British Journal of Dermatology (1978) 98, 25.
Oral psoralen photochemotherapy of atopic eczema WARWICK L.MORISON, JOHN A.PARRISH AND THOMAS B.FITZPATRICK Department of Dermatology, Harvard Medical School, Boston, Massachusetts 02114, U.S.A. Accepted for publication 8 August 1977
SUMMARY
Oral administration of 8-methoxypsoralen followed by exposure to a high-intensity longwave ultraviolet treatment system resulted in clearing of atopic eczema in 15 patients. Paired-comparison studies demonstrated that this treatment was superior both to conventional ultraviolet light therapy and to no treatment. Short-term observation suggests that regular therapy is necessary to maintain remission of the disease.
Atopic eczema is a common disorder which usually first appears in childhood, runs a variable course over months to years, and frequently persists into adult life. The condition is genetically determined and is one manifestation of the atopic diathesis which includes a tendency to form reaginic antibodies and to have symptomatic asthma, hay fever, and eczema. The cardinal symptom of atopic eczema is pruritus and this gives rise to the clinical features of widespread excoriations and lichenification. The disfigurement and intractable pruritus may result in a considerable disturbance of the patient's physical, social, and psychological well-being. Atopic eczema is also a source of chronic frustration for the physician. Topical and, to a much lesser extent, oral corticosteroids are currently the mainstay of treatment in all but the mildest cases. Even when used in large doses, these usually provide only partial symptomatic relief. Apart from the morbidity of the condition itself, the treatment also results in a significant morbidity. Topical corticosteroids can cause atrophy and telangiectasia of the skin while oral steroids, as well as the prolonged use of topical steroids on diseased skin, can result in systemic side effects. It is a clinical observation that some patients with atopic eczema are often better during the summer months. This led to the present study of the value of phototherapy. Oral psoralen photochemotherapy using sunlight has been widely used in vitiligo for many years and more recently oral methoxsalen in combination with a high-density longwave ultraviolet light system (GTE Sylvania) have been shown to control psoriasis effectively (Parrish et al., 1974) and to be beneficial in some patients with vitiligo (Parrish et al., 1976) and mycosis fungoides (Gilchrest et al., 1976). The treatment involves the ingestion of psoralens (P) followed, at a specified interval, by exposure to longwave ultraviolet radiation (UV-A), abbreviated PUVA. The present study was designed to evaluate PUVA therapy of atopic eczema and to compare PUVA with conventional ultraviolet irradiation (UV-B). 25
26
W.L.Morison, J.A.Parrish and T.B.Fitzpatrick PATIENTS AND METHODS
Fifteen Caucasians with severe atopic eczema imcontrolled by conventional topical and oral corticosteroid therapy were treated. The age range of the group was 9-63 years, with a mean of 27 years. All had a personal and/or family history of atopy and at the time of evaluation had a clinical picture consistent with the diagnosis of severe atopic eczema. The clinical features are listed in Table i. TABLE I. Clinical picture. Area of body involved: 30-100% (mean: 80%) Lesions Acute and sub-acute eczema Chronic lichenification Secondary infection Nail dystrophy Scalp involvement Chronic blepharitis
15
6 4 3 4 4
Design of the study
The patients were divided into three groups each of five patients. Group I. Whole-body PUVA therapy. One site, 4 x 4 cm on the buttock, was shielded with an aluminum plate during UV-A exposures and served as a control area in four of the patients. Group 2. PUVA versus no treatment. In a bilateral comparison, PUVA was used on one side of the body and no treatment apart from lubricants was given to the other side. The untreated side was shielded with two layers of cotton sheeting during irradiation. Group 3. PUVA versus UV-B. In a bilateral comparison, PUVA was used on one side of the body and UV-B treatment was given to the other side. UV-B treatments were always given prior to psoralen ingestion. In Group i, the control site was kept covered during the treatments until 99% of the other areas had been cleared of eczema, and then the control site was treated and cleared. In Groups 2 and 3, the bilateral comparison was continued until 95% (rule of 9 for large areas; palm of hand = 1%, for small areas) of the PUVA-treated side had been cleared of eczema and then the other side was cleared with PUVA therapy. Other medications
