It encompasses the glucocorticoids biology, mechanism of action, its doses & uses in various rheumatological diseases. Adverse events & its prevention are also discussed.

1. Glucocorticoids in
Rheumatological diseases
Dr. Shinjan Patra

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

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

8. • Possible Teratogenic effect- Reduced growth,
poor psycho-motor development, oral cleft.
• Dose > 1 mg/kg avoided
• Prednisolone & Prednisone- safe in lactating
mothers.

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

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

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

15. Cortisol Circadian Secretion

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

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.

31. Thank you……