>> Clinical Guidelines

Guidelines for topical PUVA: a report of a workshop of the British Photodermatology Group

S.M.HALPERN,  A.V.ANSTEY,*  R.S.DAWE,†  B.L.DIFFEY,¥  P.M.FARR,§  J.FERGUSON,¶  J.L.M.HAWK,**  S.IBBOTSON,§ J.M.McGREGOR,**  G.M.MURPHY,††  S.E.THOMAS,¥¥ AND L.E.RHODES
Dermatology Unit, University Clinical Departments, University of Liverpool,
Liverpool L69 3GA, U.K.
*Department of Dermatology, Royal Gwent Hospital, Newport
†Department of Dermatology, Glasgow Western Infirmary, Glasgow
¥Regional Medical Physics Department, Newcastle General Hospital, Newcastle upon Tyne
§Department of Dermatology, Royal Victoria Infirmary, Newcastle upon Tyne
¶Photobiology Unit, Department of Dermatology, Ninewells Hospital, Dundee
**Department of Photobiology, St Thomas' Hospital, London
††Department of Dermatology, Beaumont Hospital, Dublin
¥¥Dermatology Department, Barnsley General Hospital, Barnsley

Accepted for publication 20 August 1999

Summary

Psoralen photochemotherapy [psoralen ultraviolet A (PUVA)] plays an important part in dermatological therapeutics, being an effective and generally safe treatment for psoriasis and other dermatoses. In order to maintain optimal efficacy and safety, guidelines concerning best practice should be available to operators and supervisors. The British Photodermatology Group (BPG) have previously published recommendations on PUVA, including UVA dosimetry and calibration, patient pretreatment assessment, indications and contraindications, and the management of adverse reactions¹.  While most current knowledge relates to oral PUVA, the use of topical PUVA regimens is also popular and presents a number of questions peculiar to this modality, including the choice of psoralen, formulation, method of application, optimal timing of treatment, UVA regimens and relative benefits or risks as compared with oral PUVA. Bath PUVA, i.e. generalized immersion, is the most frequently used modality of topical treatment, practised by about 100 centres in the U.K., while other topical preparations tend to be used for localized diseases such as those affecting the hands and feet. This paper is the product of a recent workshop of the BPG and includes guidelines for bath, local immersion and other topical PUVA. These recommendations are based, where possible, on the results of controlled studies, or otherwise on the consensus view on
current practice.

Key words: photochemotherapy, psoralens, PUVA, therapy

Pretreatment assessment

Recommendations concerning pretreatment assessment and contraindications for topical psoralen photochemotherapy [psoralen ultraviolet A (PUVA)] are largely the same as those published for oral PUVA¹.  However, topical PUVA is preferable to oral PUVA in the following circumstances.

1. In patients with hepatic dysfunction.
2. In patients with gastrointestinal disturbance and where absorption is uncertain, e.g. after ileostomy.
3 In patients with cataracts.
4 Where compliance with eye protection may be poor.
5 To permit shorter irradiation times (particularly in black patients, where very high UVA doses are otherwise needed, and in claustrophobic individuals and children).
6 Where psoralen-drug interactions are anticipated, e.g. with warfarin.

Indications for generalized immersion bath psoralen ultraviolet A

Psoriasis
A variety of psoralen concentrations and treatment regimens have been used for generalized plaque psoriasis. Studies of 8-methoxypsoralen (8-MOP) bath PUVA with concentrations ranging from 0.5 to 4.6 mg/L and treatments given two to four times weekly, report clearance in 60-90% of patients (mean 16-21 treatments) and total UVA dose of 25-27 J/cm².^2-4  Treatment with 0.33 mg/L trimethylpsoralen (TMP) bath PUVA, two to seven times weekly, resulted in a good or excellent response in 92% of patients (mean 18 treatments) and total UVA dose of about 20 J/cm²,⁵ while another study with a similar TMP regimen found good or excellent results in 67% of 51 treatment courses⁶.  The use of 5-MOP bath PUVA is little reported; however, a non-randomized study of 8-MOP and 5-MOP bath PUVA in a small number of patients showed that, at the same concentration (0.0003%), there was no significant difference in efficacy, but 5-MOP appeared more phototoxic and pigmentogenic⁷.  Of four comparative studies of oral and bath PUVA (one TMP, three 8-MOP)^8-11, only one is a prospective randomized trial¹⁰.  All suggested a similar response rate, with clearance being achieved with the same number of treatments. The total UVA dose was three to six times lower with bath PUVA, but as discussed later, this does not necessarily imply reduced carcinogenicity.

Hence, bath PUVA is clearly a useful treatment for chronic plaque psoriasis, and appears equally effective to oral PUVA. In keeping with oral PUVA, however, it should be reserved for second-line therapy¹.  As the above studies have not been designed to examine the most effective protocols our recommendations are based on the consensus current practice of British Photodermatology Group (BPG) members (see later section).

Other disorders
There is a paucity of evidence concerning the efficacy of bath PUVA in other dermatoses, although there are reports (Table 1a) of its value in lichen planus^12-15, systemic sclerosis and generalized morphoea^16,17, urticaria pigmentosa^13,18, mycosis fungoides¹⁹, polymorphic light eruption²⁰, prurigo simplex subacuta²¹, nodular prurigo^12,22, aquagenic pruritus^23,24, and lymphomatoid papulosis²⁵.

