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Access through your institution Buy or subscribe We thank the authors for their thoughtful letter regarding our Review article (Pope, J. E. et al. State-of-the-art evidence in the treatment
of systemic sclerosis. _Nat. Rev. Rheumatol_. 19, 212–226 (2023))1, as they raise some interesting points (Andréasson, K. et al. Is classifying SSc-ILD drugs as either immunosuppressive or
anti-fibrotic misleading? _Nat. Rev. Rheumatol_. https://doi.org/10.1038/s41584-023-01013-4 (2023))2. We agree that it is simplistic to categorize drugs as either immunosuppressant
(anti-inflammatory) or anti-fibrotic when considering the treatment of interstitial lung disease (ILD) and pulmonary fibrosis in systemic sclerosis (SSc) and also when considering the
complex nature of SSc in other organs, such as pulmonary arterial hypertension (PAH) and skin disease. For instance, mycophenolate mofetil (MMF) is described as a strong immunosuppressive,
but it also has anti-proliferative and anti-fibrotic effects3. Other important work demonstrates that fibrosis and inflammation co-occur in fibrotic lungs and can alter and/or upregulate
each other’s processes4. Janus kinase (JAK) inhibitors might have beneficial effects in SSc and ILD, although randomized controlled trials need to be performed. In vitro, JAK inhibitors
affect M1 macrophages, which are mainly pro-inflammatory, and profibrotic M2 macrophages. Inhibition of JAK signalling has important anti-inflammatory effects, with reduced expression of
certain markers (CD86, MHCII and TLR4) in M1 macrophages and reduced secretion of markers of M2a activation (CD206 and CCL18), which suggests that immunosuppressive effects can occur in
conjunction with less-studied anti-fibrotic actions5. This is a preview of subscription content, access via your institution ACCESS OPTIONS Access through your institution Access Nature and
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which are calculated during checkout ADDITIONAL ACCESS OPTIONS: * Log in * Learn about institutional subscriptions * Read our FAQs * Contact customer support REFERENCES * Pope, J. E. et al.
State-of-the-art evidence in the treatment of systemic sclerosis. _Nat. Rev. Rheumatol._ 19, 212–226 (2023). Article CAS PubMed PubMed Central Google Scholar * Andréasson, K. et al. Is
classifying SSc-ILD drugs as either immunosuppressive or anti-fibrotic misleading? _Nat. Rev. Rheumatol._ https://doi.org/10.1038/s41584-023-01013-4 (2023). Article PubMed Google Scholar
* Nambiar, A. M., Anzueto, A. R. & Peters, J. I. Effectiveness and safety of mycophenolate mofetil in idiopathic pulmonary fibrosis. _PLoS ONE_ 12, e0176312 (2017). Article PubMed
PubMed Central Google Scholar * Wigén, J., Elowsson-Rendin, L., Karlsson, L., Tykesson, E. & Westergren-Thorsson, G. Glycosaminoglycans: a link between development and regeneration in
the lung. _Stem Cells Dev._ 28, 823–832 (2019). Article PubMed Google Scholar * Lescoat, A. et al. Combined anti-fibrotic and anti-inflammatory properties of JAK-inhibitors on macrophages
in vitro and in vivo: perspectives for scleroderma-associated interstitial lung disease. _Biochem. Pharmacol._ 178, 114103 (2020). Article CAS PubMed Google Scholar * Barnes, H. et al.
Cyclophosphamide for connective tissue disease-associated interstitial lung disease. _Cochrane Database Syst. Rev._ 1, CD010908 (2018). PubMed Google Scholar * Wollin, L. et al.
Antifibrotis and anti-inflammatory activity of the tyrosine kinase inhibitor nintedanib in experimental models of lung fibrosis. _J. Pharmacol. Exp. Ther._ 349, 209–220 (2014). Article
PubMed Google Scholar * Shah, P. V. et al. A review of pirfenidone as an anti-fibrotic in idiopathic pulmonary fibrosis and its probable role in other diseases. _Cureus_ 13, e12482 (2021).
PubMed PubMed Central Google Scholar * Joshi, S. R. et al. Sotatercept analog suppresses inflammation to reverse experimental pulmonary arterial hypertension. _Sci. Rep._ 12, 7803
(2022). Article CAS PubMed PubMed Central Google Scholar Download references AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Division of Rheumatology, St Joseph’s Health Care, London,
Ontario, Canada Janet E. Pope * Department of Medicine, Schulich School of Medicine & Dentistry, University of Western Ontario, London, Ontario, Canada Janet E. Pope Authors * Janet E.
Pope View author publications You can also search for this author inPubMed Google Scholar CORRESPONDING AUTHOR Correspondence to Janet E. Pope. ETHICS DECLARATIONS COMPETING INTERESTS J.E.P.
declares that she has research grants from AbbVie, Bayer, BI, BMS, Frensenius Kabi, Lilly, Mallinckrodt Pharmaceuticals, Merck, Roche and Seattle Genetics; that she has consulted for
AbbVie, Amgen, BI, BMS, Celltrion, EMERALD, Frensenius Kabi, Galapagos, Gilead, Janssen, Lilly, Mallinckrodt Pharmaceuticals, Medexus, Merck, Mitsubishi Tanabe Pharma, Novartis, Pfizer,
Roche, Sandoz, Samsung, Sanofi, Sobi, Teva and Viatris; and that she has been a speaker or attended an advisory board for AbbVie, Amgen, BI, BMS, Frensenius Kabi, Galapagos, Gilead, Janssen,
Lilly, Merck, Novartis, Pfizer, Sandoz, Sanofi and UCB. RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Pope, J.E. Reply to: Is classifying SSc-ILD
drugs as either immunosuppressive or anti-fibrotic misleading?. _Nat Rev Rheumatol_ 19, 676 (2023). https://doi.org/10.1038/s41584-023-01014-3 Download citation * Published: 21 August 2023 *
Issue Date: October 2023 * DOI: https://doi.org/10.1038/s41584-023-01014-3 SHARE THIS ARTICLE Anyone you share the following link with will be able to read this content: Get shareable link
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