Patients were permitted unrestricted use of emollients and Atarax (hydroxyzine hydrochloride). Four of the five patients receiving whole-body PUVA therapy had their previous therapy of oral and topical steroids tapered off during the early phase of PUVA treatment to avoid the problem ofa rebound effect. All corticosteroids were stopped prior to the study on the other patients so that none of the patients in the bilateral comparison study used any topical or oral steroids. Laboratory investigations
The serum bilirubin, serum glutamic oxalacetic transaminase, lactic acid dehydrogenase, alkaline
PUVA of atopic eczema
27
phosphatase, blood urea nitrogen, creatinine, and IgE were measured, and a complete blood count, urinalysis, and culture of skin bacterial fiora were performed prior to commencing therapy and were monitored during the study. PUVA treatment Oral 8-methoxypsoralen (o-6 mg/kg body weight) was ingested 2 h before exposure to UV-A radiation. The initial dose of UV-A (range i •5-3-5 J/cm^) was determined by the patient's sunburn and suntan history, and this dose was increased by 0-5-1-0 J/cm^ each treatment provided there was no significant erythema present. Treatments were given three times a week during the clearance phase with a minimum of 48 h between each treatment because a PUVA-induced erythema usually does not peak until at least 48 h. Once a patient was judged to be at least 99% free of chnically apparent disease and pruritus, frequency of treatments was reduced to weekly for 4-6 treatments. If during that time there was no exacerbation of eczema, the frequency was again reduced to one treatment every other week. Whole-body irradiation was provided by either a bed unit or an upright unit. The characteristics of these systems have been described previously (Parrish et al., 1974; Levin & Parrish, 1974). UV-B treatment The initial dose of UV-B radiation (range 30-180 mj/cm^ of 275-320 nm radiation) was also determined by the patient's sunburn and suntan history. This dose was increased by 10-25% ^^ch treatment with the aim of maintaining a trace erythema. When a symptomatic erythema developed, depending on the degree, either the UV-B dose was held constant or treatment was withheld until the erythema had subsided. Treatments were given five times each week with a minimum of 24 h between each treatment. The characteristics of the UV-B irradiator have been described (Parrish et ah, 1976). RESULTS
The response to whole-body PUVA therapy, PUVA compared to no treatment, and PUVA compared to UV-B, are summarized in Table 2. In the patients in Group i, eczema was cleared from 99% of TABLE 2. Treatment response Group I Whole-body PUVA Control site Group 2 PUVA side Untreated side Group 3 PUVA side UV-B side
Eczema 99% clear in 20-58 treatments Increased eczema in all patients Eczema 95% clear in 12-21 treatments No change Eczema 95% clear in 7-12 treatments Eczema increased in 4, no change in i, in 13-19 treatments
the body surface in 20-58 PUVA treatments while the covered, control sites developed more severe eczema. In Group 2 patients, the PUVA-treated side was cleared to < 5% eczema in 12-21 treatments and at that time the eczema on the untreated side was unchanged in all patients. At the end of the bilateral comparison, pruritus was present only on the untreated side. In Group 3 patients, the PUVAtreated side was cleared to < 5 % eczema in 7-12 treatments. Over the same period, 13-19 UV-B
28
W.L.Morison,J.A.Parrish and T.B.Fitzpatrick
treatments were given to the other side. On the UV-B-treated side the eczema had increased in severity and extent in 4 patients and was unchanged in the other patient. Clearance of eczema to < 1% in all fifteen patients required 18-59 treatments (mean: 36 treatments) over 50-202 days (mean: ioi days) and afinalclearance dose of 7-24 J/cm^ of UV-A (mean: 13 J/cm^). The first sign of improvement was a decrease of the pruritus in 10 patients and a decrease in the extent and severity of the eczema in 5 patients. Improvement was noticeable after 4-21 treatments and thereafter was slowly progressive. At the time of 99% clearance, all patients were almost entirely free of pruritus. There was no apparent correlation in this study between the type of eczema and the response to treatment. The maintenance treatment requirements varied. Eleven patients required continuation of weekly treatments, three were controlled by one treatment every second week, and the other patient stopped treatment of her own accord and after 3 months was still free of eczema having no treatment at all. During the follow-up maintenance phase of 4-16 months (mean: 9 months), seven patients had an exacerbation of their eczema involving more than 5% of body surface. In three patients this exacerbation was