Trimethylpsoralen Bath PUVA Is a Remittive Treatment for Psoriasis Vulgaris Evidence That Epidermal Immunocytes Are Direct Therapeutic Targets

OBSERVATION Trimethylpsoralen Bath PUVA Is a Remittive Treatment for Psoriasis Vulgaris Evidence That Epidermal Immunocytes Are Direct Therapeutic Targets

Todd R. Coven, MD; Frank P. Murphy, MD; Patricia Gilleaudeau, RN, BSN; Irma Cardinale, BS; James G. Krueger, MD, PhD

Background: Psoriasis vulgaris can be effectively treated ment and 93% at the end of treatment. Furthermore, with trimethylpsoralen (TMP) bath PUVA therapy (pso- following TMP bath PUVA therapy, the numbers of epi- ralen plus UVA), but no data exist on the extent to which dermal CD1a+ Langerhans cells were markedly reduced, psoriatic pathology is affected by this treatment, or on and CD86+ cells were eliminated. Through in vitro assays, its cellular mechanism of action. TMP was found to be about 10 000-fold more active as a lymphotoxic agent compared with 8-methoxypsoralen (8- Observations: Eleven patients with recalcitrant psoria- MOP). Additionally, at physiologic concentrations, lym- sis vulgaris were treated with TMP bath PUVA therapy and phocytes were killed more readily by TMP PUVA (TMP observed through clinical and histological measures. Clini- plus UVA) than were keratinocytes. cal resolution of psoriasis was achieved in 10 of 11 patients. Histopathological resolution of epidermal hyper- Conclusions: Treatment with TMP bath PUVA was ef- plasia (marked by keratin 16 expression) was achieved in fective in treating moderate to severe psoriasis, even in 90% of individuals treated with TMP bath PUVA. Epider- darker pigmented individuals. It is likely that this treat- mal acanthosis was reduced by 40% at 2 weeks and 66% ment ameliorates psoriasis through direct effects on ac- by the end of treatment. Epidermal improvement corre- tivated leukocytes in lesional skin. lated best with reduction in intraepidermal T lymphocytes, which were reduced by 76% at 2 weeks of treat- Arch Dermatol. 1998;134:1263-1268

ONVENTIONAL PUVA lular effects of TMP vs 8-MOP in psoriatic therapy (oral administra- skin lesions during treatment. In this study, tion of 8-methoxypsor- we examined the clinical, epidermal, and im- alen [8-MOP] followed by munologic effects of TMP bath PUVA UV-A irradiation) has been therapy on lesional skin. Trimethylpsor- used successfully for more than 20 years to alen was found to clear psoriatic plaques C 1-3 treat difficult cases of psoriasis. While while reversing pathological hyperplasia and short-term adverse effects such as nausea epidermal infiltration by CD3+ and CD86+ and malaise limit treatment in some pa- immunocytes. tients, there is increasing concern over PUVA-induced cutaneous carcinomas and RESULTS melanomas that will effectively limit its long- term use in most patients.4-9 Bath PUVA therapy has been suggested as a poten- CLINICAL OUTCOME MEASURES tially safer alternative to conventional The Table summarizes the clinical re- sponses to TMP bath PUVA therapy in our For editorial comment patient population. These patients had skin see page 1286 types ranging from Fitzpatrick types II to VI, but more than 50% of patients who PUVA.10-14 Bath PUVA therapy (using tri- completed treatment had skin types V or methylpsoralen [TMP]) has been used for VI. All patients had significant improve- more than 20 years in Sweden and Finland ment in clinical severity measures. Two without an observed increase in the num- weeks after starting treatment, a 25% mean ber of skin cancers.10-14 Trimethylpsor- improvement in plaque severity was mea- alen, which is more hydrophobic than sured (PϽ.001). At the end of treatment, From the Laboratory for 8-MOP, could potentially differ in its mecha- an 83% mean reduction in disease sever- Investigative Dermatology, nism of action in psoriasis, especially via ity was measured (PϽ.001). All patients The Rockefeller University, topical application. Unfortunately, no data showed clinical benefit, with 10 of 11 pa- New York, NY. exist that delineate the pathological or cel- tients having clear skin or only trace dis-

