Table 1.

Potential therapies targeting the pathophysiology of each phase of chronic graft-versus-host disease.

cGvHD Phase	Phase 1	Phase 2	Phase 3
Pathophysiology	Acute inflammation and tissue injury activates the innate immune system including the complement system leading to the recruitment of pathogenic cell populations	Loss of tolerance mechanisms disrupts the homeostasis of the adaptive immune system	Aberrant tissue repair mechanism leading to excessive end organ fibrosis and scarring
Relevant monogenic diseases	Primary immune deficiencies (PID) with inflammatory bowel disease (IBD)-like pathology MyD88 and IRAK-4 deficiencies Complement deficiencies	Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome LPS-responsive beige-like anchor protein (LRBA) deficiency Cytotoxic T lymphocyte antigen-4 (CTLA-4) haploinsufficiency Autosomal dominant hyper-IgE syndrome (AD-HIES) IL-12/23 receptor beta 1 (IL-12/23Rβ1) and IL-12/23 cytokine p40 subunit deficiency Glut1 deficiency Leptin deficiency Wiskott-Aldrich syndrome (WAS) B cell activating factor (BAFF) receptor deficiency Gain-of-function mutations in PIK3CD X-linked agammaglobulinemia (XLA)	Matrix metalloproteinase-2 (MMP-2) deficiency Stiff skin syndrome (SSS)
Potential therapies	Treatment of gut dysbiosis: selective use of antibiotics, pre- and probiotics, fecal microbiota transplantation (FMT) TLR inhibition: MyD88 and IRAK-4 inhibitors Statins Hydroxychloroquine Complement inhibitors: Eculizumab [anti-C5 monoclonal antibody (mAb)], narsoplimab (IgG-4 mAb against MASP-2), and coversin (C5 inhibitor)	Thymic transplantation: Medullary thymic epithelial cells (mTECs) Reduce donor T cell migration: Sphingosine 1-phosphate receptor (S1PR) agonists Increase number and function of regulatory T cells (Tregs): Rapamycin (mTOR inhibitor), abatacept (CTLA4-Ig), hydroxychloroquine, low dose IL-2, extracorporeal photopheresis, and infusion of donor-specific or third party Tregs. Targeting the Th17 subset: ROCK2 inhibitor KD025, tocilizumab (mAb against IL-6 receptor), ustekinumab (IL-12 and IL-23 antagonist), pirfenidone Targeting T cell metabolic reprogramming: Inhibition of glycolysis, leptin, glutamate-oxaloacetate transaminase (GOT1), and glutaminase (GLS) Targeting B cell mediated autoimmunity: Rituximab (anti-CD20 mAb), belimumab (anti-BAFF mAb), Syk inhibitors, PI3K inhibitors, ibrutinib (BTK inhibitor)	Target activation of collagen-producing fibroblasts and myofibroblasts: Imatinib mesylate (tyrosine kinase inhibitor), sonidegib (sonic hedgehog pathway inhibitor) Increase levels of dermal MMP-2: Narrowband ultraviolet-B light therapy Integrin inhibition: Natalizumab (mAb against α4-integrin) and vedolizumab (α4β7 inhibitor)

The bolded text in italics describes the mechanism/class of medications that addresses the pathophysiology of that phase of cGvHD.