LIGHT SENSITIVE ERUPTIONS TREATED WITH ATABRINE AND CHLOROQUINE JOHN M. KNOX, M.D.,JOHNH. LAMB,Ml)., BEDFORDSHELMIRE, M.D.,AND ROBERT J. MORGAN, M.D. In April 1951 a 50-year-old female, a Red Cross worker recently returned from India, came to one of us (J. M. K.) at Keesler Air Force Base, Biloxi, Mississippi. While in India she had taken atabrine for its antimalarial action. During the period that her skin was yellowed by atabrine pigmentation she had noticed a conspicuous decrease in the severity of a long-standing light-sensitive eruption, prurigo aestivale. The annoying disease was beginning to reappear arid she preferred a return of the yellow discoloration to the eruption. Her response tG atabrine was so noteworthy that later a man 28 years of age with a plaque-like, light-sensitive eruption of the face was given a similar therapeutic trial with the same success. The improvement noted in these two cases, plus the appearance of reports by Page (la) and others (ib, c, d) on atabrine in discoid lupus erythematosus encouraged a clinical evaluation of this drug for the treatment of light-sensitive eruptions. Black (2), in a report of the use of mepacrine in lupus erythematosus, tested four patients with actinic dermatitis with this preparation. No description of the types of dermatitis was recorded. Two female patients were cleared; they had had the disease each summer for 11 and 30 years respectively. The condition of the other two patients (who were males) was unaltered by this drug.
DISCUSSION Figure 1 gives a summary of the 18 cases of various types of solar dermatitis. The dosage varied among the various investigators reporting, however, all seemed to achieve the same results. The longest periods of treatment so far on two cases were for 2 consecutive summers, a total of 9 months and 7 months respectively. The drug was taken in three instances to ameliorate the "summer flare" commonly seen in all cases of light sensitivity. The majority of the cases were treated iii the spring and summer of 1953. No reactions were noted in this series. However, since this group was collected, in one case of prurigo aestivalis of 30 years' duration the drug was discontinued because of "chills" and a feeling of being warm although no fever was recorded. The results of the use of these drugs have been very encouraging with no failures as yet. Case no. 4 (L. G.), whose full history was reported in a previous publication (3), had been on continuous hormone therapy, plus applying a light-screening ointment (Neo-Afil) ,*for 19 months with only 30 % improvement. His clearing with atabrine has been the most gratifying of all of the cases and is worth special mention.
*Neo-Afil—aproduct of the Texas Pharmacal Company, San Antonio, Texas is an oint- ment base with menthyl-anthranolate as the screening agent. Received for publication August 24, 1953. 11 FIGURE 1 Chart showing summary of 13 cases of polymorphic light scnsitjce eruptions
NAME SEX AGE DURATION LOCATION TYPE OP EEUPTION SEVERITY PREVIOUS THERAPY DOSAGE PERIOD OP THERAPY RESULTS
Case 1 F 50 Several Loft urns, Deck Prurigo aestl- Moderate Case 1—NODE Mepacrine routino* April 1551 to 90—100% clear J. K. years rIght arm valis sept 1951 during period skin is yellowed Case 2 K 2h 3 years Face Plaque Mild Case 2—Bisulotli, sun-screen Mepacrine routine Aug. 1951 to Nov. 00—100% effective; J. K. crealo, antilliotamines 1551 loinimal skin discoloration Case 3 M 5% Slnce 2 Face, ears, neck Ilydroa vacelol- Moder- Case 3—Topical applications, Mepacrine one-halt April 1952 to Oct. 75% improved; J. K. years of & extreuuties torlue ately sulfapyridine, antillista- routine dose 1952 best his skin lsas C &J. L. age severe Inines, KS in sulfa, calcium Feb. 1953 to pres- been lactate ent Case 4 K 47 4 years Face, hands Plaqse-like and Severe Case 4—Anteron, ortone MepacrineO.lgm.t.i.d. March 1553 to 90% clear J. L. verrucoas 33 days, then 0.1 gm. present bid. Case 5 M 53 5 or 7 Face, ears, neck Polymorphic Modec- Case 5—None Mepacrine one 0.1 gm. May 1953 to pres- Clear—l00% 2. L. years ately tablet t.i.d. 27 days, ent severe then bid. Case 0 F 44 5 or S trms, neck Prurlgo aestl- Moderate