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      Steroid-refractory chronic graft-versus-host disease: treatment options and patient management

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          Abstract

          Chronic graft-versus-host disease (cGVHD) is one of the major causes of late mortality after allogenic hematopoietic stem cell transplantation. Moderate-to-severe cGVHD is associated with poor health-related quality of life and substantial disease burden. While corticosteroids with or without calcineurin inhibitors comprise the first-line treatment option, the prognosis for patients with steroid-refractory cGVHD (SR-cGVHD) remains poor. The mechanisms underlying steroid resistance are unclear, and there are no standard second-line treatment guidelines for patients with SR-cGVHD. In this review, we provide an overview on current treatment options of cGVHD and use a series of theoretical case studies to elucidate the rationale of choices of second- and third-line treatment options for patients with SR-cGVHD based on individual patient profiles.

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          Graft-versus-host disease.

          James LM Ferrara, John Levine, Pavan Reddy … (2009)
          Haemopoietic-cell transplantation (HCT) is an intensive therapy used to treat high-risk haematological malignant disorders and other life-threatening haematological and genetic diseases. The main complication of HCT is graft-versus-host disease (GVHD), an immunological disorder that affects many organ systems, including the gastrointestinal tract, liver, skin, and lungs. The number of patients with this complication continues to grow, and many return home from transplant centres after HCT requiring continued treatment with immunosuppressive drugs that increases their risks for serious infections and other complications. In this Seminar, we review our understanding of the risk factors and causes of GHVD, the cellular and cytokine networks implicated in its pathophysiology, and current strategies to prevent and treat the disease. We also summarise supportive-care measures that are essential for management of this medically fragile population.
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            National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: I. The 2014 Diagnosis and Staging Working Group report.

            Madan H Jagasia, Hildegard T Greinix, Mukta Arora … (2015)
            The 2005 National Institutes of Health (NIH) Consensus Conference proposed new criteria for diagnosing and scoring the severity of chronic graft-versus-host disease (GVHD). The 2014 NIH consensus maintains the framework of the prior consensus with further refinement based on new evidence. Revisions have been made to address areas of controversy or confusion, such as the overlap chronic GVHD subcategory and the distinction between active disease and past tissue damage. Diagnostic criteria for involvement of mouth, eyes, genitalia, and lungs have been revised. Categories of chronic GVHD should be defined in ways that indicate prognosis, guide treatment, and define eligibility for clinical trials. Revisions have been made to focus attention on the causes of organ-specific abnormalities. Attribution of organ-specific abnormalities to chronic GVHD has been addressed. This paradigm shift provides greater specificity and more accurately measures the global burden of disease attributed to GVHD, and it will facilitate biomarker association studies.
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              Glucocorticoid resistance in inflammatory diseases.

              Peter Barnes, Ian Adcock (2009)
              Glucocorticoid resistance or insensitivity is a major barrier to the treatment of several common inflammatory diseases-including chronic obstructive pulmonary disease and acute respiratory distress syndrome; it is also an issue for some patients with asthma, rheumatoid arthritis, and inflammatory bowel disease. Several molecular mechanisms of glucocorticoid resistance have now been identified, including activation of mitogen-activated protein (MAP) kinase pathways by certain cytokines, excessive activation of the transcription factor activator protein 1, reduced histone deacetylase-2 (HDAC2) expression, raised macrophage migration inhibitory factor, and increased P-glycoprotein-mediated drug efflux. Patients with glucocorticoid resistance can be treated with alternative broad-spectrum anti-inflammatory treatments, such as calcineurin inhibitors and other immunomodulators, or novel anti-inflammatory treatments, such as inhibitors of phosphodiesterase 4 or nuclear factor kappaB, although these drugs are all likely to have major side-effects. An alternative treatment strategy is to reverse glucocorticoid resistance by blocking its underlying mechanisms. Some examples of this approach are inhibition of p38 MAP kinase, use of vitamin D to restore interleukin-10 response, activation of HDAC2 expression by use of theophylline, antioxidants, or phosphoinositide-3-kinase-delta inhibitors, and inhibition of macrophage migration inhibitory factor and P-glycoprotein.
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                Author and article information

                Contributors
                Daniel Wolff:
                ORCID: http://orcid.org/0000-0001-7015-3190
                daniel.wolff@ukr.de
                Journal
                Journal ID (nlm-ta): Bone Marrow Transplant
                Journal ID (iso-abbrev): Bone Marrow Transplant
                Title: Bone Marrow Transplantation
                Publisher: Nature Publishing Group UK (London )
                ISSN (Print): 0268-3369
                ISSN (Electronic): 1476-5365
                Publication date (Electronic): 3 July 2021
                Publication date PMC-release: 3 July 2021
                Publication date (Print): 2021
                Volume: 56
                Issue: 9
                Pages: 2079-2087
                Affiliations
                [1 ]GRID grid.411941.8, ISNI 0000 0000 9194 7179, Department of Internal Medicine III, , University Hospital Regensburg, ; Regensburg, Germany
                [2 ]GRID grid.411074.7, ISNI 0000 0001 2297 2036, Hospital das Clinicas da Faculdade de Medicina da Universidade de São Paulo (HC-FMUSP), ; São Paulo, Brazil
                [3 ]Vila Nova Star Hospital and IDOR, Rede D’Or, São Paulo, Brazil
                [4 ]GRID grid.13648.38, ISNI 0000 0001 2180 3484, Department of Stem Cell Transplantation, , University Medical Center Hamburg, ; Hamburg, Germany
                [5 ]GRID grid.34477.33, ISNI 0000000122986657, Clinical Research Division, Fred Hutchinson Cancer Research Center and Department of Medicine, , University of Washington, Seattle, ; Seattle, WA USA
                Author information
                http://orcid.org/0000-0001-7015-3190
                http://orcid.org/0000-0001-5103-9966
                Article
                Publisher ID: 1389
                DOI: 10.1038/s41409-021-01389-5
                PMC ID: 8410585
                PubMed ID: 34218265
                SO-VID: b7b90589-39b7-4464-8940-21edd105268b
                Copyright © © The Author(s) 2021
                License:

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                Date received : 13 January 2021
                Date revision received : 14 June 2021
                Date accepted : 22 June 2021
                Funding
                Funded by: FundRef https://doi.org/10.13039/100008272, Novartis Pharmaceuticals Corporation (NPC);
                Award ID: n/a
                Award ID: n/a
                Award ID: n/a
                Award Recipient :
                Categories
                Subject: Review Article
                Custom metadata
                issue-copyright-statement © Springer Nature Limited 2021

                ScienceOpen disciplines: Transplantation
                Keywords: graft-versus-host disease,drug therapy
                Data availability:
                ScienceOpen disciplines: Transplantation
                Keywords: graft-versus-host disease, drug therapy

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