Falk-Symposium 153

Immunosuppression with tacrolimus, everolimus and

sirolimus

Dr. Klaus Fellermann, ZIM IRobert-Bosch-Hospital, Stuttgart

General issues of immunosuppression

• eligible: is everybody a good candidate• timing: for how long should we go• worthwile: impact on QOL• costs: does it save money

Cell cycle arrest at different stages of cell division

G0 G0 G1 Sstim

u li

resting T-cellearly activation

late activation

DNA synthesis

mitosis

OKT3ATG

CyAFK506

sirolimuseverolimus

MMFazathioprine

Calcineurin inhibitors – mode of action

Cyclosporine A in active Crohn´s disease controlled trials

n response (%) CyA-dose treatment

CyA placebo p (mg/kg) durat. (mo.) ster. (%)

Brynskov (1989) 71 59 32 0.03 5-7.5, p.o. 3 34Feagan (1994) 305 40 48 ns 5, p.o. 18 61Jewell (1994) 146 36 43 ns 5, p.o. 12 77Stange (1995) 182 35 27 ns 5, p.o. 4 100

Brynskov JewellStange

total 1.39 [0.67;2.9]

Peto Odds Ratio[95% CI]

0,1 1 10 100

Fellermann et al., Inflamm Bowel Dis 2003; 9:198

Outcome following colectomy/IPAA for UC

1 yr. 2 yr. 10 yr.

pouchitis 18 % 48 %

2nd attack 64 %

pouch failure 2 % 9 %

occasional 19 % 25 %incontinence

sexual dysfunction 14 % 8 %

Meagher et al., Br J Surg 1998; 85:803

Need for cyclosporine A

3rd day of i.v. treatment: > 8 bowel movements/d or 3<x<8 bowel movements/d

and CRP > 45 mg/L

85 % risk of colectomy

Predictors of failure to intensive intravenous treatment

Travis et al., Gut 1996; 38:905

Need for cyclosporine A

Carbonnel et al., Aliment Pharmacol Ther 2000; 14:273

2 out of 1. attack lasting > 6 weeks2. severe endoscopic lesions3. Truelove Witts criteria (dichotomized)

75-86 % risk of failure

Predictors of failure to intensive intravenous treatment

CyA vs. colectomy/IPAA

Hyde et al., Dis Col Rectum 2001; 44:1436

surgical major 24 % 15.8 %minor 16 % 5.2 %

medicalmajor 8 % 10.5 %minor 20 % 31.6 %

no mortality, no opportunistic infections

no CyA CyA(n=25) (n=19)

Colectomy and ileostomy -perioperative complications

QOL with CyA vs. colectomy/IPAA

• no differences in IBDQ, VAS, Örelandscore

• fewer bowel movements in CyA patients• higher demand for medication in CyA

patients• higher rate of unplanned hospitalization in

IPAA patients

Cohen et al., Inflamm Bow Dis 1999; 5:1

Cyclosporine A plus azathioprine in steroidrefractory ulcerative colitis

0

25

50

75

100

short term long term

rem

issi

on (%

)1985-1992 1993-2000

Lichtiger et al., Gastroenterology 2001; 120:A626

Cyclosporine A

Cyclosporine A vs. methylprednisolone for severe ulcerative colitis

D´Haens et al., Gastroenterology 2001; 120:1323

0369

121518

acute 6 mo. 12 mo.pa

tient

s (n

)0369

121518

acute 6 mo. 12 mo.

patie

nts

(n)

Methylprednisolone Cyclosporine A

remission no response or relapse

Cyclosporine A

Arts et al., Inflamm Bowel Dis 2004; 10:73

Cyclosporine A

Cyclosporine A plus azathioprine insteroidrefractory ulcerative colitis

early colectomy in 14/86, late colectomy in 18/72CyA i.v. 2-4 mg/kg/d levels 250-450 ng/ml

p.o. 8 mg/kg/d levels 150-250 ng/ml

long term no colectomy colectomy

n 54 18

i.v. duration (d) 8.9 +/- 1.7 9.2 +/- 1.8levels (ng/ml) 307 +/- 63 360 +/- 66

p.o. duration (d) 118 +/- 47 85 +/- 39levels (ng/ml) 193 +/- 56 185 +/- 52

Arts et al., Inflamm Bowel Dis 2004; 10:73

Cyclosporine A

Cyclosporine A plus azathioprine insteroidrefractory ulcerative colitis

months since i.v. CyA0 6 12 18 24 30pr

obab

ility

to a

void

col

ecto

my

(%)

