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 Table of Contents  
Year : 2017  |  Volume : 12  |  Issue : 1  |  Page : 38-47

Pulmonary hypertension associated with connective tissue disease

1 Department of Pulmonary Medicine, PSG Institute of Medical Sciences and Research, Coimbatore, Tamil Nadu, India
2 Department of Medicine, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India

Date of Web Publication23-Feb-2017

Correspondence Address:
Molly Mary Thabah
Department of Medicine, Jawaharlal Institute of Postgraduate Medical Education and Research, Dhanvantri Nagar, Puducherry - 605 006
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0973-3698.199124

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Pulmonary hypertension (PH) is an important cause of morbidity and mortality in connective tissue diseases (CTDs). CTDs may cause PH due to several mechanisms; pulmonary arterial hypertension, associated interstitial lung disease, neuromuscular disease, and/or sleep disordered breathing leading to hypoxia, associated thromboembolic PH, and pulmonary venous hypertension due to left ventricular dysfunction. PH can be measured on echocardiography, but the gold standard for diagnosis is right heart catheterization. PH-specific therapy in addition to immunosuppression is the most common treatment used though data are scant. In this narrative review, we discuss the epidemiologic burden, clinical presentation, evaluation, and management of PH in CTDs.

Keywords: Connective tissue disease, mixed connective tissue disease, progressive systemic sclerosis, pulmonary hypertension, systemic lupus erythrematosus

How to cite this article:
Rajagopala S, Thabah MM. Pulmonary hypertension associated with connective tissue disease. Indian J Rheumatol 2017;12:38-47

How to cite this URL:
Rajagopala S, Thabah MM. Pulmonary hypertension associated with connective tissue disease. Indian J Rheumatol [serial online] 2017 [cited 2023 Feb 5];12:38-47. Available from:

  Introduction Top

Pulmonary hypertension (PH) is defined by a resting mean pulmonary arterial pressure (mPAP) of ≥25 mm Hg as measured by right heart catheterization (RHC).[1] Pulmonary arterial hypertension (PAH) is a subgroup of PH characterized by precapillary PH, as defined by a pulmonary capillary wedge pressure <15 mm Hg and a pulmonary vascular resistance (PVR) >3 Wood Units, in the absence of other causes of precapillary PH such as lung diseases, chronic thromboembolic PH (CTEPH), or other rare diseases. A wide variety of diseases cause PH [Table 1]; the current classification approaches this from the etio-physiological basis for elevated pulmonary pressures.[2] The right-sided system is a low-pressure system; normal pulmonary arterial systolic pressures (PASP) ranges from 15 to 30 mm Hg, diastolic pressures from 4 to 12 mm Hg and normal mPAP is ≤20 mm Hg. mPAP values between 21 and 24 mm Hg are elevated, but are of uncertain clinical significance.[1] Irrespective of cause, chronic elevation of pulmonary arterial pressures (PAPs) ≥25 mm Hg leads to right ventricular (RV) strain, dilatation, dysfunction, and failure.[3] Connective tissue diseases (CTDs) are the second most common cause of PAH, after idiopathic PAH (iPAH).[4],[5] CTDs may cause PH due to several mechanisms; PAH (Group 1), PH associated with CTD-interstitial lung disease (ILD), neuromuscular disease and/or sleep disordered breathing leading to hypoxia (often secondary to steroid therapy for CTD and weight gain, Group 3), associated CTEPH (Group 4) and pulmonary venous hypertension due to left ventricular dysfunction secondary to cardiomyopathy or accelerated atherosclerosis (systolic or diastolic, Group 2).[6] Pulmonary venoocclusive disease (PVOD) may also be associated with CTD (especially systemic sclerosis [SSc]) and lead to development of PAH.[7] Elucidation of the mechanism in an individual has crucial management and prognostic implications as discussed below. This narrative will discuss the epidemiologic burden, pathophysiology, and evaluation and management of patients with CTD-PAH.
Table 1: World Health Organization classification of pulmonary hypertension[1],[2]

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  Prevalence of Pulmonary Hypertension in Connective Tissue Diseases and Limitations in Available Data Top

