The Journal of Association of Chest Physicians

: 2022  |  Volume : 10  |  Issue : 2  |  Page : 67--74

Pulmonary manifestations of systemic sclerosis

Supriya Sarkar 
 Department of Pulmonary Medicine, College of Medicine and Sagore Dutta Hospital, Kolkata, India

Correspondence Address:
Supriya Sarkar
Department of Pulmonary Medicine, Uttarayan Apartment, 466 S K B Sarani, Kolkata 700030


Abstract Systemic sclerosis (SSc) is an autoimmune connective tissue disease that primarily involve skin. Pulmonary involvements are important as they influence the outcome of SSc. Interstitial lung diseases (SSc-ILD), pulmonary arterial hypertension (PAH), aspiration pneumonia are common pulmonary lung diseases found in SSc.

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Sarkar S. Pulmonary manifestations of systemic sclerosis.J Assoc Chest Physicians 2022;10:67-74

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Sarkar S. Pulmonary manifestations of systemic sclerosis. J Assoc Chest Physicians [serial online] 2022 [cited 2023 Mar 28 ];10:67-74
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Systemic sclerosis (SSc), also called scleroderma, is an autoimmune disease of the connective tissue and is characterized by the accumulation of collagen and matrix protein in skin and internal organs. SSc may be “limited cutaneous” (affecting the skin of the face, hands, and feet only) or “diffuse cutaneous” (involving the skin of the trunk and in addition may progress to involve visceral organs such as lungs, kidneys, heart, gastrointestinal (GI) tract, and musculoskeletal system). The prognosis of limited cutaneous scleroderma is good with around 75% survival rate by 10 years, whereas that of diffuse cutaneous scleroderma is around 55%. The prognosis depends on visceral involvement mainly of the kidney, lungs, and heart.

Pathogenesis of SSc

The etiology of SSc is not clear. Genetic factors appear to be of limited value. Environmental etiology is also not identifiable. It has been identified that there is a combination of dysregulated immune response, vasculopathy, and fibrosis involved in pathogenesis of SSc. It is postulated that initial insult in SSc is on vascular endothelium resulting in endothelial cell activation and the subsequent release of endothelin-1. There is platelet activation and leukocyte recruitment. There is vasculopathy and activation of transforming growth factor-beta (TGF-β). Ultimately there is recruitment and activation of fibroblasts, their transformation into myofibroblasts, and there is fibrosis of the skin and other organs.

Manifestation of SSc

The skin is thickened and scarred resulting in tight, reddish, or scaly skin. Digital ulcers involving fingertips and rarely over knuckles may be found. Blood vesicles over the affected skin may be visible. Raynaud’s phenomenon is characterized by painful sequential color changes over fingers and toes, particularly after exposure to cold (white color due to vasoconstriction, blue due to cyanosis, and red due to vasodilatation). It may precede the development of other clinical manifestations for years. CREST syndrome consisting of calcinosis, Raynaud’s phenomenon, oesophageal dysfunction, sclerodactyly, and telangiectasia is a form of limited scleroderma. More than 80% of patients have vascular manifestations. Calcinosis (deposition of calcium under the skin) may be found near the elbows, knees, or other joints. Affection of GI tract results in gastroesophageal reflux disease (GERD), gastric and intestinal dysmotility, and indigestion. Involvement of the heart and kidney may cause congestive heart failure and scleroderma renal crisis, respectively. Cardiac involvement in the form of diastolic dysfunction is found in around 17% of cases; however, systolic dysfunction is extremely uncommon (1.7–2%). Interstitial lung disease (ILD), scleroderma renal crisis, and cardiac systolic dysfunction are associated with adverse prognoses.

Diagnosis of SSc

In established disease, the diagnosis is straightforward, particularly evident during the general survey. Patients are not able to open their mouths completely and doctors find it difficult to see the lower palpable conjunctiva. The presence of skin induration in symmetric distribution; the presence of Raynaud’s phenomenon; and typical visceral manifestations usually establish the diagnosis. The detection of autoantibodies such as antinuclear antibodies, anti-centromere antibodies, and anti-topoisomer antibodies (anti-scl70) is sometimes helpful. Full-thickness biopsy of skin and biopsy of internal organs are seldom required for confirmation of diagnosis.