0

20

40

60

80

100

pat. at risk

86 45 33 21 13

months post i.v. CyA0 6 12 18 24 30 36 42re

spon

ders

kee

ping

rem

issi

on (%

) 0

20

40

60

80

100

pat. at risk

54 34 12 5

limitations: 3 deaths (3.5 %) due to infections (aspergillosis, pneumocystis)

Cyclosporine A in ulcerative colitislong term experience

Campbell et al., Eur J Gastroenterol Hepatol 2005; 17:79

Cyclosporine A

early colectomy in 20/76, late colectomy in 24/56CyA i.v. 4 mg/kg/d levels < 300 ng/ml

p.o. 5 mg/kg/d levels 150-300 ng/mlmedian follow up 2.9 yrs.

Need for cyclosporine A

Cohen et al., Am J Gastroenterol 1999; 94:1587

Maintenance of CyA response –Role for AZA/6-MP

months0 6 12 18 24 60 70

prob

abili

ty o

f av

oidi

ng c

olec

tom

y (%

)0

20

40

60

80

100

CyA alone

CyA + AZA/6-MP

all

• 42 patientsimmediate response 86%sustained response 62%

• addition of AZA/6-MP in 77%delayed surgery by 7 months

• eventual outcomeof intial responderssurgical 50% AZA/6-MPnon-surgical 77% AZA/6-MP

Need for cyclosporine A

Doménech et al., Aliment Pharmacol Ther 2002; 16:2061

Omitting oral CyA bridging –Role for AZA/6-MP

• 27 patientsimmediate response 75%

• addition of AZA/6-MP 2-2.5 mg/kg

• median time to flare12 months overall ¾ relapsedcolectomy 55%

months0 12 24 36 48 60 72 84

cum

ulat

ive

prob

abili

ty (%

)

0

20

40

60

80

100

flare up

colectomy

2 vs. 4 mg/kg cyclosporine A for acute severe ulcerative colitis

van Assche et al., Gastroenterology 2003; 125:1025

Cyclosporine A

2 mg/kg (1.82 +/- 0.32), blood levels 150-250 ng/ml 4 mg/kg (2.65 +/- 0.47), blood levels 250-350 ng/ml

0

20

40

60

80

100

1 2 3 4 5 6 7 8

days

resp

onde

rs (%

)

2 mg/kg4 mg/kg

Low-dose cyclosporine A for acute severe ulcerative colitis

Rayner et al., Aliment Pharmacol Ther 2003; 18:303

Cyclosporine A

31 patients

immediate 24 (77%) responders 7 (23%) colectomies

10 (32%) eventualcolectomies

sustained 14 (45%) responders 17 (55%) failures

i.v. 2 mg/kg, blood levels 100-300 ng/mlp.o. 5 mg/kg, blood levels 100-200 ng/ml

Oral microemulsion cyclosporine A in steroidrefractory ulcerative colitis

Actis et al., Am J Gastroenterol 2000; 95:830

Cyclosporine A

20 patients

immediate 18 (90%) responders 2 (10%) colectomies

4 (22%) eventualcolectomies

2 (11%) failure/drop out

sustained 12 (60%) responders 8 (40%) failures

5 mg/kg Neoral, trough levels 200 ng/ml, 3 months

Metaanalysis on cyclosporine A in ulcerative colitis

Shibolet et al., Cochrane database of systematic reviews 2005; CD 004277

Cyclosporine A

Limited data, though encouraging

... nothing new on the planet

Sandborn et al., Gastroenterology 2003; 125:380

Tacrolimus (FK506)

FK506 in fistulizing Crohn´s disease

Oral FK506 is effective for improving fistula drainage but not for remission ????

