The metabolic adverse effects of glucocorticoids arise directly from GR (glucocorticoid receptor)-mediated transactivation of metabolic gene programs that evolved to mobilize substrates during physiological stress. When activated chronically by pharmacological glucocorticoid concentrations, these same programs drive the constellation of metabolic complications that constitutes iatrogenic Cushing syndrome: hyperglycemia, central adiposity, dyslipidemia, and skeletal muscle atrophy. Understanding the mechanisms of each complication is prerequisite to managing them and to counseling patients about monitoring requirements.
Glucocorticoid-induced hyperglycemia results from simultaneous stimulation of hepatic glucose production and suppression of peripheral glucose utilization, acting through distinct mechanisms in different tissues. In the liver, GR-alpha transactivation drives upregulation of the key gluconeogenic enzymes PEPCK (phosphoenolpyruvate carboxykinase) and G6Pase (glucose-6-phosphatase), increasing hepatic glucose output from amino acid and glycerol substrates. GR-alpha simultaneously upregulates glycogen synthase kinase 3, promotes glycogen breakdown, and induces expression of the transcriptional coactivator PGC-1alpha (peroxisome proliferator-activated receptor gamma coactivator 1-alpha), which amplifies gluconeogenic gene transcription. In skeletal muscle and adipose tissue, glucocorticoids reduce GLUT4 (glucose transporter type 4) translocation to the plasma membrane in response to insulin, impairing insulin-stimulated glucose uptake independently of any change in circulating insulin levels.1 The resulting insulin resistance is characterized by fasting hyperglycemia that is typically modest, but postprandial glucose excursions that can be substantially elevated, reflecting the blunted tissue response to meal-stimulated insulin release. In patients with pre-existing insulin resistance or type 2 diabetes, pharmacological glucocorticoid therapy can precipitate a marked deterioration in glycemic control requiring acute dose escalation of antidiabetic medications.
The clinical pattern of glucocorticoid-induced hyperglycemia has important practical implications for monitoring and management. Because hepatic gluconeogenesis is continuously stimulated, fasting glucose is elevated but postprandial glucose rises are more pronounced and extend further into the afternoon and evening. This pattern differs from the predominantly fasting hyperglycemia of early type 2 diabetes and means that HbA1c (hemoglobin A1c) underestimates the degree of postprandial dysglycemia, particularly when glucocorticoid therapy has been initiated within the preceding 8 to 12 weeks. Point-of-care glucose monitoring at 2 hours after the largest meal of the day is the most sensitive way to detect glucocorticoid-induced postprandial excursions. Timing of the steroid dose matters: once-daily morning dosing produces a predictable glucose peak in the afternoon, suggesting that short-acting insulin or a dose of a dipeptidyl peptidase-4 (DPP-4) inhibitor or sodium-glucose cotransporter-2 (SGLT-2) inhibitor timed to the steroid peak may be more effective than basal insulin alone in managing the pattern.2
Glucocorticoid-induced dyslipidemia is characterized by elevation of total cholesterol, LDL (low-density lipoprotein) cholesterol, and VLDL (very low-density lipoprotein) triglycerides, with variable effects on HDL (high-density lipoprotein) cholesterol. The mechanism involves GR-mediated upregulation of hepatic lipogenic enzyme expression, increased flux of free fatty acids from glucocorticoid-stimulated lipolysis in adipose tissue to the liver (where they are esterified and packaged into VLDL), and reduced LDL receptor expression in some tissues. The dyslipidemia is generally proportional to dose and duration of therapy and contributes to the accelerated atherosclerosis seen with chronic glucocorticoid use, compounding the direct cardiovascular effects discussed in Section 4. In patients on long-term therapy above prednisone 7.5 mg per day equivalent, lipid monitoring at baseline and at 3-month intervals with initiation of statin therapy at standard cardiovascular risk thresholds is appropriate.3
Steroid myopathy is a GR (glucocorticoid receptor)-mediated adverse effect characterized by proximal limb muscle weakness and wasting that is pharmacologically distinct from inflammatory myopathy and managed differently. The mechanism involves GR-dependent transcriptional upregulation of MuRF1 (muscle RING finger protein 1) and MAFbx (muscle atrophy F-box protein), two E3 (enzyme 3) ubiquitin ligases that target myofibrillar proteins including myosin heavy chain for proteasomal degradation. Glucocorticoids also suppress muscle protein synthesis by inhibiting the mTOR (mechanistic target of rapamycin) signaling pathway downstream of insulin-like growth factor 1 (IGF-1), creating a net catabolic state in skeletal muscle. Clinically, steroid myopathy presents as symmetrical proximal weakness affecting shoulder and pelvic girdle muscles, with preserved deep tendon reflexes and normal or only mildly elevated creatine kinase (CK), in contrast to inflammatory myositis where CK is typically markedly elevated. The distinction is practically important because inflammatory myopathy is treated with increased glucocorticoids while steroid myopathy requires dose reduction.1 Fluorinated glucocorticoids (dexamethasone, triamcinolone) carry a higher risk of steroid myopathy than non-fluorinated agents at equivalent anti-inflammatory doses, a pharmacological distinction relevant to agent selection in patients at high myopathy risk.
