vascular complications of systemic sclerosis future directions in treatment of systemic sclerotic...
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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
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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.
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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)
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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%
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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.
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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
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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.
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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.
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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
(%)
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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.
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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
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Visceral Vascular Disease: Systemic Sclerosis
Renal crisis
PAH
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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.
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SRC Risk Factors
• Diffuse scleroderma
• Rapidly progressive skin involvement
• First 4 yr of diagnosis
• Male gender
• Anti-RNA polymerase III
• Prednisone use
• Cyclosporin
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Other Possible Risk Factors
• New-onset anemia
• Cardiac involvement including pericardial effusions or CHF
• Contractures of large joints
• High skin score
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SRC – Pathogenesis
• Marked elevations of renin
• Endothelial wall injury with
– intimal proliferation
– vasospasm
– decreased renal perfusion
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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
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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)
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SRC – Other Treatment
• ACE inhibitors (not angio II)– decrease renin– increase bradykinin
• Add any treatment to control the hypertension
• Prostacyclins
• ? Statins
• ? ET-1 blockers
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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
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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
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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
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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
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Vasculopathy in Scleroderma
Masson-Trichrome Stain of Digital Artery in SSc
• Striking fibrotic intimal hyperplasia
• Adventitial fibrosis
• Arterial lumen severely compromised
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Digital Vascular Injury in SSc
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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
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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
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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
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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
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Ulcers and Amputations
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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.
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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
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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