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Therapeutic Approaches to Systemic Sclerosis: Recent Approvals and Future Candidate Therapies

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Abstract

Systemic sclerosis is the rheumatic disease with the highest individual mortality. The severity of the disease is determined by the extent of fibrotic changes to cutaneous and internal organ tissues, the most life-threatening visceral manifestations being interstitial lung disease, SSc-associated-pulmonary arterial hypertension and myocardial involvement. The heterogeneity of the disease has initially hindered the design of successful clinical trials, but considerations on classification criteria have improved patient selection in trials, allowing the identification of more homogeneous groups of patients based on progressive visceral manifestations or the extent of skin involvement with a focus of patients with early disease. Two major subsets of systemic sclerosis are classically described: limited cutaneous systemic sclerosis characterized by distal skin fibrosis and the diffuse subset with distal and proximal skin thickening. Beyond this dichotomic subgrouping of systemic sclerosis, new phenotypic considerations based on antibody subtypes have provided a better understanding of the heterogeneity of the disease, anti-Scl70 antibodies being associated with progressive interstitial lung disease regardless of cutaneous involvement. Two targeted therapies, tocilizumab (a monoclonal antibody targeting interleukin-6 receptors (IL-6R)) and nintedanib (a tyrosine kinase inhibitor), have recently been approved by the American Food & Drug Administration to limit the decline of lung function in patients with SSc-associated interstitial lung disease, demonstrating that such better understanding of the disease pathogenesis with the identification of key targets can lead to therapeutic advances in the management of some visceral manifestations of the disease. This review will provide a brief overview of the pathogenesis of SSc and will present a selection of therapies recently approved or evaluated in this context. Therapies evaluated and approved in SSc-ILD will be emphasized and a review of recent phase II trials in diffuse cutaneous systemic sclerosis will be proposed. We will also discuss selected therapeutic pathways currently under investigation in systemic sclerosis that still lack clinical data in this context but that may show promising results in the future based on preclinical data.

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Abbreviations

α-MSH:

Alpha-melanocyte-stimulating hormone

ACR-CRISS:

American College of Rheumatology Composite Response Index for Clinical Trials in Early Diffuse Cutaneous Systemic Sclerosis

FDA:

American Food & Drug Administration

BAFF:

B cell-activating factor

BLyS:

B Lymphocyte Stimulator

BTK:

Bruton’s tyrosine kinase

CRP:

C-reactive protein

CCR3:

C-C chemokine receptor type 3

CTGF:

Connective tissue growth factor

cGMP:

Cyclic guanosine monophosphate

CYC:

Cyclophosphamide

dcSSc:

Diffuse cutaneous systemic sclerosis

DLco:

Diffusing lung capacity of carbon monoxide

EndoMT:

Endothelial to mesenchymal transition

EMT:

Epithelial to mesenchymal transition

EUSTAR:

European Scleroderma Trials and Research group

ECM:

Extracellular matrix

FGF:

Fibroblast growth factor

FVC:

Forced vital capacity

HAQ-DI:

Health assessment questionnaire-quality index

IL-6:

Interleukin 6

ILD:

Interstitial lung disease

IVIg:

Intravenous Immunoglobulins

JAK:

Janus kinase

LcSSc:

Limited cutaneous systemic sclerosis

mRSS:

Modified Rodnan total Skin thickness Score

MMF:

Mycophenolate mofetil

PROs:

Patient reported outcomes

PDGF:

Platelet-derived growth factor

PKG:

Protein kinase G

PAH:

Pulmonary arterial hypertension

RCT:

Randomized controlled trial

SLS-I:

Scleroderma Lung Study I

SLS-II:

Scleroderma Lung Study II

SRC:

Scleroderma renal crisis

sGC:

Soluble guanylate cyclase

SSc:

Systemic sclerosis

TLR:

Toll-like receptor

TGF-β:

Transforming growth factor-β

UCLA GIT 2.0:

University of California Los Angeles Scleroderma Clinical Trials Consortium gastrointestinal tract 2.0

VEGF:

Vascular endothelial growth factor

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Funding

Dr. Khanna was supported by the NIH/NIAMS K24-AR063120 and R01- AR-070470. Dr. Lescoat was funded by the French network of the University Hospitals HUGO (Hôpitaux Universitaires du Grand Ouest) (AAP JCM2020) and a grant from Rennes University Hospital (CORECT Visiting Grant 2020). Dr. Roofeh was funded by the NIH/NIAMS T32-AR007080. Dr. Lafyatis was funded by NIH/NIAMS P50 AR060780.