Case 5—None Chloroquine 0.25 gm. May 1953 to pres- Clear—l00% 2. L. & years valls t.i.d. 1 weok, then ent P 2. K. 0,25 gm. hid. Case 7 F 35 3 years Face, neck, Prurigo noda Moder- Case 7—None Chloroquinet0.25 gns June 1953 to pres- 95% improved J. L. & forearsus lads ately bid. ent 2. K, severe B Case S M 09 20 years Face Plaque Moder- Case S—None Mepacrine routine 3 months Completerecov- B. S. ately ery Case S 55 00 4 months Face, hands Eceematold .Moder- Case 9—ACTH Mepacrine routine 4 months Complete recov- B. S. ately cry severe C Case 10 F 40 10 years All exposed PrIIrIgo Severe Case 10—gold Mcpacrine routine S months Completerecov- B. S. areas ery Case 51 F 20 2 months All exposed Prurigo Severe Case li—None Mepacrine routine Maximally ins- B. S. areas proved Case 12 F 20 Several .411 exposed Eczematoid Severe Case 12—Gold Mepaorine routine Improving B. 5. years areas Case 13 51 25 0 years Checks, tem- Plaque Moderate Case 33—Coldsodium tlliosul- Mopacrine .1 gm bid., Nov. 1952 to Feb. 90—03% improve. K. 51. pIes, forehead fate, chorionic gonadotropin, K 14 days, then .1 gm 1953 ment testosterone daily Case 14 K 27 4 months Pre-aural Prurigo Mild Case 14—Sun-screens, zinc ux- Mepscrine .1 gm bid., Nov. 1952 to Feb. 95% improved R. K. ide ointment X 14,then .1gm daily 1553 Case 15 K 50 1 year Both cheeks Colloid milium Moderate Case 15—Nono Mepacrine routine Month of Dec. 95% impruved R. K. as seen with 1952 light-sensi- tivity Case 18 F 7 Recurrent Nose, cheeks Plaqoo Muderate Case 16-—Kutapressin, sun- Mepacrioe .1 gm daily Dec. 1952 to Jan. Improving R. M. for 2 and chin screens, ammoniatod mer- 1951 years cory March 1951 to Apr. 1551 Case 17 F 6 2 years Face, ears and Ilydroa vaccin- Severe Case 17—Antihistamines, cur- Mcpacrioe .1 gm daily Juoe 1953 to July 100% recovery R. M. hands iforme tisone,ACTH, light-screens, 1953 dicalcium phosphate, gan- trisin, methoschol, crude liver extract, chorionic go- nsdotropin, serum globulin r12 for measles caused 58% im- prosemeof Case 18 M 26 20 years Face, ears and Verrucouo, so- Severe Case 18—Chorionie gonado- April 1953 to 100% recovery K. M. hoods br, kerotosis tropin, fl-i gr. b.i.d. cirrhosis present B-ci regimco, light-screens B the remissions. * Mepacrine routine for Shelmire's cases was 0.1 gm. t.i.d. fur 1 week, .1 gm. hid. thereafter. Knox and Lomb found .1 gm. b.i.d. necessary to maintain Chloroquine has been the preferred chenucol in all cases of lupils erythcsnotosus and light-eruptions seen by Knox and Lomb since May 1953, with a few cxrsptions. Treatment time is too short for inclusion in this series, a ccz 14 THE JOURNAL OF INvEsTIGATIvE DERMATOLOGY
Although often beneficial, previous means of treatment, including antihista- mines, topical sun-screening applications, vitamins and gold sodium thiosulfate, have been relatively unsatisfactory. The gonadotropic hormone and testosterone have been curative in many cases of those who have taken the medication for many months. Treatment is expensive and a large number of patients become discouraged because of the slowness of improvement. Response to treatment with atabrine or chloroquine has been quicker and successful in a higher per- centage of cases. To determine the permanence of the remissions, we must await time and further summers for study. Their use, though, will be well-established if they can be taken in the spring and summer of successive years just to prevent the recurrence of the eruptions. Toxic and allergic reactions from atabrine and chloroquine have been men- tioned in other reports. One danger in the use of the drugs in the hot climates in which these light eruptions are common (Texas, Oklahoma and other south- western states) is acute s\veat retention. The drug is excreted in the sweat and is known to interfere in some cases with normal sweating. Blank (4) reports, hov- ever, that in his wartime experiences those who suffered atrophy of the sweat glands and sweat retention always had an associated dermatitis. This fact makes it necessary to be alert for the appearance of any mild dermatitis, i.e., pityriasis rosea-like, seborrheic or lichenoid dermatoses, while giving these drugs.