In the absence of controlled studies to examine the efficacy of bath PUVA in generalized disorders other than chronic plaque psoriasis, we suggest that a common sense approach is to try a course of bath PUVA in the above conditions if other measures have failed and oral PUVA is felt less appropriate.

^a See text for chronic plaque psoriasis

Indications for topical hand and foot psoralen ultraviolet A

Topical PUVA has been extensively used and appears of value in the treatment of chronic hand and foot dermatoses, namely hyperkeratotic and dyshidrotic eczema, and hyperkeratotic and palmoplantar pustular psoriasis (PPP) (Table 1b)^26-34 However, randomized comparative studies of the efficacy of oral and topical PUVA are scarce. A retrospective review of 15 patients treated with oral 8-MOP and 25 with local immersion 8-MOP for chronic hand and foot dermatoses found the two modalities to be equally effective²⁶.  Using 8-MOP local immersion (1 mg/L), 93% (13 of 14) of patients with dyshidrotic eczema and 86% (12 of 14) of patients with hyperkeratotic eczema cleared or showed considerable improvement²⁷; both the dyshidrotic and hyperkeratotic forms required a similar mean number of treatments (12 and 15) and total UVA dose (21 and 28 J/cm²) for clearance.

Reports of the effect of PUVA in PPP are conflicting. In uncontrolled studies of topical 8-MOP PUVA, clearance has varied from 30% (three to 10) with local immersion or 0.1% ointment to 87% (13 of 15) with 0.15% emulsion^32,33.  In the latter study, similar response rates were found with topical and oral PUVA but maintenance treatment was noted to be required to prevent early relapse³³.  The clearance rate for oral 8-MOP PUVA in PPP has been reported as 86% (31 of 36) for palmar but only 15% (5 of 34) for plantar involvement³⁵.  However, a double-blind, placebocontrolled study of topical PUVA (0.75% 8-MOP emulsion, n = 27) for PPP, found similar improvements in both the treated and untreated groups³⁴.  In contrast to the findings in generalized plaque psoriasis, for palmar psoriasis local immersion with 5-MOP may be more effective than 8-MOP, when used in similar concentrations⁷.  Moreover, in a comparative trial of oral and topical PUVA with etretinate, the etretinate was noted to be significantly more effective than either modality of PUVA³⁶.  Therefore, although local PUVA may be beneficial in other chronic hand and foot dermatoses, the case for recommending it in PPP is less convincing.

TMP, trimethylpsoralen; 8-MOP, 8-methoxypsoralen

Indications for other forms of topical psoralen ultraviolet A

There are a few reported studies of the use of other topical psoralen preparations such as paints, ointments and lotions (Table 1a), these having been applied principally in chronic hand and foot dermatoses (see previous section), but also sometimes used for the treatment of other sites. Disorders treated include vitiligo^37,38, morphoea,39 mycosis fungoides⁴⁰, atopic dermatitis⁴¹ and uraemic pruritis⁴².  Various products, concentrations and protocols are employed, and very little is known about their optimal use. Burning and patchy pigmentation can be a problem⁴³, and the inadvertent spread of preparations on to unaffected skin can occur. Thus while they may provide a practical alternative to immersion psoralen for the treatment of localized disease, their use clearly demands greater medical supervision.

Use of adjunctive treatment

It is anticipated that adjunctive treatments of benefit in oral PUVA might also increase the efficacy of bath PUVA, but currently no controlled trials of sufficient power have been performed. However, six studies report the combination of topical PUVA regimens with oral retinoids (re-PUVA) to be beneficial in psoriasis, often with more rapid clearance and reduced total UVA dose^44-49.  Re-PUVA with either etretinate or acitretin appeared equally effective, and no differences were seen in relapse rates between topical 8-MOP alone or re-PUVA^46,47.  There are also isolated reports of the use of topical PUVA with anthralin⁵⁰, and with tacalcitol⁵¹, and a single case report showing improvement of chronic actinic dermatitis with combined cyclosporin and bath PUVA therapy⁵².

Adverse effects

Skin phototoxicity
Comparative studies with oral 8-MOP PUVA have shown a far greater incidence of erythema or burning than with TMP baths⁸ (40% vs. 16%) but roughly similar rates with bath 8-MOP^9-11.  In the past, difficulties with TMP solubility have led to unusual patterns of phototoxic burning due to the uneven distribution in the bath water⁵³.  It has also been stated that erythema is more protracted with bath than oral PUVA, lasting perhaps for 1 week even at threshold level^54,55.  Furthermore, increased sensitivity is reported to occur at about the fourth day of treatment, with the minimal phototoxic dose (MPD) decreasing by about 50%^9,56,57; this may partly relate to the simple build-up of subclinical erythemal reactions due to the multiple PUVA treatments given per week in some studies.  Additionally, it has been noted that a prolonged susceptibility to photosensitization can occur for up to 72 h after treatment (personal observation, J.Ferguson, Ninewells Hospital, Dundee, U.K.) despite the clearance of free drug from the skin⁵⁸.  A possible explanation for this might be that following the initial irradiation, psoralen DNA monoadducts occur which persist far longer in the skin than free psoralen, and with subsequent irradiation result in increased photosensitivity due to conversion to bifunctional adducts⁵⁹.  This is theoretical, however, and needs further study, and until more information is available, it is recommended that photoprotective measures (i.e. adequate clothing, no sunbathing) are taken by patients both during the course and for up to a week after the course is completed.

