Pulmonary Hypertension in Rheumatic Disease

📋 Key Information Summary

📋

Pulmonary arterial hypertension (PAH) in connective tissue disease (CTD) is classified as WHO Group 1; systemic sclerosis (SSc) carries the highest risk with a 10–15% lifetime prevalence of SSc-PAH.
Annual transthoracic echocardiography (TTE) screening is mandatory for all SSc patients from diagnosis — earlier screening is recommended if new symptoms arise.
Right heart catheterisation (RHC) remains the gold standard for confirmation: mean pulmonary artery pressure (mPAP) ≥ 20 mmHg and pulmonary vascular resistance (PVR) ≥ 2 Wood units (WU).
The DETECT algorithm (2012) provides a validated screening pathway for SSc patients to identify those requiring RHC referral.
Differentiate WHO Group 1 PAH from Group 2 (left-heart disease) and Group 3 (ILD-associated PH) — treatment strategies differ substantially.
Anti-centromere antibody positivity and limited cutaneous SSc are associated with a higher risk of isolated PAH; diffuse SSc with anti-Scl-70 increases ILD-PH risk.
Low DLCO on pulmonary function testing (PFTs) is a key early marker — a DLCO < 60% predicted in a patient without significant fibrosis should prompt investigation for PAH.
Targeted PAH therapies include endothelin receptor antagonists (bosentan, ambrisentan, macitentan), PDE-5 inhibitors (sildenafil, tadalafil), soluble guanylate cyclase stimulators (riociguat), and prostacyclin analogues (epoprostenol, iloprost, selexipag).
Upfront combination therapy is recommended for intermediate- and high-risk patients per current ESC/ERS and Australian practice.
BNP and NT-proBNP are essential prognostic markers; serial measurement guides treatment escalation.
WHO functional class (I–IV) is the strongest single predictor of prognosis and guides treatment intensity.
Referral for lung transplantation should be considered early for patients who fail to respond to optimised combination therapy or present in WHO FC III–IV.
Aboriginal and Torres Strait Islander peoples with SSc face delayed diagnosis due to limited access to specialist screening and echocardiography services in remote areas.
SSc-associated digital vasculopathy and renal crisis must be managed in parallel with PAH therapy; bosentan may reduce digital ulcer recurrence.
SSc-PAH carries a guarded prognosis (median survival ~3 years without treatment) but targeted therapy has substantially improved outcomes.

Introduction & Australian Epidemiology

Pulmonary hypertension (PH) is a serious and potentially life-threatening complication of connective tissue diseases (CTDs), particularly systemic sclerosis (SSc). It is characterised by progressive remodelling of the pulmonary vasculature, leading to elevated pulmonary artery pressure, right ventricular failure, and death if untreated. Early detection through systematic screening and institution of targeted vasodilator therapy are the cornerstones of improved patient outcomes.

In Australia, SSc-associated PAH (SSc-PAH) is the most common form of CTD-PAH. The Australian Scleroderma Cohort Study (ASCS) has demonstrated a PAH prevalence of approximately 12% among SSc patients, with the limited cutaneous subset and anti-centromere antibody positivity carrying the greatest risk. Other CTDs associated with PAH include systemic lupus erythematosus (SLE), mixed connective tissue disease (MCTD), Sjögren syndrome, and inflammatory myopathies, though these are substantially less common.

PH in CTD can arise from multiple pathophysiological mechanisms classified by the WHO clinical grouping system. Differentiating WHO Group 1 PAH (pulmonary arterial hypertension) from Group 2 (left-heart disease) and Group 3 (lung disease–associated PH) is critical because treatment approaches diverge. SSc patients may harbour overlapping mechanisms, making accurate classification essential before commencing targeted therapy.

Australian data from the AIHW and the Australasian Society of Clinical Immunology and Allergy (ASCIA) registries indicate that the median age at SSc-PAH diagnosis is approximately 60 years, with a female predominance (3–4 : 1). Mortality remains significant, though the introduction of combination targeted therapy over the past two decades has reduced 3-year mortality from approximately 50% to under 30% in optimally treated cohorts.

