Raynaud et ulceres

Nouveaux traitements du syndrome de Raynaud et des ulcères digitaux des connec6vites Pr Yannick Allanore Rhumatologie A, Hôpital Cochin, Université Paris Descartes

Raynaud & Ulcères dans les Connec6vites 1. Généralités sur le syndrome de Raynaud 2. Traitements du Raynaud 3. Traitements des ulcères digitaux

Raynaud & Ulcères dans les Connec6vites 1. Généralités sur le syndrome de Raynaud 2. Traitements du Raynaud 3. Traitements des ulcères digitaux

RAYNAUD SECONDAIRE 1. Signes d’accompagnement 2. Age de début 3. Auto-Anticorps 4. Capillaroscopie

Signes associés Examen clinique • Dermatologie – Doigts boudinés – Télangiectasies – Troubles pigmentaires – Ulcères – Calcinose

• Rhumatologie – Canal carpien – Arthrites

Transi6on d’un Raynaud primaire vers forme secondaire 639 patients avec RP; suivi 2531 patient-années: apparition CTD dans 12,5 % cas, moy. 3 pour 100 patientannée (Spencer-Green et al, 1998) • Age, decennies

N=236

• Age de début PR (decennies) • Durée PR

1.10 (0.82-1.47);0.533 2.59 (1.40-4.80);0.003

0.87 (0.81-0.94);<0.001

Début du PR à 40 ans ….secondaire Début du PR à 20 ans ….. primaire

≈ 20% de transition sur 10 ans Hirschl Arthritis & Rheum 2006

Auto anticorps

TRANSITION RP VERS SCS Etude rétrospective à partir de 768 sujets avec PR isolé 288 ont données complètes: 49,8 ans, 255 femmes, 44% anticorps +, Suivi médian 24 mois (2-96 mois): • 34 transition vers ScS • 11 polyarthrite rhumatoïde • 3 lupus • 2 myopathies inflammaotires • 1 Sharp • 25 connectivites indiférenciées Ingegnoli et al, Rheumatology 2010

Devenir des syndromes de Raynaud Predicteur

N° de patients

SSc à 5 ans

SSc à 10 ans

SSc fin du suivi

Capillaroscopie N et auto-Ac neg

446

6 (1,3)

7 (1,6)

8 (1,8)

Capillaroscopie aN et auto Ac neg

31

7 (22.6)

7 (22.6)

8 (25.8)

Capillaroscopie N mais Auto-Ac pos

65

14 (21.5)

21 (32.3)

23 (35.4)

Capillaroscopie aN + auto-Ac

44

29 (65.9)

32 (72.7)

35 (79.5)

Total

586

56 (9.5)

67 (11.4)

74 (12.6)

<0.0001

<0.0001

<0.0001

P

Koenig et al, A&R 2008;58:3902-3912

1,6% Ă 10 ans

22,6% Ă 10 ans

32,3% Ă 10 ans

72,7% Ă 10 ans

Histoire naturelle ScS UCTD

Pré-ScS

ScS

Fibrose avérée

Raynaud & Ulcères dans les Connec6vites 1. Généralités sur le syndrome de Raynaud 2. Traitements du Raynaud 3. Traitements des ulcères digitaux

Système nerveux central Norépinéphrine Neuropeptides

Nerfs périphériques

Vasodilatateurs Monoxyde d’azote Prostacyclines

CML

Vasoconstricteurs

α2 adrénorecepteurs Endothéline-1

Cell Endo.

Cell sanguines

Thromboxane

Plaquettes Sérotonine

Méta-­‐analyse Inhibiteurs calciques: Raynaud primaire

FIG. 1. Calcium channel blockers vs placebo. Frequency of RP attacks over a 1-week period.

