Sclérodermie systémique Pronostic

Pôle de Médecine Interne, Centre de référence pour les vascularites

nécrosantes et la sclérodermie systémique, hôpital Cochin, Assistance

publique-Hôpitaux de Paris, Paris

Université Paris Descartes, Inserm U1016, Institut Cochin, Paris

Luc Mouthon

Skin score

Visceral involvement

SYSTEMIC SCLEROSIS : EVOLUTION

Diffuse

Limited cutaneous

0 10 2 4 6 8

Raynaud’s syndrome

Kidney

ILD + PAH

Myositis

Bowell

ILD

PAH

Bowell

0 10 2 4 6 8 Years

Lung

Elements pronostiques (I)

The 9 years survival rate was 38% with severe visceral involvement

72% without visceral involvement (p < 0.001)

Steen V, Arthritis Rheum 2000: 2437

Éléments pronostiques (II)

• Les séries récentes montrent une diminution de la mortalité – survie à 10 ans de 80% à 92% dans les formes

limités

– survie à 10 ans de 62 à 76% dans les formes diffuses

• Cela semble en grande partie liée à l’amélioration des traitements à visée vasculaire

• Caractères péjoratifs d’une atteinte viscérale en particulier pulmonaires, cardiaques et rénales.

Mortalité

Pronostic de la sclérodermie systémique

Étude Patients Survie à 5 ans Survie à 10

ans

Farmer 1960 236 51%

Tuffanelli 1962 727 70% 59%

Bennett 1971 67 73% 40%

Medsger1971 309 60% 35%

Medsger1973 358 44%

Barnett 1978 113 70% 55%

Eason 1981 47 60% 42%

Wynn 1985 64 69% 51%

Giordano 1986 90 72% 32%

Altman 1991 264 63% 42%

Bulpitt 1993 48 68%

Wells 1994 68 85%

Seibold 2000 68 85%

Surmortalité liée à la ScS

Ferri et al, Medicine, 2002

Changes in causes of systemic sclerosis

related deaths between 1972 and 2001

Steen VD, Medsger T, Ann Rheum Dis 2007, Feb 28 EPub

Principales causes de décès

rapportées dans la littérature

Source N

décès

Imputé à la

ScS

HTAP/Pulm Infection Cardiaque ou

vasc

Cancer Dig Rein

Gouet (Gouet et al,

1986) 29 6,9% /

3,4%

3,4% 48,3% 13,8

%

10,3

%

Scussell-Lonzetti

(Scussel-

Lonzetti et al,

2002)

309 53% 15,1% 19,7

%

Jacobsen

(Jacobsen et al,

1998)

160 25,6% 6,3% /

1,9%

11,9% 30% 18,9

%

5,6% 10,6

%

Hesselstrand

(Hesselstrand et

al, 1998)

49 30,6% 20,4% 20,4% 24,5

%

8,2% 2%

Lee (Lee et al, 1992) 61 44,3% 32,8% 3,3% 23% 3,8% 6,6% 11,5

%

Kettaneh A, Sclérodermies, 2007

ScS diffuse et atteinte d’organe

Steen , Arthr Rheum 2000; 43: 2437-2444 2000

Autoanticorps

Survie à 10 ans des patients atteints de

ScS

- 93 % avec anticorps anticentromère

- 66 % avec Ac anti-Scl70

- 30 % chez les patients ayant des anti-

ARN polymérase.

Kuwana M, Arthritis Rheum 1994; 37: 75-83

Demographic and clinical factors associated

with in-hospital death among patients with

systemic sclerosis.

Data were obtained on all hospitalizations in South Carolina for patients who were ever hospitalized between 1996 and 2000 with a diagnosis of SSc.

Proportions of in-hospital deaths among blacks (23.0%) and others (27.7%) were higher than among whites (15.6%), a finding that remained after adjustment for other sociodemographic and clinical factors (black/white odds ratio: 1.70).

Black and other non-white patients with SSc appear to experience an elevated risk of death during their hospital stays.

Nietert PJ, J Rheumatol 2005

Race and association with disease manifestations and

mortality in scleroderma: a 20-year experience at the Johns

Hopkins Scleroderma Center and review of the literature (I).

Between 1990 and 2009, 409 African American and 1808 white patients with SSc were evaluated at a single university medical center.

African American patients presented to the center at a younger mean age than white patients (47 vs. 53 yr; p < 0.001).

Two-thirds of white patients manifested the limited cutaneous subset of disease, whereas the majority of African American patients manifested the diffuse cutaneous subset (p < 0.001).

