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October (2) 2001, Volume 28, Number 8, Pages 807-808
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Correspondence
Intraoral psoralen ultraviolet A irradiation (PUVA) treatment of refractory oral chronic graft-versus-host disease following allogeneic stem cell transplantation
S A Menillo1, S L Goldberg2, P McKiernan2 and A L Pecora2

1Department of Dentistry, Hackensack University Medical Center, 20 Prospect Avenue, Suite 400, Hackensack NJ 07601, USA

2Adult Blood and Marrow Transplantation Program, Hackensack University Medical Center, 20 Prospect Avenue, Suite 400, Hackensack NJ 07601, USA

Oral manifestations of chronic GVHD are common, affecting 80% of >100 day survivors of BMT who develop cGVHD. Mucosal erythema forming a telangiectatic pattern, mucosal atrophy with loss of keritinization or surface structure, lichenoid changes, oral pain including sensitivity to acidic foods, and xerostomia are the most frequently reported findings. Treatment of oral cGVHD can be challenging since immunosuppressive therapy may increase the risk of serious infections. Intra-oral psoralen ultraviolet A irradiation (PUVA) treatment is a novel treatment approach for localized cGVHD. We report a patient with refractory oral cGVHD that rapidly responded to this treatment using standard dental equipment.

A 42-year-old Caucasian male underwent an HLA-identical, ABO-compatible sibling allogeneic PBSC transplant for AML-M5, while in first remission, using oral busulfan 16 mg/kg and intravenous cyclophosphamide 120 mg/kg. The stem cell dose was 7.26 ´ 106 CD34/kg. GVHD prophylaxis consisted of tacrolimus and short course methotrexate. His early transplantation course was complicated by grade II acute GVHD (skin 2, liver 0, gut 0), which was well controlled on a maximum of 1 mg/kg prednisone therapy. Prednisone was tapered off by day 100, and tacrolimus was tapered from full therapeutic levels (10-15 ng/dl) by 15% per month. At 6 months following BMT, while still on 50% therapeutic tacrolimus, he developed shallow oral cGVHD ulcerations and was treated with cyclosporin topical rinses. By the 10th month post transplant, he developed moderate swallowing difficulties, slight elevations in hepatocellular enzymes (twice normal), but normal bilirubin. Full therapeutic dose tacrolimus, oral decadron rinses, and ursodeoxycholic acid were started, with normalization of hepatocellular enzymes and ulcer improvement over 1 month. He remained stable until the 17th month when, following a typical viral upper respiratory tract infection, he experienced acute worsening of the oral ulcerations and hyperbilirubinemia (8.5 mg/dl). Prednisone 1 mg/kg/day and mycophenolate mofetil 1 g twice a day were added and bilirubin normalized. However, his oral lesions continued to worsen, leading to inability to take sufficient solid or liquids with weight loss. Nineteen months following transplant he was referred for intraoral PUVA therapy while tacrolimus, prednisone 0.5 mg/kg/day, mycophenolate mofetil, prophylactic acyclovir, penicillin, and bactrim continued. He had diffuse ulcerations throughout the buccal mucosa and large lesions (>3 cm in diameter) on the dorsal and ventral surfaces of the tongue, lesions of the hard and soft palate, a 4 cm lesion extending from the right commisure towards the midline of the lower lip, and two lesions on the lip at the left commisure and in the lingual vestuble at the midline. General viral cultures, including HSV, of the lesions were negative.

The patient received oral oxsoralen 20 mg (ICN Pharmaceuticals Inc, Costa Mesa, CA, USA) followed 1 h later by intraoral UV-A therapy using an Elipar Visio dental composite curing light (Espe Dental AG, Plymouth Meeting, PA, USA) held by the operator for varying time periods (see Table 1), graded lesser to greater over the course of treatment. This standard dental light source emits a blue light with a wavelength of 400-480 nm with an intensity of approximately 500 nW/cm2. Initially, since the intraoral lesions were widespread the tip of the light curing wand was positioned at the center of the patient's oral cavity and then moved approximately 1 cm over the center of individual lesions. After achieving responses, towards the end of the therapeutic course, the light curing wand was held over individual lesions at a distance of approximately 1 cm. He was advised to avoid sun exposure and wear UV-protective sunglasses.

The patient underwent 30 treatment sessions (three times per week) over 3 months. Initially he experienced 'tingling' of the mouth. After three treatments he noted decrease in oral pain and visual improvement of lip lesions. However, at the time of the scheduled fifth treatment he noted increasing discomfort and signs of prior tissue repair had disappeared. Therapy was held for 1 week to allow possible 'burn' injury to heal. Subsequent treatments resulted in steady improvement. The lesions in the buccal mucosa, which had been the most severe in both size and painfulness, were the first to completely resolve. These were followed by healing of the lesions of the ventral surface of the tongue, palate, and lips, respectively. A lesion of the dorsal tongue, measuring approximately 1 cm, never healed completely but became painless at the time of conclusion of therapy. During the course of treatment the patient regained the ability to eat, gained 14.4 kg (15%), and was slowly tapered off tacrolimus.

