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GLUCOCORTICOIDEN: ALTIJD SCHADELIJK VOOR HET BOT?
HANS BIJLSMA
Director,
AMSTERDAM RHEUMATOLOGY CENTER, Professor of rheumatology
UNIVERSITY MEDICAL CENTER UTRECHT THE NETHERLANDS
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GCs in 2013: babyboomer coming of age
First RA patient treated 1948
After 65 years retirement ?
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Balance: benefits & risks
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Utrecht study monotherapy
• EARLY, DMARD-naive, RA
• 10 mg prednisone versus placebo
• Two years duration
• Sulphasalazine rescue after 6 months
Ann Intern Med 2002; 136: 1
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Total score: effects after 2 and 5 years
Placebo Prednisone
Tota
l sco
re
Tota
l sco
re
Probability score (%) Time (months)
Placebo Prednisone
Radiologic score for both erosions and joint space narrowing in hands and feet
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COBRA
0 16 28 40 56
Weeks
MTX Pred
COBRA treatment protocol SSZ
Dos
e
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Damage progression: 5 years data
P =0.008
0
10
20
30
40
0 1 2 3 4 5
Damage progression (Sharp/van der Heijde score)
Years
Arthritis Rheum 2002:46:347-356.
Rad
iolo
gic
dam
age
(S
harp
/van
der
Hei
jde
scor
e)
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Results – 2 year studies Cochrane review, Kirwan et al 2007
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EULAR Task Force on GC therapy
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EULAR TASK FORCE ON GLUCOCORTICOIDS
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osteoporosis
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Influence of glucocorticoids on bone remodelling.
Schett G et al. Ann Rheum Dis 2010;69:1415-1419
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Effect of low dose prednisone (10 mg/day during 1 week) on markers of bone metabolism in healthy volunteers
WF Lems et al, Br J Rheum 1998; 37: 23-33.
.
**
**: p <0,05
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Glucocorticoids and fractures (Van Staa et al. J Bone Miner Res 2000)
Dose RR hip RR vertebral
< 2.5 0.99 1.55
2.5 – 7.5 1.77 2.59
> 7.5 mg predn/day
2.27 5.18
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Glucocorticoids alter the BMD Fracture Threshold
Steroid users
Nonusers
Femoral neck BMD
Lumbar spine BMD
40
30
20
10
0
40
30
20
10
0
% F
ract
ures
-=4.5 -3.5 -2.5 -1.5 -0.5
-4.5 -3.5 -2.5 -1.5 -0.5 0.5
van Staa. Arth Rheum 2003; 48: 3224-9
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“Some data suggest that low dose GCs may even benefit the bones of patients with RA”
• disease activity: ↓ • pro-inflammatory cytokines (anti-TNF, IL-1, IL-6,
IL-17) inducing degradation of bone: ↓ • weightbearing activity: ↑
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Influence of inflammation on bone remodelling.
Schett G et al. Ann Rheum Dis 2010;69:1415
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Double edged sword
Inflammation as such impairs glucose metabolism.
Glucocorticoids as such impair glucose metabolism.
Glucocorticoids reduce inflammation and as such improve glucose metabolism.
Same holds also for • osteoporosis • cardiovascular risk • …….. Buttgereit, ARD 2011; 70:1881-3
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Glucose and insulin levels during oral glucose tolerance test (Hoes, ARD 2011).
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Prospective study data – osteoporosis now manageable ?
• Preventive and therapeutic guidelines:
– Always calcium and vitamin D – Bisphosphonates on indication
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Start glucocorticoids
General advice
Dosage and fractures in medical history
High dosage (> 15 mg/d)
or fracture
Intermediate dosage (7.5 – 15 mg/d)
low dosage < 7.5 mg/d)
postmenopausal women men > 70 years
Premenopausal women men < 70 years
DXA X-SPINE
High risk Start bisphosphonate low risk
1 – 3 years
Look for special circumstances
.
