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- 1. GLUCOCORTICOIDEN: ALTIJD SCHADELIJK VOOR HET BOT? HANS BIJLSMA Director, AMSTERDAM RHEUMATOLOGY CENTER, Professor of rheumatology UNIVERSITY MEDICAL CENTER UTRECHT THE NETHERLANDS
- 2. GCs in 2013: babyboomer coming of age First RA patient treated 1948 After 65 years retirement ?
- 3. Balance: benefits & risks
- 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. 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. COBRA 0 16 28 40 56 Weeks MTX Pred COBRA treatment protocol SSZ Dose
- 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. Results – 2 year studies Cochrane review, Kirwan et al 2007
- 9. EULAR Task Force on GC therapy
- 10. EULAR TASK FORCE ON GLUCOCORTICOIDS
- 12. osteoporosis
- 13. Influence of glucocorticoids on bone remodelling. Schett G et al. Ann Rheum Dis 2010;69:1415-1419
- 14. 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
- 15. 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
- 16. 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
- 17. “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: ↑
- 18. Influence of inflammation on bone remodelling. Schett G et al. Ann Rheum Dis 2010;69:1415
- 19. 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
- 20. Glucose and insulin levels during oral glucose tolerance test (Hoes, ARD 2011).
- 21. Prospective study data – osteoporosis now manageable ? • Preventive and therapeutic guidelines: – Always calcium and vitamin D – Bisphosphonates on indication
- 22. 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 .
- 25. • 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
- 26. 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
- 27. 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) )
- 28. 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
- 29. 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
- 30. 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
- 31. 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
- 32. 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
- 33. 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 * * * *
- 34. 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 *
- 35. 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
- 36. Patient meeting Patients’ and rheumatologists’ perspectives on glucocorticoids
- 37. 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
- 38. 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
- 39. 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
- 40. ( …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
- 41. • 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)
- 42. New glucocorticoids • Targetted time release • Co-medication drugs • Liposomes • SEGRAs • NO=release • Many others
- 43. 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
- 44. 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
- 45. 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
- 46. 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
- 47. 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)
- 48. 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.
- 49. • 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#
- 50. 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
- 52. Thank you for your attention