We noted dramatic improvement with intraoral PUVA in refractory oral cGVHD. Our patient had experienced significant pain and weight loss as a result of the oral lesions that progressed despite oral steroid and cyclosporin rinses and systemic tacrolimus, mycophenolate mofetil, and ursodeoxycholic acid. The intraoral PUVA therapy was easily accomplished in an outpatient setting using standard dental equipment available in most community settings.

Successful use of intraoral PUVA treatment for oral cGVHD in two patients was first reported by Atkinson in 1986.1 Since then, rare reports of intraoral PUVA use have appeared. At Johns Hopkins, over a 14-year period, seven patients were treated with a hand-held UVA light source using a glass fiber extension (National Biologic Corporation, Ohio USA). Applications of 0.5 J/cm2 and increased by 0.5 J/cm2 as tolerated two to four times/week, for an average of 26 treatments, resulted in four complete responses, two partial responses, and one response upon the addition of topical steroids.2 Using an outdated Nuvalight activator light (Caulk Inc) used in the 1970s to cure dental sealant, a patient with refractory oral cGVHD achieved a response with 17 treatments.3 Intraoral ultraviolet B irradiation (without psoralen) 0.02 mJ/cm2 two to three times/week (dose escalated by 0.02 mJ/cm2 every fourth session) was also effective in two patients with cGVHD lesions.4

Several mechanisms of action of PUVA therapy may be responsible for its effectiveness in cGVHD.5 Eight-methoxyopsoralen rapidly diffuses into nucleated cells and upon exposure to UVA irradiation covalently binds DNA thereby inhibiting proliferation and mitosis, and causing rapid induction of apoptosis of activated T cells.6,7 Treated monocytes exhibit an activated phenotype with increased phagocytic and antigen presenting activity facilitating processing of apoptotic T cells leading to induction of anticlonotypic immunity. PUVA causes alterations in the idotypes expressed by clones of autoreactive T cells through upregulaton of class I expression triggering the induction of specific autoregulatory T cells, most likely CD8 with suppressive or cytoxic capabilities.8,9 PUVA also interferes with the function of Langerhans cells, including antigen processing and IL-1 production, reduction of T lymphocyte responses, and decreases in IL-2 and IL-1 production.

References

1 Atkinson K, Weller P, Ryman W, Biggs J. PUVA therapy for drug-resistant graft-versus-host disease. Bone Marrow Transplant 1986; 1: 227-236, MEDLINE

2 Vogelsang GB, Wolff D, Altomonte V et al. Treatment of chronic graft-versus-host disease with ultraviolet irradiation and psoralen. Bone Marrow Transplant 1996; 17: 1061-1067, MEDLINE

3 Redding SW, Callander NS, Haveman CW, Leonard DL. Treatment of oral chronic graft-versus-host disease with PUVA therapy. Oral Surg Oral Med Oral Pathol Oral Radiol Endodo 1998; 85: 183-187,

4 Elad S, Garfunkel AA, Enk CD et al. Ultraviolet B irradiation: a new therapeutic concept for the management of oral manifestations of graft-versus-host disease. Oral Surg Oral Med Oral Pathol Oral Radiol Endo 1999; 88: 444-450,

5 Rook AH, Suchin R, Kao DM et al. Photopheresis: Clinical applications and mechanisms of action. J Invest Dermatol 1999; 4: 85-90,

6 Song PS, Tapley KJ. Photochemistry and photobiology of psoralens. Photochem Photobiol 1979; 29: 1177-1197, MEDLINE

7 Yoo EK, Rook AH, Elenitas R et al. Apoptosis induction by ultraviolet light A and photochemotherapy in cutaneous T cell lymphoma: relevance to mechanism of action. J Invest Dermatol 1996; 107: 235-242, MEDLINE

8 Lambert M, Ronai Z, Weinstein IB et al. Enhancement of major histocompatibility class I protein synthesis by DNA damage in cultured human fibroblasts and keratinocytes. Mol Cell Biol 1989; 9: 847-850, MEDLINE

9 Ware R, Jiang H, Braunstein N et al. Human CD8 T lymphocyte clones specific for T-cell receptor V beta families expressed on autologous CD4 T cells. Immunity 1995; 2: 177-184, MEDLINE

Tables

Table 1 Intraoral PUVA treatment

Received 11 May 2001; accepted 13 August 2001
October (2) 2001, Volume 28, Number 8, Pages 807-808
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