Topical Glucocorticoids

• Glucocorticoids remain among the most commonly prescribed anti-inflammatory agents in dermatology and all of medicine; large number of disorders respond to these drugs.
• Proper use of systemic glucocorticoids requires a working knowledge of the hypothalamic–pituitary–adrenal (HPA) axis.
• Proper use of topical and intralesional glucocorticoids requires awareness of formulations and potencies.
• Broad range of potential adverse effects, which can be minimized by various strategies.
• Clinical usage guidelines facilitate proper dosing/administration for both short- and long-term therapy.

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• 1950 — Nobel Prize in Medicine awarded to Hench and associates for initial work on beneficial effects/toxicities of corticosteroids for rheumatic disorders.
• 1951 — Sulzberger and colleagues first reported use of systemic cortisone and ACTH as therapies for inflammatory skin diseases.
• 1952 — Sulzberger and Witten successfully treated eczematous eruptions with topical hydrocortisone.
• 1982 — Johnson and Lazarus introduced high-dose pulse intravenous glucocorticoid therapy to dermatology, for pyoderma gangrenosum.
• Past 40 years: development of other anti-inflammatory/immunomodulatory drugs allowing a "steroid-sparing" effect and minimization of long-term systemic glucocorticoid risks.

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• All steroids (including glucocorticoids) share the basic four-ring cholesterol structure: three hexane rings + one pentane ring (chemical structure of hydrocortisone/cortisol).
• Structural modifications → systemic agents with different potencies, mineralocorticoid effects, durations of action (biologic half-life), and metabolism — collectively termed corticosteroids.
• Similar structural changes yield topical agents with differing solubility, lipophilicity, percutaneous absorption, and glucocorticoid receptor-binding activity.
• Table 14.11 (cross-reference) defines glucocorticoid structural classes relevant to allergic cross-reactivity.
• Active vs inactive (prodrug) agents:
• Hydrocortisone = active; has a hydroxyl group at the 11 position.
• Cortisone = inactive; has a ketone group at position 11; requires hepatic 11-hydroxylation to become hydrocortisone.
• Prednisone = inactive; requires identical hepatic 11-hydroxylation to become prednisolone (active).
• In severe hepatic disease, this conversion is impaired → best to use an agent that does NOT require metabolic activation, e.g. prednisolone.

• Hypothalamus → corticotropin-releasing hormone (CRH) released in small pulses into pituitary circulation.
• Anterior pituitary responds to CRH → synthesizes and pulsatile-secretes ACTH.
• ACTH stimulates the middle layer of the adrenal cortex to generate/release cortisol.
• Basal adrenal cortisol production: ~20–30 mg/day in an adult (equivalent to 5–7.5 mg/day of prednisone); can increase up to 10-fold under maximal stress.
• ACTH has some role in adrenal androgen production but is NOT significantly involved in aldosterone (major mineralocorticoid) production.
• Major mineralocorticoid control mechanisms: renin–angiotensin system and serum potassium levels.
• Three main control mechanisms for endogenous cortisol secretion:

1. Negative feedback: plasma cortisol inhibits CRH (hypothalamus) and ACTH (pituitary) secretion.
2. Pulsatile/circadian ACTH secretion: pulses increase several hours after sleep onset, peak shortly before waking; peak cortisol release typically at ~6–8 a.m. in a typical sleep cycle (adjusts with different sleep cycles to occur just before waking).
3. Neural effects: emotional/physical stress via catecholamines from brainstem, extra-hypothalamic CRH sources, and vasopressin.

• Free (unbound) glucocorticoid fraction enters cells → binds cytoplasmic glucocorticoid receptor within a protein complex including heat shock protein 90 (HSP90), p23, and immunophilins FKBP51/FKBP52.
• After binding: FKBP52 replaces FKBP51 → facilitates nuclear translocation.
• In nucleus: ligand-bound glucocorticoid receptor homodimers bind glucocorticoid response elements (GREs) in gene promoter regions → activation (more often) or repression (less often) of transcription.
• ~10–100 genes per cell directly regulated by glucocorticoids.
• Glucocorticoid receptor monomers also indirectly affect gene expression by interacting with/inhibiting other transcription factors:
• NF-κB: important transcription factor inducing genes for cytokines, adhesion molecules, inflammatory enzymes, growth factors involved in chronic inflammation — glucocorticoid receptor inhibits directly and indirectly → dramatically reduces inflammation.
• AP-1 (activator protein 1): heterodimeric transcription factor (c-jun, c-fos, activating transcription factor) controlling growth factor/cytokine genes — also inhibited.
• Direct transactivation > transrepression: ↑ expression of anti-inflammatory proteins (e.g. IκB-α, IL-1 receptor antagonist, IL-10); ↓ expression of POMC, CRH, osteocalcin, keratins.
• Indirect transrepression > transactivation: ↓ expression of proinflammatory cytokines, chemokines, adhesion molecules, and enzymes.

• Decreased production of cytokines/proinflammatory molecules:
• Tumor necrosis factor (TNF)
• Granulocyte–macrophage colony-stimulating factor (GM-CSF)
• IL-1, IL-2, IL-6, IL-8
• ICAM-1, E-selectin
• Leukotrienes and prostaglandins (via decreased phospholipase A2 and cyclooxygenase activity)
• Effects on inflammatory cells:
• Neutrophils: increased release from bone marrow (→ neutrophilia, larger circulating pool); decreased infiltration into inflammation sites (reduced endothelial adhesion molecules/chemoattractants); decreased apoptosis; milder effects on phagocytosis/bactericidal function.
• Lymphocytes: redistribution of T cells to lymphoid depots (→ transient lymphopenia); decreased activation/proliferation of effector T cells (helper > cytotoxic) via decreased IL-2 signaling and antigen presentation; decreased B cell function/antibody production (at high doses); increased apoptosis; increased regulatory T cell function.
• Eosinophils: decreased release from bone marrow and recruitment to inflammation sites; increased apoptosis.
• Monocytes/macrophages: decreased production, differentiation, antigen presentation.
• Mast cells: decreased maturation, cytokine production, high-affinity IgE receptor (FcεRI) expression, and mediator release.
• Erythrocytes: decreased destruction (reduced autohemolysis and erythrophagocytosis).