The proportion seropositive for anticentromere antibody was nearly 3-fold greater among white patients, at 34%, compared to African American patients (12%; p < 0.001).

Nearly a third of African American (31%) patients had autoantibodies to topoisomerase, compared to 19% of white patients (p = 0.001).

Notably, African American patients experienced an increase in prevalence of cardiac (adjusted odds ratio [OR], 1.6; 95% confidence interval [CI], 1.3-2.2), renal (OR, 1.6; 95% CI, 1.2-2.1), digital ischemia (OR, 1.5; 95% CI, 1.4-2.2), muscle (OR, 1.7; 95% CI, 1.3-2.3), and restrictive lung (OR, 6.9; 95% CI, 5.1-9.4) disease.

Gelber AC et al, Medicine 2013

Race and association with disease manifestations and

mortality in scleroderma: a 20-year experience at the Johns

Hopkins Scleroderma Center and review of the literature (I).

• Overall, 700 (32%) patients died (159 African American; 541 white).

• Cumulative incidence of mortality at 10 years: 43% among African American patients vs 35% among white patients (log-rank p = 0.0011).

• Compared to white patients, African American patients experienced an 80% increase in risk of mortality (relative risk [RR], 1.8; 95% CI, 1.4-2.2), after adjustment for age at disease onset and disease duration.

• Adjustment by sex, disease subtype, SSc-specific autoantibody status, socioeconomic measures of educational attainment and health insurance status, diminished these risk estimates (RR, 1.3; 95% CI, 1.0-1.6).

• The heightened risk of mortality persisted in strata defined by age at disease onset, diffuse SSc, anticentromere seropositivity, decade of care at the center, and among women.

• These findings support the notion that race is related to a distinct phenotypic profile in scleroderma, and a more unfavorable prognosis among African Americans, warranting heightened diagnostic evaluation and vigilant care of these patients.

Gelber AC et al, Medicine 2013

Disease-related nutritional risk and mortality in systemic sclerosis

Single-centre prospective cohort study: 160 SSc patients (median age, 62 yr).

Nutritional risk assessed by the Malnutrition Universal Screening Tool (MUST), a screening tool that combines anthropometric parameters of nutritional status (body mass index [BMI] and percentage of unintentional weight loss [WL]) with the presence of an "acute disease" (disease activity score ≥3 according to Valentini's criteria).

Prevalence of high nutritional risk (MUST score ≥2): 24.4% [95%CI, 17.4-31.3].

Hazard analysis (median follow-up duration = 46 months [25th-75th percentile, 31-54]), high nutritional risk was significantly associated with mortality (HR = 8.3 [95%CI, 2.1-32.1]).

Performance of the model based on nutritional risk including disease activity (Harrell's c = 0.74 [95%CI, 0.59-0.89]) was superior to that based on active disease alone (HR = 6.3 [95%CI, 1.8-21.7]; Harrell's c = 0.68 [95%CI, 0.53-0.84]).

In SSc outpatients MUST significantly predicts mortality.

The combined assessment of nutritional parameters and disease activity significantly improves the evaluation of mortality risk.

Cereda E et al. Clin Nutr 2013

Pronostic en fonction du

type d’atteinte viscérale

• When major

visceral

involvement occurs

in scleroderma, the

outcome is poor

– Lung fibrosis

– Cardiac

involvement

– Renal insufficiency

– Pulmonary

hypertension

SYSTEMIC SCLEROSIS

Ferri et al, Medicine, 2002

Severe organ involvement in SSc with diffuse scleroderma

Steen VD, Medsger T, Arthr Rheum 2000; 43: 2437-2444

Pronostic: l’atteinte cutanée proximale et la

rapidité d’installation sont les éléments

pronostiques importants

Ferri et al, Medicine, 2002

Shand L, et al. Arthritis Rheum 2007; 56:2422-31.

Disease duration and skin score in

dcSSc

Change in skin score over 3 years in the subgroups Survival in the subgroups

High baseline/improvers

Disease duration

12 24 36 10

20

30

40

50

Low

baseline/improvers

High baseline/non-improvers

mR

SS

High baseline/

improvers, n = 40

Low baseline/

improvers, n = 67

252 180 108 36 0

20

40

60

80

100

p=0.003

High baseline/

non-improvers, n = 24 C

um

ula

tive s

urv

ival

(%)

Disease duration

Koh et al. Br J Rheumatol 1996;35:989-93.

0

10

20

30

40

50

60

70

80

90

100

0 1 2 3 4 5 6 7 8 9 10 11 12 13

Délai depuis le diagnostic (ans)

Surv

ie (

%)

HTAP

Poumon

(sans HTAP)

Aucun

SURVIE DES PATIENTS ATTEINTS DE SCLÉRODERMIE

Steen V, Arthritis Rheum 1994. 37:1283.