Pathophysiology & Classification

WHO Classification of Pulmonary Hypertension

The Dana Point/Venice classification (updated at the 6th World Symposium, Nice 2018) categorises PH into five groups. CTD-related PH most commonly falls into Group 1 (PAH), but left-heart disease (Group 2) and interstitial lung disease (Group 3) are frequent confounders in the rheumatic disease population.

WHO Group	Mechanism	CTD Relevance	Targeted PAH Therapy
Group 1 — PAH	Pulmonary arteriopathy; endothelial dysfunction, smooth muscle proliferation, in situ thrombosis; plexiform lesions	SSc (limited > diffuse), SLE, MCTD, Sjögren, PM/DM	Yes — primary indication
Group 2 — Left-heart disease	Passive back-pressure from diastolic or systolic LV dysfunction, valvular disease	SSc cardiac involvement, SLE myocarditis	No — treat underlying heart disease
Group 3 — Lung disease	Hypoxic vasoconstriction, vascular bed destruction from fibrosis	SSc-ILD (anti-Scl-70), antisynthetase syndrome, SLE-ILD	Generally not (except select combined cases)
Group 4 — CTEPH	Chronic organised thromboembolic obstruction	Rare in CTD; antiphospholipid syndrome association	Surgical PEA; riociguat for inoperable
Group 5 — Unclear/multifactorial	Haematological, metabolic, miscellaneous	Sarcoidosis, chronic haemolytic anaemia	Case-by-case

Pulmonary Vasculopathy in SSc

SSc-PAH is driven by a triad of vascular pathology:

Endothelial dysfunction: Excess endothelin-1 (ET-1) secretion, reduced nitric oxide (NO) and prostacyclin production. This underpins the rationale for ERA and PDE-5i therapy.
Smooth muscle and fibroblast proliferation: Intimal hyperplasia and medial hypertrophy of pulmonary arterioles, narrowing the vascular lumen.
In situ thrombosis: A procoagulant milieu within the pulmonary microvasculature.

Unlike idiopathic PAH (IPAH), SSc-PAH typically shows less plexiform lesion formation and more diffuse distal arteriolar disease. The right ventricle adapts poorly to the increased afterload, and right ventricular (RV) failure is the usual terminal event.

Differentiating SSc-PAH from ILD-PH

A critical distinction: patients with extensive SSc-associated ILD (forced vital capacity [FVC] < 70% predicted, fibrosis on HRCT) may develop PH secondary to lung destruction (WHO Group 3). In mixed PH-ILD, treatment with targeted PAH therapy is controversial and should involve multidisciplinary specialist discussion. Isolated PAH (Group 1) in SSc typically shows relatively preserved lung volumes with disproportionately reduced DLCO.

WHO Functional Classification

Class I

No Limitation

Ordinary physical activity does not cause undue dyspnoea, fatigue, chest pain, or presyncope.

Routine follow-up; screening-detected cases

Class II

Slight Limitation

Comfortable at rest. Ordinary activity causes dyspnoea or fatigue.

Initiation of oral targeted therapy

Class III

Marked Limitation

Comfortable at rest. Less-than-ordinary activity causes symptoms.

Combination oral therapy; consider prostacyclin

Class IV

Inability to Carry Out Any Activity

Signs of right heart failure at rest. Any physical activity worsens symptoms.

IV epoprostenol; urgent transplant referral

Diagnosis & Screening

Screening Strategy in SSc

Given the insidious onset and poor prognosis of SSc-PAH, systematic screening is essential. The Australian Scleroderma Interest Group and international guidelines recommend:

Annual transthoracic echocardiography (TTE) for all SSc patients from the time of diagnosis.
Annual PFTs including DLCO — a falling DLCO disproportionate to FVC decline is a red flag.
Symptom reassessment at every visit — progressive exertional dyspnoea, fatigue, reduced exercise tolerance, or syncope warrant urgent evaluation.
Biomarkers: BNP or NT-proBNP at baseline and annually.