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• Duration differs for intramuscular administration (see below).
• Mineralocorticoid potency: cortisone and hydrocortisone have significant mineralocorticoid potency; prednisone/prednisolone have slight effect; methylprednisolone and triamcinolone have NO mineralocorticoid activity — most appropriate when mineralocorticoid effects must be avoided.
• Plasma half-life is a POOR indicator of duration of biologic action — duration best assessed by period of ACTH suppression after a single dose.
• Duration of biologic activity is critical for choosing agents for alternate-day therapy: intermediate-acting agents should be used; long-acting agents should be AVOIDED (no recovery period for HPA axis).

• Oral glucocorticoids absorbed in the jejunum; peak plasma levels at 30–90 minutes after intake.
• Food may delay absorption but does NOT decrease the amount absorbed.
• Primary plasma carrier protein: corticosteroid-binding globulin (CBG), aka transcortin — high-affinity, low-capacity; binds most endogenous cortisol and low-dose exogenous glucocorticoids.
• Higher glucocorticoid doses: additional low-affinity, high-capacity binding to albumin.
• Exogenous glucocorticoids bind these carriers with less avidity than endogenous cortisol.
• As exogenous glucocorticoid fills CBG sites → increased low-affinity albumin binding → greater free (unbound), biologically active fraction.
• Hepatic or renal disease (decreased binding proteins) → increases free fraction of exogenous glucocorticoids → augments both therapeutic effects AND toxicities.

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• Severe dermatitis: contact dermatitis (various forms); acute exacerbations of atopic dermatitis (risk of rebound flare upon discontinuation); photodermatitis; exfoliative erythrodermas.
• Bullous dermatoses: pemphigus (all forms); bullous pemphigoid; mucous membrane (cicatricial) pemphigoid; linear IgA bullous dermatosis; epidermolysis bullosa acquisita; gestational pemphigoid; erythema multiforme (major).
• Vasculitis: cutaneous (various types); systemic (various types).
• Autoimmune connective tissue diseases: lupus erythematosus; dermatomyositis; systemic sclerosis (selected patients); eosinophilic fasciitis; morphea (severe generalized and linear variants); mixed connective tissue disease; relapsing polychondritis.
• Neutrophilic dermatoses: Sweet syndrome (acute febrile neutrophilic dermatosis); pyoderma gangrenosum; Behçet disease.
• Other disorders: sarcoidosis; lichen planus; panniculitis (some types); urticaria/angioedema (acutely); DRESS; arthropod bites/stings.
• Many more conditions respond to topical/intralesional glucocorticoids (eczematous/papulosquamous disorders, localized inflammatory processes).

• Used short-term (~3 weeks or less) for acute conditions (e.g. extensive allergic contact dermatitis).
• Longer courses (months–years) → consider adding a glucocorticoid-sparing agent.
• Intermediate-duration agent (e.g. prednisone) usually given as a single early-morning dose → least HPA suppression.
• Severe acute dermatoses: divided twice-daily dosing possible for better initial control (vs more frequent IV administration); convert to single AM dose ASAP.
• Split-dose therapy: parallel increases in efficacy AND toxicity; total daily mg as split dose ≈ biologically equivalent to a slightly higher single morning dose.
• Typical prednisone initial dose for moderate conditions: 40–60 mg/day in average-weight adults, or ~1 mg/kg/day in children.
• Prednisone = often intermediate-acting glucocorticoid of choice for short- and long-term therapy — inexpensive, many dosage forms.
• Methylprednisolone used if mineralocorticoid effects must be avoided.
• Prednisone/methylprednisolone also used for alternate-morning therapy (allows HPA axis recovery in last 12 hours of off-day).
• Osteoporosis and cataracts — two important long-term side effects NOT minimized by alternate-morning dosing.

• Occasionally used for acute dermatoses.
• Serious conditions (pemphigus vulgaris, SLE) better treated by other routes (need for higher initial doses, more dosage control).
• Advantages: guaranteed compliance (physician-administered); steady release from depot preparation.
• Disadvantages: oral AM doses more physiologic, more predictable absorption, allow precise tapering, can be given alternate-morning; risk of lipoatrophy or sterile abscess at injection site (especially with triamcinolone) if not injected deeply enough.
• Betamethasone and dexamethasone: IM duration of action <1 week — preferred for self-limited dermatoses.
• Triamcinolone acetonide and methylprednisolone acetate: longer-acting IM agents (~3 weeks effect) — should NOT be given more than 4–6 times per year (continuous effect ≥3 weeks per injection, requiring HPA recovery time — easy to underestimate as "intermittent/safe").

• IV doses may be necessary in life-threatening dermatologic conditions.
• Total daily dose ≥2 mg/kg methylprednisolone, divided every 6–8 hours, for acute/critical situations.
• IV pulse therapy: methylprednisolone 0.5–1 g IV over 2 hours daily for 1–5 days.
• Formerly inpatient with cardiac monitoring (risk of arrhythmias, rare sudden death from rapid administration causing acute electrolyte shifts).
• Coadministration of potassium and slow 2-hour infusion usually prevent cardiac effects → allows outpatient use.
• Followed by maintenance oral glucocorticoid therapy.

