Systemic Sclerosis (SSc)

Systemic sclerosis (SSc) is a rare, chronic autoimmune disease that can affect various organs, including the skin, lungs, heart, kidneys, and gastrointestinal tract. SSc is characterized by fibrosis and vascular abnormalities that can lead to organ dysfunction and failure.¹

Treatment of SSc is challenging due to the heterogeneous manifestations of the disease. Therapies used for SSc management typically target active organ-specific complications, and some can target more than 1 active organ system.²

Therapies Targeting Immunomodulation in SSc

The hallmark of SSc is the development of fibrosis following the excessive deposition of extracellular matrix in several organ systems. This fibrosis is powered by myofibroblast differentiation and dysregulation induced by profibrotic mediators, such as transforming growth factor-β (TGF-β). Therapeutic agents available for use in SSc can target both the innate and adaptive immune systems while also displaying antifibrotic effects. Antifibrotic agents can also have anti-inflammatory activity.²

Cytoxan

Cytoxan® (cyclophosphamide) is a regulatory T-cell modulator that induces decreased secretion of interferon γ (IFN-γ) and interleukin (IL)-12. A clinical trial has shown that 12 months of treatment with this drug was linked to significant benefits in terms of cutaneous fibrosis and health-related quality of life.³ This therapy is typically used in the treatment of diffuse cutaneous SSc (dcSSc) and SSc associated with interstitial lung disease (ILD), although not as a first-line therapy due to its unfavorable safety profile, which includes an increased risk of developing malignancies.³

Read more about SSc treatment

CellCept

CellCept® (mycophenolate mofetil) is an inhibitor of inosine monophosphate dehydrogenase that prevents the proliferation of both B and T cells. This therapy is the first-line treatment for SSc associated with ILD and dcSSc. The SLS2 study reported the benefits of CellCept in these patients, which included a better tolerability than Cytoxan. Anemia was the most commonly reported adverse event.³

Read more about SSc clinical trials

Actemra

Actemra® (tocilizumab) is a recombinant humanized antihuman IL-6 receptor monoclonal antibody. IL-6 is a proinflammatory cytokine that is increased in patients with SSc. The extent of skin involvement in SSc correlates with levels of this cytokine. Actemra suppresses the downstream signaling of IL-6.³ Actemra is currently approved for use in patients with rheumatoid arthritis, Castleman disease, and juvenile idiopathic arthritis. It has also been approved by the US Food and Drug Administration (FDA) for use in patients with ILD deriving from SSc.⁴ 

Ofev

Ofev® (nintedanib) is a triple kinase inhibitor that inhibits vascular endothelial growth factor receptor, fibroblast growth factor receptor, and platelet-derived growth factor receptor. This antifibrotic agent suppresses fibroblast proliferation by interfering with signaling pathways in endothelial cells, pericytes, and smooth muscle cells.⁴ Ofev has demonstrated antifibrotic effects in patients with idiopathic pulmonary fibrosis and has therefore been studied as a potential therapy in SSc. The SENSCIS study included patients with ILD associated with SSc and was the basis of FDA approval of the drug in 2019.⁴ However, Ofev is not commonly used as a first-line therapy in ILD associated with SSc because it was not associated with improvements in patient-reported outcomes or the treatment of cutaneous fibrosis.³ 

Read more about SSc experimental therapies

Hematopoietic Stem Cell Transplantation

A significant improvement in both cutaneous disease and ILD may be expected with a hematopoietic stem cell transplantation (HSCT). HSCT is often used as a second-line therapy in patients with early dcSSc when other strategies do not produce results or as a first-line therapy in selected patients.³ However, this therapy carries notable risks, including SSc relapse, secondary autoimmune diseases, gonadal failure, and a higher risk of transplant-related mortality. Because of this, treatment should be reserved for carefully selected patients who meet qualifications.⁵

Read more about SSc prognosis

Other Immunosuppressant Therapies

Other immunosuppressive agents that can be used in the treatment of SSc include methotrexate (for managing skin disease), Imuran® (azathioprine; for managing skin and lung diseases), and Plaquenil® (hydroxychloroquine; for managing skin disease).¹

Therapies Targeting Vascular Modulation in SSc

Vascular events in SSc, such as Raynaud phenomenon, digital ulcers, pulmonary arterial hypertension, erectile dysfunction, and scleroderma renal crisis, are often addressed through vasodilation. Dihydropyridines, such as Norvasc® (amlodipine) and nifedipine (sold as Adalat® and Procardia®, among others), are typically used as first-line agents to manage Raynaud phenomenon.³ Prostaglandin 2 analogs, such as intravenous Ventavis® (iloprost) and epoprostenol (sold as Flolan® and Veletri®) or Orenitram® (oral treprostinil) can also be administered in patients presenting with severe refractory Raynaud phenomenon with digital ischemia.³

For the management of pulmonary arterial hypertension, approved endothelin receptor antagonists such as Letairis® (ambrisentan), Tracleer® (bosentan), and Opsumit® (macitentan), as well as phosphodiesterase isoenzyme 5 inhibitors like Revatio® (sildenafil) and Adcirca® (tadalafil), are used.³ 

Treatment of scleroderma renal crisis includes angiotensin-converting enzyme (ACE) inhibitors such as Capoten® (captopril). However, these agents are not recommended as prophylactic treatment due to associations with increased morbidity and mortality.¹

Read more about SSc complications

References

1. Adigun R, Goyal A, Hariz A. Systemic sclerosis. In: StatPearls [Internet]. Treasure Island, FL: StatPearls Publishing; 2023. Updated May 8, 2022. Accessed April 13, 2023.

2. Bukiri H, Volkmann ER. Current advances in the treatment of systemic sclerosis. Curr Opin Pharmacol. 2022;64:102211. doi:10.1016/j.coph.2022.102211

3. Volkmann ER, Andréasson K, Smith V. Systemic sclerosis. Lancet. 2023;401(10373):304-318. doi:10.1016/S0140-6736(22)01692-0

4. Ebata S, Yoshizaki-Ogawa A, Sato S, Yoshizaki A. New era in systemic sclerosis treatment: recently approved therapeutics. J Clin Med. 2022;11(15):4631. doi:10.3390/jcm11154631

5. Walker UA, Saketkoo LA, Distler O. Haematopoietic stem cell transplantation in systemic sclerosis. RMD Open. 2018;4(1):e000533. doi:10.1136/rmdopen-2017-000533

Reviewed by Hasan Avcu, MD, on 4/19/2023.

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Diana Diez Gaspar, PharmD, PhD

Diana earned her PhD and PharmD with distinction in the field of Medicinal and Pharmaceutical Chemistry at the Universidade do Porto. She is an accomplished oncology scientist with 10+ years of experience in developing and managing R&D projects and research staff directed to the development of small proteins fit for medical use.