rheumatology: clinical use of steroids

conditions that corticosteroids can treat

• acute gouty arthritis

• rheumatoid arthritis (RA)

• osteoarthritis (intra-articular)

• systemic lupus erythematosus (SLE)

• ankylosing spondylitis

• bursitis

• tenosynovitis

• polymyalgia rheumatica

• acute rheumatic carditis

• mixed connective tissue disorders

• polymyositis

• demaomyositis

• can also be used for oncologic diseases or chemotherapy pre-treatment

aldosterone

• a mineralocorticoid involved in electrolyte and volume homeostasis

  • it’s secreted in response to low blood pressure → it works by increasing blood pressure and blood volume by increasing sodium reabsorption (water retention)

  • it also is regulated by high potassium levels → increased potassium excretion

• it acts on the distal tubules and collecting duct of the kidney

• secreted from the adrenal cortex – zona glomerulosa

• regulated by the RAAS system

Addison’s disease

• primary adrenal insufficiency (low aldosterone AND cortisol)

cortisol

• a glucocorticoid (GC) involved in the regulation of the breakdown/metabolism of fats, carbohydrates, and protein

• it’s main role is managing the body's stress response, increasing blood sugar and blood pressure, and regulating metabolism, immune function, and inflammation, helping fuel the "fight-or-flight" reaction and restore balance afterward

  • it works to increase blood glucose and suppress the immune and inflammatory response

  • mobilizes energy and helps the body handle stress

• regulates the secretion of ACTH and CRH from the anterior pituitary and hypothalamus via negative feedback

• acts on the vast majority of human tissues

• secreted from the adrenal cortex – zona glomerulosa

  • our body makes around 5 mg daily

Cushing’s disease

• high cortisol levels

Cushing’s disease symptoms (Cushingoid symptoms)

• fat redistribution around the face (moon face)

• buffalo hump (fat on the neck, making it thicker and rougher)

• central obesity (around the stomach)

  • fat trunk or abdomen

• thin extremities (arms, legs)

• thinning of the bones

• atrophy of the skin and dermal connective tissues

• muscle wasting and weakness (steroid myopathy)

• easy bruising, delayed healing

• hypertension

• DM (cortisol is an insulin antagonist)

• androgen excess in females (irregular menses, infertility, acne, etc)

• growth retardation

• psychiatric effects (steroid encephalopathy)

cortisol regulation of the HPA axis

1. the hypothalamus secretes CRH which stimulates the anterior pituitary

2. the anterior pituitary secretes ACTH through the blood which acts on and stimulates the adrenal cortex

3. the adrenal cortex releases cortisol, which acts on various tissues in the body

   1. cortisol also provides negative feedback to both the hypothalamus and pituitary to limit secretion of CRH and ACTH

secretion of cortisol

• this relies on the body’s natural circadian rhythm, as its peak secretion occurs early in the morning, around 6-7 am

  • because of this, dosing at night can mess with someone’s sleep

  • this is also why it is usually dosed in the morning, to mimic the body’s natural patterns

brand name for fludrocortisone

• brand name

  • Florinef

mineralocorticoids → drugs

• fludrocortisone

  • a very potent mineralocorticoid that also has high glucocorticoid activity but is used only for its mineralocorticoid effects

MOA of fludrocortisone

• binds to mineralocorticoid receptors in the distal convoluted tubules and collecting ducts of the kidneys, mimicking the action of aldosterone

• once bound it:

  • increases sodium reabsorption → water retention → increased BP

  • increases potassium excretion → hypokalemia

  • can increase the risk of metabolic acidosis due to H+ ion excretion as well

indications for fludrocortisone

• replacement therapy for adrenocortical insufficiency (Addison’s disease)

• salt-wasting syndrome

• not FDA approved: severe orthostasis

side effects of fludrocortisone

• fluid imbalance

• edema

• increased BP

• CHF

• hypokalemia

very high potency TOPICAL glucocorticoids → drugs

• clobetasol proprionate

• halobetasol proprionate

• betamethasone diproprionate ointment

high potency TOPICAL glucocorticoids → drugs

• betamethasone diproprionate cream/gel

• fluocinonide

medium potency TOPICAL glucocorticoids → drugs

• betametasone valerate ointment

• fluocinolone acetate

• fluticasone proprionate

• hydrocortisone

• mometasone

• triamcinolone

low potency TOPICAL glucocorticoids → drugs

• aclometasone diproproprionate

• dexamethasone

• fluocinolone

• hydrocortisone

MOA of glucocorticoids

• they passively diffuse into cells due to their lipophilic nature, allowing them to bind to intracellular glucocorticoid receptors located in the cytoplasm, allowing heat shock proteins to dissociate