• WHO categorizes topical glucocorticoids into 4 major potency groups spanning 7 classes — Class 1 = ultra high (super-potent) → Class 7 = very low potency.
• Classes developed from vasoconstrictor assays and double-blind clinical studies; degree of vasoconstriction in normal skin correlates with clinical efficacy (response of psoriatic lesions treated 2–3 weeks).
• Vehicle greatly influences percutaneous absorption/therapeutic efficacy; brand-name vs generic formulations of same agent/concentration/vehicle may have different potencies (cross-ref Table 124.3); insurance-driven generic substitution can alter effectiveness.
• Ointment formulation often more potent than same molecule in cream/lotion (occlusive vehicles ↑ percutaneous absorption via ↑ SC hydration). Gel preparations also tend to be readily absorbed.
• Selecting a topical preparation: (1) choose potency based on lesion type/location/thickness/extent; (2) choose vehicle based on hydration/drying need, body location, irritation/sensitization potential.
• Lotions: elegant for face.
• Creams: rub in well.
• Ointments: advantageous for dry lesions.
• Gels/foams: useful in hairy areas or for drying effect.
• Face and body folds: avoid high-potency preparations if possible — risk of skin atrophy (both sites) and steroid rosacea/perioral dermatitis (face).
• "Pulse dosing" (e.g. twice daily weekends only) may reduce epidermal atrophy risk with potent agents.
• Beyond decreasing potency/frequency, no other modification is certain to reduce atrophy/steroid rosacea risk.
• Mometasone furoate and fluticasone propionate: low percutaneous absorption, rapid hepatic metabolism → minimized systemic bioavailability.
• Fluticasone propionate also highly lipophilic, high glucocorticoid receptor affinity, WITHOUT significant androgen/progesterone/estrogen/mineralocorticoid receptor binding.

Potency Ranking of Commonly Used Topical Glucocorticoids

• Class 1 — Ultra high (super-potent):
• Betamethasone dipropionate ointment* and gel* 0.05%
• Clobetasol propionate ointment, cream, gel, lotion, foam, solution ("scalp application")†, spray, and shampoo 0.05%
• Desoximetasone spray 0.25%
• Diflorasone diacetate ointment* 0.05%
• Fluocinonide cream 0.1%
• Flurandrenolide tape 4 mcg/cm²
• Halobetasol propionate ointment, cream, lotion, and foam 0.05%
• Class 2 — High:
• Amcinonide ointment 0.1%
• Betamethasone dipropionate ointment, cream, and lotion 0.05%
• Clobetasol propionate cream 0.025%
• Desoximetasone cream, ointment 0.25% or gel 0.05%
• Diflorasone diacetate cream* and ointment 0.05%
• Fluocinonide cream, ointment, gel, and solution 0.05%
• Halcinonide cream, ointment, and solution 0.1%
• Halobetasol propionate lotion 0.01%
• Mometasone furoate ointment 0.1%
• Triamcinolone acetonide ointment 0.5%
• Class 3:
• Amcinonide cream and lotion 0.1%
• Betamethasone dipropionate cream, lotion‡, and spray¶ 0.05%
• Betamethasone valerate ointment 0.1% and foam 0.12%¶
• Diflorasone diacetate cream 0.05%
• Fluticasone propionate ointment 0.005%
• Triamcinolone acetonide ointment 0.1% or cream 0.5%
• Class 4 — Moderate (medium):
• Betamethasone valerate foam 0.12%¶
• Desoximetasone cream 0.05%
• Fluocinolone acetonide ointment 0.025%
• Flurandrenolide ointment 0.05%
• Hydrocortisone valerate ointment 0.2%
• Mometasone furoate cream and lotion 0.1%
• Triamcinolone acetonide cream and ointment (Kenalog®) 0.1% or spray 0.2%
• Class 5:
• Betamethasone dipropionate lotion 0.05%‡
• Betamethasone valerate cream and lotion 0.1%
• Clocortolone pivalate cream 0.1%
• Fluocinolone acetonide cream 0.025% or oil and shampoo 0.01%
• Fluticasone propionate cream and lotion 0.05%
• Flurandrenolide cream and lotion 0.05%
• Hydrocortisone butyrate cream, ointment, lotion, and solution 0.1%
• Hydrocortisone probutate cream 0.1%
• Hydrocortisone valerate cream 0.2%
• Prednicarbate cream and ointment 0.1%
• Triamcinolone acetonide ointment 0.025% or lotion 0.1%
• Class 6 — Low:
• Alclometasone dipropionate cream and ointment 0.05%
• Betamethasone valerate lotion 0.05%
• Desonide cream, gel, ointment, lotion, and foam 0.05%
• Fluocinolone acetonide cream and solution 0.01%
• Triamcinolone acetonide cream and lotion 0.025%
• Class 7:
• Dexamethasone sodium phosphate cream 0.1%
• Hydrocortisone (acetate) cream, ointment, gel, lotion, and solution 0.5%–2.5%
• Methylprednisolone acetate cream 0.25%
• Footnotes: *Optimized vehicle. †In some classifications, class 2. ‡Depending upon classification, class 3 or class 5. ¶Depending upon classification, class 3 or class 4.
• Note: different concentrations exist for betamethasone valerate, clobetasol, desoximetasone, fluocinolone, halobetasol, and triamcinolone acetonide across classes — concentration alone does not determine class.

• Maximum strength: Loteprednol suspension 0.5%; Prednisolone suspension and solution 1%; Rimexolone suspension 1%.
• Moderate strength: Fluorometholone ointment 0.1% and suspension 0.1% or 0.25%; Loteprednol suspension 0.2%; Prednisolone suspension and solution 0.125%.
• Lower strength: Betamethasone solution 0.1%* (*not available in the US); Dexamethasone ointment 0.05%, suspension and solution 0.1%; Difluprednate emulsion 0.05%; Medrysone suspension 1%.

• Useful for localized disorders when topical therapy fails and systemic therapy should be avoided.
• Triamcinolone acetonide suspension diluted to desired concentration; injected in small amounts, usually with a 30-gauge needle.
• Thick dermal lesions (e.g. keloids): concentrations as high as 20–40 mg/ml to decrease excessive connective tissue.
• Other disorders: risk of dermal/fat atrophy → use more dilute concentration, as low as 2 mg/ml.
• Allows bypassing thickened SC barrier and/or treating dermal/perifollicular inflammatory processes directly (e.g. granuloma annulare, nodulocystic acne, alopecia areata) at higher local concentration, reducing epidermal atrophy risk.

• Exogenous glucocorticoids can induce secondary adrenal insufficiency, related to dose AND duration.
• Adrenal suppression usually occurs after 4 weeks of treatment with doses just above physiologic levels; earlier with higher doses.
• Lessened by single morning dose; decreased further by intermediate-acting agent on alternate mornings.