There are no community-based prevalence studies about CTD as a cause of PH. Most of our understanding of disease prevalence is from registry-based studies of RHC-confirmed PH that have their own biases. Comparing worldwide rates of CTDs as a cause of PH is further complicated by the inadequacy of RHC data and reporting of echocardiography-based PH diagnosis alone. Although PH can be measured on echocardiography, the gold standard for diagnosis is RHC. There are several problems with the use of echocardiography as the sole diagnostic modality for PH. Echocardiography uses Doppler ultrasound to estimate pulmonary artery pressure. The maximum tricuspid regurgitant (TR) jet is recorded and PASP is calculated using formula PASP = (4 × [TRV]2 + RAP), where RAP is right atrial pressure, TRV is TR velocity measured in m/s. PH is likely if PASP is >50 mm Hg and TRV is >3.4 and unlikely if TRV is ≤2.8. However, as noted above, the diagnosis of PH needs direct measurement of PAP by RHC. Correlation coefficient of PASP between echocardiography and RHC is high at 0.84 for left heart disease, but is much lower (0.58) for right heart disease. Moreover, the difference between the echocardiography and RHC pressures differs by ≥10 mm Hg in 37.6%.[8] Recent data, however, suggests excellent correlation between PH by RHC and RVSP by echocardiography when TR signal is interpretable (area under the curve 0.97 for RVSP and 0.98 for RVSP and eccentricity index (P > 0.05).[9] Tricuspid regurgitation jet, needed to quantify PASP, however, may be absent in up to 20%–39% of patients. In clinical practice, RHC is often restricted to patients with an intermediate probability of moderate PAH, when performed. In registries, CTD as a cause of PAH ranges from 15% to 30%, with SSc accounting for 62%–94% of the patients with CT-PAH [Table 2].[10] In Asian populations, systemic lupus erythrematosus (SLE) has been reported to cause a higher proportion of up to 35%–49% of patients with PH, possibly reflecting the higher prevalence of SLE in this population [Table 2].[11],[12]
Table 2: Prevalence of pulmonary hypertension in connective tissue disease syndromes

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  Pulmonary Hypertension in Systemic Sclerosis Top

Pulmonary complications are the leading cause of death in SSc.[13] This includes the development of ILD, PH or both. Precapillary PH prevalence ranges from 5% to 15% (15% rule) [Table 2].[10] In the DETECT study [Figure 1] that enrolled patients with SSc and risk factors for PH (SSc for >3 years and a diffusing capacity of the lung for carbon monoxide (DLCO) <60% predicted), all patients underwent RHC; 19% of this cohort had RHC confirmed PAH. Another 6% each was contributed by ILD and left heart disease.[14] PH in SSc may be asymptomatic in 22% but is still associated with 64%–89% 2-year mortality.[15] Risk factors include age, long-standing disease, limited SSc, advanced or worsening ILD (low forced vital capacity [FVC] and diffusion capacity for carbon monoxide [DLco]) surrogate markers (clinical [Raynaud's, extensive telangiectasia] and immunological [anti-centromere, anti-U1-ribonucleoprotein, and nucleolar pattern antinuclear antibodies]) markers of the above.[13] Exercise-induced PH has also been recognized as a risk factor, with 20% developing overt PH later. The Cochin index utilizing age, FVC, and DLco/VA has been proposed for prediction of PH in SSc; however, only 17% in the highest quartile have PH and it has not been externally validated yet.[16]
Figure 1: Flowchart showing the DETECT study methodology to screen systemic sclerosis patients for Pulmonary artery hypertension

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  Pulmonary Hypertension in Other Connective Tissue Diseases Top

PH is rare in other CTDs and cohort-level RHC studies are unavailable for any of the other CTD syndromes. In country-based registries of SLE, PH has been reported to occur between 3.8% and 5% of SLE [Table 2] and mixed connective tissue disease (MCTD) based on echocardiography screening; this seems to be similar in both Asian and Western data.[6],[12]

PH is rare in patients with rheumatoid arthritis. Cohort studies have reported a prevalence of 20%–26.7% based on PASP >30 mm Hg; however only 4% (2/50) had values ≥40 mm Hg that are likely to be associated with mPAP ≥25 mm Hg in RHC.[17] Similar data about prevalence is available from smaller cohorts of patients with dermatomyositis and primary Sjogren's syndrome [Table 2].

