6. frank buttgereit. 40 gc update
TRANSCRIPT
Medizinische Klinik m.S. Rheumatologie & Klinische Immunologie
Universitätsmedizin Charité
Glucocorticoids in the treatment of rheumatic diseases - an update 2016
Frank Buttgereit
Charité1727 Frederick William I, King of Prussia,
decreed: " This hospital should
be called ' Charité '. "
Charité means: benevolence, compassion, respect and dedication = christian values that served as the motto
1710 founded as a humble plague hospital outside the Berlin city walls
Frank Buttgereit reports receiving consultancy fees, honoraria and/or travel expenses from Horizon Pharma, Mundipharma, and Pfizer, and grant/study support from
Horizon Pharma and Mundipharma.
Frank Buttgereit is a member of the “EULAR Glucocorticoid task force” and of the groups having
developed the “Recommendations for the management of RA - 2014 update” within EULAR, and the
“2015 ACR/EULAR PMR management recommendations”.
Financial and competing interest disclosure
• Clinical use of glucocorticoids (GC)• Mechanisms of GC action• Adverse GC effects• New developments SEGRAs/DAGRs liposomal GCs (non-genomic mechanisms)
MR/DR Prednisone
Agenda
Glucocorticoids …
• have been in use for more than 65 years • exceed many other drugs in terms of
numbers of patients treatedvariety of applicationspharmacological experience in humans
• are still the most important and most frequently employed class of immunosuppressive drugs, with a steady rise in therapeutic use in recent years
• are in use to treat about 60% of RA patients more or less continuously Thiele, Buttgereit & Zink, Arthritis Rheum (2005)
18% 27%40%
6%15%
≤7,5mg (1996) >7,5mg (1996) <5mg (2013) 5-7,5mg (2013) >7,5mg (2013)
Glucocorticoide 55%50%
Osteoporosemittel
Analgetika
Coxibe
trad. NSAR
parenterales Gold
Sulfasalazin
Biologika
Leflunomid
Methotrexat
0% 10% 20% 30% 40% 50% 60% 70%49%
20%
11%
38%
3%
6%
26%
14%
60%
17%
9%
61%
11%
13%
45%
1995 2013
Treatment of RA in Germany: Data from the Kerndokumentation
18% 27% 6%14% 34% 13%
<5mg 5-7,5mg >7,5mg <5mg (BD ≤ 1Jahr) 5-7,5mg (BD ≤ 1Jahr) >7,5mg (BD ≤ 1Jahr)
Glucocorticoide 50% 61%
Osteoporosemittel
Analgetika
Coxibe
trad. NSAR
parenterales Gold
Sulfasalazin
Biologika
Leflunomid
Methotrexat
0% 10% 20% 30% 40% 50% 60% 70%42%
11%
4%
28%
5%
6%
6%
7%
59%
49%
20%
11%
38%
3%
6%
26%
14%
60%
Alle BD ≤ 1Jahr
Treatment of RA in Germany: Signs and symptoms for 1 year at max.
QUEST-RA
Sokka et al.Ann Rheum
Dis(2007;66;149
1)
Anti-inflammatory and immunosuppressive actions of
glucocorticoids
• Inhibiting leukocyte traffic and access of leukocytes to the site of inflammation
• Interfering with functions of leukocytes, fibroblasts and endothelial cells
• Suppressing the production and actions of humoral factors involved in the inflammatory
process
p65 p50
p65 p50
- Lipocortin-1- IkBa
IP3, Ca 2+, PKC
NFk-B
cation transportphospholipid turnover
GCR with HSP 90
- IL-1, IL-6, TNFa - Phospholipase A2
- COX 2
p65 p50
IkBa
Buttgereit et al., Arthritis Rheum (1998)Buttgereit et al., Arthritis Rheum (2004)
Stahn & Buttgereit, Nat Clin Pract Rheum (2008) Buttgereit et al., Arthritis Rheum (2011)
Genomic effects
Non-genomiceffects
p65 p50
p65 p50
- Lipocortin-1- IkBa
IP3, Ca 2+, PKC
NFk-B
cation transportphospholipid turnover
GCR with HSP 90
- IL-1, IL-6, TNFa - Phospholipase A2
- COX 2
p65 p50
IkBa
TransrepressionTransactivation
These effects are most important!
