Glucocorticoid Use and Abuse in SLE
Glucocorticoid Use and Abuse in SLE
It is well known that GCs produce a wide spectrum of adverse effects at many organ levels. These effects are mainly related to their genomic mechanism of action, and are dose and time dependent.
In a historic cohort study of patients with RA in low-dose, long-term therapy with prednisone, the authors showed that daily prednisone doses between 10 and 15 mg/day strongly correlated with the development of adverse effects such as fractures, serious infections and cataracts [odds ratio (OR) = 32.3, 95% CI 4.6, 220].
In the musculoskeletal system, GCs can cause osteoporosis, osteonecrosis and myopathy. Osteoporosis is one of the most common adverse effects of chronic use of GCs, even at low doses. GCs inhibit osteoblastic function, leading to decreased bone formation, loss of BMD and consequently to an increased risk of fracture. Bone loss starts at the beginning of GC treatment and maximizes at 6 months, which decreases after the therapy is stopped. It affects mainly bone with high trabecular content, like vertebrae. A meta-analysis by van Staa et al. found a strong correlation between cumulative doses and loss of BMD as well as between daily doses and risk of fracture. The authors conclude that prednisone doses >5 mg/day or equivalent increase the risk of fracture during the treatment period. Osteonecrosis is another severe side effect of GCs. It has been suggested that it is more related with high prednisone doses than with cumulative doses. It is worth mentioning that there is a paradoxical action of GCs in RA bone damage. GCs at low doses used for short periods have been shown to reduce periarticular osteoporosis and radiographic disease progression, whereas when used for long periods and/or at higher doses GCs are highly damaging for bone.
Endocrine and metabolic adverse effects of GCs are important aspects to take into account. GCs increase the risk of hyperglycaemia in a dose- and time-dependent manner in diabetic as well as non-diabetic patients. It has been suggested that hyperglycaemia may appear at doses as low as 2.5 mg/day of prednisone-equivalent. The capacity of GCs to induce redistribution of body fat is well known, and it occurs even at low doses. Cushing syndrome is dose and time dependent. It can become evident from the first month of treatment and at doses as low as 5 mg prednisone-equivalent per day. GCs at high doses also lower the levels of oestrogens and testosterone. However, the occurrence of infertility or decreased libido has not been proved.
GCs have been suggested as an independent risk factor for cardiovascular diseases. Wei et al., using a record linkage database, compared 68.781 GC users to 82.202 non-users, most of them with IBD or chronic obstructive pulmonary disease. They found that doses >7.5 mg/day significantly increased the risk for myocardial infarction and cerebrovascular events. Of note, the association between GC use and cardiovascular events remained after adjustment for traditional cardiovascular risk factors. A recent systematic review showed a poor association between cardiovascular risk and long-term prednisone-equivalent doses up to 10 mg/day. The authors found an increase in insulin resistance but no effects on the lipid profile or blood pressure. However, they found a trend of increasing risk of major cardiovascular events with exposure to such doses. This trend persisted even after adjustment on RA severity, activity or comorbidities.
Another remarkable adverse effect is related to the potential of GCs to increase susceptibility to major infections, a well-known cause of morbidity and mortality in many inflammatory diseases. This effect may increase with dose and duration of treatment, although it is not clear if there is a threshold below which GC therapy is safe. A population-based cohort of 609 RA patients found that GCs were strong predictors of infection in both the univariate and multivariate analyses. A nested case–control study of 16 207 RA patients from Quebec showed that GC therapy increases the risk of non-serious infections in patients >65 years of age in a dose–response manner. Patients treated with doses <5 mg/day of prednisone-equivalent had a relative risk of 1.1 (95% CI 0.99, 1.22) compared with those treated with doses >20 mg/day, which had a relative risk of 1.85 (95% CI 1.68, 2.05).
Another chapter to consider is the dermatological impact of GCs. The dermatological manifestations include cutaneous atrophy, striae, purpura, easy bruisability, impaired wound healing, acne and hair defects. Although there are no accurate data regarding dose and time of occurrence for these cutaneous adverse effects, it has been suggested that long periods of treatment with medium to high doses of GCs are needed for them to appear. Ophthalmological adverse effects can be very disabling. They include cataracts and an increased risk of glaucoma, which may lead to visual field loss and even blindness. The presence of previous glaucoma and a family history of glaucoma are recognized risk factors for ocular hypertension associated with the use of GCs. It has been suggested that open angle glaucoma is more common in patients exposed to doses ≥7.5 mg/day prednisone-equivalent for >1 year. Cataracts were found more frequently in RA patients treated with a mean of 6 mg/day of prednisone-equivalent for a mean of 6 years compared with RA patients not treated with prednisone. It is important to highlight that although intraocular pressure may return to normal after stopping the GC treatment, cataracts may be irreversible.
Finally, GCs may produce many psychological and behavioural disorders, including disturbances of mood, cognition, sleep as well as psychosis. The most common adverse effects of short-term GC treatment are euphoria and hypomania, whereas long-term therapy may induce depressive symptoms. Such disturbances are related to dose and may occur immediately after the initiation of treatment and even after discontinuation of treatment. The Boston Collaborative Drug Surveillance Program found that the incidence of psychiatric manifestations was 1.3% in patients receiving 40 mg/day prednisone-equivalent or less and 18.4% in patients receiving doses >80 mg/day.
