GLUCOCORTICOIDEN: ALTIJD SCHADELIJK VOOR HET BOT?

HANS BIJLSMA

Director,

AMSTERDAM RHEUMATOLOGY CENTER, Professor of rheumatology

UNIVERSITY MEDICAL CENTER UTRECHT THE NETHERLANDS

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

•  Sulphasalazine rescue after 6 months

Ann Intern Med 2002; 136: 1

Total score: effects after 2 and 5 years

Placebo Prednisone

Tota

l sco

re

Tota

l sco

re

Probability score (%) Time (months)

Placebo Prednisone

Radiologic score for both erosions and joint space narrowing in hands and feet

COBRA

0 16 28 40 56

Weeks

MTX Pred

COBRA treatment protocol SSZ

Dos

e

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.

Rad

iolo

gic

dam

age

(S

harp

/van

der

Hei

jde

scor

e)

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, Br J Rheum 1998; 37: 23-33.

.

**

**: p <0,05

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

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

% F

ract

ures

-=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

“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: ↑

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.

Glucocorticoids reduce inflammation and as such improve glucose metabolism.

Same holds also for • osteoporosis • cardiovascular risk • …….. Buttgereit, ARD 2011; 70:1881-3

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 vitamin D –  Bisphosphonates on indication

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 risk Start bisphosphonate low risk

1 – 3 years

Look for special circumstances

.

•  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

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

Left Right

shoulder

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)

)

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

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

Primary outcome – erosion score

•  Absolute erosion score after 2 years of treatment

cumulative %

Eros

ion

scor

e at

2yr

s

0

MTX + placebo MTX +

prednisone

10

20

50

20 40 60 80 100

Secondary outcome – clinical variables

time (months)

VAS

pain

(mm

, mea

n)

MTX + placebo MTX +

prednisone

10

20

30

50

60

0 6 12 18 24

40

*

•  Visual analogue scale of pain during trial

CRP during trial

time (weeks)

CR

P (m

ean)

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

AC

R re

spon

se (%

)

PRED PLAC PRED PLAC

2 years 1 year

•  ACR20/50/70 response

*

*

*

*

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

*

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)

sBM

D (g

/cm

2 )

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)

sBM

D (g

/cm

2 )

2 years 10 mg prednison versus placebo: all patients Ca,Vit D and bisphosphonates

Patient meeting

Patients’ and rheumatologists’ perspectives on glucocorticoids

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

Doctors Patients

Patients’ and rheumatologists’ perspectives on glucocorticoids

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

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

( …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

•  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 indicated Osteoporosis: Monitoring indicated

yes no Monitoring in daily practice

Developing recommendations (example)

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-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

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

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

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

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 (in press)

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.

•  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#

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

Thank you for your attention