British Journal of Dermatology (1991) 124, 443-448.

ADONIS 0007096391001070

The action spectrum between 320 and 400 nm for clearance of psoriasis by psoralen photochemotherapy P,M,FARR, B,L,DIFFEY,* E.M.HIGGINS AND J,N,S,MATTHEWS! Department of Dermatology, Royal Victoria infirmary, Newcastle upon Tyne, U.K. 'Regional Medical Physics Department, Dryburn Hospital, Durham, U.K. ^Department of Medical Statistics, University of Newcastle upon Tyne, Newcastle upon Tyne, V,K, Accepted for publication 19 November 1990

Summary

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We have compared the effectiveness of oral 8-methoxypsoralen photochemotherapy (PUVA) using ultraviolet fluorescent lamps with peak emission at either 325, 352 or 370 nm in the treatment of 24 patients with psoriasis. The forearms of each patient were treated three times weekly with two of the three lamps. The erythemal sensitivity of each patient was tested before the first treatment to ensure that equally erythemal doses of radiation were given from each of the lamps, A side-to-side comparison was used to assess response to treatment at weekly intervals for the 6 weeks of the trial. The lamp with peak emission at 325 mn was shown to be significantly superior to either of the other lamps in terms of response assessed at weekly intervals, and time to clearance of psoriasis. An action spectrum, constructed from the median doses required for clearance of psoriasis using each of the lamps, showed that the effectiveness of the radiation decreased exponentially with increasing wavelength throughout the UVA waveband, such that radiation at 320 nm was an order of magnitude more effective than at 360 nm. This suggests that lamps with peak emission around 32 5 nm will be more effective than those conventionally used in PUVA units with a peak emission at 3 52 nm. Lamps with peak emission around 325 nm are also highly effective in the treatment of psoriasis with phototherapy alone. Thus a single treatment unit containing these lamps couid be used either for PUVA or ultraviolet phototherapy of psoriasis, avoiding duplication or irradiation equipment.

The radiation sources used in psoralen photochemotherapy of psoriasis (PUVA) are almost invariably UVA fluorescent lamps with a fluorescence spectrum extending from about 320 to 400 nm, with a peak at around 352 nm. The choice of this particular spectral power distribution was based not on knowledge of the therapeutic action spectrum, but because in the early 19 70s when the treatment of psoriasis by PUVA was introduced, availability of high intensity, wide area UVA sources was limited to lamps with this spectrum. Research on the action spectrum for healing of psoriasis by ultraviolet radiation alone' has led to the development of lamps with emission spectra tailored to the therapeutic action spectrum. These new lamps are said to be clinically more effective than those used conventionally in the treatment of psoriasis,^ '* The action spectrum for clearance of psoriasis by psoralen photochemotherapy is unknown, but if it does not correspond to the action spectrum for PUVA erythema, development of more effective lamps which exploit this difference may be possible. Correspondence: Dr P.M.Farr, Department of Dermatology, Royal Victoria Infirmary, Newcastle upon Tyne NEl 4LP, U.K.

Action spectroscopy, in most photobioiogical research, involves the use of an irradiation monochromator to deliver a narrow waveband of radiation. Technical factors limit the irradiation field with this technique to less than about 10 cm^. This small field size presents problems when treating lesions of psoriasis over several weeks. An alternative technique, and the one adopted here, is to use a number of large area lamps with different emission spectra and to deduce the therapeutic action spectrum by a process of induction.

Methods Ultraviolet radiation sources and dosimetry

Fifteen 60 cm fluorescent lamps were mounted in a cylindrical configuration (27-cm diameter) within three identical housings (Fig, 1), allowing uniform irradiation of a patient's hand and arm placed along the central axis into the 'cylinder' of radiation. Each lamp bousing was fitted with commercially available fluorescent lamps with peak emission (Fig, 2) at either 32 5 nm (Wolff Helarium B1-01-40W; Kosmedico, Stuttgart, Germany), 352 nm (TL 40W/09R: Philips, Eindhoven, The Nether443

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P,M.FARR et al.