DETECT Algorithm (for SSc)

The DETECT algorithm (Coghlan et al., Ann Rheum Dis 2014) is a validated two-step screening tool for SSc patients with disease duration ≥ 3 years and DLCO < 60% predicted. Step 1 uses clinical and simple laboratory variables to generate a risk score; Step 2 adds echocardiographic and BNP data to determine the need for RHC referral.

ℹ️

DETECT Step 1 variables: Telangiectasia, anti-centromere antibody, FVC % predicted / DLCO % predicted ratio, NT-proBNP, urate, right-axis deviation on ECG, and pericardial effusion on echo.

Transthoracic Echocardiography (TTE) Criteria

TTE estimates the pulmonary artery systolic pressure (PASP) from the tricuspid regurgitation velocity (TRV) using the modified Bernoulli equation plus estimated right atrial pressure. Key thresholds:

PASP > 40 mmHg or TRV > 3.0 m/s — suggestive of PH, warrants RHC.
RV dilation, hypertrophy, or dysfunction on echo — increases pre-test probability.
Pericardial effusion — associated with worse prognosis and higher likelihood of PAH.

⚠️

Important: Echocardiography is a screening tool only. It can both over- and underestimate pulmonary pressures. RHC is required for definitive diagnosis and haemodynamic characterisation.

Right Heart Catheterisation (RHC) — Gold Standard

RHC is mandatory to confirm PAH and classify the haemodynamic severity. The haemodynamic definitions (updated 6th World Symposium, 2018):

Parameter	Definition
Pre-capillary PH	mPAP ≥ 20 mmHg AND PAWP ≤ 15 mmHg AND PVR ≥ 2 WU
Isolated post-capillary PH	mPAP ≥ 20 mmHg AND PAWP > 15 mmHg AND PVR < 2 WU
Combined pre- and post-capillary PH	mPAP ≥ 20 mmHg AND PAWP > 15 mmHg AND PVR ≥ 2 WU

In SSc, pure pre-capillary PAH (Group 1) should show PAWP ≤ 15 mmHg. A raised PAWP suggests left-heart involvement and should redirect treatment focus. Acute vasodilator testing with inhaled nitric oxide or IV epoprostenol should be performed at RHC to identify vasoreactive responders (rare in SSc-PAH but important when present).

Additional Investigations

Available

Pulmonary Function Tests (PFTs)

FVC, TLC, DLCO (corrected for haemoglobin). DLCO < 60% predicted with preserved FVC is a hallmark of SSc-PAH. MBS Item 11503.

Available

Six-Minute Walk Test (6MWT)

Distance < 300 m and/or oxygen desaturation ≥ 5% are poor prognostic markers. Serial 6MWT monitors treatment response.

Available

BNP / NT-proBNP

BNP > 50 pg/mL or NT-proBNP > 300 pg/mL raises concern; very high levels (> 1400 pg/mL NT-proBNP) indicate high risk. MBS Item 66836.

Available

HRCT Chest

Excludes ILD as the predominant cause of PH. Fibrosis extent guides WHO group classification.

Available

Serology

Anti-centromere Ab (higher SSc-PAH risk), anti-Scl-70 (higher ILD-PH risk), ANA, U1-RNP (MCTD association).

Available

V/Q Lung Scan

Screen for chronic thromboembolic PH (WHO Group 4). Mismatched perfusion defects warrant CT pulmonary angiography.

Specialist

Cardiac MRI

Assesses RV size, function, and myocardial fibrosis. Increasingly used in specialist centres for prognostication.

Risk Stratification & Severity Scoring

Risk stratification at baseline and during follow-up determines treatment intensity. The ESC/ERS and REVEAL risk calculators integrate WHO FC, 6MWD, BNP/NT-proBNP, RHC haemodynamics, and echo parameters. In clinical practice, a simplified three-strata approach is commonly used:

Low Risk

Favourable Prognosis

WHO FC I–II; 6MWD > 440 m; BNP < 50 or NT-proBNP < 300; mPAP mildly elevated; RA pressure < 8 mmHg; CI ≥ 2.5 L/min/m².