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©1998 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 PATIENTS AND METHODS exposure. The patients were supplied with an emollient (Aquabase) to apply to their skin as desired. The TMP was purchased as 5-mg tablets for oral PATIENTS administration (ICN Pharmaceuticals, Costa Mesa, Calif). An ethanol solution was prepared by crushing tablets and Thirteen patients (11 men and 2 women) with long- extracting the powder, then combining it with 20 mL of standing psoriasis vulgaris (mean disease duration, 16 years) absolute ethanol at 60°C for 12 to 24 hours, after which were sequentially enrolled into our TMP bath PUVA study. the solution was filtered to remove suspended filler. A These patients had 10% to 90% (mean, 44%) skin surface measured amount of TMP solution (25 mg in 100 mL of involvement and had been treated previously with a vari- ethanol) was added to 150 L of lukewarm water in a bath- ety of agents. Six patients had Fitzpatrick skin types V or tub (final concentration, 0.167 mg/L). The patient then VI. Eleven of 13 patients completed the study, while 2 pa- sat submerged up to the neck for 15 minutes. Following tients were noncompliant with treatment and were dropped the bath, the patient dried off with a towel and immedi- from the study. Data from 1 of the 11 patients who com- ately entered the light box while wearing UV-protecting pleted the study (who achieved clinical clearing) were not glasses and a groin shield. The phototherapy unit (model included in histological analyses because the final biopsy 57000, Psoralite Corporation, Columbia, SC) delivered was refused. approximately 13 mJ/cm2 of UVA (measured with a UVA meter from National Biological Corporation, Twinsburg, TREATMENT Ohio).

Minimum phototoxic dose (MPD) testing to UVA was per- HISTOLOGICAL ANALYSIS formed by soaking an extremity (usually an arm) in a TMP solution of 0.167 mg/L for 15 minutes and then exposing Biopsies of lesional skin were performed before treat- 2 ϫ 2-cm patches to UVA in amounts ranging from 0.2 to ment, after 2 weeks of treatment, and at the end of treat- 2.0 J/cm2. Photopatches were read at 12, 24, 48, and 72 hours ment. Skin biopsy specimens were frozen in optimum cut- following UVA exposure. The starting UVA dose was 50% ting temperature compound solution for histological to 75% of the MPD. In patients for whom the MPD was in- analysis. Cryostat sections were stained with CD3 (Becton determinate, conservative initial exposures of 0.2 to 0.4 Dickinson, San Jose, Calif), Ks8.12 (Sigma Aldrich Inc, St J/cm2 were given. Treatment was delivered on an alternate- Louis, Mo), CD1a (Becton Dickinson), or CD86 (FUN-1 day schedule. Subsequent doses were increased by 0.1 to clone, Pharmingen, San Diego, Calif) monoclonal antibod- 0.5 J/cm2, depending on skin type and lack of phototoxic ies as previously described.15 Epidermal thickness was mea- effects from prior treatment. The goal for each treatment sured on digitized micrographs using the National Insti- was to attain slight (+/-) erythema following UVA tutes of Health Image software.16

Reduction in Disease-Related Parameters During Treatment*

2-wk Parameters End of Treatment Parameters

Patient Epidermal CD3+ Cells CD3+ Cells Epidermal CD3+ Cells CD3+ Cells No. PSI Thickness in Epidermis in Dermis PSI Thickness in Epidermis in Dermis 1 20.00 10.45 35.67 1.19 93.33 71.61 98.25 73.91 2 26.67 20.74 37.29 −23.94 93.33 55.90 38.14 48.59 3 21.43 45.77 79.65 33.49 92.86 85.65 99.57 82.78 4 38.46 48.38 88.82 31.78 76.92 57.82 100.00 71.03 5 15.38 40.61 73.53 −20.83 38.46 68.56 97.06 72.02 6 23.08 43.50 94.16 34.72 76.92 62.78 97.81 45.28 7 16.67 48.00 91.16 53.45 91.67 53.69 98.90 70.16 8 30.77 60.10 96.32 33.68 92.31 56.42 99.39 58.76 9 20.00 35.37 93.17 50.13 86.67 81.36 99.60 49.61 10 37.50 42.40 66.52 27.39 87.50 64.76 99.10 48.18 Mean 25.00 39.53 75.63 22.11 83.00 65.86 92.78 62.03

*PSI indicates scores on the Psoriasis Severity Index. All data are presented as percentage of reduction.