Patients

Figure 1. The cylindrical irradiation chamber housing 1 5 fluorescent lamps. The line drawing omits the protective outer casing and demonstrates the position of a hand grip.

lands) or 370 nm (TL 40W/10R: Philips), These lamps are subsequently referred to as 325-, 352- and 370-nm lamps, respectively. An ultraviolet photodiode, mounted inside each lamp housing, was connected to a specially designed 'dose computer' which controlled the exposure time depending upon the pre-set dose and ultraviolet irradiance. The photodiode in each lamp housing was calibrated with a spectroradiometer (model 742; Optronic Labs Inc, Orlando, FL, U,S,A,) and statements of ultraviolet irradiance and dose refer to unweighted values.

and irradiation

protocol

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We studied 24 patients (16 female, eight male: age range 18-54 years) who were due to receive whole-body PUVA treatment for psoriasis. The only requirement for entry into the trial was that both forearms were affected by psoriasis to approximately the same extent. Patients were allocated randomly (in balanced blocks of six) to be treated with two ofthe fluorescent lamp units (one for each arm). All exposures took place 2 h after ingestion of 8-methoxypsoralen (0 6 mg/kg). On the patients' first attendance a 1-cm-diameter site on uninvolved skin of the inner aspect of each forearm was exposed to a single dose of radiation from the appropriate lamps (Table 1), At 72 h after exposure the intensity of erythema at each site was measured using a reflectance instrument' and the increase in erythema index over background levels calculated.'' Based on this value and the known slope of the PUVA erythema dose-response curve for each of the lamp types' (P.M. Farr and B,L, Diffey, unpublished data), the starting dose of UVA was chosen individually for each patient, and was designed to be 40% of the minimal phototoxic dose (Table 1). Treatment was given three times weekly (Monday, Wednesday, Friday) for 6 weeks and doses were increased by 40% after each block of three treatments (1 week). Assessment of response was made by one clinician (E,M.H.) who was unaware of the types of lamp being used in individual patients. Before the trial, and then at weekly intervals, the severity of psoriasis on each patient's forearms was judged as being equal, more severe on one arm than the other, or completely clear. The same clinician noted whether erythema was present. The 40% weekly increment in dose was abandoned

0-0001 300

350

350

400

Wavelength (nm) Figure 2, The spectral power distribution ofthe three ultraviolet fluorescent lamps, (a) 32 5-nm lamp (Wolff Helarium Bl -01-40W)- (b) 3 52-nm lamp (Philips TL40W/09R): (c) 370-nm lamp (Philips TL40W/10R).

ACTION SPECTRUM FOR PSORALEN PHOTOCHEMOTHERAPY

Table 1, The starting doses for treatment with each lamp calculated from the increase in erythema index (AE) measured 72 h after irradiation of a test site with 2 J/cm- (325-nm lamp), 10 J/cm^ (352nm lamp) and 30 J/cm^ (370-nm lamp). (Minimal erythema corresponds to AE = 0;05: moderate erythema AE = 0 1 : severe erythema

Increase in erythema index 72 h after irradiation

Starting dose (J/cm^ ) 325-nm lamp

352-nm lamp

370-nm lamp

0,7 0-7 0-7 1

1,4 2 2

2.5 3-5 3-5 5

>()-10 0-09-010 008-009 OO7-OO8 006-007 0 0 5 - 0 06 004-0-05 agree closely with the observed median doses (column 2, Table 4) derived from the data in Table 2. We chose an exponential function to represent the clearance

10"'-

-s

10-

310

340

370

400

Wavelength (nm)

Figure 3. Exponential action spectrum and 95% confidence limits for Ihe clearance of psoriasis by oral S-methoxypsontlen photochemo therapy.

action spectrum from J2() to 400 nm not on biological grounds, but because our data allowed sensible estimates for pi/.) only if we use a curve defined by two parameters, and because exploratory analyses with more complicated curves gave similar results at wavelengths greater than 320 nm. There is too little relevant information in our data to attempt estimation ofa p{/.) for wavelengths less than 320 nm. The conclusion of this analysis is that due to the limited number of lamps used in the study it is not possible to derive a good estimate of p(/) throughout the ultraviolet spectrum. However, for wavelengths greater than 320 nm our data suggest that the dose for clearance of psoriasis increases in an approximately exponential manner with increasing wavelength. Phototherapy (without psoralen sensitization) using lamps with peak emission at 325 nm is also effective in clearing psoriasis.'* With the doses and frequency of irradiation used in this study it is unlikely that the response we observed is independent of the action of psoralen. However, it is possible that the radiation from the 325-nm lamps acted synergistically through both Table 4. Median UVR do.ses required for clearance of psoriasis and the clearance doses calculated from equation (!)

Lamp

Median observed clearance dose (J/cm'

CalcuUited clearance dose (J/cm^)

J52 J70

32 129 J91

32 128 391

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P.M.KARR et ul.