Oral monotherapy or combination; reassess 3–6 months

Intermediate Risk

Guarded Prognosis

WHO FC III; 6MWD 165–440 m; BNP 50–300 or NT-proBNP 300–1100; moderate haemodynamic impairment.

Upfront dual combination therapy; reassess 3–6 months

High Risk

Poor Prognosis

WHO FC IV; 6MWD < 165 m; BNP > 300 or NT-proBNP > 1100; RA pressure > 14 mmHg; CI < 2.0; signs of RV failure.

Parenteral prostacyclin + combination oral; urgent transplant referral

⚠️

Treatment-to-target approach: Patients not achieving low-risk status at 3–6 month reassessment should have therapy escalated. The goal is to reach and maintain low-risk haemodynamics.

Empirical & Initial Therapy

Supportive therapies should be initiated alongside targeted agents. In CTD-PAH, upfront combination therapy is now standard for patients at intermediate or high risk.

Supportive Measures

Diuretics: Loop diuretics (furosemide 20–80 mg PO daily, or IV for acute decompensation) for volume overload and RV failure. Titrate to euvolaemia.
Supplemental oxygen: Maintain SpO₂ ≥ 90% at rest and during exertion. MBS-subsidised home oxygen available via State/Territory programmes.
Anticoagulation: Routine anticoagulation is not recommended for SSc-PAH due to bleeding risk (especially GI telangiectasia). Consider only if thromboembolic aetiology or immobilisation.
Exercise rehabilitation: Supervised pulmonary rehabilitation improves 6MWD and quality of evidence; available at major centres.
Pregnancy avoidance: ERA and PDE-5i are teratogenic — reliable contraception is mandatory. WHO FC III–IV carries extreme pregnancy risk.

Targeted PAH Therapies — Three Pathways

Current targeted therapies act on three molecular pathways involved in pulmonary vascular remodelling:

Pathway	Drug Class	Australian-Approved Agents
Endothelin pathway	Endothelin receptor antagonists (ERAs)	Bosentan, ambrisentan, macitentan
NO–sGC–cGMP pathway	PDE-5 inhibitors; sGC stimulators	Sildenafil, tadalafil; riociguat
Prostacyclin pathway	Prostacyclin analogues; IP receptor agonists	Epoprostenol (IV), iloprost (inhaled), selexipag (oral)

Directed / Pathogen-Specific Therapy — Drug Details

Endothelin Receptor Antagonists (ERAs)

💊

Bosentan

Tracleer® · ERA (dual ETA/ETB receptor antagonist)

Adult dose 62.5 mg PO BD for 4 weeks, then 125 mg PO BD. Take with or without food.

Paediatric dose Weight-based: 31.25 mg BD (10–20 kg), 62.5 mg BD (20–40 kg), 125 mg BD (> 40 kg)

Route Oral

Key monitoring LFTs monthly (hepatotoxicity risk). Haemoglobin at baseline and 3-monthly (anaemia risk). Teratogenic — pregnancy test monthly.

Renal adjustment No dose adjustment. Caution if CrCl < 30 mL/min (limited data).

Hepatic adjustment Contraindicated if AST/ALT > 3× ULN. Discontinue if LFTs > 5× ULN or rise with symptoms.

Interactions CYP3A4/2C9 inducer. Reduces cyclosporin and warfarin levels. Avoid with glibenclamide (increased hepatotoxicity risk).

PBS status Authority Required — PAH confirmed by RHC; specialist-initiated.

💊

Ambrisentan

Volibris® · Selective ETA receptor antagonist

Adult dose 5 mg PO daily initially; titrate to 10 mg PO daily if tolerated.

Route Oral

Key monitoring LFTs less frequent than bosentan (lower hepatotoxicity risk). Oedema — common but usually mild. Teratogenic.

Renal adjustment No adjustment required.

PBS status Authority Required — PAH confirmed by RHC; specialist-initiated.

💊

Macitentan

Opsumit® · Dual ETA/ETB receptor antagonist (tissue-penetrating)

Adult dose 10 mg PO once daily. No titration needed.