Alternate-Morning Glucocorticoid Therapy

• "Off" days allow HPA axis recovery.
• Decreases risks of: growth suppression; myopathy; hypertension; opportunistic infections; electrolyte imbalances (e.g. hypokalemia, hypocalcemia).
• Does NOT substantially alter risks of osteoporosis or cataracts.
• Fluctuations in glucose levels can make diabetes mellitus harder to manage.

• Entire HPA axis affected by exogenous glucocorticoids: hypothalamus suppressed first, recovers quickest; adrenals suppressed last, recover slowest.
• After high-dose therapy for months–years: ACTH levels may not normalize for several months; full adrenal recovery (normal serum cortisol) may take up to 1 year.
• Altered stress responsiveness possible (infection, surgery) → weakness, fatigue, anorexia, nausea, fever; rarely hypotension or shock.
• Small IV glucocorticoid doses may be needed before major surgical procedures; minor procedures under local anesthesia do NOT require replacement therapy.
• Endocrinology consultation for rare addisonian crisis.
• Glucocorticoid withdrawal syndrome (even without overt adrenal insufficiency): arthralgias, myalgias, headache, mood changes, fatigue, nausea, decreased appetite — from rapid tapering; thought due to low intracellular glucocorticoid levels; treated by returning to previous dose with slower taper.
• Primary screening test for basal HPA function: morning serum cortisol (AM dose omitted, level checked 6–8 a.m.).
• Impaired basal function suggested by cortisol <10 mcg/dl.
• ACTH stimulation test (cosyntropin): serum cortisol at baseline and 30/60 min after IV or IM administration of 250 mcg (standard-dose; weight-adjustable in young children) or 1 mcg (low-dose, possibly more sensitive).
• Further HPA/adrenal stress-response evaluation (endocrinology referral): ACTH stimulation test, corticotropin-releasing factor test, insulin hypoglycemia test, metyrapone test.

• High-quality tapering studies for chronic dermatologic disease are lacking.
• Endocrinology-suggested indications to taper (rather than stop abruptly) following oral use:

1. 40 mg/day prednisone (or equivalent) for >1 week.
2. Any glucocorticoid dose daily for >3 weeks.
3. Repeated glucocorticoid doses in the evenings.
4. A glucocorticoid course within 1 year of stopping long-term therapy, or in patients with other adrenal-insufficiency risk factors.

• (Little evidence directly supports these recommendations.)
• Oral glucocorticoids should be single morning dose when possible to reduce adrenal insufficiency risk.
• If disease flares during taper: resume last controlling dose, then taper more slowly.
• Regimen influenced by: severity/chronicity of underlying disease, onset of effectiveness of coadministered steroid-sparing agent, patient age/comorbidities (diabetes, psychiatric disease, hypertension, osteoporosis).
• Acute moderate conditions (e.g. allergic contact dermatitis): generally 2–3 week course.
• Serious chronic conditions (pyoderma gangrenosum, SLE, dermatomyositis, vasculitis): longer courses, slow taper over 6–8+ weeks.
• General tapering schedule for courses >3–4 weeks (with close disease monitoring):
• >40 mg/day prednisone (or equivalent) — decrease by 5–10 mg weekly.
• 20–40 mg/day — decrease by 5 mg weekly.
• 10–20 mg/day — decrease by 2.5 mg weekly.
• 5–10 mg/day — decrease by 1 mg every 2–3 weeks.
• Conversion to alternate-day therapy once prednisone ~20–30 mg/day:
• Simplest method: multiply previous daily dose by 2–2.5× for on-day dose; taper off-day dose rapidly.
• Alternative: increase on-day dose by 5 mg increments and decrease off-day dose similarly, until therapy is doubled on-day and stopped off-day.
• Simultaneous taper + alternate-morning conversion: decrease dose by 5 mg on alternate morning until patient takes the same dose every other morning as previously taken daily.

• Herpes simplex keratitis: contraindication to local (ocular) glucocorticoid treatment.
• Active tuberculosis and systemic fungal infections: usually contraindications to systemic therapy.
• Previous hypersensitivity to an IV preparation (rare): precludes further use of that drug.
• Relative contraindications to systemic therapy: active peptic ulcer disease; severe depression or psychosis; extensive chronic dermatosis (e.g. psoriasis) likely to flare after rapid taper — use only when benefits clearly outweigh risks.

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• Short-term therapy usually extremely safe for self-limited/acute dermatoses.
• Long-term supraphysiologic therapy → increased incidence of more serious effects; most are dose-related.

• Mood changes, anxiety, insomnia
• GI intolerance (nausea, vomiting)
• Hyperglycemia
• Fluid/sodium retention
• Increased appetite, weight gain
• Acneiform eruptions
• Increased infections
• Amenorrhea
• Muscular weakness, muscle effects
• Impaired wound healing

• Musculoskeletal: osteoporosis; osteonecrosis (e.g. hip); growth retardation; muscle atrophy; myopathy.
• Ophthalmologic: cataracts; glaucoma; infection; hemorrhage; exophthalmos.
• Gastrointestinal: nausea, vomiting; gastroesophageal reflux; peptic ulcer disease; intestinal perforation; pancreatitis; esophagitis (reflux or candidal).
• Metabolic: hyperglycemia; hyperlipidemia; obesity; hypocalcemia; hypokalemic alkalosis.
• Cardiovascular: hypertension; peripheral edema; atherosclerosis.
• Gynecologic, obstetric: amenorrhea; fetal effects (rare adrenal insufficiency; cleft palate in animal studies).
• Hematologic, cellular: leukocytosis; lymphopenia; eosinopenia; immunosuppression with increased infection risk.
• Nervous system: mood/personality changes; psychiatric problems, psychosis; seizures; pseudotumor cerebri; peripheral neuropathy; epidural lipomatosis.
• Cutaneous: atrophy, striae, telangiectasia; vascular fragility, purpura; acne, acneiform eruptions; hirsutism; infections.
• HPA axis: suppression; adrenal (addisonian) crisis; withdrawal syndrome.