Why?
Buttgereit et al., Arthritis Rheum (1998)Buttgereit et al., Arthritis Rheum (2004)
Stahn & Buttgereit, Nat Clin Pract Rheum (2008) Buttgereit et al., Arthritis Rheum (2011)
Because: Via these effects glucocorticoids
... reduce clinical signs and symptoms
of inflammation
... retard radiographicprogression of the
disease.
Because: Via these effects glucocorticoids
... reduce clinical signs and symptoms
of inflammation
... retard radiographicprogression of the
disease.
Key results after the 2 years of the trial: Patients with no erosions: 82% (with GC) vs. 70% (w/o GC) Remission was reached more often and earlier on in the
strategy with prednisone compared to the strategy with placebo
Weight gain: 2,9 kg (with GC) vs 1,3 kg (w/o GC) (p = 0.03)
Bakker MF, Jacobs JW, Welsing PM, et al. Low-dose prednisone inclusion in a methotrexate based, tight
control strategy for early RA: a randomized trial (CAMERA II study) Ann Intern Med. 2012; 156:329–39.
Patients and InterventionRA patients; treated with a tight control scheme of climbing dosages of methotrexate PLUS either 10 mg prednisone daily or placebo
ConclusionGC have a beneficial effect on joint structure.
Osteo-blasts
Osteo-clasts
IL-1&6
Effect of TNFa and IL1 on bone resorption
Osteoclastprecursor cells
T cells
RANKL
Antagonist OPG: = soluble receptor+
+
TNFa RANK
RANK
Glucocorticoids
immunosuppressioninflammation
Benefits Risks
osteoporosismyopathyoedema
lipid metabolismcatabolismglaucomacataract
Glucocorticoid therapy in rheumatology
Neurosarcoidosis – a potentially lifethreatening disease
large GC-dosages over months
Cushingoid phenotype severe osteoporosis (vertebral fractures)
van der Goes et al., Ann Rheum Dis, 2010
Ann Rheum Dis. 2016 March 1, [Epub ahead of print]
Key results
Robust evidence wasoften lacking.
Dose categories:≤ 5 mg/d
> 5 - 10 mg/d> 10 mg/d
The level of harm of GCdepends on both
dose and
patient-specific factors.
Risikofaktorauflistung
Additional risk factors for osteoporosis:
• female sex• low body weight• low bone mineral density• family history of osteoporosis• prevalent fractures• low calcium intake
Protective factors for osteoporosis:
• sufficient Vit D & calcium intake• exercise, muscle strengthening• prescription on indication:
e.g. bisphosphonates, osteoanabolic drugs, SERMs
Glucocorticoid dosage
Ris
ks o
f the
dis
ease
Ris
ks o
f the
ther
apy
Aim: A balanced benefits/risk ratio
How to optimise treatments with glucocorticoids (GC)? What are sensible approaches in order to reach this aim?