Both conditions present with proximal weakness in patients on glucocorticoids for inflammatory disease. Steroid myopathy: onset gradual after months of therapy; CK normal or mildly elevated; no inflammatory changes on muscle biopsy (type II fiber atrophy only); electromyography (EMG) normal or shows myopathic pattern without fibrillation; responds to dose reduction. Inflammatory myositis (inadequately treated disease flare): CK markedly elevated; active inflammatory infiltrate on biopsy; EMG shows fibrillation potentials; responds to increased immunosuppression. When clinical distinction is uncertain, CK and inflammatory markers (ESR, CRP) help but may not be definitive; muscle MRI showing selective type II fiber changes supports steroid myopathy; muscle biopsy is the gold standard for equivocal cases.
Beyond the metabolic complications, glucocorticoids affect the central nervous system and eyes through mechanisms that are dose-dependent, partially reversible, and underrecognized in clinical practice. Neuropsychiatric effects span a spectrum from therapeutic mood elevation at low doses to frank psychosis at high doses, with individual vulnerability varying considerably. Ocular complications are chronic and structural, requiring baseline ophthalmological evaluation in patients anticipated to require prolonged therapy.
HPA (hypothalamic-pituitary-adrenal) axis suppression by exogenous glucocorticoids operates through the negative feedback mechanisms described in Module 1: GR (glucocorticoid receptor)-alpha binding to negative glucocorticoid response elements in the ACTH (adrenocorticotropic hormone) precursor POMC (pro-opiomelanocortin) gene promoter and the CRH (corticotropin-releasing hormone) gene promoter suppresses endogenous cortisol production. The clinical consequence is impaired cortisol stress response capacity, ranging from a blunted but present response at moderate doses and short durations, to complete adrenocortical atrophy with absent cortisol reserve at high doses sustained beyond 3 to 4 months. Recovery of HPA axis function after glucocorticoid cessation follows a predictable but variable course: basal cortisol secretion typically recovers within weeks to months, but full restoration of the cortisol stress response may take 6 to 12 months after prolonged high-dose therapy. During the recovery phase, patients remain at risk for adrenal crisis during physiological stress even if basal morning cortisol has normalized, because the reserve capacity for stress-induced ACTH and cortisol surges recovers more slowly than basal secretion.4
Neuropsychiatric adverse effects of glucocorticoids follow a dose-dependent spectrum that reflects the density and distribution of GR (glucocorticoid receptor) expression in limbic brain structures, particularly the hippocampus, amygdala, and prefrontal cortex. At low to moderate doses (prednisone equivalent up to 20 mg per day), the most common effects are mild euphoria, improved energy, and insomnia, which patients often experience as beneficial in the short term but which contribute to difficulty tapering. At moderate to high doses (prednisone 20 to 60 mg per day), more disruptive effects emerge: irritability, emotional lability, anxiety, and clinically significant insomnia. At high doses (prednisone equivalent greater than 60 mg per day), serious psychiatric complications including major depression, hypomania, mania, and frank psychosis (steroid psychosis) can occur, with an estimated incidence of 5 to 10% for any psychiatric complication at doses above 40 mg per day prednisone equivalent.5 The mechanism involves GR-mediated suppression of hippocampal neurogenesis through reduction of BDNF (brain-derived neurotrophic factor) expression, hippocampal GR saturation altering glutamatergic and serotonergic neurotransmission, and HPA axis dysregulation that is intrinsically linked to mood disorder pathophysiology. Steroid psychosis typically resolves within days to weeks of dose reduction but may require temporary antipsychotic treatment during the acute phase.
