IIIII
I
I
Combined UVA-UVB versus UVB phototherapy for atopic dermatitis: A paired-comparison study Jan Jekler, MD, and Olle LarkS, MD, PhD
GSteborg, Sweden
In a paired-comparison study 30 patients with atopic dermatitis underwent treatment with a combination of UVA and UVB radiation (UVAB) on one side of the body and UVB on the other. Treatment was administered three times a week for a maximum of 8 weeks. Each patient was evaluated with respect to eight effectvariables. Statistically significant differences in favor of UVAB were observed for all analyzed variables, namely total score (p = 0.002), pruritus score (p = 0.04), and overall evaluation score (p = 0.03). No statistically significant differences in healing rate were seen; 25 of 30 UVB-treated, and 26 of 30 UVAB-treated, body halves healed or were considerably improved. Patient preference was overwhelmingly in favor of UVAB; 23 of 24 patients who completed an evaluation form preferred this treatment. Only 1 of 24 preferred UVB. (J AM AcaD DERMATOL 1990;22:49-53.) In the management of atopic dermatitis different treatment modalities have been advocated. The role of ultraviolet radiation (UVR) remains controversial, 14 although the beneficial effects of UVB have been reported. 5 The objective of our study was to clarify whether a combination of UVB (280 to 315 nm) and U V A (315 to 400 nm) radiation (UVAB) is more effective t h a n UVB alone in the treatment of atopic dermatitis. A bilateral randomized comparison was used. MATERIAL AND METHODS Material Patients. Thirty-nine patients entered the study, and informed consent was obtained from all patients. Nine of the patients withdrew: one was using oral prednisolone for chronic respiratory disease; one with severe pruritus was using a potent topical corticosteroid; one had been using a moderately potent topical steroid, hydrocortisone-17a-butyrate, believing it was identical to hydrocortisone; two were excluded because of asymmetric atopic dermatitis lesions; and the other four withdrew of their own accord. The final study population comprised 30 patients (11 men, 19 women) with a mean age of 24.8 years (range 15 to 40 years) and a mean disease duration of 20.5 years
(range 4 to 40 years). Five patients had skin type II, 22 had type III, two had type IV, and one had type V. All patients fulfilled the diagnostic atopic dermatitis criteria of Hanifin and Rajka. 15 The following exclusion criteria were developed: use of topical preparations other than hydrocortisone and emollients during and 2 weeks before study, oral corticosteroid therapy, asymmetric lesions, phototherapy or sun bath 4 weeks before study, and patient age younger than 15 years. Equipment. The UVB equipment comprised 14 Philips TL 12 40W and 14 Philips TL 12 20W fluorescent tubes (Philips, Roosendaal, The Netherlands) arranged in a cubicle. The irradiance at body distance was 0.85 mW/ cm2 UVB and 0.40 m W / c m 2 UVA. Measurements were performed with an International Light Radiometer/ Photometer IL 1350 (International Light Inc., Newburyport, Mass.) with the use of IL SED 240 as UVB probe and IL SED 015 as U VA probe. The spectral distribution is shown in Fig. 1. The UVAB equipment comprised 24 Wolff Helarium System tubes BI-12-100W (Cosmedico, Stiittgart, West Germany) in an arrangement similar to that used for UVB treatment. The irradiance, measured with the same photometer and probes used for UVB, was 0.02 mW/cm 2 UVB and 5.5 mW/cm 2 UVA. The emission spectrum is shown in Fig. 1. Methods
From the Department of Dermatology, University of G6teborg, Sahlgren's Hospital. Supported by grants from the Edvard Welander Foundation.
Accepted for publicationFeb. 21, 1989. Reprint requests:Jan Jekler, MD, Departmentof Dermatology,Sahtgren's Hospital.S-413 45 Grteborg,Sweden. 16/1/12147
At each treatment patients were irradiated with UVAB on one side of the body and with UVB on the other; right or left side was randomly determined. The side not irradiated was shielded with two layers of thick dark cotton sheeting. Each patient's minimal erythema dose (MED) for UVB and UVAB was determined before treatment was begun. 49
50
Journal of the American Academy of Dermatology
Jekler and Lark;5
Table I. Score means and ranges before and after treatment with UVB and U V A B Mean (range) total score
.8
Pretreatment 10.8 (7-19) After UVB 6.1 (0-17) After UVAB 5.2 (0-15)
Mean (range) pruritus score
Mean (range) overall evaluation score
2.4 (1-3)
1.7 (1-3)
1.2 (0-3) 1.0 (0-3)
0.80 (0-3) 0.65 (0-2)
UVAB, Combined UVA-IJVB radiation.
.4
.2
0 250 275 300 325 350 375 400 Wavelength(r ) Fig. 1. Spectral distribution of Philips TL 12 (a) and Wolff Helarium System B 1-12 (b) fluorescent tubes used for UVB and UVAB treatments, respectively.
