LEUKOPENIA, A COMPLICATION OF CHLOROMYCETIN THERAPY OF CHRONIC DISCOID LUPUS

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1 LEUKOPENIA, A COMPLICATION OF CHLOROMYCETIN THERAPY OF CHRONIC DISCOID LUPUS ERYTHEMATOSUS * HARRY M. ROBINSON, JR., M.D., ISRAEL ZELIGMAN, M.D., ALBERT SHAPIRO, M.D., AND MORRIS M. COHEN, M.D. Chioromycetin has recently been administered in the treatment of different types of lupus erythematosus. H. M. Robinson, Sr. (1) treated thirteen patients with the chronic discoid type; of these, five completely cleared, six improved, one showed no improvement, and one developed acute disseminated lupus erythematosus. Johnson, et al., (2) treated three cases of systemic lupus erythematosus without benefit. Hopkins (3) presented a case of subacute disseminated lupus erythematosus who had been treated with chloromycetin; the patient's temperature was normal thirteen days following the institution of treatment and the eruption faded. Cormia (4) stated that he had studied a patient with subacute lupus erythematosus who had been aggravated by chlorampheaicol. We have recently been studying the effects of chloromycetin therapy on many dermatoses, and in the course of our investigation have treated fourteen patients who had chronic discoid lupus erythematosus. We have noted the appearance of leukopenia as a complication of therapy in four of these individuals. Blood counts were performed at periodic intervals prior to and following the institution of therapy. All the patients hut one received an initial dose of two grams of chloromycetin, followed by 0.5 grams four times daily. The remaining patient received a dose of one gram, followed by 0.5 grams, every six hours. The following are case reports of the four patients who developed leukopenia while under treatment for chronic discoid lupus erythematosus with chloromycetin. CASE REPORTS Case 1: H. H., a 38 year old white female was first seen at the Skin Clinic of the University Hospital on June 7, A clinical diagnosis of chronic lupus erythematosus was made and confirmed by biopsy. No improvement was observed following therapy with injections of bismuth subsalicylate. Examination on January 4, 1951 disclosed an crythematous plaque measuring 1.5 cm. in diameter on the right cheek. Several similar but smaller lesions were present on both cheeks. The blood count was as follows: hemoglobin 14.3 grams 99%, red blood cells 4,850,000, white blood cells, 5,700 with a normal differential count. Treatment with chloromycetin was begun on January 4, 1951 with an initial dose of 2 grams, followed by doses of 0.5 gm. every 6 hours. By January 26th, some decrease in erythema was noted in some of the smaller lesions. On February 3rd, the hemogram was * From the Department of Dermatology, School of Medicine, University of Maryland, Baltimore, Maryland. The Chloromycetin used in this study was furnished by Parke, Davis and Company, Detroit, Michigan. This report is part of a longterm study of the value of chloromycetin, in the treatment of dermatoses. Received for publication January 21,

2 200 THE JOURNAL OF INVESTIGATIVE DERMATOLOGY normal, but on February 25th, the white blood cell count had decreased to 3,000 with a normal differential count. Chloromycetin was discontinued. Blood counts were taken at frequent intervals and showed a gradual return to normal. On May 14, 1951 the leukocyte count was 7,300 and the differential count normal. There were no symptoms associated with the leukopenia. I I v I 1 GaS. 2 rnni _ I Z5%2OO 20% 2O 15%l$c0 r r r $ t I 1 z Case 2: E. M., a 22 year old colored female, was first seen on January 5, 1951 at the University Hospital Skin Clinic. Admission examination revealed fifteen sharply defined, atrophic, erythematous plaques 1 to 2 cm. in diameter on both cheeks, forehead, chin and lower back. Histologic examination confirmed the clinical diagnosis of chronic discoid lupus erythematosus. Smears from the serum buff y coat were negative for the "L. E. cell." Urinalyses were negative. Treatment with chloromycetin was initiated on January 5, 1951 with a dose of 2 gms., followed by 0.5 gms. four times daily. Four days after the start of therapy with tbis drug the white blood count was 4,400. On January 34th, decreased erythema was noted but the drug was discontinued because of stomatitis, glossitis and leukopenia with neutropenia; the white blood count was 4,400 and the differential count revealed 37% neutrophiles. On January 31st, the leukocyte count was 6,700, of which 52% were neutrophiles. Chloromycetin was readministered on February 23rd, but three days later the drug was discontinued again because of recurrent glossitis. The glossitis disappeared a week later, but on March 7, 1951, the white count had decreased to 4,000 and the neutrophiles count to 37%.