PSC (posterior subcapsular cataract) is a structural ophthalmic complication of glucocorticoid therapy that occurs with both systemic and topical (including inhaled and intranasal) glucocorticoids. The mechanism involves GR-dependent effects on lens epithelial cells in the posterior lens capsule: glucocorticoids alter the metabolic activity of these cells and promote abnormal accumulation of protein aggregates (predominantly high-molecular-weight crystallins) in the posterior subcapsular region, reducing lens transparency. PSC develops slowly over months to years of therapy and is dose- and duration-dependent, with cumulative lifetime dose being a stronger predictor than current dose. Unlike age-related nuclear cataracts, PSC is not directly related to oxidative stress and does not respond to antioxidant supplements. The clinical presentation is typically early visual disturbance with bright light or driving at night (glare), with preserved central vision until later stages. Baseline ophthalmological evaluation with slit-lamp examination is recommended before initiating therapy anticipated to exceed 6 months, and annual evaluation thereafter.3
Glucocorticoid-induced IOP (intraocular pressure) elevation, also called steroid-induced glaucoma, results from GR-dependent effects on trabecular meshwork cells in the aqueous humor drainage pathway. Trabecular meshwork cells express GR-alpha at high density, and glucocorticoid activation upregulates expression of myocilin (MYOC) and extracellular matrix proteins including fibronectin and laminin, increasing outflow resistance in the trabecular meshwork and reducing aqueous humor drainage. Elevated IOP develops in approximately 30 to 40% of patients on long-term systemic glucocorticoids, with a subset (5 to 10%) developing IOP elevations sufficient to produce glaucomatous optic nerve damage. The IOP response is heritable and partially predicted by a positive family history of primary open-angle glaucoma. Patients who have a strong IOP response to glucocorticoids are termed steroid responders; this phenotype is more common in individuals with primary open-angle glaucoma and their first-degree relatives.6 IOP monitoring every 3 months in patients on long-term systemic glucocorticoids is standard, with ophthalmological referral for IOP greater than 21 mmHg.
Before initiating therapy >6 months: slit-lamp examination for lens changes, IOP measurement, fundoscopic examination for optic nerve baseline.
Every 3 months during therapy: IOP measurement; refer to ophthalmology if IOP >21 mmHg or if rate of rise is greater than 5 mmHg per visit.
Annually: full slit-lamp and fundoscopic examination for PSC (posterior subcapsular cataract) progression, glaucomatous cupping, and visual field changes.
Steroid responders (IOP >21 mmHg on glucocorticoids): consider switch to agent with lower IOP response (e.g., from prednisolone to rimexolone for ophthalmic applications, or from systemic to inhaled where disease allows); add topical prostaglandin analogue or beta-blocker if IOP remains elevated after dose reduction.
GIO (glucocorticoid-induced osteoporosis) is the most common cause of secondary osteoporosis and the most prevalent serious skeletal complication of long-term glucocorticoid therapy. The fracture risk associated with glucocorticoid use exceeds what would be predicted from bone mineral density alone, because glucocorticoids impair bone quality through mechanisms beyond simple bone loss. Prevention is pharmacologically well-supported and should be initiated proactively rather than after the first fragility fracture.
The cellular mechanisms driving GIO operate simultaneously on both sides of the bone remodeling unit. On the bone-forming side, glucocorticoids suppress osteoblast differentiation from mesenchymal precursor cells by inhibiting Wnt/beta-catenin signaling, which is the principal pathway driving osteoblast lineage commitment. GR (glucocorticoid receptor)-alpha activation additionally promotes apoptosis of mature osteoblasts and osteocytes through direct transcriptional induction of pro-apoptotic factors, reducing the lifespan of bone-forming cells. The net result is reduced osteoid synthesis, impaired mineralization, and progressive loss of trabecular bone architecture. On the bone-resorbing side, glucocorticoids increase expression of RANKL (receptor activator of nuclear factor kappa-B ligand) by osteoblasts and bone marrow stromal cells while simultaneously suppressing OPG (osteoprotegerin), the soluble decoy receptor that normally neutralizes RANKL and limits osteoclast activation. The resulting shift in the RANKL-to-OPG ratio toward RANKL dominance drives osteoclast differentiation, activation, and prolonged survival, increasing bone resorption.7 Glucocorticoids also impair calcium absorption in the gastrointestinal tract by suppressing calcium transport proteins in enterocytes, and increase renal calcium excretion, creating secondary hyperparathyroidism that further drives osteoclast activation to maintain serum calcium.