severe and involved > 60% of the body surface. In six patients these flare-ups followed a reduction in the frequency of treatment during the stepwise procedure of finding the correct frequency for maintenance in the individual patient. One patient flared-up during the autumn and gave a history of autumnal exacerbations over the previous 4 years. The best indicator of a developing exacerbation was a return of pruritus, and this usually preceded the appearance of eczema by a week or more. All exacerbations responded to a return to two or three treatments per week as used in the clearance phase plus, in five patients, an increase in the dose of UV-A. A marked exacerbation of eczema occurred in all Group 2 and 3 patients as their topical and oral steroid therapy was tapered prior to commencing PUVA therapy. In three patients the exacerbation of eczema was major and required hospitalization in two cases. Group i patients, who were gradually tapered off steroid therapy as their eczema came under control with PUVA, did not have any poststeroid exacerbations. During the therapy, nail dystrophy cleared in the three patients in whom the nails were affected although this took several months. The scalp cleared in three of the four patients with scalp involvement without any specific treatment. After careful consideration and a detailed explanation to the patients, each patient with symptomatic blepharitis was given a short course of treatment (4-10 exposures) without goggles but with their eyes closed during the whole of the treatment. This was successful in clearing the blepharitis in three of the four patients affected and those patients have remained clear even though all have resumed wearing goggles. Four patients complained of nausea, two only when the psoralen was ingested without food, and the other two only occasionally and this was unrelated to food ingestion. Six patients had a localized symptomatic erythema on PUVA-treated areas early in the course of treatment. Four of the five patients treated with UV-B also had a symptomatic localized erythema. One patient showed postinfiammatory depigmentation at the time of initial evaluation, while in three others loss of normal pigmentation was concealed by overlying hchenification and only became evident as therapy progressed. Because such depigmented areas readily developed phototoxicity, UV-A dosimetry had to be extremely accurate in these patients. In addition, three patients developed subungual haemorrhages of the fingernails, also presumably due to phototoxicity and this required wearing an opaque nail polish until the nails recovered. During this study, recurrent herpes labialis was noted in three patients who gave a past history of the infection. In addition, herpes infection of the face with ocular involvement pccurred in two patients, one of whom had no past history of herpes. These patients fully recovered with idoxuridine therapy locally and resumed PUVA treatments. No abnormalities of the serum bilirubin, serum glutamic oxaloacetic transaminase, lactic acid de-
PUVA of atopic eczema
29
hydrogenase, alkaline phosphatase, blood urea nitrogen and creatinine assays, the complete blood coimt and urinalysis, developed during the treatment in any of the patients. Serum IgE levels and quahtative cultures of bacterial skin flora showed no significant change either during the bilateral comparison studies or over the course of clearing and maintenance treatment. DISCUSSION
This study has shown in 15 patients that PUVA therapy is an effective clearance treatment for atopic eczema and that once the eczematous state has been brought under control it is possible to maintain a clear state with continued maintenance treatment. Furthermore, bilateral comparison studies showed that treatment with PUVA was clearly superior to UV-R therapy. It is interesting to note that all four patients who showed a worsening of their eczema on the UV-R-treated side gave a history of improvement during the summer months. Factors other than solar UV-R radiation (e.g. salt water, absence of stress, other portions of the solar electromagnetic spectrum) may be responsible for this improvement. Patients in these bilateral comparison studies did not receive any topical corticosteroids during the course of treatment. Lubricants alone were permitted as topical therapy. The response to PUVA therapy in atopic eczema patients differs from that seen in psoriatic patients in several important respects. The number of treatments required to achieve signs of improvement and the number required to reach a cleared state are about twice that required in treating psoriasis (Parrish, 1976). In addition, a much more aggressive approach to maintenance therapy