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• Multicentre study; inclusion period: 2003 – 2009
Inclusion criteria: early RA (<1 year) 1987 revised ACR criteria ≥ 18 years DMARD & glucocorticoid
naïve
• MTX-based tight control & randomized double-blind
placebo or prednisone 10 mg
CAMERA-II: Computer-Assisted Management of Early Rheumatoid Arthritis
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CAMERA-II – adding placebo or prednisone to a tight control MTX treatment
Both: tight control treatments
• Monthly visits • Computer decision
model
(SJC, TJC, ESR, VASgh) • Aimed at remission
elbow
wrist
MCP
PIP
MTP
ankle
knee
Left Right
shoulder
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CAMERA-II – design
• MTX-based tight control treatment • Prednisone or placebo
Prednisone 10 mg/day or placebo start: 10 mg/wk
time
15 mg/wk 20 mg/wk
25 mg/wk 30 mg/wk
Adalimumab (if needed)
)
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CAMERA-II – design
• MTX-based tight control treatment • Prednisone or placebo
Prednisone 10 mg/day or placebo start: 10 mg/wk
time
15 mg/wk 20 mg/wk
25 mg/wk 30 mg/wk
Adalimumab (if needed) TREATMENT DECREASES
WHEN REMISSION REACHED
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CAMERA-II – baseline data
MTX + pred MTX + plac
(n=116) (n=119) n % n %
Female gender 69 60 71 60 RF positive 63 54 72 61 mean SD mean SD
Age (years) 55 14 53 13 ESR (mm/h1st) 36 25 34 24 CRP (mg/l) 31 36 25 27
Morning stiffness (min) 88 52 88 60 VASgeneral (mm) 58 22 56 23 VASpain (mm) 49 26 49 25
TJC 17 9 14 9 SJC 15 9 14 8 SHS (median, IQR) 0 0–0.5 0 0–0
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Primary outcome – erosion score
• Absolute erosion score after 2 years of treatment
cumulative %
Eros
ion
scor
e at
2yr
s
0
MTX + placebo MTX +
prednisone
10
20
50
20 40 60 80 100
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Secondary outcome – clinical variables
time (months)
VAS
pain
(mm
, mea
n)
MTX + placebo MTX +
prednisone
10
20
30
50
60
0 6 12 18 24
40
*
• Visual analogue scale of pain during trial
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CRP during trial
time (weeks)
CR
P (m
ean)
MTX + placebo MTX +
prednisone
5
15
25
35
0 4 20 36 52 72 92 108
CAMERA-II
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CAMERA-II – ACR response
ACR70 ACR50 ACR20
10
20
30
40
50
60
70
80
AC
R re
spon
se (%
)
PRED PLAC PRED PLAC
2 years 1 year
• ACR20/50/70 response
*
*
*
*
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Adverse events MTX + PRED MTX + PLAC
Serious adverse event 2 5 Died 1 0 Hospitalization 1 5
Cataract 1 0 Glaucoma 0 0
Gastrointestinal Nausea 51 152 Diarrhea 18 16 Epigastric pain 14 17
Liver toxicity ALAT >ULN 30 87 ASAT >ULN 16 38
Pneumonitis 1 0 Infections 6 7
Antibiotic Tx 1 0 Peripheral fractures 1 0
Hypertension 11 18 Diabetes mellitus 1 1
*
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sBMD lumbar spine
0.6
0.7
0.8
0.9
1
1.1
1.2
1.3
1.4
0 12 24 Time (months)
sBM
D (g
/cm
2 )
sBMD left hip
0.6
0.7
0.8
0.9
1
1.1
1.2
1.3
1.4
0 12 24 Time (months)
sBM
D (g
/cm
2 )
2 years 10 mg prednison versus placebo: all patients Ca,Vit D and bisphosphonates
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Patient meeting
Patients’ and rheumatologists’ perspectives on glucocorticoids
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Ranking adverse events
Osteoporosis
CVD
Peptic ulcer
DM / glucose int. Weight gain
Renal dysfunction
Cataract
Hypertension
Myopathy
Fatigue
Moon face Glaucoma
Palpitations
Dyspnea
DM / glucose int.
