British Journal of Dermatology (1990) 122, Supplement 36, 117-125.
Side-effects of psoralen photochemotherapy (PUVA) K. WOLFF Department of Dermatology i, University of Vienna, Vienna, Austria
SUMMARY
Although psoralen photochemotherapy (PUVA) is one of the most effective forms of therapy for psoriasis, the risk of potential long-term side-effects is, as yet, not clearly determined. Chronic degenerative and pigmentary skin changes similar to those of chronic solar exposure occur after long-term PUVA treatment; PUVA also causes non-melanoma skin cancers in man, although there is, as yet, no consensus as to what cumulative phototoxic PUVA dose is carcinogenic. Long-term multicentre studies from the U.S.A. indicate a definite risk of squamous cell carcinoma for long-term PUVA-treated patients, whereas European studies reveal no overall increase in skin cancers in similar patients except for those exposed to other carcinogens. Assignment to PUVA should be based on the risk:benefit ratio for the individual patient. Careful patient selection is therefore mandatory and should be limited to those who can be monitored and controlled by informed, competent and conscientious physicians.
Psoralen photochemotherapy (PUVA)' is one of the most effective forms of therapy for psoriasis.^ It induces a complete clinical remission within a reasonably short period of time and, as maintenance therapy, can produce a remission for an extended period. In combination with retinoids,^ the clinical efficacy of PUVA is greatly improved and is likely to minimize the potential long-term side-effects. There is now considerable clinical experience regarding the short-term safety of PUVA, but the risk of potential long-term side-effects is, as yet, not clearly determined. ACUTE SIDE-EFFECTS AND TOXICITY OF PUVA
Side-effects (Table i) are related to overdosing with long-wave ultraviolet (UVA) radiation or the patient's inability to tolerate the psoralens used in the treatment. The most frequent side-effect due to overexposure is erythema.'' Pruritus is also UVA dose-related, and a few patients experience painful burning sensations in the exposed skin towards the end-phase of treatment. Correspondence: Professor K.Wolff, Department of Dermatology i. University of Vienna, Alser Strasse 4, A-1090 Wien, Austria. 117
K.Wolff TABLE I. Immediate side-effects of PUVA (n = 3175) Interruption (clearing phase)
Interruption (maintenance (phase)
(%)
(%)
6-7
135
1-7 1-4 0-6
1-5
0-3 0-4 0-3
2-0
O-I
O-I
O-I
2-0
0-2
0-5
O-I
Frequency Side-effect
(%)
Erythema Pruritus Nausea Headache Koebner reaction
32-4 25-6
D iscontinuation of PUVA (%)
2-9
Henseler et al?
Overdose phenomena usually arise in areas not normally exposed to natural sunlight. Careful observation of the criteria for dosimetry and the guidelines for treatment' will reduce these adverse events. Transient nausea is relatively common with 8-MOP (8-methoxypsoralen; methoxsalen) used as a photosensitizer,"* but occurs only rarely with 5-MOP (5-methoxypsoralen).' Only on rare occasions is the nausea so severe as to necessitate discontinuation of treatment. Other shortterm side-effects include acne-like eruptions, polymorphous light eruption-like rashes, subungual haemorrhages due to phototoxic reactions and transient hypertrichosis ofthe face.' These are all reversible and disappear on discontinuation of treatment. Laboratory data
As psoralens in excessive doses are hepatotoxic in laboratory animals, there has been concern in the past as to liver damage in humans. Laboratory examinations performed over many years have not revealed evidence of impaired hepatic function and, although a slight increase in blood urea nitrogen (BUN) and creatinine has been docvimented in one series, there is no evidence to suggest impairment ofrenal function in large-scale studies.*'' Analysis ofthe laboratory data from several studies has not revealed significant abnormal findings in those patients who have received PUVA over a prolonged period of time (Table 2). One study reported an increased incidence of antinuclear antibodies in PUVA-treated patients,'" but other studies have shown no such relationships.""'' Potential long-term risks of PUVA On the basis of in vitro experiments and animal studies, psoralens and UVA are known to have mutagenic and carcinogenic effects.'''"'' It is to be expected that these effects are of relevance to man. Potential long-term side-effects of PUVA therapy include chronic actinic skin damage, cutaneous tumours, ocular damage and immunological alterations. It is assumed that these adverse effects depend on the total cumulative phototoxic dose received over a prolonged period of time and are probably only apparent after an extended period of latency.^"' Chronic actinic skin damage
Chronic PUVA treatment may produce changes in the skin that resemble premature ageing induced by sunlight. Both dermal and epidermal changes have been reported, but studies of chronically exposed skin have revealed contradictory results. A phenomenon described as focal epidermal dystrophy'* was reported in one study to affect 50% of patients treated for up to i
Side-effects of PUVA
119
TABLE 2. Laboratory test results from the U.S.A. i6-centre PUVA study*
Test
Positive change
No
change
Haematocrit
422
WBC
396 359
133 31 138
392 411
59 70
Bilirubin Alkaline phosphatase SGOT LDH BUN
Creatinine Uric acid
Negative change
P value (sign test)
Mean change
Side-effects of psoralen photochemotherapy (PUVA) K. WOLFF Department of Dermatology i, University of Vienna, Vienna, Austria
SUMMARY
Although psoralen photochemotherapy (PUVA) is one of the most effective forms of therapy for psoriasis, the risk of potential long-term side-effects is, as yet, not clearly determined. Chronic degenerative and pigmentary skin changes similar to those of chronic solar exposure occur after long-term PUVA treatment; PUVA also causes non-melanoma skin cancers in man, although there is, as yet, no consensus as to what cumulative phototoxic PUVA dose is carcinogenic. Long-term multicentre studies from the U.S.A. indicate a definite risk of squamous cell carcinoma for long-term PUVA-treated patients, whereas European studies reveal no overall increase in skin cancers in similar patients except for those exposed to other carcinogens. Assignment to PUVA should be based on the risk:benefit ratio for the individual patient. Careful patient selection is therefore mandatory and should be limited to those who can be monitored and controlled by informed, competent and conscientious physicians.
