Clinical bottom line
Chronic cutaneous graft-versus-host disease (cGVHD) remains a challenging complication after allogeneic hematopoietic stem cell transplantation, with significant morbidity from skin involvement. Emerging systemic treatments, including Janus kinase (JAK) inhibitors and other immunomodulatory agents, show promise in improving skin manifestations and quality of life. Current evidence supports cautious optimism regarding their efficacy and safety, but data remain limited and heterogeneous. Phototherapy remains an important adjunctive modality. Clinicians should individualize therapy considering disease phenotype, severity, and patient comorbidities while awaiting more robust clinical trial data.
What the evidence shows
Chronic cutaneous GVHD is characterized by diverse clinical presentations ranging from lichenoid to sclerotic skin changes, reflecting complex immunopathology involving donor T cells, fibrosis, and dysregulated inflammation (Cowen et al., 2009; Schultz et al., 2009). Skin involvement often portends a protracted disease course and impaired quality of life (Cohen et al., 2013).
Systemic immunosuppressants remain the mainstay of treatment, but recent advances have focused on targeted therapies. Ruxolitinib, a JAK1/2 inhibitor, has demonstrated efficacy in systemic cGVHD and, more recently, in a topical formulation for non-sclerotic cutaneous cGVHD (Study of the Safety and Efficacy of Ruxolitinib Cream, 2019). This topical approach showed favorable safety and clinical improvement in skin lesions, suggesting a potential role in localized disease. However, systemic JAK inhibitors have broader immunomodulatory effects and are under active investigation for cutaneous manifestations.
Phototherapy, particularly narrowband UVB and extracorporeal photopheresis, remains an established skin-directed therapy with immunomodulatory and anti-fibrotic effects (Nykaza et al., 2026; Kim et al., 2019). Phototherapy can improve both lichenoid and sclerotic skin changes, though responses vary and long-term safety data are limited.
Other systemic agents, including calcineurin inhibitors, corticosteroids, and extracorporeal photopheresis, have variable efficacy and toxicity profiles (Chavan et al., 2011). Newer biologics and antifibrotic agents are under early evaluation but lack robust evidence.
Caveats and uncertainty
The heterogeneity of cGVHD skin phenotypes complicates treatment response assessment and trial design. Many studies are small, observational, or single-arm, limiting generalizability. The topical ruxolitinib trial (2019) focused on non-sclerotic disease, so efficacy in sclerotic phenotypes remains unclear. Long-term safety of JAK inhibitors, particularly infection risk and malignancy potential, requires further study.
Phototherapy protocols vary widely, and optimal timing, dosing, and combination strategies are not standardized. Moreover, phototherapy may be less effective in deeply fibrotic skin.
The pathophysiology of cGVHD involves complex immune and fibrotic pathways, and no single agent addresses all mechanisms. Combination therapies may be necessary but increase risks of immunosuppression.
How this may change practice
Clinicians should consider integrating emerging systemic therapies such as JAK inhibitors into treatment algorithms for chronic cutaneous GVHD, particularly for patients with refractory or non-sclerotic skin disease. Topical ruxolitinib may offer a safer alternative for localized lesions, potentially reducing systemic immunosuppression burden.
Phototherapy remains a valuable adjunct, especially for lichenoid and early sclerotic changes, and should be incorporated when feasible.
Ongoing clinical trials and real-world registries will be critical to define optimal treatment sequences, combination regimens, and long-term safety. Multidisciplinary collaboration with transplant and dermatology specialists is essential for individualized care.