Treatment of oral graft-versus-host disease with intraoral nbUVB phototherapy.

PURPOSE: There are limited treatment options available for hematopoietic stem-cell transplant patients (HSCT) with oral graft-versus-host disease (GVHD). Intraoral phototherapy is a novel, yet promising therapeutic regimen. RESEARCH QUESTION: To assess the safety and effectiveness of intraoral narrowband UVB (nbUVB) phototherapy in the treatment of oral GVHD. METHODS: This case series evaluated 10 patients with refractory oral GVHD, who were treated at Northwestern Memorial Hospital with nbUVB between July 2019 and October 2023. Primary outcomes were to evaluate the safety and efficacy of phototherapy. Efficacy was measured by objective improvement in symptom scores and subjective improvement in patient reported symptoms. Safety was determined by the withdrawal due to adverse events. Total nbUVB exposure, number of treatments, and change in systemic immunosuppressive medications were also examined. RESULTS: The study cohort comprised 10 patients who developed oral GVHD at a median of 9.5 months after HSCT. The total median dose of nbUVB was 36 J/cm2, and the median number of sessions was 55. All 10 patients demonstrated some degree of improvement in symptoms. Notably, there was a reduction in the number of patients who reported symptoms of oral pain (83%), bleeding (67%), xerostomia (50%), and oral sensitivity (78%) after initiating phototherapy. There was also a statistically significant decrease in the levels of pain, erythema, and edema (p ≤ 0.001, < 0.001, 0.01, respectively). Most patients tolerated phototherapy well, but 1 patient withdrew from treatment due to adverse effects. Seventy-five percent of patients who were on immunosuppressive medications were able to decrease or stop these medications. CONCLUSION: This case series suggests that nbUVB phototherapy is well tolerated and efficacious in patients with oral GVHD.

Impact of chronic graft-versus-host disease on quality of life and cognitive function of long-term transplant survivors after allogeneic hematopoietic stem cell transplantation with total body irradiation.

BACKGROUND: Total body irradiation (TBI)-based-conditioning before allogeneic hematopoietic stem cell transplantation (allo-HSCT) is standard of care in patients with acute myeloid leukemia (AML) but can cause long-term morbidity. Data on the impact of chronic Graft-versus-host disease (cGvHD) on cognitive function (CF) and quality of life (QoL) of long-term transplant survivors are sparse. METHODS: We analyzed patient-reported outcomes focusing on progression-free AML patients and 1st allo-HSCT applying a standardized TBI-technique with an average dose rate of 4 cGy/min to the total body and lung shielding in case of doses > 8 Gy. Instruments included the Functional Assessment of Cancer Therapy-Bone marrow transplant (FACT-BMT, version 4), the FACT-Cognition Function (FACT-Cog, version 3) and the Patient Health Questionaire-4 (PHQ-4). We put focus on the impact of cGvHD and compared the results to normative data derived from the general population. RESULTS: Out of 41 eligible patients contacted, 32 (78.0%) patients with a medium follow-up of 154 months (Interquartile range 113, 191 months) participated in the study. Eleven patients (34.4%) had active cGvHD, 11 (34.4%) resolved cGvHD and 10 (31.3%) never had cGvHD. Patients with active cGvHD had poorer FACT-BMT, FACT-Cog and higher PHQ-4 scores compared to patients with resolved cGvHD or who never had cGvHD. Outcomes were similar in patients with resolved cGvHD and those who never had cGvHD. Patients with active cGvHD had similar FACT-Cog, but lower FACT-BMT in comparison to normative data. However, the overall patient sample had similar FACT-BMT and FACT-Cog in comparison to normative data. CONCLUSION: Our data indicate that CF of long-term survivors upon TBI-based allo-HSCT is not impaired, even in the presence of active cGvHD. However, active cGvHD has a negative impact on QoL. Trial registration  The local Ethics Board of the University of Regensburg approved this study (Number 20-1810_1-101).

Photobiomodulation Therapy Alleviates Tissue Fibroses Associated with Chronic Graft-Versus-Host Disease: Two Case Reports and Putative Anti-Fibrotic Roles of TGF-ß.

