Connective Tissue Disease-associated Pulmonary Arterial Hypertension

Connective tissue disease associated pulmonary arterial hypertension is pre-capillary pulmonary arterial hypertension in a patient with an autoimmune rheumatic disease. Systemic sclerosis is the commonest cause. Others are systemic lupus erythematosus, mixed connective tissue disease, Sjogren syndrome, rheumatoid arthritis and dermatomyositis.

Pulmonary arterial hypertension develops in about 8 to 12% of patients with systemic sclerosis, with the highest risk in limited disease with anticentromere antibodies and disease duration over 3 years. It occurs in about 1 to 5% of lupus and a higher share of mixed connective tissue disease.

Outcome in systemic sclerosis is worse than in IPAH. About 1 in 7 patients die within the first year. Lupus and mixed disease patients can respond to immunosuppression.

Pulmonary hypertension in these patients may also arise from interstitial lung disease (group 3), left heart disease (group 2), thromboembolism or pulmonary veno occlusive disease, and these need to be separated because treatment differs.

Pathophysiology.

Vascular injury with endothelial dysfunction, inflammation, autoantibodies against endothelial cells and fibroblasts, and vascular fibrosis produce obliterative pulmonary arteriopathy.

In lupus and mixed disease, immune complex and inflammatory vasculitis are more prominent, which explains the response to immunosuppression. In systemic sclerosis, fibroproliferative remodelling dominates, and immunosuppression does not help.

Right ventricular function is often poorer than in IPAH at equal pulmonary vascular resistance, because of coexisting myocardial fibrosis, microvascular disease and pericardial effusion.

Exertional dyspnoea, fatigue, chest pain, syncope and oedema, which are often attributed to the underlying disease or to interstitial lung disease. Signs of the underlying disease: Raynaud phenomenon, sclerodactyly, digital ulcers, telangiectasia, calcinosis, arthritis, rash, serositis and sicca symptoms. Signs of right heart failure appear late.

• Annual screening in systemic sclerosis (disease duration over 3 years, or diffusing capacity under 60%): echocardiography, pulmonary function tests with diffusing capacity, NT-proBNP, and a ratio of forced vital capacity to diffusing capacity over 1.6 as a flag.
• Right heart catheterisation to confirm: mean pulmonary artery pressure over 20 mmHg, wedge pressure of 15 mmHg or less, pulmonary vascular resistance over 2 Wood units. A wedge pressure of 16 to 18 mmHg needs further assessment because left ventricular diastolic dysfunction is common. Fluid or exercise testing helps.
• High resolution CT to define interstitial lung disease. Severe interstitial disease (forced vital capacity under 60% or fibrosis over 20% of lung volume) points to group 3 disease.
• Autoantibody profile (antinuclear antibody, anticentromere, anti-topoisomerase I, anti-U1 RNP, anti-dsDNA, antiphospholipid antibodies), complement, creatinine, urine protein.
• Ventilation perfusion scan to exclude thromboembolic disease. Echocardiography or MRI for left ventricular function and pericardial effusion.
• Vasoreactivity testing is not useful in systemic sclerosis.
• Risk stratum (annual mortality under 5%, 5 to 10%, over 10%): low risk is functional class I or II, 6-minute walk over 440 m, NT-proBNP under 300 ng/L, right atrial pressure under 8 mmHg; intermediate is class III, 165 to 440 m, NT-proBNP 300 to 1100, right atrial pressure 8 to 14 mmHg; high is class IV, under 165 m, NT-proBNP over 1100, right atrial pressure over 14 mmHg, syncope.

Differential diagnosis.

• Pulmonary hypertension from interstitial lung disease or left heart disease.
• Chronic thromboembolic disease (antiphospholipid syndrome) and pulmonary veno occlusive disease.
• Scleroderma cardiomyopathy and pericardial disease.
• Idiopathic pulmonary arterial hypertension with coexisting autoimmunity, and anaemia or hypoxia from other causes.

Specific therapy. All drugs are continued long term. Therapy follows the usual risk based practice, with initial combination in most patients.