must be adopted. In psoriatic patients, a decrease in the frequency of maintenance treatment below the level necessary to control the disease may be followed by a slow return of the disease. In atopic eczema patients, the disease seems to recur rapidly if adequate maintenance is not given. Therefore, the eczema patients must strictly adhere to the maintenance schedule and they also must be carefully monitored for the return of pruritus, the first sign of a developing exacerbation. The long-term maintenance requirements of PUVA therapy in atopic eczema are not known. Finally, eczema patients differed from psoriatic patients psychologically, being more anxious, questioning and introverted. As a result they require much more support and, hence, more physician time than do psoriatic patients undergoing similar PUVA therapy. The occurrence of herpes simplex infection during therapy is a worrisome observation. An increased frequency of herpes labialis is noted in psoriatic patients receiving PUVA and UV-R treatments (Morison, personal observation). Patients with atopic eczema are prone to widespread herpes simplex infection and the addition of a therapy known to precipitate such infections may create a serious risk in some patients. However, since both cases of widespread herpes simplex infection occurred in patients while they had extensive eczema it is not possible to decide whether this risk exists in patients who are clear and on maintenance treatment. Vigilance on the part of the physician and education of the patient are essential for early diagnosis and adequate management of herpes simplex. The long-term effects of PUVA therapy are still being evaluated and will probably not be fully known for years. The two principal areas of concern are skin carcinogenesis and cataracts, both of which have been shown to occur in animals (Griffin, 1959; Logan, 1961), but as yet have not been reported in himians undergoing treatment. Patients in the present study had initial eye examinations and a yearly follow-up is planned. The mechanism by which PUVA therapy induces an improvement in skin disease is not known. Inhibition of DNA synthesis may benefit the hyperproliferative state of psoriasis (Parrish et al., 1974) and a cytotoxic effect on abnormal dermal cells may be the therapeutic mechanism in mycosis fungoides (Gilchrest et al., 1976). However, in atopic eczema there is no increase in epidermal turnover and the inflammatory infiltrate in the dermis does not contain abnormal cells. The pathogenesis of atopic
30
W.L.Morison, J.A.Parrish and T.B.Fitzpatrick
eczema is largely unknown but an immunological disturbance has been suggested by many studies, and such a disturbance is possibly mediated by cells in the dermis. PUVA may well interfere with the function and viability of such cells and thus suppress the disease state. The observation in this study that eczema not exposed to PUVA did not clear indicates that the effect of PUVA is local and not systemic. However, until more is known about the action of PUVA and the aetiology of the disease, any suggestion as to the mechanism of the effect observed in the present study must remain conjectural. This study is preliminary and provides only a short follow-up of the maintenance phase. A full evaluation of the role of PUVA therapy in the treatment of atopic eczema will require a larger study and a longer follow-up. However, at this point it appears to offer promise as a therapy for a condition which can be physically and psychologically crippling and for which there is no safe or effective treatment. ACKNOWLEDGMENTS
The authors are grateful to Paul Wychules, Shari Rose, Otto Coontz, and Susan Shadbeghian of the Phototherapy Unit of the Massachusetts General Hospital, whose enthusiasm and attention to detail made this study possible. REFERENCES GILCHREST, B.A., PARRISH, J.A., TANENBAUM, L . , HAYNES, H.A. & FITZPATRICK, T.B. (1976) Oral methoxsalen
photochemotherapy of mycosis fungoides. Cancer, 38, 683. GRIFFIN, A.C. (1959) Methoxsalen in ultraviolet carcinogenesis in the mouse. Journal of Investigative Dermatology, 32, 367LEVIN, R.E. & PARRISH, J.A. (1974) Phototherapy of vitiligo. Lighting Design and Application, 4, 38. LOGAN, D . (1961) Photosensitization and cataracts. Archives of Ophthalmology, 66, 28. PARRISH, J.A., FITZPATRICK, T.B., SHEA, C . & PATHAK, M.A. (1976) Photochemotherapy of vitiligo with oral
psoralen and a new high-intensity longwave ultraviolet light (UV-A) system. Archives of Dermatology, 112, 1531. PARRISH, J.A., FITZPATRICK, T.B., TANENBAUM, L . & PATHAK, M.A. (1974) Photochemotherapy of psoriasis with
oral methoxsalen and longwave ultraviolet light. New England Journal of Medicine, 291, 1207.