  Pulmonary Hypertension in Connective Tissue Diseases: the Indian Scenario Top

Data on the prevalence of PH in CTDs in India is scarce. We performed a literature search in PubMed using the search terms “PAH” or “PH” and India. In addition, we also performed three other searches using the terms SSc and India; MCTD and India; SLE and India. This was supplemented by a search in IndMed and the Internet search engine Google using the terms “PAH” or “PH.” The search returned 1675 articles. Abstracts and full texts, where available, were retrieved and data abstracted in a predetermined proforma for information about PH in CTDs in India. Case reports, reviews and observational studies about CTDs cohorts in general were not included. Our search retrieved five studies (two each for SSc and SLE and one for MCTD).[18],[19],[20],[21],[22],[23] There were no articles related to Sjogren's or rheumatoid arthritis. Data from the individual studies on the prevalence of PH in CTDs from India and their limitations are summarized in [Table 3].
Table 3: Published Indian data on prevalence of pulmonary hypertension in connective tissue diseases

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  Pathophysiology Top

Development of PAH is likely a multi-hit process, with pulmonary endothelial injury and immune dysregulation being key events. The initiating event and subsequent pathway for development of PH in most patients remains unclear. Intact bone morphogenetic protein receptor (BMPR2)-signaling pathway is needed for normal lung vascular wound healing. However, few patients with sporadic iPAH or CTD-PAH have BMPR2 mutations and <20% of those with mutations develop PAH. Inactivating or loss of function mutations of BMPR2/transforming growth factor-β and its regulatory pathways (including activin A receptor type II-like-1, SMAD proteins) are permissive for the development of PH due to apoptosis and vascular smooth muscle and endothelial cells proliferation.[24] Several epigenetic factors in this pathway affected by methylation or silencing mRNAs may also be involved in the development of PAH. Impaired T-regulator cell activity in the face of endothelial apoptosis has been theorized to lead to vascular proliferation.[24] Anti-endothelial cell antibodies have also been implicated in the pathogenesis of PAH. They engage endothelial cells, activate complement pathways and platelet binding and induce endothelial cell apoptosis. Precursor and stem cells from the marrow reach the vascular tree, leading to an immune response at the vascular wall. The end result is a “plexiform pulmonary lesion” with angio-obliteration, predominantly localized at vessel bifurcations. Angio-proliferative cells in iPAH show hallmarks of malignancy, and a hypothesis of “quasi-malignancy” has been proposed.[25]

Pathologically, vasoconstriction and remodeling of the small-to-medium sized pulmonary arterioles is the most prominent finding. Abnormalities include proliferation of endothelial cells and intimal thickening, medial hypertrophy, and thickening of the adventitia. Marked interstitial inflammation and fibrotic changes are more prominent in CTD-associated PH when compared to iPAH.[25]

Increased PVR leads to elevated RV afterload and subsequent RV hypertrophy.[26] Over time, secondary changes such as oxidative stress, apoptosis, inflammation, fibrosis and remodeling of the RV leads to dysfunction and failure.[24]

  Clinical Findings of Pulmonary Arterial Hypertension in Connective Tissue Disease Top

Clinical symptoms include exertional dyspnea or fatigue out of proportion to the degree of ILD or in the absence of ILD. Chest pain, hemoptysis and syncope are symptoms of advanced of PH. Examination may reveal a loud pulmonic component of S2, left parasternal lift and a TR murmur. Elevated jugular venous pressure, an RV third heart sound, pedal edema, hepatomegaly and ascites may be seen in advanced RV failure. Clubbing in the presence of PH suggests the presence of ILD, PVOD or associated autoimmune cirrhosis. Clinical examination clues to an underlying CTD in a patient with PAH include telangiectasia, digital ulceration, sclerodactyly and velcro crepitations. Electrocardiography may demonstrateP pulmonale, right-axis deviation, RV hypertrophy, RV strain and bundle branch blocks. Chest radiography or computed tomography (CT) may reveal enlarged pulmonary arteries, attenuation of peripheral pulmonary vasculature, or RV enlargement. Pulmonary function testing often reveals a diffusing capacity that is decreased out of proportion to the severity of the restrictive defect (when present). The role of echocardiography, Doppler and RHC is discussed below.

Serological testing is useful when PAH is evident, and the syndromic diagnosis of CTD is made later. Thyroid function testing, liver function tests and HIV-ELISA should also be obtained in all patients with suspected CTD-PAH.

Six-min walk tests, N-terminal pro brain naturetic peptide (NT-Pro-BNP) levels and arterial blood gas analysis are often obtained at baseline to give predictive information and for follow-up assessments.