ease at the conclusion of treatment. The 1 patient who amined for disease-related pathology using histochemis- failed to undergo a final skin biopsy (who achieved clini- try and computer-assisted image analysis. As shown in the cal clearing) was not included in the histological data set. Table, mean epidermal thickness was reduced by 40% after 2 weeks (PϽ.001) and 66% by the end of treatment HISTOLOGICAL ANALYSIS (PϽ.001). To determine whether pathological keratin expression was reversed by this treatment, biopsy speci- Biopsy specimens obtained from lesional skin before treat- mens were examined for the expression of keratin 16 ment, after 2 weeks, and at the end of treatment were ex- (Figure 1). Keratin 16 was expressed in suprabasal ke-

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A D

B E

C F

Figure 1. Keratin 16 expression in psoriatic lesional epidermis before (A), at 2 weeks (B), and after trimethylpsoralen (TMP) therapy (C). The effects of TMP bath plus UVA therapy on epidermal and dermal T-lymphocyte infiltration as visualized by CD3 + antibody staining on skin biopsy specimens obtained from another patient before (D), at 2 weeks (E), and after treatment (F).

ratinocytes in all pretreatment biopsy specimens and con- sions are presented in the Table. Two weeks after start- tinued to be expressed in 9 of 10 patients after 2 weeks of ing PUVA treatment, there was a striking reduction in PUVA treatment. At the conclusion of treatment, keratin intraepidermal T lymphocytes (mean decrease, 76%; 16 was expressed in only 1 of the 10 psoriatic lesions. Be- PϽ.001), but only a modest reduction (mean decrease, cause keratin 16 is expressed only in hyperplastic epider- 22%) in T lymphocytes located in the papillary dermis. mis undergoing “regenerative” maturation,17 these stain- By the end of treatment, intraepidermal T lymphocytes ing results indicate reversal of regenerative growth by TMP had been reduced by 93% and dermal lymphocytes had bath PUVA treatment. been reduced by 62%. After 2 weeks of treatment, re- Previous studies have suggested that T lympho- ductions in epidermal acanthosis were highly corre- cytes may be the major cellular target of PUVA (8-MOP lated with reductions in intraepidermal CD3+ cells plus UVA) therapy.18,19 Accordingly, we sought to deter- (r = 0.87), and less correlated with dermal T- mine the lymphocyte-depleting effects of TMP PUVA lymphocyte reductions (r = 0.58). For all study points therapy in psoriatic tissue and to measure direct lym- (Figure 1) epidermal thickness was more highly corre- photoxic effects of TMP in vitro. The effects of TMP bath lated with the number of epidermal T lymphocytes com- PUVA therapy on CD3+ lymphocytes in psoriatic le- pared with dermal cells. These data are consistent with

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A B

C D

E F

Figure 2. The effects of trimethylpsoralen (TMP) bath plus UVA therapy on expression of CD1a and CD86 in dendritic cells in normal skin (A and B), lesional plaques (C and D), and treated lesional skin (E and F). Arrows indicate dendritic CD86+ Langerhans cell, with close-up in lower right corner (D). Black bars indicate 100 µm.

epidermal changes being induced primarily by the in- pear to be depleted from psoriatic lesions by TMP bath traepidermal T-lymphocyte subset. PUVA treatment. The ability of PUVA to decrease inflammation in psoriatic lesions could also be mediated through its deplet- IN VITRO STUDIES ing actions on Langerhans cells.20-24 In the unaffected skin of patients with psoriasis, CD1a+ Langerhans cells are pres- Finally, we sought to determine the relative cytotoxic ef- ent throughout the epidermis, but few cells express de- fects of TMP and 8-MOP on activated lymphocytes. Pre- tectable levels of the costimulatory molecule B7-2 (CD86), vious studies indicated that 8-MOP plus UVA can selec- as shown in Figure 2 . In contrast, CD1a+ cells are mostly tively induce T lymphocytes to undergo apoptotic cell located in more differentiated regions of lesional epider- death.18,19 We used several different assays to evaluate the mis and numerous CD86+ cells are also present in these effects of TMP on mitogen-activated peripheral blood T lym- areas. Following TMP bath PUVA therapy, there was a phocytes. Since apoptotic cells eventually disintegrate into marked reduction in the number of CD1a+ cells in the subcellular apoptotic fragments, PUVA-induced cyto- epidermis, and CD86+ cells were eliminated. Hence, toxic effects can be quantified by measuring reductions in Langerhans cells (particularly activated CD86+ cells) ap- a particular target cell population. Hence, the cytotoxicity