Fracture risk in GIO does not track linearly with BMD (bone mineral density) measured by DXA (dual-energy X-ray absorptiometry). At any given BMD T-score, glucocorticoid-treated patients have a higher fracture probability than glucocorticoid-naive patients because bone quality deterioration (including reduced trabecular microarchitecture integrity, impaired osteocyte mechanosensing, and altered bone matrix composition) occurs faster than BMD decline. The FRAX (Fracture Risk Assessment Tool) algorithm, which calculates 10-year probability of major osteoporotic fracture and hip fracture from clinical risk factors and optionally BMD, has a glucocorticoid adjustment that partially accounts for this discrepancy: FRAX scores should be increased by approximately 15% for major fracture probability and 20% for hip fracture probability in patients receiving prednisone greater than 7.5 mg per day for more than 3 months, to account for the bone quality effect not captured by DXA-measured BMD alone. Vertebral fractures, which are the most common GIO fracture type and can be clinically silent, require lateral spine imaging (radiograph or VFA [vertebral fracture assessment]) at baseline and with significant height loss or new back pain.8
The ACR (American College of Rheumatology) guidelines provide the most widely used framework for GIO prevention and treatment, stratifying intervention thresholds by fracture risk category. For patients initiating glucocorticoid therapy anticipated to last 3 months or longer at any dose, calcium 1000 to 1200 mg per day and vitamin D 600 to 800 IU (international units) per day (with higher doses if 25-hydroxyvitamin D levels are below 20 ng per mL) are recommended universally as the foundation of bone protection. For patients at medium or high fracture risk (defined by FRAX-adjusted 10-year major fracture probability greater than 10% for medium risk or greater than 20% for high risk, or by prevalent vertebral or hip fracture regardless of FRAX score), pharmacological bone protection with an oral bisphosphonate (alendronate or risedronate) is recommended. Zoledronic acid by annual intravenous infusion is an alternative for patients unable to tolerate oral bisphosphonates due to upper gastrointestinal adverse effects or adherence problems.9
Bisphosphonates reduce fracture risk in GIO through their mechanism of inhibiting osteoclast-mediated bone resorption: they are taken up into bone mineral and are selectively ingested by osteoclasts during bone resorption, where they inhibit farnesyl pyrophosphate synthase in the mevalonate pathway, impairing osteoclast cytoskeletal function and promoting osteoclast apoptosis. Clinical trial evidence demonstrates 50 to 70% relative risk reduction in vertebral fractures with alendronate or risedronate in glucocorticoid-treated patients. Denosumab, a monoclonal antibody targeting RANKL that directly neutralizes the key signal driving osteoclast activation in GIO, is an alternative for patients who cannot tolerate bisphosphonates or in whom they are contraindicated (estimated GFR (glomerular filtration rate) below 30 to 35 mL per minute per 1.73 m2 is a relative contraindication to oral and IV bisphosphonates). An important denosumab consideration is that its anti-resorptive effect wanes rapidly after the injection interval is extended or a dose is missed, and rebound bone loss with increased fracture risk has been observed after denosumab discontinuation; transition to a bisphosphonate before stopping denosumab is recommended.9
Teriparatide, the recombinant 1–34 amino acid fragment of PTH (parathyroid hormone), is the only approved bone anabolic agent specifically studied in GIO and is preferred for patients at very high fracture risk (FRAX-adjusted 10-year major fracture probability greater than 20%, or patients with two or more prevalent vertebral fractures). Unlike bisphosphonates and denosumab, which primarily reduce bone resorption, teriparatide stimulates osteoblast differentiation and activity directly through PTH receptor 1 (PTH1R) signaling, increasing bone formation and improving trabecular microarchitecture. Head-to-head trials have demonstrated teriparatide superiority over alendronate for new vertebral fracture prevention in GIO, reflecting its bone quality benefit beyond simple BMD increase. The 24-month treatment limit (regulatory restriction for teriparatide) requires transition to an antiresorptive agent afterward to preserve the anabolic gains; transition to a bisphosphonate within 3 months of teriparatide completion is the standard approach.10
At initiation of glucocorticoid therapy anticipated to last 3 or more months: assess fracture risk with FRAX (adjusted for GC dose), measure baseline DXA of lumbar spine and hip, obtain lateral spine imaging if height loss or back pain, check 25-hydroxyvitamin D level. Start calcium and vitamin D universally. For medium or high fracture risk: start alendronate 70 mg weekly or risedronate 35 mg weekly. Reassess BMD every 12 months while on therapy. Stop protective bisphosphonate only after glucocorticoid is discontinued and fracture risk has returned to low. In women of reproductive age on glucocorticoids: bisphosphonates are teratogenic and contraindicated in women planning pregnancy; denosumab is also not recommended; calcium, vitamin D, and close monitoring are the mainstay until pregnancy planning is resolved.