OBJECTIVE: Patients who receive allogeneic hematopoietic stem cell transplantation may experience oral complications due to chronic graft-versus-host disease (cGVHD). The manifestations may include progressive sclerosis-like changes that may involve various body sites, including the oropharynx. METHODS AND RESULTS: We present two cGVHD cases of oropharyngeal fibrotic changes that affected functions that were treated with photobiomodulation (PBM) therapy. These case reports suggest that PBM therapy represents an additional, innovative approach affecting discrete phases in cGVHD-associated fibrotic changes. CONCLUSIONS: We discuss these observations in the context of currently understood molecular mechanisms, especially induction of transforming growth factor beta and NFκB that appear to be counter-intuitive to their known roles in matrix synthesis and inflammation that contribute to tissue fibroses. The clinical benefit noted in the two cases presented clearly indicates that there are distinct mechanistic and biological insights in the regulation of these molecular pathways in determining therapeutic efficacy with PBM therapy.

Case of thymoma-associated cutaneous graft-versus-host disease-like disease successfully improved by narrowband ultraviolet B phototherapy.

Thymoma-associated graft-versus-host disease (GVHD)-like disease is a rare paraneoplastic disease seen in patients with thymoma. Here, we describe the first case of thymoma-associated GVHD-like disease localized to the skin that was successfully improved by a combination of systemic corticosteroids and whole-body narrowband ultraviolet (UV)-B phototherapy. The patient had developed toxic epidermal necrolysis-like erosive skin lesions over the whole body. Although systemic corticosteroids were effective up to a point, we were unable to begin the steroid taper. The addition of systemic narrowband UV-B phototherapy improved the skin manifestation of this disease, allowing corticosteroids to be reduced to a third of the original dose. Histopathologically, it was confirmed that the proportion of Foxp3-positive lymphocytes in the skin increased after narrowband UV-B irradiation. We propose that whole-body narrowband UV-B phototherapy is a good therapeutic option for the skin manifestation of thymoma-associated GVHD-like disease.

Fototerapia UVB banda estrecha en el tratamiento de la enfermedad injerto contra huésped crónica cutánea: reporte de caso / Narrowband UVB phototherapy for the treatment of cutaneous chronic graft versus host disease: case report

Resumen La enfermedad injerto contra huésped crónica (EICHc) es una complicación frecuente en los pacientes que reciben trasplante de progenitores hematopoyéticos (TPH) alogénico, siendo la piel el órgano más frecuentemente afectado. La EICHc cutánea se presenta con lesiones esclerodermiformes y no esclerodermiformes y frecuentemente requiere tratamiento con inmunosupresores sistémicos, fotoféresis extracorpórea o fototerapia. Los inmunosupresores tienen el potencial de producir importantes efectos adversos, por lo que terapias con mejor perfil de seguridad son claramente necesarias. Presentamos el caso de una paciente de 11 años a quien se le realizó un TPH haploidéntico como tratamiento de una leucemia linfocítica aguda. En su evolución desarrolló EICHc cutánea esclerodermiforme. La paciente recibió tratamiento con luz ultravioleta B de banda estrecha (UVBbe), respondiendo satisfactoriamente en los 2 primeros meses. Existen múltiples reportes y series de casos exitosos sobre el tratamiento con fototerapia en distintas modalidades. En relación a la fototerapia con UVBbe, la literatura es escasa, sin embargo, muestran importantes resultados tanto en las formas esclerodermiformes y no esclerodermiformes de la EICHc cutánea y un buen perfil de seguridad. De todas formas, se requieren estudios prospectivos controlados a gran escala para determinar su efectividad como terapia adjuvante o incluso de primera línea y para definir los esquemas terapéuticos y dosis más efectivas.

