233

PHOTOSBNSITIVITY DUE TO CERTAIN DRUGS.*

DANILO V. STEVANOVIC, M.D., M.Sc.(Cantab.)-

Department of Dermatology, Medical Faculty, Belgrade.

T H E experimental findings in the cases reported here may help to ehicidatethe mechanism of the production of light eruptions due to drugs.

INVESTIGATION.

All tests were carried out in pairs on the back of each patient. One test area wasthen exposed to the rays of the sim twenty-four hours later (the responses arc morepronounced than with quartz lamp). Results were read daily for seven consecutivedays. The areas of positive simple tests to phcnergan (promcthazine) and largactil(chlorproniazine) were exposed after forty-eight hours. Promethazine was used as a2-5% sohition for intramuscular use and as 2% ointment. Chlorpromazine was usedin 2-5% solution for intravenous use.

Case 1.—A woman, aged 40, was given hydrocortisone and tetracyclinc ointmentand dragees of promethazine to take three times daily for lichenified eczema of theright leg. On the seventh day. after normal exposure to May sunlight, a diffuseerythema with slight oedema appeared on all exposed parts of the l^ody. The rednesssubsided after four days. A patch test with promethazine powder was then carriedout. showing after twenty-four hours strong erythema and oedema, which within thenext twenty-four hours after a casual exposure to sunlight developed into largevesicles. There was also a recurrence of the eruption at al! j^reviously affected sites.The patient was then referred to me for further investigation. Erythema again sub-sided com2:>letely within the next five days.

Skin Tests.—Patch tests with promethazine were positive only after forty-eighthours. There was intense oedema l ut no visil3le vesiculation. In ten controls theseconcentrations never produced any reaction on the skin. In addition, the patientwas tested with chlorpromazine, with sulphaiiilamide poAvder—by both patch andscratch tests, and with novocaine and j^araphenylendiamine. There was a positivereaction with vesiculation to the latter only. After the exposure to light, test reac-tions from promethazine became more oedematous, but no visible vesiculation wasseen. The surrounding area l)ecame redder. Reactions from chlor])romazine consistedof redness and swelling. Other tests were unchanged.

Histological examination.—Biopsy specimens were taken froui the areas patchtested with promethazine and chlorpromazine and subsequently exposed to lightseventy-two hours after the patch tests were performed. Spongiosis with oedemaand pcrivascular infiltration in the dermis com])osed mainly of lymphocytes wasfound in reactions to the former drug ; only perivascular infiltration with no grosschanges in the epidermis was found in the latter.

She could walk in sunshine with im])unity after a week. Three weeks later, patchtests were performed with the solution of promethazine \\\\\Q\\ had deliberately beenleft exposed to sunlight for seven days and which had turned bluish-black and alsowith the usual promethazine ointment. Both patch tests were positive and \\ereaggravated by ex])osure to light. The patient experienced irritation in the pre-viously affected sites.

* Paper read at the Fortieth Annual Meeting of the British Association of Dermatology.

234 DANILO V. STEVANOVIC

Case 2.—A Avoman, aged 41, took three tablets of sulphaguanidine in a period oftwo hours. Seven hours later hy the afternoon of a sunny day she noticed diffuseredness of the uncovered parts of both arms ; the redness of the face assumed a bat'swing distribution. The following day, after a short exposure to sunlight, the rednessbecame so intense that it necessitated a short treatment with prednisone. Aftertwo weeks she could AA'alk freely in the sun.

Ski}i tests.—Patch and scratch tests were carried out with snlphanilamide. sulpha-thiazole and sulphaguanidine, and patch tests with promethazine. chlorpromazine,novocaine and paraphenylendiamine. Only the patch and scratch tests from sulph-anilamide were positive, the latter with visible vesicles. After the light exposure, thepatch tests areas showed increased redness, oedema and vesiciilation. Patch testswith promethazine and chlorpromazine followed by exposure to light were positive,er_\^hema and oedema being visible. Others with light were negative.

Hisiological examination.—Bio])sy specimens were taken from the areas of patchtests with sulphanilamide and promethazine solution subsequently exposed to lightforty-eight hours after the performance of the test. The former showed spongiosisand intraepidermal vesiculation. In the upper corium there was a predominantlyperivascular infiltrate ; slight intercellular oedema wdth vasodilatation and mainlyperivascular infiltration composed of lymphocytes was seen in the latter.

Case 3.—A housewife aged 34 developed an erythemato-papular eruption of theuncovered parts of hands, arms and sternoclavicular triangle on the seventh day oftreatment with promethazine l>y mouth.