Oral psoralen photochemotherapy of atopic eczema WARWICK L.MORISON, JOHN A.PARRISH AND THOMAS B.FITZPATRICK Department of Dermatology, Harvard Medical School, Boston, Massachusetts 02114, U.S.A. Accepted for publication 8 August 1977
SUMMARY
Oral administration of 8-methoxypsoralen followed by exposure to a high-intensity longwave ultraviolet treatment system resulted in clearing of atopic eczema in 15 patients. Paired-comparison studies demonstrated that this treatment was superior both to conventional ultraviolet light therapy and to no treatment. Short-term observation suggests that regular therapy is necessary to maintain remission of the disease.
Atopic eczema is a common disorder which usually first appears in childhood, runs a variable course over months to years, and frequently persists into adult life. The condition is genetically determined and is one manifestation of the atopic diathesis which includes a tendency to form reaginic antibodies and to have symptomatic asthma, hay fever, and eczema. The cardinal symptom of atopic eczema is pruritus and this gives rise to the clinical features of widespread excoriations and lichenification. The disfigurement and intractable pruritus may result in a considerable disturbance of the patient's physical, social, and psychological well-being. Atopic eczema is also a source of chronic frustration for the physician. Topical and, to a much lesser extent, oral corticosteroids are currently the mainstay of treatment in all but the mildest cases. Even when used in large doses, these usually provide only partial symptomatic relief. Apart from the morbidity of the condition itself, the treatment also results in a significant morbidity. Topical corticosteroids can cause atrophy and telangiectasia of the skin while oral steroids, as well as the prolonged use of topical steroids on diseased skin, can result in systemic side effects. It is a clinical observation that some patients with atopic eczema are often better during the summer months. This led to the present study of the value of phototherapy. Oral psoralen photochemotherapy using sunlight has been widely used in vitiligo for many years and more recently oral methoxsalen in combination with a high-density longwave ultraviolet light system (GTE Sylvania) have been shown to control psoriasis effectively (Parrish et al., 1974) and to be beneficial in some patients with vitiligo (Parrish et al., 1976) and mycosis fungoides (Gilchrest et al., 1976). The treatment involves the ingestion of psoralens (P) followed, at a specified interval, by exposure to longwave ultraviolet radiation (UV-A), abbreviated PUVA. The present study was designed to evaluate PUVA therapy of atopic eczema and to compare PUVA with conventional ultraviolet irradiation (UV-B). 25
26
W.L.Morison, J.A.Parrish and T.B.Fitzpatrick PATIENTS AND METHODS
Fifteen Caucasians with severe atopic eczema imcontrolled by conventional topical and oral corticosteroid therapy were treated. The age range of the group was 9-63 years, with a mean of 27 years. All had a personal and/or family history of atopy and at the time of evaluation had a clinical picture consistent with the diagnosis of severe atopic eczema. The clinical features are listed in Table i. TABLE I. Clinical picture. Area of body involved: 30-100% (mean: 80%) Lesions Acute and sub-acute eczema Chronic lichenification Secondary infection Nail dystrophy Scalp involvement Chronic blepharitis
15
6 4 3 4 4
Design of the study
The patients were divided into three groups each of five patients. Group I. Whole-body PUVA therapy. One site, 4 x 4 cm on the buttock, was shielded with an aluminum plate during UV-A exposures and served as a control area in four of the patients. Group 2. PUVA versus no treatment. In a bilateral comparison, PUVA was used on one side of the body and no treatment apart from lubricants was given to the other side. The untreated side was shielded with two layers of cotton sheeting during irradiation. Group 3. PUVA versus UV-B. In a bilateral comparison, PUVA was used on one side of the body and UV-B treatment was given to the other side. UV-B treatments were always given prior to psoralen ingestion. In Group i, the control site was kept covered during the treatments until 99% of the other areas had been cleared of eczema, and then the control site was treated and cleared. In Groups 2 and 3, the bilateral comparison was continued until 95% (rule of 9 for large areas; palm of hand = 1%, for small areas) of the PUVA-treated side had been cleared of eczema and then the other side was cleared with PUVA therapy. Other medications