Route Oral

Key monitoring LFTs at baseline then as clinically indicated. Lower hepatotoxicity vs bosentan. Anaemia — check FBC. Teratogenic.

Renal adjustment No dose adjustment. No data in severe renal impairment.

PBS status Authority Required — PAH confirmed by RHC; specialist-initiated.

PDE-5 Inhibitors

💊

Sildenafil

Revatio® · PDE-5 inhibitor

Adult dose 20 mg PO TDS (PAH dose — distinct from erectile dysfunction dosing).

Route Oral

Key monitoring Headache, flushing, dyspepsia. Contraindicated with nitrates (severe hypotension). Visual disturbance (blue tinge) — uncommon.

Renal adjustment Reduce to 20 mg BD if CrCl < 30 mL/min.

PBS status Authority Required — PAH confirmed by RHC; specialist-initiated.

💊

Tadalafil

Adcirca® · PDE-5 inhibitor

Adult dose 40 mg PO once daily. Take with or without food.

Route Oral

Key monitoring Similar side-effect profile to sildenafil. Longer half-life (~17 h). Contraindicated with nitrates.

Renal adjustment 20 mg daily if CrCl 30–50 mL/min. Avoid if CrCl < 30 mL/min.

PBS status Authority Required — PAH confirmed by RHC; specialist-initiated.

Soluble Guanylate Cyclase Stimulator

💊

Riociguat

Adempas® · sGC stimulator

Adult dose 1 mg PO TDS initially; titrate by 0.5 mg TDS every 2 weeks to max 2.5 mg TDS. Target systolic BP ≥ 95 mmHg.

Route Oral

Key monitoring Hypotension (dose-limiting). Contraindicated with PDE-5 inhibitors (dangerous hypotension). Contraindicated with nitrates. Teratogenic.

PBS status Authority Required — Inoperable CTEPH or PAH; specialist-initiated.

Prostacyclin Analogues & IP Receptor Agonists

💉

Epoprostenol

Flolan® / Veletri® · Prostacyclin analogue (IV continuous infusion)

Adult dose Start 2 ng/kg/min IV continuous infusion via central line; titrate by 1–2 ng/kg/min every 15 min to haemodynamic effect. Typical maintenance 20–40 ng/kg/min.

Route Intravenous (continuous ambulatory infusion pump)

Key monitoringFlushing, jaw pain, diarrhoea, limb pain. Risk of catheter sepsis, rebound PH on abrupt cessation. Requires specialist centre management.

PBS status Authority Required — WHO FC III–IV PAH; specialist-initiated in designated centres.

🌬️

Iloprost

Ventavis® · Prostacyclin analogue (inhaled)

Adult dose 2.5–5 mcg via nebuliser 6–9 times daily (minimum 6 doses/day).

Route Inhalation

Key monitoringFlushing, cough, syncope during inhalation. Each session takes 5–10 minutes. Useful as add-on to oral combination therapy.

PBS status Authority Required

💊

Selexipag

Uptravi® · Oral IP receptor agonist

Adult dose 200 mcg PO BD initially; increase by 200 mcg BD weekly to max 1600 mcg BD (tolerability-limited).

Route Oral

Key monitoringDiarrhoea (most common — manage with loperamide), jaw pain, headache, flushing. Non-inferior to IV treprostinil in the GRIPHON trial. Teratogenic.

Renal adjustment Start at 200 mcg once daily if CrCl < 15 mL/min (limited data).

PBS status Authority Required

Recommended Combination Regimens

Current ESC/ERS and Australian expert consensus recommend upfront combination therapy for intermediate- and high-risk patients:

Risk Category	First-Line Combination	Escalation
Low risk (WHO FC I–II)	ERA + PDE-5i (e.g. ambrisentan + tadalafil)	Add selexipag or switch to triple therapy
Intermediate risk (WHO FC III)	Dual oral: ERA + PDE-5i	Add selexipag or inhaled iloprost; consider IV epoprostenol
High risk (WHO FC III–IV)	IV epoprostenol + dual oral therapy	Transplant listing if refractory

🚫

Never combine riociguat with PDE-5 inhibitors — this causes severe, potentially fatal hypotension. If switching from a PDE-5i to riociguat, allow ≥ 24 h washout (sildenafil) or ≥ 48 h (tadalafil).