PRONOSTIC DE LA FIBROSE PULMONAIRE

100

80

60

40

20

0 0 2 4 6 8 10

Durée en années

Survie (%)

1 3 5 7 9

Fibrose pulmonaire minime (n=467)

Fibrose pulmonaire modérée (n=213)

Fibrose pulmonaire sévère (n=116)

p < 0.01

Interstitial Lung Disease in Systemic Sclerosis

A Simple Staging System Goh NSL, AJRCCM 2008

Pronostic de la PID Le pronostic des PID de la ScS est meilleur que celui de la fibrose pulmonaire idiopathique

Wells, AJRCCM 1994;149:1583-90

Race noire et asiatique, sexe masculin, atteinte cardiaque et les formes précoces de Scs sont le plus souvent associées à une forme sévère de PID (Jacobsen S et al. Clin Rheumatol 1997;16:384-90) mais ces données ne sont pas confirmées par d’autres études

Peters-golden M et al. Medicine 1984;63:221-31

Les principaux éléments permettant de définir le pronostic des PID associées à la ScS sont:

-PID d’emblée sévère

-PID rapidement progressive définie par une perte de 10% de CVF/CPT ou 15% de DLCO en 1 an

-Le type histologique de la PID n’a pas démontré de valeur pronostique au cours de la ScS

Bouros et al. AJRCCM

Medsger, J Rheum 1996; 23: 639-427

Sclérodermie systémique et HTAP: pronostic

Medsger, J Rheum 1996; 23: 639-427

HYPERTENSION ARTÉRIELLE PULMONAIRE

100

80

60

40

20

0 0 2 4 6 8 10

Durée en années

Survie (%)

1 3 5 7 9

Sclérodermie limitée avec HTAP (n=61)

Sclérodermie diffuse

avec HTAP (n=15)

Comparison of survival in SSc-PAH and iPAH

Rubenfire M et al. Chest 2013

Comparison of survival in patients diagnosed prior to 2002 and after 2002

Rubenfire M et al. Chest 2013

3ème journée française de l’HTAP Paris – 20 et 21 Octobre 2005

Comparison of Survival in SSc in the “Modern Era”

Rubenfire M et al. Chest 2013

Survival of PAH-SSc versus ILD-PH-SSc

Mathai et al. A & R 2009

Outcomes in systemic sclerosis-related lung

disease after lung transplantation

• From 1998 to 2012, persons undergoing LT for SSc-LD were age and

gender matched in a 2:1 fashion to controls undergoing LT for nCTD-ILD.

• Survival was similar in 23 persons with SSc-LD and 46 controls who

underwent LT (P = 0.47).

• For the SSc-LD group, 1- and 5-year survival was 83% and 76% compared

with 91% and 64% in the nCTD-ILD group, respectively.

• There were no differences in bronchiolitis obliterans syndrome (P = 0.83).

Rates of acute rejection were less in SSc-ILD (P = 0.05).

• Esophageal dysfunction was not associated with worse outcomes (P>0.55).

• Persons with SSc-LD appear to have similar survival and bronchiolitis

obliterans syndrome as persons transplanted for nCTD-ILD. The risk of

acute rejection after transplantation may be reduced in persons with SSc-

LD. Esophageal involvement does not appear to impact outcomes.

Sottile PD et al. Transplantation 2013

CARDIAC INVOLVEMENT

Steen V, Arthritis Rheum 1996: 39:677

Crise rénale sclérodermique :

Étude rétrospective multicentrique

0 10 20 30 40 50 60 0

25

50

75

100

Sans dialyse Avec dialyse

Suivi (mois)

Pro

bab

ilit

é (

%)

Teixeira et al, ARD 2008

3ème journée française de l’HTAP Paris – 20 et 21 Octobre 2005

Factors predictive of renal crisis

Diffuse skin involvement

Rapid progression of skin thickening

Disease course < 4 years

Anti-RNA-polymerase III-antibodies

Newly manifested anaemia

Newly manifested cardiac involvement

Pericardial effusion

Heart insufficiency

Previous high-dose CS therapy

Steen VD. Am J Med 1984; 76:779-86.

Steen VD. Rheum Dis Clin North Am 2003; 29:315-33.

Pronostic des crises rénales

sclérodermiques

Steen et

al. (2)

Walker et

al. (6)

DeMarco

et al. (5)

Penn et

al. (8)

Teixeira

et al.

(7)

Guillevin

et al. (67)

Hudson

et al.