Buttgereit et al., Lancet (2005)
• To synthesise GCs with mineralocorticoid but anti-inflammatory activity• e.g. prednisone/prednisolone, 1955
• To deliver GCs directly to the site of inflammation• e.g. intra-articular injections
• To optimise dosing regimens (‘give as much as necessary, but as little as possible’)• Development of recommendations and guidelines
• To develop of innovative GCs or GC receptor ligands• e.g. SEGRAs, nitrosteroids (NO-Glucocorticoids)
• To improve treatment with conventional GCs• liposomal glucocorticoids• prednisone + dipyridamole combination drug• chronotherapy with MR prednisone
Published14th of June 2016
Polymyalgia rheumatica Giant cell arteritis
Induction therapyStart glucocorticoid (GC): oral prednisone
equivalent 12.5 - 25 mg/day # ;Consider adding methotrexate §
Induction therapyStart glucocorticoid (GC): oral
prednisone equivalent 40 - 60 mg/d &,¥ ;Consider adding methotrexate §
Initial taperingTaper daily GC dose by 10 mg every 2 weeks to 20 mg/d
Clinical improvementafter 2 – 4 weeks
Clinical improvementafter 2 – 4 weeks
Remission
Treatment-free remission possibly after 1 – 3 years of
therapy; may be longer
Flare managementIncrease GC to pre-relapse dose; taper within 4-8 weeks to dose at which the relapse occurred;Consider adding
methotrexate 7.5–10mg/week
Initial taperingTaper GC dose to 10 mg/day within 4 – 8 weeks
Further taperingTaper daily oral GC dose by e.g. 1 mg every 4 week until discontinuation;
Subsequent withdrawal of methotrexate on
individual basis
Treatment-free remission
possibly after 1 – 3 years of therapy; may be longer
Flare managementIncrease GC to prere-
lapse dose or by up to 5-10mg/day; taper within 4-8 weeks to pre-relapse dose; repeat induction therapy for ischemic
complications; Consider adding 7.5 – 15 mg
methotrexate per week
Further taperingTaper daily oral GC dose more slowly, e.g. by 1 -
2.5 mg decrements every 2 – 8 weeks until discontinuation;
Subsequent withdrawal of methotrexate on
individual basis
Remission
Signs & symptoms reappear
Signs & symptoms reappear
• Clinical use of glucocorticoids (GC)• Mechanisms of GC action• Adverse GC effects• New developments SEGRAs/DAGRs liposomal GCs (non-genomic mechanisms)
MR/DR Prednisone
Agenda
How to optimise treatments with glucocorticoids (GC)? What are sensible approaches in order to reach this aim?
• To synthesise GCs with mineralocorticoid but anti-inflammatory activity• e.g. prednisone/prednisolone, 1955
• To deliver GCs directly to the site of inflammation• e.g. intra-articular injections
• To optimise dosing regimens (‘give as much as necessary, but as little as possible’)• Development of recommendations and guidelines
• To develop innovative GCs or GC receptor ligands• e.g. SEGRAs, nitrosteroids (NO-Glucocorticoids)
• To improve treatment with conventional GCs• liposomal glucocorticoids• chronotherapy with MR prednisone
Buttgereit et al., Lancet (2005)
• To synthesise GCs with mineralocorticoid but anti-inflammatory activity• e.g. prednisone/prednisolone, 1955
• To deliver GCs directly to the site of inflammation• e.g. intra-articular injections
• To optimise dosing regimens (‘give as much as necessary, but as little as possible’)• Development of recommendations and guidelines
• To develop innovative GCs or GC receptor ligands• e.g. SEGRAs, nitrosteroids (NO-Glucocorticoids)
• To improve treatment with conventional GCs• liposomal glucocorticoids• chronotherapy with MR prednisone
How to optimise treatments with glucocorticoids (GC)? What are sensible approaches in order to reach this aim?
SElective Glucocorticoid Receptor Agonists
(also: DAGR = Dissociated Agonist of the Glucocorticoid Receptor)
Buttgereit et al., Lancet (2005)
Mechanisms in Rheumatology ©2001
Classical genomic pathway of glucocorticoid action
Transactivation
Transrepression
Adversereactions
Trans-repression
Trans-activation
Anti-inflammatory
effects
OsteoporosisGrowth retardation
Skin atrophy Cushingoid appearance
Diabetes Glaucoma
Inhibition of several different processes of
cellular (e.g. migration)and humoral immunity (e.g. TNFa, COX 2)
HPA insufficiency
IkBLipocortin 1
Buttgereit et al., Lancet (2005)
DAGR = Dissociated Agonist of the Glucocorticoid Receptor
Adversereactions
Trans-repression
Trans-activation
Anti-inflammatory
effects
OsteoporosisGrowth retardation
Skin atrophy Cushingoid appearance
Diabetes Glaucoma
Inhibition of several different processes of
cellular (e.g. migration)and humoral immunity (e.g. TNFa, COX 2)
HPA insufficiency
IkBLipocortin 1
Buttgereit et al., Lancet (2005)
DAGR = Dissociated Agonist of the Glucocorticoid Receptor
EULAR 2015; SAT0221 Buttgereit et al.