Cardiovascular and infectious complications contribute substantially to the excess morbidity and mortality associated with long-term glucocorticoid therapy. Cardiovascular risk is elevated by multiple converging mechanisms operating through the vasculature, the kidney, and the metabolic milieu. Infectious risk is proportional to the degree of immunosuppression and is predictable enough to permit targeted prophylaxis strategies that substantially reduce the incidence of preventable opportunistic infections.
Glucocorticoid-induced hypertension arises through multiple mechanisms operating in parallel. In the kidney, glucocorticoids at pharmacological concentrations overwhelm the capacity of 11beta-HSD2 (11-beta-hydroxysteroid dehydrogenase type 2) to inactivate cortisol before it reaches the mineralocorticoid receptor (MR) in the distal nephron; the excess cortisol activates MR, promoting sodium and water retention and potassium excretion through upregulation of ENaC (epithelial sodium channel) and the Na/K-ATPase. This mineralocorticoid overflow effect is most pronounced with hydrocortisone and prednisolone, which have significant intrinsic mineralocorticoid activity, but occurs to some extent with all glucocorticoids at high doses. In the vasculature, glucocorticoids suppress eNOS (endothelial nitric oxide synthase) expression and activity, reducing nitric oxide (NO)-mediated vasodilation and increasing peripheral vascular resistance. Glucocorticoids also increase vascular sensitivity to vasopressors including angiotensin II and catecholamines through upregulation of their respective receptors on vascular smooth muscle, contributing to elevated mean arterial pressure.11 RAAS (renin-angiotensin-aldosterone system) activation by volume changes and direct glucocorticoid-stimulated renin gene expression provides an additional pressor input. The resulting hypertension typically responds well to the addition of antihypertensive therapy, with RAAS-blocking agents (angiotensin-converting enzyme inhibitors or angiotensin receptor blockers) being preferred when concomitant proteinuria, diabetes, or heart failure is present.
Accelerated atherosclerosis with long-term glucocorticoid use is multifactorial and extends beyond the hypertension and dyslipidemia discussed in Section 1. Glucocorticoids directly promote endothelial dysfunction by suppressing prostacyclin production, which is anti-thrombotic and vasodilatory, while maintaining thromboxane A2 synthesis, shifting the prostanoid balance toward platelet aggregation and vasoconstriction. They also impair endothelial repair by reducing endothelial progenitor cell mobilization from the bone marrow. Central adiposity driven by GR (glucocorticoid receptor)-mediated induction of lipoprotein lipase in omental fat depots creates a pro-inflammatory visceral fat mass that secretes adipokines including TNF-alpha (tumor necrosis factor-alpha), IL-6 (interleukin-6), and resistin, all of which contribute to insulin resistance and endothelial inflammation. The cumulative cardiovascular risk burden from glucocorticoid-induced hypertension, dyslipidemia, hyperglycemia, central adiposity, endothelial dysfunction, and prothrombotic state explains why patients on chronic glucocorticoid therapy have substantially higher rates of myocardial infarction, stroke, and heart failure than the general population, even after adjustment for the underlying inflammatory disease.3
AF (atrial fibrillation) risk is significantly elevated in patients on glucocorticoids, with meta-analyses estimating an approximately 2-fold increase in new-onset AF risk compared with non-users. Proposed mechanisms include glucocorticoid-driven electrolyte abnormalities (hypokalemia from mineralocorticoid overflow), direct GR-mediated effects on atrial cardiomyocyte ion channel expression and electrical remodeling, and the cardiovascular risk factor milieu described above. The risk appears to be dose-dependent and is most elevated at high prednisone equivalent doses greater than 30 to 40 mg per day. Patients at baseline AF risk who require high-dose glucocorticoid therapy warrant electrocardiographic monitoring and optimization of modifiable AF risk factors.11