  • once bound, they translocate into the nucleus where they bind to glucocorticoid response elements (GREs) on DNA, altering gene transcription and protein synthesis

  • this alteration of gene transcription leads to upregulation of anti-inflammatory proteins and downregulation of pro-inflammatory proteins → inhibits leukocyte traffic and access to the site of inflammation

• most importantly, it binds to almost tissues in the body, causing a wide variety of biological effects

  • because of this, there are also a wide variety of routes of administration!!

indications for topical glucocorticoids

• eczema

• atopic dermatitis

• psoriasis

• contact dermatitis

• vitiligo

indications for low potency topical glucocorticoids

• patients with:

  • thin skin

  • acute inflammatory lesions

indications for medium/high potency topical glucocorticoids

• patients with chronic, hyperkeratotic, lichenified (thickened) regions

• its use for long periods of time can also cause thinning of the skin

indications for ointment glucocorticoids

• patients with thick, rough, lichenified legions of skin → it enhances penetration of the drug

indications for cream glucocorticoids

• patients with acute and subacute dermatoses (skin conditions), and/or moist skin and intertriginous areas (eg. armpits, inner thighs, under breasts, between toes/fingers, etc)

indications for solution, gel, spray glucocorticoids

• for the scalp, or where non-oil based vehicles are needed

duration of therapy for medium-high topical glucocorticoids

• < 3 weeks

  • can cause irreversible skin atrophy → can NOT be used chronically!

duration of therapy for medium topical glucocorticoids in areas of thin skin

• < 2 weeks

duration of therapy for diaper rash

• 3-7 days with the mildest potency topical

  • if it doesn’t clear within 3-5 days with OTC hydrocortisone, it likely isn’t inflammatory in nature and might be fungal, for example

considerations for chronic topical glucocorticoid use

• intermittent treatment is preferred

  • for example, using every other day, weekends only, etc,

  • used for flares

  • can also be used if systemic treatment is not effective

side effects of TOPICAL glucocorticoids

• skin atrophy

• acne

• abnormal pigmentation

• purpura (a rash of purple spots on the skin caused by internal bleeding from small blood vessels)

• delayed skin healing → due to immunosuppression

• infection → due to immunosuppression

• photosensitivity → counsel pts about sunburn and sunscreen

short-acting ORAL glucocorticoids → drugs

• cortisone

• hydrocortisone

  • these steroids have more mineralocorticoid (aldosterone) side effects than glucocorticoid (cortisol) side effects effects because they’re more potent at the mineralocorticoid receptor

intermediate-acting ORAL glucocorticoids → drugs

• prednisone

• prednisolone

• triamcinolone

• methylprednisolone

  • these are extremely potent glucocorticoids

long-acting ORAL glucocorticoids → drugs

• dexamethasone

• betamethasone

duration of action of short-acting GCs

• 8-12 hrs

duration of action of intermediate-acting GCs

• 18-36 hrs

duration of action of long-acting GCs

• 36-54 hrs

equivalent dose of oral cortisone

• 25 mg

equivalent dose of oral hydrocortisone

• 20 mg

equivalent dose of oral prednisone/prednisolone

• 5 mg

equivalent dose of oral methylprednisolone

• 4 mg

equivalent doses of oral triamcinolone

• 4 mg

equivalent dose of oral dexamethasone

• 0.75 mg

equivalent dose of oral betamethasone

• 0.6 - 0.75 mg

potency of short-acting GCs

• GC < MC

  • are more potent at the mineralocorticoid receptor → aldosterone-like side effects!!

potency of intermediate-acting GCs

• GC >>>> MC

  • much more potent glucocorticoids than mineralocorticoids

low-dose oral GCs

• ≤ 7.5 mg (prednisone equivalent dose)

• considered maintenance therapy

  • not for use for severe flares

medium-dose oral GCs

• > 7.5 mg to ≤ 30 mg (prednisone equivalent dose)

• used to treat primarily chronic, mild-moderate conditions

high-dose oral GCs

• > 30 mg to ≤ 100 mg (prednisone equivalent dose)

• used for sub-acute diseases (active disease or flares)

  • great for severe flare ± functional impairment ± inflammation at multiple joints

• can have severe side effects, so treatment MUST be short-term

• should also be tapered quickly

very high-dose oral GCs

• > 100 mg (prednisone equivalent dose)

