Future Directions in Treatment of Systemic Sclerotic Complications

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Future Directions in Treatment of Systemic
Sclerotic Complications
VASCULAR COMPLICATIONSOF SYSTEMIC
SCLEROSIS

• Janet Pope, MD
• ProfessorDivision of RheumatologySt. Josephs
  Health CentreUniversity of Western Ontario,
  LondonLondon, Ontario, Canada

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VASCULAR COMPLICATIONSOF SYSTEMIC
SCLEROSIS
DISCLOSURE STATEMENT Janet Pope, MD
Grants/Research/Advisory Boards Actelion
Pharmaceuticals Encysive 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
Undetermined 15.3
Isolated 54.8
Secondary to fibrosis 29.8
Pope J. J Rheumatol. 2005321273-1278.
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Predictors of SSc-PAH

• Some elevated PAPs on echo are stable over years
• 65 with PASP gt35 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. 2005523698-3700.
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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
FVC / DLCO lt1.8 (n337)
Probability of survival
p0.007
FVC / DLCO 1.8 (n169)
Duration of disease (yr from onset)
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 N45 HistoricalStandard Flolan N47 Open Label Extension Bosentan N44
1 yr survival 81 68 86
2 yr survival 71 47 73
Williams MH et al. Heart. 200692926-932. Denton
C et al. Ann Rheum Dis. 2006651336-1340.
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TRUST CTD-PAH Class III Bosentan RxTime to
Clinical Worsening
100
75
Patients without events ()
50
25
0
12
0
48
36
24
Time (weeks)
Patientsat risk
53
52
45
40
35
25
14
49
42
Denton C. Presented at EULAR 2006, ACR 2006.
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TRUST Survival Analysis
Patients without events ()
Time (weeks)
Patientsat risk
53
53
52
50
48
37
22
53
52
Excellent one-year survival with bosentan
treatment
Denton C. Presented at EULAR 2006, ACR 2006.
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One-Year Survival
96
1 vs. 5 deaths
79
Percent Survival
HR 0.17 (95 CI 0.02, 1.42)
N26 N20
STRIDE unpublished data.
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Visceral Vascular Disease Systemic Sclerosis
PAH
Renal crisis
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SRC Increases All-Cause Scleroderma Mortality
Survival ()
Normal kidneys
SRC
Years with SSc before death
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

• Raynauds 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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Bosentan Reduces No. of PatientsWith New Digital
Ulcers
ITT with baseline DU
ITT
100
90
80
70
Patients with n or more ulcers ()
60
50
40
30
20
10
0
1
4
7
10
1
4
7
10
Number of new ulcers (n)
Number of new ulcers (n)
Placebo
Bosentan
Korn JH et al. Arthritis Rheum.
2004503985-3993.
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RAPIDS-1 AND RAPIDS-2
RAPIDS-1 RAPIDS-2
16 weeks Bos Pbo 24 weeks Bos Pbo
Patients (n) 43 90 98
Ulcers at baseline () 1.9 2.2 3.7 3.6
New DUs (n) 1.4 2.7 -48 (p0.008) 1.9 2.7 -30 (p0.035)
Healing NS NS
79
Korn JH et al. Arthritis Rheum.
2004503985-3993. Seibold J, EULAR 2006. Pope J.
ACR 2006.
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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