The initial dose of UVB was set at 80% of the MED. I t was then increased each treatment session by 20%. With the appearance of erythema, the dose was reduced by 50% and thereafter the 20% increase schedule was resumed. The mean initial dose was 37 millijoule/cm2 (range 20 to 82 milfijoule/cm2); the mean final dose was 204 millijoule/cm2 (range 15 to 575 millijoule/cm2). For UVAB phototherapy a dose increment schedule was set at 5, 7, 10, 12, 15, 17.5, 20, 22.5, and 25 minutes. T h e dose that preceded the MED was set as the initial dose. Successive dose increments were performed at every other treatment until a maximum of 25 minutes (corresponding to 30 millijoule/cm2 UVB and 8.3 joule/cm 2 UVA). When erythema appeared, the dose was reduced to the preceding dose. In the treatment of patients with unsensitive skin (MED ~ 1 5 min; 18 millijoule/cm2 UVB, 5.0 joule/era 2 UVA), the steps at 17.5 and 22.5 minutes were omitted. The mean initial doses were 13 millijoule/cm2 (range 6 to 18 millijoule/cm2) UVB and 3.7 joule/cm 2 (range 1.7 to 5.0 joule/cm 2) UVA. The corresponding mean final doses were 29 millijoule/cm2 (range 18 to 30 millijoule/cm2) UVB and 8.0 joule/cm 2 (range 5.0 to 8.3 joule/cm 2) UVA. Treatments were given three times a week for 8 weeks or until healing occurred. In some cases, treatment was
terminated after 6 weeks (one patient) or 7 weeks (six patients). Patients were assessed by the same observer (J. J.) on entry into the study and subsequently every other week. Eight variables were recorded: pruritus, lichenification, scaling, xerosis, vesiculation, excoriations, erythema, and an overall evaluation. Each variable was assigned a score from 0 to 3: 0, none; 1, slight; 2, moderate; and 3, severe. The sum of the scores was designated as the total score. Healing also was evaluated separately on a scale from 3 to - 1: 3, healed; 2, considerably improved; 1, somewhat improved; 0, unchanged; and - I, worsened. Healing was defined as the absence of papules, excoriations, vesicles, lichenification, and scaling. The designation "considerably improved" was used when a body half was almost healed, whereas "somewhat improved" indicated slight to moderate improvement. The percentage of skin involvement was calculated by the rule of nine. Patients were asked whether equal amounts of emollients and topical hydrocortisone preparations had been used on both body halves. Treatment of the face and the hands was not included in the evaluation. The decision not to evaluate the effects of UVR on facial eczema was based on the difficuries in covering half the face. Atopic hand eczema was excluded from the study. After termination of therapy, each patient was asked to complete an assessment form. The questions asked concerned (1) comparison of the two treated sides with respect to pruritus, xerosis, and an overall evaluation; (2) treatment preference ("which treatment do you prefer ?"); and (3) side effects. Statistical analysis. Wilcoxon's matched-pair signed rank test (two-tailed) was used. RESULTS Statistically significant differences in favor of U V A B therapy were seen for the most important variables, that is, total score (p = 0.002), pruritus score ( p = 0 . 0 4 ) , and overall evaluation score (p = 0.03). Score means and ranges are shown in Table I. Changes in the mean total score, plotted against time of treatment, are depicted in Fig. 2. The
Volume 22 Number I J a n u a r y 1990
UVA-UVB vs UVB phototherapy of atopic dermatitis
Table II. Evaluation of heating after UVB and UVAB treatment UVB (n = 30)
Evaluation (healing score)
Healed (3) Considerably improved (2) Somewhat improved (1) Unchanged (0) Worsened ( - 1)
4 21 4 0 1
25
UVAB (n = 30)
6 20 3 0 1
51
Mean total score 11 10 9
26
8 7
UVB
6 I
UVAB, Combined UVA-UVB radiation.
~ U V A B
5
Table III. Patient evaluation of three variables after completion of UVB and UVAB therapy according to 24 completed assessment forms
Pruritus Xerosis Overall evaluation
l u v s - iJVAB VAB 0 0 0
16 12 10
8 12 14
4 3 2 1 i
o
wll
2
9
,;,
weeks
UVAB, Combined UVA-UVB radiation.
Fig. 2. Changes in mean total score during treatment with UVB and UVAB.
