Can adverse effects of glucocorticoid therapy be prevented and treated?

KEYWORDS:

• Adverse effects
• glucocorticoids
• osteoporosis
• pharmacotherapy
• peptic ulcer disease

1. Introduction

Glucocorticoids are frequently used in the treatment of autoimmune inflammatory diseases and vasculitis. In the United States, the estimated prevalence of use is 1.2% in the general population [1], despite the fear for adverse effects [2]. These may indeed occur, but their severity is highly variable. Glucocorticoid-induced adverse effects differ according to duration of therapy and dosages used [3,4].

Although most studies are focused on therapeutic efficacy instead of adverse effects, the impression is that low-dose glucocorticoid therapy (i.e. ≤7.5 mg/day prednisone or equivalent) is relatively safe [5–7]. A recent literature search and expert consultation on the four most worrisome adverse effects of glucocorticoid therapy (osteoporosis, hyperglycemia/diabetes mellitus, cardiovascular diseases, and infections) showed that the level of harm of glucocorticoids depends on duration, dose, and patient-specific factors and that the risk of harm is low for the majority of patients on long-term treatment with dosages of ≤5 mg prednisone equivalent per day [7].

However, fear and uncertainty persist among patients and rheumatologists [2] since adverse effects are often not systematically assessed in trials and because it is not appreciated that adverse events are related to high dosages or long duration of treatment. Another reason is the difficulty of discriminating glucocorticoid-induced side effects from negative effects and complications of the disease (e.g. is a decrease in bone mineral density (BMD) caused by active rheumatoid arthritis, and/or is it an adverse effect of glucocorticoids?; see Figure 1). In this respect, also confounding by indication is important, i.e. patients with more severe disease are more likely to receive (higher actual and cumulative doses of) glucocorticoids. So, not all negative effects and events in patients on glucocorticoid therapy are definitely glucocorticoid-induced adverse effects, but some irrefutably are. Fortunately, some of these can be prevented or treated. Adverse effects that can be influenced by medication are listed in Table 1.

Table 1. Glucocorticoid-related adverse effects which can be prevented or treated with medication.

Glucocorticoid-related adverse effect	Prevention possible	Treatment possible	Medication
Osteoporosis	+	+	Prevention: calcium, vitamin D, bisphosphonates Treatment: calcium, vitamin D, bisphosphonates, teriparatide, and denosumab^b
Gastric ulcer disease, in case of comedication with NSAIDs or other risk factors^a	+	+	Prevention and treatment: proton-pump inhibitors
Hypertension	−	+	Regular treatment
Diabetes mellitus	−	+	Regular treatment
Dyslipidemia	−	+	Regular treatment
Infections	Partly	+	Prevention: vaccination and patient instruction to seek medical help in early stage Treatment: antibiotics, antiviral, and antifungal agents
Neuropsychiatric effects	−	+	Regular treatment
Glaucoma	+	+	Prevention: regular treatment for increased intraocular pressure Treatment: regular treatment

+: prevention or treatment is possible; −: no prevention or treatment; NSAID: nonsteroidal anti-inflammatory drug.

^aRisk factors are age >65 years, history of peptic ulcer disease, high-dose NSAID therapy, and comedication with anticoagulants.

^bNot yet licensed for treatment of glucocorticoid-induced osteoporosis.

Figure 1. Glucocorticoids as well as inflammatory disease activity can have negative effects on bone mass, muscle mass, lipids, endothelium, glucose metabolism, infection risk, and pregnancy outcome. Since glucocorticoids are capable of effectively dampening the disease activity, the net effect of glucocorticoids is unclear. Reproduced from [8].

In this review, we will discuss the drugs used in the prevention and treatment of glucocorticoid-related adverse effects. In addition, we will point out several general measures which can prevent these adverse effects.

2. Main body of article

2.1. General principles

For prolonged treatment, the glucocorticoid dosage should be kept to a minimum, and a glucocorticoid taper should be attempted in case of remission or low disease activity [9]. An exception is the use of glucocorticoids in early rheumatoid arthritis, not only for their symptomatic effect, but also as disease-modifying drug, i.e. to limit joint damage [10]. Disease-modifying effects have only been shown for high-dose treatment and tapering schemes during half a year and for low- and low-to-medium dose treatments during 1 to 2 years [10]. The reason to continue glucocorticoid therapy should be checked regularly. Starting a glucocorticoid-sparing agent such as methotrexate should be considered.

2.2. Informing and advising patients

First, adverse effects of glucocorticoid therapy should be discussed with the patient before therapy is started [9]. Detailed discussion of common adverse effects is an integral part of the management of any disease, of chaired decision-making, and of patient education. Since perspectives on glucocorticoid treatment of doctors and patients not always correspond, actively asking patients to share their fears might help in discussing and removing concerns.

