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PUVA-bath photochemotherapy and isotretinoin in sclerodermatous graft-versus-host disease

European Journal of Dermatology. Volume 18, Numéro 6, 667-70, Novembre-Décembre 2008, Therapy

DOI : 10.1684/ejd.2008.0517

Summary

Auteur(s) : Kamran Ghoreschi, Peter Thomas, Marius Penovici, Johanna Ullmann, Christian A Sander, Georg Ledderose, Gerd Plewig, Hans-Jochem Kolb, Martin Röcken , Department of Dermatology, Eberhard Karls University, Liebermeisterstr. 25, 72076 Tübingen, Germany, Department of Dermatology, Ludwig-Maximilians University, Munich, Germany, Hematopoietic Cell Transplantation, Department of Medicine III, Clinical University of Munich, Germany, Department of Dermatology, AK St. Georg, Hamburg, Germany.

Illustrations

ARTICLE

Auteur(s) : Kamran Ghoreschi¹, Peter Thomas², Marius Penovici³, Johanna Ullmann³, Christian A Sander⁴, Georg Ledderose³, Gerd Plewig², Hans-Jochem Kolb³, Martin Röcken¹

¹Department of Dermatology, Eberhard Karls University, Liebermeisterstr. 25, 72076 Tübingen, Germany
²Department of Dermatology, Ludwig-Maximilians University, Munich, Germany
³Hematopoietic Cell Transplantation, Department of Medicine III, Clinical University of Munich, Germany
⁴Department of Dermatology, AK St. Georg, Hamburg, Germany

accepté le 23 Juillet 2008

Bone marrow transplantation (BMT) and donor lymphocyte infusions are most efficient in treating selected severe hematologic malignancies. The incidence of chronic graft-versus-host disease (GVHD), a major long-term side effect of BMT, is still high and occurs in up to 50% of patients [1]. Chronic GVHD almost always involves the skin and may present either as lichenoid GVHD, sclerodermatous GVHD or as an eosinophilic fasciitis-like disease [2]. Pronounced and deep sclerosis associated with sclerodermatous or eosinophilic fasciitis-like chronic GVHD frequently leads to severe disability and impairment of motility. Immunosuppressive agents such as corticosteroids, cyclosporine, azathioprine or thalidomide are generally of no or only little help in these two types of chronic cutaneous GVHD. An effective standard therapy is still missing [1]. Phototherapy with 8-methoxypsoralen bath and UVA irradiation (PUVA-bath) photochemotherapy or UVA1 is the only effective treatment established for sclerosing skin diseases, such as localized scleroderma, which may dramatically improve severe sclerosis in these patients [3-7]. Surprisingly, this therapeutic effect was not reported for oral PUVA therapy, as it is established for acute or lichenoid GVHD. Whereas all phototherapy modalities may improve acute cutaneous GVHD, none of them has been shown to prevent the development of chronic cutaneous GVHD [8, 9]. Sclerodermatous GVHD (sGVHD) may even develop during oral PUVA therapy [8]. The first case reports indicate that individual patients with sGVHD benefit from PUVA-bath photochemotherapy or UVA1 phototherapy [10-14]. Based on these data and clinical observations, we report our experience with PUVA-bath photochemotherapy in a retrospective analysis of fourteen consecutive patients with sGVHD. A subset of the patients additionally received low-dose isotretinoin, since the related retinoid etretinate has been previously described to improve sGVHD [15].

Patients and methods

We treated the patients (age range 21-62y) with therapy-refractory sGVHD with PUVA-bath photochemotherapy [5]. Chronic GVHD appeared more than 120 days after allogenic transplantation for different diagnoses (table 1). Diagnosis of sGVHD was based on the typical clinical picture with superficial and deep sclerosis of the skin and the underlying tissues. Prior to the initiation of PUVA-bath photochemotherapy, patients were treated with immunosuppressive drugs, including oral glucocorticosteroids, azathioprine, mycophenolate mofetil, methotrexate or cyclosporine. No systemic immunosuppression was given during phototherapy except of methylprednisolone ≤ 20 mg daily. PUVA-bath photochemotherapy was performed as described [3]. Briefly, patients received 8-methoxypsoralen in warm bath water of 30 °C at a concentration of 0.5 mg/L for 20 minutes and UVA irradiation was performed using a Waldmann PUVA 3003 device (wavelength 315 nm-400 nm, maximum 365 nm). All patients treated were skin type II or III. PUVA-bath therapy was initiated with 0.05-0.2 J/cm², and if signs of phototoxicity were absent, the dose was raised every third treatment by 0.1-0.5 J/cm². Treatment was given three to four times a week. Low-dose isotretinoin was administered orally at 10 or 20 mg daily, starting in parallel to the phototherapy. Topical treatment was limited to ointments containing urea. Partial response (PR) was ≥ 50% improvement (as determined by restoration of motility or regression of sclerosis) and complete response (CR) was ≥ 75% improvement (almost complete restoration of motility or regression of sclerosis).
Table 1 Description of patients treated with PUVA-bath photochemotherapy ± isotretinoin and clinical outcome