DAS28-4(CRP) Mean & Mean Change from Baseline
L4
3.5
4.0
4.5
5.0
5.5
6.0
0 2 4 6 8Week
Obs
erve
d m
ean
(SE)
0 2 4 6 8Week
–2
–1
0
Mea
n Δ
from
BL
(SE)
DAGR 1 mgDAGR 5 mg
DAGR 10 mgDAGR 15 mg
Prednisone 5 mg Prednisone 10 mg
Placebo
HbA1c: by Week (active treatment + taper periods)
L4
Taper–0.28–0.24–0.20–0.16–0.12–0.08–0.04
0.000.040.080.120.16
–1 0 2 3 4 5 6 7 8 9 10 11 12Weeks
DAGR 1 mgDAGR 5 mg
DAGR 10 mgDAGR 15 mg
Prednisone 5 mg Prednisone 10 mg
Placebo
Mea
n (S
E) Δ
from
scr
eeni
ng
• To synthesise GCs with mineralocorticoid but anti-inflammatory activity• e.g. prednisone/prednisolone, 1955
• To deliver GCs directly to the site of inflammation• e.g. intra-articular injections
• To optimise dosing regimens (‘give as much as necessary, but as little as possible’)• Development of recommendations and guidelines
• To develop innovative GCs or GC receptor ligands• e.g. SEGRAs, nitrosteroids (NO-Glucocorticoids)
• To improve treatment with conventional GCs• liposomal glucocorticoids• chronotherapy with MR prednisone
How to optimise treatments with glucocorticoids (GC)? What are sensible approaches in order to reach this aim?
Buttgereit et al., Lancet (2005)
Metselaar et al. Arthritis Rheum (2003)Metselaar et al. Ann Rheum Dis (2004) Barrera et al. Presented at ACR (2008)
PEG
PEG
Long-circulating liposomal prednisolone
• Encapsulation of GC in long-circulating PEG liposomes• Small-sized (nm-range) liposomes with
long circulation time accumulation in arthritic joints (>10-5M) genomic + non-genomic actions
• Effective in animal models (AIA, CIA) • Single liposome injection
complete remission of inflammatory response for almost a week
Metselaar et al., Ann Rheum Dis 2004;63:348-353 Results ( I )
Model: murine Collagen
type II-induced arthritis
Same dose of unencapsulated prednisolone phosphate: was only slightly effective after repeated daily injections
Single injection of 10 mg/kg liposomal prednisolone phosphate: strong + lasting (1 week !) resolution of joint inflammation
Long-circulating liposomal glucocorticoids
Metselaar et al. Arthritis Rheum (2003)Metselaar et al. Ann Rheum Dis (2004) Barrera et al. Presented at ACR (2008)
PEG
PEG
Long-circulating liposomal prednisolone
• Encapsulation of GC in long-circulating PEG liposomes• Small-sized (nm-range) liposomes with
long circulation time accumulation in arthritic joints (>10-5M) genomic + non-genomic actions
• Effective in animal models (AIA, CIA) • Single liposome injection
complete remission of inflammatory response for almost 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
• To synthesise GCs with mineralocorticoid but anti-inflammatory activity• e.g. prednisone/prednisolone, 1955
• To deliver GCs directly to the site of inflammation• e.g. intra-articular injections
• To optimise dosing regimens (‘give as much as necessary, but as little as possible’)• Development of recommendations and guidelines
• To develop innovative GCs or GC receptor ligands• e.g. SEGRAs, nitrosteroids (NO-Glucocorticoids)
• To improve treatment with conventional GCs• liposomal glucocorticoids• chronotherapy with MR prednisone
How to optimise treatments with glucocorticoids (GC)? What are sensible approaches in order to reach this aim?
