Polymorphous Light Eruption

POLYMORPHOUS LIGHT ERUPTION THE EFFECT OF CHLOIIOQIJINE PHOSPHATE IN MODIFYING REACTIONS TO ULTRA-VIOLET LIGHT *

MILTON M. CAHN, M.D., EDWIN J. LEVY, M.D. AND BERTRAM SHAFFER, M.D.

The clinical use of chioroquine phosphate (7-chloro-4(4-diethylamino-1 methyl-

butylamino) Quinoline), for the suppression of polymorphous light eruptions has been noted in a previous publication (1). The mode of action of chioroquine in producing this effect is not known. It has been suggested that chloroquine might act as a blocking or filtering agent for ultraviolet light. Therefore, this study was undertaken to determine the effect of chloroquine phosphate on the minimal erythema dose of hot quartz ultraviolet light in normal individuals, and in patients with polymorphous light eruption. To probe further the mode of action of chioroquine, its effect on other types of skin reactions was studied; this included the reactions to histamine, trichophyton filtrate, and poison ivy antigen on normal skin. METHOD

Twenty-one white adults (10 men, 11 women) with a history of the papular and plaque-like type of polymorphous light eruption were included in this study. All of these patients had had excellent results with the use of chioroquine for the suppression of their eruption, but at the time of this investigation none had received chioroquine for at least 6 months. The following procedures were done on these patients and also on 21 normal white male adults who served as a control group: 1. The minimal erythema dose (m.e.d.) of ultraviolet light was determined for each individual using exposures from an Hanovia Hot Quartz ultraviolet lamp to 5 centimeter square areas on the upper back. 2. Each of the patients and controls was exposed to doses of ultraviolet light from this same lamp equivalent to 3, 4, 5, 6, 7, and 8 minimal erythema doses.

3. Chloroquine phosphate was administered to patients and controls for a

period of one month in the dosage of 500 mg. dailyfor the first week, then 250 mg.

daily for the next three weeks. They were then reexposed to the same graded doses of ultraviolet light. In addition, the following procedures were carried out on normal subjects who had no history of polymorphous light eruption: 1. One (1) drop of 1:100,000 histamine solution was tested through a needle puncture on the flexor surface of the forearm of 10 subjects. * From the Department of Dermatology (Donald M. Pillsbury, M.D., Director), University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania. This study was supported by a grant from the Smith, Kline and French Laboratories, Philadelphia. Presented at the Sixteenth Annual Meeting of The Society for Investigative Dermatology, Inc., Atlantic City, N. J., June 5, 1955. 201

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FIG. 1. (a) Typical papular eruption due to sunlight exposure in a patient with polymorphous light eruption. (b) Experimentally reproduced papular eruption in test site of same patient after exposure to 5 minimal erythema doses of hot quartz ultra violet light. Prior to chloroquine therapy. (c) Same patient after one month of chloroquine therapy. No papules are seen in test site after exposure to 5 med. 202

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2. Ten (10) known reactors by previous testing to poison ivy antigen (pentadecyl-catechol 1:1000) were patch tested to make certain they had maintained their reactivity. 3. Ten individuals who had previous positive reactions to trichophyton filtrate (1:30) were retested to ascertain reactivity. 4. Each of these 30 subjects was given chloroquine for one month (500 mg. daily for one week, and then 250 mg. daily for the next three weeks). At the end

of this time the skin tests were repeated. RESULTS

1. Prior to chloroquine therapy, the minimal erythema dose (m.e.d.) was the same in patients with polymorphous light eruption and in normal subjects. 2. After chloroquine therapy, the minimal erythema reaction was not altered either quantitatively or qualitatively in patients with polymorphous light eruption or in normal subjects.

3. Prior to the administration of chloroquine, 11 of the 21 patients with the history of polymorphous light eruption developed papules in the skin test sites which had received 5 or more m.e.d. of hot quartz ultraviolet light (Figs. la, b). 4. After the administration of chloroquine phosphate for one month none of these 21 patients developed papules in any of the areas now exposed to 5 or more m.e.d. of hot quartz ultraviolet light (Fig. ic). None of the 21 control subjects developed papules at site of exposure although all developed normal erythemic reactions.