Psoralen photochemotherapy (PUVA)' is one of the most effective forms of therapy for psoriasis.^ It induces a complete clinical remission within a reasonably short period of time and, as maintenance therapy, can produce a remission for an extended period. In combination with retinoids,^ the clinical efficacy of PUVA is greatly improved and is likely to minimize the potential long-term side-effects. There is now considerable clinical experience regarding the short-term safety of PUVA, but the risk of potential long-term side-effects is, as yet, not clearly determined. ACUTE SIDE-EFFECTS AND TOXICITY OF PUVA
Side-effects (Table i) are related to overdosing with long-wave ultraviolet (UVA) radiation or the patient's inability to tolerate the psoralens used in the treatment. The most frequent side-effect due to overexposure is erythema.'' Pruritus is also UVA dose-related, and a few patients experience painful burning sensations in the exposed skin towards the end-phase of treatment. Correspondence: Professor K.Wolff, Department of Dermatology i. University of Vienna, Alser Strasse 4, A-1090 Wien, Austria. 117
K.Wolff TABLE I. Immediate side-effects of PUVA (n = 3175) Interruption (clearing phase)
Interruption (maintenance (phase)
(%)
(%)
6-7
135
1-7 1-4 0-6
1-5
0-3 0-4 0-3
2-0
O-I
O-I
O-I
2-0
0-2
0-5
O-I
Frequency Side-effect
(%)
Erythema Pruritus Nausea Headache Koebner reaction
32-4 25-6
D iscontinuation of PUVA (%)
2-9
Henseler et al?
Overdose phenomena usually arise in areas not normally exposed to natural sunlight. Careful observation of the criteria for dosimetry and the guidelines for treatment' will reduce these adverse events. Transient nausea is relatively common with 8-MOP (8-methoxypsoralen; methoxsalen) used as a photosensitizer,"* but occurs only rarely with 5-MOP (5-methoxypsoralen).' Only on rare occasions is the nausea so severe as to necessitate discontinuation of treatment. Other shortterm side-effects include acne-like eruptions, polymorphous light eruption-like rashes, subungual haemorrhages due to phototoxic reactions and transient hypertrichosis ofthe face.' These are all reversible and disappear on discontinuation of treatment. Laboratory data
As psoralens in excessive doses are hepatotoxic in laboratory animals, there has been concern in the past as to liver damage in humans. Laboratory examinations performed over many years have not revealed evidence of impaired hepatic function and, although a slight increase in blood urea nitrogen (BUN) and creatinine has been docvimented in one series, there is no evidence to suggest impairment ofrenal function in large-scale studies.*'' Analysis ofthe laboratory data from several studies has not revealed significant abnormal findings in those patients who have received PUVA over a prolonged period of time (Table 2). One study reported an increased incidence of antinuclear antibodies in PUVA-treated patients,'" but other studies have shown no such relationships.""'' Potential long-term risks of PUVA On the basis of in vitro experiments and animal studies, psoralens and UVA are known to have mutagenic and carcinogenic effects.'''"'' It is to be expected that these effects are of relevance to man. Potential long-term side-effects of PUVA therapy include chronic actinic skin damage, cutaneous tumours, ocular damage and immunological alterations. It is assumed that these adverse effects depend on the total cumulative phototoxic dose received over a prolonged period of time and are probably only apparent after an extended period of latency.^"' Chronic actinic skin damage
Chronic PUVA treatment may produce changes in the skin that resemble premature ageing induced by sunlight. Both dermal and epidermal changes have been reported, but studies of chronically exposed skin have revealed contradictory results. A phenomenon described as focal epidermal dystrophy'* was reported in one study to affect 50% of patients treated for up to i
Side-effects of PUVA
119
TABLE 2. Laboratory test results from the U.S.A. i6-centre PUVA study*
Test
Positive change
No
change
Haematocrit
422
WBC
396 359
133 31 138
392 411
59 70
Bilirubin Alkaline phosphatase SGOT LDH BUN
Creatinine Uric acid
Negative change
P value (sign test)
Mean change