• Female patients: slower GC metabolism/clearance (estrogen effect); lower baseline bone density; often given higher dose per kg if not weight-adjusted.
• Postmenopausal women, elderly patients: increased osteoporosis risk, especially with limited physical activity.
• Pediatric patients: temporary growth retardation; increased likelihood of striae distensae in adolescents.
• Patients with SLE, dermato/polymyositis, or rheumatoid arthritis: long-term use → higher risk of aseptic bone necrosis, muscle atrophy, or osteoporosis, respectively.
• Patients with hepatic disease (e.g. from alcoholism): decreased GC/lipid metabolism → high serum triglycerides.
• Patients with hypoalbuminemia: increased free GC fraction → greater side effects.
• Patients who smoke and/or have high alcohol intake: increased risk of osteoporosis and peptic ulcer disease.

• One of the most prevalent long-term systemic glucocorticoid side effects.
• Without preventative measures, develops in 30%–50% of chronically treated patients.
• Rapid bone mineral density decline within first 3 months; rate of loss peaks at 6 months.
• Postmenopausal White women: highest fracture risk (lowest pretreatment bone mass).
• Young men: greatest amount of bone loss (highest pretreatment bone mass).
• Osteopenia/osteoporosis development is NOT avoided by alternate-morning schedules.
• Trabecular bone (axial skeleton — vertebrae, ribs): metabolic turnover rate 8× that of cortical bone (long bones) → much more prone to demineralization.
• Mechanism — direct effects: reduced osteoblast proliferation/function, increased osteoblast apoptosis, promotes osteoclast proliferation.
• Mechanism — indirect effects: increased urinary calcium excretion, reduced intestinal calcium absorption → decreased serum calcium → stimulates PTH release → drives osteoclastic bone resorption.
• Detection: plain radiographs insensitive until 20%–60% of bone mass lost. Best measurement: DEXA (dual-energy X-ray absorptiometry) — sensitivity, reproducibility, low radiation.
• Baseline DEXA (hip + lumbar spine) recommended for long-term glucocorticoid patients; repeat every 1–3 years at same sites.
• T scores: standard deviations from healthy control mean.
• Osteopenia: T score between −1 and −2.5.
• Osteoporosis: T score < −2.5 (i.e. −2.6 or below).
• Endocrinology consultation for significant osteopenia/osteoporosis.

Algorithm for Prevention/Treatment of Osteoporosis (ACR 2023 recommendations)

• Applies to adults on GC equivalent to prednisone ≥2.5 mg/day for ≥3 months.
• Counseling/interventions for all patients: smoking cessation/tobacco avoidance; restrict alcohol (≤2 drinks/day); weight-bearing/resistance exercise, balanced diet, healthy weight; calcium 800–1000 mg + vitamin D 600–800 IU daily (recommended even if duration <3 months).
• Adults ≥40 years: use WHO FRAX® tool for 10-year major osteoporotic fracture risk; if GC dose >7.5 mg/day, increase risk estimate ×1.15 (major osteoporotic) and ×1.2 (hip fracture).
• Alternative: estimate risk group by T score and age; factors that may shift to higher risk group: BMI <20–25 kg/m² or >10% recent weight loss; parental hip fracture history; current smoking or ≥3 alcoholic drinks/day; higher daily/cumulative GC dose (e.g. >20 mg/day prednisone for ≥3–6 months); BMD decline exceeding least significant change.
• Risk categories:
• Low risk: FRAX <10% major osteoporotic and ≤1% hip fracture, AND BMD T score above −1.
• Moderate risk: FRAX 10–19% major osteoporotic/1.1–2.9% hip fracture OR BMD T score between −1 and −2.4.
• High risk: FRAX ≥20–29% major osteoporotic/3–4.4% hip fracture OR BMD T score between −2.5 and −3.4.
• Very high risk: prior osteoporotic fracture OR FRAX ≥30 major osteoporotic/≥4.5 hip fracture OR BMD T score ≤−3.5 OR high-dose GC treatment** (defined as prednisone ≥30 mg/day for >30 days or cumulative dose ≥5 g in past year).
• Treatment: oral bisphosphonate; repeat FRAX + BMD testing every 1–2 years (moderate/high risk).
• Alternative therapy for moderate/high risk: teriparatide (fragmented recombinant PTH) 20 mcg SC daily; abaloparatide (PTH-related protein analog) 80 mcg SC daily; denosumab (anti-RANKL antibody) 60 mg SC every 6 months; raloxifene 60 mg PO daily (postmenopausal women); romosozumab (anti-sclerostin).
• Adults <40 years with increased risk (previous osteoporotic fracture or high-dose GC treatment [very high risk]; or GC ≥7.5 mg/day for ≥6 months AND BMD Z score <−3 or significant BMD loss [moderate risk]):
• No childbearing potential: oral bisphosphonate, alternatives as for ≥40 years.
• Childbearing potential but not planning pregnancy + effective birth control: oral bisphosphonate or (alternative) teriparatide.
• First-line oral bisphosphonate regimens: alendronate 70 mg PO weekly or 5–10 mg PO daily; risedronate 35 mg PO weekly or 5 mg PO daily.
• First-line IV bisphosphonate: zoledronate 5 mg IV yearly.
• Premenopausal women planning pregnancy during treatment and patients with eGFR <35 ml/min should NOT receive bisphosphonates; IV regimens for those unable to tolerate oral therapy; alternative regimens: ibandronate 150 mg PO monthly, or pamidronate 90 mg IV then 30 mg IV every 3 months.
• If BMD testing delayed, consider starting bisphosphonate in high-risk patients.
• Assessments beginning within 6 months of GC initiation: dose/duration/history of GC use; fall risk and osteoporotic fracture history; other risk factors (malnutrition, significant weight loss/low body weight, hypogonadism, secondary hyperparathyroidism, thyroid disease, family history of hip fracture, alcohol ≥3 units/day, smoking); height/weight, muscle strength testing, assessment for undiagnosed fractures; baseline DEXA (hip + lumbar spine), repeat every 1–2 years; annual clinical fracture risk reassessment during GC treatment.
• Children on GC ≥3 months: clinical fracture risk assessment within 6 months then annually; ages 4–17 — calcium 1 g + vitamin D 600 IU daily; history of osteoporotic fracture + GC dose ≥0.1 mg/kg/day — treat with oral bisphosphonate.
• Additional osteoporosis risk factors: androgen-deprivation therapy in men; rheumatoid arthritis (especially in women).
• Zoledronate 4–5 mg IV yearly or pamidronate 30 mg IV every 3 months are alternatives.
• Osteonecrosis of the jaw: potential bisphosphonate complication, most often with high-dose IV administration in patients with underlying malignancy (e.g. multiple myeloma), occasionally with invasive dental work.
• Atypical subtrochanteric/diaphyseal femur fractures reported with long-term bisphosphonate therapy but larger studies show very low absolute risk.
• All bisphosphonates (especially long half-life ones, e.g. ibandronate) should be avoided in premenopausal women who might become pregnant — cross placenta, teratogenic (fetal skeletal abnormalities).
• Bisphosphonates should NOT be given if eGFR <35 ml/min.
• Teriparatide and abaloparatide: increase bone formation.
• Denosumab: monoclonal antibody vs RANKL; blocks osteoclast maturation → decreased bone resorption; not renally cleared, usable with eGFR <35 ml/min; side effects: hypocalcemia, dermatitis, osteonecrosis of jaw, increased infection risk, fetal harm.
• Raloxifene: SERM, less anti-resorptive potency than bisphosphonates; alternative for select postmenopausal women (e.g. high invasive breast cancer risk); limited by increased cardiovascular disease/thrombosis risk.
• Estrogen/progestin therapy: NO LONGER first-line for postmenopausal osteoporosis (increased risk of breast cancer, stroke, MI, VTE).
• Romosozumab: monoclonal antibody targeting sclerostin, increases bone density; not first-line (cardiovascular disease/thrombosis risk).
• Discontinuation of denosumab, teriparatide, abaloparatide, or romosozumab may cause rapid bone loss/increased fracture risk → sequential bisphosphonate therapy for at least 1 year recommended.