Patient	Gender, Age	Diagnosis prior to BMT	PUVA-bath Photochemo-therapy +/– Isotretinoin	Total Number of Treatments	Total UVA J cm^–2	Ulceration Development/ Healing	Results	Follow up
1	f, 45	CML	-	105	505.4	+/+	CR	Alive and well
2	f, 53	AML	-	39	19.3	+/+	PR	Alive and well
3	m, 62	CML	-	55	124.0	+/–	NE	Died from pneumonia
4	m, 27	ALL	-	25	19.0	+/–	PR	Died after 2 years
5	f, 53	PLM	-	89	343	+/+	PR	Alive and well
6	f, 43	CML	-	27*	20,55	+/–	NE	Died from sepsis
7	f,39	AML	-	42	138.5	–	CR	Died from sepsis
8	f, 21	CML	-	28	35.8	+/–	PR	Relapse of GVHD
9	f, 55	CML	-	88	278.08	+/+	PR	Alive and well
10	f, 29	AML	+	38	15.5	–	CR	Alive and well
11	f, 49	CML	+	59*	57.75	+/+	PR	Alive and well
12	f, 46	CML	+	28*	11.55	+/+	NE	Alive
13	f, 38	ALL	+	12	7.5	–	CR	Alive and well
14	m, 43	AML	+	48	171.8	+/+	PR	Alive and well

Results

The PUVA-bath photochemotherapy regimens of the 14 patients were adapted individually depending on the severity of GVHD and the patients’ photosensitivity. Nine of the 14 patients received PUVA-bath photochemotherapy alone and five received the phototherapy in combination with isotretinoin. The number of treatments varied from 12 to 105, the total UVA dose from 7.5-505 J/cm² (table 1). Since GVHD may exacerbate during the first weeks of phototherapy, PUVA-bath photochemotherapy was initiated at very low doses between 0.05 and 0.2 J/cm² UVA. The UVA dose was increased very moderately and the increment did not exceed 0.2-0.3 J/cm² UVA during the first weeks. Clinical response was determined by restoration of motility, intensity of the inflammation-induced erythema, skin and subcutaneous hardness. Among the patients who received only PUVA-bath photochemotherapy, two had a complete response (CR) and five a partial response (PR). Two patients did not respond to phototherapy, their chronic GVHD progressed rapidly and they died from bacterial pneumonia or sepsis. One patient with PR died because of a leukemic relapse one year after phototherapy and one with CR died six months after PUVA-bath photochemotherapy because of sepsis. Among the five patients who received isotretinoin in combination with PUVA-bath photochemotherapy two had CR and two PR (table 1). One patient interrupted the therapy. Skin thickness decreased during phototherapy in 5 out of 6 patients followed by 20-MHz ultrasonography. All patients tolerated the PUVA-bath photochemotherapy well without classical side effects. However, treatment was complicated by the unexpected formation of multiple skin ulcers in ten of the fourteen patients (table 1). These ulcers developed rapidly in all patients during the first six weeks of PUVA-bath photochemotherapy (figures 1A and B). Importantly, when PUVA-bath photochemotherapy was continued until the regression of sclerosis, the ulcers healed within a short delay (figures 1C and D).

