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