Review Article

Cutaneous graft-versus-host disease: From acute reactions to chronic sequelae

Caroline Possanner^‡, Maria Sanz Codina^‡, Florian Winkler^‡, Luisa Thebault^‡, Christoph Müller^‡, Ara Cho^‡, Wolfgang Bauer^‡, Georg Stary^‡§, Wolfgang Weninger^‡, Johanna Strobl^‡§

‡ Department of Dermatology, Medical University of Vienna, Vienna, Austria

§ CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria

Corresponding author: Johanna Strobl ( johanna.strobl@meduniwien.ac.at )

Academic editor: Johann W. Bauer

This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY-NC 4.0), which permits to copy and distribute the article for non-commercial purposes, provided that the article is not altered or modified and the original author and source are credited.

Citation: Possanner C, Sanz Codina M, Winkler F, Thebault L, Müller C, Cho A, Bauer W, Stary G, Weninger W, Strobl J (2026) Cutaneous graft-versus-host disease: From acute reactions to chronic sequelae. SKINdeep 2: e199609. https://doi.org/10.1553/skindeep.2026.199609

Abstract

Graft-versus-host disease (GVHD) is a frequent immune-mediated complication following allogeneic hematopoietic stem cell transplantation (HSCT), caused by a fundamental function of the immune system – the ability to distinguish between self and non-self.

As a multi-systemic disorder, GVHD is characterized by tissue inflammation and fibrosis, primarily affecting the skin and mucosal surface, gastrointestinal tract, liver, and lungs. Given the potential involvement of multiple organs, a wide spectrum of clinical manifestations may be observed.

Since cutaneous and mucosal manifestations are not only the most frequent finding in GVHD, but often the earliest and most clinically apparent, dermatologists play a critical role in early recognition and diagnosis. The cutaneous involvement can be complex and diagnostically challenging. This review aims to provide a comprehensive overview of the diverse skin manifestations in acute and chronic GVHD to facilitate a correct and timely diagnosis. Furthermore, we summarize current therapeutic options for GVHD subtypes to support appropriate treatment and optimize clinical outcomes.

Key words:

Graft-versus-host disease, allogeneic hematopoietic stem cell transplantation, inflammatory skin diseases

List of abbreviations

aGVHD, Acute graft-versus-host disease

allo-HSCT, Allogeneic-hematopoietic stem cell transplantation

APC, Antigen-presenting cells

ATG, Anti-thymocyte globulin

BAFF, B-cell activating factor

BSA, Body’s surface area

cGVHD, Chronic graft-versus-host disease

CSF1R, Colony stimulating factor 1 receptor Inhibitor

CTL, Cytotoxic T lymphocyte

DAMP, Danger-associated molecular pattern

DAPI, 4',6-diamidino-2-phenylindole

DLI, Donor lymphocyte infusion

ECM, Extracellular matrix

ECP, Extracorporeal photopheresis

EMA, European Medicines Agency

FasL, Fas-Ligand

FDA, Food and Drug Administration

G-CSF, Granulocyte colony-stimulating factor

GM-CSF, Granulocyte-macrophage colony-stimulating factor

GVHD, Graft-versus-host disease

GVL, Graft versus leukemia

H&E, Hematoxylin-Eosin stain

HLA, Human Leukocyte Antigen

HSCT, Hematopoietic stem cell transplantation

HSV, Herpes Simplex Virus

IFN-γ, Interferon gamma

IL-1, Interleukin-1

IL-10, Interleukin-10

IL-12, Interleukin-12

IL-17, Interleukin-17

IL-1β, Interleukin-1β

IL-2, Interleukin-2

IL-22, Interleukin-22

IL-6, Interleukin-6

LP, Lichen planus

LPS, Lipopolysaccharide

M, Macrophage

MAGIC, Mount Sinai acute GVHD International Consortium

mTOR, Mechanistic Target of Rapamycin Inhibitor

NIH, National Institutes of Health

NK, Natural killer cell

PAMP, Pathogen-associated molecular pattern

PDGF, Platelet-Derived Growth Factor

PTCy, Post-transplant cyclophosphamide

ROCK2, Rho-associated protein kinase Inhibitor2

SJS/TEN, Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis

Tfh, T-follicular helper cells

TGF-β, Transforming growth factor-beta

TLR, Toll-like receptor

TNF-α, Tumor necrosis factor alpha

TRAIL, Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand

Treg, Regulatory T-cell

T_RM, Tissue-resident memory T-cells

UVA, Ultraviolet A

1. Background

Allogeneic HSCT has transformed the treatment of a wide array of hematologic malignancies and genetic diseases. However, GVHD resulting from alloreactive donor T-cell responses against host tissues remains the major non-relapse complication and limits application to severe cases. Depending on host and graft factors, between 40 to 60% of patients who have undergone HSCT are affected by GVHD in its acute form. The incidence of chronic GVHD post-HSCT ranges from 30% to 70% [1]. Furthermore, GVHD accounts for around 15% of deaths following HSCT [2]. Skin involvement can be found in 75–90% of acute GVHD cases and 70–90% of chronic GVHD cases [3, 4].

In rare cases, GVHD can also occur after blood product transfusions, solid organ transplantation, and even autologous HSCT [2]. In the allogeneic HSCT setting, human leucocyte antigen (HLA) mismatch is the strongest determinant of GVHD occurrence, but minor histocompatibility antigens are also thought to play a role in its pathophysiology [1, 2, 5].

Other risk factors include advanced age of the recipient or donor, gender disparity between host and donor, myeloablative conditioning regimens, nonconventional GVHD prophylaxis, the use of peripheral blood stem cells as the graft source, and the use of peripheral G-CSF (granulocyte colony-stimulating factor) – mobilized blood stem cells. However, in the latter case, there is only an association with chronic GVHD, not with the acute forms [1, 6, 7].

Despite its substantial morbidity and mortality, GVHD is associated with a positive effect known as graft versus leukemia (GVL), whereby donor-derived immune cells recognize and eliminate residual malignant host cells. Through this enhanced antineoplastic activity, the GVL effect contributes substantially to long-term disease control and reduced relapse rates following allogeneic HSCT. GVL is particularly desired in patients receiving reduced-intensity conditioning regimens, in whom direct cytotoxic eradication of malignant cells is limited and relies heavily on immune-mediated tumor control. Consequently, depending on the patient’s underlying disease, remission status at transplantation, and conditioning regimen, mild GVHD has been considered a clinical correlate of beneficial donor immune activity [1, 2, 8]. However, this relationship is complex, as increasing GVHD severity is associated with substantial treatment-related morbidity and mortality, underscoring the need to balance preservation of GVL activity with prevention of excessive tissue damage [9, 10].

2. GVHD classification

A distinction is made between the acute and chronic forms of GVHD. Both aGVHD and cGVHD are the result of the interaction between cellular/immune mediators from the immunological graft and host tissues. Although there are some features in which the two syndromes overlap, there are significant differences in aspects of the underlying pathophysiology, pathology, clinical manifestations, and management [11].

Originally, GVHD was classified depending on the timing of presentation after HSCT into acute and chronic, with a 100-days cutoff. The manifestation of GVHD within the initial 100 days post-transplantation was categorized as acute, while those occurring after 100 days were designated as chronic, irrespective of clinical presentation. Since then, expanding transplant practices affecting the recipient’s immune status, such as reduced-intensity conditioning regimes, infusion of donor lymphocytes (DLI), and second allogenic HSCT, have altered the classical onset of both acute and chronic manifestations. Furthermore, the tapering and withdrawal of systemic immunosuppression have been frequently associated with the relapse of acute GVHD following 100 days of HSCT [2, 6]. Consequently, the NIH consensus conference redefined these classifications based on clinical manifestations, thereby establishing two primary categories of GVHD, each further subdivided into additional categories [2, 12–14].

Classic aGVHD presents within 100 days of transplantation with typical clinical features of aGVHD.
Persistent, recurrent, or late-onset aGVHD manifests with clinical features of classic aGVHD >100 days after transplantation.
Classic cGVHD presents >100 days after transplantation with classic clinical features of cGVHD.
Overlap syndrome may occur at any time post-transplant with features of both acute and chronic GVHD.

3. GVHD pathophysiology

Despite advances in HLA typing, prophylaxis, and immunomodulatory therapies, GVHD remains a principal cause of morbidity and mortality, and impaired long-term quality of life in transplant recipients. Beyond the historical distinction by time of onset, aGVHD and cGVHD are now recognized to reflect overlapping yet mechanistically distinct immunopathological processes. Acute GVHD is primarily driven by conditioning-induced tissue damage, early inflammatory responses, and donor T-cell-mediated cytotoxicity, whereas chronic GVHD engages complex interactions between T-cells, B cells, innate immune cells, and fibroblasts, resulting in sustained inflammation, autoimmunity, and fibrosis (Fig. 1) [4, 15, 16].

Figure 1.

Model of GVHD pathophysiology in 3 phases. The conditioning regimen causes significant tissue damage and dysbiosis, resulting in the secretion of pro-inflammatory cytokines, such as tumor necrosis factor (TNF-α) and interleukins 1 and 6 (IL-1 and IL-6), and the leakage of lipopolysaccharide (LPS). These activate antigen-presenting cells (APCs) in Phase (1). Associated loss of microbial diversity and its metabolites results in disruption of epithelial and immune homeostasis. In Phase (2), host APCs activate mature donor T-cells contained in the stem cell inoculum. Donor T-cells proliferate and differentiate into Th1 and Th17 cells, which activate CD4+ and CD8+ cytotoxic T lymphocytes (CTLs), as well as natural killer (NK) cells, leading to tissue damage. Fas-Ligand (FasL) and Perforin contribute to target cell apoptosis. In Phase (3), effector T-cells, together with pro-inflammatory cytokines such as IFN-γ, IL-2, IL-17, and IL-22, attack epithelial cells in the skin, liver, lungs and gastrointestinal tract. This phenomenon is exacerbated by LPS leakage, leading to the recruitment of myeloid cells, including macrophages (M), which further intensify the cytokine storm. Created in BioRender. Strobl, J. (2026) https://BioRender.com/84l8czt.

3.1 Acute skin GVHD pathophysiology

As detailed above, aGVHD typically occurs within the first 100 days after HSCT, though “late acute” forms may present beyond this window due to delayed immune reconstitution or prolonged immunosuppression. The canonical pathophysiological framework consists of three interconnected phases involving tissue injury, donor T-cell activation, and effector-mediated target organ damage. This model has been substantially refined by recent advances emphasizing the critical contribution of innate immunity, host tissue-resident immune cells, and cytokine networks [4, 15, 17–19].