COMMENT Sulzberger (5) suggests that "the mechanism of therapeutic action of atabrine in lupus erythematosus is still unelucidated. Is it via a local light-screening or photodynamic mechanism in the skin? Or is it based on antiplasmodial or antiprotozoal action or action against other infecting agents? Does it act through metabolic effects? Liver damage? Competition with essential enzyme or coenzyme systems? Is it conceivably a cortisone-like action, or does it produce some kind of reticuloendothelial blockade or some specific or nonspecific immunologic effect?" These same questions can be asked for action of mepacrine and chloroquine in solar dermatitis. Ginsburg and Shallenburger (6) and Kierland et al. (7) found that patients ingesting atabrine demonstrate a fluorescent phenomenon. Using fluorescence as a method of study, Hermann and Miller (8) conjectured that atabrine has had an affinity for keratinous structure. Impressively large concentrations of the drug were found in the nails, hair and horny layer of the epidermis. Excretion in the sebum, keratin and sweat was observed. Page found that the time required to administer a minimum erythema dose of ultraviolet light was increased after mepacrine had been given for 10 days and that it returned to normal 10 days after discontinuance of the drug. These two above-named phenomena seem to point to the light-screening effect as the most plausible theory of its effect on polymorphic light-sensitive eruptions; however, this may not be the only action. Other factors may be involved, i.e.: 1. Stimulation of the pigment mechanism in the skin. 2. General metabolic effect, that is, stimulus to adrenal or gonads (gonado- tropic or adrenotropic effects). LIGHT SENSITIVE ERUPTIONS 15
3. Local chemical prevention of changes in the ground substances, that is, change from collagen to collacin, a constant finding in the dermis of these cases. If light-screening is the plausible explanation of the action of these drugs in both lupus erythematosus and polymorphic light-sensitive eruptions, sunlight must have a much more profound effect on the metabolism of certain human beings than was previously suspected, and it may be a much greater etiologic factor in lupus erythematosus than was formerly thought by previous authors on this subject. However, in spite of a similarity in the effectiveness of these antimalarial drugs in both lupus erythematosus and solar dermatitis, it is still our belief that discoid lupus erythematosus and polymorphic light-sensitive eruptions, although difficult to differentiate microscopically, are distinct clinical entities. We have not yet seen a case of one disease change into the other. Chloroquine diphosphate has a somewhat similar chemical structure to mepacrine although it has one less benzene ring. Even though this chemical does not produce fluorescence as does mepacrine it appears to be equally as beneficial as atabrine in both lupus erythematosus and solar dermatitis. The amount of these agents necessary to prevent actinic dermatitis probably varies in each case and must be determined by the physician. It is hoped that small amounts or even traces may be all that are necessary in these light erup- tions. Osborne (9), in a personal communication, has observed a patient with a light-urticaria who stays clear on 3 tablets of chioroquine (750 mgm.) but, upon dropping to 2 tablets daily, begins to break out. Chloroquine may be the drug of choice in both light-sensitive dermatitis and lupus erythematosus since it is less toxic and the yellow pigmentation does not occur. Three patients with discoid lupus erythematosus who had responded well to atabrine were switched to chioroquine because they had objected somewhat to the yellowish color of the skin from atabrine. The patients after having been on chloroquine 2 tablets daily for one month developed a peculiar, tired feeling and extreme nervousness. Blood count in each case was normal and L.E. cell test was negative. X-ray examinations of the lungs showed no changes or signs of tuberculous activity. The chloroquine was discontinued and the patients' nerv- ous symptoms seem to be improved. Further reports about chloroquine will be forthcoming because it is being tried in lupus erythematosus by many dermatologists over the country. One such report by Goldman et al. (10) of its use in lupus erythematosus agrees with our above observations.
SUMMARY 1. Improvement was noted in 18 individuals with light-sensitive eruptions following systemic administration of atabrine or chloroquine. 2. As yet no explanation seems to explain all of the factors in the beneficial effect of these drugs on patients with actinic dermatitis.
REFERENCES
1. a. PAGE, F.: Treatment of lupus erythematosus with mepacrine. Lancet 261:755—758 1951. 16 THE JOURNAL OF INVESTIGATIVE DERMATOLOGY
b. SUMMERVILLE, J., DEVINE, D. C. AND LOGAN, J. C. P.: Lupus erythematosus treated with mepaerine. Brit. J. Dermat., 64: 417—419, 1952. c. CRAMER, 4. A. AND LEWIS, C. W.: Atabrine in the treatment of discoid iupus ery- thematosus. J. Invest. Dermat., 19: 393—395, 1952. d. WELLS, C. C.: Treatment of chronic discoid lupus erythematosus with atabrine. 4. Invest. Dermat., 19: 405, 1952. 2. BLACK, H.: The treatment of lupus erythematosus with mepacrine and paraaminoben- zoic acid. Brit. J. Derm., 65: 195—203, 1953. 3. MOEGAN, H. 4., SHAcKELFORD, P. 0. AND LAMB, J. H.: Unusual forms of solar dermati- tis. Arch. Derm. & Syph., 67: 369—379, 1953. 4. BLANK, H.: Discussion in Arch. Derm. and Syph., 67: 641, 1953. 5. SULZBERGRR, M.: Year Book of Dermatology & Syphilology, 92, 1952. 6. GINsBURG, J. E. AND SHALLENBURGER, P. L.: Wood's light fluorescence phenomenon in quinicrine medication. 4. A. M. A., 131: 808—809, 1946. 7. KIRELAND, H. H., SHRARD, C., MASON, H. L., AND LOBITS, W. C.: Fluorescence of nails from quinicrine hydrochloride. 4. A. M. A., 131: 809—810, 1946. 8. HERMAN, F. AND MILLRE, 0. B.: Pharmacologic and pathogenetic effects of mepacrine chloride (atabrine rN) on human skins. Aeta Dermato-Venereal, 32: 304—332, 1952. 9. OSBORNE, EARL D.: Personal communication. Buffalo, New York. 10. GOLDMAN, LEON, COLE, D. P. AND PRESTON, H. H.: Chloroquine diphosphate in treat- ment of discoid lupus erythematosus. J. A. M. A., 152: 1428—1429, 1953.