5. No alteration in the reactions to histamine, trichophyton filtrate, or poison ivy antigen was noted in any of the normal subjects who had received chloroquine phosphate for 1 month. DISCUSSION

Papular eruptions have been reproduced experimentally in test sites in patients with the papular and plaque-like type of polymorphous light eruption by using ultraviolet light rays of wave lengths shorter than 3150 A (2, 3). These reproduced eruptions are clinically and histologically indistinguishable from the presenting eruption. This papular response is not related to the normal erythemic reaction to ultraviolet light, and 5 or more m.e.d. are required for its production. Chloroquine can suppress this papular response. A study of the ultraviolet light absorption spectrum for chloroquine (Fig. 2) shows that absorption is minimal between 2700 A and 3100 A. Chloroquine has a peak of absorption of ultraviolet light in the range between 3200 A and 3400 A. If chloroquine produced its protective effect by blocking the action of ultraviolet light it would therefore have to be in this latter range. However, the normal proteins of the skin have spectral absorption peaks at about 2800 A (3); also, the action spectrum for erythema production shows a peak at 2950 A with a sharp fall to almost zero at 3100 A (Fig. 2). There is also strong evidence that wave lengths shorter than 3100 A are responsible for the production of poly-

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\ ACTION SPECTRUM ERYTHEMA PRODUCTION

,ZVABSORPTION SPECTRUM CHLOROQUINE PHOSPHATE

3400 A 3200 R 3000 A 2800 A IFiG. 2. Solid line: represents absorption spectrum of chioroquine phosphate. 1)otted line:

represents the action spectrum for erythema production in normal human skin (after Blum).

morphous light eruption (2, 3). Thus, chioroquine does not act as a light filter by blocking those rays that produce the papular type of polymorphous light eruption; nor does it block those rays responsible for the erythema reaction. SUMMARY AND CONCLUSIONS

Chioroquine phosphate has no effect on the minimal erythema response of the

skin to hot quartz ultraviolet light either in normal individuals or in patients with the papular types of polymorphous light eruption. Chloroquine does not alter the skin response of normal individuals to histamine, trichophyton filtrate, or poison ivy antigen. Chloroquine will inhibit the papular response to hot quartz ultraviolet light in patients with polymorphous light eruption. These studies indicate that chloroquine produces its effect by modifying the reaction pattern of the patient with polymorphous light eruption in a manner which suppresses the abnormal but not the normal responses to ultraviolet light in the sunburn spectrum. REFERENCES 1. CAHN, M. M., Lzvy, E. J. AND SHAFFER, B.: The use of chloroquine diphosphate (Aralen)

and quinacrine (Atabrine) hydrochloride in the prevention of polymorphous light eruptions. J. Invest. Dermat., 22: 93—96, 1954. 2. BLUM, H. F.: Photodynamic Action and Diseases Caused by Light, American Chemical Society Monograph Series, No. 85. New York, Reinhold Publishing Corporation, 1941.

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3. CAHN, M. M., LEVY, E. J., SHArPER, B. AND BEERMAN, H.: Lupus erythematosus and

polymorphous light eruptions. An experimental study on their possible relationship. J. Invest. I)ermat., 21: 375—393, 1953.

DISCUSSION DR. LEON GOLDMAN (Cincinnati, Ohio): I would agree with Dr. Wilson that this is a fine presentation. It is the first approach, I think, in the clinical pathology, to try to determine the mechanism of the local action of chloroquine. In our assay experiments with chloroquine, we have found and still find that it collects in the skin for an appreciable time after its oral administration, but, as yet, we have no definite ideas as to the exact location in the skin or to its local enzymatic mechanism of modifying these abnormal light reactions. DR. Louis A. BRUNSTING (Rochester, Minn.): It is remarkable to be able to present such a number of patients with polymorphic light eruption and, especially, to show the results of repeated examinations. I am sure that many of such milder cases are overlooked or are classified as dermatitis venenata, lymphocytoma, or even lupus erythematosus. Ordinarily, photosensitive reactions in humans cannot be reproduced artificially except in the case of urticaria solaris. I am not convinced that the papules that have been provoked are the exact replica of the initial condition. Microscopic evidence would tend to confirm this. The role of chloroquine in controlling some forms of photosensitivity is not clearly understood. Photosensitivity in animals and in certain instances, in humans, is associated with disturbance of hepatic function. Some abnormality in the breakdown of chlorophyll products may also be concerned; this is true in photosensitive diseases in sheep. Perhaps some day it will be possible to assemble all these fragments of the puzzle to make a logical explanation. DR. STEPHEN ROTHMAN (Chicago, Ill.): Recalling the beautiful work of Dr. Beerman and associates, I would like to ask if the diagnosis of lupus erythematodes was ruled out in all these cases. I was struck with the similarity of the absorption spectrums of chloroquine and the sensitivity spectrum of our case of solar urticaria (Beal, P., J. Invest. Dermat., 11: 415, 1948). Possibly such patients could be protected with chloroquine ointments. The implication of the presenters' remarkable findings is that the action spectrum of their papular reaction is different from that of the physiological sunburn reaction. This could be proved directly by experiments with filters or with a monochromator. DR. ABRAHAM J. ORFUSS (New York, N.Y.): In a series of about eight similar