3.1.1 Conditioning-induced tissue damage

Pre-transplant conditioning regimens using chemotherapeutic agents and/or total body irradiation induce widespread cellular stress and cell death, leading to epithelial and endothelial injury. This initial damage is not immunologically inert; it generates a highly inflammatory microenvironment through the release of danger-associated molecular patterns (DAMPs). Simultaneously, disruption of epithelial barriers facilitates the translocation of pathogen-associated molecular patterns (PAMPs), including lipopolysaccharide (LPS), which activate Toll-like receptor (TLR) signaling pathway and promote inflammasome activation [4]. These events result in the robust production of proinflammatory cytokines, including TNF-α, IL-1β, IL-6, and IL-12, establishing a cytokine-rich milieu that primes alloimmune responses. Residual host antigen-presenting cells (APCs) that survive conditioning play a pivotal role in initiating diseases by upregulating HLA molecules, increasing expression of costimulatory molecules (CD80/86, CD40), and secreting pro-inflammatory cytokines [20]. Damage to organ barriers further amplifies inflammation through translocation of microbial products, which may further activate innate immune pathways through TLR4 [4, 15, 21].

In human skin, epidermal Langerhans cells form a specialized cell population capable of presenting host antigens to donor T-cells. Notably, Langerhans cells are relatively resistant to conditioning-induced depletion and may persist after transplantation despite the replacement of other host dendritic cell and macrophage populations. Experimental studies have shown that persistent recipient Langerhans cells can promote the development of cutaneous GVHD, whereas their depletion or replacement by donor Langerhans cells is associated with protection against skin GVHD [20].

Moreover, conditioning does not uniformly eliminate tissue-resident immune populations. Longitudinal analyses of human skin after allo-HSCT have demonstrated that a substantial proportion of host-derived CD69⁺ tissue-resident memory T-cells (T_RM) survive myeloablative radiochemotherapy and persist in the skin after transplantation. In contrast to circulating T-cells, these cutaneous T_RM display relative resistance to genotoxic stress and show minimal transcriptional signatures of apoptosis at the time of transplantation. Thus, aGVHD develops within a tissue microenvironment that still contains a stable pool of host-derived, functionally competent T_RM rather than a purely donor-cell-repopulated niche [19].

In addition to classical APCs, recent transcriptomic and spatial analyses of human skin lesions have highlighted a substantial expansion of M2-polarized CD68⁺CD11b⁺ macrophages in aGVHD skin lesions. Both donor-derived and residual host macrophages coexist in early lesions and rapidly converge toward a shared tissue-resident transcriptional profile, underscoring their plasticity. Notably, these macrophages predominantly exhibit a CD163⁺ tissue-remodeling phenotype characterized by IL-10 and TGF-β expression and low IFN-γ production, suggesting that, in early aGVHD, macrophages may not solely propagate inflammation but may also exert regulatory and reparative functions within the damaged skin microenvironment [22].

3.1.2 Donor T-cell activation

Donor T-cells interact with host antigens through both direct presentation (host APCs presenting alloantigen) and indirect antigen presentation (donor APCs presenting processed host antigens). In the skin, persistent recipient Langerhans cells may serve as important APCs for direct alloantigen presentation and contribute to local T-cell activation. Even in HLA-matched settings, disparities in minor histocompatibility antigens provoke robust alloimmune responses [23].

Activated donor T-cells expand and differentiate into Th1 cells producing IFN-γ and IL-2, Th17 cells producing IL-17 and IL-22, and cytotoxic CD8⁺ cells, while regulatory T-cell (Treg) deficiencies or their malfunction contribute to impaired tolerance [15].

The persistence of host-derived T_RM adds an additional layer to this classical paradigm. Clonal tracking analyses have shown that pre-existing host αβTCR clones persist long term in the skin and can undergo in situ proliferation following transplantation. Increased abundance and expansion of host T_RM at the time of HSCT correlate with subsequent development of cutaneous GVHD. These findings suggest that local host-versus-graft immune interactions may coexist with donor-driven alloreactivity, challenging the notion that aGVHD is exclusively mediated by newly engrafted donor T-cells.

Although aGVHD has long been considered a predominantly Th1-driven cytotoxic process, emerging evidence indicates that immune polarization may differ between target organs. In particular, studies of acute cutaneous GVHD have identified a skin-specific Th2-skewed signature, characterized by upregulation of IL-4, IL-13, and the Th2-associated chemokine CCL17, along with infiltration by IL-4- and IL-22-producing CD4⁺ T-cells. In addition to Th2 cells, Th22 cells appear enriched in lesional skin. IL-22 acts directly on keratinocytes, modulating differentiation and inducing antimicrobial peptides and proinflammatory mediators, which may further perpetuate T-cell recruitment and local inflammation. These observations suggest that, in addition to the established role of Th1-mediated alloreactivity in systemic GVHD, tissue-specific microenvironments shape distinct immune polarization patterns within individual target organs, particularly the skin [24].

3.1.3 Effector phase (tissue injury)

The interaction of donor T-cells, innate immune cells, and inflammatory cytokines results in effector-mediated tissue damage. Key cytotoxic pathways include Perforin/granzyme-mediated cytolysis, Fas–FasL apoptotic signaling, TNF-α–induced apoptosis and necroptosis, and recruitment of macrophages and neutrophils, amplifying damage through reactive oxygen species and proteases [4, 15].

3.2 Chronic skin GVHD pathophysiology

CGVHD is a multisystem alloimmune and autoimmune syndrome involving inflammation, immune dysregulation, and fibrotic tissue remodeling that may emerge following aGVHD or develop independently. Impaired immune tolerance, aberrant B-cell and T-cell interactions, innate immune activation, and progressive tissue fibrosis characterize its pathophysiology [16].

3.2.1 Loss of thymic and peripheral tolerance

The thymus is highly sensitive to conditioning and inflammation associated with GVHD. Thymic epithelial damage compromises negative selection, enabling the release of autoreactive T-cells into the periphery [23]. At the same time, reduced thymic output can diminish Treg production, further destabilizing immune homeostasis. Moreover, peripheral tolerance is compromised by decreased Treg survival, expansion of effector memory T-cells, and dysregulated costimulatory signaling, fostering persistent autoreactivity.

3.2.2 B cell-dysregulation and autoantibody production

B cells play a central role in cGVHD pathogenesis, distinguishing it immunologically from aGVHD. Prolonged inflammation has been shown to induce elevated levels of BAFF (B-cell activating factor), which enables the survival of autoreactive B cells that would normally undergo deletion [21, 23]. The consequences of this include autoantibody production (e.g., anti–PDGFR antibodies), the expansion of T follicular helper (Tfh) cells – with germinal center hyperactivity, enhanced antigen presentation by B cells, and autoantibody-mediated fibroblast activation contributing to fibrosis [16, 25].

3.2.3 T-cell-dysregulation

In contrast to the Th2 predominance observed in acute cutaneous GVHD, chronic lichenoid cutaneous GVHD demonstrates a mixed Th1/Th17 immune signature. Lesional skin shows upregulation of IFN-γ, IL-12/IL-23p40, IL-17, and IL-23p19, along with increased Th1-associated chemokines such as CCL5, CXCL9, and CXCL10. There is a relative enrichment of IFN-γ- and IL-17-producing CD8⁺ T-cells, suggesting a cytotoxic Th1/Th17-driven process. Chronic sclerotic GVHD also displays a Th1 signature, with an abundance of mast cells and higher expression of TRAIL-receptors TRAIL- R2/-R3/-R4 compared to chronic lichenoid GVHD, as demonstrated by Brüggen et al [24].

Additionally, cGVHD is characterized by the unilateral expansion of Th17 cells, which promotes inflammation and tissue injury. Th2 cells are associated with fibrotic processes via IL-4 and IL-13, while Tfh cells drive aberrant B-cell activation. As described above, reduced Treg function and decreased T-cell receptor diversity further impair tolerance [16].

3.2.4 Fibrosis and aberrant tissue repair

Fibrogenesis is a defining feature of chronic sclerotic GVHD, especially in skin, fascia, lung, liver, and joints. It results from persistent immune activation, myofibroblast accumulation, disruption of normal tissue architecture, and excessive deposition of type I and III collagen [16].

3.2.5 Innate immune cell and stromal contributions

Dendritic cells, macrophages, neutrophils, and fibroblasts sustain chronic inflammation and fibrosis. Macrophages, in particular, contribute to TGF-β secretion, fibroblast activation, and extracellular matrix (ECM) deposition. Stromal cells and fibroblasts become activated into myofibroblasts, producing excessive collagen. TGF-β, PDGF, and IL-13 are major drivers of this fibroinflammatory remodeling [16, 26].

4. Acute GVHD

4.1 Clinical manifestations of aGVHD

Clinical manifestations of aGVHD include specific derangements in the skin, liver, and gastrointestinal tract, and occasionally the eyes and oral mucosa. The disease is often characterized by a maculopapular skin eruption, diarrhea, and cholestatic liver disease (diagnosed by elevated bilirubin levels), and may be associated with recurrent infections. aGVHD onset typically occurs within a timeframe ranging from two to 42 weeks following stem-cell transplantation [6]. The clinical grading and staging of aGVHD is determined by the extent of skin, liver, upper, and lower GI tract involvement. Initially, individual organ involvement is assessed, followed by determination of the overall GVHD grade by the combination of organ stages, with the severity of the condition ranging from stages 1–4. Multiple systems for GVHD severity assessment exist in the literature. Tables 1, 2 present the most common staging and grading systems, respectively, with the overall grade determined according to modified Glucksberg criteria, which overlap significantly with the Mount Sinai International Consortium (MAGIC) criteria [6, 15].

Table 1.

Download as

CSV

XLSX

aGVHD staging of individual organ involvement [6]. Liver involvement is assessed using total bilirubin level (mg/dL), skin GVHD is staged according to percentage body surface area (% BSA) affected by a maculopapular eruption.

Clinical stage	Lower GI (diarrhea, mL/d)	Upper GI	Liver (bilirubin level, mg/dL)	Skin (% BSA)
0	<500		<2	No erythema, exanthema
1	500–1000	Persistent nausea, vomiting, anorexia	2–3	<25%
2	1000–1500		3–6	25–50%
3	>1500		6–15	>50%
4	Severe abdominal pain +/- ileus		>15	Bullae/ Desquamation

Table 2.