Summary Chronic graft-vs-host disease (GVHD) is a frequent complication in patients who receive allogeneic hematopoietic cell transplants (HCTs), and the skin is the most common site of involvement. Chronic cutaneous GVHD can present with sclerotic or nonsclerotic changes and often requires treatment with systemic immunosuppressants, extracorporeal photopheresis, or phototherapy. Immunosuppressants carry the potential of causing important side effects, so additional modes of therapy with better security profiles are clearly needed. We report a case of an eleven year old girl, who received allogeneic HCTs to treat acute lymphocytic leukemia. She developed sclerotic chronic GVHD. The patient underwent treatment with narrowband UV-B phototherapy, and a significant improvement was seen over the first 2 months. There are a number of successful series and case reports on different forms of phototherapy. In relation to narrowband UV-B phototherapy, literature is scarce, although shows important results in sclerotic and nonsclerotic forms of chronic cutaneous GVHD and a good safety profile have been seen. Anyway, large-scale controlled prospective trials are needed to evaluate the effectiveness of phototherapy as adjuvant o even first-line therapy, and to establish the most effective therapy schemes and doses.

Treatment of cutaneous and/or soft tissue manifestations of corticosteroids refractory chronic graft versus host disease (cGVHD) by a total nodal irradiation (TNI).

The management of corticosteroids refractory chronic graft versus host disease (cGVHD) remains controversial. Retrospective analysis of patients treated at the Integrated Center of Oncology by total nodal irradiation (TNI) was performed to evaluate its therapy potency. TNI delivers a dose of 1 Gy in a single session. The delimitation of the fields is clinical (upper limit: external auditory meatus; lower limit: mid-femur). No pre-therapeutic dosimetry scanner was necessary. Evaluation of the efficacy was by clinical measures at 6 months after the treatment. Twelve patients were treated by TNI between January 2010 and December 2013. TNI was used in second-line treatment or beyond. The median time between allograft and TNI was 31.2 months, and the median time between the first manifestations of cGVHD and TNI was about 24.2 months. Of the 12 patients, nine had a clinical response at 6 months (75%), including five complete clinical responses (41.6%). Five patients could benefit from a reduction of corticosteroid doses. Three patients had hematologic toxicity. TNI could be considered as an option for the treatment of a cutaneous and/or soft tissues corticosteroids refractory cGVHD. However, prospective randomized and double-blind trials remain essential to answer the questions about TNI safety and effectiveness.

Phototherapy for sclerosing skin conditions.

Phototherapy is an effective treatment strategy for a variety of sclerosing skin conditions. There are a number of phototherapeutic modalities used for the treatment of sclerosing skin conditions, including ultraviolet (UV)A1, broadband UVA, psoralen plus UVA, and narrowband UVB phototherapy. As controlled trials with validated outcome measures are lacking for these therapies, existing evidence is largely level II for morphea and is even more minimal for scleroderma and other sclerosing disorders (scleroderma, lichen sclerosus, and chronic graft-versus-host disease, among others). Studies do suggest that phototherapy may be effective for many of these disorders, including those that have been unresponsive to other therapies. Phototherapy remains an attractive therapeutic option for patients due to its efficacy and favorable risk-versus-benefit profile. Phototherapy also offers a therapeutic alternative to systemic immunosuppressives for patients who cannot tolerate these medications.

Total nodal irradiation in patients with severe treatment-refractory chronic graft-versus-host disease after allogeneic stem cell transplantation: Response rates and immunomodulatory effects.

BACKGROUND AND PURPOSE: The use of total nodal irradiation (TNI) has been reported as an immunomodulatory therapy for different diseases including chronic graft-versus-host disease (cGVHD). MATERIAL AND METHODS: We retrospectively analyzed 13 patients with treatment-refractory cGVHD receiving TNI with 1×1Gy from 2001 to 2014. In 10 of 13 patients immunomodulatory effects of TNI were measured. RESULTS: At time of TNI all patients had severe cGVHD (involving the skin: n=12), fascia (n=6), oral mucosa (n=8), eye (n=8), and lung (n=5). Nine of 13 patients had corticosteroid-refractory cGVHD. In 7 of 13 patients (54%) a partial response (PR) could be achieved. In 3 patients (23%) cGVHD manifestations remained stable, 2 patients progressed. One patient was not evaluable due to follow-up <1 month. At 3 months after TNI, best responses could be achieved in skin, and oral involvement including steroid sparing activity. TNI was well tolerated with adverse effects limited to reversible thrombocytopenia and neutropenia. Immunomodulatory effects on peripheral blood cells could be demonstrated including an increase of CD4+ T cells in the group of responders. CONCLUSIONS: TNI represents an effective immunomodulating therapy in treatment-refractory cGVHD.