Other acute effects
Pruritus appears to be equally common following oral and bath PUVA, occurring in 10-40% of patients, but bath PUVA has the advantage that gastrointestinal symptoms such as nausea are avoided. Although rare, contact dermatitis and photocontact dermatitis have been reported with TMP and 8-MOP baths^5,60.

Eye phototoxicity
The current practice in the majority of units in the U.K. is not to recommend eye protection following bath PUVA. There is no published evidence of an increased incidence of cataract development in humans following oral or bath PUVA, and we can therefore only make an indirect judgement extrapolated from comparative information on plasma levels following oral and bath PUVA (Table 2). Both TMP and 8-MOP may be detected in plasma to variable degrees after topical administration^6,61-69, but the concentrations of 8-MOP are generally very much lower than after oral dosing^64,65.  However, psoralen concentrations can be high with the application of paint/emulsion formulations to large areas, and comparable plasma levels with those with oral PUVA have been recorded for total body treatment with 0.15% 8-MOP emulsion;66 on the other hand, such levels were found to be undetectable after 0.1% methoxsalen lotion to plaques covering less than 2% total surface area or to palmoplantar skin^67,68.  In contrast, TMP is poorly absorbed when given orally which explains why oral/bath concentrations are similar for this drug^6,62,63,70 It has also been shown that psoriasis disease severity may influence psoralen absorption with greater plasma levels detected in patients with higher psoriasis area and severity index scores⁶⁹.  We therefore recommend that protective spectacles are advised on the day of treatment for patients with very extensive disease (i.e. . 30% surface area), in children, and in individuals with severe atopic eczema due to their increased lifetime risk.

Skin cancer
The risk of non-melanoma skin cancer (NMSC) is now recognized following multiple treatments with oral PUVA, with an 11-13-fold relative risk of squamous cell carcinoma (SCC) and 3-7-fold relative risk of basal cell carcinoma (BCC) after more than 260 treatments⁷¹.  No equivalent data exist for topical PUVA and there is currently insufficient evidence to conclude that this treatment is any safer.

In vitro work confirms the mutagenicity of TMP, 8-MOP and 5-MOP plus UVA, and in mice a dose relationship exists for SCC with both topical 8-MOP and 5-MOP plus UVA⁷².  A melanocytic tumour has also been reported in one series of mice treated with topical PUVA⁷³.  Currently, there is insufficient evidence to reach a conclusion on the relative risk of topical and oral PUVA. In humans, studies to date have been limited by sample size and length of follow-up, with insufficient power to examine the long-term risk of NMSC associated with the use of topical PUVA^74,75.  It is generally held that the carcinogenic risk reflects the number of phototoxic episodes (i.e. the number of psoralen plus UVA treatments), rather than either the total UVA dose or the route of psoralen delivery. It is also likely that cancer risk is related to treatment efficacy; thus the lower cumulative UVA dose required for clearance with bath PUVA should not be interpreted as implying a lower carcinogenic risk, particularly as higher psoralen concentrations may be present in the skin thus making the overall effect of bath PUVA the same as for oral PUVA. While no excess risk of skin cancer has yet been reported in association with bath PUVA, keratoses and lentigines are common⁴⁶ and until there is good evidence to the contrary, it should probably be assumed that, for disease clearance, bath PUVA is as carcinogenic as oral PUVA. It is therefore recommended, as for oral PUVA, to keep bath PUVA treatments to a minimum.

Protocols for topical psoralen ultraviolet A

Drug protocols
It is evident from the preceding sections that many questions remain unanswered concerning the optimal protocols for topical PUVA. In the absence of studies to address these issues, we recommend that the consensus current practice may be used for guidance. Most U.K. units use bath 8-MOP at a concentration of 2.6 mg/L (up to 3.7 mg/L), while the more phototoxic TMP is used at a concentration of 0.33 mg/L. A 15-min psoralen bath, given at a comfortably warm temperature, is then followed by immediate exposure to UVA (Appendix 2).

Some support for the above protocol is provided by diffusion theory and experimental permeability results.  The lag time before a diffusing substance appears in appreciable quantity in the viable epidermis is a function of stratum corneum thickness and the diffusion coefficient. In excised normal skin in vitro the lag time for 8-MOP in aqueous solution at 32 °C for a stratum corneum thickness of 10 µm is 4 min, for 20 µm 15 min, and for 30 µm it would rise to 33 min⁷⁶.  However, diffusion will be influenced by factors such as vehicle characteristics⁷⁷ or the presence of emollients on the surface of the skin. Additionally, abnormalities of the stratum corneum as in psoriasis may lead to an increased permeability to psoralens when compared with unaffected skin. Further, while in vitro the penetration of normal epidermis by 8-MOP continues to rise in the 15-20 min after a 15-min bath⁷⁶, MPDs in vivo appear to be similar for irradiation times from 0 to 20 min after bathing, prior to falling off significantly^78-81.  Using a 1% 8-MOP lotion the response to non-interval or 2 h interval PUVA on symmetrical plaques was found to be similar but with an increased risk of burning with delayed treatment⁸².  Generally, the current practice of irradiating immediately after bathing therefore appears consistent with theory. In contrast, the lag time in palmoplantar skin is increased to 30-40 min⁸³, implying that immediate irradiation of this site is inappropriate.