Download as

CSV

XLSX

Overall aGVHD grading: modified Glucksberg criteria [6]. The overall GVHD grade is determined by combinatorial organ scoring, as detailed in Table 1.

Grade	Skin stage	Liver stage	Lower GI stage	Upper GI stage
I	1–2	0	0	0
II	3	1	1	1
III		2–3	2–4
IV	4	4

4.2 Cutaneous findings and outcomes in aGVHD

AGVHD skin disease is often preceded by pruritus and dysesthesia, followed by the sudden onset of erythematous, maculopapular, morbilliform eruptions (Figs 2, 3). Early skin manifestations typically appear two to eight weeks after HSCT and present as folliculocentric blanching, erythematous macules, or papules with a predilection for ears and cheeks, sides of the neck, palms, soles, and upper back. Late onset aGVHD (> 100 days after HSCT) presents with clinical features of classic acute GVHD and may be discerned from chronic GVHD by sparing of flexural sites, lack of lichenoid features, and type of concomitant organ involvement (Fig. 4).

Figure 2.

Mild to moderate presentations of aGVHD. A) Macular eruption of the face in a patient presenting with skin aGVHD grade 1. B, C) Fine macular exanthema of the abdomen and upper arm in a patient with skin GVHD grade 2. D) Maculopapular eruption of the left upper extremity in a patient with skin GVHD grade 2.

Figure 3.

Severe aGVHD. A–C) Affection of >50% BSA with confluent macular eruption on the ventral and dorsal trunk (A, B), and bulla formation on the limb (C) in a patient presenting with skin GVHD grade 4 and concomitant gastrointestinal GVHD (overall GVHD modified Glucksberg grade IV).

Figure 4.

Late onset form of aGVHD. Maculopapular eruption of the dorsal trunk (A) and lower extremities (B), skin aGVHD grade 1–2, in a patient presenting after withdrawal of immunosuppressive therapy >100 days after HSCT.

Mild to moderate forms of acute cutaneous GVHD (Fig. 2) may either resolve spontaneously or in response to first-line therapy (see chapter below), potentially leaving post-inflammatory dyspigmentation. In more severe reactions (Fig. 3), lesions may extend to the trunk and progress to erythroderma with bulla formation, desquamation, and necrosis. The latter can remain localized to pressure sites or can disseminate. In the most severe cases, epidermolysis can be observed, clinically resembling toxic epidermal necrolysis [27–31].

Acute cutaneous GVHD is staged from 0 to 4 according to the presence of symptoms (maculopapular eruption, erythroderma with blisters or epidermolysis) and the percentage of the body’s surface area (BSA) affected, as detailed in Table 1 [29].

GVHD accounts for at least 25% of transplant-related deaths following allogeneic HSCT [32]. The mortality risk associated with aGVHD varies depending on the severity of the condition. Grade I acute GVHD carries limited direct mortality risk and does not typically require systemic treatment. Grade II disease confers a moderate mortality risk, while grades III and IV are associated with reported mortality risks up to 80%. In Europe, an EBMT study of 102,557 patients demonstrated improving outcomes over time, attributable to improved conditioning and prophylaxis regimens: 3-year survival after grades II–IV acute GVHD increased from 38% (1990–1995) to 45% (2011–2015), while 3-year survival after the more severe grades III–IV subset increased from 22% to 29% over the same period. Correspondingly, 3-year non-relapse mortality after grades II–IV declined from 47% to 36% [33].

A critical prognostic determinant across all grades is the response to first-line corticosteroid therapy, which declines markedly with increasing disease severity—from 86% in grade II to 55% in grade III and 30% in grade IV—underscoring the clinical urgency of early and accurate grading [34, 35]. Steroid-refractory aGVHD represents the highest risk subset, with 70.2% mortality at a median of 117.5 days from diagnosis, and patients with maximum grade III/IV disease or lower gastrointestinal involvement had mortality rates of 80.2% and 85.7%, respectively [34].

4.3 Mucosal lesions in aGVHD

Compared to chronic GVHD, in aGVHD, involvement of the oral or genital mucosa is an uncommon occurrence. Its diagnosis is complicated due to other factors resulting in mucositis and development of oral lesions during the first 28 days following transplant, including conditioning chemotherapy, concurrent radiation, neutropenia, herpes simplex infection (HSV), and treatment with cytokines such as granulocyte-macrophage colony-stimulating factor (GM-CSF). Notably, oral mucositis was an exceedingly common adverse event after allo-HSCT, but did not correlate with the occurrence of cutaneous or gastrointestinal aGVHD in a cohort from Vienna, Austria [36].

Nevertheless, oral lesions described in aGVHD include erythematous, erosive, ulcerated, and lichenoid lesions associated with clinical signs of salivary gland dysfunction, xerostomia, and pain. Lesions that persist or exacerbate for more than three weeks after HSCT, particularly when involving the hard palate, as chemotherapy-induced mucositis rarely affects this area of the mouth, are considered indicative of aGVHD [2, 29, 37, 38].

4.4 Diagnosis of aGVHD of the skin

In the absence of concomitant extracutaneous manifestations, the diagnosis of aGVHD may be challenging. The clinical findings are non-specific and can be difficult to distinguish from other skin eruptions that commonly occur in post-HSCT patients, most notably morbilliform drug eruptions and viral exanthema. Furthermore, the lack of pathognomonic histopathologic features underscores the importance to establish a correlation between clinical and pathological findings [39].

Overlap syndrome is defined by the concurrent presence of features of both acute and chronic GVHD and is associated with significantly higher morbidity and mortality. Clinically, an erythematous or maculopapular eruption resembling acute GVHD may develop in patients with an established diagnosis of cutaneous or extra-cutaneous chronic GVHD. Gastrointestinal involvement may manifest as nausea, vomiting, or diarrhea, while hepatic involvement can present with cholestatic hepatitis and abnormal liver function tests. Histological features may overlap with those of both acute and chronic GVHD [8, 40, 41].

Besides detailed anamnesis and close clinical inspection, skin biopsies should be considered as a standard procedure in line with European consensus recommendations. The National Institutes of Health (NIH) advises that a skin biopsy is indicated in suspected cutaneous GVHD lacking diagnostic features and is regularly performed to exclude differential diagnoses. However, these procedures should never result in delays to management, since early treatment is associated with improved prognosis. It is important to note that no direct relation exists between clinical and histopathological grading, except for advanced stages, with epidermal detachment. Therefore, a clinical-histopathological correlation is essential [2, 40, 42].

4.4.1 Histologic findings in aGVHD

Histopathologic findings show interface dermatitis, vacuolar degeneration of the basal layers, dyskeratosis, scattered apoptotic keratinocytes in all levels of the epidermis closely associated with lymphocytes (“satellite cell necrosis”), and a mild superficial lymphocytic infiltrate (Fig. 5). Interface changes can typically also be observed at the hair follicles and the eccrine glands. These findings are characteristic of, but not specific to, acute GVHD. Clinical and pathologic mimickers include drug hypersensitivity reactions and viral exanthemas. Therefore, the combination of clinical and histopathological findings of GVHD can serve as an important diagnostic indicator [43], although a clinic-pathological correlation is necessary to reach a final diagnosis. According to Lerner et al., aGVHD can be divided into four histopathological grades as detailed in Table 3 [45].

Figure 5.

Histopathological findings of aGVHD. A) aGVHD, clinical grade 2: hematoxylin–eosin stain (H&E) shows a multiform-like inflammatory pattern with numerous dyskeratotic keratinocytes and widespread vacuolar alteration of the basal cell layer, accompanied by attached lymphocytes. Intraepidermal satellitosis with satellite cell necroses is present. The upper dermis exhibits a sparse perivascular lymphocytic infiltrate. B) aGVHD, clinical grade 4: H&E shows the epidermis separated from the dermis, with prominent ballooning degeneration of keratinocytes and dyskeratotic cells. Epidermotropic lymphocytes are present. Dermis shows marked edema with perivascular lymphoplasmacytic infiltrates and associated pigment incontinence. C) aGVHD, immunofluorescence imaging of T-cells. CD3-positive cells (pink) in the upper dermis, epidermis, and at the dermo-epidermal junction, and 4',6-diamidino-2-phenylindole (DAPI) counterstaining in a cryoembedded skin biopsy of a patient presenting with aGVHD clinical grade 2 (Table 3).

Table 3.

Download as

CSV

XLSX

Histopathologic staging of aGVHD [44].

Grade	Histopathologic features
I	Focal or diffuse vacuolar alteration of basal cells
II	Vacuolar alteration of basal cells; spongiosis and dyskeratosis of epidermal cells
III	Formation of subepidermal cleft in association with dyskeratosis and spongiosis
IV	Extensive epidermal necrosis with complete detachment of epidermis

4.4.2 Differential diagnosis of aGVHD

Especially in cases where the skin is the solely affected organ, the frequent overlapping of both clinical and histopathological features of aGVHD with other inflammatory skin diseases can pose difficulties in establishing a definite diagnosis.

Potential differential diagnoses include viral exanthemas [27, 40, 51, 52], erythema multiforme [44], engraftment syndrome (eruption of lymphocyte recovery) – characterized by an increase in neutrophil granulocytes, high fever, erythematous exanthema, and pulmonary infiltrate [1, 54, 55], radiation dermatitis [12] and hypersensitivity reactions including morbilliform drug eruptions, Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis (SJS/TENs) [2, 44, 46] and toxic erythema resulting from conditioning chemotherapy [48]. The most common causes of drug eruptions in the post-HSCT setting are sulfonamides and beta-lactam antibiotics [44–47]. Accurate diagnosis of cutaneous aGVHD, therefore, relies on careful clinical assessment, histopathologic evaluation, and close clinicopathologic correlation.

5. Chronic GVHD

5.1 Clinical manifestations of cGVHD

CGVHD can directly evolve from aGVHD (progressive chronic form), follow a disease-free period, or develop independently of prior GVHD signs de novo, and is a major cause of morbidity in long-term survivors of allo-HSCT [27, 30]. The classic presentation, characterized by the distinctive signs and symptoms of cGVHD with no time restrictions, is distinguished from an overlap syndrome, in which both acute and chronic GVHD symptoms are present. CGVHD is a multisystem disease that can affect one or several organs at a time: Skin and oral mucosa involvement are the most common presentations, followed by liver, eye, intestinal, and lung involvement in decreasing order of frequency [8, 27, 30, 40].