Pulmonary manifestations of SSc

Patients with the extensive cutaneous disease are more prone to have visceral involvement. Mortality due to scleroderma renal crisis, a leading cause of death, is now reduced due to (i) early detection by regular measurement of blood pressure and serum creatinine level, particularly in patients receiving glucocorticoids, and (ii) use of higher doses of angiotensin converting enzyme (ACE) inhibitors and angiotensin-II receptor blockers. Lung involvements will primarily determine the outcome of SSc and they are attracting more attention. Pulmonary manifestations of SSc include scleroderma - interstitial lung diseases (SSc-ILD), pulmonary hypertension (PH), aspiration pneumonia, and some other less common conditions such as pulmonary hemorrhage, pleural effusion, pneumothorax, bronchiectasis, and drug-induced pneumonitis. Malignancies such as lymphoma and adenocarcinoma also occur in patients suffering from SSc.

Aspiration pneumonia

Scleroderma, particularly diffuse cutaneous, affects the GI tract. Oesophageal involvement commonly manifests as reflux esophagitis resulting in peptic stricture or benign narrowing of the esophagus caused by progressive scarring. Oesophageal dysmotility particularly at the lower esophageal sphincter may cause aspiration of gastric contents. The resultant GERD and aspiration pneumonia are important manifestations of SSc.

Treatment is usually with proton pump inhibitors (PPI) and prokinetic agents. It is important to note here that PPI may interfere with drug absorption, particularly mycophenolate mofetil (MMF). At least two hours gap between them is essential. In endoscopic laser phototherapy, octreotide may be used in nonresponsive cases. For indigestion and blotting metronidazole, erythromycin and tetracycline may be used.

Interstitial lung diseases (SSc-ILD)

The presence of ILD in SSc is a bad prognostic sign and will determine the prognosis. Evidence of ILD is found in about 90% of patients at autopsy and 85% of patients by high-resolution computed tomography (HRCT). Clinically significant ILD is found in 16–43% of patients with SSc. Risk factors include male gender, African American race, diffuse skin involvement, GERD, and positive anti-scl70. Pathologically, the condition is characterized by expansion of alveolar interstitium, accumulation of collagen and matrix protein, thickening of the alveolar septum, obliteration of alveolar space, loss of pulmonary vascular bed, and multiple pulmonary emboli.

Diagnosis of SSc-ILD

Early SSc-ILD may be asymptomatic. As the disease progresses, patient may develop a cough, progressive dyspnea, fatigue, and chest pain. Velcro crackles at lung bases are often present. Pulmonary function tests usually show a restrictive pattern with decreasing forced vital capacity (FVC) and total lung capacity (TLC). Diffusion capacity of the lung with carbon monoxide (DLCO) decreases in more than 70% of patients. In the first 3 years, FVC declines rapidly by around 30% per year and the decline usually settled down by the 4th year.

Chest X-ray shows a bilateral symmetrical reticular pattern usually at lung bases. HRCT of the thorax is helpful in the early identification of SSc-ILD. The radiological pattern of ILD in SSc is commonly that of nonspecific interstitial pneumonia and less commonly that of usual interstitial pneumonia. Ground-glass opacity (GGO) with or without reticular opacity is the main finding. GGO in SSc indicates fine fibrosis and deposition of matrix protein and is not always suggestive of alveolitis. Other CT findings include mediastinal lymphadenopathy, nodules, traction bronchiectasis, and honeycombing.

Bronchoalveolar lavage (BAL) can demonstrate inflammation with neutrophils (>2%) and eosinophils (>3%), but BAL is usually performed to exclude infection and other diseases. In atypical cases, lung biopsy may be required. Recently emphasis has been given to KL-6, a glycoprotein found in type II pneumocytes and alveolar macrophages, for monitoring ILD in SSc.

Management of SSc-ILD

General management of SSc-ILD includes smoking cessation, supplementary oxygen (O2) for hypoxemia, treatment of GERD, management of GI dysmotility, vaccination, and pulmonary rehabilitation. It is most important to identify the patients who need specific management as the condition may be self-limiting (around the 4th year) and medicines used have serious side effects.

When to treat SSc-ILD

Factors that determine the decision are patients’ symptoms (degree of dyspnea), pulmonary function status, and HRCT findings. A rapid decline of FVC ≥10% within 3 to 12 months, a rapid decline of DLCO ≥20%, or a decrease of FVC/DLCO ≥10% may be a reliable indicator for starting treatment.