cases, where we tried to reproduce polymorphic light eruptions, using various sources of ultraviolet light, we were not able to reproduce the eruption on the test sites, in spite of the fact that we used carbon arc lamps as well as hot mercury vapor lamps. I was a little bit surprised at the ease with which these eruptions were reproduced by the presenters. The only way in which we could reproduce

the eruption was actually exposing the patient completely to ordinary sunlight. DR. SAMUEL AYRES, III (Los Angeles, Calif.): I think these very interesting experiments tend to confirm our own personal experience with chioroquine, mdi-

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eating the very broad range of entities that it affects, and suggesting there is some common denominator in its mode of action, not related solely to light sensitivity nor to allergic mechanisms. Haydu, in trying to explain this mode of action of chioroquine after observing its inhibitory effect on rheumatoid arthritis, suggested that it works by inhibiting the tissues' requirements for adenosine triphosphate. In any event, whether that is the explanation or not, it would seem to me that there is some very general action which explains its extremely broad field of usefulness. DR. MARION B. SULZBERGER (New York, N. Y.): In addition to thanking them for this really splendid clinical investigation, I would like to ask Dr. Levy

and co-workers how it was that they did not get more reaction at the sites to which they gave exposures of five times the minimal erythema dose of ultraviolet light? I would have thought that when one administers five times the minimal erythema dose to a site one would get a sharp reaction, perhaps with blistering, not merely an erythema. Such sharp reactions would of course tend to obliterate the other responses and to impair the ability to see and read the papular responses. I think that in the studies to which Dr. Orfuss referred and which were carried out at our New York Skin and Cancer Unit, we probably did not administer as much as five erythema doses of ultraviolet light to a given

site; and that might account at least in some measure, for the differences in results. DR. STEPHEN ROTHMAN (Chicago, Ill.): I do not believe that five threshold erythema doses cause blistering. There is intense erythema and edema but no blistering. DR. MILTON M. CAHN (in closing): I want to thank the discussers for the wonderful discussion and try to answer some of the questions. The mechanism of action of chloroquine is not known. Dr. Goldman inferred that it might collect in the skin, with no idea as to its location. We have not done

histochemical studies, although this has been suggested to us by Dr. Peter Flesch of our department, and we may, at some future date, go into that. To Dr. Brunsting's comments on getting these cases together—it is quite a task. We have been gathering cases over the last three or four years and fortunately keeping the patients together. We have a series of almost 40. In our article on polymorphous light eruptions we showed that the biopsy picture of the presenting eruption is similar to that of the experimentally reproduced eruption. (Cahn, M. M., Levy, E. J., Shaffer, B., & Beerman, H. Lupus Erythematosus and Polymorphous Light Eruptions. An Experimental Study on Their Possible Relationship. J. Invest. Dermat. 21: 375—396, 1953.) It may be difficult to distinguish between lupus erythematosus and polymorphous light eruption both clinically and histologically in many instances, and in some cases it resembles lymphocytoma. Chloroquine may act by inhibiting certain liver functions and actions, although we have not been able to demonstrate any alterations by the usual liver function studies. In this series lupus erythematosus was ruled out by careful

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clinical examination and appropriate laboratory studies, including the L.E. cell phenomenon. There is a similarity in the type of curve shown for the absorption spectrum of chloroquine and the action spectrum for true urticaria solare. Both curves show peaks around 3660 A—the spectrum emission of Wood's light. We have not been able to experimentally produce polymorphous light eruption using natural sunlight through window glass; we have only been able to reproduce the eruption using rays in the sunburn spectrum. It is not possible to reproduce the eruption in every case, and in only 11 of our 21 patients in this series were we able to do so. The reasons for failure are given in our paper previously quoted. We have not observed any adverse reactions after giving five to ten minimal erythema doses of ultraviolet light.

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