Infectious complications from glucocorticoid-induced immunosuppression are broadly proportional to the cumulative degree of immune suppression: the dose, duration, and specific immune cell populations affected. Common bacterial infections (pneumonia, urinary tract infection, skin and soft tissue infection) are increased approximately 2-fold at prednisone equivalent doses greater than 10 mg per day.12 Opportunistic infections reflecting cell-mediated immunity impairment become clinically relevant at doses greater than 20 mg per day for more than 4 weeks. PCP (Pneumocystis jirovecii pneumonia), caused by the ubiquitous opportunistic fungus Pneumocystis jirovecii (previously classified as a protozoan), is the most consistently preventable opportunistic infection in glucocorticoid-treated non-HIV patients. The threshold for PCP prophylaxis with TMP-SMX (trimethoprim-sulfamethoxazole) in patients not receiving other immunosuppressants is generally prednisone equivalent greater than 20 mg per day for more than 4 weeks; when glucocorticoids are combined with other immunosuppressants (methotrexate, azathioprine, mycophenolate, calcineurin inhibitors, or biologics), the threshold is lower, typically prednisone greater than 10 mg per day for more than 4 weeks.12
PCP prophylaxis with TMP-SMX one double-strength tablet three times weekly (or once daily) is the standard of care when prednisone equivalent exceeds 20 mg per day for more than 4 weeks in glucocorticoid monotherapy, or 10 mg per day for more than 4 weeks when combined with additional immunosuppressants. Alternatives for sulfonamide intolerance: dapsone 100 mg daily or atovaquone 1500 mg daily. Varicella-zoster virus (VZV) reactivation as herpes zoster is significantly more common in patients on glucocorticoids; recombinant zoster vaccine (Shingrix) is recommended for patients 50 and older before initiating therapy or between cycles when the immunosuppressive burden is lowest, as the live attenuated varicella vaccine (Varivax) is contraindicated in significantly immunosuppressed patients. Tuberculosis (TB) reactivation risk requires IGRA (interferon-gamma release assay) or tuberculin skin test screening before initiating long-term therapy in patients with risk factors; latent TB (positive IGRA without active disease) should be treated with isoniazid prophylaxis before beginning glucocorticoid therapy if possible.
The drug interactions of glucocorticoids fall into two categories: pharmacokinetic interactions that alter glucocorticoid plasma concentrations through CYP3A4 (cytochrome P450 3A4) modulation, and pharmacodynamic interactions that compound or counteract glucocorticoid effects on specific organ systems. Steroid-sparing strategies are pharmacologically justified and clinically necessary in any patient requiring glucocorticoid doses above 7.5 mg prednisone equivalent per day for more than 3 months, as the chronic adverse effect burden at these doses substantially exceeds the risk of most steroid-sparing agents.
CYP3A4 (cytochrome P450 3A4) is the principal enzyme responsible for glucocorticoid metabolism, and its activity determines plasma glucocorticoid concentrations following any given dose. CYP3A4 inducers accelerate glucocorticoid metabolism and reduce plasma concentrations, potentially causing loss of therapeutic effect or precipitating adrenal crisis in dependent patients. The most potent inducers clinically are rifampin (rifampicin), which can reduce prednisolone area under the curve by 45 to 75% and has caused acute rejection episodes in transplant patients; enzyme-inducing antiepileptic drugs including phenytoin, carbamazepine, and phenobarbital; efavirenz and nevirapine (non-nucleoside reverse transcriptase inhibitors); and hypericum (St. John's wort). Patients on these combinations require higher glucocorticoid doses to maintain therapeutic effect, and must be monitored carefully when the inducer is discontinued, as the normal enzyme activity returns over 2 to 4 weeks and the previously compensatory glucocorticoid dose may then produce toxic concentrations.13
CYP3A4 inhibitors increase glucocorticoid plasma concentrations, producing toxic effects at standard doses. The most clinically relevant inhibitors are azole antifungals (ketoconazole, itraconazole, voriconazole), ritonavir-boosted antiretroviral regimens (where ritonavir's potent CYP3A4 inhibition raises fluticasone ICS (inhaled corticosteroid) levels 350-fold), clarithromycin, and grapefruit juice at high consumption volumes. The ritonavir-fluticasone combination deserves specific prescriber attention because the pharmacokinetic interaction can cause iatrogenic Cushing syndrome even with standard-dose inhaled fluticasone, and the interaction is not always appreciated when HIV (human immunodeficiency virus) care and respiratory care are managed by different providers.
