www.elsevier.com/locate/autrev

Autoimmunity Reviews 3 (2004) 313–320

Pulmonary hypertension in autoimmune rheumatic diseases

Patricia E. Carreira

Servicio de reumatologıa, Hospital 12 de Octubre, Avda. de Cordoba S/N, 28041 Madrid, Spain

Received 4 November 2003; accepted 8 November 2003

Available online 20 December 2003

Abstract

Arterial pulmonary hypertension (PH) might be a complication of some autoimmune rheumatic diseases, specially

systemic sclerosis. This form of arterial PH is indistinguishable from primary PH, characterised by the presence of plexiform

lesions. Although for many years plexiform lesions have been considered end-stage scarring lesions, they are composed by

actively proliferating endothelial cells that share many features with cancer cells. Endothelial cells within plexiform lesions

in all forms of arterial PH show a decrease in the expression of vasodilator and anti-proliferative factors, and an increase in

the expression of vasoconstrictor and angiogenic and mitogenic factors. These cells also show important alterations in

growth and apoptosis key regulatory genes. Plexiform lesions are surrounded by inflammatory cell infiltrates, probably

providing cytokines that may contribute to the endothelial cell proliferative process. All these data suggest that arterial PH

might be seen as a proliferative endothelial cell process, which would open new therapeutic approaches for this devastating

disease.

D 2003 Elsevier B.V. All rights reserved.

Keywords: Pulmonary hypertension; Systemic sclerosis; Endothelial cells

Pulmonary hypertension (PH) is present when current disease: arterial PH, PH with left heart

the median pulmonary artery pressure is higher

than 25 mmHg at rest or higher than 30 mmHg

during exercise [1]. Multiple classifications have

been developed for this disease, since PH can arise

primarily or secondarily to different pulmonary

pathologies. In 1998, a WHO expert meeting took

place in Evian, where a more descriptive classifi-

cation was proposed [2]. This classification has

been reviewed in a recent new WHO meeting, in

Venice in June 2003. The new proposal for PH

classification includes five main groups, according

to the presence or absence of additional or con-

1568-9972/$ - see front matter D 2003 Elsevier B.V. All rights reserved.

doi:10.1016/j.autrev.2003.11.004

E-mail address: carreira@h12o.es (P.E. Carreira).

disease, PH with lung disease and/or hypoxemia,

PH due to chronic thromboembolism and a mis-

cellaneous group (Table 1).

Rheumatologists are interested in this condition

because it can appear in some autoimmune diseases.

Arterial PH associated to autoimmune diseases is

clinically, hemodynamically and prognostically indis-

tinguishable from primary PH [3], and most therapeu-

tic strategies used in primary PH have confirmed its

efficacy in rheumatic diseases associated PH [4],

specially in systemic sclerosis (SSc) [5].

The normal lung vascular bed is a low-pressure

circuit, able to adapt to increased blood flow by

dilation of small arterioles, without increasing vascu-

Table 1

Proposal of clinical classification

(1) Pulmonary arterial hypertension (PAH)

(a) Idiopathic

(b) Familiala

(c) Related to collagen vascular disease, CHD, portal

hypertension, HIV, drugs and toxins, other

(d) PAH with significant venous and/or capillary

involvement

(e) Persistent PH in the newborn (PHN)

(2) PH with left heart disease

(a) Atrial ventricular heart disease

(b) Valvular heart disease

(3) PH with lung disease and/or hypoxemia

(a) Chronic obstructive pulmonary disease

(b) Interstitial lung disease

(c) Sleep disorders; alveolar hypoventilation;

chronic exposure to high altitude

(d) Developmental abnormalities

(4) PH due to chronic thromboembolism

(a) Thromboembolic obstructions of proximal

pulmonary arteries

(b) Thromboembolic obstructions of distal

pulmonary arteries

(c) Pulmonary embolism of other nature (tumour,

parasites, foreign material)

(5) Miscellaneous

(a) Sarcoidosis, histiocytosis X, lymphangiomatosis,

comprehension of pulmonary

vessels (adenopathies and tumours,

fibrosing mediastinitis), Type 1

glycogen storage diseases, lipid storage

diseases such as Gaucher’s disease

Third World Symposium on Pulmonary Hypertension, Venice, June

23–25, 2003.a Familial PAH is defined as a demonstrated familial presence of

PAH (at least one affected relative). In the future, a positive genetic

blood test (BMPR2 mutation?), may define this category.

