Table 2:

Evidence-based treatment options for systemic sclerosis

	Mechanism of action	Benefit in systemic sclerosis	Safety issues
Diffuse cutaneous systemic sclerosis: mycophenolate is commonly used as first-line therapy for diffuse cutaneous systemic sclerosis. Rituximab, cyclophosphamide, and haematopoietic stem-cell transplantation are most often used for treatment-refractory diffuse cutaneous systemic sclerosis
Mycophenolate	Inhibits de-novo production of guanosine nucleotides, impairing both T-cell and B-cell proliferation	Clinically meaningful decrease in modified Rodnan skin score	Generally well tolerated and myelosuppression occurs rarely
Cyclophosphamide	Modulates regulatory T cells, leading to the decreased secretion of interferon γ and IL-12	Clinically meaningful decrease in mRSS and decrease in mRSS compared with placebo	Myelosuppression occurs commonly and haematuria and malignancy are also concerns
Rituximab	Anti-CD20 monoclonal antibody that depletes peripheral B cells	Decrease in mRSS compared with placebo	Opportunistic infection and increased risk of severe COVID-19 infection and inadequate response to COVID-19 vaccination
Haematopoietic stem-cell transplantation	Stem-cell extraction and chemotherapy, followed by transplantation of multipotent haematopoietic stem cells to reconstitute immune system	Greater decrease in mRSS compared with cyclophosphamide	Opportunistic infection, infertility, secondary malignancies, and increased mortality in patients with certain comorbidities
Interstitial lung disease: mycophenolate is commonly used as first-line therapy for interstitial lung disease. Nintedanib, rituximab, cyclophosphamide, and HSCT are most often used as second-line therapies for interstitial lung disease. Tocilizumab can be considered as first-line or second-line therapy for patients with early interstitial lung disease with signs of active systemic inflammation
Mycophenolate	Inhibits de-novo production of guanosine nucleotides, impairing both T-cell and B-cell proliferation	Clinically meaningful improvement in forced vital capacity, radiographic fibrosis, and self-reported dyspnoea	Generally well tolerated and myelosuppression occurs rarely
Cyclophosphamide	Selectively modulates regulatory T cells, leading to the decreased secretion of interferon γ and IL-12	Clinically meaningful improvement in FVC, radiographic fibrosis, and self-reported dyspnoea	Myelosuppression occurs commonly, and haematuria and malignancy are also concerns
Nintedanib	Inhibits several tyrosine kinases	Slowed the decline in FVC compared with placebo	Diarrhoea occurs commonly and baseline systemic sclerosis gastrointestinal involvement should be evaluated before introducing this agent
Rituximab	Anti-CD20 monoclonal antibody that depletes peripheral B cells	Stabilised FVC compared with a decline in FVC in placebo	Opportunistic infection, increased risk of severe COVID-19 infection, and inadequate response to COVID-19 vaccination
Tocilizumab	Humanised monoclonal antibody that blocks the IL-6 receptor	Stabilised FVC compared with a decline in FVC in placebo	Opportunistic infection and might cause dyslipidaemia
Haematopoietic stem-cell transplantation	Stem-cell extraction and chemotherapy, followed by transplantation of multipotent haematopoietic stem cells to reconstitute immune system	Less of a decline in FVC and fewer cases of respiratory failure compared with cyclophosphamide	Opportunistic infection, infertility, and secondary malignancies
Pulmonary arterial hypertension: monotherapy or combination therapy with sildenafil and tadalafil and bosentan and ambrisentan are commonly used as first-line therapy for systemic sclerosis associated with pulmonary arterial hypertension. Selexipag, riociguat, and prostacyclin therapy are most often used as second-line therapies
Sildenafil and tadalafil	Promote vasodilation via nitric oxide-cyclic guanosine monophosphate enhancement	Improved exercise capacity, haemodynamics, and functional class	Hypotension, particularly when used in combination with other vasodilator therapies
Bosentan and ambrisentan	Inhibit endothelin-A and endothelin-B receptor signalling	Improved exercise capacity, haemodynamics, and functional class	Lower extremity oedema and liver-function test abnormalities
Selexipag	Selective oral prostacyclin receptor agonist that results in vasodilation of the pulmonary vascular bed	Reduction in the number of hospitalisations and disease progression	Headache, diarrhoea, and nausea
Riociguat	Stimulates soluble guanylate cyclase, regardless of nitric oxide concentrations, to produce more cyclic guanosine monophosphate, resulting in vasodilation	Improved exercise capacity, haemodynamics, and functional class	Gastro-oesophageal reflux disease, diarrhoea, nausea, dizziness, and headache
Prostacyclin therapy (eg, reprostinil, epoprostenol, iloprost, and beraprost)	Prostacyclin agonist that promotes relaxation of smooth muscle, inhibition of platelet aggregation, and vasodilation of pulmonary arteries	Improved exercise capacity, haemodynamics, and functional class	Headache, diarrhoea, and nausea
Raynaud phenomenon and digital ulcers: calcium channel blockers are commonly used as first-line therapy for Raynaud phenomenon. Sildenafil and tadalafil or bosentan are often used as second-line therapies for Raynaud phenomenon and first-line therapies for digital ulcers. Fluoxetin and iloprost are often considered for patients with treatment-refractory Raynaud phenomenon and digital ulcers
Calcium channel blockers	Inhibit calcium entry into cells resulting in vascular smooth-muscle relaxation and reduction in systemic vascular resistance	Reduction in frequency and severity of Raynaud phenomenon	Lower-extremity oedema
Fluoxetine	Promotes vasodilation and disruption of normal platelet aggregation	Reduction in frequency and severity of Raynaud phenomenon	Sexual dysfunction, dry mouth, and anxiety
Sildenafil and tadalafil	Promote vasodilation via nitric oxide-cyclic guanosine monophosphate enhancement	Varying evidence to support their use in the treatment and prevention of Raynaud phenomenon and digital ulcers	Hypotension, particularly when used in combination with other vasodilator therapies
Iloprost	Promotes vasodilation via prostacyclin pathway	Prevention of new and healing of existing digital ulcers	Headache and hypotension
Bosentan	Inhibits endothelin-A and endothelin-B receptor signalling	Reduction in development of new digital ulcers	Lower-extremity oedema and liver-function test abnormalities

Randomised controlled trials in systemic sclerosis have largely focused on the treatment for systemic sclerosis skin disease, systemic sclerosis associated with interstitial lung disease, systemic sclerosis associated with pulmonary arterial hypertension, systemic sclerosis-related Raynaud phenomenon, and digital ulcers. FVC=forced vital capacity. IL=interleukin. mRSS=modified Rodnan skin score.