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©1998 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 of 8-MOP or TMP for T lymphocytes was assessed by enu- lymphocytes (as well as Langerhans cells that support on- merating CD3+ cells through flow cytometry. T lympho- going T-lymphocyte activation) are the main cellular tar- cyte numbers were reduced 89% by treatment with 0.01 gets for therapeutic improvement. Epidermal psoralen lev- ng/mL of TMP PUVA, 98% by treatment with 0.1 ng/mL els have been measured at higher than 250 pg/g from of TMP PUVA, and 92% by treatment with 100 ng/mL bathing in TMP solutions equivalent to those used in this of 8-MOP plus UVA. Cultures showed T-lymphocyte size study.35 Since TMP concentrations of only 10 pg/mL were and granularity shifts that typify apoptosis19 and subge- highly cytotoxic for activated T lymphocytes in our in nomic DNA fragmentation using flow cytometry.18 Based vitro studies, actual psoralen levels attained in the epi- on relative concentrations of psoralens required to pro- dermis from in vivo treatment should be sufficient to tar- duce cytotoxicity, mitogen-activated T lymphocytes ap- get T lymphocytes (even if UVA levels that penetrate epi- peared to be about 10 000-fold more sensitive to TMP dermis are Ͻ2 J/cm2). The marked depletion of than to 8-MOP. intraepidermal T lymphocytes following TMP bath PUVA Finally, the relative sensitivity of epidermal kera- therapy is consistent with the direct cytotoxic effects on tinocytes vs lymphocytes to TMP PUVA therapy was mea- this cell type, but the reduced T-lymphocyte infiltration sured using flow cytometry–based viability and cell count- could also be mediated by elimination of CD86+ den- ing assays. As was the case for 8-MOP PUVA therapy,18 dritic cells from skin lesions. Conceivably, topically ap- lymphocytes were killed by TMP PUVA therapy, but ke- plied TMP might have limited penetration in the epider- ratinocytes were relatively resistant (data not shown). mis such that cross-linking of DNA occurs mostly in differentiated cell layers (where CD3+ and CD86+ cells COMMENT predominate). It is theoretically possible that therapeutic effects could be separable from carcinogenic effects Currently, psoriasis is considered to be an immune- based on differential psoralen distribution and differ- mediated disease in which activated T lymphocytes trig- ences in the location of target cells. ger rapid keratinocyte proliferation, altered epidermal dif- In the end, we found TMP bath PUVA therapy to ferentiation, and neovascularization.25 In turn, the be well tolerated and highly effective at producing clini- activation of T lymphocytes is regulated by dendritic cells cal and histological resolution of psoriasis. The ability in psoriatic lesions that have up-regulated B7 costimu- of TMP bath PUVA therapy to eliminate activated Langer- latory molecules and can serve as potent stimulators of hans cells and T lymphocytes within the epidermis is likely resting T lymphocytes.26 The clinical importance of an to underlie its potent therapeutic actions in psoriasis. Al- immune pathoetiology is that it may be possible to de- though safety data on the carcinogenic risk of TMP bath velop immune-directed therapy that minimizes toxicity treatment are less complete than for oral 8-MOP, we be- to other cells. In fact, 8-MOP is a potent cytotoxic agent lieve that TMP bath PUVA therapy represents a sensible for T lymphocytes following activation by UVA, but it is alternative for the present. not entirely selective in its actions.18,19 Previous studies have shown that 8-MOP, when used in PUVA bath treat- Accepted for publication April 14, 1998. ment, produces profound depletion of lesion- This research was supported in part by General Re- infiltrating T lymphocytes and that pathological epider- search Center Grant M01-RR00102 from the National mal hyperplasia is reversed following a course of Center for Research Resources at the National Institutes of treatment.15 Although both TMP and 8-MOP PUVA Health, Bethesda, Md; by NIH grants CA545215, AI39214, therapy reverse pathologic keratinocyte hyperplasia (de- and AR07525 from the National Institutes of Health; and by fined by keratin 16 expression), one important differ- grants or gifts from The Carl J. Herzog Foundation, Green- ence is that epidermal Langerhans cells were strongly de- wich, Conn; the American Skin Association, New York, NY; pleted by TMP PUVA therapy in lesional psoriatic The Carson Family Charitable Trust, New York, NY; Dr James epidermis, whereas 8-MOP did not produce marked re- Murphy, New York, NY; and Jean Stein, New York, NY. ductions in lesional Langerhans cells.15 The ability of TMP Dr Coven was supported as a Rockefeller University PUVA therapy to reduce expression of CD86 in epider- Clinical Scholar from May 1996 through June 1997. mal cells (presumably Langerhans cells) provides yet an- Presented at the 58th meeting of the Society for other mechanism for immune suppression, ie, T-cell co- Investigative Dermatology, Washington, DC, April 26, stimulation should be diminished due to less B7 1997. expression on dendritic cells. We would like to thank the rotating dermatology resi- Clinical observations suggest that TMP bath PUVA dents from The New York Hospital–Cornell Medical Cen- therapy might be less carcinogenic than conventional ter, New York, NY, for their help with patient care. PUVA.10-14 In animal and bacterial model systems, TMP Reprints: James G. Krueger, MD, PhD, Laboratory for and 8-MOP have been found to be potent carcino- Investigative Dermatology, The Rockefeller University, Box gens.27-33 It is possible that TMP will be proven to be highly 178, 1230 York Ave, New York, NY 10021-6399. carcinogenic in psoriatic patients once sufficient exposure is given, and this possibility cannot be excluded with REFERENCES certainty by present data.10-14 However, if this type of treatment does eventually prove to be less carcinogenic, one 1. Parrish JA, Fitzpatrick TB, Tannenbaum L, Pathak MA. Photochemotherapy of potential explanation could be that topical psoralens cause psoriasis with oral methoxsalen and longwave ultraviolet light. N Engl J Med. different cellular effects than systemic psoralens. Based 1974;291:1207-1211. on previous studies,16,34 it is likely that intraepidermal T 2. Melski JW, Tannenbaum L, Parrish JA, Fitzpatrick TB, Bleich HL. Oral methox-