• Aka aseptic necrosis / avascular necrosis; numerous causes; uncommon but serious glucocorticoid complication.
• Additional risk factors: physical trauma, sickle cell disease, alcohol abuse, cigarette smoking, HIV infection, elevated serum triglycerides.
• Higher incidence in renal transplant recipients and patients with SLE, altered lipid metabolism, fatty liver degeneration, or alcoholism.
• Initial symptom: localized bone pain with activity, eventually at rest, requiring analgesics.
• Proximal femur = most common site; also distal femur or humeral head.
• Most patients develop osteonecrosis after 6–12 months of glucocorticoid treatment (parallels time for bone marrow fat deposition changes).
• Mechanism incompletely understood — intraosseous hypertension from fat cell enlargement may compromise terminal arterioles; fat emboli theories (from liver fat/serum triglycerides vs bone-derived).
• Standard X-rays may not show signs for up to 6 months after bone pain onset; MRI = most specific/sensitive test, recommended early for diagnosis.
• Initial treatment: conservative — trauma prevention, rest, modified weight-bearing (crutches).
• Advanced cases in young patients: hip salvage procedures — core decompression, vascularized fibular grafting, electric stimulation.
• Total joint arthroplasty often eventually unavoidable.

• Doses needed to produce growth suppression not much higher than physiologic doses.
• Alternate-morning therapy minimizes but does NOT eliminate the effect.
• Inhaled or extensive chronic topical glucocorticoid use can rarely also cause growth suppression.
• Compensatory growth spurt often occurs after discontinuation with normal eventual height.
• Chronic therapy just before/during early puberty: delays expected pubertal growth spurt; with continued therapy, compensatory growth may occasionally be prevented by epiphyseal closure.
• Mechanisms: interference with nitrogen/mineral retention; inhibition of collagen/protein matrix synthesis; decreased growth hormone release/signaling.
• Growth monitoring every 3–6 months; growth hormone therapy may be considered to restore linear growth/reverse catabolic effects.

• Uncommon complication.
• Classic (chronic) form: painless, symmetrical proximal muscle weakness, most often lower extremities.
• Begins weeks to months after initiation, usually with doses equivalent to >40 mg/day prednisone.
• Possibly more common with fluorinated glucocorticoids (dexamethasone, betamethasone, triamcinolone) but can occur with any agent.
• Alternate-morning therapy might decrease incidence.
• Diagnosis often difficult — serum muscle enzymes and EMG typically normal.
• Muscle biopsy: relatively nonspecific — variable fiber diameters, atrophy of type II fibers, no substantial inflammation/necrosis.
• Increased urinary creatine excretion can be a diagnostic clue.
• Management: gradual glucocorticoid dose reduction + physical therapy; muscle function recovery may take many months.
• With inflammatory myopathies (e.g. dermatomyositis): glucocorticoids used to treat may actually worsen muscle atrophy tendency — steroid-sparing agents often used after initial control.

Distinguishing GC-Related Myopathy from Myositis

• *Percent creatinuria = creatine (mg) / [creatine + creatinine (mg)] in 24-hour urine sample; elevated levels (>10%) not specific to myopathy.
• Also referred to as corticosteroid-induced myopathy or steroid myopathy.

• Cumulative dosage and duration of therapy are most important factors for posterior subcapsular cataracts.
• Noted with as little as 10 mg/day prednisone for 1 year.
• NOT reduced by alternate-morning schedules; continuous therapy = higher risk than intermittent.
• Children at greatest risk — develop cataracts at lower doses/shorter durations vs adults.
• Cataracts from atopic keratoconjunctivitis (atopic dermatitis) are often anterior subcapsular; can also occur posteriorly and be indistinguishable from glucocorticoid-related cataracts.
• Ophthalmologic exams recommended every 6–12 months for long-term systemic therapy.
• Progression can occur despite decreasing/discontinuing glucocorticoids, but discontinuation occasionally deters further formation or reverses lens opacification.

