Systemic hypertension causes pulmonary hypertension

Pulmonary hypertension and rheumatic diseases


After idiopathic pulmonary arterial hypertension (IPAH), pulmonary arterial hypertension (PAH) associated with connective tissue disease (CTD) represent the second largest subgroup within the PAH group. Scleroderma and mixed connective tissue disease are most commonly affected by PAH . But systemic lupus erythematosus (SLE), dermatomyositis, Sjögren's syndrome, antisynthetase syndrome and rheumatoid arthritis also show an increased risk of PAH. The pulmonary symptoms and therapy are similar to those of IPAH. An annual echocardiographic screening for pulmonary hypertension is recommended for systemic sclerosis (SSc). Such a diagnosis is recommended for the other collagenoses if symptoms are present that match pulmonary hypertension, in particular shortness of breath during exertion, fatigue or attacks of weakness. Early therapy with PAH drugs is recommended after the prognosis of a CTD-associated PAH is significantly less favorable than that of an IPAH. Special attention should be paid to collagenosis-associated pulmonary veno-occlusive disease (PVOD) as a differential diagnosis because it carries a high risk of therapy-associated side effects. Approved for collagenosis-associated PAH are endothelin receptor antagonists (ERA), phosphodiesterase 5 inhibitors (PDE5i), IP receptor agonists (IPA) and a stimulator of soluble guanylate cyclase (sGCS). In combination with immunosuppressive substances and because of the peculiarities of the underlying disease, more and more severe side effects are to be expected with PAH drugs than with IPAH patients.


After idiopathic pulmonary arterial hypertension (IPAH), connective tissue disease (CTD) -associated PAH represents the largest subgroup within the PAH group of diseases. Systemic sclerosis (SSc) and mixed connective tissue diseases are at the highest risk of PAH; however, systemic lupus erythematosus (SLE), dermatomyositis, Sjögren's syndrome, antisynthetase syndrome and rheumatoid arthritis also show an increased risk for PAH. The pulmonary symptoms and treatment are similar to those for IPAH. For SSc a yearly echocardiographic screening for PAH is recommended. In the other CTDs this diagnostic measure is recommended only if signs and symptoms of PAH occur, particularly dyspnea on exertion, fatigue or fainting / syncope. An early therapy with targeted PAH medication is recommended, as the prognosis of CTD-associated PAH is much worse compared to IPAH. A CTD-associated pulmonary veno-occlusive disease (PVOD) must be considered as a differential diagnosis, because this disease is particularly prone to treatment-associated side effects. Approved for targeted collagen-associated PAH are endothelin receptor antagonists (ERA), phosphodiesterase 5 inhibitors (PDE5i), IP receptor agonists (IPA) and stimulators of soluble guanylate cyclase (sGCS). When combined with immunosuppressants and because of the special properties of the underlying diseases, targeted PAH medications are associated with higher risks of severe side effects compared to IPAH patients.

Almost all rheumatic diseases are associated with an increased risk of pulmonary hypertension. Often, but by no means always, this pulmonary hypertension can be classified as pulmonary arterial hypertension (PAH). This is the case if a cardiac or pulmonary dysfunction is not the cause of the pulmonary hypertension. Such disorders are also more common in patients with rheumatic diseases. Unfortunately, there is no clear information on the question of how many pulmonary hypertension in rheumatic diseases can ultimately be classified as PAH. One of the reasons for this is that there are no sharp definitions in this regard.

Pulmonary hypertension is currently defined by the fact that the mean pulmonary pressure (PAP) has risen to 25 mm Hg or more in the right heart catheter examination under resting conditions [1]. At the last world conference on pulmonary hypertension in Nice 2018, it was discussed whether the definition should not be revised downwards due to the PAP normal range [2] in order to recognize values ​​from 21 mm Hg as pulmonary hypertension, at least if at the same time a clearly increased pulmonary level vascular resistance (PVR) is present. However, the old criteria still apply at the moment.

If, in patients with a PAP ≥ 25 mm Hg, the mean left atrial pressure, which is determined via a pulmonary arterial balloon catheter ("pulmonary arterial wedge pressure", PAWP), does not exceed 15 mm Hg, it is assumed that pulmonary hypertension is not the result of a Heart disease is [3]. If the vital capacity is above 70% in the pulmonary function test and if the computed tomography (CT) of the chest shows less than 10% of the lung volume, it is assumed that pulmonary hypertension is not the result of pulmonary fibrosis [4]. If pulmonary fibrosis develops as part of collagenosis, there is also an increased risk of pulmonary hypertension. In an English cohort of patients with systemic sclerosis (SSc), the combination of pulmonary hypertension and pulmonary fibrosis was associated with a particularly poor 3-year survival rate of only 28% [5]. In the approval-oriented studies for PAH drugs, however, such patients were always excluded because these diseases are not “isolated pulmonary hypertension” in the sense of PAH. The following remarks will then refer exclusively to rheumatic diseases with PAH, since there are hardly any registry or study data on the other forms of pulmonary hypertension.