P.E. Carreira / Autoimmunity Reviews 3 (2004) 313–320314

lar resistances. In arterial PH, the pressure in pulmo-

nary arteries is already high at rest, but has a dispro-

portionate increase during exercise, due to the

structural inability to accommodate the excessive

blood flow. This progressively stresses the right side

of the heart, leading to right ventricular hypertrophy

and eventually to right heart failure.

Most of the current knowledge on arterial PH

comes from studies done in primary PH, but many of

these findings have also been confirmed in PH asso-

ciated to autoimmune diseases. The aim of the present

work is to review the cellular and molecular mecha-

nisms implicated in arterial PH development, especial-

ly focused in the similarities and differences between

primary and autoimmune diseases associated PH.

1. Genetics in pulmonary hypertension

Genetic predisposition has been found in familial

PH, transmitted as an autosomal trait with low

penetrance. A heterozygous germ line mutation in

bone morphogenetic protein (BMP) receptor 2, a

member of the transforming growth factor h (TGF-

h) family, has been identified in 60% of familial cases

[6,7] and 25% of sporadic cases [8]. BMPs act

binding to BMPR1A and BMPR2 receptors,

expressed on cell surfaces adjacent to each other.

BMP binds to BMPR2 extracellular domain, which

activates BMPR1A intracellular domain. The activat-

ed BMPR1A phosphorilates the cytoplasmic signal-

ling protein Smad5, which binds to Smad4 and

migrates to the nucleus, where together with other

nuclear binding factors regulates DNA transcription.

The effect of activated BMP receptors depends on the

cell type and can result in either transcription activa-

tion or inhibition. Mutations in familial and sporadic

PH patients are found at highly conserved sites in

BMPR2, and predict either to alter the heterodimeri-

zation of this receptor with its co-receptor, BMPR1A,

or to inactivate the ligand-binding function of the

protein. Since PH only develop in 10–20% of

BMPR2 mutation carriers, it has been suggested that

some gene modifiers such as environmental factors,

hormones, immunologic mechanisms or mutations in

other regulatory genes may be necessary for the

clinical expression of the disease.

So far, these mutations have neither been found in

patients with PH associated with autoimmune diseases

nor in other secondary causes of PH [9].

2. Pulmonary hypertension in autoimmune rheu-

matic diseases

PH can appear mainly in SSc, and to a lesser

extent in other autoimmune diseases, such as sys-

temic lupus erythematosus, primary antiphospholipid

syndrome, mixed connective tissue disease (MCTD),

P.E. Carreira / Autoimmunity Reviews 3 (2004) 313–320 315

rheumatoid arthritis (RA), Sjoegren’s syndrome

(SS), polymyositis (PM) and dermatomyositis

(DM). It was also a prominent feature in two

scleroderma-like diseases: the Spanish toxic oil

syndrome (TOS), caused by ingestion of adulterated

rapeseed oil [10], and the eosinophilia myalgia

syndrome, caused by contaminated L-tryptophan

capsules [11].

In SSc, PH can appear secondary to severe

pulmonary fibrosis, or as a primary complication,

in the absence of interstitial lung disease. This

arterial PH has many similarities with all the

diseases included in the first group of PH classifi-

cation (Table 1). A third type of pulmonary vascu-

lar disease that reflects the vascular pathology of

SSc, with a more indolent course, has been recently

suggested [5]. It would include those patients with

limited SSc and slowly progressive arterial PH, and

also those who have a secondary pulmonary vas-

cular component in the context of mild interstitial

lung fibrosis. The overall incidence of PH, primary

or secondary, in SSc, varies largely depending on

the type of study, the diagnostic methods and the

criteria used for PH diagnosis [4]. Clinical studies

suggest an incidence between 2 and 30% in the

diffuse, and 10 and 60% in the limited form of the

disease, specially in patients with anti-centromere

antibodies. Transthoracic Doppler echocardiography

has shown high specificity and sensitivity to detect

PH in SSc patients, compared with the gold stan-

dard, right heart catheterisation [12]. On the basis

of the high incidence, current recommendations in

SSc include annual screening by transthoracic echo-

cardiography, even in the absence of PH symptoms

[3].