4- to 8-week mean scores do not include patients already healed, because treatment, except in two cases, was stopped when healing occurred. This explains why the 8-week score is not identical to the posttreatment score seen in Table I. W h e n the effect of the two therapies on extent of the dermatitis was compared, no statistically significant differences could be seen. With UVB treatment, the pretreatment mean value of 12% (range 1% to 41%) was reduced to 3% (range up to 37%). The corresponding values for the UVAB treatment were 12% (range 1% to 41%) and 3% (range up to 38%). Bilateral improvement, measured as the decrease in total score after UVB and UVAB therapy, respectively, was statistically significant (both p < 0.001). Twenty-five of 30 UVB-treated body halves healed or considerably improved as compared with 26 of 30 UVAB-treated ones (Table II). When healing scores were compared, no statistically significant difference could be seen. With UVB treatment, healing was achieved after 2 weeks in one patient and 6 weeks in three patients. UVAB irradiation produced healing after 2 weeks in two patients, 4 weeks in one patient, 6 weeks in two patients, and 8 weeks in one patient. Patient evaluation figures were extracted from the
assessment forms completed by 24 of 30 patients (Table III). UVAB was ranked best in overall evaluation by 14 patients, whereas the other 10 patients found the two therapies equally efficient. To a direct question concerning preference, 23 patients stated they preferred UVAB treatment, as opposed to one patient who preferred UVB. The two most common side effects encountered were xerosis and burn (overexposure erythema), the frequencies of which are shown in Table IV. The differences with respect to burn (p < 0.001) and xerosis (p -- 0.006) are statistically significant in favor of UVAB. In addition, two other adverse events were noted only on the UVB-treated body halves: in one patient polymorphic light eruption developed after 8 weeks of treatment at a dose of 403 millijoule/cm 2 (cumulative dose 3.7 joule/cm 2) and in another patient folliculitis of the leg developed after 8 weeks of treatment at a dose of 21 millijoule/cm 2 (cumulative dose 1.2 joule/cm2). Of 20 patients who were using hydrocortisone at the termination of therapy, three stated they were using more preparation on the UVB-treated than on the UVAB-treated body half; the reverse was true for one patient. The other 16 patients were using equal amounts bilaterally. Nine of 29 patients who were using emollients reported having used more on the UVB-treated than on the UVAB-treated side,
52
Journal of the American A c a d e m y of Dermatology
Jekler and Lark?)
Table IV. Frequencies of two most common side effects (xerosis and burn) encountered with UVB and UVAB treatment in 24 patients* Side effect
Xerosis Light to moderate Severe Total Burn Light to moderate Severe Total
UVB
UVAB
15
13
5
_22
20
15
15 A
3 _Q
21
3
UVAB, Combined UVA-UVB radiation. *Not all patients experienced these side effects.
whereas 20 of 29 patients used equal amounts on both body halves. Incidentally, the patient who withdrew from the study because he was using hydrocortisone-17-o~butyrate, believing it was identical to hydrocortisone, healed on both sides after 4 weeks. DISCUSSION
In our study, UVAB was more effective than UVB alone for the treatment of atopic dermatitis. The side effects, which were encountered more often with UVB, may, in part, reflect an extensive dosage regimen. Previous studies to a great extent have been uncontrolled or have not included statistical analysis (or both). Reports on PUVA have indicated its ef~cacy, 1,2, 6, 8, 11, 13,14 and perhaps superiority over other U V R therapy. Salo et al., t2 however, found no statistically significant difference between P U V A and selective ultraviolet phototherapy (combined UVA plus UVB). The potential dangers of PUVA, however, make it less attractive in the long run. In two previous paired-comparison studies, we have shown UVB to be superior to placebo and UVB in high doses (0.8 MED) to be equipotent to UVB in moderate doses (0.4 MED). 5 T h e superiority of UVAB over UVB seen in three previously published reports 3,4,7 has been confirmed in our study. The use of UVA alone, as well as infrared radiation, also has been reported to be efficacious. 1~ An argument against the paired-comparison study design is the risk of a bias produced by a systemic
effect of UVR. Results of our previous study, 5 however, in which treatment with UVB was compared with placebo in a similar manner as in the current trial, indicated this effect was of minor clinical importance, a finding supported by others (e.g., Toews et al. 16) Furthermore, a systemic effect should act in a leveling direction; that is, the statistical differences seen in our study might be even greater. The safety of phototherapy has been a matter of debate. Patients with psoriasis treated extensively with UVB have not been shown to exhibit more malignant skin tumors than control subjects.17 Furthermore, the doses given in the treatment of atopic dermatitis seem to be lower than those given for psoriasis. The carcinogenic properties of U V A in mice have been studied by Pathak et al. and Forbes (both studies cited by P arrish et al. 18). In these studies even high repetitive doses of U V A did not produce skin tumors. U V A thus seems to be even less carcinogenic than UVB. The long-term safety of U V A and UVAB is yet to be elucidated. The mechanism of action of U V R in the treatment of atopic dermatitis is unclear. U V R has immunologic effects and has been shown to reduce the number 16and derange the membrane structure 19 of Langerhans cells. It also has been shown to inhibit mast cell-mediated whealing5 ~ Recently, interferon has been found in increased levels in serum after the irradiation of healthy persons with UVB. 2a This effect may be of importance, because interferon is known to have immunomodulatory functions, some of which are suppressive, such as the inhibition of delayed type hypersensitivity.22 Furthermore, U V R exerts an antimicrobial action with inhibition of Staphylococcus aureus and Pityrosporum orbiculare, 23 the pathogenetic importance of which in atopic dermatitis has been suggested. Finally, the epidermal thickening elicited by U V R may be important. An increased thickness of the stratum corneum should make it less prone to respond with an eczematous reaction on introduction of antigens, such as the house dust mite antigen, which has been claimed to be of pathogenetic importance in atopic dermatitis. 24 This discussion may partly clarify some of the mechanisms of action of UVR but yields few clues to explain the better clinical effect of U V A B compared with UVB. A photoaugmentive effect of U V A has been proposed. 7 The less irritating properties of UVAB may also play a role.
