0
GLUCOCORTICOIDEN:
ALTIJD SCHADELIJK VOOR HET BOT?
HANS BIJLSMA
Director,
AMSTERDAM RHEUMATOLOGY CENTER,
Professor of rheum...
GCs in 2013:
babyboomer coming of age
First RA patient treated 1948
After 65 years retirement ?
Balance: benefits & risks
Utrecht study monotherapy
•  EARLY, DMARD-naive,
RA
•  10 mg prednisone
versus placebo
•  Two years duration
•  Sulphasala...
Total score: effects after 2 and 5 years
Placebo
Prednisone
Totalscore
Totalscore
Probability score (%)Time (months)
Place...
COBRA
0 16 28 40 56
Weeks
MTX
Pred
COBRA treatment protocol
SSZ
Dose
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
...
Results – 2 year studies
Cochrane review, Kirwan et al 2007
EULAR Task Force on GC therapy
EULAR TASK FORCE ON GLUCOCORTICOIDS
osteoporosis
Influence of glucocorticoids on bone remodelling.
Schett G et al. Ann Rheum Dis 2010;69:1415-1419
Effect of low dose prednisone (10 mg/day during 1 week) on
markers of bone metabolism in healthy volunteers
WF Lems et al,...
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...
Glucocorticoids alter the BMD
Fracture Threshold
Steroid users
Nonusers
Femoral neck BMD
Lumbar spine BMD
40
30
20
10
0
40...
“Some data suggest that low dose GCs may even
benefit the bones of patients with RA”
•  disease activity: ↓
•  pro-inflamm...
Influence of inflammation on bone remodelling.
Schett G et al. Ann Rheum Dis 2010;69:1415
Double edged sword
Inflammation as such impairs glucose
metabolism.
Glucocorticoids as such impair glucose
metabolism.
Glu...
Glucose and insulin levels during oral glucose
tolerance test (Hoes, ARD 2011).
Prospective study data –
osteoporosis now manageable ?
•  Preventive and therapeutic guidelines:
–  Always calcium and vit...
Start glucocorticoids
General advice
Dosage and fractures in medical history
High dosage
(> 15 mg/d)
or
fracture
Intermedi...
•  Multicentre study;
inclusion period: 2003 – 2009
Inclusion criteria:
early RA (<1 year)
  1987 revised ACR criteria
 ...
CAMERA-II – adding placebo or prednisone to a
tight control MTX treatment
Both: tight control
treatments
•  Monthly visits...
CAMERA-II – design
•  MTX-based tight control treatment
•  Prednisone or placebo
Prednisone 10 mg/day or placebo
start: 10...
CAMERA-II – design
•  MTX-based tight control treatment
•  Prednisone or placebo
Prednisone 10 mg/day or placebo
start: 10...
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
...
Primary outcome – erosion score
•  Absolute erosion score after 2 years of treatment
cumulative %
Erosionscoreat2yrs
0
MTX...
Secondary outcome – clinical variables
time (months)
VASpain(mm,mean)
MTX + placebo
MTX +
prednisone
10
20
30
50
60
0 6 12...
CRP during trial
time (weeks)
CRP(mean)
MTX + placebo
MTX +
prednisone
5
15
25
35
0 4 20 36 52 72 92 108
CAMERA-II
CAMERA-II – ACR response
ACR70
ACR50
ACR20
10
20
30
40
50
60
70
80
ACRresponse(%)
PRED PLAC PRED PLAC
2 years1 year
•  ACR...
Adverse events MTX + PRED MTX + PLAC
Serious adverse event 2 5
Died 1 0
Hospitalization 1 5
Cataract 1 0
Glaucoma 0 0
Gast...
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)
sBMD(g/cm2)
sBMD left hip
0.6
0.7
0.8
0.9
1
1.1
...
Patient meeting
Patients’ and rheumatologists’ perspectives on glucocorticoids
Ranking adverse events
Osteoporosis
CVD
Peptic ulcer
DM / glucose int.
Weight gain
Renal dysfunction
Cataract
Hypertension...
Ranking adverse events
Osteoporosis
CVD
Peptic ulcer
DM / glucose int.
Weight gain
Renal dysfunction
Cataract
Hypertension...
Goals of monitoring
•  Specific goals for monitoring in daily practice and
clinical trials
–  Daily practice: treating pat...
( …rheumatic diseases…) AND ( …GCs… ) AND ( …adverse events… )
●  Musculoskeletal
−  Osteoporosis
−  Osteonecrosis
−  Myop...
•  Prevention or treatment of AE possible? y n
−  If not: reversible? y n
•  Frequently occuring? y n
•  Severe AE? y n
• ...
New glucocorticoids
•  Targetted time release
•  Co-medication drugs
•  Liposomes
•  SEGRAs
•  NO=release
•  Many others
1.  Prednisolone + dipyridamole

combination drug#
2.  Non-PEGylated liposomal 

dexamethasone phosphate#
3.  Long-circula...
Prednisolone and dipyramidole combination drug
Approach: to combine very low prednisolone with dipyramidole
This leads to:...
Non-PEGylated liposomal dexamethasone
phosphate
•  Liposomes (295nm) with dexamethasone molecules inside
•  Taken up by mo...
Long-circulating liposomal prednisolone
• Encapsulation of GC in long-circulating PEG liposomes
•  Small-sized liposomes w...
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 s...
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	
  admi...
•  Active (red) core (1, 2 or 5mg prednisone)
within an inactive (white) coat
•  High-precision production for accurate an...
Double-blind treatment for 12 weeks1 followed by 9-month open label extension treatment
with modified-release prednisone2 ...
Thank you for your attention
Iwo glucocorticoids 16.43.40
Iwo glucocorticoids 16.43.40
Iwo glucocorticoids 16.43.40
Iwo glucocorticoids 16.43.40
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Iwo glucocorticoids 16.43.40