Another important factor is the extent of lung involvement in HRCT thorax. Extents of disease should be done by quantitative HRCT, not by visual assessment. Quantitative HRCT is a computer-aided lung informatics for pathology evaluation and rating system to quantify reticulation, GGO, honeycombing, emphysema, and normal lung. It is well accepted that no treatment is required if lung involvement is less than 10% and specific treatment is indicated if lung involvement is more than 20%. FVC should be considered when lung involvement is between 10% and 20% and specific treatment is indicated if FVC is less than 70%.

Monitoring of treatment

Clinical monitoring should be done by noting improvement of symptoms, exercise tolerance, and findings of physical examination. A lung function test should be done at 3 months intervals including spirometry, DLCO, and 6 minutes work test. HRCT is not a monitoring tool as there are no definite improvement criteria. A change of FVC ≥ 10% or change in FVC between 5% and 10% with a change in DLCO ≥ 15% is considered a significant change in pulmonary function and has got prognostic value. It is always prudent to exclude pleural involvement, pulmonary arterial hypertension (PAH), and aspiration before assessing deterioration.

Drugs with little or questionable effect on SSc-ILD

Drugs with questionable effects in SSc-ILD include D-penicillamine, glucocorticoids, methotrexate, and TNF-α antagonists. Methotrexate was found to improve skin thickness in early SSc but has little effect on visceral manifestations. Glucocorticoids were previously considered as the main medicine. It is found that glucocorticoids have little effect as GGO in SSc-ILD is not due to cellular infiltration and inflammation. Moreover, glucocorticoids may precipitate scleroderma renal crisis. Glucocorticoids should be avoided unless there are extrapulmonary indications such as arthritis and pruritus. When used, it should be used in lower doses and for a shorter duration. In that case, patients should be monitored with measurement of blood pressure and serum creatinine level for early detection of scleroderma renal crisis. Though ACE inhibitors and angiotensin-II receptor blockers have revolutionized the treatment of scleroderma renal crisis, they have no role in the prevention of scleroderma renal crisis.

Medications used in SSc-ILD for induction remission

European League Against Rheumatism (EULAR) had given recommendations for the treatment of scleroderma SSc-ILD. The options may include the following:

Oral cyclophosphamide (CYC): CYC in 1 to 2 mg/kg/day over 1 year is recommended based on the findings of scleroderma lung study I (SLS-I).[1] SLS-I was a double-blind, randomized, placebo-controlled trial conducted over 158 patients and was designed to evaluate the effectiveness and safety of CYC given for 1 year in patients with symptomatic (cough and dyspnea) and active (proved by BAL study or by HRCT thorax) SSc-ILD. CYC was found to improve dyspnea score, lung volumes (FVC and TLC), health-related quality of life, functional ability, and skin thickness. The positive effect peaked in the 18th month and persisted for 2 years. Improvements in FVC and TLC were found to be on average 2.5% and 4.1%, respectively, with P = 0.03. Surprisingly, there was no improvement in DLCO. A subanalysis of the SLS-1 revealed that CYC therapy was also associated with significant improvement in HRCT score. Subanalysis also revealed that the HRCT score and skin disease were independent predictors of response to CYC therapy. The difference between the regression slopes with CYC and placebo was significant (P < 0.009), suggesting that CYC protected against the decline of FVC in patients with fibrosis. The benefit of CYC was mainly due to the inhibition of the progression of SSc-ILD. Side effects of CYC include hematuria, leucopenia, neutropenia, anemia, and pneumonia. Patients should be monitored by complete blood count, urine analysis, and liver and renal function test every 1 to 3 months. The overall risk-benefit ratio was found to be in favor of CYC use, and the experts recommended that CYC therapy should be considered in patients with progressive lung disease.MMF: MMF is a prodrug of mycophenolic acid that inhibits inosine monophosphate dehydrogenase, an enzyme involved in the synthesis of guanosine nucleotides. Scleroderma lung study-II (SLS-II) demonstrated that MMF (500 mg twice daily initially and then increased to 1.5–3 g/day over 3–4 months) was found to have comparable efficacy but better safety profile than CYC.[2] Discontinuation and interruption of treatment due to an adverse reaction was significantly less in the MMF group. Moreover, MMF has an antifibrotic effect through inhibition of TGF-β and fibroblast proliferation. Additionally, the 6-minute walk distance increases with MMF, and a significant improvement in 5-year survival was noted in the MMF group from the onset of disease (95.4% versus 85.7%, P = 0.027) and from the initiation of treatment (91.7% versus 77.8%, P = 0.012).[3] The main adverse effects include GI, myelosuppression, and infection. GI intolerance is common in SSc, but that is not severe enough to preclude its use. EULAR recommended MMF as a preferred medicine for the initial treatment of SSc-ILD.Intravenous cyclophosphamide: Intravenous (i/v) CYC (600 mg /m2 of surface area) every 4 weekly for six doses to be followed by oral azithromycin (2.5 mg/kg/day) or oral MMF may be another option for initial treatment of SSc-ILD. The recommendation is based on the findings of fibrosing alveolitis in the scleroderma trial that demonstrated that cyclic i/v CYC is better tolerated than daily oral CYC.[4] It should be noted that in that study prednisolone (20 mg on alternate days) was coadministered in the active treatment group.Rituximab: A chimeric (human/mouse) monoclonal antibody against CD20 surface antigen is expressed on pre-B and B-lymphocytes. Rituximab results in rapid depletion of B cells from the peripheral circulation in a number of immune-mediated conditions. It may be assumed that rituximab may also be effective in SSc-ILD. Evidence for the effectiveness of rituximab as “rescue” therapy in patients with severe, life-threatening ILD is limited. One study demonstrated that rituximab 1000 mg administered on day 0 and day 14 resulted in FVC improvement of 6.7% (P < 0.01) and stability of DLCO.[5] It was concluded that rituximab may offer an effective therapeutic intervention in patients with severe, progressive non-Idiopathic Pulmonary fibrosis (IPF) ILD unresponsive to conventional immune suppression. Another study observed a median significant improvement of 18% for FVC and 22% for DLCO with rituximab.[6] Rituximab also causes the stability of progression of SSc-ILD. In a selected group of patients with severe, progressive SSc-ILD resistant to conventional immunosuppressive treatment, rituximab therapy may be considered as it was found to be associated with significant clinical and functional improvements.