Monitoring

Structured follow-up is essential for treatment-to-target management. Recommended monitoring schedule:

Baseline

WHO FC, 6MWT, BNP/NT-proBNP, RHC haemodynamics, TTE, PFTs (FVC + DLCO), FBC, LFTs (for ERA), renal function, serology.

3 months

Clinical review, 6MWT, BNP/NT-proBNP, TTE. Reassess WHO FC. Determine if low-risk status achieved — escalate if not.

6 months

Full reassessment including repeat RHC if clinical status ambiguous or deteriorating. PFTs (DLCO trend).

Ongoing (3–6 monthly)

6MWT, BNP/NT-proBNP, TTE, WHO FC at each visit. LFTs monthly for bosentan; as indicated for other ERAs. FBC 3-monthly on ERA.

Transplant referral triggers

Failure to achieve low-risk status after escalation to triple therapy; WHO FC IV despite maximal medical therapy; progressive RV failure.

Special Populations

🤰 Pregnancy

All ERAs, PDE-5i, riociguat, selexipag — teratogenic (FDA Category X). Discontinue and use reliable contraception.

Epoprostenol — the only PAH drug considered relatively safe in pregnancy. Must be managed in a specialist centre.

Pregnancy risk — WHO FC III–IV carries 30–50% maternal mortality in PAH. Pregnancy is generally contraindicated. Multidisciplinary pre-conception counselling is essential.

Breastfeeding — limited data for all agents; advise against breastfeeding during treatment.

👶 Paediatric

Bosentan — PBS-listed for paediatric PAH; weight-based dosing available.

Sildenafil — used off-label in paediatric PAH. STARTS-1 trial data available. Dose: 10 mg TDS (≤ 20 kg), 20 mg TDS (20–40 kg), 20–40 mg TDS (> 40 kg).

Epoprostenol — standard of care for severe paediatric PAH.

Juvenile SSc is rare; PAH screening should follow adult protocols when CTD is diagnosed.

👴 Elderly

All agents — start at lower doses; increased sensitivity to hypotension (PDE-5i, riociguat).

Comorbid left-heart disease is more common in elderly SSc patients — careful haemodynamic assessment (PAWP) at RHC is crucial to avoid misclassification.

Polypharmacy risk — check drug interactions (bosentan with warfarin, cyclosporin).

🫘 Renal Impairment

Bosentan — no formal adjustment; caution if CrCl < 30.

Sildenafil — reduce to 20 mg BD if CrCl < 30.

Tadalafil — 20 mg daily if CrCl 30–50; avoid if CrCl < 30.

Selexipag — 200 mcg once daily if CrCl < 15.

SSc renal crisis must be excluded — ACE inhibitors are standard for SRC but must not be confused with PAH therapy.

🫁 Hepatic Impairment

Bosentan — contraindicated if AST/ALT > 3× ULN. Monitor LFTs monthly.

Ambrisentan — avoid if AST/ALT > 3× ULN.

Macitentan — contraindicated in severe hepatic impairment (Child-Pugh C).

Sildenafil — 20 mg BD in mild–moderate impairment; avoid in severe.

🛡️ Immunocompromised

SSc patients on immunosuppressants (mycophenolate, cyclophosphamide) for ILD may have concurrent PAH. PAH therapies do not directly interact with immunosuppression but drug interactions (bosentan–cyclosporin) must be checked.

Infection risk during IV epoprostenol therapy is significant — central line care protocols are essential.

Aboriginal and Torres Strait Islander Health Considerations

Aboriginal and Torres Strait Islander Health

Epidemiology

SSc prevalence among Aboriginal and Torres Strait Islander peoples is not well characterised in national registries, though available data suggest similar or higher rates of connective tissue disease in some remote communities. The Australian Scleroderma Cohort Study has identified lower Indigenous participation in screening programmes.