psoralen-dependent and psoralen-independent mechanisms. The results of this study have shown that shortwave UVA radiation ( < i4() nm) is more effective (han longer wavelength I > i40 nm) radiation in PUVA iherapy of psoriasis. A similar wavelength dependence has been shown previously for inhibition of DNA synthesis'' and induction of sunburn cells in psoralen-sensitized mouse skin.'"* Radiation at wavelengths less than 340 nm. however, comprises only about 16% ofthe ultraviolet emission from the UVA lamps found in virtually all PUVA irradiation units (typified by the Philips TIiO9 lamp with peak emission at 3S2 nm). Lamps such as the THO (J70 nml and optically filtered high-pressure mercury lamps (which have the major part of their ultraviolet emission above 560 nm) are increasingly being recommended for I'lJVA treatment. Our results suggest that much of the ifVA radiation from these lamps will be iherapeutically ineffective. As reliable data concerning the wavelength dependence of skin cancer and other hazards of long-term PUVA treatment in man are not availahle. it is not possible to predict whether the use of 32S-nni lamps will result in different risks compared with conventional lamps (352 nm). Preliminary studies in mice treated with S-[nethoxypsoralen suggest that the action spectrum for phototumorigenesis is similar to that for erythema.'^ Because the emission spectrum ofthe 325nm lamps coincides most closely with our estimate of the action spectrum for PUVA clearance of psoriasis (Fig. 3). and will clear psoriasis with a lower cumulative ultraviolet dose over a shorter time and without a higher risk of acute side-etTects than conventional lamps, there is no reason to suppose that any long-term risks will be increased. We have shown previously that lamps with peak emission around 325 nm arc more effective than other sources, such as the 'fluorescent sunlamp' or mercury arc lamp, in combined treatment of psoriasis with ultraviolt't phototherapy and dithranol/ We have now shown that 325-nm tamps (such as the Helarium Bl01) are more effective for PUVA therapy of psoriasis than ultraviolet lamps with a higher UVA component. The implication of these findings is that either PUVA or ultraviolet phototherapy of psoriasis can he achie\ed most effectively with the same lamp. Therefore, dermatology units will no longer require separate PUVA and ultraviolet phototherapy equipment.

Acknowledgments This study was supported by a grant from the Skin Disease Research Fund. We are grateful to Or I.M.Marks ft)r allowing us to study patients under her care, to ll.A.Pitkcalhley for nursing assistance and to K.J.Oliver. M.J.Loftus and P.J.Saunders for the design and construction ofthe irradiation apparatus.

Note added in proof The Helarium lamps presently available have a different emission spectrum to those used in this study, and have a peak emission at 340 nm (rather than i2S nm). The therapeutic efficiency of these lamps for PUVA remains to be determined.

References 1 I'iirrlsh JA, Jiicnicki- K.V. Action spiTtnim tor phDUithi-rapy of psoriasis. / hnvst Dermatoi 19HI; 76: JS9-62. 2 van Weieldcn t-t. Huiin Jc Iii [-'iiitie H, Young l\. vun der t^eun |C. A nc-w development in liV'Bphoiotht-Tiipy cif psoriasis. Iir J Dermaio! t9SS: 119: 11 t9. J Uret-n C. I't-rgiison |. Uikshmipathi T. Johnson BK. ^ 1 1 run tJVB phototherapy—(in fPfcctive treatment for psoriasis. Hr / IM'rmalot 1988: ligMi-il h. 4 larr PM. Diffey lil.. Murks JM. PluMothcTapy and imtlinilin Irt'atineni of pwtriasis: new lamps for old. Hr Meii / 1487: 294: 5 DilTfy Bl.. Oliver RJ. l'"iin- I'M. A porlubU- instrument for quantifying frythi'ma induced t\v uitravioiet nidiiition. Br / Dermatol Farr PM. Diffcy Bt.. Quantitative studies un cutaneous erythema induced by ultraviolet radiaUon. Hr / Dermaiol 1984: 111: 6 7 1 Cox NH. l-aiT PM. DifTt-y BL. A comparison ofthe doserelationship for psorulfn -UVA erythema Hiid HVBorythetiui. .Xrih Ikrnuitoi 19X^)1 12S: lftSl-7. Holt Jl). Preritk'f RI.. Surviviil iinalyscs in twin studies iind matched pairs fxptTinit-nts. Hiomelrika 1974; 6 1 : I 7-JO. McCulIagh P. Nelder JA. deneraUzed Uttear Models. 2nd edn. Undon: Chupiiiiiii and Hall. 1989: 98 148. (Gardner M|. Altman IXI. Stalistits wilh Confidcme. U»ndon: British Medical lounuil. I9S4: 57. Arniitiiye P. Ik-rry tl. Stalisthtil \h-lhi\ls in Xleilical Kcsmrc/i, Oxford: Bliickwell Scientitic rtiblkatioris. t9N7: I 1 S. Aitkin M. Clayton 1>. The lltting of exponential. Weibull and extreme value distributions to loinplex cens

The action spectrum between 320 and 400 nm for clearance of psoriasis by psoralen photochemotherapy.

We have compared the effectiveness of oral 8-methoxypsoralen photochemotherapy (PUVA) using ultraviolet fluorescent lamps with peak emission at either...
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