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©1998 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 salen photochemotherapy for the treatment of psoriasis: a cooperative clinical tosis in normal and malignant T-lymphocytes. Photochem Photobiol. 1996;63: trial. J Invest Dermatol. 1977;68:328-335. 566-571. 3. Greaves MW, Weinstein GD. Treatment of psoriasis. N Engl J Med. 1995;332: 19. Yoo Ek, Rook AH, Elenitsas R, Gasparro FP, Vowels BR. Apoptosis induction of ul- 581-588. traviolet light A and photochemotherapy in cutaneous T-cell lymphoma: relevance 4. Stern RS, Nichols KT, Vakeva LH. Malignant melanoma in patients treated for to mechanism of therapeutic action. J Invest Dermatol. 1996;107:235-242. psoriasis with methoxysalen (psoralen) and ultraviolet A radiation (PUVA). N Engl 20. Koulu LM, Jansen CT. Antipsoriatic, erythematogenic, and Langerhans cell marker J Med. 1997;336:1041-1045. depleting effect of bath psoralens plus ultraviolet A treatment. J Am Acad Der- 5. Stern RS, Laird N. The carcinogenic risk of treatments for severe psoriasis. Can- matol. 1988;18:1053-1059. cer. 1994;73:2759-2764. 21. Koulu LM, Jansen CT. Effect of oral methoxsalen photochemotherapy on hu- 6. Stern RS, Lange R. Non-melanoma skin cancer occurring in patients treated man Langerhans cell number: dose-response and time-sequence studies. Arch with PUVA five to ten years after first treatment. J Invest Dermatol. 1988;91: Dermatol Res. 1982;274:79-83. 120-124. 22. Friedmann PS, Ford G, Ross J, Diffey BL. Reappearance of epidermal Langer- 7. Forman AB, Roenigk HH, Caro WA, Magid ML. Long-term follow-up of skin can- hans cells after PUVA therapy. Br J Dermatol. 1983;109:301-307. cer in the PUVA-48 Cooperative Study. Arch Dermatol. 1989;125:515-519. 23. Koulu LM, Jansen CT. Skin photosensitizing and Langerhans’ cell depleting ac- 8. Studniberg HM, Weller P. PUVA, UVB, psoriasis, and nonmelanoma skin can- tivity of topical (bath) PUVA therapy: comparison of trimethylpsoralen and 8- cer. J Am Acad Dermatol. 1993;29:1013-1022. methoxypsoralen. Acta Derm Venereol. 1983;63:137-141. 9. Honigsmann H, Wolff K, Gschnait F, Brenner W, Jaschke E. Keratoses and non- 24. Pierard-Franchimont C, Nickels-Read D, Mosbah TB, Estrada JA, Pierard GE. Early melanoma skin tumors in long-term photochemotherapy. J Am Acad Dermatol. dermato-pathological signs during bath-PUVA therapy. J Pathol. 1990;161:227- 1980;3:406-414. 231. 10. Hannuksela-Svahn A, Sigurgeirsson B, Pukkala E, et al. Trioxsalen bath PUVA 25. Norris DA, Travers JB, Leung DYM. Lymphocyte activation in the pathogenesis does not increase the risk of squamous cell skin carcinoma: a joint analysis of of psoriasis. J Invest Dermatol. 1997;109:1-4. 1124 Swedish and Finnish patients followed up for ten years. In: Altmeyer P, 26. Nestle FO, Turka LA, Nickoloff BJ. Characterization of dermal dendritic cells in Hoffman K, Stucker M, eds. Skin Cancer and UV Radiation. Berlin, Germany: psoriasis: autostimulation of T lymphocytes and induction of Th1 type cyto- Springer-Verlag Inc; 1997:434-439. kines. J Clin Invest. 