Discussion

Conducting controlled trials for sGVHD is difficult due to the limited number of patients and the severity of the disease. The incidence of sGVHD among the patients who developed chronic GVHD after allogenic hematopoietic stem cell transplantation is estimated to be in the range of 15%. Thus, the incidence of patients who suffer from the severe sclerodermatous form of chronic GVHD seems to be higher than reported in earlier studies [16]. Although different therapeutic modalities have been investigated in patients with sGVHD, an effective and reproducible therapeutic strategy is still missing [17]. Here, we show that PUVA-bath photochemotherapy is safe and effective in the treatment of steroid-resistant sGVHD as 11 of the 14 patients (78%) improved after twelve or more treatments. The wide range of treatment numbers and cumulative UVA doses in our patients reflect the need of individual treatment regimens to improve sGVHD. Even though oral PUVA and UVB seem to be effective in acute or lichenoid GVHD, they seem to be ineffective or only of little clinical benefit in sGVHD [17]. A few reports indicate that low-dose or medium-dose UVA1 phototherapy is effective in sGVHD and also extracorporeal photochemotherapy has been reported to be effective in selected patients with steroid-resistant sGHVD [12-14, 18]. Yet, these procedures need further evaluation. Our data suggest that oral isotretinoin might enhance the efficacy of PUVA-bath photochemotherapy (40% CR versus 22% CR). Even though the number of patients investigated in this study is too small for statistical evaluation, this finding is of interest as others reported that the functionally related retinoid etretinate may also improve chronic GVHD [15].

Retinoids have been suggested to inhibit transforming growth factor (TGF)-beta and collagen production. Improvement of sclerosis under PUVA-bath photochemotherapy may thus result from several mechanisms such as induction of collagenases, matrix metalloproteinases (MMP), capable of degrading of collagen bundles or inhibiting procollagen synthesis [19, 20]. Furthermore PUVA impairs cytokine production and induces apoptosis in infiltrating lymphocytes [21]. The observation that the only other treatment that seems to efficiently reduce sclerosis in larger numbers of patients with sGVHD, oral etretinate, also induced skin ulcers in one third of the patients, suggests a link between ulcer formation and regression of sclerosis [15]. Besides retinoids, only thalidomide has been related to skin ulcers in patients with chronic cutaneous GVHD. These ulcerations also improved after stopping thalidomide [22]. Importantly, formation of ulcers has not been observed in patients treated with either thalidomide, PUVA-bath photochemotherapy or retinoids for any disease other than sGVHD. Low-dose methotrexate has been reported to be well tolerated and to provide steroid-sparing effects in patients with sGVHD without clear benefit on sclerosis [23].

Interestingly, neither methotrexate nor extracorporeal photochemotherapy has been described to induce skin ulcerations [18, 23]. Thus, sGVHD may represent an unique entity where treatments such as PUVA-bath photochemotherapy and retinoids, that suppress cytokine production or reduce sclerosis, induce the risk of ulcer formation. More detailed investigation of PUVA-bath photochemotherapy and retinoids in sGVHD may help to develop effective therapies that prevent this most severe side effect and uncover the mechanisms leading to skin sclerosis in general.

Acknowledgements

Financial support: none. Conflict of interest: none.

References

1 Vogelsang GB, Lee L, Bensen-Kennedy DM. Pathogenesis and treatment of graft-versus-host disease after bone marrow transplant. Annu Rev Med 2003; 54: 29-52.

2 Aractingi S, Chosidow O. Cutaneous graft-versus-host disease. Arch Dermatol 1998; 134: 602-12.

3 Kerscher M, Volkenandt M, Meurer M, Lehmann P, Plewig G, Rocken M. Treatment of localised scleroderma with PUVA bath photochemotherapy. Lancet 1994; 343: 1233.

4 Kerscher M, Meurer M, Sander C, Volkenandt M, Lehmann P, Plewig G, Rocken M. PUVA bath photochemotherapy for localized scleroderma. Evaluation of 17 consecutive patients. Arch Dermatol 1996; 132: 1280-2.

5 Lüftl M, Degitz K, Plewig G, Röcken M. Psoralen bath plus UV-A therapy. Possibilities and limitations. Arch Dermatol 1997; 133: 1597-603.

6 Ghoreschi K, Röcken M. Phototherapy of sclerosing skin diseases. Dermatology 2002; 205: 219-20.

7 Röcken M, Ghoreschi K. Morphea and lichen sclerosus. In: Bolognia JL, Jorizzo JL, Rapini RP, eds. Dermatology. 2nd ed. Elsevier London, 2008: 1469-83.

8 Furlong T, Leisenring W, Storb R, Anasetti C, Appelbaum FR, Carpenter PA, Deeg HJ, Doney K, Kiem HP, Nash RA, Sanders JE, Witherspoon R, Thompson D, Martin PJ. Psoralen and ultraviolet A irradiation (PUVA) as therapy for steroid-resistant cutaneous acute graft-versus-host disease. Biol Blood Marrow Transplant 2002; 8: 206-12.

