OUTLINES
Introduction
Synthesis and action
Effects on immune systems
Impact on vaccination
Impact of dose
Infection risk
CORTISONE AS A SYMPTOMATIC
TREATMENT OF RHEUMATOID ARTHRITIS
Autoimmune disorders
Rheumatoid arthritis , systemic lupus erythematosus , systemic vasculitis ,
polymyalgia rheumatica , temporal arteritis , autoimmune hemolysis ,
myasthenia gravis , Graves ophthalmopathy
Dermatologic disorders
Eczema , contact dermatitis , irritant dermatitis , stasis dermatitis ,
seborrheic dermatitis , exfoliative dermatitis , psoriasis , lichen striatus ,
lichen planus , lichen nitidus , vitiligo , pruritus ani
Renal disorders
Nephrotic syndrome , lupus nephritis , rapid progressive glomerulonephritis
Malignancies
Lymphoma , leukemia , breast cancer
Graft rejection
Kidney , heart , lung , liver and other tissue transplantation
Others
Sarcoidosis, vitamin D intoxication , septic shock , cerebral edema , spinal
cord injury , hypercalcemia , Bells palsy, conjucntivitis , keratitis , etc.
SYNTHESI
S
SYNTHESIS
Adrenal production of HC and aldosterone
Cholesterol progenolone intermediate
progesterone hydroxylate at 17-,21-, and 11positions HC
Neuroendrocrine
regulation of
inflammation
Hyperactivity of
HPA: Cushings
syndrome, stress
Immunosuppres
sion
Decrease HPA
Severe
inflammation
Genomic
effects
Nongenomic
effects
Glucocorticoid
receptor
GLUCOCORTICOID
RECEPTOR
Intracellular receptor
Member of the nuclear receptor family
Present in virtually all cells, including
those of the immune system
Highest affinity for dexamethasone
Bind GR
Direct genomic effects
Enables GR to
associate with
transcriptional
coactivators or
repressors
Indirect genomic
effects
HUMAN HR PROTEIN
hGR
Primary form of GR
Vary expression
between cell type
Bind GCs
If reduced by up to 70%
not enough to prevent
effective
antiinflammatory
response
hGR
Lacks a ligand-binding
domain
Does not bind GCs
Increase expression in
GCs resistant and
decrease ability of hGR
to bind to GRE
MECHANISM OF ACTION
Nongenomic
effects
Genomic
effects
Direct effects
Indirect effects
Rhen T et al. N Engl J Med 2005;353:1711-23
TRANSCRIPTION
TRANSCRIPTION
GENOMIC MECHANISM
DIRECT EFFECTS
Binding of the receptor to GREs may result
in either enhancement or suppression of
transcription of susceptible downstream
genes
Genomic
effects
Indirect effects
Rhen T et al. N Engl J Med 2005;353:1711-23
MECHANISM OF ACTION
NON-GENOMIC MECHANISM
Inhibit prostaglandin
production
Induction and
activation of
annexin I
Induction of MAPK
phosphatase 1
Repression of
transcription of
cyclooxygenase 2
The dosage is
increased up to
approximately
200 to 300 mg of
prednisone
equivalent per
day
Negative
feedback of
ACTH production
Inhibit effect on
lymphocyte
activation
Membrane-bound receptors
The antianaphylacticactions of
glucocorticoids may be
explained by this mechanism.
OUTLINES
Introduction
Synthesis and action
Effects on immune systems
Impact on vaccination
Impact of dose
Infection risk
Effects on
leukocyte
trafficking
Effects on innate
immunity
Effects on acquired
immunity
EFFECTS ON LEUKOCYTE
TRAFFICKING
Glucocorticoids have profound effects on the
cellular functions of leukocytes and endothelial cells
Reduced ability of leukocytes to adhere to vascular
endothelium and exit from the circulation.
Entry to sites of infection and tissue injury is impaired
EFFECTS ON LEUKOCYTE
TRAFFICKING
Reduction in endothelial adhesion
Direct effects
on expression of adhesion molecules on both
leukocytes and endothelial cells
Indirect effects
the inhibitory effects of glucocorticoids on transcription
of cytokines(IL-1/TNF) that upregulate endothelial
adhesion molecule expression.
