematosus" and "Psychosis in adults: Epidemiology, clinical manifestations, and diagnostic evaluation", section on 'Medical and substance/medication-related causes'.)
●Memory impairment – Memory impairment has been associated with glucocorticoid use. As an example, a cohort study of 115 patients with RA found that glucocorticoid use was a predictor of poor cognition when controlling for depression, disease severity and duration, and C-reactive protein level [93]. Another report found that patients treated with prednisone doses of 5 to 40 mg/day for at least one year had a partial loss of explicit memory; older patients were more susceptible to memory impairment with less protracted treatment [79,94]. The effect on memory began as early as three months after the initiation of therapy. Approximately 1 percent of patients may be affected by more severe and persisting cognitive disturbances beginning during glucocorticoid treatment; this has been termed steroid dementia. In some patients, this condition may not remit for between 1 and 11 months after discontinuing the medication.
●Other symptoms – Akathisia can occur even in patients taking low doses. Rare cases of pseudotumor cerebri have been associated with glucocorticoid use, although higher doses are often effective in alleviating this generally self-limiting disorder [95].
Ophthalmologic effects — The risk of both cataracts and glaucoma is increased in patients on glucocorticoids and is dose-related [10]. (See "Cataract in adults" and "Open-angle glaucoma: Epidemiology, clinical presentation, and diagnosis" and "Angle-closure glaucoma".)
●Cataracts – Cataracts commonly occur after prolonged glucocorticoid use, even at very low doses. They are usually bilateral and develop slowly. They typically occur in a posterior subcapsular location and can usually be distinguished from senile cataracts.
There may be no minimal safe dose with respect to the risk of cataract formation, although risk is dose- and time-dependent and is more common with prednisone doses greater than 10 mg/day or with medications that have been administered for more than one year [96-98]. In a study that evaluated 122 patients with RA taking a mean dose of prednisone of 8 mg/day for an average of 6.9 years, 29 percent developed cataracts compared with 18 percent of matched controls [8]. Another study of patients with RA receiving a mean dose of 6 mg/day of prednisone for a mean of six years also found cataracts more common in patients on glucocorticoids than in patients not using prednisone (15 versus 4.5 percent) [7]. Another study indicated that even prednisone doses <5 mg/day were associated with cataracts [6].
●Increased intraocular pressure – Glucocorticoids can also increase intraocular pressure. This form of glaucoma occurs most commonly in patients who use glucocorticoid eye drops. However, it has been observed in chronic and, to a lesser extent, acute systemic glucocorticoid use, particularly among those with antecedent risk for glaucoma and those taking doses of prednisone ≥7.5 mg/day [6,99]. This risk of glaucoma associated with glucocorticoid use is discussed in more detail separately. (See "Open-angle glaucoma: Treatment", section on 'Glucocorticoids'.)
●Exophthalmos – Exophthalmos and swelling of the lids and ocular muscles are rare ophthalmologic complications of glucocorticoids [100,101].
●Central serous chorioretinopathy – A rare adverse effect of systemic, local, or even topical use of glucocorticoids is central serous chorioretinopathy [102-104]. Chorioretinopathy is associated with edema formation that can separate the retina from the choroid. Reduction of glucocorticoid dose is the most important element of treatment if it can be done without causing a dangerous exacerbation of the disease that is being treated with the glucocorticoids [105].
Immune system effects — Systemic glucocorticoids have many effects upon innate and acquired immunity that predispose to infection, resulting in a dose-dependent increase in the risk of infection, especially with common bacterial, viral, and fungal pathogens. In addition, patients taking glucocorticoids may not manifest signs and symptoms of infection as clearly, due to the inhibition of cytokine release and associated reduction in inflammatory and febrile responses. This can impair early recognition of infection. As with other glucocorticoid adverse effects, it is challenging to differentiate how the risk of infection is mediated or independently influenced by other patient factors including the underlying disorder, other comorbidities, patient age and functional status, the presence of concomitant immunosuppressive therapies, lymphopenia, and hospitalizations [106,107]. Newer data suggest that even low-dose steroids may increase infection risk [108]. The risk of infection with glucocorticoid therapy and the mechanisms underlying such risk are discussed in more detail elsewhere. (See "Glucocorticoid effects on the immune system".)
Similar to many other adverse effects of glucocorticoids, infection risk can increase even with small doses taken for prolonged periods of time (eg, 5 mg/day taken over two years), and cumulative exposure is important, as illustrated in studies of patient with RA [12,109].
Inhaled and topical glucocorticoids are usually not implicated in increased risk of systemic infections, in contrast to the effects seen with systemic agents. The side effects of inhaled and topical glucocorticoids are reviewed elsewhere. (See "Major side effects of inhaled glucocorticoids" and "Topical corticosteroids: Use and adverse effects", section on 'Adverse effects'.)
Other effects
●Hematologic effects – Pharmacologic doses of glucocorticoids often result in an increased white blood cell count (leukocytosis) that is due primarily to an increase in neutrophils (neutrophilia). This phenomenon is due to a decreased proportion of neutrophils that are adhering to the endothelium. This effect of glucocorticoids is discussed in detail elsewhere. (See "Approach to the patient with neutrophilia", section on 'Medications'.)