• Hyperglycemia: via enhanced hepatic gluconeogenesis and decreased peripheral insulin-mediated glucose uptake; relative insulin resistance from decreased cellular insulin receptor affinity.
• New-onset diabetes usually only with high-dose therapy; ketoacidosis rare.
• Most patients revert to prior glucose status within a few months of discontinuation.
• Blood glucose assessed periodically during high-dose/long-term therapy; diabetics need closer monitoring, may need switch from oral agents to insulin or higher insulin doses.
• Alternate-morning schedules usually not possible in diabetics (fluctuating insulin requirements).
• Hyperlipidemia: common, especially with prior lipid abnormalities; triglyceride elevation most frequent; some patients have HDL or LDL elevation; hypertriglyceridemia mechanism likely relative insulin insufficiency; low-saturated-fat, low-calorie diet recommended.
• Chronic therapy → weight gain with central fat redistribution ("buffalo hump", "moon facies").
• Other metabolic effects: hypokalemic alkalosis (high-dose therapy, especially agents with substantial mineralocorticoid effect); uncommon hypocalcemia (rarely → tetany in children on high-dose therapy).
• Potassium supplementation may be needed; adequate calcium intake mandatory.

• Endogenous excess (Cushing syndrome) → majority have hypertension; exogenous glucocorticoids → hypertension in only ~20% (lower mineralocorticoid effect).
• More common with pre-existing hypertension, decreased renal function, elderly, and agents with greater mineralocorticoid activity.
• Rarely affects BP in first 2 weeks — short courses in hypertensive patients almost never problematic.
• Long-term therapy in hypertensive patients: sodium restriction, possible thiazide diuretic; alternate-morning therapy may reduce BP elevation.
• Pathogenesis not fully understood — likely vasoconstriction (catecholamine potentiation, vasodilator inhibition); sodium retention (mineralocorticoid activity); intravascular volume expansion.
• Accelerated atherosclerosis: occasional with long-term therapy, especially SLE, rheumatoid arthritis, renal transplant patients; also observed in children; long noted in Cushing syndrome.
• Thromboembolic complications and atrioventricular conduction problems also reported.

• Relationship between systemic glucocorticoids and peptic ulcer disease (PUD) controversial.
• Increased PUD incidence when combined with NSAIDs or aspirin (e.g. rheumatoid arthritis patients).
• Additive risk factors: smoking, alcohol use, PUD history.
• GC-associated PUD more likely gastric than duodenal, milder pain, greater chance of major complication (hemorrhage, perforation) — glucocorticoids mask inflammation signs/symptoms and inhibit wound healing.
• Possible mechanism: decreased mucus production and mucosal cell renewal.
• Administration with food, H2 antagonists, or PPIs (in higher-risk settings) decreases PUD likelihood.
• Nausea, vomiting, GERD also minimized by food administration/acid suppression.
• Candidal esophagitis: can occur in erosive oral mucosal disease (e.g. pemphigus vulgaris) — treat with oral antifungals (e.g. fluconazole).
• Other GI effects: pancreatitis (with hypertriglyceridemia), fatty liver changes, rarely intestinal perforation.

• Increased susceptibility to bacterial, viral, fungal, parasitic infections.
• Cutaneous staphylococcal and superficial fungal infections common.
• Fever/inflammation signs may be masked → difficult early recognition.
• Alternate-morning therapy and doses <10 mg/day prednisone equivalent reduce opportunistic infection risk.
• Tuberculosis reactivation: concern in chronic therapy — assess exposure risk, TB history; if negative/uncertain, perform tuberculin skin test or interferon-γ release assay before starting.
• Chest radiograph for positive tuberculin reaction (≥5 mm induration in patients receiving ≥15 mg/day prednisone equivalent for a month or more) or positive IGRA, TB history, or other immunosuppression risk factors.
• 9-month isoniazid course recommended for untreated latent TB.
• Pneumocystis jirovecii pneumonia (PJP): increased risk with dose ≥20 mg/day prednisone equivalent for >1 month plus another immunocompromise cause.
• Susceptible: systemic inflammatory disorders (e.g. granulomatosis with polyangiitis, SLE), especially with additional immunosuppressants and/or pulmonary disease/lymphopenia.
• High-risk patients: prophylaxis with trimethoprim–sulfamethoxazole (TMP-SMX) — e.g. one DS tablet 3×/week or daily.
• HIV-positive with CD4+ <200/mm³: routine TMP-SMX prophylaxis; also consider if CD4+ >200/mm³ and on systemic glucocorticoids.
• Supraphysiologic chronic therapy → inadequate antibody responses to immunizations.
• Live-virus vaccines: should NOT be given to children/adults during, or (if treated ≥2 weeks) within a month after discontinuing, glucocorticoid therapy at dose ≥20 mg/day prednisone equivalent or ≥2 mg/kg/day in children weighing <10 kg.

• Increased cleft palate incidence noted in rodents with very large early-gestation doses; human first-trimester safety debated but clinical experience/trials show minimal offspring effects.
• Only small amounts of active prednisone reach the fetus — placental enzyme 11-hydroxysteroid dehydrogenase type 2 inactivates most crossing prednisolone.
• This enzyme has limited ability to metabolize fluorinated glucocorticoids (betamethasone, dexamethasone) — greater fetal exposure with these agents.
• Slightly increased risk of hypertension (possibly smaller fetal gestational size) and gestational glucose intolerance (with moderate–high doses).
• Large doses near delivery: fetal HPA axis suppression occasionally → pseudo-addisonian neonate.
• Glucocorticoids secreted into breast milk, but AAP considers prednisone therapy compatible with breastfeeding; delay nursing ~4 hours after dose if possible.
• Non-pregnant women: amenorrhea may occur, most frequently with IM injections — counsel premenopausal women.
• Decreased sperm counts reported in men on systemic glucocorticoids.