9 Grundmann-Kollmann M, Martin H, Ludwig R, Klein S, Boehncke WH, Hoelzer D, Kaufmann R, Podda M. Narrowband UV-B phototherapy in the treatment of cutaneous graft versus host disease. Transplantation 2002; 74: 1631-4.

10 Bonanomi S, Balduzzi A, Tagliabue A, Biagi E, Rovelli A, Corti P, Crippa D, Uderzo C. Bath PUVA therapy in pediatric patients with drug-resistant cutaneous graft-versus-host disease. Bone Marrow Transplant 2001; 28: 631-2.

11 Leiter U, Kaskel P, Krahn G, Gottlober P, Bunjes D, Peter RU, Kerscher M. Psoralen plus ultraviolet-A-bath photochemotherapy as an adjunct treatment modality in cutaneous chronic graft versus host disease. Photodermatol Photoimmunol Photomed 2002; 18: 183-90.

12 Grundmann-Kollmann M, Behrens S, Gruss C, Gottlöber P, Peter RU, Kerscher M. Chronic sclerodermic graft-versus-host disease refractory to immunosuppressive treatment responds to UVA1 phototherapy. J Am Acad Dermatol 2000; 42: 134-6.

13 Ständer H, Schiller M, Schwarz T. UVA1 therapy for sclerodermic graft-versus-host disease of the skin. J Am Acad Dermatol 2002; 46: 799-800.

14 Wetzig T, Sticherling M, Simon JC, Hegenbart U, Niederwieser D, Al-Ali HK. Medium dose long-wavelength ultraviolet A (UVA1) phototherapy for the treatment of acute and chronic graft-versus-host disease of the skin. Bone Marrow Transplant 2005; 35: 515-9.

15 Marcellus DC, Altomonte VL, Farmer ER, Horn TD, Freemer CS, Grant J, Vogelsang GB. Etretinate therapy for refractory sclerodermatous chronic graft-versus-host disease. Blood 1999; 93: 66-70.

16 Skert C, Patriarca F, Sperotto A, Cerno M, Filì C, Zaja F, Stocchi R, Geromin A, Damiani D, Fanin R. Sclerodermatous chronic graft-versus-host disease after allogeneic hematopoietic stem cell transplantation: incidence, predictors and outcome. Haematologica 2006; 91: 258-61.

17 White JM, Creamer D, du Vivier AW, Pagliuca A, Ho AY, Devereux S, Salisbury JR, Mufti GJ. Sclerodermatous graft-versus-host disease: clinical spectrum and therapeutic challenges. Br J Dermatol 2007; 156: 1032-8.

18 Couriel DR, Hosing C, Saliba R, Shpall EJ, Anderlini P, Rhodes B, Smith V, Khouri I, Giralt S, de Lima M, Hsu Y, Ghosh S, Neumann J, Andersson B, Qazilbash M, Hymes S, Kim S, Champlin R, Donato M. Extracorporeal photochemotherapy for the treatment of steroid-resistant chronic GVHD. Blood 2006; 107: 3074-80.

19 Scharffetter K, Wlaschek M, Hogg A, Bolsen K, Schothorst A, Goerz G, Krieg T, Plewig G. UVA irradiation induces collagenase in human dermal fibroblasts in vitro and in vivo. Arch Dermatol Res 1991; 283: 506-11.

20 Gruss C, Reed JA, Altmeyer P, McNutt NS, Kerscher M. Induction of interstitial collagenase (MMP-1) by UVA-1 phototherapy in morphea fibroblasts. Lancet 1997; 350: 1295-6.

21 Fisher GJ, Kang S. Phototherapy for scleroderma: biologic rationale, results, and promise. Curr Opin Rheumatol 2002; 14: 723-6.

22 Schlossberg H, Klumpp T, Sabol P, Herman J, Mangan K. Severe cutaneous ulceration following treatment with thalidomide for GVHD. Bone Marrow Transplant 2001; 27: 229-30.

23 Giaccone L, Martin P, Carpenter P, Moravec C, Hooper H, Funke VA, Storb R, Flowers ME. Safety and potential efficacy of low-dose methotrexate for treatment of chronic graft-versus-host disease. Bone Marrow Transplant 2005; 36: 337-41.