Management of refractory SSc-ILD[7],[8]

In refractory cases, it is important to exclude other potential factors that may cause deterioration of patients’ condition, such as aspiration, pleural effusion, pericardial effusion, cardiac disease, and PH. Medicines that can be considered for refractory SSc are as follows:Switch of therapy: It is recommended that if the patient was receiving cyclophosphamide, it should be changed to rituximab and vice versa.Antifibrotic therapy: As per the newer classification of ILD, the new entity progressive fibrosing ILD, characterized by dominating fibrosis patterns that progress rapidly from any primary disease, should be treated with antifibrotic agents.Nintedanib: A tyrosine kinase inhibitor reduces the decline of FVC. SENSCIS trial with 150 mg of nintedanib administered orally twice daily demonstrated its beneficial effect.[9] Nintedanib was found to stabilize the decline of FVC (the annual rate of decline in FVC was lower with nintedanib than with placebo). No significant difference was noted regarding skin thickness, lung symptoms, and quality of life. Diarrhea was the commonest side effect. Adding nintedanib may be beneficial in patients not responding to CYC or MMF.Pirfenidone: It is an antifibrotic drug that may be a low-cost alternative to nintedanib. LOTUSS study demonstrated that pirfenidone (1200–1800 mg/day) reduced dyspnea, increased VC, and was found to be well tolerated along with MMF.[10]Tocilizumab: The efficacy and safety trial with tocilizumab, an interleukin 6 receptor-α inhibitor, using a weekly dose of subcutaneous 162 mg showed that it prevented the decline in FVC% at 48 weeks significantly (P = 0·0373).[11] But there was no change in skin thickness and there was an increased risk of serious infections.

Hemopoietic stem cell transplantation (HSCT): The Autologous Stem Cell Transplantation International Scleroderma trial demonstrated that HCST had initial treatment-related mortality and morbidity in the first year and was followed by long symptom-free survival.[12] Causes of treatment-related mortality include viral infection, lymphoma, acute myocardial infarction, heart failure, and acute respiratory distress syndrome. HSCT may be considered in very selected cases of rapidly progressive SSc with risk of organ failure.