• used for acute diseases or exacerbations, usually in the inpatient/hospital setting

• can have dramatic side effects, so treatment MUST be short-term

IV pulse therapy with oral GCs

• dosed at ≥ 250 mg daily for a short period of time (1-5 days) (prednisone equivalent dose)

• used for severe or life-threatening or organ-threatening diagnoses like…

  • MS flares

  • vasculitis

  • spinal cord suppression

• it provides a rapid, powerful immunosuppression, and is followed by an oral taper

• has low incidence of side effects

alternate day dosing regimen

• typically > 10 mg (prednisone equivalent doses)

• you give 2.5 - 3.5x the usual daily dose every other day instead of daily

  • so for example, you’d give 60 mg qod instead of 30 mg qd

• used for non-symptom manifestations of mild-moderate diagnosis → used for chronic STABLE disease management

• also useful to prevent or minimize HPA axis suppression and adrenal insufficiency, as well as long-term side effects

• not recommended for initial therapy

  • more so used for patients whom require long-term therapy (eg. asthma, lupus, RA)

  • not suitable for acute or severe diseases, as some patients may develop flares on “off” days

split day dosing regimen

• this is giving the total daily dose divided into 2–4 doses throughout the day

  • for example → total daily dose is 40 mg, but you give 20mg in the morning and 20 mg in the afternoon

  • an example of this is Medrol Dosepak, where you taper the dose over 21 days and take tablets multiple times a day

• it’s indicated for rapid control of active disease, as it maintains more constant blood levels of the drug, allows for better symptom control, and is useful for acute flares or severe inflammation

• patients may switch to once daily dosing if it affects sleep (like taking tablets too close to bedtime), or for compliance reasons (like forgetting to take their afternoon dose)

once daily dosing

• indicated for maintenance therapy or control of active disease

• mimics our normal human cycle → administer in the morning

when tapering is required

• if a patient receives > 20 mg/day of oral glucocorticoids for > 2 weeks (both criteria)

  • > 2 weeks is considered long-term therapy

  • if short-term (< 2 weeks) AND low doses (< 20 mg), then it is NOT required

purpose of tapering with steroids

• prevents adrenal crisis, where the body stops making cortisol to due adrenal gland atrophy

  • the body has become so used to being “fed” cortisol that it stops making it’s own (remember negative feedback as well) → if steroids are stopped too abruptly, especially in this state where the body isn’t making any cortisol, this can be life-threatening (adrenal crisis)

• is also useful in preventing the rebound effect with rebound inflammation (also called a flare)

  • when steroids are abruptly withdrawn, the previously inhibited inflammatory pathways reactivate aggressively and the immune system can overshoot, causing symptoms to come back worse than before

  • for example → suddenly stopping asthma medication containing ICS can cause severe asthma exacerbations or flares

  • rebound is most common with high doses ± long duration ± abrupt discontinuation

• essentially, it allows the HPA axis to recover (adjust to making more cortisol), allows the immune system to adjust, and prevents immune system overshoot

adrenal crisis

• a life-threatening medical emergency caused by extremely low cortisol levels, leading to:

  • severe fatigue, dizziness, weakness

  • confusion

  • rapid heart rate

  • excessive sweating

  • low blood pressure

  • low blood glucose

  • abdominal pain

  • vomiting

  • potentially shock or coma

• it can be triggered not only by abruptly discontinuing steroid intake, but also from stress like infection (sepsis), surgery, trauma, etc

  • it happens because the body needs more cortisol, but the adrenals can’t make it

• it requires immediate treatment with steroid injections (like hydrocortisone) to prevent fatal outcomes

• this is like a consequence of HPA suppression!

hypothalamus-pituitary axis (HPA) suppression

• a physiologic adaptation that the body makes due to long-term steroid treatment, where the body stops making cortisol

  • recall that cortisol is an inhibitor of ACTH → constant exposure to cortisol via steroids shuts down ACTH stimulation and thus the body stops secreting its own cortisol

  • when the adrenal glands stop producing their own cortisol, it can cause adrenal atrophy (shrinking)!