3 TABLE I CASE DURA TION OF WBC AND WBC AND ACE SEX RACE DURATION CHLORO MENT CLINICAL RESPONSE TO NRUTROPNILES NEUTROPHILES WBC AND TOTAL TREAT NEOTROPDILES AFTER WITN REMARES CHLOROMYCETIN PRIOR TO DURINO MYCETIN WITH DRAWAL OF CHLORO CHLOROMYCETSN TREATMENT THERAPY MYCETIN gtns. days W 5 yrs New lesions developed. WBC 8200 WBC 7620 WBC 8040 No improvement of old lesions 2 38 F Vt 9 mos Slight improvement WBC 5700 WBC 3000 WBC 7500 Chloromycetin discontinued 3 22 F N 3 yrs Decrease in erythema N 70% N 63% N 61% because of leukopenia No origi WBC 4400 WBC 6600 Neutropenic leukopenia nal ho N 29% N 51% noted within 4 days. Cbsmogram sitis and stomatitis ap a peared 4 30 F N 5 yrs Decrease in erythema WBC 7800 WBC 6000 WBC 3800 Leukopenia following initi N 44% N 42% N 27 62% ation of therapy. Glossitis C and stomatitis appeared 5 31 F W 3 yrs More erythema WBC 6500 WBC 4700 WBC 8300 Leukocyte count returned to N 70% N 65% N 78% normal within 6 weeks after cessation of drug 6 38 M W 17 yrs Marked improvement WBC 6640 WIIC 6800 WBC M W 4 yrs No change WBC 6800 WBC 5840 WBC W 5 mos No change WBC 6400 WBC i\i W 4 mos Very slight improve WBC 5600 WBC 5800 WBC 7200 mont F W 11 mos New lesions appeared WBC 4250 WBC 4550 WBC 5600 during treatment \I W 3 yrs No change WBC 6200 WBC F W 5 yrs No change WBC 5600 WBC 6640 WBC W 3 mos New lesions appeared WBC 6440 WBC 6800 during treatment F N 1 yrs No change WBC 5500 WBC 4500 c N 55% N 60%