Skin tests.—Patch tests with promethazine and chlorpromazine, and patch andscratch tests with sulphanilamide. were negative. Patch tests "with promethazineand chlorpromazine sul)sequently exposed to light showed erythema, oedema andinfiltration. Histological examination of the area tested with promethazine exposedtwenty-four hours later to light revealed only oedema and vasodilatation with lym-phocytic infiltration in the dermis. No sjiongiosis was seen.

Case 4.—A man aged 43, a manual worker, after taking chlorpromazine tabletsfor four days noticed scattered paj^ules on the trunk, i.e. parts not exposed tosunlight.

Slcin tests.—A patch test with chlorpromazine w as positive, while that with pro-methazine w as negative. After exposure to light, the patch test with chlor|)romazineshow ed definite though only slightly increased redness ; the test wdth promethazinealso became positive.

Histological examination.^^'xo^^y specimens were taken from the chlorpromazineand promethazine test sites after seventy-two and forty-eight hours respectively.The former showed an eczematous reaction with small abortive vesicles, w hile thelatter exhibited only oedema, vasodilation and perivascular infiltration composed oflymphocytes in the dermis.

DISCUSSION.

Redness and slight oedema in the first patient were produced after an ex-posure which in normal subjects failed to produce any reaction, indicating thather minimal erythema threshold was lowered. The aggravation of the positivepatch test after the exposure could be the result of a photoallergic, or rather aphotodynamic mechanism. Spongiosis was already present in the simple testand cannot be used with certainty as evidence in favour of the photoallergicmechanism. An area patch tested with chlorpromazine and then exposed tolight showed no eczematous features histologically. Redness was more intensethan in ten controls in whom a positive reaction to patch testing followed by

PHOTOSKNSITIVITY DUE TO CERTAIN DRUGS 235

light could be also produced with the 0-5% solution for intramuscular use, pre-sumably because of the increased photosensitizing effect of chlorpromazine onskin in which the minimal erythema threshold was already lowered, in thiscase by promethazine. Thus strictly speaking, this was not a true cross photo-sensitivity between promethazine and chlorpromazine since it was not depend-ent on their structural formulae, but was merely the result of the capacity ofboth to produce photosensitization.

In Case 2, the area of patch test with sulphanilamide followed by exposureto light showed histologically an eczeniatoiis reaction, while that with pro-methazine was non-eczematous. One could speculate on a possible crossphotosensitivity between sulphanilamide and the two phenothiazine derivatives ;a reduction in the latter two could produce a primary amine which might bestructurally similar to that of sulphanilaniide. It should be mentioned alsothat in my controls, solutions of chlorpromazine and promethazine which wereexposed to sunlight and changed colour did not lose their photosensitizingproperty. Although I do not believe in such a possibility, I mention the fre-quently observed positive test to paraphenylendiamine in patients allergicto promethazine (Sidi et al., 1955). Sulphanilamide, however, applied in bothpatch and scratch tests in controls did not produce any erythema after exposure.In this case the same mechanism as in Case 1 could be equally involved.

In the third patient, simple patch tests were negative, while those to pro-methazine and chlorpromazine followed by light showed redness and swelling.As the eruption followed the ingestion of promethazine, this test area wasbiopsied, with non-eczematous histological findings. In this case, with adistribution similar to the first two cases, a different (photodynamic) mech-anism may be involved. Cross photosensitivity as the explanation of thepositive reaction to chlorpromazine and light would be illogical, since there wasno allergic sensitivity to promethazine.

In the fourth patient, the patch test to chlorpromazine was positive ; it wasaggravated after exposure. There was, however, no light eruption. The patchtest to promethazine also became positive after exposure to light. Histologically,only the former showed an eczematous reaction. Although the histologicallyeczematous reaction was aggravated by sunlight, photoallergy cannot be ac-cepted as the explanation since there was no light eruption. We must thensuppose that in this case the positive test was aggravated by the phototoxicmechanism. Considering only the positive tests to the two phenothiazinederivatives aggravated by sunlight, it cannot be said which was produced bythe photoallergic and which by the phototoxic mechanism. A positive scratchtest to sulphanilamide in a patient without a light eruption, however, is notaggravated by sunlight, neither is the same negative test in controls.