• this happens gradually, over weeks-months → it can lead to adrenal crisis!

how to minimize risk of HPA axis suppression

1. use lowest effective dose

2. use alternate day dosing when appropriate

3. discontinue therapy as soon as possible

immunologic side effects of ORAL glucocorticoids

• increased susceptibility to infections

• decreased inflammatory responses

• suppressed delayed hypersensitivity

• neutrophilia (high neutrophils)

• leukocytosis (high WBCs)

  • glucocorticoids increase WBC count mainly by redistribution (demargination), not by making more cells

  • if a patient comes in with very high neutrophils and WBCs but no signs of infection (eg. fever, elevated CRP, other clinical signs), then you should suspect (long-term) steroid use!

leukopenia

• low WBCs in blood

musculoskeletal side effects of ORAL glucocorticoids

• osteoporosis

• fractures

• osteonecrosis

• myopathy

  • ESPECIALLY with frequent intra-articular (local) injections!

GI side effects of ORAL glucocorticoids

• pancreatitis

• peptic ulcers and GI bleeds associated with NSAID use

  • oral glucocorticoids alone do not strongly cause peptic ulcers or GI bleeds, but they increase the risk, and that risk becomes much more clinically significant when combined with NSAIDs (multiplicative risk rather than additive risk)

  • systemic GCs decrease prostaglandin synthesis (indirectly), which are responsible for mucosal defenses

  • oral GCs also inhibit fibroblasts activity and impair wound healing → coupled with how they reduce pain, inflammation, and fever, ulcers or bleeds may progress silently until they’re severe

  • can give PPI prophylactically for long-term use at high doses

dermatologic side effects of ORAL glucocorticoids

• acne

• hirsutism

• purple striae

• skin fragility/thinning

• eccymoses (a bruise, a dark purple or bluish patch on the skin caused by blood leaking from damaged vessels into surrounding tissue) → goes away with discontinuation

neuropsychiatric side effects of ORAL glucocorticoids

• altered mood (more mentally alert or “hyper”)

• emotional lability

• euphoria

• insomnia

• depression

• psychosis

• pseudotumor cerebri (aka idiopathic intracranial hypertension → dangerously high pressure inside the skull due to excess CSF buildup)

ophthalmologic side effects of ORAL glucocorticoids

• cataracts

• glaucoma

endocrine-metabolic side effects of ORAL glucocorticoids

• glucose intolerance → DM patients may require increased (short-acting) insulin requirements

• weight gain

• hunger

• fat redistribution (Cushingoid symptoms)

• growth suppression → avoid giving to children! prevents joint closure

• muscle wasting

• impaired wound healing

• fluid retention

• hypokalemia → this is because some GCs (like hydrocortisone) have potent mineralocorticoid activity, causing aldosterone-like effects

• impotence

• irregular menses

• HPA suppression

• acute renal insufficiency (rare)

early, systemic manifestations of oral GCs (< 2 weeks)

• insomnia

• enhanced appetite

• weight gain

• emotional lability

• leukocytosis

• hyperglycemia

sustained, systemic manifestations of oral GCs (> 2 months)

• Cushingoid symptoms

• HPA suppression

• infection

• osteoporosis

• impaired wound healing

delayed, systemic manifestations of oral GCs (< 2 weeks)

• osteonecrois

• ecchymosis

• cataracts

• growth retardation

• fatty liver

• atherosclerosis

rare side effects of systemic, oral GCs

• psychosis

• glaucoma

• pancreatitis

• pseudotumor cerebri

contraindications to oral glucocorticoids

1. live vaccines

   • the CDC recommends that patients receiving ≥ 20 mg/day of prednisone for ≥ 2 weeks should NOT receive a live vaccine

     • MMR, varicella, intranasal flu, yellow fever

   • for inactivated vaccines, there is a concern for adequate vaccine response if the patient is receiving ≥ 20 mg/day of prednisone

     • note: inactivated vaccines are safe, but may be LESS effective

     • flu shot, COVID, pneumococcal, Tdap, Hep A/B, HPV, etc.

   • avoid live vaccines in patients on steroids in general

2. systemic fungal infections

   • pneumocystis (PCP) prophylaxis is often given to prevent PJP pneumonia → Bactrim

   • PJP has a higher risk in pts taking ≥ 20 mg prednisone

considerations for the influenza vaccine with oral GC use

• the general consensus per the CDC is that live attenuated vaccines should NOT be given to patients taking ≥ 20 mg prednisone for ≥ 2 weeks (equivalent doses)

• however, regardless if the patient is taking ≥ 20 mg prednisone, the inactivated flu shot SHOULD be given

  • this is because the risk from influenza itself is high AND the vaccine is safe in these pts — however, the concern for adequate response is still there → the CDC’s official stance is that inactivated vaccines can be administered safely at any prednisone dose; the issue is potentially suboptimal immunity, not a safety contraindication like with live vaccines