The role of phototherapy in cutaneous chronic graft-vs-host disease: a retrospective study and review of the literature.

INTRODUCTION AND OBJECTIVES: Cutaneous chronic graft-vs-host disease (GVHD) is a common complication of hematopoietic stem cell transplantation. Phototherapy is a therapeutic option for patients with skin involvement and for those who require high doses of corticosteroids. We analyze the cases treated in our department and review the literature. MATERIAL AND METHODS: All patients with GVHD treated with phototherapy in the dermatology department of Hospital Universitario y Politécnico la Fe in Valencia, Spain between March 2011 and October 2014 were identified. Data were gathered retrospectively. RESULTS: There were 16 patients: 10 treated with psoralen-UV-A and 6 with narrowband-UV-B. Complete response was achieved in 9 patients and partial response in 7; 2 patients with partial responses relapsed after treatment. Ten patients were able to decrease their dose of corticosteroids during treatment, and a further 3 decreased the number of other immunosuppressant drugs. No serious adverse effects occurred. CONCLUSIONS: Phototherapy is a good therapeutic option for patients with chronic GVHD with extensive cutaneous involvement, as well as for those who fail to respond to topical treatment or who have become steroid-dependent. The main benefits are that, as the treatment targets the skin, it reduces corticosteroid requirements and has a good safety profile. Treatment must be individualized and, in our experience, both the initial dose and the maximum dose per session can be lower than for other diseases.

Ultraviolet A1 phototherapy beyond morphea: experience in 83 patients.

BACKGROUND/PURPOSE: Ultraviolet A1 (UVA1) phototherapy has been used for over 15 years in the United States, primarily for the treatment of localized sclerosis and various sclerosing disorders. The objective was to describe use of UVA1 for dermatoses beyond localized sclerosis at two academic institutions. METHODS: Data from 83 patients treated with low- (20-40 J/cm(2) ), medium- (>40-80 J/cm(2) ), and high- (>80-120 J/cm(2) ) dose UVA1 phototherapy was retrospectively analyzed. The mean individual treatment dose (J/cm(2) ), the mean number of sessions, and the mean total dose (J/cm(2) ) were evaluated. Effectiveness was assessed by reviewing clinical examination notes from office visits. RESULTS: Good therapeutic efficacy was seen in patients with systemic sclerosis (SS, 16 patients), graft-versus-host disease (GVHD, 25 patients), and nephrogenic systemic fibrosis (NSF, 17 patients). A statistically significant a dose-response association was observed in the cases of SS, GVHD and NSF. Likelihood of clinical improvement from UVA1 phototherapy was very likely for medium- and high-dose regimens in SS, while this level of improvement was only observed in GVHD and NSF patients receiving high-dose UVA1. CONCLUSION: UVA1 phototherapy is effective and safe in the treatment of GVHD, NSF, SS, and mast cell disorders. High-dose regimens appear to be more effective than medium- and low-dose regimens for NSF and GVHD, while medium- and high-dose regimens outperform low-dose UVA1 in SS.

Narrow-band UVB phototherapy for management of oral chronic graft-versus-host disease.