Second, there are several healthy lifestyle advices. Cessation of smoking, increasing physical activity, and supporting a healthy body weight will reduce the risk of developing diabetes, hypertension, and cardiovascular disease. Similarly, physical activity, cessation of smoking, and preventing underweight are important in the prevention of osteoporotic fractures [7].

Third, patients should be aware of the increased infection risk (relative risk: 1.20, 95% confidence interval [CI]: 1.15–1.25) [11] and the suppression of symptoms of infection by glucocorticoids. They should seek medical help in an early stage of an infection.

Fourth, the physician should consider increasing the daily dose of glucocorticoids to prevent tertiary adrenal insufficiency in stressful medical conditions, e.g. surgery. Administration of glucocorticoids leads to negative feedback on the hypothalamus and pituitary glands, resulting in decreased secretion of corticotropin-releasing hormone and adrenocorticotropic hormone (ACTH). As a result, the cortisol secretory capacity of the fasciculata-reticularis zone of the adrenal cortex may decrease. The outer glomerulosa zone is not dependent on ACTH secretion; therefore, its ability to produce mineralocorticoids is not impaired.

Prediction of secondary adrenal insufficiency is not reliable, but its prevalence appears to depend on both the dose and the duration of glucocorticoid treatment. In clinical practice, it seems appropriate to anticipate on potential adrenal insufficiency in patients who received 7.5 mg prednisone or equivalent for at least 3 weeks. Furthermore, in case of acute injury or stress (e.g. with surgery), adequate adaptation of the glucocorticoid dose is important. Often a temporary increase of the dose to 15 mg/day is sufficient for minor surgery.

3. Pharmacotherapy

There are three glucocorticoid-related adverse effects for which preventive medication could be considered: osteoporosis, peptic ulcer disease, and infections.

In the prevention of glucocorticoid-induced osteoporosis, pharmacotherapy plays a major role. Glucocorticoids inhibit bone formation by decreasing the number of osteoblasts and hampering their function [12,13]. Glucocorticoids also increase bone resorption by stimulating the formation and action of osteoclasts and decrease intestinal absorption of calcium and increase renal calcium excretion [13–16].

Active vitamin D3 stimulates the formation and action of osteoblasts [17], leading to increased bone formation [18]. However, it is not effective enough to prevent glucocorticoid-induced osteoporosis [19]. Bisphosphonates induce apoptosis of osteoclasts and inhibit bone resorption [20].

The efficacy of the combination of calcium, vitamin D3, and bisphosphonates in clinical practice has been shown in multiple meta-analyses [21–25]. However, at similar BMD levels, postmenopausal women taking glucocorticoids have considerably higher fracture risk than postmenopausal women not on glucocorticoids [26]. This is due to the negative effect on bone quality too of glucocorticoids.

The bone anabolic agent teriparatide is also effective for the management of glucocorticoid-induced osteoporosis [27–29], and greater increases in BMD and fewer new vertebral fractures were found with teriparatide compared to bisphosphonates [30]. Guidelines on indications and choices for specific drugs differ somewhat between countries. Postmenopausal women and men aged 70 years or higher are at increased risk, and chronic oral glucocorticoid treatment with >5 mg prednisone equivalent daily may already lead to a reduction in BMD and a rapid dose-dependent increase in the risk of fracture [31–32].

No study investigated gastroprotective measures in glucocorticoid users specifically. The rationale for gastroprotective medication is given by the slightly increased risk for gastrointestinal adverse effects by treatment with glucocorticoids (relative risk: 1.1, CI: 0.5–2.1 [33] and odds ratio: 1.73, CI: 1.34–2.23 [34]) and the around threefold to fourfold increased risk when glucocorticoid treatment is combined with use of nonsteroidal anti-inflammatory drugs (NSAIDs) [33,34]. Several treatment regimens have been shown to be gastroprotective. So, mainly when glucocorticoids are combined with NSAIDs or when patients have additional risk factors for peptic ulcer disease, gastroprotective measures are indicated. Proton-pump inhibitors and misoprostol (nowadays used less frequently because of its abdominal adverse effects) reduce the risk of gastric and duodenal ulcers in patients taking conventional NSAIDs [35,36] and are often used. Cyclo-oxygenase-2 inhibitors can be considered instead of conventional NSAIDs because they cause less gastrointestinal toxicity [37–39], but they increase the cardiovascular risk [40], which is already elevated in inflammatory diseases.