Volume 22 Number 1 January ! 990
UVA-UVB vs UVB phototherapy of atopic dermatitis
REFERENCES 1. Atherton DJ, Carabott F, Glover MT, et al. The role of psoralen photochemotherapy (PUVA) in the treatment of severe atopic eczema in adolescents. Br J Dermatol 1988;118:791-5. 2. Binet O, Aron-Bruneti6re R, Cun6o M, et al. Photochimioth6rapie par vole orale et dermatite atopique. Ann Dermatol Venereol 1982;109:589-90. 3. Falk ES. UV-light therapies in atopic dermatitis. Photodermatol 1985;2:241-6. 4. Hannuksela M, Karvonen J, Husa M, et al. Ultraviolet light therapy in atopic dermatitis. Acta Derm Venereol (Stockh) 1985;suppl 114:137-9. 5. Jelder J, Lark5 O. UVB phototherapy of atopic dermatitis. Br J Dermatol 1988;119:697-705. 6. Kavli G. Fotokjemoterapi med psoralen og langb61get ultrafiolett lys. 11/2~irserfaring fra hudavdelingen i Troms6. Tidsskr Nor Laegeforen 1978;98:269-71. 7. Midelfart K, Stenvold S-E, Volden G. Combined UVB and UVA phototherapy ofatopie eczema. Dermatologica 1985; 171:95-8. 8. Morison WL, Parrish JA, Fitzpatrick TB. Oral psoralen photochemotherapy ofatopie eczema. Br J Dermatol 1978; 98:25-30. 9. Potekaev NS, Sevidova LY, Vladimirov VV, et al. Selective phototherapy and dimoeiphon immunocorrective therapy in atopic dermatitis. Vestn Dermatol Venerol 1987;9:39-42. 10. Pullman H, M6res E, Reinbach S. Wirkung yon Infrarotund UVA-Strahlen auf die menschliche Haut und ihre Wirksamkeit bei der Behandlung des endogenen Ekzems. Z Hautkr 1985;60:171-7. 11. Rajka G. Recent therapeutic events. Cimetidine and PUVA. Acta Derm Venereol (Stockh) 1980;suppl 92: 117-8. 12. Salo O, Lassus A, Juvakoski T, et al. Behandlung der Dermatitis atopica und der Dermatitis seborrhoica mit selektiver UV-Phototherapie und PUVA. Eine vergleichende Studie. Dermatol Monatsschr 1983;169:371-5. 13. Sannwald C, Ortonne JP, Thivolet J. La photochimio-
14. 15. 16.
17.
18.
19. 20. 21. 22. 23. 24.
53
th6rapie orale de l'ecz6ma atopique. Dermatologica 1979; 159:71-7. Soppi E, Viander M, Soppi A-M, et ai. Cell-mediated immunity in untreated and PUVA treated atopic dermatitis. J Invest Dermatol 1982;79:213-7. Hanifin JM, Rajka G. Diagnostic features of atopic dermatitis. Acta Derm Venereol (Stockh) 1980;suppl 92: 44-7. Toews GB, Bergstresser PR, Streilein JW, et al. Epidermal Langerhans cell density determines whether contact hypersensitivity or unresponsiveness follows skin painting with DNFB. J Immunol 1980;124:445-53. Lark5 O, Swanbeck G. Is UVB treatment of psoriasis safe? A study of extensively UVB-treated psoriasis patients compared with a matched control group. Acta Derm Venereol (Stockh) 1982;62:507-12. Parrish JA, Anderson RR, Urbach F, et al. U V A : biological effects of ultraviolet radiation with emphasis on human responses to longwave ultraviolet. New York: Plenum, 1978:167-8. Aberer W, Schuler G, Stingl G, et al. Effects of UV-light on epidermal Langerhans ceils. J Invest Dermatol 1980; 74:458. Gollhausen R, Kaidbey K, Schechter N. UV suppression of mast cell-mediated whealing in human skin. Photodermatol 1985;2:58-67. Livden JK, Bjerke JR, Degre M, et ai. The significance of interferon in photoimmunology. Acta Derm Venereol (Stockh) 1987;(suppl 134):43-6. DeMaeyer E, DeMaeyer-Guignard J, Vandeputte M. Inhibition by interferon of delayed type hypersensitivity in the mouse. Proc Natl Acad Sci USA 1975;72:1753-7. Faergemann J, Lark6 O. The effect of UV light on human skin microorganisms. Acta Derrn Venereol (Stockh) 1987; 67:69-72. Norris PG, Schofield O, Camp RDR. A study of the role of house dust mite in atopie dermatitis. Br J Dermatol 1988;118:435-40.