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Authors and Affiliations

  1. Department of Internal Medicine and Clinical Immunology, Rennes University Hospital, Rennes, France

    Alain Lescoat

  2. Univ Rennes, CHU Rennes, Inserm, EHESP, Irset (Institut de Recherche en Santé, Environnement et Travail) - UMR_S 1085, Rennes, France

    Alain Lescoat

  3. Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA

    Alain Lescoat, David Roofeh & Dinesh Khanna

  4. Michigan Scleroderma Program, University of Michigan, Ann Arbor, MI, USA

    Alain Lescoat, David Roofeh & Dinesh Khanna

  5. Department of Allergy and Rheumatology, Nippon Medical School Graduate School of Medicine, Tokyo, Japan

    Masataka Kuwana

  6. Division of Rheumatology and Clinical Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    Robert Lafyatis

  7. INSERM U1016 and CNRS UMR8104, Institut Cochin, Paris, France

    Yannick Allanore

  8. Université de Paris, Université Paris Descartes, Paris, France

    Yannick Allanore

  9. Service de Rhumatologie, Hôpital Cochin, AP-HP.CUP, Paris, France

    Yannick Allanore

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  1. Alain Lescoat
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  2. David Roofeh
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  3. Masataka Kuwana
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  4. Robert Lafyatis
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  5. Yannick Allanore
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  6. Dinesh Khanna
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All authors made substantial contributions to the writing of this review, revised it critically for important intellectual content, approved the version to be published and agreed to be accountable for all aspects of this review. All authors agreed with the content of this review and gave explicit consent to submit.

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Correspondence to Dinesh Khanna.

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Conflict of Interest

AL: Nothing to disclose. DR: Nothing to disclose. MK: Grant support from Boehringer-Ingelheim, Ono Pharmaceuticals, Consultant: AbbVie, Boehringer-Ingelheim, Corbus, Mochida, Kissei, Galapagos NV, Speaker bureau: Asahi Kasei Pharma, Astellas, Boehringer-Ingelheim, Chugai. GSK, Janssen. Mitsubishi-Tanabe, Nippon Shinyaku. RL: has served as a consultant for Pfizer, Bristol Myers Squibb, Boehringer-Ingleheim, Formation, Sanofi, Boehringer-Mannheim, Merck and Genentech/Roche; holds or recently had research grants from Corbus, Formation, Moderna, Regeneron, Pfizer and Kiniksa and holds equity in Thirona Bio. YA: Grant support from Alpine ImmunoSciences, Roche and Sanofi. Consultant: Bayer, Boehringer Ingelheim, Genentech/Roche, Medsenic, Sanofi-Aventis. DK: Grant support from NIH, Immune Tolerance Network, Bayer, BMS, Horizon, Pfizer. Consultant: Acceleron, Actelion, Abbvie, Amgen, Bayer, Boehringer Ingelheim, CSL Behring, Corbus, Gilead, Galapagos, Genentech/Roche, GSK, Horizon, Merck, Mitsubishi Tanabe Pharma, Sanofi-Aventis, and United Therapeutics. Stocks: Eicos Sciences, Inc (less than 5%). Leadership/Equity position – Chief Medical Officer, CiviBioPharma/Eicos Sciences, Inc.

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Lescoat, A., Roofeh, D., Kuwana, M. et al. Therapeutic Approaches to Systemic Sclerosis: Recent Approvals and Future Candidate Therapies. Clinic Rev Allerg Immunol 64, 239–261 (2023). https://doi.org/10.1007/s12016-021-08891-0

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