48 patients, placebo controlled10 weeks, 0.2 mg/kg/d FK506 p.o.

FK506 plac. p

improvement 43 % 10% 0.004

remission 10 % 8 % 0.86

follow-up [months]0 6 12 18 24 30 36 42 48 54

cole

ctom

y fr

ee [%

]

0

20

40

60

80

100

14 pat.• FK506 dose

0.2 mg/kg p.o. for 2-3 Mo

• FK506 levelsinitial 10-15 ng/mlfinal 5-10 ng/ml

6-MP after 4-6 wk.1-1.5 mg/kg

Lichtiger scoreno renal impairment

FK506 for severe ulcerative colitis in childhood

Bousvaros et al., J Pediatr 2000; 137:794

FK5066-MP

Tacrolimus (FK506)

FK506 plus azathioprine for treatment resistent ulcerative/ind. colitis

0

10

20

30

40

0 14 28 90 180

patie

nts

(n)severe moderate mild colectomy

days

Fellermann et al., Inflamm Bow Dis 2002; 8:317

Tacrolimus (FK506)

Colectomy free survival

time of follow up (days)0 200 400 600 800 1000

Col

ecto

my

free

(%)

0

20

40

60

80

100

time (days) 180 360 540 720 900pat. at risk 27 17 15 12 8

Colectomy free survival (i.v. vs. p.o.)

time of follow up (days)0 180 360 540 720

Col

ecto

my

free

(%)

0

20

40

60

80

100

i.v.p.o.

pat. at risk 14 11 10 9 13 6 5 3

Fellermann et al., Inflamm Bow Dis 2002; 8:317

Tacrolimus (FK506)

FK506 plus azathioprine for treatment resistent ulcerative/ind. colitis

Oral FK506 as rescue in severe and refractory inflammatory bowel disease

Tacrolimus (FK506)

Baumgart et al., Aliment Pharmacol Ther 2003; 17:1273

31 patients (6 CD, 23 UC)median treatment 12 mo., 0.1 mg/kg/d FK506, trough levels 4-6 ng/ml

response 90 % remission 65 %steroid taper 83 %

Högenauer et al., Aliment Pharmacol Ther 2003; 18:415

9 UC patientsmedian treatment 15 weeks, 0.15 mg/kg/d FK 506, trough levels 10-20 ng/ml

response 89 % remission 67 %

Randomized dose finding study of oral FK506 in refractory ulcerative colitis

Tacrolimus (FK506)

2 weeks, 63 patients, trough level high 10-15 ng/ml

low 5-10 ng/ml

DAI score at week 2(0-12) high low plac.

complete (0) 0 0 0partial (red. >4) 13 (68%) 8 (38 %) 2 (10%)none 6 (32 %) 13 (62 %) 18 (90 %)

remission (<3) 20 % 11 % 6 %mucosal healing 78 % 44 % 13 %

no difference at week 2+10 (open label)Ogata et al., Gut in press

Any new kids on the block ?

... talk about wishful thinking

New goal – mTOR

Everolimus/Sirolimus

inhibition of p70 S6 kinase, binding to FKBP12

block growth factor mediated proliferation

cell cycle arrest at G1

Everolimusapproved for renal and cardiac transplantationefficacy: equal to MMF in renal Tx

superior to Aza in cardiac Tx

less CMV infections, reduced graft vasculopathy

Sirolimusapproved for renal transplantation

Adverse event profile

Hyperlipidemia (30-40 %)creatinine elevation (CYP3A4)

future: calcineurin inhibitor reduction/withdrawalsteroid replacement

Everolimus

tested negative in chronic active Crohn´s disease

... Wrong dose ? Wrong indication ? Wrong comedication ?

Conclusion

Tacrolimus is a plausible alternative to cyclosporine in severe UC

Long term outcome is of major concern (QOL, costs)

No data on mTOR inhibitors