Osteoporosis
Weight gain
Infections
CVD
Atherosclerosis
Peptic ulcer
Cataract
Myopathy
AEs due to interactions Osteonecrosis
Impaired wound healing
Dyslipidemia
Hypertension
Doctors Patients
Patients’ and rheumatologists’ perspectives on glucocorticoids
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Ranking adverse events
Osteoporosis
CVD
Peptic ulcer
DM / glucose int. Weight gain
Renal dysfunction
Cataract
Hypertension
Myopathy
Fatigue
Moon face Glaucoma
Palpitations
Dyspnea
DM / glucose int. Osteoporosis
Weight gain
Infections
CVD
Atherosclerosis
Peptic ulcer
Cataract
Myopathy
AEs due to interactions Osteonecrosis
Impaired wound healing
Dyslipidemia
Hypertension
Patients’ and rheumatologists’ perspectives on glucocorticoids
Patients Doctors
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Goals of monitoring
• Specific goals for monitoring in daily practice and clinical trials
– Daily practice: treating patients safely limited set of recommendations
– Clinical trials: … and obtaining high-quality data on the occurrence of adverse events more extensive set of recommendations
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( …rheumatic diseases…) AND ( …GCs… ) AND ( …adverse events… )
● Musculoskeletal − Osteoporosis − Osteonecrosis − Myopathy
● Endocrine & metabolic − Glucose metabolism − Body weight & fat distribution − Menstrual disturbances
● Cardiovascular − Dyslipidemia − Hypertension − Heart failure − Atherosclerosis & CVD − Renal dysfunction, edema, elektrolyte
disturbances
● Drug interactions
● Ophthalmologic − Cataract − Glaucoma
● Gastrointestinal − Peptic ulcer disease − Pancreatitis
● Infections
● Psychological − Psychosis − Mood disturbances
● Skin − Cutaneous atrophy − Acne, hirsutism, alopecia, bruisability
Methods: Literature search
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• Prevention or treatment of AE possible? y n
− If not: reversible? y n
• Frequently occuring? y n
• Severe AE? y n
• Cost-effectiveness? y n
• Reliable scoring possible? y n
Skin atrophy: Monitoring not indicated Osteoporosis: Monitoring indicated
yes no Monitoring in daily practice
Developing recommendations (example)
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New glucocorticoids
• Targetted time release • Co-medication drugs • Liposomes
• SEGRAs • NO=release • Many others
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1. Prednisolone + dipyridamole combination drug#
2. Non-PEGylated liposomal dexamethasone phosphate#
3. Long-circulating liposomal prednisolone#
4. Modified-release prednisone#
Phase I
Approved
Animal model
Animal model
PEG, polyethylene glycol
+
PEG
PEG
Improved treatment with conventional GC: current status
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Prednisolone and dipyramidole combination drug
Approach: to combine very low prednisolone with dipyramidole
This leads to: enhanced anti-inflammatory activity in immune cells, but no increase in GC-induced adverse effects elsewhere
Results: • ↓ TNFα, IL-6 and MMP-9 release in human PBMC • Effective in animal models (CIA, AIA) with sub-therapeutic dose &
no increase in adverse events (e.g. on bone, HPA suppression)
+
Zimmermann et al. Arthritis Res Ther 2009;11:R12 Lehár et al. Nat Biotech 2009;27:659–66
AIA, adjuvant-induced arthritis; CIA, collagen-induced arthritis, IL-6, interleukin-6; HPA, hypothalamic-pituitary-adrenal; MMP-9, matrix metallopeptidase-9; PBMC, peripheral blood mononuclear cells; TNFα, tumour necrosis factor-α
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Non-PEGylated liposomal dexamethasone phosphate
• Liposomes (295nm) with dexamethasone molecules inside • Taken up by monocytes and macrophages, accumulate in spleen • No free dexamethasone