Pathology and pathophysiology

It has long been known that the small pulmonary vessels in the context of collagenoses can develop a remodeling that is very similar to idiopathic PAH (IPAH) histologically and functionally. This remodeling then leads to an increase in pulmonary arterial pressure. Typically, patients with collagenoses achieve lower pulmonary pressure values ​​than patients with IPAH. There are probably several reasons for this: The patients with collagenoses are on average older and in older age the pressure values ​​are no longer as high as in younger patients [6]. However, there is also evidence that the collagenoses lead to impairment of the cardiac reserve [7]. This is expressed in the fact that with a given afterload (increased PAP) the cardiac output is reduced more and the preload (right atrial pressure) is increased more. It has not been well proven experimentally, but it is to be expected that only a small increase in cardiac output is possible during exercise. Such a finding was the strongest predictor of mortality in a collective with predominantly IPAH patients [8]. This correlation would also explain why the collagenosis patients in all studies stand out for a particularly strongly reduced 6-minute walk test.

In white-skinned people, SSc is most strongly associated with pulmonary hypertension of all types of collagenosis. In the Asian region, on the other hand, systemic lupus erythematosus (SLE) appears to be the most common cause of collagenosis-associated PAH [9]. It is not uncommon to find mixed collagenosis among patients with collagenosis-associated PAH. Much rarer are patients with rheumatoid arthritis, dermatomyositis, Sjögren's syndrome or antisynthetase syndrome. PAH is rare in such patients, but in individual cases it can be particularly severe and aggressive. In SLE, an improvement in pulmonary hemodynamics has been repeatedly reported under immunosuppressive therapy. Unfortunately, such experiences have not been made with other collagenoses.

"The pathomechanism of pulmonary vascular remodeling has not been finally elucidated"

The pathomechanism of pulmonary vascular remodeling has not been definitively elucidated in any of these diseases. It can be assumed that in the context of autoimmunity, vascular-active substances arise that lead to constriction and proliferation of the pulmonary vascular walls. In a multicenter study from Germany, activating autoantibodies against the endothelin A receptor and the angiotensin 1 receptor were detected, which can certainly contribute to vasoconstriction and proliferation of the vascular wall [10]. The autoantibodies were confirmed in an independent American cohort, although the authors of this study have doubts about the specificity of this finding for collagenoses [11].

A special feature of collagenoses is the accumulation of collagen in the interstitium. In SSc, there is a characteristic increase in collagen 14 and collagen 18 in the pulmonary vessels. Endostatin is the most important breakdown product of collagen 18 and can also be detected in the circulation [12]. Endostatin has strong angiostatic properties, that is, it reduces the vascularization of the tissue and thus its supply of oxygen and nutrients. In two independent cohorts, increased concentrations of endostatin in the blood were detected in SSc with PAH [12, 13]. Interestingly, there is a genetic polymorphism that affects the formation of endostatin. Even a genotype with increased endostatin formation is associated with a significantly poorer prognosis for SSc-associated PAH [13]. The circulating endostatin levels are more strongly correlated with cardiac function than with pulmonary vascular pressure [12]. This suggests that endostatin has a particularly important role in right ventricular failure. This can be explained by its angiostatic properties, which are possibly critical for the perfusion of the myocardium.

Two subgroups are distinguished in SSc: diffuse systemic sclerosis and so-called limited SSc. In the latter, patients mostly show anti-centromere antibodies, while patients with diffuse SSc show predominantly Scl-70 antibodies and rarely develop isolated severe PAH. Some of the patients with limited SSc were previously referred to as CREST syndrome (CREST: calcinosis cutis, Raynaud's syndrome, esophageal involvement, sclerodactyly, telangiectasia). Some of these patients develop "isolated" PAH. The term “isolated” is used to clarify that thin-slice computed tomography (CT) does not show any clear signs of pulmonary fibrosis in such cases and that there is no evidence of left heart disease. Although many patients with limited SSc never develop PAH, this subgroup represented the majority of patients with collagenosis-associated PAH who participated in the controlled randomized trials for the targeted PAH drugs and thus contributed to the approval in this indication.