BOUND VOLUMES AVAILABLE TO SUBSCRIBERS Bound volumesof the JOURNALOFTHEAMERICANACADEMYOFDERMATOLOGYare available to subscribers (only) for the 1990issues from the Publisher at a costof $55.00 ($68.00international) for volume22 (January-June) and volume23 (July-December).Shippillg chargesare included. Each bound volume contains a subject and author index and all advertising is removed. Copies are shipped within 60 days after publication of the last issue in the volume.The bindingis durable buckram with the journal name, volumenumber, and year stamped in gold on the spine. Payment must accompany all orders. ContactThe C.V. MosbyCompany,Circulation Department. 11830Westline Industrial Drive, St. Louis, MO 63146-3318. USA: phone (800) 325-4177, ext. 351. Subscriptions must be in force to qualify. Bound volumes are not available in place o f a regular journal subscription.
I
I
Combined UVA-UVB versus UVB phototherapy for atopic dermatitis: A paired-comparison study Jan Jekler, MD, and Olle LarkS, MD, PhD
GSteborg, Sweden
In a paired-comparison study 30 patients with atopic dermatitis underwent treatment with a combination of UVA and UVB radiation (UVAB) on one side of the body and UVB on the other. Treatment was administered three times a week for a maximum of 8 weeks. Each patient was evaluated with respect to eight effectvariables. Statistically significant differences in favor of UVAB were observed for all analyzed variables, namely total score (p = 0.002), pruritus score (p = 0.04), and overall evaluation score (p = 0.03). No statistically significant differences in healing rate were seen; 25 of 30 UVB-treated, and 26 of 30 UVAB-treated, body halves healed or were considerably improved. Patient preference was overwhelmingly in favor of UVAB; 23 of 24 patients who completed an evaluation form preferred this treatment. Only 1 of 24 preferred UVB. (J AM AcaD DERMATOL 1990;22:49-53.) In the management of atopic dermatitis different treatment modalities have been advocated. The role of ultraviolet radiation (UVR) remains controversial, 14 although the beneficial effects of UVB have been reported. 5 The objective of our study was to clarify whether a combination of UVB (280 to 315 nm) and U V A (315 to 400 nm) radiation (UVAB) is more effective t h a n UVB alone in the treatment of atopic dermatitis. A bilateral randomized comparison was used. MATERIAL AND METHODS Material Patients. Thirty-nine patients entered the study, and informed consent was obtained from all patients. Nine of the patients withdrew: one was using oral prednisolone for chronic respiratory disease; one with severe pruritus was using a potent topical corticosteroid; one had been using a moderately potent topical steroid, hydrocortisone-17a-butyrate, believing it was identical to hydrocortisone; two were excluded because of asymmetric atopic dermatitis lesions; and the other four withdrew of their own accord. The final study population comprised 30 patients (11 men, 19 women) with a mean age of 24.8 years (range 15 to 40 years) and a mean disease duration of 20.5 years
(range 4 to 40 years). Five patients had skin type II, 22 had type III, two had type IV, and one had type V. All patients fulfilled the diagnostic atopic dermatitis criteria of Hanifin and Rajka. 15 The following exclusion criteria were developed: use of topical preparations other than hydrocortisone and emollients during and 2 weeks before study, oral corticosteroid therapy, asymmetric lesions, phototherapy or sun bath 4 weeks before study, and patient age younger than 15 years. Equipment. The UVB equipment comprised 14 Philips TL 12 40W and 14 Philips TL 12 20W fluorescent tubes (Philips, Roosendaal, The Netherlands) arranged in a cubicle. The irradiance at body distance was 0.85 mW/ cm2 UVB and 0.40 m W / c m 2 UVA. Measurements were performed with an International Light Radiometer/ Photometer IL 1350 (International Light Inc., Newburyport, Mass.) with the use of IL SED 240 as UVB probe and IL SED 015 as U VA probe. The spectral distribution is shown in Fig. 1. The UVAB equipment comprised 24 Wolff Helarium System tubes BI-12-100W (Cosmedico, Stiittgart, West Germany) in an arrangement similar to that used for UVB treatment. The irradiance, measured with the same photometer and probes used for UVB, was 0.02 mW/cm 2 UVB and 5.5 mW/cm 2 UVA. The emission spectrum is shown in Fig. 1. Methods
From the Department of Dermatology, University of G6teborg, Sahlgren's Hospital. Supported by grants from the Edvard Welander Foundation.
Accepted for publicationFeb. 21, 1989. Reprint requests:Jan Jekler, MD, Departmentof Dermatology,Sahtgren's Hospital.S-413 45 Grteborg,Sweden. 16/1/12147
At each treatment patients were irradiated with UVAB on one side of the body and with UVB on the other; right or left side was randomly determined. The side not irradiated was shielded with two layers of thick dark cotton sheeting. Each patient's minimal erythema dose (MED) for UVB and UVAB was determined before treatment was begun. 49
50
Journal of the American Academy of Dermatology
Jekler and Lark;5
Table I. Score means and ranges before and after treatment with UVB and U V A B Mean (range) total score
.8
Pretreatment 10.8 (7-19) After UVB 6.1 (0-17) After UVAB 5.2 (0-15)
Mean (range) pruritus score
Mean (range) overall evaluation score
2.4 (1-3)
1.7 (1-3)
1.2 (0-3) 1.0 (0-3)
0.80 (0-3) 0.65 (0-2)
UVAB, Combined UVA-IJVB radiation.