The interaction between glucocorticoids and warfarin is complex and incompletely understood, but the net clinical effect is variable INR (international normalized ratio) changes that require close monitoring at the time of glucocorticoid initiation, dose changes, or discontinuation. The proposed mechanisms include glucocorticoid-induced changes in factor synthesis and catabolism in the liver, altered warfarin protein binding (since glucocorticoids compete with warfarin for albumin binding sites at high doses), and the anti-inflammatory effect of glucocorticoids reducing the physiological INR-elevating effect of the inflammatory state for which warfarin may have been started. In practice, the INR should be measured within 1 to 2 weeks of initiating or significantly changing a glucocorticoid dose in any patient on warfarin, and warfarin dosing adjusted accordingly. The interaction with NSAIDs (non-steroidal anti-inflammatory drugs) is pharmacodynamic rather than pharmacokinetic: both glucocorticoids and NSAIDs independently suppress the prostaglandin-mediated gastric mucosal defense mechanisms, and their combination produces substantially greater GI (gastrointestinal) mucosal injury risk than either agent alone, with the relative risk of peptic ulcer complications estimated at 15-fold compared with neither drug, versus approximately 3-fold for each agent used alone.2 Proton pump inhibitor prophylaxis is indicated for patients receiving both agents simultaneously.
Steroid-sparing agents are agents used adjunctively with glucocorticoids to permit a lower glucocorticoid dose to maintain disease control, or to allow glucocorticoid discontinuation entirely. The pharmacological basis of steroid-sparing differs by agent class. MTX (methotrexate), the most widely used steroid-sparing agent in rheumatological and inflammatory diseases, inhibits dihydrofolate reductase and impairs purine synthesis in rapidly dividing immune cells, reducing T cell and B cell proliferation and inflammatory cytokine production through adenosine-mediated anti-inflammatory mechanisms at low doses; its steroid-sparing effect is demonstrated in RA (rheumatoid arthritis), inflammatory myopathies, vasculitis, and psoriatic disease, typically permitting a 30 to 50% reduction in prednisone dose within 3 to 6 months of initiation. AZA (azathioprine) is a prodrug converted to 6-mercaptopurine, which inhibits de novo purine synthesis and impairs lymphocyte proliferation; it is used as a steroid-sparing agent in inflammatory bowel disease, autoimmune hepatitis, myasthenia gravis, and organ transplantation, but its onset of action (3 to 6 months) and TPMT (thiopurine methyltransferase) genotype-dependent toxicity require careful patient selection and monitoring.13
MMF (mycophenolate mofetil) is a prodrug hydrolyzed to mycophenolic acid, which selectively inhibits IMPDH (inosine monophosphate dehydrogenase) type II, the isoform preferentially expressed in activated lymphocytes. This selectivity limits purine synthesis in T and B cells while sparing other rapidly dividing cells, producing a more targeted immunosuppressive effect with less hematological and hepatic toxicity than azathioprine. MMF is the preferred steroid-sparing agent in lupus nephritis (with hydroxychloroquine and low-dose prednisone as the backbone), IgA nephropathy, and many transplant maintenance protocols, and increasingly in inflammatory bowel disease and other autoimmune conditions where azathioprine is not tolerated. For disease-specific steroid-sparing that exploits non-immunosuppressive mechanisms, the IL-6 (interleukin-6) receptor antagonist tocilizumab in giant cell arteritis permits a more rapid prednisone taper with lower relapse rates, as demonstrated in the GiACTA trial, while JAK (Janus kinase) inhibitors in RA and other inflammatory arthropathies allow substantial prednisone dose reduction by targeting the downstream signaling of multiple pro-inflammatory cytokines simultaneously.14
Live attenuated vaccines (MMR [measles-mumps-rubella], varicella, yellow fever, intranasal influenza) are contraindicated in patients on prednisone equivalent greater than 20 mg per day for more than 2 weeks, due to risk of disseminated infection from the vaccine strain. Inactivated vaccines (injectable influenza, pneumococcal, hepatitis A and B, recombinant zoster Shingrix) are safe at any degree of immunosuppression, though immunogenicity is reduced; they should be administered before initiating glucocorticoid therapy when possible, or at the lowest achievable dose during maintenance therapy. Pneumococcal vaccination (PCV20 or PCV15 followed by PPSV23) is specifically recommended for all adult patients on pharmacological glucocorticoid therapy regardless of age, given the markedly increased risk of invasive pneumococcal disease in the immunocompromised host. Annual inactivated influenza vaccination is universally recommended.