  • they should NOT receive the flu nasal spray vaccination, because this is a LIVE vaccine

  • for other inactivated vaccines, if the patient is taking ≥ 20 mg prednisone for ≥ 2 weeks, they should NOT be given the vaccine and vaccine administration should be deferred until tapered to < 20 mg/day of prednisone so that they can have an optimal response to the vaccine when they are not immunocompromised

warnings/precautions for oral glucocorticoids

• active infections

• diabetes

• osteoporosis

• peptic ulcers

• electrolyte imbalances

• stress, trauma, or surgery

• HPA suppression

drug interactions with oral GCs

• CYP3A4 inhibitors cause reduced elimination and metabolism of prednisone:

  • ketoconazole

• CYP3A4 inducers cause increased elimination and metabolism of prednisone:

  • phenytoin

  • carbamazepine

  • rifampin

  • phenobarbital

• NSAIDS !! → cause increased risk of peptic ulcers and GI bleeds

• furosemide and amphotericin B: can exacerbate hypokalemia

• levels of salicylate (ASA) may be decreased as well

brand name for prednisone delayed-release (DR) tablets

• brand name

  • Rayos

considerations for prednisone DR tablets (Rayos)

• can be used for chronotherapy for patients with rheumatoid arthritis (RA), as it’s designed to release medicine hours after taking it to match the body's natural inflammatory cycle, reducing morning stiffness and improving efficacy by aligning with peak symptoms

• in this formulation, the prednisone is inside an inactive shell that prevents the prednisone from being released for about 4 hours, making it work later in the day when the body naturally produces less of its own steroids

  • shell is pH dependent

• should be taken with food

• counsel the patient not to crush, split, or chew

• administer at bedtime, around 10 pm

purpose of empiric steroid dosing

• the risk of adrenal insufficiency may last up to 12 months after steroid therapy ends

• thus, empiric supplementation is provided in times of stress, meaning giving steroids based on clinical judgment, not on confirmed lab results, because the risk of not giving them is higher than the risk of giving them

  • this refers to replacing or mimicking normal cortisol production — it’s NOT being used as high-dose anti-inflammatory therapy → it’s meant to cover what the body should be making under stress

• times of stress are things like sepsis, major trauma, surgery, severe medical illness, etc.

  • during these times, the body normally increases cortisol output by 3–10x the normal amount!

  • but, if the patient has been taking long-term ± high-dose steroids, their adrenal gland might not be adjusted to be producing enough cortisol as it normally should, and this is why we must supplement them with steroids

• oral prednisone → used for minor surgery or procedures

• IV hydrocortisone → used for more major events or severe illnesses

monitoring for oral GCs

• labs

  • glucose

  • electrolytes

  • WBC

• stool test for occult blood loss (GI bleeding or ulcers)

• DEXA scan for bone mineral density

• growth and development (especially in children)

• Cushingoid symptoms

• BP

• ophthalmologic exams

patient counseling for oral steroids

• take in the morning with food

• never stop therapy abruptly

• inform of side effects

• missed doses:

  • if taking daily, take as soon as you remember, but skip if it’s almost time for the next dose

  • if taking every other day, take as soon as you remember if it’s the same morning, if not, skip that day and take the next morning

• monitor/limit salt intake and BP

• monitor appetite, as it might make you feel more hungry more often → weight gain

• supplement with potassium, calcium, and vitamin D if necessary

  • prevents hypokalemia and osteoporosis

glucocorticoid-induced osteoporosis

• occurs within the first 6-12 months of therapy

  • due to decreased bone formation and increased bone resorption

• depending on the risk, treatment may be needed for prednisone doses between 5-7.5 mg daily

• according to the ACR guidelines:

  • all adults taking prednisone > 2.5 mg/day for ≥ 3 months should optimize calcium and vitamin D intake

    • calcium: 800-1000 mg/day

    • vitamin D: 600-800 IU/day

  • patients should also make lifestyle modifications (eg. balanced diet, maintaining recommended weight range, smoking cessation, weight-bearing exercise, limiting alcohol intake)

osteoporosis treatment/prophylaxis for patients with low fracture risk

• optimize calcium and vitamin D intake

• lifestyle modifications

• no prescription therapy

osteoporosis treatment/prophylaxis for patients with moderate-severe fracture risk

• prescription medications

  • first-line: oral bisphosphonates

  • alternatives: IV bisphosphonates, teriparatide, denosumab

• optimize calcium and vitamin D intake

• lifestyle modifications