Reviewing previous " photoallergic " cases we see that both of those reportedby S. Epstein (1957, 1960) had also positive reactions to a simple patch test

236 DANILO V. STEVANOVIO

with phenergan. His first patient who was also tested with thorazine showed apositive reaction only after exposure to light ; it was explained as being dueto cross photosensitivity. The first case of Schulz et al. (1956) had also a positivereaction to a plain patch test with megaphen. i.e. chlorpromazine. In theirsecond case, which the authors thought it justifiable to include in this groupbecause the minimal erythema threshold was lowered, a simple patch test wasnegative while after light exposure it became positive. In the remaining threecases also with light eruptions, skin changes were regarded as being due tothe photodynamic effect of drug. H. J. Epstein et al. (1957) found amongseventy-two persons who were taking chlorpromazine nine with an exaggeratedresponse to the '' B " carbon arc exposure ; two patients developed increasedreactions while not taking the drug. They commented that it appeared that atleast a small percentage of patients treated with chlorpromazine would becomeabnormally sensitive to certain wavelengths in the solar spectrum.

Patients who developed photoallergic eczema after using sulphanilamideointment (Burckhardt, 194S). an oral antidiabetic drug (Burckhardt, 1957a)and a " blankophore '' (Burckhardt, 1957b), had negative reactions to simplepatch tests which became positive after exposure to light. These could be accept-ed as photoallergic. In another of my patients who developed a light eruptionafter the use of sulphanilamide the findings were similar. A simple scratchtest, however, was positive. It is known that in simple contact sensitivity tosulphanilamide, as well as photosensitivity, patch testing gives erratic results(Peterkin, 1945), which might partly account for some negative findings. Theterm " photoallergy " could be used with certainty only for those cases in whichpatch tests (and scratch tests with sulphanilamide) were negative, while patchtests followed by light slowed histologicalty an eczematous reaction. We mustaccept that ' photoallergy " can be associated with plain contact allergy. Itis, however, impossible to prove the former histologically or clinically, sincein both photoallergic and photodynamic effects the clinical picture is the same,except when it is eczematous. I also think that the minimal erythema thresholdis lowered in both mechanisms for a certain length of time, varying from caseto case ; otherwise I do not see how such erythema could be elicited after acasual exposure. Summarizing, it seems to me that most light eruptions due todrugs are due to the photodynamic mechanism, with a negative reaction to asimple patch test but a positive test after its exposure to light, showing noeczematous reaction, in an eruption localized on the exposed parts and condi-tioned by sunlight. It is independent of but can appear in association withsimple contact sensitivity. The following comments on the subject of photo-allergy may also be applied to photodynamism : " The tests with light aloneproduce an increased erythema and not an eczematous reaction ", or '* afterthe use of the drug has been discontinued the fiorid sensitivity nsnally dis-appears within a few days or weeks'' (Ippen, 1960). '* Sunlight alone has

PHOTOSENSITIVITY DUE TO CERTAIN DRUGS 237

ceased to be an aggravating factor " (Epstein, 1960). The term '' phototoxic "should be restricted to reactions to the same drugs which can be produced inall subjects. The number of patients showing light eruptions due to these drugsis surpiisingly small considering their photosensitizing properties and wide use.It may therefore be justifiable to make a distinction between phototoxic andphotodynamic properties. A photodynamic reaction is by its nature very similarto a photoallergic and in both the blood vessels probably react abnormally,but there is no eczematous reaction.

If. however, one accepts that an eczematous reaction to a patch test followedby exposure to light is not a prerequisite for the diagnosis of photoallergy. lighteruptions could then be regarded as photoallergic, photosensitivity disappearingsooner or later. If such is the case, the specificity ascribed above to photodynamicaction should go to photoallergy ; photodynamic action and photoxicity be-come synonymous.

No deflnite answer can yet be given. More experimental study is neededespecially of cases photosensitive to sulphonamides, since there is no epidermalphototoxic effect with that di'ug. The possibilities mentioned above may alsobe considered.

SUMMARY.

Three cases of light eruptions due to drugs are reported and the experimentalfindings are given. The mechanism involved in their production is discussed.

REFERENCES.

BuRCKHARDT, W. (1948) Dermatologica, Basel, 96, 280.(1957a) Ibid., 115. 747.

— • (1957b) Hautarzt, 8, 486.EPSTEIN, H . J., BRUNSTING, L . A., MAGNUS, C. and SCHWARZ, B . E . (1957) J. invest. Derm., 28.

329.EPSTEIN. S. (1960) Arch. Derm., Chicago, 81. 175.

and RowE, J. R. (1957) J . invest. Derm., 29, 319.IPPEN, H . (1960) Arch. klin. exp. Derm., 211, 261.PETERKIN, G. A . G. (1945) Brit. med. ./.. ii. 1.SCHULZ, K. H., WiSKEMANN, A. and WTTLF, K . (1956) Arch. klin. exp. Derm., 202. 285.SiDi, E., HiNCKY, M. and GERVAIS, A. (1955) J. invest. Derm., 24. 345.