When prolonged glucocorticoid treatment is expected, or when glucocorticoids are part of an immunosuppressive regimen, pneumococcal and influenza vaccination (preferably before start of therapy) should be strongly considered [41]. In specific circumstances, prophylactic antibiotic treatment may be prescribed (i.e. cotrimoxazole as prophylactic agent against Pneumocystis jiroveci infections).

Medical conditions, which may occur in every person not on glucocorticoids, but can be related to glucocorticoids as well, such as hypertension, dyslipidemia, diabetes, infections, and neuropsychiatric symptoms are treated similarly in both situations.

4. Conclusion

Osteoporosis, peptic ulcer disease, and infections are glucocorticoid-related adverse effects, which are or can be preventively treated with medication. Treatment strategies such as combined therapy with calcium, vitamin D3, and bisphosphonates are effective.

5. Expert opinion

During the past years, more insight has been gained into mechanisms of glucocorticoid-related adverse effects. This has not led to new therapies in clinical practice yet although there are two important expected developments in the field of pharmacotherapy.

5.1. Advances in prevention or treatment of glucocorticoid-induced osteoporosis

Denosumab is approved for the treatment of postmenopausal osteoporosis, and we expect it to be licensed also for the treatment of glucocorticoid-induced osteoporosis in the coming years. The first reports for this indication show good efficacy [42,43]. Denosumab is a human monoclonal antibody binding to receptor activator of nuclear factor κ-B-ligand (RANKL), a cytokine stimulating formation and activation of osteoclasts. So by neutralizing RANKL, the formation, activity, and survival of osteoclasts are inhibited. A recent meta-analysis showed no significant difference in safety and reduction of fracture risk between denosumab and bisphosphonate therapy although higher gains in BMD were obtained with denosumab [44]. More advantages of denosumab are the safety of the drug in patients with renal insufficiency and the lower risk of discontinuation [45]. Effects of denosumab up to 8 years of treatment are promising with continuing gains in BMD [46].

More drugs against osteoporosis are under investigation. A recent phase 2 study report on romosozumab, a monoclonal antibody that binds to sclerostin, showed promising results [47]. For odanacatib, a non-lysosomotrophic reversible inhibitor of cathepsin K, phase 2 studies up to 8 years of treatment showed increases in BMD at multiple sites [48]. More information on efficacy and serious adverse effects (such as osteonecrosis of the jaw and atypical femoral shaft fractures reported with use of bisphosphonates and denosumab) of these drugs are expected.

5.2. New glucocorticoid delivery systems and preparations

In the past decade, modified-release prednisone has been developed [49], of which the release of glucocorticoids can be adapted to the circadian rhythms of endogenous cortisol by taking the medication at bedtime. This results in a shorter duration of morning stiffness in patients with rheumatoid arthritis [49].

Other experimental compounds are long-circulating glucocorticoid-containing liposomes, which migrate to the site of inflammation, enhancing at the target-site accumulation of glucocorticoids, and hopefully thus improving the balance between efficacy and adverse effects [50]. A recent publication showed that [¹⁸F] fluorodeoxyglucose uptake in inflamed joints as measure of joint inflammation was suppressed after treatment with prednisolone-containing pegylated (PEG) liposomes of antigen-induced arthritis in mice [51]. Histological analyses showing less inflammation (p < 0.05) and bone erosion (p < 0.05) in treated mice confirmed the therapeutic efficacy. Long-circulating glucocorticoid-containing PEG liposomes have been shown to be well tolerated and effective in a phase 1 study of 12-week duration in 16 patients with rheumatoid arthritis. A single intravenous liposome injection (150 mg prednisone equivalent) resulted in a faster and more pronounced decrease in disease activity score compared with an equivalent intramuscular injection of 120 mg methylprednisolone [52].

Exciting also is the development of new glucocorticoid preparations with an improved benefit–risk profile. Research on selective glucocorticoid receptor agonists (SEGRAs), also called dissociated agonists of the glucocorticoid receptor, is based on the finding that some glucocorticoid actions (so-called transrepression mechanisms) are to a greater extent responsible for the desired anti-inflammatory and immunomodulating effects than other actions (so-called transactivation mechanisms) that are associated with frequently occurring metabolic adverse effects. Of course, increased infection risk is a consequence of the desired immunosuppressive effect. Convincing clinical data on SEGRAs are lacking. A positive result on efficacy has been published recently [53], but complete study results have not been published yet.

Declaration of interest

F. Buttgereit has received consultancy fees, honoraria and travel expenses from Merck Serono, Horizon Pharma (formerly Nitec Pharma) and Mundipharma Int. Ltd. and Roche, and grant support from Merck Serono and Horizon Pharma. J Bijlsma received consultancy fees from Enceladus and SUN Pharma. The authors have no other 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 apart from those disclosed.

Additional information

Funding

This paper was not funded.