Management

of
vasculopathy in
systemic sclerosis

Keio University School of Medicine,

Department of Rheumatology
Shuntaro Saito
Management of pulmonary
hypertension in systemic sclerosis
Classification of Pulmonary
Hypertension
Nice Symposium,
1. Pulmonary arterial hypertension
France 2013
3. Pulmonary hypertension due to lung
diseases
 1.1 Idiopathic PAH
 3.1 COPD
 1.2 Heritable PAH
 3.2 IntersJJal lung disease
 1.3 Drug and toxin induced
 3.3 Other pulmonary diseases
 1.4 Associated with:
4. Chronic thromboembolic pulmonary
  1.4.1 ConnecJve Jssue disease
hypertension (CTEPH)
 1’Pulmonary veno-occlusive disease
5. Unclear mulJfactorial mechanisms
(PVOD)
 5.1 Hematologic disorders: chronic
2. Pulmonary hypertension due to leP
 hemolyJc anemia, myeloproliferaJve
 heart disease
 disorders, splenectomy
 2.1 LeP ventricular systolic dysfuncJon
 5.2 Systemic disorders: sarcoidosis,
 2.2 LeP ventricular diastolic dysfuncJon
 pulmonary hisJocytosis 
 2.3 Valvular disease
 5.3Metabolic disorders: glycogenstorage
 disease, Thyroid disorders

We must care about many types of PH in the management in SSc-PH

Improving survival rate in SSc-
PAH
-we can deal with SSc-PAH now-
Cumula6ve survival rate

Upfront strategy
; individualized approach

Development of
PAH treatment

6me a7er PAH diagnosis

•  Shirai Y etal. Data from Keio University.
Development of PAH treatment in Japan

Selexipag (2016)
Beraprost(1999) Tadalafil (2009) Iloprost (2015)

Treprostenol (2014)
Epoprostenol (1999) Sildenafil (2008)

1995 2000 2005 2010 2015

Bosentan (2005)

Ambirsentan (2010) Macitentan (2015)

Riociguat (2015)
 Treatment options of PAH in
Japan
Type Drug
Endothelin receptor antagonist Bosentan
Ambrisentan
Macitentan
PDE-5 inhibitor Sildenafil
Tadalafil
soluble guanylate cyclase (sGC) Riociguat
sJmulator
Prostacycline Epoprostenol
derivaJves Beraprost
Iloprost
TreprosJnil
Prostacycline receptor agonist Selexipag
5 categories, 11 types of medica6on
Point of action in PAH drug
Selexipag Bosentan
Ambrisentan
Macitentan
Epoprostenol
Beraprost
Iloprost
Trepros6nil
IP Receptor

Riociguat
NO
Ca2+ influx
Ac6va6on of Rho kinase

Sildenafil
Tadalafil
Vaso-dila6on Vaso-constric6on
Suppression of prolifera6on of VSMC Cellular prolifera6on of VSMC
 Treatment Algorism for Idiopathic PAH(IPAH)
General measures
Treatment naive
PAH confirmed by
Expert center
Supportive therapy
Acute vasoreactivity test
Ca Channel blocker (IPAH/HPAH only)
Vaso-reactive
Non-vasoreactive

Low or Intermediate Risk High Risk

（WHO FC I〜III） （WHO FC IV）

Initial Initial
Initial combination
monotherapy Combination
Including iv PCA
Therapy

Inadequate Clinical Response

Double or Triple sequential Therapy

Inadequate Clinical Response

Consider for Lung Transplantation

ESC/ERC Guideline for diagnosis and treatment of PH. Eur Heart J. 2016; 37: 67-119
Evidence in IPAH,
monotherapy
Evidence in IPAH, initial combination
therapy
 Evidence in IPAH,
sequential combination therapy

ESC/ERC Guideline for diagnosis and treatment of PH. Eur Heart J. 2016; 37: 67-119
PH medica6on
-How to use-
 Endothelin receptor antagonist
Bosentan Ambrisentan Macitentan
Dosage form 62.5mg, tablet 5mg, tablet 10mg, tablet
Dose 2 tablet, bid 1 tablet, once daily 1 tablet, once daily
(125mg/day) (5mg/day)➡ (10mg/day)
for 4week➡ 2 tablet, once daily
4 tablet, bid (10mg/day)
(250mg/day)
Side effect Liver enzyme Leg edema (5-10%) Headache (5%)
elevaJon (10%) Headache (10%) Liver enzyme
Headache (10%) elevaJon (0.5-5%)
Leg edema (5%) Leg edema (0.5-5%)