Lung transplantation: If facilities are available, lung transplantation may be considered in carefully selected patients not responding to medical treatment after evaluation of GI, renal, and cardiac function. Following lung transplantation, the survival rates in 1st and 5th years are not different in SSc patients compared to ILD of other causes. Female sex and the presence of PAH are bad prognostic factors. However, contrary to the general belief, GERD does not influence the outcome of lung transplantation in SSc-ILD.[13] Double lung transplantation is the usual type of transplantation. The presence of PAH does not justify heart-lung transplantation if right ventricular functions are not grossly altered.

Pulmonary hypertension in SSc

PH is defined as a mean pulmonary arterial pressure >20 mmHg. PAH is defined as PH with a pulmonary capillary wedge pressure (PCWP) <15 mmHg and pulmonary vascular resistance (PVR) ≥3 wood units. Mean arterial pressure (MAP) can be calculated as MAP = 1/3[SBP + 2(DBP)], where SBP is systolic blood pressure and DBP is diastolic blood pressure. Another way to calculate the MAP is MAP = 1/3(SBP – DBP) + DBP, where SBP – DBP is pulse pressure. PH is generally classified into following categories:

Category 1: PAH with normal PCWP that includes idiopathic (sporadic, familial, exposure to drugs or toxins, persistent PH of the newborn, pulmonary capillary hemangiomatosis) and PH associated with collagen vascular disease, portal hypertension, HIV infection, and so on.

Category 2: Pulmonary venous hypertension (elevation in PAP with elevation in PCWP) that includes left-sided atrial or ventricular heart diseases, left-sided valvular heart disease, pulmonary venous obstruction, and pulmonary veno-occlusive disease (PVOD).

Category 3: PH associated with hypoxemic lung disease characterized by chronic hypoxia with mild elevation of PAP that includes chronic obstructive lung disease, ILD, sleep-disordered breathing, alveolar hypoventilation disorders, chronic exposure to high altitude, and developmental abnormalities.

Category 4: PH due to chronic thromboembolic disease with documentation of pulmonary arterial obstruction for >3 months that includes chronic pulmonary thromboembolism and nonthrombotic pulmonary embolism (tumor, foreign material, etc.).

Category 5: PH association with a systemic disease where a causal relationship is not clearly understood and it includes sarcoidosis, chronic anemias, histiocytosis X, lymphangiomatosis, and schistosomiasis.

PH is a major complication of SSc that adversely affects its prognosis. About 15% of SSc patients have PH that can occur in isolation or with ILD. Isolated PH is common in limited cutaneous SSc and with the presence of anticentromere antibodies. PAH is the leading cause of death in SSc and affects up to 12% of all patients with SSc. The mortality rate within 3 years of PAH diagnosis was found to be 50%.[14]

Mechanisms of PH in SSc

PH in SSc may be due to isolated or a combination of many heterogeneous mechanisms and associated with a number of clinical phenotypes. The basic mechanisms can be explained by a range from postcapillary PH to severe precapillary PH, from no ILD to extensive ILD, and from limited cutaneous SSc to diffuse cutaneous SSc.[15] SSc-ILD causes chronic hypoxia that leads to PH due to pulmonary arterial vasoconstriction. PH can therefore be explained by lung fibrosis (PH – Category 3). ILD-associated PH is most common in the diffuse cutaneous SSc. PH may be due to the direct involvement of arteries causing pulmonary arterial vasculopathy (PH – Category 1), which is more common in limited cutaneous SSc. PH in SSc may be due to heart involvement in SSc (PH – Category 2). PH may be due to PVOD-like lesions (PH – Category 1) pathologically characterized by diffuse obstruction of the small pulmonary veins and radiologically characterized by centrilobular ground-glass opacities and septal lines. ILD-associated PH has a dismal prognosis, even worse than that of isolated SSc-PAH.

Clinical manifestations of SSc-PAH

Patients with early PAH are generally asymptomatic. Usually, the presence of PH is very difficult to identify clinically as symptoms may be minimum and/or those may be masked by symptoms of SSc-ILD itself. The initial symptoms are typically exertional dyspnea and reduced exercise capacity. Physical examination may show tachypnea, a prominent pulmonary second heart sound, palpable right ventricular heave, elevated jugular venous pressure, dependent edema, and so on. Unexplained dyspnea or exercise limitations, dyspnea out of proportion to radiology or lung function results, exertional near-syncope, an isolated decline of DLCO, presence of manifestations of PAH or right ventricular failure are important features to suspect associated PH.