• "Steroid psychosis" = potentially misleading term for broad spectrum of neuropsychiatric effects.
• Effects on behavior, affect, cognition — only small portion experience delusions/psychotic symptoms.
• Mood changes range from euphoria, irritability, mania to hopelessness, depression.
• Attention, memory, psychomotor speed, sleep may be affected.
• Depression: tends to develop with longer-term use.
• Manic symptoms: more often with short-term or pulsed administration.
• Most frequently occur with doses >40 mg/day prednisone equivalent, within first few weeks; can also develop during tapering.
• Risk factors: blood–brain barrier damage, hypoalbuminemia, female sex, older age, longer-acting glucocorticoid use, previous primary psychiatric condition or prior neuropsychiatric reaction to glucocorticoids.
• Management: discontinue or taper to ≤40 mg/day prednisone equivalent if possible; psychiatric consultation as needed; low-dose olanzapine helpful for psychotic and affective symptoms.
• Pseudotumor cerebri: possible complication of high-dose/long-term therapy — headache, nausea, vomiting, visual changes, papilledema; typically develops after rapid taper/discontinuation; managed by returning to higher dose then more gradual taper; reversible but risk of visual loss.
• Seizures: uncommon, primarily seizure-prone patients on high doses.
• Other infrequent effects: EEG changes, tremor enhancement, peripheral neuropathy, epidural lipomatosis.

• Broad range, many similar to endogenous Cushing syndrome: purpura, telangiectasias, atrophy, striae, pseudoscars, acneiform or rosacea-like eruptions, facial plethora.
• One study: almost half of patients developed skin changes after 3 months at mean prednisone dose of 30 mg/day.
• Localized telangiectasias, atrophy, hypopigmentation: from chronic topical glucocorticoid use (especially long-term daily potent agents or use under occlusion) and from intralesional therapy — intralesional administration occasionally causes findings in a linear pattern along lymphatic drainage pathways.
• Systemic glucocorticoid-induced acne/folliculitis: monomorphic papulopustules on chest and back.
• Acne vulgaris often worsened by continuous glucocorticoid therapy; inflammatory/cystic lesions may be temporarily improved by very short intermittent systemic courses or intralesional cyst injections.
• Acneiform/rosacea-like perioral, perinasal, or periorbital eruption: from inhaled glucocorticoids or topical facial application (especially more potent agents).
• Long-term continuous potent topical glucocorticoid use on face or groin: erythema, edema, papulopustules, burning sensation upon discontinuation — termed "topical steroid addiction" in social media.
• Other systemic cutaneous effects: acanthosis nigricans, telogen effluvium, hirsutism, hypertrichosis (localized hypertrichosis can occur at topical application sites).
• Systemic/topical glucocorticoid therapy impairs wound healing by inhibiting fibroblast function and collagen production → decreased angiogenesis, decreased extrafibrillar matrix ("ground substance") production, decreased re-epithelialization.

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• Table 125.11 (in source) addresses drug interactions with glucocorticoids and medical conditions that may require glucocorticoid regimen alteration (table content not reproduced in extracted source text — refer to original chapter table for complete interaction list).

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• Cortisone and prednisone are prodrugs; require hepatic 11-hydroxylation to hydrocortisone and prednisolone respectively — use prednisolone in severe hepatic disease.
• Methylprednisolone and triamcinolone: zero mineralocorticoid activity.
• Long-acting agents (dexamethasone, betamethasone) should NOT be used for alternate-day therapy — no HPA recovery window.
• Plasma half-life ≠ duration of biologic action; duration measured by ACTH suppression.
• Basal cortisol production ≈ 20–30 mg/day ≈ 5–7.5 mg/day prednisone.
• Osteoporosis and cataracts are NOT prevented by alternate-morning dosing.
• T score ≤−2.5 = osteoporosis; −1 to −2.5 = osteopenia.
• DEXA > plain radiographs for detecting osteoporosis (X-rays insensitive until 20–60% bone loss).
• Proximal femur = most common osteonecrosis site; MRI = most sensitive imaging.
• GC myopathy: normal CK/EMG, atrophy without inflammation on biopsy — contrast with myositis (elevated CK, abnormal EMG, inflammation/necrosis on biopsy, worsens as GC dose decreases).
• Children develop cataracts at lower doses/shorter duration than adults.
• TMP-SMX PJP prophylaxis threshold: prednisone ≥20 mg/day for >1 month + another immunosuppression cause.
• Fluorinated glucocorticoids (betamethasone, dexamethasone) cross the placenta more readily — 11β-HSD2 preferentially inactivates prednisolone.
• Live-virus vaccines contraindicated during/after (~1 month) high-dose (≥20 mg/day prednisone equivalent) glucocorticoid therapy.

• Effects depend on strength, application site, coexistent sun damage, patient predisposition.
• Atrophy, striae, telangiectasia, skin fragility, purpura most frequent. Fluorinated corticosteroids on the face of fair-skinned individuals: most striking telangiectasia. Occlusion enhances changes.
• Management: reduce strength or substitute pimecrolimus/tacrolimus; weekly pulse dosing reduces side effects; adjuncts (topical doxepin, pramoxine, menthol/camphor). Telangiectases usually disappear a few months after stopping.
• Facial application over weeks-months: persistent erythema with telangiectases, small pustules. Perioral dermatitis and rosacea may be caused by topical corticosteroids — reported even from 1% hydrocortisone.
• Authors do NOT recommend chronic topical corticosteroids of ANY strength for rosacea. Topical calcineurin inhibitor alternative — but can also induce rosacea-like eruption; if this occurs, open a pustule and check for Demodex overgrowth.
• Repeated face/scrotum/vulva application → marked atrophy, including red scrotum syndrome; tissue "addiction" — withdrawal causes severe itching/burning/erythema. Can produce epidermal atrophy with hypopigmentation.
• Large-area use: sufficient absorption to suppress the hypothalamic-pituitary axis; may affect growth in children with AD, lead to addisonian steroid dependency, Cushing syndrome. Atopic children with >50% BSA involvement have short stature. Bone mineral density reduced in adults with chronic AD requiring corticosteroids stronger than hydrocortisone.

• Intralesional injection may produce subcutaneous atrophy at site; may migrate along lymphatics → linear, atrophic, hypopigmented hairless streaks (may take years to resolve).
• Avoid by injecting directly into the lesion (not the fat), minimal concentration/volume. Triamcinolone acetonide, NOT hexacetonide, for cutaneous lesions.
• IM injections: always into buttocks with a long needle (≥1.5 inches in adults). Deltoid injection can cause subcutaneous atrophy — depression/depigmentation, painless, cosmetically bothersome, fills in over years.