VASCULAR COMPLICATIONSOF SYSTEMIC SCLEROSIS

Future Directions in Treatment of Systemic Sclerotic Complications

Janet Pope, MDProfessor

Division of RheumatologySt. Joseph’s Health Centre

University of Western Ontario, LondonLondon, Ontario, Canada

VASCULAR COMPLICATIONSOF SYSTEMIC SCLEROSIS

DISCLOSURE STATEMENT

Janet Pope, MD

Grants/Research/Advisory BoardsActelion PharmaceuticalsEncysive Pharmaceuticals Inc.Pfizer

Off-label uses for products may be discussed.

Prevalence of SSc-PAH

Study No. Prevalence (%)

Japan 125 16

Britain 930 13

USA 815 11

Canada 344 5

France 67 37

Burlington 34 35

Canada 539 25 (10% Class III-IV)

France 599 8

USA 909 27 (abnormal echos)

Canadian SSc-PAH Distribution25% Had Elevated PAP on Echo

Pope J. J Rheumatol. 2005;32:1273-1278.

Isolated: 54.8%

Secondary to fibrosis: 29.8%

Undetermined: 15.3%

Predictors of SSc-PAH

• Some elevated PAPs on echo are stable over years

– 65% with PASP >35 mm Hg did not deteriorate over 3 yr

• Dropping DLCO % predicted and rising FVC/ DLCO ratio may be better predictors of PAH progression in the early stages

Steen V. Arthritis Rheum. 2005;52:3698-3700.

PAH in Scleroderma

• Think about it in long-standing limited systemic scleroderma patients

• It can occur in diffuse scleroderma at any stage of the disease with or without associated pulmonary fibrosis

• Even patients with fibrosis may benefit from treatment of secondary PAH

• No obvious autoantibodies associated with SSc-PAH

• ? BNP

Ratio of % FVC to % DLCO Influences Survival in Systemic Sclerosis

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 200.5

0.6

0.7

0.8

0.9

1.0

Duration of disease (yr from onset)

Pro

bab

ility

of

surv

ival

% FVC / % DLCO <1.8 (n=337)

% FVC / % DLCO ≥1.8 (n=169)

p=0.007

Disproportionate and/or isolated reduction in gas exchange (diffusing capacity) is dominant determinant of survival in all forms of SSc lung.

Seibold JR. Personal communication.

Survival in SSc-PAH with Bosentan is Improving

Current RxBosentan

N=45

HistoricalStandard &

Flolan

N=47

Open Label Extension Bosentan

N=44

1 yr survival %

81 68 86

2 yr survival %

71 47 73

Williams MH et al. Heart. 2006;92:926-932.Denton C et al. Ann Rheum Dis. 2006;65:1336-1340.

TRUST: CTD-PAH Class III Bosentan RxTime to Clinical Worsening

Denton C. Presented at EULAR 2006, ACR 2006.

Time (weeks)

100

25

0

50

75

120 483624Patientsat risk

53 52 45 40 35 25 1449 42

Patients without events

(%)

TRUST: Survival Analysis

Excellent one-year survival with bosentan treatment

Time (weeks)

100

25

0

50

75

120 483624Patientsat risk

53 53 52 50 48 37 2253 52

Patients without events

(%)

Denton C. Presented at EULAR 2006, ACR 2006.

STRIDE unpublished data.

One-Year Survival

Percent Survival

WeeksN=27N=25

0 4 8 12 16 20 24 28 32 36 40 44 48 520

10

20

30

40

50

60

70

80

90

100

Sitaxsentan

Bosentan

N=26N=20

96%

79%

HR: 0.17 (95% CI: 0.02, 1.42)

1 vs. 5 deaths

Visceral Vascular Disease: Systemic Sclerosis

Renal crisis

PAH

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 5 10 15 20 25

Years with SSc before death

Survival(%)

SRC Increases All-Cause SRC Increases All-Cause Scleroderma MortalityScleroderma Mortality

Normal kidneys

SRC

Firas, submitted 2006.