OBJECTIVES: Oral chronic graft-versus-host disease (cGVHD) is a debilitating complication following allogeneic hematopoietic cell transplantation. The objective of this study was to evaluate the safety and efficacy of intraoral narrow-band ultraviolet B (NB-UVB) phototherapy in the management of oral cGVHD. METHODS: Patients with oral cGVHD were treated using a custom NB-UVB unit for a course of 24 phototherapy sessions. Treatments were initiated at 50 mJ/cm(2) and increased by 10% at each visit unless toxicity was noted. Toxicity and response were assessed weekly. RESULTS: Eleven patients received a median of 22 (range 4-39) NB-UVB treatments; 5 patients completed 24 treatments and elected to receive a median of 7 additional treatments. Median symptom scores (0-10) for sensitivity, pain, and dryness at baseline/end of therapy were 7.5, 3, 1, and 3, 1, 2, respectively. Taking into account all patient-reported outcomes, 7/11 patients had improvement and 2/11 worsened. At least partial improvement was reported in 8/11 patients with none reporting worsening. Overtreatment occurred in 10/11 patients with all graded mild or moderate and resolving in 1-2 days. CONCLUSIONS: Intraoral NB-UVB may be effective for management of refractory oral cGVHD. Further optimization of treatment parameters, as well as minimal erythema dose testing, and inclusion of a control arm are necessary in the consideration of future studies.

Narrowband ultraviolet B phototherapy ameliorates acute graft-versus-host disease by a mechanism involving in vivo expansion of CD4+CD25+Foxp3+ regulatory T cells.

Narrowband ultraviolet B phototherapy (NB-UVB) is a therapeutic alternative for haematopoietic stem cell transplantation-related skin graft-versus-host disease (GVHD). The beneficial effects of this intervention may be induced by direct irradiation of inflammatory cells in the skin; however, the putative involvement of indirect effects on systemic immunity has not been elucidated. To address this issue, 11 acute skin GVHD patients refractory to standard corticosteroid treatment and with no gut/liver involvement were treated with NB-UVB irradiation. The median number of treatments was 10 times, with a mean cumulative exposure of 6.36 J/cm(2). No other immunosuppressive therapy was initiated during irradiation. Eight patients achieved an objective complete response, two had a partial response, and one showed no change. None of the patients experienced progressive skin GVHD or newly diagnosed gut/liver GVHD. NB-UVB was well tolerated, with no patients discontinuing irradiation due to toxicity. We additionally demonstrated by flow cytometry that NB-UVB irradiation induces the increment of the proportion of regulatory T cell (Tregs) in patients' peripheral blood. These results suggest that NB-UVB may exert beneficial effects on steroid-refractory skin GVHD through the expansion of Tregs.

Narrowband ultraviolet B phototherapy for the treatment of steroid-refractory and steroid-dependent acute graft-versus-host disease of the skin.

BACKGROUND: Acute graft-versus-host disease (aGvHD) is a common complication of allogeneic stem cell transplantation. It is usually treated with high doses of corticosteroids and other immunosuppressive agents. When cutaneous features are predominant, narrowband ultraviolet B (NB-UVB) phototherapy may be an attractive option for its steroid-sparing effect. OBJECTIVE: We sought to examine the clinical efficacy of NB-UVB in the treatment of steroid-refractory and steroid-dependent cutaneous aGvHD. METHODS: We conducted a retrospective chart review of patients with steroid-refractory and steroid-dependent aGvHD, who received NB-UVB between 2005 and 2009 at our institution. RESULTS: We identified 14 patients with aGvHD treated with NB-UVB between 2005 and 2009. The median number of treatments was 15, administered over a median of 43 days. Eight of 14 patients (57%) achieved a complete response at the end of treatment; an additional 3 patients (21%) achieved a partial response; and 3 patients (21%) showed no improvement at the time when phototherapy was discontinued (nonresponders). Four patients developed chronic graft-versus-host disease (GvHD). Three of the 8 complete responders remained free of GvHD at 6 months' follow-up. LIMITATIONS: The rarity of steroid-refractory aGvHD limited the study to a small number of participants. Because GvHD is variable in its presentation and course, and life-threatening in many cases, large controlled prospective trials for potential therapies are difficult. CONCLUSIONS: NB-UVB is a viable option for the treatment of steroid-refractory and steroid-dependent aGvHD of the skin.

Narrowband ultraviolet B phototherapy in the treatment of cutaneous graft-versus-host disease in oncohaematological paediatric patients.