• Effective in animal models (CIA, AIA) • CIA: single liposome injection gave
comparable suppression of flare to daily administration of free dexamethasone for 7 days
• No impact on HPA axis, blood glucose compared to significant effect with free dexamethasone
• AIA: liposome injection (but not free dexa- methasone) prevented joint destruction
• It seems that this approach does allow persistent therapeutic effect of targeted high GC concentration with separation of benefits/risks
Rauchhaus et al. Arthritis Res Ther 2009;11:R190 Rauchhaus et al. Ann Rheum Dis 2009;68:1933–4
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Long-circulating liposomal prednisolone
• Encapsulation of GC in long-circulating PEG liposomes • Small-sized liposomes with
↓ uptake into macrophages ↑ circulation time Accumulation in arthritic joints (>105M) → genomic + non-genomic actions
• Effective in animal models (AIA, CIA) • Single liposome injection → complete remission
of inflammatory response for almost a week • unencapsulated prednisolone much weaker even at daily
doses for a week • Effective in phase I, 12-week study of 16 patients with RA
• A single liposome injection (150mg i.v.) → faster/more pronounced decrease in DAS & better improvement of ACR criteria (compared with 120mg methylprednisolone i.m.)
• Liposomes well-tolerated Metselaar et al. Arthritis Rheum 2003;48:2059–66 Metselaar et al. Ann Rheum Dis 2004;63:348–53
Stahn & Buttgereit. Nat Clin Pract Rheumatol 2008;4:525–33 Barrera et al. Presented at ACR 2008
PEG
PEG
ACR, American College of Rheumatology; DAS; disease activity score; RA, rheumatoid arthritis
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10.00 pm 2.00 am 6.00 am 10.00 am 2.00 pm
IL-6 ↑
Endothelial activation ↑ Cell recruitment ↑ Activity of proteases ↑ MMP secretion ↑ B-cell function ↑ VEGF levels ↑ Pain mediators ↑
Clinical symptoms such as morning stiffness ↓
IL-6
A
B
Reduced articular and
systemic effects morning stiffness ↓ ↓
time of day
IL-6
leve
l
Buttgereit et al. Arthritis Rheum (in press)
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Release
6 p.m. 10 p.m. 2 a.m. 6 a.m. 10 a.m.
Stiffness and Pain
High
Cytokine Release
Dosing
Targe&ng )me of administra)on
Inflammatory Cytokine Levels and Pain and Stiffness Scores
Morning administration is too late to mediate the nocturnal cytokine peak, while 2 a.m. administration is optimal but impractical.
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• Active (red) core (1, 2 or 5mg prednisone) within an inactive (white) coat • High-precision production for accurate and
consistent central core positioning
• Tablet designed to be taken at approximately 10.00 pm • Programmed release of active core
4 hours after administration (approximately 2.00 am) to antagonize the increase in proinflammatory cytokines
• Pharmacokinetic profile of 5mg MR prednisone has been shown to be very similar to that of 5mg IR prednisone – apart from the 4 hours delay
From bench to bedsite: The design of modified release prednisone#
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Double-blind treatment for 12 weeks1 followed by 9-month open label extension treatment with modified-release prednisone2 (total duration of study 12 months)
Week 0 Week 12
DMARDs at a stable dose
Concomitant medication at a stable dose
≥1 week screening
phase 12 weeks double-blind phase
Predniso(lo)ne at a stable individual dose
(2.5–10mg/day)
Conventional prednisone at same stable dose taken in
the morning (7–8 am)
Modified-release prednisone at same stable dose taken in
the evening (10pm)
1. Buttgereit et al. Lancet 2008;371:205–14 2. Buttgereit et al. Ann Rheum Dis 2010;69 :1275-80
CAPRA-1: study design
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Thank you for your attention