FIG. 2. Calcium channel blockers vs placebo. Frequency of RP attacks over a 1-week period (two trials removed due to heterogeneity). indicated on a 5-point scale, with a WMD of !1.04 [!1.51, !0.56], with placebo aNifedipine nd Pope. compared Rheumatology 2005;44:145–150 P ¼ 0.0015 (Fig. 4). Clinically this can again be viewed Thomson approxiThe results obtained in the large subset of trials comparing mately as a 33% reported improvement in ischaemic attacks.

Méta-­‐analyse Inhibiteurs calciques: Raynaud primaire 148

A. E. Thompson and J. E. Pope

FIG. 3. Calcium channel blockers vs placebo. Severity of RP attacks on a 10 cm visual analogue scale.

Thomson and Pope. Rheumatology 2005;44:145–150

channel blockers on digital skin temperature, patient/ physician global assessment, or prevention/healing of digital ulcers.

When the trial with nicardipine was removed

trial of nicardipine alone revealed no statistically significant reduction in the frequency or severity of ischemic attacks, although the results did favor nicardipine and the sample size was small (n # 15) (32).

Méta-­‐analyse Inhibiteurs calciques: Raynaud 2nd

Table 2. Results of studies of the effect of all calcium-channel blockers versus placebo on the frequency and severity of ischemic attacks in patients with systemic sclerosis–associated Raynaud’s phenomenon* Frequency of ischemic attacks Authors, year (ref.)

Treatment group, Placebo group, mean $ SD (n) mean $ SD (n)

Ettinger et al, 1984 (29) Kahan et al, 1983 (30) Kahan et al, 1985 (31) Kahan et al, 1987 (32) Rodeheffer et al, 1983 (34) Thomas et al, 1987 (35)

29.00 $ 29.05 (8) 20.80 $ 32.26 (10) 20.58 $ 16.48 (7) 25.80 $ 17.35 (15) 13.11 $ 15.20 (9) 18.20 $ 22.13 (9)

36.60 $ 25.85 (8) 56.20 $ 30.99 (10) 36.00 $ 11.82 (7) 30.60 $ 14.00 (15) 15.00 $ 12.57 (9) 22.40 $ 22.13 (10)

Total

(58)

(59)

Weight, % 7.0 6.6 19.5 30.0 24.7 12.1 100.0

Severity of ischemic attacks WMD (95% CI) %7.60 (%34.55, 19.35) %35.40 (%63.13, %7.67) %15.42 (%30.44, %0.40) %4.80 (%16.08, 6.48) %1.89 (%14.78, 11.00) %4.20 (%24.13, 15.73) %8.31 (%15.71, %0.91)

Treatment group, Placebo group, mean $ SD (n) mean $ SD (n)

3.58 $ 2.08 (7) 1.93 $ 0.80 (15) %1.33 $ 1.00 (9)

6.31 $ 1.57 (7) 2.20 $ 0.41 (15) %0.66 $ 0.71 (9)

(31)

(31)

Weight, %

WMD (95% CI)

18.6

%1.39 (%2.60, %0.18) %0.41 (%1.14, 0.31) %0.74 (%1.70, 0.23)

52.0 29.4

100.0

%0.69 (%1.21, %0.17)

* For frequency of ischemic attacks, !2 # 6.00, 5 degrees of freedom (df), P # 0.31 in the test for homogeneity, and Z # 2.20, P # 0.03 in the test for overall effect. For severity of ischemic attacks, !2 # 1.84, 2 df, P # 0.4 in the test for homogeneity, and Z # 2.59, P # 0.01 in the test for overall effect. WMD # weighted mean difference; 95% CI # 95% confidence interval (random-effects model).

ARTHRITIS & RHEUMATISM Vol. 44, No. 8, August 2001, pp 1841–1847 © 2001, American College of Rheumatology Published by Wiley-Liss, Inc.

Bosentan et Raynaud’s Single-­‐centre, randomized, prospec4ve, double-­‐blinded. 16 pa4ents received either 62.5mg bosentan twice daily for 4 weeks, followed by 125mg twice daily for 12 weeks or matching doses of placebo.

