.

1. Medizinische Klinik m.S. Rheumatologie & Klinische Immunologie
Universitätsmedizin Charité
Glucocorticoids in the treatment of
rheumatic diseases - an update 2016
Frank Buttgereit

2. Charité
1727 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

4. 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

5. • 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

6. Glucocorticoids …
• have been in use for more than 65 years
• exceed many other drugs in terms of
numbers of patients treated
variety of applications
pharmacological 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)

7. 18% 27%
40%
6%
15%
≤7,5mg (1996) >7,5mg (1996)
<5mg (2013) 5-7,5mg (2013) >7,5mg (2013)
Glucocorticoide
55%
50%
49%
20%
11%
38%
3%
6%
26%
14%
60%
17%
9%
61%
11%
13%
45%
0% 10% 20% 30% 40% 50% 60% 70%
Osteoporosemittel
Analgetika
Coxibe
trad. NSAR
parenterales Gold
Sulfasalazin
Biologika
Leflunomid
Methotrexat
1995 2013
Treatment of RA in Germany:
Data from the Kerndokumentation

8. 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%
42%
11%
4%
28%
5%
6%
6%
7%
59%
49%
20%
11%
38%
3%
6%
26%
14%
60%
0% 10% 20% 30% 40% 50% 60% 70%
Osteoporosemittel
Analgetika
Coxibe
trad. NSAR
parenterales Gold
Sulfasalazin
Biologika
Leflunomid
Methotrexat
Alle BD ≤ 1Jahr
Treatment of RA in Germany:
Signs and symptoms for 1 year at max.

9. QUEST-RA
Sokka et al.
Ann Rheum Dis
(2007;66;1491)

10. 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

11. p65 p50
p65 p50
- Lipocortin-1
- IkBa
IP3, Ca 2+, PKC
NFk-B
cation transport
phospholipid 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-genomic
effects

12. p65 p50
p65 p50
- Lipocortin-1
- IkBa
IP3, Ca 2+, PKC
NFk-B
cation transport
phospholipid 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)

13. Because:
Via these effects glucocorticoids
... reduce clinical
signs and symptoms
of inflammation
... retard radiographic
progression of the
disease.

14. Because:
Via these effects glucocorticoids
... reduce clinical
signs and symptoms
of inflammation
... retard radiographic
progression of the
disease.

15. 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 Intervention
RA patients; treated with a tight control scheme of climbing dosages
of methotrexate PLUS either 10 mg prednisone daily or placebo
Conclusion
GC have a beneficial effect on joint structure.

16. Osteo-
blasts
Osteo-
clasts
IL-1&6
Effect of TNFa and IL1 on
bone resorption
Osteoclast
precursor cells
T cells
RANKL
Antagonist OPG:
= soluble receptor
+
+
TNFa RANK
RANK
Glucocorticoids

17. immunosuppression
inflammation 
Benefits Risks
osteoporosis
myopathy
oedema
lipid metabolism
catabolism
glaucoma
cataract
Glucocorticoid therapy in rheumatology

18. Neurosarcoidosis – a potentially
lifethreatening disease
 large GC-dosages over months
 Cushingoid phenotype
 severe osteoporosis
(vertebral fractures)

20. van der Goes et al., Ann Rheum Dis, 2010

21. Ann Rheum Dis. 2016 March 1, [Epub ahead of print]

22. Key results
Robust evidence was
often lacking.
Dose categories:
≤ 5 mg/d
> 5 - 10 mg/d
> 10 mg/d
The level of harm of GC
depends on both
dose
and
patient-specific factors.