The incidence of this complication in other

autoimmune disease is still less well known. In

SLE, PH can be secondary to valvular or thrombo-

embolic disease, particularly in patients with anti-

phospholipid antibodies, rarely secondary to

interstitial lung fibrosis, and occasionally as primary

vascular disease. As in SSc, prevalence of PH in

SLE varies depending on the type of study. Retro-

spective studies estimate a prevalence of 0.5–6%

[4]. Prospective studies in asymptomatic patients

find a higher prevalence, from 9 to 14% [13], but

most cases have mild pulmonary artery pressure

elevation, whose clinical significance is unknown

[4]. PH has been rarely described in RA, as a

complication of interstitial lung fibrosis, pulmonary

vasculitis, thromboembolic or cardiac disease. One

prospective echocardiographic study shows a 6%

frequency of PH secondary to lung disease, and a

21% prevalence of mild arterial PH, in unselected

RA patients [14]. The clinical significance of this

finding is not known, since the prevalence of RA in

severe arterial PH is extremely low. Prevalence of

PH in MCTD patients varies between 23 and 50%,

although this is difficult to interpret, because many

patients are later diagnosed of SSc or other autoim-

mune rheumatic disease [4]. PH has also rarely

reported in SS and PM/DM. Given the low inci-

dence of severe arterial PH in all these autoimmune

diseases, current recommendations include Doppler

echocardiography only when patients have symp-

toms suggestive of PH [3].

When severe PH is diagnosed, patients with auto-

immune rheumatic diseases should follow the same

treatment strategy than primary PH patients. Immu-

nosuppressors have been suggested, as a possible

therapy, for this group of patients [3].

3. Endothelial lesion in pulmonary hypertension

3.1. Plexiform lesion as a primary event in PH:

endothelial cell tumour-like structure

Normal pulmonary arteries are composed by

three layers: endothelial cell monolayer, media of

smooth muscle cells and collagenous adventitia. In

PH, there is a wide range of morphologic changes

in the structure of small and large pulmonary

arteries, known as pulmonary vascular remodelling

[15]. Injury to endothelium is nowadays considered

the first step of vascular remodelling. Causes of

damage might include mechanical factors (shear

stress), hypoxia and other biochemical factors as

free radicals, some drugs, infections as HIV, and

immunologic factors, such as antibody binding,

immune complexes deposition, cellular infiltration

and inflammation. In TOS, where 20% of patients

developed severe plexogenic PH, direct endothelial

injury by the toxic agent has been proposed as the

initial trigger of PH, in specifically susceptible

patients [10].

Fig. 1. Plexiform lesions in a pulmonary artery from the lung of a patient with arterial PH secondary to TOS. The vessel wall is engrossed by

smooth muscle cell proliferation in the median layer (white arrows). In some areas of the artery, the vessel lumen is almost completely occluded.

Around the vessel wall and filling also the arterial lumen can be seen numerous proliferative lesions, composed by endothelial cells (black

arrows). Lung tissue around the vessels shows a normal structure, without evidence of interstitial inflammation. (Image kindly provided by Dr

M. Teresa Sotelo, from the Pathology Department, Hospital 12 de Octubre, Madrid, Spain.)

P.E. Carreira / Autoimmunity Reviews 3 (2004) 313–320316

On the basis of classical pathological studies,

vasoconstriction has been considered the initial

cause of PH for many years [16,17]. Theoretically,

maintained vasoconstriction would lead to vascular

damage and the typical vascular remodelling seen in

PH. However, in contrast to the obligatory endothe-

lial cell monolayer seen in normal pulmonary arter-

ies, arterial PH vessels show intraluminal growth of

P.E. Carreira / Autoimmunity Reviews 3 (2004) 313–320 317

endothelial cells, forming intravascular tumourlets,

known as plexiform lesions (Fig. 1), even in early

PH patients [15,18]. The concept of excessive vaso-

constriction as the main mechanism in PH develop-

ment fails to provide explanation for this endothelial

tumour-like proliferation. As confirmed by cellular

markers [19,20], these lesions are composed of

proliferating endothelial cells, with an altered phe-

notype that share many features with cancer cells:

lost of mechanisms to stop proliferation and the

ability to differentiate, evasion of apoptosis, and

increased angiogenesis. Three-dimensional recon-

struction of plexiform lesions from PH of different

origins has also found that these lesions appear

either isolated or immediately distal to concentric-

obliterative lesions, which never appear isolated

[19]. This suggests that plexiform lesions are a

primary event, independent of a component of

vasoconstriction from medial smooth muscle cell

hypertrophy.

