6. Frank Buttgereit. 40 gc update

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





• 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








SElective Glucocorticoid Receptor Agonists

(also: DAGR = Dissociated Agonist of the Glucocorticoid Receptor)


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


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


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








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

http://ard.bmjjournals.com/content/vol63/issue4/images/large/ar9944.f1.jpeg

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








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


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


Thank you !

Health & Medicine

6. Frank Buttgereit. 40 gc update