23. Risikofaktorauflistung

24. 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

25. Glucocorticoid dosage
Risksofthedisease
Risksofthetherapy
Aim: A balanced benefits/risk ratio

26. 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

27. Published
14th of June 2016

29. Polymyalgia rheumatica Giant cell arteritis
Induction therapy
Start glucocorticoid (GC): oral prednisone
equivalent 12.5 - 25 mg/day # ;
Consider adding methotrexate §
Induction therapy
Start glucocorticoid (GC): oral
prednisone equivalent 40 - 60 mg/d &,¥ ;
Consider adding methotrexate §
Initial tapering
Taper daily GC dose by 10 mg every 2 weeks to 20 mg/d
Clinical improvement
after 2 – 4 weeks
Clinical improvement
after 2 – 4 weeks
Remission
Treatment-free remission
possibly after 1 – 3 years of
therapy; may be longer
Flare management
Increase 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 tapering
Taper GC dose to 10 mg/day within 4 – 8 weeks
Further tapering
Taper 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 management
Increase 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 tapering
Taper 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

30. • 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

31. 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)

32. • 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)

33. Mechanisms in Rheumatology ©2001
Classical genomic pathway
of glucocorticoid action
Transactivation
Transrepression

34. Adverse
reactions
Trans-
repression
Trans-
activation
Anti-
inflammatory
effects
Osteoporosis
Growth 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
IkB
Lipocortin 1
Buttgereit et al., Lancet (2005)
DAGR = Dissociated Agonist of
the Glucocorticoid Receptor

35. Adverse
reactions
Trans-
repression
Trans-
activation
Anti-
inflammatory
effects
Osteoporosis
Growth 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
IkB
Lipocortin 1
Buttgereit et al., Lancet (2005)
DAGR = Dissociated Agonist of
the Glucocorticoid Receptor
EULAR 2015; SAT0221 Buttgereit et al.

36. 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 8
Week
Observedmean(SE)
0 2 4 6 8
Week
–2
–1
0
MeanΔfromBL(SE)
DAGR 1 mg
DAGR 5 mg
DAGR 10 mg
DAGR 15 mg
Prednisone 5 mg
Prednisone 10 mg
Placebo

37. HbA1c: by Week
(active treatment + taper periods)
L4
Taper
–0.28
–0.24
–0.20
–0.16
–0.12
–0.08
–0.04
0.00
0.04
0.08
0.12
0.16
–1 0 2 3 4 5 6 7 8 9 10 11 12
Weeks
DAGR 1 mg
DAGR 5 mg
DAGR 10 mg
DAGR 15 mg
Prednisone 5 mg
Prednisone 10 mg
Placebo
Mean(SE)Δfromscreening

38. • 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)

39. 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

40. 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

41. 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

43. • 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)

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 (2011)

45. Hydrophobic Surface
Adsorbs
Air Bubbles
Water Is Penetrating The
Shell, Rupture Starts
Rupture Continues…Shell Opens At Lag Time
Timepoint
Core Is Being ReleasedCore Is Being DissolvedDrug Release Completed
1 hour2 hours345
Start
Lag Phase
Lag Time
Point10%
50%
80%
100%
0 5 10
Time (Hours)
DissolutionRate
>5 hours
MR Prednisone (modified release): Design

46. CAPRA-11 CAPRA-1 extension2 CAPRA-23
Design Randomised
Double-blind
Double-dummy
Active control
Open label Randomised
Double-blind
Placebo-controlled
Patients On stable low-dose GC
(2.5–10mg/day)
Stable DMARD allowed
From CAPRA-1 Not on GC
Stable DMARD
allowed
Study
treatments
Continue same dose
conventional
prednisone (morning
dose) OR
Same dose modified-
release prednisone
(evening dose)
All patients continue
on stable dose, taken
as modified-release
prednisone
(evening dose)
Placebo OR
Modified-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

47. 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%

48. CAPRA-11 CAPRA-1 extension2 CAPRA-23
Design Randomised
Double-blind
Double-dummy
Active control
Open label Randomised
Double-blind
Placebo-controlled
Patients On stable low-dose GC
(2.5–10mg/day)
Stable DMARD allowed
From CAPRA-1 Not on GC
Stable DMARD
allowed
Study
treatments
Continue same dose
conventional
prednisone (morning
dose) OR
Same dose modified-
release prednisone
(evening dose)
All patients continue
on stable dose, taken
as modified-release
prednisone
(evening dose)
Placebo OR
Modified-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)

49. 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

50. Buttgereit et al. Ann Rheum Dis (2013)
CAPRA-2: change in duration of
morning stiffness
Significant reduction in duration of morning stiffness in patients taking
modified-release prednisone in the evening compared with placebo

51. 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)

52. Thank you !