Consideration for further evaluation for thromboembolism, obstructive sleep apnea or PVOD is made based on clinical and imaging findings. PVOD is suggested by the presence of at least two of the following on CT; centrilobular nodules, septal thickening, and lymphadenopathy; histopathology obtained by a surgical lung biopsy is needed for definitive diagnosis.[7]

  Screening and Evaluation of a Patient With Suspected Connective Tissue Disease-Pulmonary Arterial Hypertension Top

SSc has a high prevalence of PH and this may be asymptomatic in up to 22% of patients at diagnosis. PH associated with SSc is associated with 64%–89% 2-year mortality.[15] Early detection may improve symptoms and prolong survival, and this provides a strong rationale for screening for PH in patients with SSc. However, there is no consensus on the best method of screening for PH in asymptomatic patients with SSc. Routine echocardiography is not advocated for asymptomatic patients and those with normal spirometry/DLco with SSc as it has very low yield (<0.6%) and false negatives (see above); echocardiography alone may miss 31% of SSc-PAH patients captured using a structured evaluation.[27] A systematic search of published screening algorithms in SSc with RHC confirmed PAH suggested that the positive predictive value of the studied algorithms ranged from 20.4% to 87%.[28],[29] The methodological problems of these studies have been clarified in the DETECT study [Figure 1], screening protocol].[14] Another two-step simplified validated protocol is the Australian scleroderma interest group model [Figure 2] and both algorithms were comparable in performance, out-performing transthoracic echocardiography (TTE)-based recommendations for PH screening in SSc.[30]
Figure 2: Flowchart showing the Australian Scleroderma Interest Group model to screen systemic sclerosis patients for pulmonary artery hypertension

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Patients with breathlessness, presyncopal symptoms are directly evaluated by TTE, with subsequent referral for RHC based on TTE findings. Elucidation of the mechanism of PH is simultaneously performed in all patients. RHC is often needed to definitely diagnose PH and its severity and for excluding left heart disease and left-to-right shunts when echocardiography is inconclusive.[31] Pulmonary angiography may be simultaneously performed if CT-angiography has not performed earlier. Vasodilator reactivity testing during RHC is not recommended in patients with CTD-PAH.[1]

  Management of Patients With Connective Tissue Disease-Pulmonary Arterial Hypertension Top

General measures

Patients with CT-PAH have formed 20%–30% of the cohort in most trials of PAH therapy and hence treatment is generally similar to iPAH. Supplemental oxygen is prescribed for all patients with hypoxemia and CTD-PH, as documented by a resting PaO2 between 55 and 60 mm Hg.[32] We routinely prescribe supplemental oxygen for our patients with CTD-ILD associated PH and sleep or exercise-induced hypoxemia, though this not evidence-based, with a target of oxygen saturation of greater ≥90%. Diuresis may benefit patients with edema and hepatic congestion; care should be taken to avoid hypokalemia and metabolic alkalosis, which can precipitate arrhythmias and depress ventilatory drive.[33] Anticoagulation has strong rationale in PAH; however, evidence for efficacy is lacking.[1] Retrospective data suggest that SSc-PAH have poorer outcomes with anticoagulation due to higher risk of bleeding than iPAH [34] and we do not routinely anticoagulate our patients with CTD-PAH except in the setting of proven venous thromboembolism, severe heart failure or atrial fibrillation.[35] Correction of anemia and/or iron status should be considered in all patients. Exercise training is beneficial for PH and pulmonary rehabilitation improves New York Heart Association (NHYA) functional class and peak oxygen consumption.[1] We routinely offer a 12-week program to all our patients with NYHA II–III CTD-PAH along with appropriate nutritional counseling, vaccination, and assessment for anxiety and/or depression. The role of digoxin in CTD-PAH patients without atrial tachyarrhythmia is unclear. Birth control and discussion of the risks of pregnancy must be discussed in all women in PAH in the reproductive age-group; the toxicities of cyclophosphamide (CYC), including the risk of infertility should also be discussed in CTD-ILD patients with PAH who are about to start CYC. Appropriate vaccinations for pneumococcal pneumonia and influenza prevention are recommended in all patients with CT-PAH before starting on any immunological therapies An algorithm to the management of a newly diagnosed patient with CTD-PAH is presented in [Figure 3].
Figure 3: Flowchart for management of a newly diagnosed patient with connective tissue disease-pulmonary arterial hypertension

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Management of connective tissue disease-pulmonary arterial hypertension (Group 1)

PAH-specific therapies in CTD-PAH [Table 4] target pulmonary vasoconstriction, cellular proliferation, and vascular remodeling by modulating the prostacyclin, endothelin-1 and nitric oxide pathways. An important caveat to the below discussion is that SSc-PAH has been the most studied etiology and that immunosuppression in addition to PAH-specific therapies may be appropriate in SLE and MCTD-PAH.
Table 3a: Risk assessment in pulmonary hypertension