(65).

No. of patients

Dialysed patients,

%

Temporarily, %

Permanently, %

Died while on

dialysis, %

Deceased at 5

years, %

195

43

23

19

ND

19*

16

31

6

25

ND

31

18

ND

ND

ND

ND

50

110

64

23

42

18

41

50

56

16

22

18

31

91

54

14

39

26

40

75

53

ND

25 (at

one

year)

ND

36**

Mouthon et al. Revision - 2014

Mesure de l’activité de la

ScS

Index Européen d’activité globale de la

sclérodermie systémique (Valentini 2003)

Item Score

Score modifié de Rodnan > 14 1

Scléroedème 0,5

Delta – peau 2

Nécroses digitales 0 ,5

Delta – vasculaire 0,5

Arthrites 0,5

DLCO < 80% 0,5

Delta – cœur & poumons 2

Vitesse de sédimentation > 30 mm 1° h 1,5

Hypocomplémentémie 1

Total maximum 10

Organes Stade 0

(normal)

Stade 1

(discret)

Stade 2

(modéré)

Stade 3

(sévère)

Stade 4

(terminal)

Etat

général

Perte de poids

< 5%

Hématocrite >

37%

Hb > 12,2 g/dl

Perte de poids = 5

-10%

Hématocrite = 33 -

37%

Hb = 11 - 12,2 g/dl

Perte de poids =

10-15%

Hématocrite= 29-

32%

Hb = 9,7 – 10,9

g/dl

Perte de poids=

15-19%

Hématocrite = 25-

28%

Hb = 8,3-9,6 g/dl

Perte de poids

>20%

Hématocrite <

25%

Hb < 8,3 g/dl

Vasculaire

périphé

rique

Raynaud absent

ou ne

requérant

pas de

traitement

Raynaud requérant

un traitement

vasodilatateur

Cicatrices

pulpaires

ponctuelles

Ulcérations

digitales

Gangrène

digitale

Peau Score de

Rodnan

modifié = 0

Score de Rodnan

modifié = 1-14

Score de Rodnan

modifié = 15-

29

Score de Rodnan

modifié = 30-

39

Score de

Rodnan

modifié >

40

Articulation

s et

tendon

s

Distance index-

paume <

0,9 cm

Distance index-

paume = 1 -1,9

cm

Distance index-

paume = 2-3,9

cm

Distance index-

paume = 4 –

4,9 cm

Distance index-

paume > 5

cm

Muscles Force

musculaire

proximale

normale

Force musculaire

proximale peu

altérée

Faiblesse

musculaire

proximale

modérée

Faiblesse

musculaire

proximale

sévère

Nécessité

d’aides

pour

déambuler

Echelle de sévérité de la ScS par organes, révisée (Medsger 2003)

Echelle de sévérité de la ScS par organes, révisée (Medsger 2003)

Organes Stade 0 (normal) Stade 1

(discret)

Stade 2

(modéré)

Stade 3

(sévère)

Stade 4

(terminal)

Tube

digestif

Radiographies

oeso-

gastriques et

du grêle

normales

Hypopéristaltisme

du bas

œsophage et

anomalies du

transit du grêle

Nécessité

d’antibiotique

s pour

pullulation

microbienne

Malabsorption,

épisodes de

pseudo-

obstruction

Nécessité

d’hyperali

mentation

artificielle

Poumons DLCO > 80%

CVF > 80%

Pas de fibrose à

la

radiographie

pulmonaire

PAPs<35 mm

Hg

DLCO = 70-79%

CVF = 70 - 79%

Râles crépitants

des bases

Fibrose visible à la

radio

pulmonaire

PAPs=35-49 mm

Hg

DLCO = 50-69%

CVF = 50-69%

PAPs= 50-64 mm

Hg

DLCO < 50%

CVF < 50%

PAPs> 65 mm Hg

Nécessité d’une

oxygénothé

rapie

Cœur ECG normal

Fraction

d’éjection

>50%

ECG défaut de

conduction

Fraction

d’éjection = 45-

49%

ECG arythmies

Fraction

d’éjection =

40-44%

ECG arythmies

requérant un

traitement

Fraction

d’éjection =

30-40%

Insuffisance

cardiaque

Fraction

d’éjection <

30%

Reins Pas de crise

rénale

Créatininémie<

13mg/l

Crise rénale avec

créatininémie <

15 mg/l

Crise rénale avec

créatininémie

= 15-24 mg/l

Crise rénale avec

créatininémie

= 25-50 mg/l

Crise rénale

avec

créatininém

ie > 50 mg/l

ou nécessité

de dialyse