Nguyen et al. Rheumatology 2010;49:583–587

NOS L-arginine

L-citrulline °NO

Endothelial cells

°NO

PDE5 inhibitors Guanylate cyclase

Smooth muscle cells

GTP

cGMP

PDE5

PKG

Vasorelaxation

Proliferation

5’GMP

Figure 2. Symptoms of the 16 study patients with secondary Raynaudâ&#x20AC;&#x2122;s phenomenon while taking sildenafil and placebo.

Fries R et al. Circulation 2005;112:2980-2985

Copyright Š American Heart Association

Figure 6. Blood pressure (BP) and heart rate during treatment with placebo and sildenafil in the study patients (n=18). bpm indicates beats per minute.

Fries R et al. Circulation 2005;112:2980-2985

Copyright Š American Heart Association

PDE5-­‐Inhibitors

Agarwal (2010) Caglayan (2012) Fries (2005) Herrick (2011) Schiopu (2009) Shenoy (2010) Total (95% CI)

Placebo

Mean

SD

N

Mean

SD

N

3.4

2.44

27

4.3

2.75

26

3.16 2.2 2.8 2.43 3.86

1.94 1.6 2.04 2.01 2.25

47 16 20 39 24

3.45 3.0 2.6 2.53 5.2

2.15 2.0 2.35 2.22 2.59

173

Weight

Mean Difference IV, Fixed, 95%CI

47 16 25 39 24

4.3% 36.7% 16.3% 5.0% 25.1% 12.6%

-­‐0.90 [-­‐2.27, 0.47] -­‐0.29 [-­‐0.76, 0.18] -­‐0.80 [-­‐1.51, -­‐0.09] 0.20 [-­‐1.07, 1.47] -­‐0.10 [-­‐0.67, 0.47] -­‐1.34 [-­‐2.14, -­‐0.54]

177

100.0%

-­‐0.46 [-­‐0.74, -­‐0.17]

Heterogeneity: Chi² = 8.97, df = 5 (P = 0.11); I² = 44%

Test for overall effect: Z = 3.16 (P = 0.002)

Raynaud Condi6on Score

-­‐4 -­‐2 0 2 4

Favours PDE-­‐5 Inhibitors

Favours Placebo

Rous%t et al, Ann Rheum Dis, in press

PDE5-­‐Inhibitors Agarwal (2010) Caglayan (2012) Fries (2005) Herrick (2011) Schiopu (2009) Shenoy (2010) Total (95% CI)

Placebo

Mean Difference

Mean

SD

N

Mean

SD

N

Weight

1.92 2.44 1.25 2.67 2.08 2.29

1.56 1.67 2.0 1.68 1.72 1.42

27 47 16 20 39 24

2.84 2.89 1.86 2.75 2.1 3.37

1.89 1.91 2.56 2.0 1.78 1.86

26 47 16 25 39 24

5.3% 30.1% 27.3% 4.0% 20.9% 12.5%

-­‐0.92 [-­‐1.85, 0.01] -­‐0.44 [-­‐0.83, -­‐0.05] -­‐0.61 [-­‐1.02, -­‐0.20] -­‐0.08 [-­‐1.16, 1.00] -­‐0.02 [-­‐0.49, 0.45] -­‐1.08 [-­‐1.69, -­‐0.47]

177

100.0%

-­‐0.49 [-­‐0.71, -­‐0.28]

173

IV, Fixed, 95%CI

Heterogeneity: Chi² = 9.21, df = 5 (P = 0.10); I² = 46%

Test for overall effect: Z = 4.47 (P < 0.0001)

Daily frequency of RP alacks

-­‐3 -­‐2 -­‐1 0 1 2 3

Favours PDE-­‐5 Inhibitors

Favours Placebo

Rous%t et al, Ann Rheum Dis, in press

PDE5-­‐Inhibitors Agarwal (2010) Caglayan (2012) Fries (2005) Herrick (2011) Schiopu (2009) Shenoy (2010) Total (95% CI)