●Effect on serum creatinine – Glucocorticoid use may increase plasma creatinine without impacting the glomerular filtration rate [110]. Serum cystatin C does not appear to be affected [111].
●Tooth pain – Dental hypersensitivity-like tooth pain associated with glucocorticoids has been described and was reported in almost 18 percent of patients in one study [112].
SPECIAL POPULATIONS
Young children — Growth impairment is commonly seen in children receiving glucocorticoids. The effect is most pronounced with daily therapy, may be less with an alternate-day regimen, and can occur with inhaled glucocorticoids. The effects of glucocorticoid therapy on growth in children are discussed in detail separately. (See "Causes of short stature", section on 'Glucocorticoid therapy'.)
Children are more susceptible to cataract formation compared with adults. (See "Cataract in children", section on 'Glucocorticoids'.)
Menstruating females — Some female patients who are menstruating may report delayed, irregular, heavier, or lighter menstruation [33]. This can happen even after a one-time injection of glucocorticoids [113].
Pregnancy — The risks associated with glucocorticoid use during pregnancy and lactation are discussed elsewhere. (See "Safety of rheumatic disease medication use during pregnancy and lactation", section on 'Glucocorticoids'.)
GENERAL TREATMENT CONSIDERATIONS AND MONITORING — We try to limit the adverse effects of glucocorticoids by taking the following steps:
●Use the lowest dose of glucocorticoids for the shortest period of time needed to achieve the treatment goals
●Assess for preexisting comorbid conditions that may increase risk, and optimize the management of those conditions
●Use preventative interventions when available (ie, immunizations to prevent infections, exercise and treatments to prevent osteoporosis)
●Monitor patients for adverse effects and pursue corrective interventions when possible (table 2)
Further guidance on the use of glucocorticoids, including setting treatment goals and dosing, is detailed elsewhere. (See "Determinants of glucocorticoid dosing".)
Assessment for preexisting comorbid conditions — Preexisting conditions that should be assessed for and treated when glucocorticoids are to be instituted include [114]:
●Diabetes mellitus and prediabetes
●Poorly controlled hypertension
●Heart failure and peripheral edema
●Obesity and overweight
●Cataract or glaucoma
●Peptic ulcer disease
●Presence of infection, especially latent infections
●Low bone density or osteoporosis
Use of preventive interventions
Vaccine recommendations — Patients who require an extended course of glucocorticoids should receive appropriate immunizations prior to the institution of therapy if clinically feasible; vaccination may vary based on the indication for glucocorticoid use. Vaccines for patients with autoimmune inflammatory rheumatic conditions are outlined in the following table (table 3). The immune response to vaccines may be compromised by glucocorticoid administration at doses of ≥20 mg/day of prednisone. Recommendations for managing vaccinations in specific patient populations who may be taking glucocorticoids are described elsewhere. (See "Immunizations in autoimmune inflammatory rheumatic disease in adults" and "Immunizations in hematopoietic cell transplant candidates and recipients" and "Immunizations in solid organ transplant candidates and recipients" and "Immunizations in adults with cancer".)
The safety of live virus vaccines is described briefly below but is reviewed in detail separately. (See "Measles, mumps, and rubella immunization in adults" and "Vaccination for the prevention of chickenpox (primary varicella infection)" and "Vaccination for the prevention of shingles (herpes zoster)".)
In general, live virus vaccines may be administered to patients who have taken:
●Prednisone or its equivalent in doses of less than 20 mg/day for 14 days or less
●Glucocorticoids used for long-term physiologic replacement
●Glucocorticoids administered topically, by aerosol, or by intraarticular or bursal injection, provided that there is no clinical or laboratory evidence of immunosuppression
For patients taking 20 mg/day or more of prednisone or its equivalent, the combination measles-mumps-rubella (MMR) vaccine and other live virus vaccines should not be administered for one month after the cessation of glucocorticoid therapy.
Prevention of opportunistic infection — As described above, it is well known that glucocorticoids are associated with an increased risk of infection (see 'Immune system effects' above). In some circumstances, the use of prophylaxis for an opportunistic infection with Pneumocystis jirovecii pneumonia (PJP) is recommended. However, this varies with the dose and duration of glucocorticoid therapy, as well as for the underlying disease being treated and concomitant immunosuppression (see appropriate topic reviews). We typically recommend PJP prophylaxis when glucocorticoids are given at doses above 20 mg/day for more than four weeks to patients who have another cause of immunocompromise. (See "Treatment and prevention of Pneumocystis pneumonia in patients without HIV", section on 'Indications'.)
Prevention of osteoporosis — Depending on the length of the course of glucocorticoid treatment, osteoporosis prevention may be pursued at the start of therapy. Adequate dietary or supplementary calcium and vitamin D intake should be encouraged. Guidance for the prevention and treatment of glucocorticoid-induced osteoporosis is discussed in detail separately. (See "Prevention and treatment of glucocorticoid-induced osteoporosis".)