Access to screening

Annual echocardiography and specialist rheumatology/cardiology review are often unavailable in remote and very remote Australia. Patient-assisted travel schemes (PATS) exist but are underutilised. Telehealth-enabled TTE interpretation is emerging but not yet standardised nationally.

Delayed diagnosis

Aboriginal and Torres Strait Islander patients with SSc are more likely to present with advanced PAH (WHO FC III–IV) due to delayed access to rheumatology services, lower awareness of screening protocols in primary care, and competing health priorities (diabetes, renal disease, cardiovascular disease).

Cultural safety

Engagement of Aboriginal Health Workers and Practitioners (AHWPs) in PAH screening education is essential. Culturally appropriate patient education materials should address chronic disease management holistically, acknowledging the intersection of PAH with comorbid conditions.

Medication access

All targeted PAH therapies are PBS Authority Required and require specialist initiation. For patients in remote areas, medication delivery via Section 100 / Remote Area Aboriginal Health Services (RAAHS) or Closing the Gap PBS co-payment programmes may improve adherence. Pharmacy access in remote communities remains a barrier.

Recommendations

Establish telehealth pathways linking remote primary care to specialist PAH centres (e.g. Royal Adelaide Hospital, St Vincent's Sydney, Alfred Melbourne). Integrate PAH screening into existing chronic disease health checks (MBS Item 715). Fund culturally safe educational programmes for AHWPs on recognising SSc-related symptoms requiring escalation.

📚 References

1. Galiè N, Humbert M, Vachiery JL, et al. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J. 2016;37(1):67-119.
2. Coghlan JG, Denton CP, Grünig E, et al. Evidence-based detection of pulmonary arterial hypertension in systemic sclerosis: the DETECT study. Ann Rheum Dis. 2014;73(7):1340-1349.
3. Humbert M, Kovacs G, Hoeper MM, et al. 2022 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J. 2022;43(38):3618-3731.
4. Proudman SM, Stevens WM, Sahhar J, Celermajer D. Pulmonary arterial hypertension in systemic sclerosis: the need for early detection and treatment. Intern Med J. 2007;37(7):485-494.
5. Nikpour M, Hissaria P, Byron J, Sahhar J, Micallef M, Pender M, et al. Prevalence, correlates and clinical usefulness of antibodies to RNA polymerase III in systemic sclerosis: a cross-sectional analysis of data from an Australian cohort. Arthritis Res Ther. 2011;13(6):R211.
6. Galie N, Barberà JA, Frost AE, et al. Initial use of ambrisentan plus tadalafil in pulmonary arterial hypertension. N Engl J Med. 2015;373(9):834-844 (AMBITION trial).
7. Pulido T, Adzerikho I, Channick RN, et al. Macitentan and morbidity and mortality in pulmonary arterial hypertension. N Engl J Med. 2013;369(9):809-818 (SERAPHIN trial).
8. Sitbon O, Channick R, Chin KM, et al. Selexipag for the treatment of pulmonary arterial hypertension. N Engl J Med. 2015;373(26):2522-2533 (GRIPHON trial).
9. Ghofrani HA, Galiè N, Grimminger F, et al. Riociguat for the treatment of pulmonary arterial hypertension. N Engl J Med. 2013;369(4):330-340 (PATENT-1 trial).
10. Australian Institute of Health and Welfare (AIHW). Scleroderma in Australia. Cat. no. PHE 292. Canberra: AIHW; 2021.
11. Launay D, Sobanski V, Hachulla E, Humbert M. Pulmonary hypertension in systemic sclerosis: different phenotypes. Eur Respir Rev. 2017;26(145):170056.
12. The Royal Australian College of General Practitioners (RACGP). Guidelines for preventive activities in general practice (Red Book), 9th edn. East Melbourne: RACGP; 2016 (updated 2018).
13. National Aboriginal Community Controlled Health Organisation (NACCHO). Aboriginal and Torres Strait Islander health performance framework: Tier 2 — Determinants of health. Canberra: Australian Government; 2020.