As differences in water temperature can alter the absorption kinetics of psoralens and thereby the MPD^84,85, bath temperature should remain constant from treatment to treatment in order to reduce the risk of burning or undertreatment. A temperature of 37°C appears optimal⁸⁵ and is comfortable for the patient. While a 15-min bathing time is generally given, it has been noted (personal observation, S.Thomas, Barnsley Hospital, U.K.) that there is no apparent loss in efficacy if the immersion time is reduced to 5 min. However, it is recommended that the 15-min bathing time is retained until further evidence is available.

In local immersion hand and foot PUVA, 8-MOP is generally used at a concentration of 3 mg/L (1.2% 8-MOP, 0.5 mL/2 L water) for a 15-min soak, and from the above evidence we now recommend that a delay of at least 30 min is allowed before irradiation (Appendix 3). Preferences in preparations for the treatment of local disease vary widely depending on individual experience (Appendix 4), and where there are problems with 8-MOP emulsion, paint or gel formulations for hand and foot dermatoses, it is appropriate to change to the standard local immersion regimen.

UVA protocols
In PUVA generally, erythema is the limiting factor with regard to the UVA dose that can be given at each treatment, and therefore basic information on the MPD, dose-response characteristics and time-course is necessary to devise an efficient treatment regimen.  A number of additional variables may affect the erythemal response in bath PUVA, including the type and formulation of psoralen, skin penetration, variation with body site, duration of bath and timing of irradiation. This may explain why the MPDs reported for bath 8-MOP^9,55,86-88 and TMP^86,89 show large variations, and why erythema is more problematic during courses of bath than oral PUVA, at least for TMP⁸.  Comparative studies of bath TMP and 8-MOP PUVA confirm that in equivalent concentrations, TMP is up to 30 times more phototoxic^54,86.  Studies of bath 8-MOP PUVA in chronic plaque psoriasis usually report initial UVA doses of between 0.2 and 0.5 J/cm², and while some studies use fixed dose increments, others report increments of 20-50% of the preceding dose, which are made every one to three visits.

In the absence of controlled trials to address optimal UVA-irradiation protocols for topical PUVA, the BPG makes recommendations based on the practice of its members (Appendices 2-4). In addition, in some areas it has been assumed that the same principles apply to bath PUVA as to oral PUVA. It is recommended first, that the initial UVA dose is based on an MPD test wherever possible, to avoid either painful erythema or, conversely, under-treatment. The determination of individual responses leads to a reduction in cumulative UVA dose and number of treatments in oral PUVA, and it is assumed that this will also occur in bath PUVA.  The MPD test, defined as the lowest dose of UVA causing a perceptible erythema, should be performed on unexposed skin, and it is vital that the test site is fully immersed in psoralen prior to irradiation.  Secondly, it is recommended that the initial UVA dose should be 40-50% of the MPD, reflecting the greater tendency to burn compared with oral PUVA, where the initial dose is usually 70% of the MPD¹.  It is vital when transferring a patient from oral to bath PUVA to repeat the MPD test, in view of the generally lower UVA doses required. Thirdly, dose increments of 20-40% are recommended, with an increase every treatment. In vitiligo, however, it is appropriate to commence at a lower UVA dose of 0.1 J/cm², and increase at fixed increments of 0.1 J/cm², while higher UVA doses are recommended to treat the thicker skin of palmoplantar disorders.

Practical and financial considerations

Differences in the use of oral and topical PUVA necessitate the consideration of a number of practical issues. First, bathing facilities must be available and close nurse supervision is required throughout. The additional time taken for bathing may also reduce the throughput of patients, although this is somewhat countered by the reduction in irradiation times. The much lower exposure time required with bath PUVA can itself be problematic as there is a greater chance of error leading to accidental overtreatment, particularly if high-output machines are employed. Post-treatment bathing is unnecessary as cutaneous absorption and binding dynamics suggests that no free psoralen will remain on the skin surface, but of course exposed skin such as on the hands should still be protected from strong sunlight after local treatment.

A cost-effectiveness analysis of data collected across four centres during a Scottish phototherapy and PUVA audit in 1997 (personal communication, R.Dawe, Glasgow Western Infirmary, U.K.) revealed that courses of both bath and other topical PUVA were consistently more expensive than oral PUVA. This related predominantly to the increased nursing time required, although the greater cost of topical preparations was also a contributing factor.

Conclusions

Currently, oral PUVA is better established and studied than topical PUVA, and many questions remain concerning the efficacy, safety and optimal protocols of the latter. Thus, the carcinogenic risks of topical PUVA are unknown, and there is presently little firm evidence to suggest that the risk will be any lower than that of oral PUVA. However, advantages include shorter irradiation times and a lack of gastrointestinal and systemic side-effects, and access of phototherapy units to facilities for both modalities is therefore desirable in order to permit a wider range of patients to be treated. Finally, as for oral PUVA, it is important that PUVA units have well trained staff to perform treatments, who should work closely with the dermatologist responsible for the prescribing and supervision of treatment.

