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Is biological therapy in systemic sclerosis the answer?

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Abstract

Systemic sclerosis is a systemic fibrosing disorder associated with significant morbidity and mortality, with no universally accepted disease-modifying therapy. Significant advances in the understanding of systemic sclerosis in recent years have guided the exploration of biological drugs in systemic sclerosis. In this narrative review, we summarize the published literature on biologic therapies in systemic sclerosis. A double-blind randomized trial, and an open label trial of tocilizumab (which antagonizes the interleukin 6 receptor), identified potential benefits in skin and lung fibrosis in systemic sclerosis; however, these differences failed to attain statistical significance. Two open-label trials compared rituximab (which depletes B lymphocytes) to conventional treatment/ cyclophosphamide in systemic sclerosis-associated interstitial lung disease (ILD), and revealed significant improvements in lung functions and skin disease with rituximab. Significant observational data also support the use of rituximab in skin, lung, muscle and joint manifestations of systemic sclerosis. Abatacept (which blocks T lymphocyte activation) has demonstrated utility for skin and joint disease in systemic sclerosis; a recent clinical trial failed to demonstrate benefits in improving skin thickness compared to placebo. Agents targeting type I interferons, interleukin 17 pathway, CD19 and plasma cells hold promise in systemic sclerosis; however, high-quality evidence is lacking. The results of different ongoing clinical trials targeting B lymphocytes, T lymphocytes, various cytokines (interleukins 6, 17, 4, 13, IL-1α), platelet-derived growth factor receptor, proteasome, integrins or oncostatin M may help guide future therapeutic regimens with biological agents in systemic sclerosis.

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Abbreviations

ABA:

Abatacept

ANI:

Anifrolumab

BAFF:

B cell activating factor

BEL:

Belimumab

BLys:

B lymphocyte activating factor

CI:

Confidence intervals

CTLA4:

Cytotoxic T lymphocyte associated antigen 4

DLCO:

Diffusion lung capacity for carbon monoxide

EUSTAR:

European Scleroderma Trials and Research Group

FRE:

Fresolizumab

FVC:

Forced vital capacity

GVHD:

Graft-versus-host disease

IFN:

Interferon

IL:

Interleukin

ILD:

Interstitial lung disease

INE:

Inebilizumab

MMF:

Mycophenolate mofetil

mRSS:

Modified Rodnan skin score

PDGFR:

Platelet derived growth factor receptor

RCT:

Randomized controlled trial

RTX:

Rituximab

SSc:

Systemic sclerosis

STAT3:

Signal transducer and activator of transcription 3

TOC:

Tocilizumab

TGFβ:

Transforming growth factor beta

Th:

T helper

TNFα:

Tumour necrosis factor alpha

TNFi:

TNF inhibitors

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Authors and Affiliations

  1. Department of Clinical Immunology and Rheumatology, Sanjay Gandhi Postgraduate Institute of Medical Sciences (SGPGIMS), Lucknow, 226014, India

    Durga Prasanna Misra & Vikas Agarwal

  2. Department of Clinical Immunology and Rheumatology, Kalinga Institute of Medical Sciences, Bhubaneswar, India

    Sakir Ahmed

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  1. Durga Prasanna Misra
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  2. Sakir Ahmed
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  3. Vikas Agarwal
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Contributions

The conception and design of the study—DPM, VA; acquisition of data, analysis and interpretation of data—DPM, SA, VA. Drafting the article—DPM, SA; Revising it critically for important intellectual content—VA. Final approval of the version to be submitted—DPM, SA, VA. Agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved—DPM, SA, VA.

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Correspondence to Durga Prasanna Misra.

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Durga Prasanna Misra declares that he has no conflict of interest, including no relationship with pharmaceutical companies. Sakir Ahmed declares that he has no conflict of interest, including no relationship with pharmaceutical companies. Vikas Agarwal declares that he has no conflict of interest, including no relationship with pharmaceutical companies.

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Misra, D.P., Ahmed, S. & Agarwal, V. Is biological therapy in systemic sclerosis the answer?. Rheumatol Int 40, 679–694 (2020). https://doi.org/10.1007/s00296-020-04515-6

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