5.1.1 Cutaneous findings of cGVHD

Chronic cutaneous GVHD presents heterogeneously, and clinical manifestations can be broadly classified into two categories, namely, non-sclerotic/lichenoid and sclerotic, according to the NIH consensus criteria. The non-sclerotic form naturally refers to all clinical manifestations of cutaneous cGVHD in the absence of sclerosis, whilst the sclerotic form refers to all superficial and deep sclerotic manifestations [40].

However, a multitude of clinical presentations of cGVHD are recognized, reflecting a spectrum of epidermal and dermal changes. Cutaneous and extracutaneous diagnostic criteria for cGVHD that have been published were compiled in the NIH Consensus Project. The NIH Consensus expert panel has identified lichen planus-like lesions, sclerotic skin manifestations, and poikilodermatous changes in the skin as clinical manifestations that are diagnostic of cGVHD [14].

5.1.1.1 Non-sclerotic/lichenoid cGVHD

Lichen planus-like cGVHD may present as erythematous/violaceous, flat-topped papules or plaques with or without surface reticulations or a silvery or shiny appearance on direct light, appearing with a predilection for the dorsal hands and feet, forearms, and trunk (Fig. 6). Lesions resemble idiopathic lichen planus. However, they frequently exhibit a greater extent and involve atypical areas, such as the face, neck, palms (Fig. 7), and soles. Fine scaling and pruritus may also be present. Lichen planus-like cGVHD may also manifest in a follicular distribution, thereby mimicking the appearance of keratosis pilaris. Lesions in sites of herpes zoster scars or following Blaschko’s lines have also been reported. Although lichen planus-like GVHD is occasionally regarded as an earlier form of GVHD than sclerotic GVHD, it does not necessarily precede the development of sclerotic disease manifestations. Other common non-sclerotic presentations include psoriasis-like lesions, eczema-like lesions, and keratosis pilaris-like lesions. Despite all this, the most typical eruptions in the non-sclerotic cGVHD setting are a lichen planus-like eruption and poikiloderma (skin atrophy, pigmentary changes, telangiectasia) [2, 27, 40, 56]. The latter belongs to common chronic sequelae presenting as dyspigmentation, including post-inflammatory hyperpigmentation, vitiligo-like changes, leukoderma, and poikiloderma (Fig. 8). Vitiligo-like lesions may also occur in the absence of detectable antecedent lesions, sometimes in conjunction with alopecia areata and ichthyosis. Notably, cGVHD-associated dyspigmentation was reported to significantly affect patients’ quality of life, especially in patients with skin of color [57].

Figure 6.

Lichen planus-like cGVHD. A, B) Erythematous papules on the dorsal trunk (A), and the upper arm (B) of a patient presenting with chronic GVHD. During disease progression, these lesions became predilection sites for sclerotic features.

Figure 7.

Involvement of the palms in cGVHD. A) non-sclerotic cGVHD presenting with acral erythema and deep-seated vesicles, and B) acral erythema with yellowish hue and hyperkeratosis.

Figure 8.

Dyspigmentation in cGVHD. A, B) Poikiloderma and postinflammatory hyperpigmentation on the face and lower extremities of a patient previously presenting with lichenoid GVHD. C, D) Sharply demarcated, vitiligo-like hypopigmentation associated with cGVHD.

5.1.1.2 Sclerotic cGVHD

Sclerotic skin manifestations can occur in any location but may either present in areas of resolving lichen planus-like lesions or in areas of previously healthy skin. The depth of cutaneous sclerosis is the primary determinant of the clinical presentation. In contrast to systemic sclerosis, body surface area involvement in sclerotic GVHD is often discontinuous. Lesions have been observed to manifest preferentially in areas of skin trauma (Koebner phenomenon) [58–61].

Sclerosis may occur superficially in the dermis or deep in the subcutaneous tissue and fascia, and can occur with or without prior non-sclerotic disease. Superficial sclerotic manifestations are often clearly defined by visual inspection, and the change in dermal thickness can be confirmed by gently pinching the skin. Clinical manifestations encompass lichen sclerosis-like and morphea-like cutaneous lesions, as well as deep sclerotic features with reduced joint mobility (Fig. 9) [31].

Figure 9.

Sclerotic cGVHD. A) early sclerotic GVHD features, including edema and dermal thickening of the lower extremities. B–D) Morphea-like sclerotic features and dyspigmentation on the ventral and dorsal trunk (B, C), and lower extremities (D) of a patient with cGVHD. E) Eosinophilic fasciitis-like cGVHD with inverse vein sign of the upper arm.

Lichen sclerosus-like lesions present due to superficial sclerosis, involving the papillary dermis. Clinically, patients may initially note dryness and wrinkling of the skin (cigarette paper-like texture) that appears white and shiny. When sclerosis manifests in the superficial dermis, the resulting lesions bear a resemblance to lichen sclerosus, a dermatosis characterized by epidermal atrophy and superficial dermal fibrosis. Lichen sclerosus-like lesions manifest as discrete to coalescent, gray to white guttate papules or plaques, often with follicular plugs, a shiny appearance, and leathery consistency, typically located on the upper back [4, 40, 43, 58, 61].

In morphea-like lesions, sclerosis primarily affects deeper skin layers, involving the reticular dermis and subcutis. The affected skin frequently presents as localized, patchy areas with a shiny appearance and a leathery consistency, often accompanied by dyspigmentation (Fig. 9). Through widespread dermal and subcutaneous sclerosis, lesions may progressively become indurated and firmer. Sometimes, the formation of hidebound induration of the skin is accompanied by alopecia as a secondary complication arising from the elimination of adnexal structures [2, 40, 43, 59, 62].

In deep sclerotic and eosinophilic fasciitis-like cGVHD, sclerosis affects deeper, subcutaneous structures. Clinical indicators of sclerosis include shiny skin with loss of hair follicles, a reduced ability to pinch the skin, and a rippled, cellulite-like appearance in fat-bearing areas. Subcutaneous fibrosis contributes to this texture through thickening of the fibrous septae within the subcutis, particularly on the medial arms and thighs, mimicking eosinophilic fasciitis. In cases of eosinophilic fasciitis-like GVHD, deep sclerosis is frequently accompanied by an acute onset of pain and edema followed by induration with a rippled appearance. The “thickened or tight skin” appears smooth, waxy, and indurated and is caused by deep and diffuse sclerosis over a wide area. Fascial involvement is usually diagnosed in the later stages of the chronic period and may result in the appearance of prominent linear markings, known as the ‘groove sign’, and contractures that restrict the range of motion (Fig. 9E) [2, 40, 43, 58].

Further indications of sclerotic progression encompass the presence of calcinosis of the skin (Fig. 10). Calcinosis cutis is a condition in which calcium salts are deposited in the skin and subcutaneous tissue. It represents one of the sequelae of sclerosis and is usually detected as a radiological finding in the context of several medical conditions, including sclerodermatous cGVHD [40, 43, 63, 64].

Figure 10.

Calcinosis cutis as sequela of cGVHD. A) Bilateral calcinosis cutis lesions on the mammae and B) MRI of the thorax showing well-circumscribed subcutaneous foci, consistent with calcium deposits within the superficial soft tissues of both breasts, in a patient with sclerotic cGVHD.

5.1.2 Oral lesions in cGVHD

Mucosal manifestation is the second most prevalent form of cGVHD, with symptoms including xerostomia and oral pain. Involvement of the oral mucosa can also resemble idiopathic lichen planus (LP) and present with white, arboriform lines and erosive manifestations. The presence of mucoceles and Wickham striae of the lips, tongue, buccal mucosa, and palate (Fig. 11A, B), along with erosive changes (Fig. 11C), has been identified as a significant finding of chronic graft-versus-host disease (cGVHD), as outlined in the NIH Consensus Criteria. Other oral features include painful ulcers, mucosal atrophy, pseudomembranes, and symptoms of sicca syndrome that can interfere with the patient’s oral intake [2, 13, 14, 37, 43].

Figure 11.

Oral involvement in cGVHD. A, B) Wickham striae on the tongue (A) and buccal mucosa (B). C) Erosions and ulcerations of the palate.

5.1.3 Genital lesions in cGVHD

Genital mucosa involvement may impair sexual function and quality of life substantially in patients of all genders. Vaginal disease develops an average of 10 months after transplantation, manifesting as dryness, excoriations, ulcerated or thickened mucosa, narrowed or obliterated introitus, with risk of frequent vaginal infections and dyspareunia. Severe vulvovaginal involvement may result in vaginal stenosis, labial resorption, or complete agglutination of the introitus, leading to hematocolpos. In men, genital involvement may present as fibrosis and scarring of the prepuce and glans penis, and genital involvement may resemble idiopathic lichen planus and lichen sclerosus [4, 27, 40, 65, 66].

5.1.4 Hair and nail disorders in cGVHD

Hair changes in cGVHD include both scarring (permanent hair loss due to follicular destruction in lichenoid and sclerotic GVHD) and nonscarring forms (telogen effluvium, alopecia areata-like inflammation) of alopecia. Additionally, papulosquamous eruptions and pruritus of the scalp, changes in hair structure (coarse or dull hair), and changes in hair pigmentation, including premature graying, may occur.

Nail changes can be observed in 50% of patients with cGVHD, ranging from mild nail dystrophy to total nail loss (anonychia). Examples of associated nail abnormalities include dystrophy, thickening, thinning, vertical ridging, splitting or brittle nails, onycholysis, and pterygium (Fig. 12) [2, 13, 14, 40, 43].

Figure 12.

Nail involvement in cGVHD. A) Pterygium unguis inversum and partial anonychia. B) Vertical ridging.

5.2 Diagnosis of mucocutaneous cGVHD

The NIH has published guidelines for classifying clinical manifestations and skin involvement in the context of cGVHD (Tables 4, 5). These guidelines aim to facilitate the diagnostic process, recommending that each manifestation be categorized into one of four distinct groups. The first category, diagnostic features, encompasses the presence of poikiloderma, lichen planus-like, lichen sclerosus-like, morphea-like, and deep sclerotic eruptions, and is sufficient for the diagnosis of cGVHD in the absence of skin biopsies or additional tests. The second category, distinctive manifestations, comprises depigmentation, vitiligo-like and papulosquamous lesions, which, although indicative of cGVHD, are not sufficient for a definitive diagnosis. The third category encompasses other features, which include more unspecific eruptions, such as keratosis pilaris, sweat gland impairment, hypopigmentation, and hyperpigmentation. The final category comprises common manifestations, including erythema, maculopapular eruption, and pruritus, which are present in both acute and cGVHD. The presence of at least one diagnostic manifestation or one distinctive feature confirmed by biopsy, laboratory tests, or radiology in the same or another organ is necessary for cGVHD diagnosis [3].