References

1. British Photodermatology Group. Guidelines for PUVA. Br J Dermatol 1994; 130: 246-55.
2. Collins P, Rogers S. Bath-water delivery of 8-methoxypsoralen therapy psoriasis. Clin Exp Dermatol 1991; 16: 165-7.
3. Gomez MI, Perez B, Harto A et al. 8-MOP bath PUVA in the treatment of psoriasis: clinical results in 42 patients. J Dermatol Treat 1996; 7: 11-12.
4. Streit V, Wiedow O, Christophers E. Treatment of psoriasis with polyethylene sheet bath PUVA. J Am Acad Dermatol 1996; 35: 208-10.
5. Hannuksela M, Karvonen J. Trioxsalen bath plus UVA effective and safe in the treatment of psoriasis. Br J Dermatol 1978; 99: 703-7.
6. Salo OP, Lassus A, Taskinen J. Trioxsalen bath plus UVA treatment of psoriasis. Acta Derm Venereol (Stockh) 1981; 61:551-4.
7. Calzavara-Pinton PG, Zane C, Carlino A, De Panfilis G. Bath-5-methoxypsoralen-UVA therapy for psoriasis. J Am Acad Dermatol 1997; 36: 945-9.
8. Turjanmaa K, Salo H, Reunala T. Comparison of trioxsalen bath and oral methoxsalen PUVA in psoriasis. Acta Derm Venereol (Stockh) 1985; 65: 86-8.
9. Lowe NJ, Weingarten D, Bourget T, Moy LS. PUVA therapy for psoriasis: comparison of oral and bath-water delivery of 8-methoxypsoralen. J Am Acad Dermatol 1986; 14: 754-60.
10. Collins P, Rogers S. Bath-water compared with oral delivery of 8-methoxypsoralen PUVA therapy for chronic plaque psoriasis. Br J Dermatol 1992; 127: 392-5.
11. Calzavara-Pinton PG, Ortel B, Honigsmann H et al. Safety and effectiveness of an aggressive and individualized bath-PUVA regimen in the treatment of psoriasis. Dermatology 1994; 189: 256-9.
12. Karvonen J, Hannuksela M. Long term results of topical trioxsalen PUVA in lichen planus and nodular prurigo. Acta Derm Venereol (Suppl.) (Stockh) 1985; 120: 53-5.
13. Vaatainen N, Hannuksela M, Karvonen J. Trioxsalen baths plus UV-A in the treatment of lichen planus and urticaria pigmentosa. Clin Exp Dermatol 1981; 6: 133-8.
14. Kerscher M, Volkenandt M, Lehmann P et al. PUVA-bath photochemotherapy of lichen planus. Arch Dermatol 1995; 131: 1210-1.
15. Helander I, Jansen CT, Meurman L. Long-term efficacy of PUVA treatment in lichen planus: comparison of oral and external methoxsalen regimens. Photodermatology 1987; 4: 265-8.
16. Kerscher M, Meurer M, Sander C et al. PUVA bath photochemotherapy for localized scleroderma. Arch Dermatol 1996; 132: 1280-2.
17. Kanekura T, Fukumara S, Matsushita S et al. Successful treatment of scleroderma with PUVA therapy. J Dermatol 1996; 23: 455-9.
18. Godt O, Proksh E, Streit V, Christophers E. Short and long-term effectiveness of oral and bath PUVA therapy in urticaria pigmentosa and systemic mastocytosis. Dermatology 1997; 195: 35-9.
19. Fischer T, Skough M. Treatment of parapsoriasis en plaque, mycosis fungoides and Sezary's syndrome with trioxsalen baths followed by ultraviolet light. Acta Derm Venereol (Stockh) 1979; 59: 171-3.
20. Jansen CT, Karvonen J, Malmiharju T. PUVA therapy for polymorphous light eruptions: comparison of systemic methoxsalen and topical trioxsalen regimens and evaluation of local protective mechanisms. Acta Derm Venereol (Stockh) 1982; 62: 317-20.
21. Streit V, Thiede R, Wiedow O, Christophers E. Foil bath PUVA in the treatment of prurigo simplex subacuta. Acta Derm Venereol (Stockh) 1996; 76: 319-20.
22. Vaatainen N, Hannuksela M, Karvonen J. Local photochemotherapy in nodular prurigo. Acta Derm Venereol (Stockh) 1979; 59: 544-7.
23. Jahn S, von Kobyletzki G, Behrens S et al. Puva bath photochemotherapy successful in aquagenic pruritus. (Letter.) H G Z Hautkr 1997; 72: 821-4.
24. Smith RA, Ross JS, Staughton RCD. Bath PUVA as a treatment for aquagenic pruritus. (Letter.) Br J Dermatol 1994; 131: 584.
25. Volkenandt M, Kerscher M, Sander C et al. PUVA bath photochemotherapy resulting in rapid clearance of lymphomatoid papulosis in a child. Arch Dermatol 1995; 131: 1094.
26. Hawk JLM, Le Grice P. The efficacy of localized PUVA therapy for chronic hand and foot dermatoses. Clin Exp Dermatol 1994; 19: 479-82.
27. Schempp CM, Muller H, Czech W et al. Treatment of chronic palmoplantar eczema with local bath-PUVA therapy. J Am Acad Dermatol 1997; 36: 733-7.
28. Sheehan-Dare RA, Goodfield MJ, Rowell NR. Topical psoralen photochemotherapy (PUVA) and superficial radiotherapy in the treatment of chronic hand eczema. Br J Dermatol 1989; 121: 65-9.
29. Stege H, Berneburg M, Ruzicka T, Krutmann J. Creme-PUVAPhotochemotherapie. Hautarzt 1997; 48: 89-93.
30. Abel EA, Goldberg LH, Farber EM. Treatment of palmoplantar psoriasis with topical methoxsalen plus long-wave ultraviolet light. Arch Dermatol 1980; 116: 1257-61.
31. De Rie MA, Eendenburg JP, Versnick AC et al. A new psoralencontaining gel for topical PUVA therapy: development and treatment results in patients with palmoplantar and plaquetype psoriasis, and hyperkeratotic eczema. Br J Dermatol 1995; 132: 964-9.