When large cohorts of SSc patients were systematically examined for pulmonary hypertension, 5–12% were found to have overt PAH. Studies with higher prevalence figures should be interpreted with great caution because either no right heart catheterization was performed or the pulmonary function and CT criteria for excluding non-PAH PH were not rigorously checked.

For SSc-associated PAH, but also for all other collagenosis-associated PAH cases, there is a female to male ratio of 4: 1 to 8: 1. The median age at diagnosis is often over 60 years. The survival time is significantly shorter than in comparable hemodynamically affected patients with IPAH. In fact, it can be assumed that the mortality is almost 3 times higher than that of IPAH. In principle, the pulmonary symptoms are very similar to those in patients with IPAH. At diagnosis, however, the pulmonary arterial pressure values ​​are significantly lower than in patients with IPAH. In addition to the above-mentioned pathophysiological differences, this may be related to the fact that collagenosis patients are often already under medical care because of their collagenosis and therefore PAH is given increased attention.


Thin-layer CT plays a special role in diagnostics because, on the one hand, interstitial lung changes must be expected in the case of collagenoses and because the patients can be affected by obstructive remodeling not only in the pulmonary arteries but also in the pulmonary veins. They then develop the clinical picture of pulmonary veno-occlusive disease (PVOD). PVOD can be identified on CT by thickened interlobular septa and multiple centrilobular islands of edema. In addition, it is not infrequently associated with pleural effusions and thickened mediastinal lymph nodes. According to the current classification, these cases belong to group 1'4.1 “Pulmonary veno-occlusive disease and / or pulmonary hemangiomatosis; associated with: connective tissue disease ".

The development of an isolated PAH in SSc is associated with a decrease in the diffusion capacity for carbon monoxide (DLCO) [14]. Therefore, a decreased DLCO below 60% of the norm is considered an indicator of a possible PAH. The same applies to an increase in BNP (“brain natriuretic peptide”), which is almost always increased in collagenosis-associated PAH. However, this marker is unspecific and increases with any type of left ventricular dysfunction. The DETECT study systematically looked for factors associated with overt PAH in SSc patients with a DLCO <60%. The echocardiography per se showed a disappointing informative value in the limit value range of the PAP around 25 mm Hg, but a reasonable risk score for a PAH in SSc could be derived in combination with the other markers [15]. In general, a right heart catheter examination is mandatory prior to initiating PAH therapy, solely to prove PAH (pressure and PVR criteria) and to safely rule out accompanying left heart disease.

"A lowered DLCO below 60% of the norm is considered a PAH indicator"

The guidelines recommend an echocardiographic evaluation for all collagenosis patients with shortness of breath during exercise or other possible symptoms of PAH. In asymptomatic patients, however, this recommendation only applies to the SSc. An annual echocardiographic check-up is expressly recommended for these patients, because the manifestation of PAH is to be expected in almost 15% of cases within an average interval of 7 years. If the PAP is between 21 and 24 mm Hg at the first examination, the risk is almost four times higher [16]. In our own prospective study on a cohort of SSc patients, there was no significant increase in PAP at rest over an observation period of 4 years, but an increase in PVR, an increase in pulmonary pressure when exposed to 50 W on the ergometer and a decrease in the highest achieved oxygen uptake (peak VO2). PAH became manifest in 3% of patients [17]. This means that the pulmonary pressure at rest is not really sensitive to the subtle progression of pulmonary vascular remodeling in SSc, but that the ergometry and especially the hemodynamics under stress enables an improvement in the sensitivity.


The therapy of PAH in rheumatological diseases follows the same principles as the therapy of IPAH. However, the therapeutic effects are usually less impressive and the side effects are more severe. Many patients with rheumatological diseases nowadays receive immunosuppressive therapies or biologics, although none of these drugs is supported by guidelines for long-term therapy [18]. Their frequent use can lead to interactions with the PAH drugs, and the complications of such drugs can exacerbate the side effects and complications of PAH drugs. This is particularly relevant when immunosuppressive therapies lead to acute septic complications that result in vasomotor collapse with systemic hypotension. This complication can be significantly aggravated under the action of PAH drugs, all of which are known to be powerful vasodilators.

In contrast to IPAH, it is very rare to find patients who belong to the group of "calcium antagonist responders". However, if such a responder is identified on the basis of the acute hemodynamic criteria during the right heart catheter examination, it must be expected that, despite regular intake of the calcium channel blocker, the pulmonary hypertension will progress after a few months or years and that alternatively or additionally other targeted PAH drugs will have to be used.