Buttgereit et al., Lancet (2005)
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 (2011)
Hydrophobic Surface Adsorbs
Air Bubbles
Water Is Penetrating The Shell, Rupture StartsRupture Continues…Shell Opens At Lag Time
TimepointCore Is Being ReleasedCore Is Being DissolvedDrug Release Completed
1 hour2 hours345
Start
Lag PhaseLag Time Point10%
50%
80%
100%
0 5 10
Time (Hours)
Dis
solu
tion
Rat
e
>5 hours
MR Prednisone (modified release): Design
CAPRA-11 CAPRA-1 extension2 CAPRA-23
Design RandomisedDouble-blindDouble-dummyActive control
Open label RandomisedDouble-blindPlacebo-controlled
Patients On stable low-dose GC (2.5–10mg/day)Stable DMARD allowed
From CAPRA-1 Not on GCStable DMARD allowed
Study treatments
Continue same dose conventional prednisone (morning dose) ORSame dose modified-release prednisone (evening dose)
All patients continue on stable dose, taken as modified-release prednisone(evening dose)
Placebo ORModified-release prednisone 5mg/day (both evening doses)
1° endpoint Change in duration of morning stiffness
ACR20 response
Duration 12 weeks 9 months 12 weeks
CAPRA, circadian administration of prednisone in rheumatoid arthritis; GC, glucocorticoid; DMARD, disease-modifying anti-rheumatic drug
1. Buttgereit et al. Lancet (2008) 2. Buttgereit et al. Ann Rheum Dis (2010)3. Buttgereit et al. Ann Rheum Dis (2013)
Overview of phase III clinical studies in rheumatoid arthritis: CAPRA-1 (+ extension) and CAPRA-2
CAPRA-1: Results (db phase & open follow-up)
Sustained Reduction in Morning Stiffness
Duration of Morning Stiffness: Relative Change from Baseline (ITT)
Buttgereit et al., Ann Rheum Dis (2010)Buttgereit et al., Lancet (2008)
IL-6: ~50% VAS pain: ~10 DAS28: ~1 ACR20: ~37%
CAPRA-11 CAPRA-1 extension2 CAPRA-23
Design RandomisedDouble-blindDouble-dummyActive control
Open label RandomisedDouble-blindPlacebo-controlled
Patients On stable low-dose GC (2.5–10mg/day)Stable DMARD allowed
From CAPRA-1 Not on GCStable DMARD allowed
Study treatments
Continue same dose conventional prednisone (morning dose) ORSame dose modified-release prednisone (evening dose)
All patients continue on stable dose, taken as modified-release prednisone(evening dose)
Placebo ORModified-release prednisone 5mg/day (both evening doses)
1° endpoint Change in duration of morning stiffness
ACR20 response
Duration 12 weeks 9 months 12 weeks
CAPRA, circadian administration of prednisone in rheumatoid arthritis; GC, glucocorticoid; DMARD, disease-modifying anti-rheumatic drug
Overview of phase III clinical studies in rheumatoid arthritis: CAPRA-1 (+ extension) and CAPRA-2
1. Buttgereit et al. Lancet (2008) 2. Buttgereit et al. Ann Rheum Dis (2010)3. Buttgereit et al. Ann Rheum Dis (2013)
Significant increase in proportion of patients with improved disease control after 2 weeks of treatment with modified-release prednisone compared with placebo
Buttgereit et al. Ann Rheum Dis (2013)
CAPRA-2: ACR20 responder rate over time
Buttgereit et al. Ann Rheum Dis (2013)
CAPRA-2: change in duration of morning stiffnessSignificant reduction in duration of morning stiffness in patients taking modified-release prednisone in the evening compared with placebo
Adverse events (>1%) *n (%)
Modified-release prednisone (N = 231)
Placebo(N = 119)
Arthralgia 24 (10.4) 24 (20.2)
Rheumatoid arthritis 15 (6.5) 11 (9.2)
Nasopharingitis 11 (4.8) 4 (3.4)
Headache 9 (3.9) 5 (4.2)
Bronchitis 3 (1.3) 5 (4.2)
Hypertension 5 (2.2) 1 (0.8)
Diarrhoea 4 (1.7) 1 (0.8)
Rash 4 (1.7) 1 (0.8)
Back pain 3 (1.3) 1 (0.8)
Hematuria 1 (0.4) 3 (2.5)
Peripheral oedema 2 (0.9) 2 (1.7)
Vomiting 3 (1.3) 1 (0.8)
* Independent of causality assessment
CAPRA-2: safety and tolerability
Similar tolerability profile with modified-release prednisone and placebo
Buttgereit et al. Ann Rheum Dis (2013)
Thank you !