Table 4.

Download as

CSV

XLSX

US NIH Grading System for cGVHD [14].

Score	Skin	Mouth	Genital tract
I	≤18% BSA, no sclerosis	Mild symptoms, not significantly limiting oral intake	Mild symptoms, no impact on sexual function
II	19–50% BSA, superficial sclerosis	Mild symptoms partially limiting oral intake	Moderate signs, discomfort on examination
III	>50% BSA, deep sclerosis, impaired mobility	Severe symptoms strongly limiting oral intake	Advanced signs, stenosis, severe ulcerations, pain

Table 5.

Download as

CSV

XLSX

Signs and symptoms of mucocutaneous cGVHD [8].

	Diagnostic features	Distinctive features	Other features	Common features
Skin	Poikiloderma, LP-like features, Sclerosis / Morphea	Depigmentation	Changes in sweating	Erythema, maculopapular eruption, pruritus
Mouth	LP-like features, hyperkeratosis, sclerosis, ulcers pseudomembranes	Xerostomia, mucoceles, atrophy	Pain	Gingivitis, mucositis, erythema
Genital tract	LP-like features, vaginal stenosis, ulcers	Erosions, fissures
Nails	Brittle nails, striations, onycholysis, nail loss	Dystrophic nails
Hair / scalp		Alopecia, papulosquamous lesions	Fine, uneven, dull hair, early graying

In the absence of diagnostic clinical findings, the NIH consensus recommendation is for a skin biopsy to confirm the diagnosis of cGVHD. While tissue biopsies are generally advised to confirm a diagnosis, they are not necessarily required if a patient exhibits diagnostic signs or symptoms. While biopsies may be indicative of either chronic or acute GVHD, they are not specific for either condition [38, 40].

5.2.1 Histologic findings in cGVHD

The cutaneous histological findings can resemble those observed in the acute form of GVHD, exhibiting interface dermatitis accompanied by vacuolar degeneration and lymphocyte satellitosis, but vary according to the type of skin involvement (Fig. 13) [2, 40, 44, 67, 68]. The minimum histological criteria that must be met for diagnosis are the presence of apoptosis in the basement membrane of the epidermis or the external root sheath of a hair follicle or the acrosyringium. These findings may be accompanied by a lichenoid infiltrate [8].

Figure 13.

Histopathologic findings in cGVHD. A) H&E stain of an acral skin biopsy (palm) of a patient presenting with chronic lichenoid GVHD demonstrates a mild interface dermatitis characterized by basal vacuolar alteration, scattered dyskeratotic keratinocytes, and a superficial lymphocytic infiltrate. Occasional melanophages are present within the upper dermis. B) H&E stain of a skin biopsy (lower back) of a patient presenting with sclerotic GVHD showing subtle interface dermatitis accompanied by marked sclerosis involving the full thickness of the dermis.

Lichenoid lesions mimic idiopathic lichen planus and are characterized by acanthosis and hypergranulosis, clinically corresponding to desquamation, which is not typically observed in cases of idiopathic lichen planus. In addition, an interface dermatitis with keratinocyte necrosis and a band-like lymphocytic infiltrate that is less pronounced than in idiopathic lichen planus can be observed. In some cases, periadnexal inflammation, particularly around the eccrine glands, is evident.

Sclerotic lesions may or may not demonstrate overlying epidermal changes of lichen planus-like disease and are represented by collagen homogenization (sclerosis) of the dermis and/or subcutaneous tissues with little or no epidermal involvement. Sclerotic GVHD involving the subcutaneous tissue can demonstrate a lymphocytic infiltrate at the dermal-fat interface, with thickened septae.

Lichen sclerosus-like lesions present with collagen alterations confined to the superficial/papillary dermis, and associated epidermal atrophy with edema, hyperkeratosis, and follicular plugging.

Morpheaform-like lesions demonstrate thickened collagen bundles in the dermis with loss of adnexal structures. In the absence of epidermal changes, these may be indistinguishable from specimens from true morphea or systemic sclerosis. As with these other disorders, specimens from lesions of chronic sclerotic GVHD often have a square or “box car” shape to the biopsy [2, 43, 45, 67, 68].

5.2.2 Differential diagnosis of cGVHD

Cutaneous chronic GVHD is clinically heterogeneous, and a distinct differential diagnosis is required for each clinical manifestation. Several disorders exhibit clinical and histopathological features similar to those seen in cGVHD, which may impede the diagnostic process. Potential differential diagnoses include LP, lichen sclerosus, morphea, systemic sclerosis, scleroderma, eosinophilic fasciitis, lichenoid drug eruptions, pityriasis lichenoides chronica, subacute cutaneous lupus erythematosus and psoriasis, which can all occur in HSCT-recipients independent of donor-host reaction [40].

6. Interdisciplinary management of acute and chronic cutaneous GVHD

6.1 Prophylaxis and prevention

Standard prophylaxis for GVHD, including cutaneous manifestations, consists of a calcineurin inhibitor (either tacrolimus or cyclosporine A) combined with methotrexate or mycophenolate mofetil [69]. T-cell depletion strategies, such as anti-thymocyte globulin (ATG) and post-transplant cyclophosphamide (PTCy), are increasingly used to reduce both aGVHD and cGVHD incidence. ATG is recommended for matched unrelated donor transplants, and recent randomized trials demonstrate that PTCy-based regimens (e.g., PTCy plus tacrolimus and mycophenolate mofetil) significantly lower the rates and severity of GVHD, including cutaneous involvement, compared to standard prophylaxis [70, 71].

Abatacept, a selective T-cell co-stimulation blocker, is FDA-approved for aGVHD prophylaxis in combination with a calcineurin inhibitor and methotrexate for matched or single-allele mismatched unrelated donor transplants. Large registry analyses show improved survival and relapse-free outcomes with abatacept plus calcineurin inhibitor/methotrexate compared to calcineurin inhibitor/methotrexate alone or calcineurin inhibitor/methotrexate plus ATG, and outcomes similar to PTCy-based regimens [72].

Currently, no reliable predictive tool exists to forecast GVHD occurrence safely; risk stratification is based on clinical and transplant-related factors. Graft manipulation techniques, such as ex vivo T-cell depletion, are also under investigation for prevention [15, 73].

6.2 Treatment of acute skin GVHD

Topical corticosteroids are the standard treatment for limited cutaneous aGVHD, with potent agents such as clobetasol propionate commonly used. Their efficacy is supported by clinical experience, although high-quality evidence is limited [74, 75]. Potency should be tailored to the site and severity, with low-potency steroids preferred for sensitive or facial areas and higher-potency agents for thicker skin or more pronounced lesions. Topical calcineurin inhibitors (tacrolimus ointment, pimecrolimus cream) may be considered, especially for sensitive areas or as steroid-sparing agents, albeit these are more established in cGVHD and have less robust data in aGVHD [74].

For more extensive skin involvement or internal organ disease in aGVHD, the most up-to-date consensus is initiation of systemic corticosteroids (oral prednisone or intravenous methylprednisolone at 1–2 mg/kg/day) as first-line therapy [69, 15]. Approximately half of patients respond to corticosteroids, but steroid-refractory disease is common [76, 77].

For steroid-refractory aGVHD, the preferred second-line agent is ruxolitinib, a Janus kinase (JAK1/2) inhibitor, which is FDA- and EMA-approved and has demonstrated superior response rates and durable control compared to best available therapy [69, 78]. The consensus regimen for patients aged ≥12 years is 10 mg orally twice daily. Initial dosing may begin at 5 mg twice daily and increase to 10 mg twice daily after 3 days if tolerated. Lower or shorter dosing regimens (e.g., 5 mg twice daily) are sometimes used in clinical practice for patients with cytopenias or other dose-limiting toxicities [69].

Other second-line and adjunctive options include extracorporeal photopheresis, used for steroid-refractory or steroid-dependent aGVHD, especially with skin involvement. The procedure involves leukapheresis followed by ex vivo exposure of peripheral blood mononuclear cells to 8-methoxypsoralen and ultraviolet A (UVA) irradiation, after which the treated cells are reinfused into the patient. The treatment is typically administered on two consecutive days every week during the initial phase, with intervals subsequently extended according to clinical response. Therapy is generally continued for at least 3–6 months [79].

Additional second-line treatment options involve mycophenolate mofetil (may be added for additional immunosuppression), mTOR inhibitors (e.g., sirolimus) used in select cases, often as adjuncts, TNF-alpha antagonists (e.g., etanercept, infliximab, in gastrointestinal GVHD) considered for refractory cases, but associated with increased infectious risk, as well as alemtuzumab, anti-thymocyte globulin, and other cellular therapies used in highly refractory cases, with variable efficacy and increased risk of infection [69].

In summary, systemic corticosteroids are the cornerstone of initial therapy for aGVHD, with ongoing calcineurin inhibitor-based prophylaxis. Ruxolitinib is the preferred second-line agent for steroid-refractory disease, and other immunosuppressive and cellular therapies are considered in refractory cases, but these are associated with increased infectious risk and lack robust comparative data.

Compared to classic aGVHD, overlap GVHD is associated with greater disease severity and reduced overall survival [80]. Due to exclusion of this complicated constellation from many clinical studies, there is no distinct algorithm for overlap GVHD management. Generally, treatment follows cGVHD principles, with therapy selection guided by the predominant clinical manifestations, organ involvement, disease severity, and patient comorbidities [81].

6.3 Treatment of chronic skin GVHD

Systemic corticosteroids (prednisone 1 mg/kg/day) remain the standard first-line therapy for cGVHD. Prolonged corticosteroid use is associated with significant morbidity, including increased risk of opportunistic infections [69, 82]. Skin-directed therapies, such as topical corticosteroids and topical calcineurin inhibitors, are adjuncts for cutaneous involvement; caution is warranted with topical tacrolimus in patients on systemic tacrolimus due to potential toxicity [69, 82].

For steroid-refractory cGVHD, four agents are FDA-approved: ibrutinib (Bruton’s tyrosine kinase inhibitor), ruxolitinib (Janus kinase 1/2 inhibitor), belumosudil (ROCK2 inhibitor), and axatilimab (CSF1R inhibitor, not available in Europe outside of studies). Ibrutinib is approved after failure of one or more lines of systemic therapy, ruxolitinib after failure of one or two lines, belumosudil after at least two prior lines, and axatilimab for patients failing at least two prior lines [83]. These agents have distinct mechanisms and efficacy profiles, and selection is individualized based on organ involvement, prior therapies, and comorbidities [84, 85].