Character of the ETA and ETB (dual) SelecJve ETA ETA and ETB (dual)
medicaJon receptor antagonist receptor antagonist receptor antagonist
Prohibited to use Careful Careful
with CyA/Tac administraJon with administraJon with
Evidence in digital CyA/Tac CyA/Tac
ulcer
 PDE-5 inhibitor and soluble
guanylate cyclase (sGC) stimulator
Sildenafil Tadalafil Riociguat
Dosage form 20mg, tablet 40mg, tablet 0.5,1,2.5mg, tablet
Dose 3 tablet, Jd 1 tablet, once daily Increase unless SBP<95
(60mg/day) (40mg/day) nor symptomaJc low BP
※Reduce to 20mg/day 1.0mg x3/day:2weeks
when Pt has liver 1.5mg x3/day:2weeks
dysfuncJon or renal 2.0mg x3/day:2weeks
dysfuncJon 2.5mg x3/day
(MAX dose, 7.5mg/day)
Side effect Flushing (5%) Flushing (5%) Headache (10%)
Headache (5%) Headache (5%) GastrointesJnal symptoms
GastrointesJnal Myalgia (5%) (10%)
symptoms (5%)
Character of the PDE-5 inhibitor PDE-5 inhibitor sGC sJmulator
medicaJon Prohibited to use Prohibited to use with Prohibited to use with
with Riociguat Riociguat sildenafil/Tadalafil
Evidence in the use of PH Evidence in CTEPH
induced by lung disease
 Epoprostenol;
Strongest Prostacyclin deriva6ves
•  conJnuously iv
•  Start with 2ng/kg/min,
Subclavian
Vein Catheter
and increase/reduce by
Catheter
placement ±1-2ng/kg/min
Superior vena cava
inser6on
•  MAX 10ng/kg/min
Catheter •  Flushing, headache,
junc6on
Extension
Adjusted
Epoprostenol
nausea occurs
Filter tube
Precision
Infusion pump
•  The only evidence in
WHO-FC 4 PH
Other prostacyclin deriva6ves
Iloprost Trepros6nil Beraprost
Dosage form inhalaJon conJnuously iv/s.c 60µg, tablet
Dose 2.5µg/Jme at 1st inhalaJon Start with 1.25ng/kg/ Increase gradually
→ min 2 tablet, bid
5.0µg/Jme x 6-9 Jmes/day when not tolerable, (120µg/day)➡
when not tolerable, Reduce to 0.625ng/kg/ 6 tablet, bid
Reduce to 2.5µg/Jme, min, (360µg/day)
6 Jmes/day is maximum Increase by ＋1.25ng/
when Pt has liver kg/min/week for
dysfuncJon or renal 4week, then increase
dysfuncJon by 2.5ng/kg/min/week
when tolerable
Side effect Headache (10%) Pain at inserted area Headache (5%)
Cough (5%) (80%) Flushing (1-5%)
Flushing (10%) Liver enzyme
Headache (10%) elevaJon (1-5%)

Character of First inhalaJon anJ-PH ConJnuously s.c➡could Mild effect

the medicaJon drug take bath
 Prostacyclin receptor agonist
:Selexipag
3.2mg
2.8mg
2.4mg
2.0mg
1.6mg
1.2mg
0.8mg
0.4mg/day

Week 1 2 3 4 5 6 7 8∼

【Dose】
•  Start with 0.2mg x2/day
•  Increase 0.2mgx2 for every week, to Maximum dose;1.6mgx
2/day when tolerable (8 step)
【Side effect】
•  Flushing (5%), Headache (5%), GastrointesJnal symptoms
(5%)
【Character】
•  Structurally different from PGI analog
Ambrisentan and Tadalafil in SSc-PAH
:subgroup analysis of the AMBITION trial

•  Combina6on therapy (Ambrisentan + Tadalafil) improved event-

free survival rate in SSc-PAH pa6ents.
➡Upfront strategy is the main stream of SSc-PAH treatment
Ann Rheum Dis 2017;76:1219–1227
Other cause of PH in SSc:
SSc-ILD, Left ventricular diastolic
dysfunction
ILD-PH PAH
➡Need PH specialist to esJmate
%FVC <70% >70% the main pathological problem
%FVC/%DLCO ≦1.5 >1.5 ➡Treat with main problem at first

Le7 heart PAH

disease
ILD PAH PAWP >15mmHg ①≦15mmHg
②<10mmHg※
Le7 TPG ≦12mmHg ①>12mmHg
(=mPAP-PAWP) ②>25mmHg※
ventricular DPG <7mmHg ①≧7mmHg
diastolic (=dPAP-PAWP) ②＞10mmHg※
dysfunc6on PVR ≦3 WU ①>3 WU
②>6.25 WU※
※higher specificity than ① in SSc
Other cause of PH in SSc: treatment in
SSc-ILD, Left ventricular diastolic
dysfunction
PAH Le7 heart disease ILD
Group 1 Group 2 Group 3
PAH treatment 〇 ✖ ▲
Upfront strategy Not effecJve PDE-5 (tadarafil)
or sequenJal Risk of PH worsening may have good effect
combinaJon
In Group 1+2/3
Immunosuppressants ✖ ✖ ▲-〇
Maybe effecJve Not effecJve IVCY/MMF+low dose
in RNP-Ab PSL
posiJve case
Le7 heart failure ✖ 〇-▲ ✖
treatment Not effecJve Ca Channel blocker→〇 Not effecJve
DiureJcs→〇
β-blocker→▲
(worsening Raynaud)
ACE-i/ARB→▲(risk in
sclerosis renal crisis)
 Pulmonary veno-occlusive
disease
(PVOD) and management of SSc-
PH

•  PVOD induces PH by occlusive lesion in pulmonary veins. Histopathologic hallmark is a

widespread fibrous inJmal proliferaJon that predominantly involves the pulmonary
venules and small veins; OPen found in the pathology of SSc-lung.
•  Histological proof is the only way to make a definiJve diagnosis of PVOD.
•  【CT findings】Diffuse centrilobular ground-glass opaciJes, thickening of interlobular
septa and lymph node enlargement support the diagnosis of PVOD
What happens in this case?
● Use of PAH treatment and improve PAH in
the case with PVOD or left ventricular
dysfunction
Pulmonary
vein

PA

LA

RV

Capillary
PVOD
Le7 ventricular PAH treatment
diastolic dysfunc6on
http://www.m.chiba-u.ac.jp/class/respir/sinryo/history_pah/index.html
【Ans; Pulmonary edema would be induced】

What should we do next?＞Use sufficient oxygen, diure6cs and

reduce/discon6nue PAH treatment

PVOD is o7en recognized a7er the event of pulmonary edema;

We should always be careful about the deteriora6on of disease
condi6on a7er ini6a6on or increase of PAH treatment in SSC-PH.