Prevention of gastroduodenal toxicity — Patients who also require concomitant treatment with nonsteroidal antiinflammatory drugs (NSAIDs) or anticoagulants may require prophylaxis to prevent gastroduodenal toxicity. (See "NSAIDs (including aspirin): Primary prevention of gastroduodenal toxicity".)
Monitoring and treatment of adverse effects — Patients should be routinely asked about adverse effects related to glucocorticoids. Intensity of monitoring will depend upon individual risk factors such as glucocorticoid dose and duration, other medications being used, and comorbidities. However, generally during treatment with glucocorticoids particular attention should be given to (table 2) [114]:
●Infection – Patients on high-dose therapy should have screening for latent infections such as tuberculosis. Respiratory symptoms in patients on moderate- to high-dose glucocorticoids should also prompt consideration of workup for PJP pneumonia, especially if patients are on prolonged glucocorticoid courses with other immunosuppressive agents and/or are not taking prophylactic PJP therapy. (See "Tuberculosis infection (latent tuberculosis) in children", section on 'Immunosuppressed children' and "Epidemiology, clinical manifestations, and diagnosis of Pneumocystis pneumonia in patients without HIV", section on 'Diagnosis'.)
●Osteoporosis – Patients who might require prolonged courses or high doses of glucocorticoids might benefit from screening for osteoporosis and consideration of treatment. (See "Clinical features and evaluation of glucocorticoid-induced osteoporosis" and "Prevention and treatment of glucocorticoid-induced osteoporosis".)
●Diabetes or glucose intolerance – Screening for glucose intolerance and type 2 diabetes may need to be intensified for patients on moderate- to high-dose glucocorticoids or on prolonged courses of low-dose therapy. Screening for type 2 diabetes is outlined in detail elsewhere. (See "Screening for type 2 diabetes mellitus".)
When glucocorticoids induce symptomatic diabetes mellitus or asymptomatic but clinically significant hyperglycemia, these conditions are generally treated pharmacologically in the same way as for patients who are not on glucocorticoid therapy. Interestingly, a small phase 2 trial found that patients on continuous prednisone for inflammatory diseases who were randomized to receive metformin demonstrated improvements in measures of metabolic activity as well as other clinical markers of disease activity compared with those receiving placebo [115]. However, there is not enough data to recommend coadministration of metformin for patients taking glucocorticoids in the absence of another clinical indication to do so. (See "Management of type 2 diabetes mellitus in children and adolescents", section on 'Pharmacologic agents' and "Overview of general medical care in nonpregnant adults with diabetes mellitus", section on 'Glycemic management'.)
●Cataracts or glaucoma – Patients on prolonged moderate- to high-dose therapy should be examined periodically by an ophthalmologist to promote early detection of cataracts and glaucoma. (See "Open-angle glaucoma: Epidemiology, clinical presentation, and diagnosis", section on 'Screening'.)
There are several tools to measure glucocorticoid toxicity, including the Glucocorticoid Toxicity Index (GTI) in adults and the Pediatric Glucocorticoid Toxicity Index (pGTI) in children [116-118]. These have primarily been used in clinical research, although they may be useful in clinical practice.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Side effects of anti-inflammatory and anti-rheumatic drugs".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topics (see "Patient education: Oral steroid medicines (The Basics)")
SUMMARY AND RECOMMENDATIONS
●Factors related to glucocorticoid toxicity – The adverse effects of glucocorticoids are both dose- and duration-dependent. The effects of glucocorticoids are mediated by cytosolic glucocorticoid receptors and subsequent genomic and nongenomic mechanisms. Genetic polymorphisms in the glucocorticoid receptor and in glucocorticoid metabolism may explain heterogeneity in glucocorticoid toxicities observed. (See 'Mechanisms of adverse effects' above and 'Glucocorticoid dose and duration' above.)
•Organ-based toxicity – Glucocorticoids have adverse effects on many organ systems (table 1). Adverse effects range from those that are temporary but challenging for patients (eg, insomnia) to those that are life-threatening (eg, serious infections). Some adverse effects, such as accelerated reductions in bone mineral density or early cataracts, may be largely asymptomatic until later manifestations develop that require medical attention (eg, acute vertebral collapse, cataract requiring surgical extraction). The following organ systems can be affected by systemic glucocorticoids to varying degrees. (See 'Organ-based toxicity of systemic glucocorticoids' above.)
●Special populations – Certain populations may experience different complications from glucocorticoid use, including young children, menstruating females, and pregnant people. (See 'Special populations' above.)
●General treatment considerations and monitoring – We try to limit the adverse effects of glucocorticoids by taking the following steps (see 'General treatment considerations and monitoring' above):
•Use the lowest dose of glucocorticoids for the shortest period of time needed to achieve the treatment goals
•Assess for preexisting comorbid conditions that may increase risk, and optimize the management of those conditions (see 'Assessment for preexisting comorbid conditions' above)
•Use preventative interventions when available, including addressing appropriate immunization requirements, prevention of opportunistic infections, and prevention of osteoporosis (see 'Use of preventive interventions' above)
•Monitor patients for adverse effects and pursue corrective interventions when possible (table 2) (see 'Monitoring and treatment of adverse effects' above)
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