32. Jansen CT, Malmiharju T. Inefficacy of topical methoxalen plus UVA for palmoplantar pustulosis. Acta Derm Venereol (Stockh) 1981; 61: 354-6.
33. Murray D, Corbett MF, Warin AP. A controlled trial of photochemotherapy for persistent palmoplantar pustulosis. Br J Dermatol 1980; 102: 659-63.
34. Layton AM, Sheehan-Dare R, Cunliffe WJ. A double-blind, placebo-controlled trial of topical PUVA in persistent palmoplantar pustulosis. Br J Dermatol 1991; 124: 581-4.
35. Agren-Jonsson S, Tegner E. PUVA therapy for palmoplantar pustulosis. Acta Derm Venereol (Stockh) 1985; 65: 531-5.
36. Lassus A, Lauharanta J, Eskelinen A. The effect of etretinate compared with different regimens of PUVA in the treatment of persistent palmoplantar pustulosis. Br J Dermatol 1985; 112: 455-9.
37. Grimes PE, Minus HR, Chakrabarti SG et al. Determination of optimal topical photochemotherapy for vitiligo. J Am Acad Dermatol 1982; 7: 771-8.
38. Halder RM. Topical PUVA therapy for vitiligo. Dermatol Nurs 1991; 3: 178-98.
39. Morita A, Sakakibara S, Sakakibara N et al. Successful treatment of systemic sclerosis with topical PUVA. J Rheumatol 1995; 22: 2361-5.
40. Nakamura M, Kobayashi S, Matsura K et al. The effects of noninterval PUVA therapy on the plaque stage of mycosis fungoides. J Dermatol 1995; 22: 196-200.
41. Ogawa H, Yoshiike T. Atopic dermatitis: studies of skin permeability and effectiveness of topical PUVA treatment. Pediatr Dermatol 1992; 9: 383-5.
42. Uesugi T, Kumasaka N, Okada Y et al. Topical chemotherapy (PUVA) for the relief of uremic pruritus in patients undergoing hemodialysis. J Dermatol Treat 1996; 7: 247-9.
43. Petrozzi JW, Kaidbey KM, Kligmann AM. Topical methoxsalen & blacklight in the treatment of psoriasis. Arch Dermatol 1977; 113: 292-6.
44. Michaelsson G, Noren P, Vahlquist A. Combined therapy with oral retinoid and PUVA baths in severe psoriasis. Br J Dermatol 1978; 99: 221-2.
45. Vaatainen N, Hollmen A, Fraki JE. Trimethylpsoralen bath plus ultraviolet A combined with oral retinoid (etretinate) in the treatment of severe psoriasis. J Am Acad Dermatol 1985; 12: 52-5.
46. Takashima A, Sunohara A, Matsunami E, Mizuno N. Comparison of therapeutic efficacy of topical PUVA, oral etretinate, and combined PUVA and etretinate for the treatment of psoriasis and development of PUVA lentigines and antinuclear antibodies. J Dermatol 1988; 15: 471-9.
47. Lauharanta J, Geiger J-M. A double-blind comparison of acitretin and etretinate in combination with bath PUVA in the treatment of extensive psoriasis. Br J Dermatol 1989; 121: 107-12.
48. Matsunami E, Takashima A, Mizuno N et al. Topical PUVA, etretinate, and combined PUVA and etretinate for palmoplantar pustulosis: comparison of therapeutic efficacy and the influences of tonsillar and dental focal infections. J Dermatol 1990; 17: 92-6.
49. Muchenberger S, Schopf E, Simon JC. The combination of oral acitretin and bath PUVA for the treatment of severe psoriasis. Br J Dermatol 1997; 137: 587-9.
50. Willis I, Harris DR. Resistant psoriasis. Arch Dermatol 1973; 107: 358-62.
51. Kiriyama T, Danno K, Uehara M. Combination of topical tacalcitol and PUVA for psoriasis. J Dermatol Treat 1997; 8: 62-4.
52. Marguery MC, Montazeri A, El Sayed F et al. Chronic actinic dermatitis: a severe case responding to cyclosporin-bath-PUVA therapy. J Dermatol Treat 1997; 8: 281-3.
53. George SA, Ferguson J. Unusual pattern of phototoxic burning following trimethylpsoralen (TMP) bath photochemotherapy (PUVA). Br J Dermatol 1992; 127: 444-5.
54. Koulu LM, Jansen CT. Skin photosensitizing and Langerhans' cell depleting activity of topical (bath) PUVA therapy: comparison of trimethylpsoralen and 8-methoxypsoralen. Acta Derm Venereol (Stockh) 1983; 63: 137-41.
55. Calzavara-Pinton PG, Ortel B, Carlino AM et al. Phototesting and phototoxic side effects in bath PUVA. J Am Acad Dermatol 1993; 28: 657-9.
56. Luftl M, Degitz K, Plewig G, Rocken M. Psoralen bath plus UV-A therapy. Arch Dermatol 1997; 133: 1597-603.
57. Koulu LM, Jansen CT. Skin phototoxicity variations during repeated bath PUVA exposures to 8 methoxypsoralen and trimethylpsoralen. Clin Exp Dermatol 1984; 9: 64-9.
58. Gold RL, Anderson RR, Natoli VD, Gange RW. An action spectrum for photoinduction of prolonged cutaneous photosensitivity by topical 8-MOP. J Invest Dermatol 1988; 90: 818-22.
59. Ortel B, Gange RW. An action spectrum for the elicitation of erythema in skin persistently sensitized by photobound 8-methoxypsoralen. J Invest Dermatol 1990; 94: 781-5.
60. Takashima A, Yamamoto K, Kimura S et al. Allergic contact and photocontact dermatitis due to psoralens in patients with psoriasis treated with topical PUVA. Br J Dermatol 1991; 124: 37-42.