Patients were permitted unrestricted use of emollients and Atarax (hydroxyzine hydrochloride). Four of the five patients receiving whole-body PUVA therapy had their previous therapy of oral and topical steroids tapered off during the early phase of PUVA treatment to avoid the problem ofa rebound effect. All corticosteroids were stopped prior to the study on the other patients so that none of the patients in the bilateral comparison study used any topical or oral steroids. Laboratory investigations
The serum bilirubin, serum glutamic oxalacetic transaminase, lactic acid dehydrogenase, alkaline
PUVA of atopic eczema
27
phosphatase, blood urea nitrogen, creatinine, and IgE were measured, and a complete blood count, urinalysis, and culture of skin bacterial fiora were performed prior to commencing therapy and were monitored during the study. PUVA treatment Oral 8-methoxypsoralen (o-6 mg/kg body weight) was ingested 2 h before exposure to UV-A radiation. The initial dose of UV-A (range i •5-3-5 J/cm^) was determined by the patient's sunburn and suntan history, and this dose was increased by 0-5-1-0 J/cm^ each treatment provided there was no significant erythema present. Treatments were given three times a week during the clearance phase with a minimum of 48 h between each treatment because a PUVA-induced erythema usually does not peak until at least 48 h. Once a patient was judged to be at least 99% free of chnically apparent disease and pruritus, frequency of treatments was reduced to weekly for 4-6 treatments. If during that time there was no exacerbation of eczema, the frequency was again reduced to one treatment every other week. Whole-body irradiation was provided by either a bed unit or an upright unit. The characteristics of these systems have been described previously (Parrish et al., 1974; Levin & Parrish, 1974). UV-B treatment The initial dose of UV-B radiation (range 30-180 mj/cm^ of 275-320 nm radiation) was also determined by the patient's sunburn and suntan history. This dose was increased by 10-25% ^^ch treatment with the aim of maintaining a trace erythema. When a symptomatic erythema developed, depending on the degree, either the UV-B dose was held constant or treatment was withheld until the erythema had subsided. Treatments were given five times each week with a minimum of 24 h between each treatment. The characteristics of the UV-B irradiator have been described (Parrish et ah, 1976). RESULTS
The response to whole-body PUVA therapy, PUVA compared to no treatment, and PUVA compared to UV-B, are summarized in Table 2. In the patients in Group i, eczema was cleared from 99% of TABLE 2. Treatment response Group I Whole-body PUVA Control site Group 2 PUVA side Untreated side Group 3 PUVA side UV-B side
Eczema 99% clear in 20-58 treatments Increased eczema in all patients Eczema 95% clear in 12-21 treatments No change Eczema 95% clear in 7-12 treatments Eczema increased in 4, no change in i, in 13-19 treatments
the body surface in 20-58 PUVA treatments while the covered, control sites developed more severe eczema. In Group 2 patients, the PUVA-treated side was cleared to < 5% eczema in 12-21 treatments and at that time the eczema on the untreated side was unchanged in all patients. At the end of the bilateral comparison, pruritus was present only on the untreated side. In Group 3 patients, the PUVAtreated side was cleared to < 5 % eczema in 7-12 treatments. Over the same period, 13-19 UV-B
28
W.L.Morison,J.A.Parrish and T.B.Fitzpatrick
treatments were given to the other side. On the UV-B-treated side the eczema had increased in severity and extent in 4 patients and was unchanged in the other patient. Clearance of eczema to < 1% in all fifteen patients required 18-59 treatments (mean: 36 treatments) over 50-202 days (mean: ioi days) and afinalclearance dose of 7-24 J/cm^ of UV-A (mean: 13 J/cm^). The first sign of improvement was a decrease of the pruritus in 10 patients and a decrease in the extent and severity of the eczema in 5 patients. Improvement was noticeable after 4-21 treatments and thereafter was slowly progressive. At the time of 99% clearance, all patients were almost entirely free of pruritus. There was no apparent correlation in this study between the type of eczema and the response to treatment. The maintenance treatment requirements varied. Eleven patients required continuation of weekly treatments, three were controlled by one treatment every second week, and the other patient stopped treatment of her own accord and after 3 months was still free of eczema having no treatment at all. During the follow-up maintenance phase of 4-16 months (mean: 9 months), seven patients had an exacerbation of their eczema involving more than 5% of body surface. In three patients this exacerbation was severe and involved > 60% of