The natural history of SSc-PAH is variable, but in many patients it follows a downhill course with the development of right heart failure and has a significantly higher mortality. Risk factors for PAH include limited cutaneous disease, late age at disease onset, severe Raynaud’s phenomenon, and the presence of antibodies to U1-RNP, U3-RNP (fibrillarin), and B23.

Diagnosis of SSc-PH

Clinical manifestations should not be ignored as in early PH in SSc resting echocardiography and pulmonary function test results may be normal. Normal values cannot exclude PH, particularly in dyspneic patients. Pulmonary function testing may show a reduced DLCO in isolation or combined with a restrictive pattern. DLCO showed a weak correlation with the presence of PH (r2 = 0.09, P = 0.006). However, DLCO can improve the detection rate by using a higher threshold value (DLCO <55% predicted).[16] It was noted that among diagnosed PAH patients a lower DLCO value was associated with more advanced PAH.

CT thorax signs suggestive of PH include (i) main pulmonary artery diameter ≥29 mm, (ii) ratio between the diameter of the main pulmonary artery and that of ascending aorta ≥1, and (iii) ratio of the segmental artery to bronchus ≥1:1.

Transthoracic echocardiography (TTE) provides a noninvasive method for estimating the pulmonary arterial pressure and is widely used for screening tests for PH. The cutoff value of echocardiographically estimated pulmonary arterial systolic pressures is not well established. The value exceeding 40 mmHg at rest suggests PAH. The lower cutoff value has more sensitivity but less specificity. Echocardiographically estimated tricuspid gradient (TG) was found to have a positive correlation (r2 = 0.44, P < 0.005) with mean pulmonary pressure.[16] Using higher thresholds (TG > 45 mmHg), echocardiography can adequately diagnose advanced PAH. The value cannot reliably exclude PH where pretest probability is high. High pretest probability factors include unexplained dyspnea, New York Heart Association functional class (NYHA) Class III or IV, corrected DLCO <50%, fall of corrected DLCO > 20%, and so on.

NYHA classification of stages of heart failure includes the following:

Class I – No symptoms and no limitation in ordinary physical activity

Class II – Mild symptoms and slight limitation during ordinary activity

Class III – Marked limitation in activity due to symptoms, for example, walking short distances and comfortable only at rest

Class IV – Severe limitations, even at rest making patients bedbound

Class V – No NYHA class listed or unable to determine

TTE can over- or underestimate PH in SSc. Exercise echocardiography, estimation of PVR by color Doppler, and the use of new contrast media (sonicated albumin) may be useful. Right heart catheterization is the gold standard to confirm the presence of PH and assess the degree and severity of PH and right heart dysfunction. In some cases, left heart catheterization may give additional information.

Vasodilator testing may be done with Epoprostenol, inhaled nitric oxide, or adenosine, and a decrease of ≥10 mm of Hg is considered a positive result. In SSc-PAH, the test is not recommended as a response is found in about 1% of cases and there is a high risk of toxicity. Similarly, exercise-induced PAH (MPAP <25 at rest and >30 mm of Hg during exercise) is not recommended as a normal adult (more than 50 years of age) may show a positive result.

Cardiac MRI has the advantage over TTE as it can visualize right ventricular morphology, myocardial inflammation, and scarring. It can also measure right ventricular volume and its ejection fraction.

Serum levels of brain natriuretic peptide (BNP) and N-terminal pro-BNP correlate with the presence and severity of PAH in SSc. Therefore, BNP measurements can be useful in screening SSc patients and in monitoring the response to treatment. The prognosis of PAH is determined by the degree of pulmonary arterial pressure elevation.

Management of PAH in SSc

Early detection of PAH, a leading cause of death in SSc, and earlier therapeutic intervention may improve prognosis.

Conventional therapy of PAH

General management includes avoidance of risk factors that precipitate the condition, O2 therapy when hypoxia is present, anticoagulant, diuretics, digoxin, glycosides, and so on. Anticoagulant has a high incidence of ulcerative gastritis and antral vascular ectasia and should be used with caution. Management of associated SSc-ILD is important in ILD associated PH.