Table 2 shows some of the most important adverse effects and their time and dose relationship.
GC Side Effects
It is well known that GCs produce a wide spectrum of adverse effects at many organ levels. These effects are mainly related to their genomic mechanism of action, and are dose and time dependent.
In a historic cohort study of patients with RA in low-dose, long-term therapy with prednisone, the authors showed that daily prednisone doses between 10 and 15 mg/day strongly correlated with the development of adverse effects such as fractures, serious infections and cataracts [odds ratio (OR) = 32.3, 95% CI 4.6, 220].
In the musculoskeletal system, GCs can cause osteoporosis, osteonecrosis and myopathy. Osteoporosis is one of the most common adverse effects of chronic use of GCs, even at low doses. GCs inhibit osteoblastic function, leading to decreased bone formation, loss of BMD and consequently to an increased risk of fracture. Bone loss starts at the beginning of GC treatment and maximizes at 6 months, which decreases after the therapy is stopped. It affects mainly bone with high trabecular content, like vertebrae. A meta-analysis by van Staa et al. found a strong correlation between cumulative doses and loss of BMD as well as between daily doses and risk of fracture. The authors conclude that prednisone doses >5 mg/day or equivalent increase the risk of fracture during the treatment period. Osteonecrosis is another severe side effect of GCs. It has been suggested that it is more related with high prednisone doses than with cumulative doses. It is worth mentioning that there is a paradoxical action of GCs in RA bone damage. GCs at low doses used for short periods have been shown to reduce periarticular osteoporosis and radiographic disease progression, whereas when used for long periods and/or at higher doses GCs are highly damaging for bone.
Endocrine and metabolic adverse effects of GCs are important aspects to take into account. GCs increase the risk of hyperglycaemia in a dose- and time-dependent manner in diabetic as well as non-diabetic patients. It has been suggested that hyperglycaemia may appear at doses as low as 2.5 mg/day of prednisone-equivalent. The capacity of GCs to induce redistribution of body fat is well known, and it occurs even at low doses. Cushing syndrome is dose and time dependent. It can become evident from the first month of treatment and at doses as low as 5 mg prednisone-equivalent per day. GCs at high doses also lower the levels of oestrogens and testosterone. However, the occurrence of infertility or decreased libido has not been proved.
GCs have been suggested as an independent risk factor for cardiovascular diseases. Wei et al., using a record linkage database, compared 68.781 GC users to 82.202 non-users, most of them with IBD or chronic obstructive pulmonary disease. They found that doses >7.5 mg/day significantly increased the risk for myocardial infarction and cerebrovascular events. Of note, the association between GC use and cardiovascular events remained after adjustment for traditional cardiovascular risk factors. A recent systematic review showed a poor association between cardiovascular risk and long-term prednisone-equivalent doses up to 10 mg/day. The authors found an increase in insulin resistance but no effects on the lipid profile or blood pressure. However, they found a trend of increasing risk of major cardiovascular events with exposure to such doses. This trend persisted even after adjustment on RA severity, activity or comorbidities.
Another remarkable adverse effect is related to the potential of GCs to increase susceptibility to major infections, a well-known cause of morbidity and mortality in many inflammatory diseases. This effect may increase with dose and duration of treatment, although it is not clear if there is a threshold below which GC therapy is safe. A population-based cohort of 609 RA patients found that GCs were strong predictors of infection in both the univariate and multivariate analyses. A nested case–control study of 16 207 RA patients from Quebec showed that GC therapy increases the risk of non-serious infections in patients >65 years of age in a dose–response manner. Patients treated with doses <5 mg/day of prednisone-equivalent had a relative risk of 1.1 (95% CI 0.99, 1.22) compared with those treated with doses >20 mg/day, which had a relative risk of 1.85 (95% CI 1.68, 2.05).
Another chapter to consider is the dermatological impact of GCs. The dermatological manifestations include cutaneous atrophy, striae, purpura, easy bruisability, impaired wound healing, acne and hair defects. Although there are no accurate data regarding dose and time of occurrence for these cutaneous adverse effects, it has been suggested that long periods of treatment with medium to high doses of GCs are needed for them to appear. Ophthalmological adverse effects can be very disabling. They include cataracts and an increased risk of glaucoma, which may lead to visual field loss and even blindness. The presence of previous glaucoma and a family history of glaucoma are recognized risk factors for ocular hypertension associated with the use of GCs. It has been suggested that open angle glaucoma is more common in patients exposed to doses ≥7.5 mg/day prednisone-equivalent for >1 year. Cataracts were found more frequently in RA patients treated with a mean of 6 mg/day of prednisone-equivalent for a mean of 6 years compared with RA patients not treated with prednisone. It is important to highlight that although intraocular pressure may return to normal after stopping the GC treatment, cataracts may be irreversible.
Finally, GCs may produce many psychological and behavioural disorders, including disturbances of mood, cognition, sleep as well as psychosis. The most common adverse effects of short-term GC treatment are euphoria and hypomania, whereas long-term therapy may induce depressive symptoms. Such disturbances are related to dose and may occur immediately after the initiation of treatment and even after discontinuation of treatment. The Boston Collaborative Drug Surveillance Program found that the incidence of psychiatric manifestations was 1.3% in patients receiving 40 mg/day prednisone-equivalent or less and 18.4% in patients receiving doses >80 mg/day.
Table 2 shows some of the most important adverse effects and their time and dose relationship.