• Ambrisentan 5 mg orally once daily, increased to 10 mg after 4 weeks (maximum 10 mg), with tadalafil 40 mg once daily (start 20 mg in mild to moderate renal or hepatic impairment; avoid when creatinine clearance is under 30 mL/min). Alternative: macitentan 10 mg once daily with tadalafil. Haemoglobin and liver tests at baseline and when indicated. Watch for fluid retention with endothelin receptor antagonists in systemic sclerosis.
• Bosentan 62.5 mg orally twice daily for 4 weeks, then 125 mg twice daily (maximum 250 mg daily) with monthly ALT and AST, may be chosen when digital ulcers are recurrent. It is contraindicated with ciclosporin and glibenclamide.
• Sildenafil 20 mg three times daily is an alternative to tadalafil. Contraindicated with nitrates and riociguat.
• Add on and high risk therapy: selexipag 200 microgram twice daily, increased weekly by 200 microgram twice daily to a maximum of 1600 microgram twice daily; riociguat 1 mg three times daily increased by 0.5 mg every 2 weeks to a maximum of 2.5 mg three times daily (not with phosphodiesterase-5 inhibitors); epoprostenol intravenously from 2 ng/kg/min or treprostinil subcutaneously or intravenously from 1.25 ng/kg/min for high risk; sotatercept 0.3 mg/kg then 0.7 mg/kg subcutaneously every 3 weeks with haemoglobin and platelet checks, using caution when gastric telangiectasia or bleeding is present.
• Calcium channel blockers are not used for pulmonary hypertension in systemic sclerosis.
• Teratogenic drugs (endothelin receptor antagonists, riociguat, sotatercept) need effective contraception and monthly pregnancy tests.

Immunosuppression.

• Lupus and mixed connective tissue disease with active inflammation: prednisolone 0.5 to 1 mg/kg orally daily for 4 weeks, then taper, with cyclophosphamide 0.5 to 1 g/m2 intravenously every 4 weeks for 6 months (reduce dose when eGFR is under 30 mL/min/1.73 m2; mesna and antiemetics; blood count before each dose). Maintenance with azathioprine 1 to 2 mg/kg daily (check thiopurine methyltransferase; full blood count and liver tests every 2 weeks for 2 months, then every 3 months) or mycophenolate mofetil 500 mg twice daily increased to 1 to 1.5 g twice daily. Add specific pulmonary arterial hypertension drugs when functional class remains III or worse, or for no response at 3 to 4 months.
• Systemic sclerosis: immunosuppression does not treat the pulmonary vasculopathy. Avoid prednisolone over 15 mg daily because of scleroderma renal crisis risk. Treat associated interstitial lung disease with mycophenolate mofetil 1 to 1.5 g twice daily, or tocilizumab 162 mg subcutaneously weekly, under rheumatology and respiratory direction.
• Hydroxychloroquine 200 to 400 mg daily in lupus (maximum 5 mg/kg of actual body weight daily; retinal screening at baseline and annually after 5 years; reduce when eGFR is under 30 mL/min/1.73 m2).

General measures. Diuretics (furosemide 40 to 120 mg orally once or twice daily with spironolactone 25 to 100 mg daily, potassium under 5.0 mmol/L and eGFR over 30), oxygen for PaO2 under 8 kPa, vaccination, supervised rehabilitation, correction of iron deficiency, and avoidance of pregnancy. Anticoagulation is not used in systemic sclerosis unless there is an independent indication, because of gastrointestinal telangiectasia and bleeding. Anticoagulate in antiphospholipid syndrome (warfarin to INR 2.0 to 3.0).

Advanced disease. Lung transplantation assessment in selected patients. Severe oesophageal disease and skin involvement need individual assessment but do not exclude it.

Monitoring. Clinical review, 6-minute walk and NT-proBNP every 3 months at first, then every 3 to 6 months. Echocardiography every 6 to 12 months. Annual pulmonary function tests and diffusing capacity. Blood pressure and creatinine at each visit in systemic sclerosis. Right heart catheterisation after treatment change or deterioration.

Referral and escalation. Refer to a pulmonary hypertension centre and rheumatology. Urgent referral for syncope, rapidly rising NT-proBNP, high risk status, or suspected renal crisis.

Special groups.

• Pregnancy: maternal mortality is high, so pregnancy is advised against. Lupus flares add risk. Switch teratogenic drugs before conception only under specialist care, though the pulmonary hypertension itself usually makes pregnancy unsafe.
• Older adults: lower starting doses and greater attention to left heart disease.
• Kidney or liver impairment: adjust cyclophosphamide, mycophenolate, tadalafil, bosentan and ambrisentan as set out.
• Region specific: rule out tuberculosis, HIV and schistosomiasis before escalating immunosuppression where these are prevalent.