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Table 3b: Suggested assessment and timing for follow-up of patients with connective tissue disease-associated pulmonary arterial hypertension (adapted from 2015 European Society of Cardiology/European Respiratory Society guidelines for diagnosis and treatment of pulmonary hypertension)

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Table 4: Treatment combinations or monotherapy

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Endothelin-1 receptor antagonists can be either nonselective, blocking signaling through A or type B endothelin-1 receptors (bosentan and macitentan), or selective, blocking signaling mediated by only type A endothelin-1 receptors (ambrisentan). Either group has been shown to increase the 6-min walk distance (6MWD) when compared to placebo and reduce mortality when compared to historical data.[1]

Nitric oxide-cyclic guanosine monophosphate enhancers: Phosphodiesterase-5 (PDE-5) inhibitors reduce catabolism of guanylate cyclase (cGMP) and enhance vasodilatation. Sildinafil (dosed at 20 mg thrice a day) and tadalafil (40 mg once a day) are available agents; tadalafil has the advantage of being administered once daily. Riociguat is a soluble stimulator of cGMP recently approved for iPAH and data on SSc-PAH are awaited.

Prostaglandin pathway: Prostacyclin has potent pulmonary vasodilator, anti-platelet aggregating and anti-proliferative properties. In iPAH, epoprostenol has been shown to improve symptoms, NYHA class, exercise capacity, cardiopulmonary hemodynamics and survival. In subsequent trials, intravenous (IV) epoprostenol also improved exercise capacity and hemodynamics in SSc-PAH compared to conventional therapy. Epoprostenol may also have long-term beneficial effects, although effect on survival is unclear. Headache, diarrhea, nausea, and jaw pain are frequent adverse effects of prostacyclin analogs. Further, epoprostenol has to be given by continuous IV infusion through a pump via a central venous line and difficulties with costs, pump loading every 8th hourly, significant adverse effects and temperature sensitivity of the diluted drug has prevented use in resource-constrained settings. Epoprostenol remains the drug of choice in SSc-PAH patients with NYHA III-IV functional class.

Treprostinil is an analog of eproprostenol and is given by continuous subcutaneous route. In a small study of 16 patients (among whom six had CTD-PAH), treprostinil improved 6MWD, NYHA functional class, and hemodynamics after 12 weeks of therapy. Although the safety profile of this drug is similar to IV epoprostenol, required maintenance doses are usually twice as much as epoprostenol. In SSc-PAH and severe PAH or debilitating Raynaud's phenomenon, the lack of requirement of ice packing and less frequent mixing of the drug offer significant advantages.

Iloprost is an inhaled analog delivered by aerosol particles small enough to ensure alveolar deposition. The usual formulation requires as many as nine daily doses because of its relatively short duration of action, with each dose requiring 10–15 min for delivery. Oral selexipag (1600 μg twice daily, GRIPHON study) is a new oral selective nonprostanoid IP prostacyclin-receptor agonist has recently been approved for iPAH; one-third in this trial had CTD-PAH.

Combination therapy (study) with oral ambrisentan and tadalafil has been associated with a 50% reduction in the rate of clinical worsening in NYHA II–III patients with PAH; these effects may be valid in CTD-PAH as well and is the current best practice for NYHA II–IV CTD-PAH.[36]

Venoocclusive disease may also be associated with CTD (especially SSc) and lead to development of PH. Vasodilator therapy may worsen PVOD by causing pulmonary edema and consideration of this possibility is important in every patient with CTD-PAH.

Management of connective tissue disease-interstitial lung disease associated pulmonary arterial hypertension (Group 3)

Specific targeted therapies have not shown to be useful in CTD-ILD associated PH. Endothelin-antagonists have been associated with increased risk of disease progression and hospitalization in idiopathic pulmonary fibrosis;[37] a trial of PDE-5 inhibitors may be attempted in patients with CTD-ILD associated PH who remain in NYHA III–IV after correction of hypoxemia.

In the absence of contraindications, lung transplantation is indicated in patients with CTD-ILD associated PH. Single lung transplantation without cardiopulmonary bypass is appropriate for most patients with moderate ILD-associated PH and emerging data suggest that this is a safe option without an increased risk of primary graft dysfunction.[38]

Management of CTD-PH (Group 3) associated with neuromuscular disease and/or sleep disordered breathing leading to hypoxia is by avoiding therapies that lower PAPs and optimizing neuromuscular disease and sleep disease management by using continuous PAP or bi-level airway pressure devices as appropriate during sleep. Supplemental oxygen may often be needed.