the body surface. In six patients these flare-ups followed a reduction in the frequency of treatment during the stepwise procedure of finding the correct frequency for maintenance in the individual patient. One patient flared-up during the autumn and gave a history of autumnal exacerbations over the previous 4 years. The best indicator of a developing exacerbation was a return of pruritus, and this usually preceded the appearance of eczema by a week or more. All exacerbations responded to a return to two or three treatments per week as used in the clearance phase plus, in five patients, an increase in the dose of UV-A. A marked exacerbation of eczema occurred in all Group 2 and 3 patients as their topical and oral steroid therapy was tapered prior to commencing PUVA therapy. In three patients the exacerbation of eczema was major and required hospitalization in two cases. Group i patients, who were gradually tapered off steroid therapy as their eczema came under control with PUVA, did not have any poststeroid exacerbations. During the therapy, nail dystrophy cleared in the three patients in whom the nails were affected although this took several months. The scalp cleared in three of the four patients with scalp involvement without any specific treatment. After careful consideration and a detailed explanation to the patients, each patient with symptomatic blepharitis was given a short course of treatment (4-10 exposures) without goggles but with their eyes closed during the whole of the treatment. This was successful in clearing the blepharitis in three of the four patients affected and those patients have remained clear even though all have resumed wearing goggles. Four patients complained of nausea, two only when the psoralen was ingested without food, and the other two only occasionally and this was unrelated to food ingestion. Six patients had a localized symptomatic erythema on PUVA-treated areas early in the course of treatment. Four of the five patients treated with UV-B also had a symptomatic localized erythema. One patient showed postinfiammatory depigmentation at the time of initial evaluation, while in three others loss of normal pigmentation was concealed by overlying hchenification and only became evident as therapy progressed. Because such depigmented areas readily developed phototoxicity, UV-A dosimetry had to be extremely accurate in these patients. In addition, three patients developed subungual haemorrhages of the fingernails, also presumably due to phototoxicity and this required wearing an opaque nail polish until the nails recovered. During this study, recurrent herpes labialis was noted in three patients who gave a past history of the infection. In addition, herpes infection of the face with ocular involvement pccurred in two patients, one of whom had no past history of herpes. These patients fully recovered with idoxuridine therapy locally and resumed PUVA treatments. No abnormalities of the serum bilirubin, serum glutamic oxaloacetic transaminase, lactic acid de-
PUVA of atopic eczema
29
hydrogenase, alkaline phosphatase, blood urea nitrogen and creatinine assays, the complete blood coimt and urinalysis, developed during the treatment in any of the patients. Serum IgE levels and quahtative cultures of bacterial skin flora showed no significant change either during the bilateral comparison studies or over the course of clearing and maintenance treatment. DISCUSSION
This study has shown in 15 patients that PUVA therapy is an effective clearance treatment for atopic eczema and that once the eczematous state has been brought under control it is possible to maintain a clear state with continued maintenance treatment. Furthermore, bilateral comparison studies showed that treatment with PUVA was clearly superior to UV-R therapy. It is interesting to note that all four patients who showed a worsening of their eczema on the UV-R-treated side gave a history of improvement during the summer months. Factors other than solar UV-R radiation (e.g. salt water, absence of stress, other portions of the solar electromagnetic spectrum) may be responsible for this improvement. Patients in these bilateral comparison studies did not receive any topical corticosteroids during the course of treatment. Lubricants alone were permitted as topical therapy. The response to PUVA therapy in atopic eczema patients differs from that seen in psoriatic patients in several important respects. The number of treatments required to achieve signs of improvement and the number required to reach a cleared state are about twice that required in treating psoriasis (Parrish, 1976). In addition, a much more aggressive approach to maintenance therapy must be