Systemic Sclerosis

Systemic sclerosis (SSc), also known as scleroderma, is a disease characterized by autoimmunity, vasculopathy, and fibrosis of the skin and internal organs. SSc has a poor prognosis, and mortality risk is estimated anywhere between two- to fivefold higher than in the general population. Most SSc-related deaths are due to complications of pulmonary fibrosis; pulmonary arterial hypertension; cardiac, renal, or gastrointestinal disease; and infections. There is no cure for any manifestation of SSc.

The American College of Rheumatology (ACR) has defined the following subsets of systemic sclerosis:

limited cutaneous SSc (lcSSc) includes CREST syndrome (calcifications, Raynaud phenomenon, esophageal hypomotility, sclerodactyly, and telangiectasia)
diffuse cutaneous SSc (dcSSc), defined by skin involvement of the trunk or proximal extremities
SSc without skin involvement(or “systemic sclerosis sine scleroderma” [ssSSc])

Clinical Manifestations

The range of systems that can be affected by systemic sclerosis are outlined in the following table:

Organ Involvement and Clinical Manifestations of Systemic Sclerosis

System	Symptoms & Signs
Skin	Scleroderma lcSSc: typically restricted to the extremities (distal to the forearms and knees), face, and neck dcSSc: involves chest, abdomen, forearms, upper arms, and shoulders Sclerodactyly Telangiectasias
Musculoskeletal	Fibrosis around tendons and nerves, manifesting as: arthralgia tendinopathy myalgia neuropathy
Vascular	Raynaud phenomenon (occurs in almost all patients with SSc) Abnormalities in nail-fold capillaries (seen best using a dermatoscope or other similar device, although more-severe abnormalities can be visualized on gross inspection) Digital ulcers or pitting
Gastrointestinal	Esophageal or intestinal dysmotility Wide-mouthed diverticula Telangiectasias Gastric antral vascular ectasia Primary biliary cirrhosis
Renal	Mild-to-moderate proteinuria Increased creatinine Hypertension Scleroderma renal crisis
Pulmonary	Interstitial lung disease Pulmonary arterial hypertension Pleuritis Endobronchial telangiectasias
Cardiac	Cardiac fibrosis Coronary artery disease Pericarditis

Raynaud phenomenon: Although not diagnostic for SSc, Raynaud phenomenon develops in almost all patients with SSc:

[Image] — **Findings in Patients with Raynaud Phenomenon**

Diagnosis

There is no single test to confirm diagnosis of SSc. The diagnosis depends on a combination of clinical, laboratory, and, in some cases, pathologic manifestations. In 2013, the ACR revised classification criteria for SSc. These guidelines are more sensitive for identifying early SSc and are useful for evaluating patients with possible SSc. Using this classification system, a score of 9 classifies a patient as having definite SSC. However, as with other classification criteria, they are intended for research purposes, and clinicians must recognize that some patients may have the disease and not meet classification criteria.

Treatment

Treatment varies depending on each individual patient’s clinical manifestations. Therapies are either immunomodulatory or they target vascular function, fibrosis, or specific symptoms (i.e., proton pump inhibitors for reflux). For an outline of important management considerations, see table 2, “Management Principles,” from Mayo Clinic Proceedings, “My Approach to the Treatment of Scleroderma.”

Current Available Treatments for SSc

Indication	Therapy	Mechanism of Action
Skin changes	Glucocorticoids (used cautiously due to potential link with renal crisis)	Anti-inflammatory Immunosuppression
Skin changes	Methotrexate Mycophenolate mofetil	Immunosuppression
Musculoskeletal changes	Glucocorticoids	Anti-inflammatory Immunosuppression
	Methotrexate Leflunomide	Immunosuppression
	Surgery for nerve entrapment	Reduction in pressure on nerve
Raynaud phenomenon	Avoidance of exposure to the cold	Prevents vasoconstriction
	Topical nitrates	Promotes vasodilation
	Calcium-channel blockers, especially dihydropyridine-type	Vasodilation
	Iloprost	Synthetic analogue of prostacyclin (prostaglandin I₂ [PGI₂])
Digital ulceration	Aspirin	Antiplatelet agent
	Sildenafil/tadalafil	Phosphodiesterase type 5 (PDE-5) inhibitor
	Bosentan	Endothelial receptor antagonist
Gastrointestinal dysmotility	Metoclopramide Erythromycin	Promotility agents
Reflux	Pantoprazole Omeprazole	Proton pump inhibitor
Renal crisis	Captopril Ramipril Perindopril	Angiotensin-converting-enzyme (ACE) inhibitor
Interstitial lung disease	Glucocorticoids	Anti-inflammatory Immunosuppression
Interstitial lung disease	Cyclophosphamide Mycophenolate mofetil Rituximab Nintedanib Tocilizumab	Immunosuppression
Pulmonary arterial hypertension	Supplemental oxygen	Improved cardiac and systemic oxygenation
	Ambrisentan Bosentan Macitentan	Endothelial receptor antagonist
	Riociguat	Stimulates soluble guanylate cyclase
	Epoprostenol Treprostinil	Synthetic prostacyclin analogue
Rapidly progressive SSc with risk of organ failure	Autologous hemopoietic stem-cell transplantation Lung transplantation	Immunomodulatory Resets immune system

Research

Landmark clinical trials and other important studies

Research

Nintedanib in Progressive Fibrosing Interstitial Lung Diseases

Flaherty KR et al. for the INBUILD Trial Investigators. N Engl J Med 2019.

In patients with progressive fibrosing interstitial lung diseases, the annual rate of decline in the FVC was significantly lower among patients who received nintedanib than among those who received placebo. Diarrhea was a common adverse event.

Nintedanib for Systemic Sclerosis-Associated Interstitial Lung Disease

Distler O et al. for the SENCIS Trial Investigators. N Engl J Med 2019.

Among patients with ILD associated with systemic sclerosis, the annual rate of decline in FVC was lower with nintedanib than with placebo; no clinical benefit of nintedanib was observed for other manifestations of systemic sclerosis. The adverse-event profile of nintedanib observed in this trial was similar to that observed in patients with idiopathic pulmonary fibrosis; gastrointestinal adverse events, including diarrhea, were more common with nintedanib than with placebo.

Mycophenolate Mofetil versus Oral Cyclophosphamide in Scleroderma-Related Interstitial Lung Disease (SLS II): A Randomised Controlled, Double-Blind, Parallel Group Trial

Tashkin DP et al. Lancet Respir Med 2016.

In this randomized, controlled trial, mycophenolate mofetil was shown to be noninferior to oral cyclophosphamide in the treatment of scleroderma-related interstitial lung disease.

A Prospective Observational Study of Mycophenolate Mofetil Treatment in Progressive Diffuse Cutaneous Systemic Sclerosis of Recent Onset

Mendoza FA et al. J Rheumatol 2012.

This prospective observational study showed improvements in skin and pulmonary function with use of mycophenolate mofetil in patients with diffuse progressive cutaneous SSc.

Cyclophosphamide versus Placebo in Scleroderma Lung Disease

Tashkin DP et al. for the Scleroderma Lung Study Research Group. N Engl J Med 2006.

In this randomized controlled trial, patients with scleroderma associated interstitial lung disease who received cyclophosphamide had modest improvements in lung function, dyspnea, thickening of the skin, and health-related quality of life than patients who received placebo.

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