In cGVHD, extracorporeal photopheresis is widely used as a steroid-sparing option, especially in patients with cytopenias or active infections [69, 86]. ECP is typically administered in cycles consisting of two consecutive treatment days. During the initial phase, cycles are generally performed weekly for approximately three months, or until GVHD stabilizes. Thereafter, treatment is usually continued every two weeks and gradually tapered according to clinical response and disease severity. The overall duration of therapy is individualized and guided by the patient’s therapeutic response [79].

Other agents used in selected cases include rituximab, imatinib, mTOR inhibitors, mycophenolate, and proteasome inhibitors [69, 87]. The management beyond second-line therapy is heterogeneous and often guided by institutional protocols and clinical trial availability [60, 66]. Post-transplant cyclophosphamide has reduced cGVHD incidence without increasing relapse or infection rates but is not a treatment for established cGVHD [69, 84].

Overall, therapy is tailored to disease severity, organ involvement, and patient-specific factors, with ongoing research into combination and biomarker-driven strategies. Ruxolitinib, ibrutinib, belumosudil, and axatilimab are the principal novel agents with proven efficacy for skin involvement in acute and chronic GVHD, with additional investigational molecules in late-phase trials showing promise for future management. Ivarmacitinib, TDI-01, rovadicitinib, and pimicotinib are other emerging agents in advanced clinical trials which target inflammatory and fibrotic pathways and have demonstrated organ-specific responses, including cutaneous disease, though these are not yet approved [88].

Notably, patients with long-standing cGVHD carry a substantially elevated risk of developing secondary malignancies, particularly cutaneous squamous cell carcinoma. The overall skin cancer risk is increased 10-fold compared to the general population, with cGVHD conferring a hazard ratio of 2.86 for any skin cancer and 3.68 specifically for SCC. Mucocutaneous GVHD involvement further increases risk, as does prolonged immunosuppression and voriconazole exposure [89]. The latter has been independently associated with cutaneous SCC through a mechanism of chronic phototoxicity and accelerated photocarcinogenesis. International guidelines recommend routine skin cancer screening for all allogeneic transplant recipients, with heightened surveillance in those with cGVHD [90]. Given this cumulative risk profile, routine dermatologic and mucosal surveillance should be considered an integral component of long-term cGVHD management [91, 92].

7. Summary and conclusion

Cutaneous GVHD is a frequent complication following allogeneic hematopoietic stem cell transplantation. As cutaneous and mucosal manifestations are often the most clinically apparent signs of systemic GVHD, dermatologists are pivotal in the early recognition and diagnosis of skin conditions. The wide spectrum of acute and chronic cutaneous manifestations can pose difficulties in distinguishing GVHD from other conditions that may present similarly, such as infections, drug reactions and inflammatory diseases, requiring a high level of clinical experience and careful clinicopathological correlation. Accurate staging and early detection of skin involvement are critical for providing timely intervention and preventing the progression of the disease to a more severe or treatment-resistant stage.

The management of cutaneous GVHD continues to rely on a stepwise approach incorporating topical and systemic therapies, which are tailored to the disease severity, extent, and patient comorbidities. Whilst systemic corticosteroids remain the first-line therapy for moderate-to-severe disease, an increasing recognition of steroid-related toxicity has driven the adoption of steroid-sparing agents and skin-directed therapies, particularly in chronic GVHD. Recent clinical advances, including the use of targeted immunomodulatory agents and phototherapy, have expanded treatment options and improved symptom control for many patients. Ongoing clinical trials and real-world studies will play a pivotal role in defining optimal treatment strategies and ensuring long-term efficacy and safety.

Acknowledgements

This project was supported by an educational grant from Incyte Biosciences Austria GmbH (JS) and a grant awarded by the LEO Foundation (LF-OC-25-002549, JS).

References

1. Cho A, Paulitschke V, Just U, Knobler R. Cutaneous manifestations of acute and chronic graft-versus-host disease. G Ital Dermatol Venereol. 2020;155:76–87. https://doi.org/10.23736/S0392-0488.19.06535-0

2. Strong Rodrigues K, Oliveira-Ribeiro C, de Abreu Fiuza Gomes S, Knobler R. Cutaneous graft-versus-host disease: diagnosis and treatment. Am J Clin Dermatol. 2018;19:33–50. https://doi.org/10.1007/s40257-017-0306-9

3. Lee SJ. Classification systems for chronic graft-versus-host disease. Blood. 2017;129:30–7. https://doi.org/10.1182/blood-2016-07-686642

4. Ferrara JLM, Levine JE, Reddy P, Holler E. Graft-versus-host disease. Lancet. 2009;373:1550–61. https://doi.org/10.1016/S0140-6736(09)60237-3

5. Flowers MED, Inamoto Y, Carpenter PA, Lee SJ, Kiem HP, Petersdorf EW, et al. Comparative analysis of risk factors for acute graft-versus-host disease and for chronic graft-versus-host disease according to National Institutes of Health consensus criteria. Blood. 2011;117:3214–9. https://doi.org/10.1182/blood-2010-08-302109

6. Nassereddine S, Rafei H, Elbahesh E, Tabbara I. Acute graft versus host disease: a comprehensive review. Anticancer Res. 2017;37:1547–55. https://doi.org/10.21873/anticanres.11483

7. Aladağ E, Kelkitli E, Göker H. Acute graft-versus-host disease: a brief review. Turk J Haematol. 2020;37:1–4. https://doi.org/10.4274/tjh.galenos.2019.2019.0157

8. Ballester-Sánchez R, Navarro-Mira M, Sanz-Caballer J, Botella-Estrada R. Review of cutaneous graft-vs-host disease. Actas Dermosifiliogr. 2016;107:183–93. https://doi.org/10.1016/j.adengl.2016.01.022

9. Weiden PL, Flournoy N, Thomas ED, Prentice R, Fefer A, Buckner CD, et al. Antileukemic effect of graft-versus-host disease in human recipients of allogeneic-marrow grafts. N Engl J Med. 1979;300:1068–73. https://doi.org/10.1056/NEJM197905103001902

10. Weisdorf D, Zhang MJ, Arora M, Horowitz MM, Rizzo JD, Eapen M. Graft vs. host disease induced graft vs. leukemia effect: greater impact on relapse and disease-free survival following reduced intensity conditioning. Biol Blood Marrow Transplant. 2012;1:1727–33. https://doi.org/10.1016/j.bbmt.2012.06.014

11. MacDonald KP, Shlomchik WD, Reddy P. Biology of graft-versus-host responses: Recent Insights. Biol Blood Marrow Transplant. 2013;19:10–4. https://doi.org/10.1016/j.bbmt.2012.11.005

12. Justiz Vaillant AA, Modi P, Mohammadi O. Graft-versus-host disease. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2026 [cited 2026 Apr 9]. Available from: http://www.ncbi.nlm.nih.gov/books/NBK538235/

13. Jagasia MH, Greinix HT, Arora M, Williams KM, Wolff D, Cowen EW, et al. 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. Biol Blood Marrow Transplant. 2015;21:389–401.e1. https://doi.org/10.1016/j.bbmt.2014.12.001

14. Filipovich AH, Weisdorf D, Pavletic S, Socie G, Wingard JR, Lee SJ, et al. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and staging working group report. Biol Blood Marrow Transplant. 2005;11:945–56. https://doi.org/10.1016/j.bbmt.2005.09.004

15. Zeiser R, Blazar BR. Acute graft-versus-host disease biology, prevention and therapy. N Engl J Med. 2017;377:2167–79. https://doi.org/10.1056/NEJMra1609337

16. Zeiser R, Blazar BR. Pathophysiology of chronic graft-versus-host disease and therapeutic targets. N Engl J Med. 2017;377:2565–79. https://doi.org/10.1056/NEJMra1703472

17. Martinez-Cibrian N, Zeiser R, Perez-Simon JA. Graft-versus-host disease prophylaxis: pathophysiology-based review on current approaches and future directions. Blood Rev. 2021;48:100792. https://doi.org/10.1016/j.blre.2020.100792

18. Strobl J, Gail LM, Kleissl L, Pandey RV, Smejkal V, Huber J, et al. Human resident memory T cells exit the skin and mediate systemic Th2-driven inflammation. J Exp Med. 2021;218:e20210417. https://doi.org/10.1084/jem.20210417

19. Strobl J, Pandey RV, Krausgruber T, Bayer N, Kleissl L, Reininger B, et al. Long-term skin resident memory T cells proliferate in situ and are involved in human graft-versus-host disease. Sci Transl Med. 2020;12:eabb7028. https://doi.org/10.1126/scitranslmed.abb7028

20. Merad M, Manz MG, Karsunky H, Wagers A, Peters W, Charo I, et al. Langerhans cells renew in the skin throughout life under steady-state conditions. Nat Immunol. 2002;3:1135–41. https://doi.org/10.1038/ni852

21. Hill GR, Ferrara JLM. The primacy of the gastrointestinal tract as a target organ of acute graft-versus-host disease: rationale for the use of cytokine shields in allogeneic bone marrow transplantation. Blood. 2000;95:2754–9. https://doi.org/10.1182/blood.V95.9.2754.009k25_2754_2759

22. Strobl J, Gail LM, Krecu L, Madad S, Kleissl L, Unterluggauer L, et al. Diverse macrophage populations contribute to distinct manifestations of human cutaneous graft-versus-host disease. Br J Dermatol. 2024;190:402–14. https://doi.org/10.1093/bjd/ljad402

23. Shlomchik WD. Graft-versus-host disease. Nat Rev Immunol. 2007;7:340–52. https://doi.org/10.1038/nri2000

24. Brüggen MC, Klein I, Greinix H, Bauer W, Kuzmina Z, Rabitsch W, et al. Diverse T-cell responses characterize the different manifestations of cutaneous graft-versus-host disease. Blood. 2014;123:290–9. https://doi.org/10.1182/blood-2013-07-514372

25. Srinivasan M, Flynn R, Price A, Ranger A, Browning JL, Taylor PA, et al. Donor B-cell alloantibody deposition and germinal center formation are required for the development of murine chronic GVHD and bronchiolitis obliterans. Blood. 2012;119:1570–80. https://doi.org/10.1182/blood-2011-07-364414

26. Kitko CL, Pidala J, Schoemans HM, Lawitschka A, Flowers ME, Cowen EW, et al. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: IIa. The 2020 clinical implementation and early diagnosis working group report. Transplant Cell Ther. 2021;27:545–57. https://doi.org/10.1016/j.jtct.2021.03.033

27. Peñas PF, Zaman S. Many faces of graft-versus-host disease. Australas J Dermatol. 2010;51:1–10. https://doi.org/10.1111/j.1440-0960.2009.00577.x

28. Friedman KJ, LeBoit PE, Farmer ER. Acute follicular graft-vs-host reaction: a distinct clinicopathologic presentation. Arch Dermatol. 1988;124:688–91. https://doi.org/10.1001/archderm.1988.01670050032014

29. Vargas-Díez E, García-Díez A, Marín A, Fernández-Herrera J. Life-threatening graft-vs-host disease. Clin Dermatol. 2005;23:285–300. https://doi.org/10.1016/j.clindermatol.2004.06.005

30. Goddard DS, Horn BN, McCalmont TH, Cordoro KM. Clinical update on graft-versus-host disease in children. Semin Cutan Med Surg. 2010;29:92–105. https://doi.org/10.1016/j.sder.2010.03.010

31. Przepiorka D, Weisdorf D, Martin P, Klingemann HG, Beatty P, Hows J, et al. 1994 Consensus conference on acute GVHD grading. Bone Marrow Transplant. 1995;15:825–8.