Methotrexate (MTX): DHFR (dihydrofolate reductase) inhibition + adenosine-mediated anti-inflammation at low doses. Onset 6–12 weeks. Indications: RA, inflammatory myopathies, vasculitis, psoriatic arthritis. Monitor LFTs (liver function tests), CBC; folate supplementation required.
Azathioprine (AZA): 6-MP (6-mercaptopurine) prodrug; de novo purine synthesis inhibition in lymphocytes. Onset 3–6 months. Check TPMT genotype before initiation (poor metabolizers: increased myelosuppression risk). Indications: IBD (inflammatory bowel disease), autoimmune hepatitis, myasthenia gravis, transplantation.
Mycophenolate mofetil (MMF): Selective IMPDH (inosine monophosphate dehydrogenase) type II inhibition in lymphocytes. Onset 4–8 weeks. Indications: lupus nephritis, transplantation, IgA nephropathy, IBD. Teratogenic; requires pregnancy prevention in women of childbearing age.
Tocilizumab: IL-6 (interleukin-6) receptor antagonist. Onset 4–8 weeks. Indications: GCA (giant cell arteritis; proven steroid-sparing), RA. Screen for TB and hepatitis B before initiating. Monitor for serious infections and lipid elevation.
Schacke H, Docke WD, Asadullah K. Mechanisms involved in the side effects of glucocorticoids. Pharmacol Ther. 2002;96(1):23–43.
doi:10.1016/S0163-7258(02)00297-8Liu D, Ahmet A, Ward L, et al. A practical guide to the monitoring and management of the complications of systemic corticosteroid therapy. Allergy Asthma Clin Immunol. 2013;9(1):30.
doi:10.1186/1710-1492-9-30Huscher D, Thiele K, Gromnica-Ihle E, et al. Dose-related patterns of glucocorticoid-induced side effects. Ann Rheum Dis. 2009;68(7):1119–1124.
doi:10.1136/ard.2008.092163Henzen C, Suter A, Lerch E, et al. Suppression and recovery of adrenal response after short-term, high-dose glucocorticoid treatment. Lancet. 2000;355(9203):542–545.
doi:10.1016/S0140-6736(99)06290-XWarrington TP, Bostwick JM. Psychiatric adverse effects of corticosteroids. Mayo Clin Proc. 2006;81(10):1361–1367.
doi:10.4065/81.10.1361Jones R, Rhee DJ. Corticosteroid-induced ocular hypertension and glaucoma: a brief review and update of the literature. Curr Opin Ophthalmol. 2006;17(2):163–167.
doi:10.1097/01.icu.0000193079.55240.18Weinstein RS. Glucocorticoid-induced bone disease. N Engl J Med. 2011;365(1):62–70.
doi:10.1056/NEJMcp1012926Kanis JA, Johansson H, Oden A, et al. A meta-analysis of prior corticosteroid use and fracture risk. J Bone Miner Res. 2004;19(6):893–899.
doi:10.1359/JBMR.040134Buckley L, Guyatt G, Fink HA, et al. 2017 American College of Rheumatology Guideline for the Prevention and Treatment of Glucocorticoid-Induced Osteoporosis. Arthritis Rheumatol. 2017;69(8):1521–1537.
doi:10.1002/art.40137Saag KG, Shane E, Boonen S, et al. Teriparatide or alendronate in glucocorticoid-induced osteoporosis. N Engl J Med. 2007;357(20):2028–2039.
doi:10.1056/NEJMoa071408Souverein PC, Berard A, Van Staa TP, et al. Use of oral glucocorticoids and risk of cardiovascular and cerebrovascular disease in a population based case-control study. Heart. 2004;90(8):859–865.
doi:10.1136/hrt.2003.020180Baddley JW, Winthrop KL, Chen L, et al. Non-viral opportunistic infections in new users of tumour necrosis factor inhibitor therapy: results of the SAfety Assessment of Biologic theRapy (SABER) study. Ann Rheum Dis. 2014;73(11):1942–1948.
doi:10.1136/annrheumdis-2013-203407Czock D, Keller F, Rasche FM, Haussler U. Pharmacokinetics and pharmacodynamics of systemically administered glucocorticoids. Clin Pharmacokinet. 2005;44(1):61–98.
doi:10.2165/00003088-200544010-00003Stone JH, Tuckwell K, Dimonaco S, et al. Trial of tocilizumab in giant-cell arteritis. N Engl J Med. 2017;377(4):317–328.
doi:10.1056/NEJMoa1613849