EFFECTS ON LEUKOCYTE
TRAFFICKING
Increased numbers of circulating neutrophils 1,2
Neutrophil migration through the vasculature to sites of
inflammation is severely impaired
Enhanced release of cells from the bone marrow
Inhibition of neutrophil apoptosis
EFFECTS ON LEUKOCYTE
TRAFFICKING
Tissue accumulation of monocytes and
macrophages is reduced
Decreased migration from the vasculature
Reduced elaboration of macrophage migration inhibition
factor
EFFECTS ON INNATE
IMMUNITY
Effects on
leukocyte
trafficking
Effects on innate
immunity
Effects on acquired
immunity
EFFECTS ON ACQUIRED
IMMUNITY
Th1
IL-2
IL-3
TNF-
IFN-
Th2
IL-4
IL-5
IL-6
IL-13
Franchimont D et al. Regul Pept 1998; 73:59
OUTLINES
Introduction
Synthesis and action
Effects on immune systems
Impact on vaccination
Impact of dose
Infection risk
IMPACT ON VACCINATION
32 healthy volunteers
62 patients with systemic lupus erythematosus
(SLE), rheumatoid arthritis, degenerative joint
disease, and other rheumatic diseases.
examined at the time of immunization and one
week, three weeks, and four months later
Administration of these vaccines was safe in
these patients with stable disease and induced
antibody responses in most individuals.
Antibody responses to A/New Jersey/76 were
significantly lower in young patients taking
glucocorticoids compared to those not taking
glucocorticoids.
Herron A et al. JAMA. 1979 Jul 6;242(1):53-6
control
OCS
ICS
IMPACT ON VACCINATION
In patients who do show evidence of
impaired vaccine response, removal of
chronic low-dose glucocorticoid treatment
may result in improved antibody
production
IMPACT ON VACCINATION
Immunosuppression due to chronic
glucocorticoid use is a contraindication to
the administration of live virus vaccines,
such as measles, mumps, rubella (MMR),
varicella, and vaccinia (small pox).
CDC 2011
Chatham WW et al. UpToDate 2014
OUTLINES
Introduction
Synthesis and action
Effects on immune systems
Impact on vaccination
Impact of dose
Infection risk
IMPACT OF DOSE
Some immunologic effects of glucocorticoids
are dose dependent
variable affinity of target genomic sites for the
complex of glucocorticoid and glucocorticoid
receptor
Administration of high-dose pulse glucocorticoids
may result in nonspecific general disruption of gene
transcription
may also have more rapid effects on leukocyte
aggregation, possibly as a consequence of effects on the
expression of leukocyte adhesion molecules and disruption
of calcium flux across membranes
Hammerschmidt DE et al. J Clin Invest 1979; 63:798
Youssef P et al. J Rheumatol 1995; 22:2065
IMPACT OF DOSE
LOW TO MODERATE DOSES
Less than 2 mg/kg per day of prednisone in
children or less than 40 mg per day in adults
OUTLINES
Introduction
Synthesis
Effects on immune systems
Impact on vaccination
Impact of dose
Infection risk
INFECTION RISK
SYSTEMIC GLUCOCORTICOID THERAPY
Dose-dependent increase: inhibitory
effects on phagocytic cell function.
With long-term, low-dose use, effects on
phagocytic cell function are minimal, but
there may be some inhibition of adaptive
immune responses with increasing
duration of therapy.
INFECTION RISK
INHALED AND TOPICAL CORTICOSTEROID
Inhaled and topical corticosteroids are
usually not implicated in increased risk of
systemic infections
INFECTION RISK
Various patient-specific factors influence infection
risk
underlying disorder
presence of concomitant immunosuppressive therapies
patient is hospitalized.
INFECTION RISK
A meta-analysis of controlled trials in
which glucocorticoids or placebo were
given
infection occurred significantly more often with
steroid therapy (12.7 versus 8.0 percent with
placebo, relative risk 1.6)
average dose of prednisone of more than 10
mg/day or a cumulative dose of greater than
700 mg.
INFECTION RISK
223 patients with lupus who were not
receiving other immunosuppressive agents
The risk of infection rose from 1.5-fold at
an average prednisone dose below 10
mg/day to over eightfold in patients
receiving doses above 40 mg/day.
INFECTION RISK
TYPES OF INFECTIONS
Herpes zoster
more commonly among patients taking lowdose
A retrospective cohort analysis of over 200
patients with RA found that eight patients
treated with glucocorticoids developed zoster
compared with only one control1
However, people receiving glucocorticoid may
have had closer surveillance, potentially leading
to more cases of herpes zoster detected.
INFECTION RISK
TYPES OF INFECTIONS
Tuberculosis
concern in patients receiving moderate to high
doses of glucocorticoids for prolonged periods
of time
INFECTION RISK
TYPES OF INFECTIONS
Opportunistic infections
only in patients with very significant
immunosuppression
prolonged glucocorticoids+immunosuppressant drugs
underlying immunosuppressive conditions
INFECTION RISK
MEASURES TO REDUCE RISK
Use of short-acting preparations (such as
prednisone) given every other day
In one retrospective report of 70 patients
with various inflammatory conditions
treated with alternate day prednisone at
mean doses of 45 to 60 mg daily, none
developed serious infections