3.2. Angiogenic factors in PH: vascular endothelial

growth factor (VEGF) and angiopoyetin-1

Pulmonary endothelial cells are very stable, with

a very low replicative capacity ( < 0.02%), suggest-

ing that normal endothelial cells probably exert a

strong negative proliferative feedback on the adja-

cent cells to maintain a monolayer. Only two fam-

ilies of growth factors act specifically on blood

vessels: the VEGF family and the angiopoyetin

family [21]. Both are highly specific, because their

receptors are expressed almost exclusively by vas-

cular endothelium.

VEGF is an obligatory endothelial cell survival

factor, critical for vessel growth during development.

Since VEGF controls endothelial cell migration and

growth, and protects against apoptosis, it may also

be critical for the maintenance of lung endothelial

cells, and for the development of the angiogenic

plexiform lesions [15,20]. These lesions express

VEGF mRNA and protein [20], and primary or

secondary PH patients have increased VEGF serum

levels, compared to normal individuals [22]. The

protective role of VEGF for endothelial cells is

supported by several findings: first, experimental

VEGF overexpression produces glomeruloid struc-

tures resembling plexiform lesions [20]. Second,

VEGF receptor-2 blockade causes increased pulmo-

nary endothelial cell death, followed by increased

endothelial cell proliferation, probably due to a

selection of apoptosis resistant cell, and more severe

PH in hypoxic rats [23]. Finally, smooth muscle

VEGF gene transfer protects from monocrotaline-

induced PH in rats [24].

Angiopoyetin-1, a 70-kDa protein produced by

smooth muscle cells, is essential for lung devel-

opment. It recruits muscle cells and gives mature

structure to the developing arteries. After devel-

opment is completed, it is minimally expressed in

the human lung [21]. Nevertheless, in PH of

various origins, angiopoyetin-1 expression is high-

ly up-regulated in the lungs, and this expression

correlates with disease severity. In cultured human

pulmonary endothelial cells, angiopoyetin-1 upre-

gulation shuts off BMPR1A (BMPR2 co-receptor)

expression, required for BPM signalling. Also,

BMPR1A lung expression is severely reduced in

several forms of non-familial PH [25]. In an

experimental rodent model, targeted lung over-

expression of angiopoyetin-1 induces hyperplasia

of vascular smooth muscle cells and subsequently

PH [25], suggesting that angiopoyetin-1 overex-

pression may be cause and not consequence in

non-familial human PH. The findings also suggest

a shared pathway for primary and secondary PH:

An inactivation of the BMPR complex, either by

a mutation in BMPR2 in familial disease, or by

regulation of BMPR1A transcription in non-famil-

ial PH, should be a hallmark of the disease. By

contrast, a recent study has found that angiopoye-

tin-1 delivery to monocrotaline-treated rats dra-

matically protects against PH development in

these animals [26]. The model also shows in-

creased endothelial cell apoptosis, prevented as

well by angiopoyetin-1 gene transfer [26]. To

unify both studies, it has been suggested that,

perhaps, the increased angiopoyetin-1 expression

observed in the lungs of patients with PH of

different causes may reflect an insufficient com-

pensatory response [27]. Also, experimental

monocrotaline-induced PH in rats might have

different pathogenesis than human PH, since

angiopoyetin-1 expression is not increased in the

lung of these animals [26]. Interestingly, VEGF

gene transfer also prevent PH development in

P.E. Carreira / Autoimmunity Reviews 3 (2004) 313–320318

monocrotaline-treated rats [24], suggesting that, as

VEGF, angiopoyetin-1 could be another protective

factor for endothelial cells, essential for PH

development.

3.3. Vasoconstriction and vasodilation balance in

PH

There is an imbalance between vasodilator and

vasoconstrictor factors in PH. Endothelial cells in

PH have a significant reduction in expressed nitric

oxide synthase [28], and prostacyclin synthase

[29], responsible for the synthesis of nitric oxide

and prostacyclin, two potent vasodilators. This

reduction would promote smooth muscle hypertro-

phy, vasoconstriction and platelet aggregation. On

the basis of these findings, therapy with diverse

prostacyclin derivatives is currently used widely in

arterial PH [30]. Endothelial cells in plexiform

lesions also express 5-lypoxygenase (5-LO), and

its membrane partner 5-LO activation protein, that

may also contribute to vascular cell growth and

vasoconstriction, specially in pulmonary vessels

exposed to hypoxia [31]. In autoimmune diseases,

expression of nitric oxide is reduced in the

exhaled air of SSc patients with PH [32], and

in cultured dermal microvascular endothelial cells

from SSc patients [33]. Prostacyclin synthase is

also decreased in the pulmonary endothelium of

autoimmune disease PH patients [29]. Endothelin-

1, potent vasoconstrictor and smooth muscle mi-

togen, is increased in plasma and lungs of

patients with primary PH and SSc [34], and

treatment with endothelin-receptor antagonist has

proved beneficial for primary and secondary PH

[34].