1994;94:202-209. 11. Hannuksela A, Pukkala E, Hannuksela M, Karvonen J. Cancer incidence among 27. Kirkland DJ, Creed KL, Mannisto P. Comparative bacterial mutagenicity studies Finnish patients with psoriasis treated with trioxsalen bath PUVA. J Am Acad Der- with 8-methoxypsoralen and 4,5Ј,8-trimethylpsoralen in the presence of near- matol. 1996;35:685-689. ultraviolet light and in the dark. Mutat Res. 1983;116:73-82. 12. Lindelof B, Sigurgeirsson B, Tegner E, Larko O, Berne B. Comparison of the car- 28. Young AR. Photocarcinogenicity of psoralens used in PUVA treatment: present cinogenic potential of trioxsalen bath PUVA and oral methoxsalen PUVA: a pre- status in mouse and man. J Photochem Photobiol. 1990;6:237-247. liminary report. Arch Dermatol. 1992;128:1341-1344. 29. Grossweiner LI. Mechanisms of photosensitization by furocoumarins. NCI Monogr. 13. Lindelof B, Sigurgeirsson B, Tegner E, et al. PUVA and cancer: a large-scale epi- 1984;66:47-54. demiological study. Lancet. 1991;338:91-93. 30. Wolff K, Honigsmann H. Safety and therapeutic effectiveness of selected psor- 14. Berne B, Fischer T, Michaelsson G, Noren P. Long-term safety of trioxsalen bath alens in psoriasis. NCI Monogr. 1984;66:159-164. PUVA treatment: an 8-year follow-up of 149 psoriasis patients. Photodermatol- 31. Cech T, Pathak MA, Biswas RK. An electron microscopic study of the photo- ogy. 1984;1:18-22. chemical cross-linking of DNA in guinea pig epidermis by psoralen derivatives. 15. Vallat VP, Gilleaudeau P, Battat L, et al. PUVA bath therapy strongly suppresses Biochim Biophys Acta. 1979;562:342-360. immunological and epidermal activation in psoriasis: a possible cellular basis 32. Pathak MA. Mechanisms of psoralen photosensitization reactions. NCI Monogr. for remittive therapy. J Exp Med. 1994;180:283-296. 1984;66:41-46. 16. Gottlieb SL, Gilleaudeau P, Johnson R, et al. Response of psoriasis to a lymphocyte- 33. Hannuksela M, Stenback F, Lahti A. The carcinogenic properties of topical PUVA:

selective toxin (DAB389IL-2) suggests a primary immune, but not keratinocyte, a lifelong study in mice. Arch Dermatol Res. 1986;278:347-351. pathogenic basis. Nat Med. 1995;1:442-447. 34. Krueger JG, Wolfe JT, Nabeya RT, et al. Successful ultraviolet B treatment of pso- 17. McKay IA, Leigh IM. Altered keratinocyte growth and differentiation in psoria- riasis is accompanied by a reversal of keratinocyte pathology and by selective sis. Clin Dermatol. 1995;13:105-114. depletion of intraepidermal T cells. J Exp Med. 1995;182:2057-2068. 18. Johnson R, Staiano-Coico L, Austin L, Cardinale L, Nabeya-Tsukifuji R, Krueger 35. Vaatainen N, Taskinen J. Penetration of trioxsalen into skin from trioxsalen baths. JG. PUVA treatment selectively induces a cell cycle block and subsequent apop- Arch Dermatol Res. 1981;270:157-158.

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