PH associated with thromboembolism (CTEPH, Group 4) is managed by anticoagulation and referral for pulmonary endarterectomy for operable disease and use of endothelin antagonists and PDE-inhibitors for inoperable disease.[1]

PH associated with cardiac dysfunction (Group 2) is managed by diuresis and optimization of cardiac medications.

Role of immunosuppressive therapy for systemic lupus erythrematosus or mixed connective tissue disease associated pulmonary arterial hypertension

Clinical evidence to support the use of immunosuppression for CTD-PAH is from case studies and small series.[39],[40],[41],[42],[43],[44],[45],[46] Most of these studies report a favorable response in SLE or MCTD-PAH but results with SSc have generally been disappointing. The only small controlled trial till date [45] randomized mild to moderate PH, as defined by echocardiography, associated with SLE (n = 34) to either monthly parenteral CYC (0.5 g/m 2) or enalapril 10 mg once daily for 6 months. A greater reduction in PASP and improvement in NYHA class was observed with CYC; however, the small sample size, choice of irrelevant surrogate outcomes, poor definition of PH and short follow-up duration prevent any useful conclusion.

Retrospective Cohorts of SLE or MTCD-PAH with intensive immunosuppressive therapy (IIT) alone have also been reported.[46],[47] In the initial cohort of all CTD-PAH treated with monthly bolus of CYC 600 mg/m 2 for at least 3 months plus oral glucocorticoid (prednisone 0.5–1 mg/day) from a French referral center (n = 28), eight of 28 patients (29%) responded with improvement in hemodynamics and NYHA class. None with SSc-PAH responded and vasodilators were not used in combination with IIT. In the subsequent cohort of SLE or MCTD-PAH treated with IIT alone, 50% (8/16) responded. Of the 30% (7/23) who were treated with a combination of IIT and vasodilators, 57% (4/7) responded.[47]

Small prospective cohorts of CTD-PAH treated with IIT show similar results; these patients were concurrently treated with vasodilators and IIT, with a significant reduction of the mPAP and functional class.[48] A small observational trial of SLE-PAH (n = 24) noted a 45% (11/24) response to monthly CYC and daily prednisolone; however, PH was defined by echocardiography alone, most patients had mild elevation in PASP (25–35 mm Hg) and were treated PDE-5 inhibitors alone.[23]

Taken together, the consistent signals from these reports support the importance of the pathologic finding of greater peri-vascular inflammation in CTD-PAH.[49] Given the poor prognosis of CTD-PAH when compared to iPAH, a trial of IIT in addition to vasodilators in SLE or MCTD-PAH (even in the absence of an overtly active disease SLE or MCTD) is appropriate. Careful patient selection to rule out any active infection, defining PH by RHC where possible, ruling out other causes of PH other than PAH, treating early PAH, using a combination of IIT and vasodilators in NYHA III–IV, use of PCP prophylaxis and a structured management protocol as outlined above may ensure best outcomes based on current evidence.

  Monitoring a Patient With Connective Tissue Disease-Pulmonary Arterial Hypertension Top

PAH is monitored by 3-monthly NYHA and current activity levels, 6 min walking (6MW) tests and NT-Pro-BNP levels [Table 3]a. Worsening is defined as a worsening NYHA class, a change in 6MW distance by at least 50 m and a decrease in DLCO by ≥5% and an elevation in NT-Pro-BNP levels in the absence of an alternative explanation.

  Prognosis of Patients With Connective Tissue Disease-Pulmonary Arterial Hypertension Top

PAH is directly associated with mortality in 88% of patients with PH and prognosis is poor when compared to iPAH.[50] Assessment parameters that may help triage patients and optimize treatment are further discussed in [Table 3]b. PAH associated with SSc is associated with increased mortality when compared to iPAH and SLE-PAH;[51] a meta-analysis of 22 studies representing a total of 2244 patients with SSc-PAH reported showed a pooled 1-, 2-, and 3-year survival rates of 81%, 64%, and 52%, respectively.[52] This has been attributed to the systemic nature of the disease as well as altered RV responses to PH. In a recent prospective registry of 131 patients with SSc-PAH, 1-, 2-, and 3-year survival rates were 93%, 88%, and 75% respectively.[13] Improved outcomes may be associated with the use of PAH-specific therapies [Table 4]; combined use of these along with immunosuppression in non-SSc CTD-PAH is expected to improve outcomes further.

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  [Figure 1], [Figure 2], [Figure 3]

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]

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