Current perspectives on the immunopathogenesis of systemic sclerosis

Figures & data

Figure 1 Etiopathogenesis of SSc.

Notes: Environmental and genetic factors contribute to the etiology of SSc. The pathogenesis of SSc involves an interplay between vascular, immunological, and fibrotic processes. Vascular injury and endothelial damage are the earliest events in the pathogenesis of SSc. Activated endothelial cells upregulate the expression of adhesion molecules and secrete chemokines, leading to inflammation and autoimmunity. Macrophages and T-cells are the predominant inflammatory cell types of the inflammatory infiltrates and produce cytokines and growth factors that drive the synthesis of extracellular matrix proteins by fibroblasts, resulting in progressive fibrosis. T-cells have also been implicated in autoantibodies production.
Abbreviations: ECM, extracellular matrix; IFN, interferon; IL, interleukin; MMP-1, matrix metalloproteinases-1; PDGF, platelet-derived growth factor; SSc, systemic sclerosis; TGFβ, transforming growth factor beta; Treg, T-regulatory cell; ?, role unknown.

Table 1 Clinical studies of immunotherapeutic candidates in systemic sclerosis

Candidate therapy	Mechanism of action	Main indication	Completed clinical studies	Ongoing clinical studies	Main finding
Cyclophosphamide	Immunosuppression	Early dcSSc		Observational/prospective (NCT02339441)
		SSc-ILD and skin involvement	Multicenter/randomized^Citation167,Citation170 (NCT000004563)		Improvement of lung function and skin score
		Skin involvement	Open label/Phase III (NCT00501995)		Results not yet reported
		Skin involvement/ILD	Single-center/nonplacebo controlled^Citation172		Benefit on skin score and lung stabilization
		SSc-ILD	Observational (NCT01762449)		No results released
		SSc-ILD	Randomized/multicenter^Citation171		Stabilization lung function. No side effects
		SSc-ILD		Randomized/double-blind controlled (NCT01862926)
		SSc-ILD		Randomized/Phase II (NCT00883129)
		SSc-ILD		Randomized/Phase III (NCT01570764)
		SSc-ILD		Observational/prospective (NCT01858259)
Methotrexate	Immunosuppression	Early dcSSc		Observational/prospective NCT02339441
		SSc-ILD		Randomized trial (NCT01858259)
		Early dcSSc	Multicenter/randomized^Citation166		Trend showing the modest improvement of skin score
Mycophenolate mofenil	Immunosuppression	Early dcSSc		Observational/prospective NCT02339441
		SSc-ILD	Open label/safety/efficacy (NCT00333437)		Small number of participants, unreliable or uninterpretable results
		SSc-ILD		Randomized/Phase II(NCT00883129)
		Skin involvement/ILD	Observational/prospective^Citation168		Marked improvement in skin involvement and stabilization of pulmonary function
		SSc-ILD		Observational/prospective (NCT01858259)
Azathioprine	Immunosuppression	SSc-ILD		Observational/prospective (NCT01858259)
Imatinib	Tyrosine kinase inhibition	Skin involvement	Randomized/Phase II^Citation180 (NCT01545427)		Adverse events, poor tolerability. Study terminated
		Skin	Randomized/Phase II^Citation179 (NCT00479934)		No efficacy
		SSc-ILD	Open label/Phase I/II^Citation181 (NCT00512902)		Improvement of lung function. Adverse events
		SSc-ILD	Nonrandomized/Phase II^Citation182		Stabilization lung function
		SSc-associated polyarthritis		Randomized/double blind (NCT01748084)
Rituximab	B-cell CD20^+ blockade	SSc-ILD	Open label/Phase II (NCT00936546)		Improvement of lung function
		SSc skin and lung fibrosis	Multicenter/nested case–control-EUSTAR cohort^Citation184		Improvement of skin and lung fibrosis
		SSc-ILD		Randomized/double-blind controlled (NCT01862926)
		Skin involvement	Open label/Phase I^Citation135,Citation183 (ISRCTN77554566)		Improvement skin score
		SSc-PAH		Randomized/Phase II/multicenter (NCT01086540)
		Joint, skin, and lung involvement		Randomized/Phase II/III (NCT01748084)
Abatacept	T-cell activation blockade			Randomized/Phase II (NCT02161406)
High-dose IVIG	Immunomodulation	Skin involvement	Randomized/placebo controlled^Citation186 (NCT00348296)		Effect on skin sclerosis
		Skin involvement		Randomized/placebo controlled (NCT01785056)
CAT-192	Anti-TGFβ	Skin involvement	Multicenter/randomized/Phase I/II trial^Citation138 (NCT00043706)		No efficacy, excess adverse events
Fresolimumab	Anti-TGFβ	Skin involvement	Open label/Phase I^Citation139 (NCT01284322)
Tucilizumab	Anti-IL-6R mAb	Skin involvement	Multicenter/randomized/Phase III (NCT01532869)		Small number of participants lead to unreliable or uninterpretable data
Rilonacept	IL-1 inhibitor			Randomized trial (NCT01538719)
QAX576	Anti-IL-13 mAb	SSc-pulmonary fibrosis	Multicenter/randomized/placebo controlled (NCT00581997)		Concerns about risk of bronchoscopy procedure in the selected patient population and frequency of severe adverse events
HSCT	Immunosuppression/immunomodulation		Open label, randomized^Citation188 (NCT00278525)		Benefits on skin score and lung function
			Open label, randomized/Phase III^Citation189 (ISRCTN54371254)		Increased treatment-related mortality. Long-term event-free survival benefit
			Open label/Phase I (NCT00282425)		Study terminated. No study results posted
			Open label/nonrandomized/Phase I (NCT00058578)		No results reported
			Open label/nonrandomized/Phase I (NCT00849745)		Study terminated. No results posted
				Multicenter randomized, open label, Phase II (NCT00114530)
				Multicenter/Phase II (NCT01413100)
Mesenchymal stem-cell transplantation	Immunosuppression/immunomodulation		Clinical report cases^Citation203,Citation204		Improvement on skin score. No major adverse events were detected
				Open label/nonrandomized (NCT02213705)

Abbreviations: dcSSc, diffuse cutaneous systemic sclerosis; EUSTAR, European Scleroderma Trial and Research; HSCT, hemopoietic stem-cell transplantation; IL, interleukin; IVIG, intravenous immunoglobulin; PAH, pulmonary arterial hypertension; SSc-ILD, systemic sclerosis-related interstitial lung disease; TGFβ, transforming growth factor beta.

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