A deficiency of vasoactive intestinal peptide

(VIP), potent systemic and pulmonary vasodilator,

has been very recently described both in serum and

in lung tissue of patients with primary PH [35]. VIP

vasodilator effects are mediated through the activa-

tion of cAMP and cGMP pathways, which also

mediate the action of prostacyclins, NO and phos-

phodiesterase inhibitors in PH. VIP has also shown

to inhibit in vitro the proliferation of pulmonary

artery smooth muscle cells. Treatment with aerosol-

ised VIP has shown to improve primary PH patients

[35].

3.4. Inflammation in PH development

Inflammation is a recognized feature of vascular

remodelling in PH lungs. Around remodelled pul-

monary arteries, there are perivascular infiltration of

lymphocytes, macrophages and mast cells [18].

These inflammatory cells express cytokines (inter-

leukin-1, interleukin-6) and growth factors (platelet-

derived growth factor, TGF-h, VEGF) that can also

contribute to vascular remodelling. Mast cells, pres-

ent in large amounts around pulmonary arterioles

from patients with PH, can release tryptase, which is

also a potent angiogenic factor. The expression of

macrophage inflammatory protein 1a (MIF-1a), a

chemokine that promotes the migration of monocytes

and T and B lymphocytes, is increased in PH lung

tissue [36], probably contributing to the recruitment

of inflammatory cells to the plexiform lesions.

3.5. Growth and apoptosis regulatory genes in PH

Several factors have been implicated in the ab-

normal endothelial proliferating cells in both primary

and secondary PH: downregulation of apoptosis

mediators expression, as TGFhR2 or Bax, and upre-

gulation of angiogenesis-related molecules expres-

sion, such as VEGF, angiopoyetin-1, and hypoxic

inducible factors (HIF) 1a and 1h. A complete

absence of apoptosis has been demonstrated in en-

dothelial cells of plexiform lesions [20]. Endothelial

cells from primary PH plexiform lesions also present

microsatellite instability in the pro-apoptotic Bax

gene [37]. This mutation confers growth advantage

to cells that escape from apoptotic cell death cas-

cades involved by Bax. It has been found an in-

creased expression of the anti-apoptotic Bcl-2 [38] in

plexiform lesions.

It has been proposed that the difference between

the primary and the secondary PH is that in

primary PH the disease is caused by somatic

mutations in key growth regulation genes, such as

TGFhR2 or Bax [38]. This loss of growth control

mechanism would allow for the clonal expansion of

a single endothelial cell after acquiring selective

growing advantages. On the other hand, different

factors, as immunologic mechanisms in autoimmune

diseases, or mechanical and biochemical factors in

other secondary forms of PH, would activate endo-

P.E. Carreira / Autoimmunity Reviews 3 (2004) 313–320 319

thelial cells to proliferate in a polyclonal way

[39,40].

Take-home messages

. Arterial PH, indistinguishable from primary PH,

can appear in some autoimmune rheumatic disease,

particularly in 5–15% of SSc patients.. Arterial PH, primary or secondary to autoimmune

rheumatic disease, is characterised by the presence

of plexiform lesions, composed by actively prolif-

erating endothelial cells, showing many features of

cancer cells.. There is an increase of vasoconstrictor factors and a

decrease of vasodilator factors in pulmonary vessels

of all cases of arterial PH.. There is an increase of proliferative endothelial cell

factors, and a decrease of anti-proliferative factors

in plexiform lesions of arterial PH.. Inflammatory cells are present around the plexiform

lesions, suggesting a role for inflammation in the

pathogenesis of this condition.. Endothelial cells in plexiform lesions of arterial

PH show alterations in key growth regulation

genes.

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The World of Autoimmunity; Literature Synopsis

d nodules

blocker) on the immunopathology of rheumatoid

m Dis 2004;63:489). They found no manifest

fore and after infliximab treatment, as all nodules

rounding the palisade layer, and an outer connective

lar symptoms associated with infliximab treatment,

atoid nodules, suggesting that different mechanisms

thritis.