32. Kiene S, Albrecht M, Theurich S, Scheid C, Skoetz N, Holtick U. Bone marrow versus peripheral blood allogeneic haematopoietic stem cell transplantation for haematological malignancies in adults. Cochrane Database Syst Rev. 2024;11: CD010189. https://doi.org/10.1002/14651858.CD010189.pub3

33. Greinix HT, Eikema DJ, Koster L, Penack O, Yakoub-Agha I, Montoto S, et al. Improved outcome of patients with graft-versus-host disease after allogeneic hematopoietic cell transplantation for hematologic malignancies over time: an EBMT mega-file study. Haematologica. 2022;107:1054–63. https://doi.org/10.3324/haematol.2020.265769

34. Holtan SG, Yu J, Paranagama D, Tang J, Choe HK, Naim A, et al. Disease progression, hospital readmissions, and clinical outcomes for patients with steroid-refractory acute graft-versus-host disease: A multicenter, retrospective study. Bone Marrow Transplant. 2022;57:1399–404. https://doi.org/10.1038/s41409-022-01736-0

35. Deeg HJ. How I treat refractory acute GVHD. Blood. 2007;109:4119–26. https://doi.org/10.1182/blood-2006-12-041889

36. Strobl J, Ballicas N, Wachter B, Revertera M, Knaus H, Wohlfarth P, et al. Dental health, conditioning and oral mucositis in allogeneic hematopoietic stem cell transplantation: a single-center study. Cytotherapy. 2025;27:1130–6. https://doi.org/10.1016/j.jcyt.2025.03.005

37. Imanguli MM, Pavletic SZ, Guadagnini JP, Brahim JS, Atkinson JC. Chronic graft versus host disease of oral mucosa: review of available therapies. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2006;101:175–83. https://doi.org/10.1016/j.tripleo.2005.08.028

38. Miranda M, Gianfreda F, Carlotta D, Armati S, Barlattani A, Bollero P. Oral manifestations of graft vs. host disease: a comprehensive review for best practice in dentistry. Medicina (Kaunas). 2023;59:1937. https://doi.org/10.3390/medicina59111937

39. Mays SR, Kunishige JH, Truong E, Kontoyiannis DP, Hymes SR. Approach to the morbilliform eruption in the hematopoietic transplant patient. Semin Cutan Med Surg. 2007;26:155–62. https://doi.org/10.1016/j.sder.2007.09.004

40. Shi CR, Ferreira AL, Kaur M, Xiang D, Caputo J, Choe HK, et al. Cutaneous chronic graft-versus-host disease: clinical manifestations, diagnosis, management, and supportive care. Transplant Cell Ther. 2024;30:513–33. https://doi.org/10.1016/j.jtct.2024.05.020

41. Pidala J, Vogelsang G, Martin P, Chai X, Storer B, Pavletic S, et al. Overlap subtype of chronic graft-versus-host disease is associated with an adverse prognosis, functional impairment, and inferior patient-reported outcomes: a chronic graft-versus-host disease consortium study. Haematologica. 2012;97:451–8. https://doi.org/10.3324/haematol.2011.055186

42. Hillen U, Häusermann P, Massi D, Janin A, Wolff D, Lawitschka A, et al. Consensus on performing skin biopsies, laboratory workup, evaluation of tissue samples and reporting of the results in patients with suspected cutaneous graft-versus-host disease. J Eur Acad Dermatol Venereol. 2015;29:948–54. https://doi.org/10.1111/jdv.12737

43. Hymes SR, Alousi AM, Cowen EW. Graft-versus-host disease. J Am Acad Dermatol. 2012;66:515.e1–534. https://doi.org/10.1016/j.jaad.2011.11.960

44. Hacisalihoglu UP, Sahin D. Incidence, histopathological features and differential diagnosis of cutaneous graft versus host disease in allogeneic bone marrow transplantation. Sisli Etfal Hastan Tip Bul. 2021;55:68–75. https://doi.org/10.14744/SEMB.2019.86729

45. Lerner KG, Kao GF, Storb R, Buckner CD, Clift RA, Thomas ED. Histopathology of graft-vs.-host reaction (GvHR) in human recipients of marrow from HL-A-matched sibling donors. Transplant Proc. 1974;6:367–71.

46. Sanz Codina M, Kostner D, Schulenburg A, Schellenbacher C, Strobl J, Drach M. Wenn die Haut zuerst warnt: TEN-like Präsentation einer akuten kutanen GvHD. hautnah. 2025;24:156–62. https://doi.org/10.1007/s12326-025-00736-3

47. Patel AR, Turner ML, Baird K, Gea-Banacloche J, Mitchell S, Pavletic SZ, et al. Voriconazole-induced phototoxicity masquerading as chronic graft-versus-host disease of the skin in allogeneic hematopoietic cell transplant recipients. Biol Blood Marrow Transplant. 2009;15:370–6. https://doi.org/10.1016/j.bbmt.2008.12.491

48. Marra DE, Mckee PH, Nghiem P. Tissue eosinophils and the perils of using skin biopsy specimens to distinguish between drug hypersensitivity and cutaneous graft-versus-host disease. J Am Acad Dermatol. 2004;51:543–6. https://doi.org/10.1016/j.jaad.2004.02.019

49. Svensson CK, Cowen EW, Gaspari AA. Cutaneous drug reactions. Pharmacol Rev. 2001;53:357–79. https://doi.org/10.1016/S0031-6997(24)01501-1

50. Byun HJ, Yang JI, Kim BK, Cho KH. Clinical differentiation of acute cutaneous graft-versus-host disease from drug hypersensitivity reactions. J Am Acad Dermatol. 2011;65:726–32. https://doi.org/10.1016/j.jaad.2010.07.042

51. Phan TL, Carlin K, Ljungman P, Politikos I, Boussiotis V, Boeckh M, et al. Human herpesvirus-6B reactivation is a risk factor for grades II to IV acute graft-versus-host disease after hematopoietic stem cell transplantation: a systematic review and meta-analysis. Biol Blood Marrow Transplant. 2018;24:2324–36. https://doi.org/10.1016/j.bbmt.2018.04.021

52. Yoshikawa T, Ihira M, Ohashi M, Suga S, Asano Y, Miyazaki H, et al. Correlation between HHV-6 infection and skin rash after allogeneic bone marrow transplantation. Bone Marrow Transplant. 2001;28:77–81. https://doi.org/10.1038/sj.bmt.1703099

53. Bolognia JL, Cooper DL, Glusac EJ. Toxic erythema of chemotherapy: a useful clinical term. J Am Acad Dermatol. 2008;59:524–9. https://doi.org/10.1016/j.jaad.2008.05.018

54. Spitzer TR. Engraftment syndrome following hematopoietic stem cell transplantation. Bone Marrow Transplant. 2001;27:893–8. https://doi.org/10.1038/sj.bmt.1703015

55. Carreras E, Fernández-Avilés F, Silva L, Guerrero M, de Larrea CF, Martínez C, et al. Engraftment syndrome after auto-SCT: analysis of diagnostic criteria and risk factors in a large series from a single center. Bone Marrow Transplant. 2010;45:1417–22. https://doi.org/10.1038/bmt.2009.363

56. Schaffer JV. The changing face of graft-versus-host disease. Semin Cutan Med Surg. 2006;25:190–200. https://doi.org/10.1016/j.sder.2006.09.001

57. Smith ZI, Rosenstein RK, Banerjee S, Pichard DC, Pavletic SZ, Cowen EW. Quality of life in patients with skin of color and chronic graft-vs-host disease. JAMA Dermatol. 2020;156:589–90. https://doi.org/10.1001/jamadermatol.2019.4857

58. Schaffer JV, McNiff JM, Seropian S, Cooper DL, Bolognia JL. Lichen sclerosus and eosinophilic fasciitis as manifestations of chronic graft-versus-host disease: expanding the sclerodermoid spectrum. J Am Acad Dermatol. 2005;53:591–601. https://doi.org/10.1016/j.jaad.2005.06.015

59. Inamoto Y, Storer BE, Petersdorf EW, Nelson JL, Lee SJ, Carpenter PA, et al. Incidence, risk factors, and outcomes of sclerosis in patients with chronic graft-versus-host disease. Blood. 2013;121:5098–103. https://doi.org/10.1182/blood-2012-10-464198

60. Skert C, Patriarca F, Sperotto A, Cerno M, Filì C, Zaja F, et al. Sclerodermatous chronic graft-versus-host disease after allogeneic hematopoietic stem cell transplantation: incidence, predictors and outcome. Haematologica. 2006;91:258–61.

