It encompasses the glucocorticoids biology, mechanism of action, its doses & uses in various rheumatological diseases. Adverse events & its prevention are also discussed.
2. Introduction & History
• Cortisone first isolated in 1935
• Hench administer cortisone to a patient of RA
as 100 mg IM daily in 1948- Within a day she
could walk from complete bedridden
condition
• Received Nobel prize in 1950 in Medicine
• GC- Most effective anti-inflammatory &
immunosuppressive till date
• Concern- Wide array of systemic side effects
3. Steroids- Structure & Classification
• Main precursor- Cholesterol- sterol skeleton
consists of 3 six-carbon hexane rings & 1 five-
carbon pentate ring
• 3 main types- Glucocorticoids &
Mineralocorticoids synthesized in Adrenal
cortex; Sex steroids from gonads as well as
adrenal.
• Prototype- Glucocorticoids- Cortisol,
Mineralocorticoids- Aldosterone
4. Biologic characteristics
• Depends on which form- Bound/ Free
• Esters- Lipid soluble- suitable for oral, IM,
intra-lesional, intra-articular
• Salts- Water soluble- suitable for IV
• No qualitative difference between
endogenous/exogenous steroids in action
• Methylation increases potency 5 times
5.
6. Drug Interactions
• Barbiturates, phenytoin, rifampicin increases
the metabolism by inducing cytochrome P-450
• Dose should be increased
• Ketoconazole, cyclosporine increases conc.
7. Pregnancy & Lactation
• GC can’t cross placenta in bound condition,
11ß-HSD catalyzes active cortisol to inactive
compounds (Dexamethasone being the
exception)
• Prednisone, Prednisolone & Methyl-
prednisolone- suitable choices
• For unborn child- Betamethasone/
Dexamethasone to be given
9. Mechanism of action
Genomic action (atleast taking 30 min)-
Activated glucocorticoid receptor-GC complex
translocated to bind specific consensus sites in
DNA (GRE) regulating the transcription of
large variety of target genes
• Transactivation leads to production of
metabolic/endocrine peptides
• Trans-suppression leads to reduced synthesis
of pro-inflammatory cytokines
10.
11. • Non-genomic effects- High doses (>40
mg/day) like Pulse therapy- act within
minutes- mostly by non-specific membrane
associated physiochemical activities.
• Decreases phagocytic effects, cytokine
production, trafficking of Macrophages,
monocytes, lymphocytes, neutrophils
• Downregulates MAP kinase, C-jun, Fos,
Prostaglandin, NF-ķB mediated cytokine
pathways
12.
13.
14. Hypothalamo-pituitary-adrenal axis
• Pro-inflammatory cytokines increase CRH-
ACTH-resultantly cortisol, but insufficient to
tackle
• ACTH/Cortisol- Reach maximum level in the
hours of awakening, minimal in evening
• After 250 mg hydrocortisone/ 50 mg
prednisolone- suppression for 1.25-1.5 days
• Patients on >7.5 mg prednisolone/day for 21
days expected to have adrenal insufficiency
symptoms
16. Standardized nomenclature for glucocorticoid doses and actions
Terminology Dosage Clinical
application
Genomic actions
(receptor
saturation
Nongenomic actions
Low dose <=7.5 Maintenance
therapy for
many rheumatic
diseases
+(<50%) ?
Medium dose >7.5 to <=30 Initially given in
primary chronic
rheumatic
diseases
++ (>50% to
<100%)
(+)
High dose >30 to <= 100 Initially given in
rheumatic
diseases with
organ
impairment
++(+)(almost
100%)
+
Very high dose >100 Initially given in
acute and/or
potentially life-
threatening
exacerbations of
rheumatic
diseases
+++([almost]
100%) ++
++
Pulse therapy >=250 for one
or a few days
SLE/Vasculitis +++(100%) +++
17. GC withdrawal regimens
• When Dose > 40 mg/day- 5-10 mg/week
• When Dose 20-40 mg/day- 5 mg/1-2 week
• When Dose <20 mg/day- 2.5-5 mg / 2-4 weeks
• When dose <10 mg/day- 1 mg/month or 2.5
mg/ 7 weeks
18.