adopted. In psoriatic patients, a decrease in the frequency of maintenance treatment below the level necessary to control the disease may be followed by a slow return of the disease. In atopic eczema patients, the disease seems to recur rapidly if adequate maintenance is not given. Therefore, the eczema patients must strictly adhere to the maintenance schedule and they also must be carefully monitored for the return of pruritus, the first sign of a developing exacerbation. The long-term maintenance requirements of PUVA therapy in atopic eczema are not known. Finally, eczema patients differed from psoriatic patients psychologically, being more anxious, questioning and introverted. As a result they require much more support and, hence, more physician time than do psoriatic patients undergoing similar PUVA therapy. The occurrence of herpes simplex infection during therapy is a worrisome observation. An increased frequency of herpes labialis is noted in psoriatic patients receiving PUVA and UV-R treatments (Morison, personal observation). Patients with atopic eczema are prone to widespread herpes simplex infection and the addition of a therapy known to precipitate such infections may create a serious risk in some patients. However, since both cases of widespread herpes simplex infection occurred in patients while they had extensive eczema it is not possible to decide whether this risk exists in patients who are clear and on maintenance treatment. Vigilance on the part of the physician and education of the patient are essential for early diagnosis and adequate management of herpes simplex. The long-term effects of PUVA therapy are still being evaluated and will probably not be fully known for years. The two principal areas of concern are skin carcinogenesis and cataracts, both of which have been shown to occur in animals (Griffin, 1959; Logan, 1961), but as yet have not been reported in himians undergoing treatment. Patients in the present study had initial eye examinations and a yearly follow-up is planned. The mechanism by which PUVA therapy induces an improvement in skin disease is not known. Inhibition of DNA synthesis may benefit the hyperproliferative state of psoriasis (Parrish et al., 1974) and a cytotoxic effect on abnormal dermal cells may be the therapeutic mechanism in mycosis fungoides (Gilchrest et al., 1976). However, in atopic eczema there is no increase in epidermal turnover and the inflammatory infiltrate in the dermis does not contain abnormal cells. The pathogenesis of atopic
30
W.L.Morison, J.A.Parrish and T.B.Fitzpatrick
eczema is largely unknown but an immunological disturbance has been suggested by many studies, and such a disturbance is possibly mediated by cells in the dermis. PUVA may well interfere with the function and viability of such cells and thus suppress the disease state. The observation in this study that eczema not exposed to PUVA did not clear indicates that the effect of PUVA is local and not systemic. However, until more is known about the action of PUVA and the aetiology of the disease, any suggestion as to the mechanism of the effect observed in the present study must remain conjectural. This study is preliminary and provides only a short follow-up of the maintenance phase. A full evaluation of the role of PUVA therapy in the treatment of atopic eczema will require a larger study and a longer follow-up. However, at this point it appears to offer promise as a therapy for a condition which can be physically and psychologically crippling and for which there is no safe or effective treatment. ACKNOWLEDGMENTS
The authors are grateful to Paul Wychules, Shari Rose, Otto Coontz, and Susan Shadbeghian of the Phototherapy Unit of the Massachusetts General Hospital, whose enthusiasm and attention to detail made this study possible. REFERENCES GILCHREST, B.A., PARRISH, J.A., TANENBAUM, L . , HAYNES, H.A. & FITZPATRICK, T.B. (1976) Oral methoxsalen
photochemotherapy of mycosis fungoides. Cancer, 38, 683. GRIFFIN, A.C. (1959) Methoxsalen in ultraviolet carcinogenesis in the mouse. Journal of Investigative Dermatology, 32, 367LEVIN, R.E. & PARRISH, J.A. (1974) Phototherapy of vitiligo. Lighting Design and Application, 4, 38. LOGAN, D . (1961) Photosensitization and cataracts. Archives of Ophthalmology, 66, 28. PARRISH, J.A., FITZPATRICK, T.B., SHEA, C . & PATHAK, M.A. (1976) Photochemotherapy of vitiligo with oral
psoralen and a new high-intensity longwave ultraviolet light (UV-A) system. Archives of Dermatology, 112, 1531. PARRISH, J.A., FITZPATRICK, T.B., TANENBAUM, L . & PATHAK, M.A. (1974) Photochemotherapy of psoriasis with
oral methoxsalen and longwave ultraviolet light. New England Journal of Medicine, 291, 1207.