SRC Risk Factors

• Diffuse scleroderma

• Rapidly progressive skin involvement

• First 4 yr of diagnosis

• Male gender

• Anti-RNA polymerase III

• Prednisone use

• Cyclosporin

Other Possible Risk Factors

• New-onset anemia

• Cardiac involvement including pericardial effusions or CHF

• Contractures of large joints

• High skin score

SRC – Pathogenesis

• Marked elevations of renin

• Endothelial wall injury with

– intimal proliferation

– vasospasm

– decreased renal perfusion

Pathogenesis

• Hyper-reninemia alone does not suffice

• Baseline measures do not predict SRC

• Frequently elevated plasma renins

• Cold-induced renin elevations

• Decreased renal blood flow

Prevention of SRC

• High index of suspicion

• Home BP monitoring in early diffuse or rapidly progressive scleroderma patients

• Avoid steroids in these patients if possible

• Treat rises of BP aggressively, immediately (treat like pregnancy-induced hypertension)

SRC – Other Treatment

• ACE inhibitors (not angio II)– decrease renin– increase bradykinin

• Add any treatment to control the hypertension

• Prostacyclins

• ? Statins

• ? ET-1 blockers

Prostacyclins in SRC

• Potent vasodilator

• Can be of benefit in severe RP, digital ulcers, and PAH in scleroderma

• It can reduce the resistance of the interlobar and cortical vessel arteries

• There are a few case reports showing improvement in SRC to control BP added to an ACE

Statins in SRC: Theoretical Benefits

Coenzyme A reductase inhibitors can:

• Decrease cellular proliferation by decreasing the prenylation of proteins

• Induce apoptosis of smooth muscle cells and fibroblasts

• Reduce ACE activity

• Inhibit endothelin production

• Inhibit type-I collagen production

ET-1 in Scleroderma Kidney

• Present in the small renal arteries in SRC

• ET-1 is important in scleroderma vasculopathy

• ET-1 can increase fibrosis

• But there are no studies reported of its use in SRC

SRC Is Under-Recognized

• Avoid triggers: steroids in early diffuse patients if possible

• Think about it

• Frequent BP monitoring

• Do not stop the ACE inhibitor

• The outcome is still not ideal

Vasculopathy in Scleroderma

Masson-Trichrome Stain of Digital Artery in SSc

• Striking fibrotic intimal hyperplasia

• Adventitial fibrosis

• Arterial lumen severely compromised

Digital Vascular Injury in SSc

Digital Ulcers

• It is unknown if digital ulcers are a marker for poor prognosis

• They occur in diffuse and limited disease and are especially severe in limited scleroderma

• They can be correlated with the presence of PH

• Endothelin level is increased in the digital arteries

Prevalence of Digital Ulcers

• Raynaud’s occurs in at least 90% of subjects with scleroderma

• Old digital ulcers (presence of pits/scars) are part of the minor criteria for the diagnosis of scleroderma

• 33% to 75% of scleroderma can have digital ulcers

What Is the Burden of Digital Ulcersin Scleroderma?

Canadian Scleroderma Research Group

• Skin ulcers on fingers: 34/200 (17%)

• Pits: 75/200 (38%)

• Active volar distal ulcers: 16/197 (8%)

• No. of active ulcers: 1.75 (SD 1.3)range 1-6

Digital Ulcers: Impact on Quality of Life

• Painful

• Interfere with activities of daily life as they affect hand function

• Some heal spontaneously

• Generally slow to heal (3-15 mo)

• Can be complicated by secondary infections

• Can require amputation or can autoamputate

Ulcers and Amputations

0102030405060708090

100

≥1 ≥4 ≥7 ≥10

Number of new ulcers (n)

Patients with n or

more ulcers (%)

≥1 ≥4 ≥7 ≥10

Number of new ulcers (n)

ITTITT ITT with baseline DUITT with baseline DU

Placebo Bosentan

Bosentan Reduces No. of PatientsWith New Digital Ulcers

Korn JH et al. Arthritis Rheum. 2004;50:3985-3993.

RAPIDS-1 AND RAPIDS-2

RAPIDS-1 RAPIDS-2

16 weeks

Bos Pbo

24 weeks

Bos Pbo

Patients (n) 79 43 90 98

Ulcers at baseline (%) 1.9 2.2 3.7 3.6

New DUs (n)1.4 2.7

-48% (p=0.008)1.9 2.7

-30% (p=0.035)

Healing NS NS

Korn JH et al. Arthritis Rheum. 2004;50:3985-3993.Seibold J, EULAR 2006.Pope J. ACR 2006.

79

Conclusions

• Vasculopathy in scleroderma is widespread and may involve many organs

• Early recognition may improve prognosis

• Different vascular beds may respond to different treatment

• Treatment may include multiple drugs to treat the vascular abnormalities and complications