.4
.2
0 250 275 300 325 350 375 400 Wavelength(r ) Fig. 1. Spectral distribution of Philips TL 12 (a) and Wolff Helarium System B 1-12 (b) fluorescent tubes used for UVB and UVAB treatments, respectively.
The initial dose of UVB was set at 80% of the MED. I t was then increased each treatment session by 20%. With the appearance of erythema, the dose was reduced by 50% and thereafter the 20% increase schedule was resumed. The mean initial dose was 37 millijoule/cm2 (range 20 to 82 milfijoule/cm2); the mean final dose was 204 millijoule/cm2 (range 15 to 575 millijoule/cm2). For UVAB phototherapy a dose increment schedule was set at 5, 7, 10, 12, 15, 17.5, 20, 22.5, and 25 minutes. T h e dose that preceded the MED was set as the initial dose. Successive dose increments were performed at every other treatment until a maximum of 25 minutes (corresponding to 30 millijoule/cm2 UVB and 8.3 joule/cm 2 UVA). When erythema appeared, the dose was reduced to the preceding dose. In the treatment of patients with unsensitive skin (MED ~ 1 5 min; 18 millijoule/cm2 UVB, 5.0 joule/era 2 UVA), the steps at 17.5 and 22.5 minutes were omitted. The mean initial doses were 13 millijoule/cm2 (range 6 to 18 millijoule/cm2) UVB and 3.7 joule/cm 2 (range 1.7 to 5.0 joule/cm 2) UVA. The corresponding mean final doses were 29 millijoule/cm2 (range 18 to 30 millijoule/cm2) UVB and 8.0 joule/cm 2 (range 5.0 to 8.3 joule/cm 2) UVA. Treatments were given three times a week for 8 weeks or until healing occurred. In some cases, treatment was
terminated after 6 weeks (one patient) or 7 weeks (six patients). Patients were assessed by the same observer (J. J.) on entry into the study and subsequently every other week. Eight variables were recorded: pruritus, lichenification, scaling, xerosis, vesiculation, excoriations, erythema, and an overall evaluation. Each variable was assigned a score from 0 to 3: 0, none; 1, slight; 2, moderate; and 3, severe. The sum of the scores was designated as the total score. Healing also was evaluated separately on a scale from 3 to - 1: 3, healed; 2, considerably improved; 1, somewhat improved; 0, unchanged; and - I, worsened. Healing was defined as the absence of papules, excoriations, vesicles, lichenification, and scaling. The designation "considerably improved" was used when a body half was almost healed, whereas "somewhat improved" indicated slight to moderate improvement. The percentage of skin involvement was calculated by the rule of nine. Patients were asked whether equal amounts of emollients and topical hydrocortisone preparations had been used on both body halves. Treatment of the face and the hands was not included in the evaluation. The decision not to evaluate the effects of UVR on facial eczema was based on the difficuries in covering half the face. Atopic hand eczema was excluded from the study. After termination of therapy, each patient was asked to complete an assessment form. The questions asked concerned (1) comparison of the two treated sides with respect to pruritus, xerosis, and an overall evaluation; (2) treatment preference ("which treatment do you prefer ?"); and (3) side effects. Statistical analysis. Wilcoxon's matched-pair signed rank test (two-tailed) was used. RESULTS Statistically significant differences in favor of U V A B therapy were seen for the most important variables, that is, total score (p = 0.002), pruritus score ( p = 0 . 0 4 ) , and overall evaluation score (p = 0.03). Score means and ranges are shown in Table I. Changes in the mean total score, plotted against time of treatment, are depicted in Fig. 2. The
Volume 22 Number I J a n u a r y 1990
UVA-UVB vs UVB phototherapy of atopic dermatitis
Table II. Evaluation of heating after UVB and UVAB treatment UVB (n = 30)
Evaluation (healing score)
Healed (3) Considerably improved (2) Somewhat improved (1) Unchanged (0) Worsened ( - 1)
4 21 4 0 1
25
UVAB (n = 30)
6 20 3 0 1
51
Mean total score 11 10 9
26
8 7
UVB
6 I
UVAB, Combined UVA-UVB radiation.
~ U V A B
5
Table III. Patient evaluation of three variables after completion of UVB and UVAB therapy according to 24 completed assessment forms
Pruritus Xerosis Overall evaluation
l u v s - iJVAB VAB 0 0 0
16 12 10
8 12 14
4 3 2 1 i
o
wll
2
9
,;,
weeks
UVAB, Combined UVA-UVB radiation.
Fig. 2. Changes in mean total score during treatment with UVB and UVAB.