Placebo

Mean Difference

Mean

SD

N

Mean

SD

N

Weight

19 40.86 20.75 40.05 40.61 33.81

20.78 54.86 19.0 38.82 63.81 38.6

27 47 16 20 39 24

67 54.4 37.3 50.6 47.0 54.89

107.1 69.24 35.0 67.4 77.6 55.5

26 47 16 25 39 24

1.8% 25.9% 29.3% 3.7% 17.1% 22.2%

-­‐48.00 [-­‐89.90, -­‐6.10] -­‐10.54 [-­‐21.59, 0.51] -­‐16.61 [-­‐27.00, -­‐6.22] -­‐10.55 [-­‐39.98, 18.88] -­‐6.39 [-­‐19.97, 7.19] -­‐21.08 [-­‐33.02, -­‐9.14]

177

100.0%

-­‐14.62 [-­‐20.25, -­‐9.00]

173

IV, Fixed, 95%CI

Heterogeneity: Chi² = 5.71, df = 5 (P = 0.34); I² = 12%

Test for overall effect: Z = 5.1 (P < 0.0001)

Daily dura6on of RP alacks (min)

50 0 50

Favours PDE-­‐5 Inhibitors

Favours Placebo

Rous%t et al, Ann Rheum Dis, in press

11.9 " 7.9

The average time to reach the minimum digital skin temperature (i.e., cold challenge mean duration) was shortest for those on the placebo treatment followed by

Fasudil, a RhoA/Rho kinase signaling pathway inhibitor

1.38

4 (33)

were taking calciumrently on oral silde-

estimated right sysardiogram performed atients).

1 ! Raynaud’s pheng scars, 3 ! active angrene.

outcomes). Tukey’s re completed using int as the outcome, nt as the predictor. ow measurements. ay analyses of varierences in time to drop from baseline

d-measures tests to digital skin temperpoint across treatared the mean digFava flow et al. across Arthri%s Care Res (Hoboken). 2012;64(6):925-­‐9. blood

Raynaud & Ulcères dans les Connec6vites 1. Généralités sur le syndrome de Raynaud 2. Traitements du Raynaud 3. Traitements des ulcères digitaux

or biochemical variables that could be attributed to

either drug.

Iloprost et Nifedipine

confidence intervals) from mean baseline in number and characteristics of attacks of Raynaud's phenomenon in patients with systemic sclerosis after infusion of iloprost and during treatment with nifedipine TABLE I-Mean percentage change (95%

Assessments higher for those

No of weeks

No of attacks:

Iloprost

Nifedipine Duration of attacks:

Iloprost

4

8

12

16

-21 6

-42-4

(-41-9 to - 10-5)

-26-2

-21-9 (-46-8 to 3- 1) -12-2 (-27-2 to 2-7)

(-75-4 to -9-5) -23-1 (-45-9 to -0-4)

-55-4 (-84 5 to 26-2) -41 5 (-71-7 to - 1 1-2)

-21-0

-16-6

-36-9

-46-8

(-49-0 to 5-8)

sclerosis after infusio as measured by veno (top); laser Doppler pulse amplitude (b analysed at each data

receiving ilopros baseline were u Figure 1 shows t was increased f ficantly reduced overall differenc cant. Microcircu increased from b was significant circulatory flow baseline. The in iloprost was acco temperature. Il