61. Martires KJ, Baird K, Citrin DE, Hakim FT, Pavletic SZ, Cowen EW. Localization of sclerotic-type chronic graft-vs-host disease to sites of skin injury: potential insight into the mechanism of isomorphic and isotopic responses. Arch Dermatol. 2011;147:1081–6. https://doi.org/10.1001/archdermatol.2011.226

62. Baumrin E, Baker LX, Byrne M, Martin PJ, Flowers ME, Onstad L, et al. Prognostic value of cutaneous disease severity estimates on survival outcomes in patients with chronic graft-vs-host disease. JAMA Dermatol. 2023;159:393–402. https://doi.org/10.1001/jamadermatol.2022.6624

63. Man J, Kalisiak M, Birchall IWJ, Salopek TG. Chronic cutaneous graft-versus-host disease manifesting as calcinosis cutis universalis on a background of widespread sclerodermatoid changes. J Cutan Med Surg. 2010;14:249–53. https://doi.org/10.2310/7750.2010.09034

64. Le C, Bedocs PM. Calcinosis Cutis. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2026 [cited 2026 Apr 9]. Available from: http://www.ncbi.nlm.nih.gov/books/NBK448127/

65. Spinelli S, Chiodi S, Costantini S, Van Lint MT, Raiola AM, Ravera GB, et al. Female genital tract graft-versus-host disease following allogeneic bone marrow transplantation. Haematologica. 2003;88:1163–8.

66. Marks C, Stadler M, Häusermann P, Wolff D, Buchholz S, Stary G, et al. German-Austrian-Swiss Consensus Conference on clinical practice in chronic graft-versus-host disease (GVHD): guidance for supportive therapy of chronic cutaneous and musculoskeletal GVHD. Br J Dermatol. 2011;165:18–29. https://doi.org/10.1111/j.1365-2133.2011.10360.x

67. Alvarado SM, Cohen OG, Lattanzio K, Haun P, Gelfand JM, Loren AW, et al. Histopathologic analysis of chronic cutaneous graft-versus-host disease. Am J Dermatopathol. 2024;46:755–60. https://doi.org/10.1097/DAD.0000000000002841

68. Shulman HM, Cardona DM, Greenson JK, Hingorani S, Horn T, Huber E, et al. Histopathologic diagnosis of chronic graft versus host disease. Biol Blood Marrow Transplant. 2015;21:589–603. https://doi.org/10.1016/j.bbmt.2014.12.031

69. Penack O, Marchetti M, Aljurf M, Arat M, Bonifazi F, Duarte RF, et al. Prophylaxis and management of graft-versus-host disease after stem-cell transplantation for haematological malignancies: updated consensus recommendations of the European Society for Blood and Marrow Transplantation. Lancet Haematol. 2024;11:e147–59. https://doi.org/10.1016/S2352-3026(23)00342-3

70. Redondo S, García-Cadenas I, Esquirol A, Portos JM, Iranzo E, Arguello-Tomas M, et al. Severity and organ distribution of graft-versus-host disease with post-transplant cyclophosphamide versus calcineurin inhibitor plus methotrexate/mycophenolate mofetil or sirolimus in allogenic HLA-matched or single-allele mismatched stem cell transplantation. Eur J Haematol. 2024;113:776–87. https://doi.org/10.1111/ejh.14294

71. Bolaños-Meade J, Hamadani M, Wu J, Al Malki MM, Martens MJ, Runaas L, et al. Post-transplantation cyclophosphamide-based graft-versus-host disease prophylaxis. N Engl J Med. 2023;388:2338–48. https://doi.org/10.1056/NEJMoa2215943

72. Kean LS, Burns LJ, Kou TD, Kapikian R, Lozenski K, Langston A, et al. Abatacept for acute graft-versus-host disease prophylaxis after unrelated donor hematopoietic cell transplantation. Blood. 2024;144:1834–45. https://doi.org/10.1182/blood.2023023660

73. Elmariah H, Bolaños-Meade J. Optimal GVHD prophylaxis. Adv Exp Med Biol. 2025;1475:77–102. https://doi.org/10.1007/978-3-031-84988-6_5

74. Rostagno E, Campanati A, Mordini N, Cannici C, Cioce M, De Cecco V, et al. Phototherapy and topical treatments for cutaneous graft vs. host disease in haematopoietic stem cell transplantation patients: a scoping review. J Eur Acad Dermatol Venereol. 2022;36:1003–15. https://doi.org/10.1111/jdv.18074

75. Peñas PF, Fernández-Herrera J, García-Diez A. Dermatologic treatment of cutaneous graft versus host disease. Am J Clin Dermatol. 2004;5:403–16. https://doi.org/10.2165/00128071-200405060-00005

76. Zeiser R, Bubnoff N von, Butler J, Mohty M, Niederwieser D, Or R, et al. Ruxolitinib for glucocorticoid-refractory acute graft-versus-host disease. N Engl J Med. 2020;382:1800–10. https://doi.org/10.1056/NEJMoa1917635

77. Patel DA, Crain M, Pusic I, Schroeder MA. Acute graft-versus-host disease: an update on new treatment options. Drugs. 2023;83:893–907. https://doi.org/10.1007/s40265-023-01889-2

78. Zeiser R, Lee SJ. Three US Food and Drug Administration–approved therapies for chronic GVHD. Blood. 2022;139:1642–5. https://doi.org/10.1182/blood.2021014448

79. Knobler R, Arenberger P, Arun A, Assaf C, Bagot M, Berlin G, et al. European dermatology forum – updated guidelines on the use of extracorporeal photopheresis 2020 – part 1. J Eur Acad Dermatol Venereol. 2020;34:2693–716. https://doi.org/10.1111/jdv.16890

80. Gorfinkel L, Raghunandan S, Watkins B, Hebert K, Neuberg DS, Bratrude B, et al. Overlap chronic GVHD is associated with adverse survival outcomes compared to classic chronic GVHD. Bone Marrow Transplant. 2024;59:680–7. https://doi.org/10.1038/s41409-024-02245-y

81. DeFilipp Z, Alousi A, Levine JE, Holtan SG, Abedin S, Gooptu M, et al. Clinical management of acute graft-versus-host disease: an evidence-based review from the ASTCT Committee on Practice Guidelines. Transplant Cell Ther. 2026 18;0. https://doi.org/10.1016/j.jtct.2026.04.053

82. Zeiser R. Novel approaches to the treatment of chronic graft-versus-host disease. J Clin Oncol. 2023;41:1820–4. https://doi.org/10.1200/JCO.22.02256

83. Martini DJ, Chen YB, DeFilipp Z. Recent FDA approvals in the treatment of graft-versus-host disease. Oncologist. 2022;27:685–93. https://doi.org/10.1093/oncolo/oyac076

84. Morishita T, Inamoto Y. Advances in treatment of chronic graft-versus-host disease. Int J Hematol. 2026;123:811–7. https://doi.org/10.1007/s12185-025-04102-0

85. Zhang X, Ren Y, Huang R, Wang X, Zhang X. Approved and emerging therapies for glucocorticoid-refractory chronic graft-versus-host disease. Curr Opin Immunol. 2025;97:102654. https://doi.org/10.1016/j.coi.2025.102654

86. Denk A, Fante MA, Heidenreich S, Greinix HT, Drouet EMW, Egger-Heidrich K, et al. Changes in chronic graft-versus-host disease treatment over time: a 15-years survey within allogeneic hematopoietic stem cell transplant centers in Germany, Austria, and Switzerland. Transplant Cell Ther. 2025;31:450.e1–450.e10. https://doi.org/10.1016/j.jtct.2025.04.017

87. Saidu NEB, Bonini C, Dickinson A, Grce M, Inngjerdingen M, Koehl U, et al. New approaches for the treatment of chronic graft-versus-host disease: current status and future directions. Front Immunol. 2020;11:578314. https://doi.org/10.3389/fimmu.2020.578314

88. Steiner L, Klein SA, Kreil S. New molecules in the therapy of chronic graft-versus-host disease. Curr Opin Hematol. 2025;32:314. https://doi.org/10.1097/MOH.0000000000000893

89. Mansilla-Polo M, López-Davia J, De Unamuno-Bustos B, Martín-Torregrosa D, Abril-Pérez C, Ezzatvar Y, et al. Skin cancer risk after hematopoietic stem cell transplantation: a systematic review and meta-analysis. Int J Dermatol. 2024;63:1691–700. https://doi.org/10.1111/ijd.17371

90. Rotz SJ, Bhatt NS, Hamilton BK, Duncan C, Aljurf M, Atsuta Y, et al. International recommendations for screening and preventative practices for long-term survivors of transplantation and cellular therapy: a 2023 update. Transplant Cell Ther. 2024;30:349–85. https://doi.org/10.1016/j.jtct.2023.12.001

91. Cowen EW, Nguyen JC, Miller DD, McShane D, Arron ST, Prose NS, et al. Chronic phototoxicity and aggressive squamous cell carcinoma of the skin in children and adults during treatment with voriconazole. J Am Acad Dermatol. 2010;62:31–7. https://doi.org/10.1016/j.jaad.2009.09.033

92. Curtis RE, Metayer C, Rizzo JD, Socié G, Sobocinski KA, Flowers MED, et al. Impact of chronic GVHD therapy on the development of squamous-cell cancers after hematopoietic stem-cell transplantation: an international case-control study. Blood. 2005;105:3802–11. https://doi.org/10.1182/blood-2004-09-3411

Additional information

Conflict of interest

The authors have declared that no competing interests exist.

Ethical statement

The authors confirm that informed consent has been obtained from the individual patients for the use of photographic material.

Artificial Intelligence (AI) use

The authors accept full responsibility for the content of the manuscript, including the disclosure of any use of AI.

Regarding the use of AI in the preparation of this manuscript, the authors declare the following: GPT

Used for: Language, style and writing

AI has solely been used for spelling and grammar assistance. The authors confirm that all scientific contents are generated and reviewed by the author themselves.

Funding

This project was supported by an educational grant from Incyte Biosciences Austria GmbH (JS) and a grant awarded by the LEO Foundation (LF-OC-25-002549, JS).

Author contributions

Conceptualization: CP, LT, JS; JS; Project Administration: CP, JS; Funding Acquisition: JS; Visualization: CP, LU, JS; Writing – Original Draft: CP, LU, MS, FW, AC; Writing – Review and Editing: all authors. No generative AI tools were used for the manuscript. All intellectual content, research design, and data analysis were conducted solely by the authors.

Author ORCIDs

C. Possanner https://orcid.org/0009-0002-7687-1710

M. Sanz Codina https://orcid.org/0000-0002-1687-5296

F. Winkler https://orcid.org/0009-0006-1514-8683

L. Thebault https://orcid.org/0000-0002-0805-9301

C. Müller https://orcid.org/0000-0002-5031-7255

A. Cho https://orcid.org/0000-0002-5555-2270

W. Bauer https://orcid.org/0000-0002-0155-1176

G. Stary https://orcid.org/0000-0003-1746-4250

W. Weninger https://orcid.org/0000-0003-3133-8699

J. Strobl https://orcid.org/0000-0003-3606-2185

Data availability

All of the data that support the findings of this study are available in the main text.