BACKGROUND: Graft-versus-host disease (GVHD) represents an important complication following allogeneic bone marrow transplantation. In recent years, narrowband ultraviolet B (NB-UVB, 311-313 nm) has been found to be a beneficial adjuvant treatment in patients refractory to first-line immunosuppressive drugs. OBJECTIVES: The aim of this study is to analyse retrospectively the clinical outcome of 10 GVHD paediatric patients treated with NB-UVB therapy. PATIENTS AND METHODS: Ten paediatric patients (six girls and four boys: median age 12.5 years, range 4-20) with cutaneous GVHD were enrolled in the study: five patients with chronic GVHD and five patients with an overlap syndrome GVHD. All patients had already been shown to be resistant to first-choice immunosuppressive protocols, and were treated with NB-UVB phototherapy until a clinical remission of skin lesions occurred. RESULTS: A complete response (absence of lesions) was achieved in 80% of the cases (eight patients) after a median number of 29 treatments, corresponding to a median of 7.5 weeks (52 days) of treatment (range 3-13 weeks), with an average cumulative dose of 28.71 J cm(-2) (range 1.02-70.38 J cm(-2)). Only two patients reported a partial remission (< 18% of body surface area involved). During the follow-up period, a complete remission after 1 year was observed in 75% of patients and after 2 years in 71% of the evaluable patients. CONCLUSIONS: This study provides evidence that NB-UVB phototherapy represents a valid second-line treatment in paediatric patients affected by GVHD and refractory to immunosuppressive first-line treatment.

Ultraviolet A phototherapy for sclerotic skin diseases: a systematic review.

BACKGROUND: Ultraviolet (UV) A-1 phototherapy is now available for a variety of skin diseases. Increasingly since 1995, there have been investigations of the efficacy of UVA-1 (340-400 nm) therapy for sclerotic skin diseases. Most studies undertaken treated patients who had localized scleroderma, but UVA-1 phototherapy is currently also used for other sclerotic skin conditions. OBJECTIVE: We sought to assess the efficacy, biological effects, and side effects of UVA-1 in a variety of sclerotic skin diseases (localized scleroderma, eosinophilic fasciitis, chronic graft-versus-host disease, lichen sclerosus et atrophicus, scleredema adultorum, necrobiosis lipoidica, POEMS disease, pansclerotic porphyria cutanea tarda, and drug-induced scleroderma-like disorders). METHODS: The authors searched for publications dated between January 1996 and November 2007 in the computerized bibliographic database, PubMed. PubMed was searched using medical subject heading terms and open searches to retrieve the latest reports. RESULTS: The evidence based on research concerning the effect of full-spectrum UVA (320-400 nm) and UVA-1 on these skin diseases is still growing, and appears promising. Up until now, good results are shown for all different doses (low, medium, and high) UVA-1 and UVA. There are insufficient data regarding use of high-dose UVA-1 and there are no comparative studies to make a clear assessment regarding the superiority of low-, medium-, or high-dose UVA-1 therapy. Although UVA-1 has various effects on, for instance, fibroblasts and inflammatory cells, the precise mode of action remains obscure. The main short-term side effects of UVA-1 therapy are erythema, pruritus, xerosis cutis, tanning, and recrudescence of herpes simplex infection. More studies are warranted to investigate the potential long-term risk of photoaging and skin cancer. Currently, UVA-1 is considered to be less carcinogenic than psoralen plus UVA (PUVA). LIMITATIONS: Because of the limited availability of randomized controlled trials and large cohort studies, it is difficult to draw firm conclusions on the long-term efficacy, optimum dose, and best treatment regimens for UVA-1 when administered to patients with sclerosing skin disorders. CONCLUSIONS: Full-spectrum UVA and UVA-1 phototherapy seem effective in the treatment of sclerotic skin diseases based on data retrieved from the literature. UVA-1 treatment can shorten the active period of localized scleroderma and pseudoscleroderma and prevent further disease progression, including contractures. Further investigations will be needed to determine any additional biological effects of UVA-1. Although long-term side effects are not yet known, UVA-1 might develop into a promising beneficial and well-tolerated treatment in the therapeutic armamentarium for sclerotic skin diseases. Long-term studies in large groups of patients are clearly needed.