(-56-9 to - 16-9) to -7-9) (-36-5 3-2) number, sures, and paronychia) before and during(-34-0Table I shows that thetomean duration, and (-70-8 to -22-8) -44-7 -25-7 12-7 -1-41 Nifedipine and by measurement of blood flow and severity of attacks of Raynaud's phenomenon was to -27-8) (-41-9 to (-61-6 to (-62-1 to (-69-0 94-3) 59-3) -9-5) e in a room in which temperature and reduced by both drugs. Half of the patients in each of attacks: Severity ere controlled (23-25° C, 30-40%).: Blood group symptoms had improved, -34-6 -6-9 -28-5 and -10-7thought that their Iloprost forearm and digits (1min/kg of tissue) was(-20-3 onetopatient that tothey had (-63-5 to -5-8) - 1 1) in each (-24-5group to 11-5)thought(-47-3 -9-8) by venous occlusion and strain gauge become -- 31-5 16-2shows that both- drugs 16-0 con-21-8 worse. Table- II Nifedipine raphy, and microcirculatory flow was(-30-2 the siderably reduced mean skin number of (-28-0 to -4-5) (-32- lesions.

(-52-6 to -10 3) to -13 3) to05) n the finger pulp by laser Doppler flowby photoplethysmography.7 Mean hand TABLE iI-Mean (SE) number of skin lesions in patients with e was measured with an AGA 680 thermo- Raynaud's phenomenon associated with systemic sclerosis before and stem with an integrator.9 Measurements during treatment with intravenous iloprost or oral nifedipine 562mild cold stress to both for 15 minutes after No of weeks r at 20° C for one minute).

0 4 8 12 16 essure was recorded as the average of three nts made with a Hawksley random zero 3-5(16) 0-5(0-2) 04(0 2)* 0-4(0-3) 0-6(0-3) nometer at each laboratory visit. Peri- Iloprost Nifedipine 4 3(0 8) 1-0(0-4) 1-3(0-4) 1-1 (0-6) 1-4 (0-5) ular resistance was calculated by dividing terial blood pressure by the blood flow. 0 Duncan multiple range test p<0-01 for both treatments at 4, 8, 12, and 16 weeks. plot analysis (F test) for repeated measure- *p=0.04 Compared with patients receiving nifedipine. used for the statistical analysis of absolute m baseline with time. Comparisons were Cooke et al. Br Med J 1989;298:561-­‐4 aseline measurements with either Student's

B

Bosentan and DU: RAPIDS-­‐1 (16 weeks; n=122) -61%; p=0.01 -48%; p=0.0083 -38%; p=NS

Korn et al, ArthriMs Rheum. 2004;50:3985-­‐93

RAPIDS 2 study: Seibold et al, ARD2010 § Design: N=188, inclusion: au moins 1 ulcère ac6f récent ou 1 ulcère « cardinal » § Résultats: • Cicatrisa6on: pas de différence: complète dans 36,8% (BOS) vs 39,3% • Nouveaux ulcères: 1,9±0,2 (BOS) vs 2,7±0,3 (p=0,035) • sHAQ: pas de différence – Améliora6on “dressing” à 24s – Améliora6on “pain” à 12 semaines

• Transaminases > 3N: 10,5 vs 1,1%

RAPIDS-2

RAPIDS2

Matucci-­‐cerinic, Ann Rheum Dis. 2011;70:32-­‐8

RAPIDS-2

Effect of sildenafil on digital ulcers in systemic sclerosis: analysis from a single centre pilot study Brueckner et al, ARD 2010

Tadalafil & secondary Raynaud (n=25) cross over 6 weeks

Secondary outcome: healing of 24/24 DU during TADA versus 3/13 during PBO period Shenoy et al, Rheumatology (Oxford). 2010;49:2420-­‐8

Prévention des lésions vasculaires par le Quinapril RCT multicentrique, 80 mg/j, 210 patients, SSc-CL ou Raynaud + auto-Ac, durée 2-3 ans.

Gliddon et al. ArthriMs Rheum. 2007;56:3837-­‐46

Conclusion ü Raynaud primaire: bénin ü Raynaud secondaire: fenêtre d’opportunité vers les connec6vites et sclérodermie ü Traitements: – Première ligne: an6-­‐calciques – Seconde ligne: an6-­‐endothéline, inhibiteurs de phosphodiesterase 5 et prostacyclines