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Door Prof. Dr. Hans Bijlsma wordt ingegaan op de balans tussen effectiviteit en veiligheid bij Glucocorticoїden (GC): leiden GC altijd tot botverlies, of kan het ontstekingsremmend effect sterker zijn dan de direct negatieve effecten op het bot? Zijn de bijwerkingen dosis-afhankelijk? Hoe kijken patiënten tegen bijwerkingen aan? Zijn er nieuwe medicamenten in aantocht met minder bijwerkingen?

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Transcript of "Iwo glucocorticoids 16.43.40"

  1. 1. GLUCOCORTICOIDEN: ALTIJD SCHADELIJK VOOR HET BOT? HANS BIJLSMA Director, AMSTERDAM RHEUMATOLOGY CENTER, Professor of rheumatology UNIVERSITY MEDICAL CENTER UTRECHT THE NETHERLANDS
  2. 2. GCs in 2013: babyboomer coming of age First RA patient treated 1948 After 65 years retirement ?
  3. 3. Balance: benefits & risks
  4. 4. 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
  5. 5. Total score: effects after 2 and 5 years Placebo Prednisone Totalscore Totalscore Probability score (%)Time (months) Placebo Prednisone Radiologic score for both erosions and joint space narrowing in hands and feet
  6. 6. COBRA 0 16 28 40 56 Weeks MTX Pred COBRA treatment protocol SSZ Dose
  7. 7. 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. Radiologicdamage (Sharp/vanderHeijdescore)
  8. 8. Results – 2 year studies Cochrane review, Kirwan et al 2007
  9. 9. EULAR Task Force on GC therapy
  10. 10. EULAR TASK FORCE ON GLUCOCORTICOIDS
  11. 11. osteoporosis
  12. 12. Influence of glucocorticoids on bone remodelling. Schett G et al. Ann Rheum Dis 2010;69:1415-1419
  13. 13. 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
  14. 14. 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
  15. 15. 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 %Fractures -=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
  16. 16. “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: ↑
  17. 17. Influence of inflammation on bone remodelling. Schett G et al. Ann Rheum Dis 2010;69:1415
  18. 18. 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
  19. 19. Glucose and insulin levels during oral glucose tolerance test (Hoes, ARD 2011).
  20. 20. Prospective study data – osteoporosis now manageable ? •  Preventive and therapeutic guidelines: –  Always calcium and vitamin D –  Bisphosphonates on indication
  21. 21. 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 riskStart bisphosphonate low risk 1 – 3 years Look for special circumstances .
  22. 22. •  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
  23. 23. 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 LeftRight shoulder
  24. 24. 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) )
  25. 25. 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
  26. 26. 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
  27. 27. Primary outcome – erosion score •  Absolute erosion score after 2 years of treatment cumulative % Erosionscoreat2yrs 0 MTX + placebo MTX + prednisone 10 20 50 20 40 60 80 100
  28. 28. Secondary outcome – clinical variables time (months) VASpain(mm,mean) MTX + placebo MTX + prednisone 10 20 30 50 60 0 6 12 18 24 40 * •  Visual analogue scale of pain during trial
  29. 29. CRP during trial time (weeks) CRP(mean) MTX + placebo MTX + prednisone 5 15 25 35 0 4 20 36 52 72 92 108 CAMERA-II
  30. 30. CAMERA-II – ACR response ACR70 ACR50 ACR20 10 20 30 40 50 60 70 80 ACRresponse(%) PRED PLAC PRED PLAC 2 years1 year •  ACR20/50/70 response * * * *
  31. 31. 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 *
  32. 32. 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) sBMD(g/cm2) 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) sBMD(g/cm2) 2 years 10 mg prednison versus placebo: all patients Ca,Vit D and bisphosphonates
  33. 33. Patient meeting Patients’ and rheumatologists’ perspectives on glucocorticoids
  34. 34. 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 DoctorsPatients Patients’ and rheumatologists’ perspectives on glucocorticoids
  35. 35. 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
  36. 36. 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
  37. 37. ( …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
  38. 38. •  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 indicatedOsteoporosis: Monitoring indicated yes no Monitoring in daily practice Developing recommendations (example)
  39. 39. New glucocorticoids •  Targetted time release •  Co-medication drugs •  Liposomes •  SEGRAs •  NO=release •  Many others
  40. 40. 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
  41. 41. 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
  42. 42. 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
  43. 43. 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
  44. 44. 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-6level Buttgereit et al. Arthritis Rheum (in press)
  45. 45. 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.
  46. 46. •  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#
  47. 47. 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
  48. 48. Thank you for your attention
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