4- to 8-week mean scores do not include patients already healed, because treatment, except in two cases, was stopped when healing occurred. This explains why the 8-week score is not identical to the posttreatment score seen in Table I. W h e n the effect of the two therapies on extent of the dermatitis was compared, no statistically significant differences could be seen. With UVB treatment, the pretreatment mean value of 12% (range 1% to 41%) was reduced to 3% (range up to 37%). The corresponding values for the UVAB treatment were 12% (range 1% to 41%) and 3% (range up to 38%). Bilateral improvement, measured as the decrease in total score after UVB and UVAB therapy, respectively, was statistically significant (both p < 0.001). Twenty-five of 30 UVB-treated body halves healed or considerably improved as compared with 26 of 30 UVAB-treated ones (Table II). When healing scores were compared, no statistically significant difference could be seen. With UVB treatment, healing was achieved after 2 weeks in one patient and 6 weeks in three patients. UVAB irradiation produced healing after 2 weeks in two patients, 4 weeks in one patient, 6 weeks in two patients, and 8 weeks in one patient. Patient evaluation figures were extracted from the
assessment forms completed by 24 of 30 patients (Table III). UVAB was ranked best in overall evaluation by 14 patients, whereas the other 10 patients found the two therapies equally efficient. To a direct question concerning preference, 23 patients stated they preferred UVAB treatment, as opposed to one patient who preferred UVB. The two most common side effects encountered were xerosis and burn (overexposure erythema), the frequencies of which are shown in Table IV. The differences with respect to burn (p < 0.001) and xerosis (p -- 0.006) are statistically significant in favor of UVAB. In addition, two other adverse events were noted only on the UVB-treated body halves: in one patient polymorphic light eruption developed after 8 weeks of treatment at a dose of 403 millijoule/cm 2 (cumulative dose 3.7 joule/cm 2) and in another patient folliculitis of the leg developed after 8 weeks of treatment at a dose of 21 millijoule/cm 2 (cumulative dose 1.2 joule/cm2). Of 20 patients who were using hydrocortisone at the termination of therapy, three stated they were using more preparation on the UVB-treated than on the UVAB-treated body half; the reverse was true for one patient. The other 16 patients were using equal amounts bilaterally. Nine of 29 patients who were using emollients reported having used more on the UVB-treated than on the UVAB-treated side,
52
Journal of the American A c a d e m y of Dermatology
Jekler and Lark?)
Table IV. Frequencies of two most common side effects (xerosis and burn) encountered with UVB and UVAB treatment in 24 patients* Side effect
Xerosis Light to moderate Severe Total Burn Light to moderate Severe Total
UVB
UVAB
15
13
5
_22
20
15
15 A
3 _Q
21
3
UVAB, Combined UVA-UVB radiation. *Not all patients experienced these side effects.
whereas 20 of 29 patients used equal amounts on both body halves. Incidentally, the patient who withdrew from the study because he was using hydrocortisone-17-o~butyrate, believing it was identical to hydrocortisone, healed on both sides after 4 weeks. DISCUSSION
In our study, UVAB was more effective than UVB alone for the treatment of atopic dermatitis. The side effects, which were encountered more often with UVB, may, in part, reflect an extensive dosage regimen. Previous studies to a great extent have been uncontrolled or have not included statistical analysis (or both). Reports on PUVA have indicated its ef~cacy, 1,2, 6, 8, 11, 13,14 and perhaps superiority over other U V R therapy. Salo et al., t2 however, found no statistically significant difference between P U V A and selective ultraviolet phototherapy (combined UVA plus UVB). The potential dangers of PUVA, however, make it less attractive in the long run. In two previous paired-comparison studies, we have shown UVB to be superior to placebo and UVB in high doses (0.8 MED) to be equipotent to UVB in moderate doses (0.4 MED). 5 T h e superiority of UVAB over UVB seen in three previously published reports 3,4,7 has been confirmed in our study. The use of UVA alone, as well as infrared radiation, also has been reported to be efficacious. 1~ An argument against the paired-comparison study design is the risk of a bias produced by a systemic
effect of UVR. Results of our previous study, 5 however, in which treatment with UVB was compared with placebo in a similar manner as in the current trial, indicated this effect was of minor clinical importance, a finding supported by others (e.g., Toews et al. 16) Furthermore, a systemic effect should act in a leveling direction; that is, the statistical differences seen in our study might be even greater. The safety of phototherapy has been a matter of debate. Patients with psoriasis treated extensively with UVB have not been shown to exhibit more malignant skin tumors than control subjects.17 Furthermore, the doses given in the treatment of atopic dermatitis seem to be lower than those given for psoriasis. The carcinogenic properties of U V A in mice have been studied by Pathak et al. and Forbes (both studies cited by P arrish et al. 18). In these studies even high repetitive doses of U V A did not produce skin tumors. U V A thus seems to be even less carcinogenic than UVB. The long-term safety of U V A and UVAB is yet to be elucidated. The mechanism of action of U V R in the treatment of atopic dermatitis is unclear. U V R has immunologic effects and has been shown to reduce the number 16and derange the membrane structure 19 of Langerhans cells. It also has been shown to inhibit mast cell-mediated whealing5 ~ Recently, interferon has been found in increased levels in serum after the irradiation of healthy persons with UVB. 2a This effect may be of importance, because interferon is known to have immunomodulatory functions, some of which are suppressive, such as the inhibition of delayed type hypersensitivity.22 Furthermore, U V R exerts an antimicrobial action with inhibition of Staphylococcus aureus and Pityrosporum orbiculare, 23 the pathogenetic importance of which in atopic dermatitis has been suggested. Finally, the epidermal thickening elicited by U V R may be important. An increased thickness of the stratum corneum should make it less prone to respond with an eczematous reaction on introduction of antigens, such as the house dust mite antigen, which has been claimed to be of pathogenetic importance in atopic dermatitis. 24 This discussion may partly clarify some of the mechanisms of action of UVR but yields few clues to explain the better clinical effect of U V A B compared with UVB. A photoaugmentive effect of U V A has been proposed. 7 The less irritating properties of UVAB may also play a role.