61. Chakrabarti SG, Grimes PE, Minus HR et al. Determination of trimethylpsoralen in blood, ophthalmic fluids and skin. J Invest Dermatol 1982; 79: 374-7.
62. Ros A-M, Wennersten G, Wallin I, Ehrsson H. Concentration of trimethylpsoralen in blood and skin after oral administration. Photodermatology 1988; 9: 121-5.
63. Fischer T, Hartvig P, Bondesson U. Plasma concentrations after bath treatment and oral administration of trioxsalen. Acta Derm Venereol (Stockh) 1980; 60: 177-9.
64. David M, Lowe NJ, Halder RM, Borok M. Serum 8-methoxypsoralen (8-MOP) concentrations after bath water delivery of 8-MOP plus UVA. J Am Acad Dermatol 1990; 23: 931-2.
65. Thomas SE, O'Sullivan J, Balac N. Plasma levels of 8-methoxypsoralen following oral or bath-water treatment. Br J Dermatol 1991; 125: 56-8.
66. Neild VS, Scott LV. Plasma levels of 8-methoxypsoralen in psoriatic patients receiving topical 8 methoxypsoralen. Br J Dermatol 1982; 106: 199-203.
67. Hallman CP, Koo JYM, Omohundro C, Lee J. Plasma levels of 8-methoxypsoralen after topical paint PUVA on nonpalmoplantar psoriatic skin. J Am Acad Dermatol 1994; 31: 273-5.
68. Pham CT, Koo JYM. Plasma levels of 8-methoxypsoralen after topical paint PUVA. J Am Acad Dermatol 1993; 28: 460-6.
69. Gomez MI, Azana JM, Arranz I et al. Plasma levels of 8-methoxypsoralen after bath-PUVA for psoriasis: relationship to disease severity. Br J Dermatol 1995; 133: 37-40.
70. de Wolf FA, Thomas TV. Clinical pharmacokinetics of methoxsalen and other psoralens. Clin Pharmacokinetics 1986; 11: 62-75.
71. Stern RS, Lange R. Non-melanoma skin cancer occurring in patients treated with PUVA five to ten years after first treatment. J Invest Dermatol 1988; 91: 120-4.
72. Young AR. Photocarcinogenicity of psoralens used in PUVA treatment: present status in mouse and man. J Photochem Photobiol 1990; 6: 237-47.
73. Alcalay J, Bucana C, Kripke ML. Cutaneous pigmented melanocytic tumour in a mouse treated with psoralen plus ultraviolet A radiation. Photodermatol Photoimmunol Photomed 1990; 7: 28-31.
74. Hannuksela A, Pukkala E, Hannuksela M, Karvonen J. Cancer incidence among Finnish patients with psoriasis with trioxsalen bath PUVA. J Am Acad Dermatol 1996; 35: 685-9.
75. Lindelof B, Sigurgeirsson B, Tegner E et al. Comparison of the carcinogenic potential of trioxsalen bath PUVA and oral methoxsalen PUVA. Arch Dermatol 1992; 128: 1341-4.
76. Anigbogu ANC, Williams AC, Barry BW. Permeation characteristics of 8-methoxypsoralen through human skin; relevance to clinical treatment. J Pharm Pharmacol 1996; 48: 357-66.
77. Gazith J, Schalla W, Bauer E, Schaefer H. 8-methoxypsoralen (8-MOP) in human skin: penetration kinetics. J Invest Dermatol 1978; 71: 126-30.
78. Neumann NJ, Ruzicka T, Lehmann P, Kerscher M. Rapid decrease of phototoxicity after PUVA bath therapy with 8-methoxypsoralen.(Letter.) Arch Dermatol 1996; 132: 1394.
79. Schempp CM, Schopf E, Simon JC. Phototesting in bath PUVA. marked reduction of 8-methoxypsoralen (8 MOP) activity within one hour after an 8-MOP bath. Photodermatol Photoimmunol Photomed 1996; 12: 100-2.
80. Reuther T, Gruss C, Behrens S et al. Time course of 8-methoxypsoralen-induced skin photosensitization in PUVA-bath photochemotherapy. Photodermatol Photoimmunol Photomed 1997; 13: 193-6.
81. Gruss C, Behrens S, Reuther T et al. Kinetics of photosensitivity in bath-PUVA photochemotherapy. J Am Acad Dermatol 1998; 39: 443-6.
82. Danno K, Horio T, Ozaki M, Imamura S. Topical 8-methoxypsoralen photochemotherapy of psoriasis: a clinical study. Br J Dermatol 1983; 108: 519-24.
83. Konya J, Diffey BL, Hindson TC. Time course of activity of topical 8-methoxypsoralen on palmoplantar skin. Br J Dermatol 1992; 127: 654-5.
84. Jansen CT. Water temperature effect in bath-PUVA treatment. J Am Acad Dermatol 1988; 19: 142-3.
85. Gruss C, Von Behrens S, Kobyletzki G et al. Effects of water temperature on photosensitization in bath-PUVA therapy with 8-methoxypsoralen. Photodermatol Photoimmunol Photomed 1998; 14: 145-7.
86. Koulu LM, Jansen CT. Antipsoriatic, erythematogenic, and Langerhans cell marker depleting effect of bath-psoralens plus ultraviolet A treatment. J Am Acad Dermatol 1988; 18: 1053-9.
87. Degitz K, Plewig G, Rocken M. Rapid decline in photosensitivity after 8-methoxypsoralen bathwater delivery. Arch Dermatol 1996; 132: 1394-5.
88. Neumann NJ, Kerscher M, Ruzicka T, Lehmann P. Evaluation of PUVA bath phototoxicity. Acta Derm Venereol (Stockh) 1997; 77: 385-7.
89. Rhodes LE, Friedmann PS. A comparison of the erythemal response to PUVA using oral 8-methoxypsoralen (8-MOP) and bath trimethylpsoralen (TMP). Br J Dermatol 1992; 127: 420-1 (Abstr.).