19. GC in Rheumatoid Arthritis
• Add-on therapy with DMARD’s at the
beginning as bridging therapy
• Low-dose prednisolone shown retardation of
radiographic progression
• Chronic prednisolone uses necessary in ILD
• Intra-articular in swollen joints, Pulse therapy
needed rarely
• BMD testing must for Osteoporosis
20. GC in SLE
• Except in mild cases with only dermatological/
arthritis symptoms- systemic GC needed in all
cases
• Severe/ Life threatening- IV pulse MP 500-
1000 mg/d for 3 days followed by
maintenance dose of 0.5-1 mg/kg/d for
atleast 4-6 months then gradual tapering
• Life long maintenance- 5-10 mg/day
• Pregnancy- Prednisolone in lowest possible
dose
21. GC in Rheumatic Fever
• For CCF- Meta-analysis have failed to
demonstrate adequate response in acute
rheumatic carditis, can be used at 1-2
mg/kg/day for maximum 3 weeks
• For Chorea- in inadequate response to
carbamazepine/valproate, 0.5 mg/kg/day-
tapering as early as possible
22. GC in SSc & Sjogren’s
• SSc- Do not influence the progression/
internal organ involvement; increased risk of
scleroderma renal crisis. Used lowest dose for
brief periods
• Sjogren’s- patients with arthritis should be
started on GC in lowest possible dose
• SpA asso uveitis/enthesitis- Topical/intra-
lesional GC
23. GC in ANCA-associated Vasculitis
• Wegener’s- Severe disease combined with CP
at 1 mg/kg/day for 1 month & then gradual
tapering for 6-9 months to induce remission
• Microscopic polyangitis- same t/t
• Churg Strauss- Same regimen- maintenance
therapy needed in most cases
24. GC in other Vasculitis
• PAN- GC + cyclophosphamide in inducing
remission followed by maintenance therapy
• Giant cell arteritis- Prednisolone 40-60
mg/day or pulse MP in vision-threatening
disease- Gradual tapering after 2 months
• Polymyalgia Rheumatica- Start at 10-20
mg/day
• Takayasu’s arteritis- Prednisolone 40-60
mg/day & surgical intervention
• Behcet’s disease- Prednisolone to start 1
mg/kg/day & tapering after 3-4 months
25. GC in Inflammatory Myopathies
• PM/DM- Prednisolone 1 mg/kg/day to start.
Tapering after 3-4 weeks over 10 weeks until
lowest possible dose that can be maintained-
DM responds better than PM
• Observe for steroid myopathy
• IBM- Prednisolone + azathioprine/MTx/MMF,
but insufficient response
26. GC in other diseases
• Sarcoidosis- Prednisolone starting dose 40
mg/day depending upon organ damage (CNS,
cardiac requires higher dose)- Try to taper <10
mg/d in 6 months
• Gout- Prednisolone 0.5 mg/kg/day for 2-5
days then tapper for 7-10 days in acute
attacks. Prophylaxis- 10 mg/d in NSAID’s &
Colchicine intolerance
• TRAPS- 1 mg/kg/day & then slow tappering
27. GC- Adverse effects
• Skeletal side effects-
Osteoporosis- BMD testing essential if
prednisolone intake > 7.5 mg for more than 3
months
Osteonecrosis- Ischemic attacks by
microscopic fat emboli. Hip/knee joint m/c
involved. MRI essential for early diagnosis
Myopathy- Proximal, gradual onset. CPK not
elevated. Muscle biopsy- atrophy of type II
fibers
28. System Involved Adverse effects
GI system • PUD risk increased specially co-administered with NSAID’s-
PPI not indicated in single use
• Candida colonization in upper GI tract
Immunological Predisposition to infections & delays diagnosis
CVS • Mineralocorticoid action- Edema/CCF/ HTN/arrhythmia
• Increased risk of Atherosclerosis
Endocrine • Glucose intolerance. Typically Post-prandial hyperglycemia
with mild fasting hyperglycemia
• Redistribution of body fat-centripetal accumulation with
sparing of extremities.
• LDL, TC, TG, VLDL all increased
Ocular Posterior sub-capsular cataract
Open angle glaucoma- Topical steroids effect
Dermatological Purple striae, easy bruising, reduced wound healing
Behavioral Psychosis- Pulse therapy, Minor mood disturbances
29. Screening & Monitoring
• Before treatment-
BP & CV risk factors
RF for osteoporosis
Metabolic Profile- FPG/PPPG/Lipid profile
Co-medications- NSAID’s & family history of PUD
Family history of glaucoma
• Monitoring during t/t- BP, cardiac insufficiency,
PPPG/FPG, lipid profile, Ocular pressure
30. Preventive Measures
• Calcium (1500 mg/d)/ Vitamin-D (400-800
IU/d) supplementation necessary.
• Modify RF for osteoporosis- smoking & alcohol
cessation, weight bearing exercises
• Consider BMD testing- If T-score < -1 then BPN
Alendronate or Risedronate
• Co-medication with NSAID’s- PPI needs to be
added.