Volume 22 Number 1 January ! 990
UVA-UVB vs UVB phototherapy of atopic dermatitis
REFERENCES 1. Atherton DJ, Carabott F, Glover MT, et al. The role of psoralen photochemotherapy (PUVA) in the treatment of severe atopic eczema in adolescents. Br J Dermatol 1988;118:791-5. 2. Binet O, Aron-Bruneti6re R, Cun6o M, et al. Photochimioth6rapie par vole orale et dermatite atopique. Ann Dermatol Venereol 1982;109:589-90. 3. Falk ES. UV-light therapies in atopic dermatitis. Photodermatol 1985;2:241-6. 4. Hannuksela M, Karvonen J, Husa M, et al. Ultraviolet light therapy in atopic dermatitis. Acta Derm Venereol (Stockh) 1985;suppl 114:137-9. 5. Jelder J, Lark5 O. UVB phototherapy of atopic dermatitis. Br J Dermatol 1988;119:697-705. 6. Kavli G. Fotokjemoterapi med psoralen og langb61get ultrafiolett lys. 11/2~irserfaring fra hudavdelingen i Troms6. Tidsskr Nor Laegeforen 1978;98:269-71. 7. Midelfart K, Stenvold S-E, Volden G. Combined UVB and UVA phototherapy ofatopie eczema. Dermatologica 1985; 171:95-8. 8. Morison WL, Parrish JA, Fitzpatrick TB. Oral psoralen photochemotherapy ofatopie eczema. Br J Dermatol 1978; 98:25-30. 9. Potekaev NS, Sevidova LY, Vladimirov VV, et al. Selective phototherapy and dimoeiphon immunocorrective therapy in atopic dermatitis. Vestn Dermatol Venerol 1987;9:39-42. 10. Pullman H, M6res E, Reinbach S. Wirkung yon Infrarotund UVA-Strahlen auf die menschliche Haut und ihre Wirksamkeit bei der Behandlung des endogenen Ekzems. Z Hautkr 1985;60:171-7. 11. Rajka G. Recent therapeutic events. Cimetidine and PUVA. Acta Derm Venereol (Stockh) 1980;suppl 92: 117-8. 12. Salo O, Lassus A, Juvakoski T, et al. Behandlung der Dermatitis atopica und der Dermatitis seborrhoica mit selektiver UV-Phototherapie und PUVA. Eine vergleichende Studie. Dermatol Monatsschr 1983;169:371-5. 13. Sannwald C, Ortonne JP, Thivolet J. La photochimio-
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th6rapie orale de l'ecz6ma atopique. Dermatologica 1979; 159:71-7. Soppi E, Viander M, Soppi A-M, et ai. Cell-mediated immunity in untreated and PUVA treated atopic dermatitis. J Invest Dermatol 1982;79:213-7. Hanifin JM, Rajka G. Diagnostic features of atopic dermatitis. Acta Derm Venereol (Stockh) 1980;suppl 92: 44-7. Toews GB, Bergstresser PR, Streilein JW, et al. Epidermal Langerhans cell density determines whether contact hypersensitivity or unresponsiveness follows skin painting with DNFB. J Immunol 1980;124:445-53. Lark5 O, Swanbeck G. Is UVB treatment of psoriasis safe? A study of extensively UVB-treated psoriasis patients compared with a matched control group. Acta Derm Venereol (Stockh) 1982;62:507-12. Parrish JA, Anderson RR, Urbach F, et al. U V A : biological effects of ultraviolet radiation with emphasis on human responses to longwave ultraviolet. New York: Plenum, 1978:167-8. Aberer W, Schuler G, Stingl G, et al. Effects of UV-light on epidermal Langerhans ceils. J Invest Dermatol 1980; 74:458. Gollhausen R, Kaidbey K, Schechter N. UV suppression of mast cell-mediated whealing in human skin. Photodermatol 1985;2:58-67. Livden JK, Bjerke JR, Degre M, et ai. The significance of interferon in photoimmunology. Acta Derm Venereol (Stockh) 1987;(suppl 134):43-6. DeMaeyer E, DeMaeyer-Guignard J, Vandeputte M. Inhibition by interferon of delayed type hypersensitivity in the mouse. Proc Natl Acad Sci USA 1975;72:1753-7. Faergemann J, Lark6 O. The effect of UV light on human skin microorganisms. Acta Derrn Venereol (Stockh) 1987; 67:69-72. Norris PG, Schofield O, Camp RDR. A study of the role of house dust mite in atopie dermatitis. Br J Dermatol 1988;118:435-40.
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