In collagenosis patients with PAH, monotherapies with endothelin receptor antagonists (ERA), phosphodiesterase-5 inhibitors (PDE5i), prostanoids or selexipag, a non-prostanoid IP receptor antagonist (IPA) and a stimulator of soluble guanylate cyclase (sGCS) have clearly been documented. However, the most impressive therapy results were achieved with the initial combination therapy with the ERA ambrisentan and the PDE5i tadalafil [19].In fact, many patients are put on combination therapy with a modern ERA and a PDE5i relatively early. These therapies are generally well tolerated, but headaches, flush syndrome, leg edema, symptomatic hypotension and chronic anemia must be expected. Hepatotoxicity is an absolute rarity among modern drugs.

Bosentan, a first generation ERA, has extensive drug interactions. This applies, for example, to vitamin K antagonists and contraceptives as well as other PAH drugs. The combination of bosentan and cyclosporin A is downright contraindicated. Bosentan has a cumulative 1 ‑ year hepatotoxicity of approx. 10% [20]. This also makes monthly checks of the transaminases necessary in the long term. To date, bosentan is the only drug approved for acral necrosis in SSc (previously: rat bite necrosis) and is therefore still prescribed relatively frequently, especially if the hemodynamic criteria for PAH are not met.

In contrast to patients with IPAH, hypoxemia occurs more frequently with PAH drugs, especially if gas exchange disorders were already recognizable before therapy. This is likely to have something to do with a disturbed vascular architecture in the lungs, which is characterized by the fact that not only narrowed but also clearly dilated microvascular pulmonary vessels occur. This problem can severely limit the options for PAH drugs in individual cases. Mixed collagenoses are particularly often affected by this clinical problem. In each individual case, a thin-slice CT of the lungs should be performed before starting therapy. If the hypoxemia increases during PAH therapy, this should be carried out again and carefully checked for signs of PVOD, as this is not a very rare pulmonary vascular manifestation of collagenosis.

"Right heart catheterization and thin-slice CT of the lungs should always be performed before therapy"

If PAH progresses in an underlying rheumatological disease and cannot be stabilized despite the best possible PAH therapy, a lung transplant is sometimes an option. Often, however, the age limit has already been exceeded or there are comorbidities that prohibit this procedure, whereby reflux esophagitis is not a contraindication in SSc. Although transplantation is associated with a higher risk in such patients than with IPAH, an underlying rheumatological disease is not considered a contraindication to lung transplantation [1]. An atrial septostomy can be used as a bridge to a lung transplant or as a palliative therapeutic measure when drug therapy is exhausted. This procedure quickly improves the filling of the left ventricle and relieves the load on the right ventricle, but it also immediately leads to a significant worsening of the hypoxemia [21]. This procedure is reserved for experienced centers for pulmonary hypertension.

conclusion for practice

  • PAH is a serious, life-threatening complication of rheumatological diseases and requires invasive work-up and the rapid initiation of targeted PAH therapy.

  • Patients with SSc and mixed collagenosis are most commonly affected, but other collagenoses are also associated with an increased risk of PAH.

  • An annual echocardiographic screening for PAH is recommended for the SSc, for the other collagenoses only if symptoms and signs of PAH are present.

  • In PAH, an interdisciplinary coordinated approach is of the utmost importance because more side effects and therapeutic interactions are to be expected than in patients with IPAH.

  • Particular attention should be paid to collagenosis-associated PVOD, which poses a particular risk of side effects and complications with PAH drugs.


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  1. Clinical Department for Pulmonology, Medical University Clinic Graz, Auenbruggerplatz 20, 8036, Graz, Austria

    Prof. Dr. H. Olschewski

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Correspondence to Prof. Dr. H. Olschewski.

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H. Olschewski is a consultant, speaker and member of various boards for Actelion, Bayer, Bellerophon, MSD, Pfizer, Novartis, Boehringer, Roche, and Inventiva.

This article does not contain any studies on humans or animals carried out by the authors.

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Olschewski, H. Pulmonary Hypertension and Rheumatic Diseases. Pulmonologist15, 396-403 (2018).

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  • Collagenoses
  • Connective tissue diseases
  • Idiopathic pulmonary arterial hypertension
  • Pulmonary veno-occlusive disease
  • Diagnostic techniques


  • Collagen diseases
  • Connective tissue diseases
  • Idiopathic pulmonary arterial hypertension
  • Pulmonary veno-occlusive disease
  • Diagnostic techniques