Specific therapy of PAH

There are three pathways involved in the pathogenesis of PAH: endothelin pathway, prostacyclin pathway, and nitric oxide pathway. Similarly, three groups of medicines are effective against PAH: (i) endothelin receptor antagonist (ERA) that acts on ETA and ETB receptors, (ii) Prostanoids acts on prostacyclin pathway, and in addition they have antiproliferative action and may inhibit platelet aggregation, and (iii) phosphodiesterase 5 inhibitors (PDE5i) that neutralize PDE that degrades cyclic guanylyl cyclase (cGMP), a vasodilator released by smooth muscle and platelets. Riociguat acts by stimulating cGMP. ERAs may be nonselective or selective to ETA receptors, but studies have failed to demonstrate any difference in their activity.

Treatment of less severe SSc-PAH

ERAs (bosentan, ambrisentan, and macitentan) improve exercise capacity and time to clinical worsening in patients with PAH in SSc. Adverse effects of ERA include peripheral edema, palpitations, headache, chest pain, nasal congestion, anemia, and abnormal liver function tests. PDE5i (sildenafil and tadalafil) improve exercise capacity and reduce the risk of clinical worsening. The most common side effects associated with PDE-5 inhibitors are flushing, dyspepsia, headache, myalgia, and diarrhea.[17] Riociguat was found to improve exercise capacity, time to clinical worsening, and hemodynamic parameters.[18] Side effects of riociguat are syncope, dizziness, hypotension, increased hepatic enzyme levels, and acute renal failure. Though the evidences are not strong, experts recommended ERA, PDE5i, and riociguat in the management of SSc-PAH.[17]

Treatment of severe SSc-PAH

Intravenous epoprostenol should be considered for the treatment of patients with severe SSc-PAH (in NYC group III and IV) as one high-quality randomized control trial (RCT) in patients with SSc indicates that continuous intravenous epoprostenol with starting dose of 2 ng/kg/min in combination with the conventional therapy (diuretics, oral anticoagulants, oxygen, and glycosides) improved exercise capacity, functional status, and hemodynamic measures in SSc-PAH.[19] However, due to its very short half-life, epoprostenol is administered by continuous infusion through a permanent indwelling central venous catheter. The indwelling catheter may cause infections, hemorrhage, and pneumothorax. Interruption due to thrombosis or other causes may lead to a life-threatening rebound of PAH. However, epoprostenol causes a statistically significant decline in PVR, mean pulmonary artery pressure, and right atrial pressure. A significant increase in the cardiac index was also noted. Experts recommended epoprostenol for the treatment of severe therapy-resistant SSC-PAH.[20]

Other protanoids approved for the treatment of PAH are (i) treprostinil, which can be used as a subcutaneous bolus, by intravenous infusion, or through inhaled route, and (ii) iloprost, which can be used through inhaled route. In severe or progressive PAH, combination therapy with different PAH-specific drugs may be helpful.

One important proposed model of SSC-PAH management is (i) for World Health Organization (WHO) II & III – start treatment with PDE5i/ERA and follow up and assess every 3 to 6 months; (ii) WHO functional classification IV – start with continuous intravenous epoprostenol; and (iii) in case of nonresponse to treatment in stage II and III or stage IV consider lung transplantation if required infrastructure is available.


Following the substantial reduction of renal complication-related mortality, the focus has been shifted to pulmonary complications of SSc as the main cause of morbidity and mortality. SSc-ILD and SSc-PAH are two major complications that determine the outcome of SSc patients. Early detection of these conditions is an important step and may be difficult as their manifestations are nonspecific. HRCT has revolutionized the diagnosis as well as quantification of SSc-ILD. For the diagnosis of SSc-PAH, the noninvasive tests such as spirometry and echocardiography cannot replace invasive right heart catheterization. General managements include smoking cessation, supplementary O2, treatment of GERD, vaccination and pulmonary rehabilitation for SSc-ILD, avoidance of risk factors, O2 therapy, anticoagulant, diuretics, digoxin, glycosides, and so on for PAH. For specific management of SSc-ILD, both CYC and MMF are equally effective though MMF has fewer side effects and subsequent interruptions. In resistant cases, alternative therapies include rituximab, anti-fibrotic agents, tocilizumab, HSCT, and so on. Specific medication for SSc-PAH includes ERAs and PDE5i for less severe cases and continuous intravenous infusion of epoprostenol for severe or progressive cases. Lung transplantation is the final treatment destination when facilities are available.

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Conflicts of interest

There are no conflicts of interest.


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