Appendix 1: Psoralen formulations

All psoralens must currently be prescribed on a named patient basis, but the registration of oral 8-MOP is in progress (personal communication: M.Bedford-Stradling, Crawford Pharmaceuticals, U.K.). Topical formulations available from the main U.K. supplier (Crawford Pharmaceuticals, Milton Keynes, U.K.), include 8-MOP bath lotion (1.2%), emulsion (0.15%), paint (0.15%, 1.0%) and gel (0.005%), and TMP bath lotion (0.05%); the latter is also available from Tayside Pharmaceuticals (Dundee, U.K.). Other products which may be purchased from abroad include TMP bath lotion (50 mg/100 mL, Orion Pharmaceuticals Ltd., Espoo, Finland) and 0.75% 8-MOP paint (Promedica, Levallois-Perret, France).

Appendix 2: Protocol for bath (generalized immersion) PUVA

Bath psoralen ultraviolet A with 8-methyoxypsoralen
1 Dissolve 30 mL of 1.2% 8-MOP lotion in 140 L water at 37 °C (final concentration 2.6 mg/L).
2 Bathe for 15 min, followed by immediate UVA exposure.
3 Initial UVA dose: either 40% of MPD (preferable) or 0.2-0.5 J/cm².
4 UVA increments: increase by 20-40% of initial dose at each treatment.
5 Frequency: twice weekly.

Bath psoralen ultraviolet A with trimethylpsoralen
1 Dissolve 50 mg TMP in 100 mL ethanol.
2 Mix in 150L water at 37 °C (final concentration 0.33 mg/L).
3 Bathe for 15 min, followed by immediate UVA exposure.
4 Initial UVA dose: either 40% of MPD (preferable) or 0.1-0.4 J/cm².
5 UVA increments: increase by 0.5 of initial dose at each treatment.
6 Frequency: twice weekly.

Appendix 3: Protocol for hand and foot immersion PUVA

8-methyoxypsoralen lotion
1 Mix 0.5 mL of 1.2% 8-MOP lotion in 2 L water (final concentration 3 mg/L).
2 Soak for 15 min, with a delay of 30 min before UVA exposure.
3 Initial UVA dose: 1-2 J/cm².
4 UVA increments: 0.5-1 J/cm².
5 Frequency: twice weekly.

Trimethylpsoralen lotion
1 Dissolve 5 mg TMP in 10 mL ethanol.
2 Mix into 15 L water.
3 Soak for 15 min, with a delay of 30 min before UVA exposure.
4 Initial UVA dose: 1-2 J/cm².
5 UVA increments: 0¥5±1 J/cm2.
6 Frequency: twice weekly.
Note: If dorsa of hands or feet are affected give 50% of dose for palms and soles.

Appendix 4: Protocol for other topical 8-methoxypsoralen PUVA

8-methyoxypsoralen emulsion
1 0.15% (may be diluted 1 : 10 if erythema occurs at lowest UVA dose).
2 Apply 15 min before UVA exposure.
3 Initial UVA dose: either 40% of MPD, or (II) 0.5-1 J/cm² (depends on site).
4 UVA increments: 0.5-2 J/cm² (depends on site).
5 Frequency: twice weekly.

8-methyoxypsoralen gel
1 0.005% solution in aqueous gel.
2 Apply thin layer over diseased area using gloved hand.
3 Ensure repeated applications are given to same area.
4 Apply 15 min before UVA exposure.
5 Initial UVA dose: either 40% of MPD, or 0.5-1 J/cm² (depends on site).
6 UVA increments: 0.5-2 J/cm² (depends on site).
7 Frequency: twice weekly.