4 202 THE JOURNAL OF INVESTIGATIVE DERMATOLOGY The leukopenia and neutropenia were still present on the final examination May 23, The initial improvement noted when chloromyeetin was first administered was no longer present on her final examination. Case 3: L. A., a 30 year old colored female was first seen on January 10, 1951 at the University Hospital Skin Clinic. Examination revealed numerous, sharply demarcated, crythematous, telangiectatie plaques in which there was adherent scaling on the cheeks, nose and the occipitoparietal areas of the scalp. Histologic examination confirmed the clinical diagnosis of chronic discoid lupus erythematosus. Serologic tests for syphilis, urinalyses and smears from the sernm huffy coat were negative. The white blood count was 7,800 with 44% neutrophiles. On January 12, 1951 treatment with chloromycetin was initiated with a dose of 2 gms., followed by doses of 0.5 gms. four times daily. On January 22nd there was a definite decrease in the erythema of the lesions, but, because of stomatitis and glossitis, administration of chloromycetin was discontinued. On January 24th, the white blood count had decreased to 6,000 with 43% neutrophiles, while the stomatitis and glossitis had improved. By January 31st, the mouth and tongue had returned to normal. On February 15th, the leukocyte count dropped to 4,900 with 27% neutrophiles. Since then, the white blood cell count has varied from 6,200 to 4,000 and the neutrophiles from 62% to 38%. When last seen, May 15, 1951, the white blood cell count was 3,500 with 45% neutrophiles. Since March 7, 1951, six weeks after cessation of chloromycetin therapy, there has been a marked exacerbation of activity of the lesions. Case 4: L. S., a 31 year old white female was first seen at the University Hospital Skin Clinic on July 20, 1948 for an eruption present on the face for four months. A clinical diagnosis of chronid discoid lupus erythematosus was made and confirmed by biopsy. Bistrimate tablets, bismuth subsalicylate in oil intramuscularly and mixed toeopherols by mouth did not benefit the patient. On January 18, 1951 cbloromycetin therapy was initiated with a dose of 1 gram, followed by 0.5 gms. every 6 hours. At the start of treatment the white blood connt was 6,500 with 70% neutrophiles. There was an increase in erythema and edema of the lesions after 6 days of this regime and chloromycetin was discontinued. The leukoeyte connt at this time had dropped to 4,700 with 64% neutrophiles. There was a continued decrease in the white blood cell count to 4,500 on February 8th, bnt by April 5, 1951 the hemogram had returned to normal with 8,300 W.B.C. per en. mm. of which 77% were neutrophiles. In addition to the four patients who developed leukopenia while under treatment with ehloromyeetin for chronic discoid lupus erythematosus, ten other individuals with the same dermatosis were treated with this drug, but did not develop any hematopoietic abnormality. The summary of treatment and results in all fourteen patients are presented in Table I. There were seven males and seven females in the group studied. Four of the seven females developed leukopenia while under treatment, but this complication was not noted in any of the males. In two of the females who developed leukopenia, neutropenia was also noted. Glossitis and stomatitis were noted in the two patients who developed neutropenia, but these reactions subsided when the drug was discontinued. COMMENT Volini, et al. (5) reported three patients in whom hematologie abnormalities were encountered during chloromycetin therapy. Two were treated for typhoid fever and one for acute brucellosis. These three individuals developed a severe,

5 LEUKOPENIA 203 but reversible, granulopenia; examination of the bone marrow disclosed granulocyte hypoplasia with both erythroid and granulocytic maturation arrest. A significant fall in the leukocyte count which could be attributed to the diminution in the number of granulocytes could be demonstrated as early as the sixth day of therapy. Both marrow and blood changes were reversible and an immediate rise of the white blood count followed discontinuation of therapy. Gill (6) observed two children who received chloromycetin for salmonella diarrhea, both of whom developed severe neutropenia within seven and two days, respectively, following initiation of treatment. The hematologic abnormality disappeared spontaneously upon discontinuation of the drug. A fatal case of aplastic anemia following prolonged chloromycetin therapy was reported by Rich, Ritterhoff and Hoffman (7). On the other hand, Binagli, Carcassi and Pirastu (8) studied the behavior of the myelogram and the peripheral blood of two patients with brucellosis and two normal persons twentyfour hours prior to the administration of chioramphenicol and twentyfour hours after completion of treatment, and their results showed no evidence of any abnormality of the blood or bone marrow. We have administered chloromycetin orally to 500 patients during the course of our investigation of the value of this drug in dermatoses. Hemograms have been followed in 92 of these cases, but hematopoietic abnormalities have only been noted in the four patients discussed in this presentation. The leukopenia and neutropenia which developed were not dependent on the total dosage of chloromycetin administered, as we have given larger doses of this drug to many individuals without encountering any blood abnormality. One patient, a white male who has chronic discoid lupus erytliematosus (Case 6), and who is still under treatment with chloromycetin, has received a total dosage of 482 grams at the time of writing and his hemogram continues to be normal. It is interesting that in our series the only individuals who developed leukopenia while receiving chloromycetin were four out of fourteen patients treated for chronic discoid lupus erythematosus. Furthermore, this reaction occurred only in females, though not in all the females treated. The exact relationship of chronic discoid lupus erythematosus to the systemic variety is still controversial, but the leukopenia observed in the four females treated for chronic discoid lupus erythematosus and the predominance of systemic lupus erythematosus (with leukopenia as a prominent manifestation) in the female may lend credence to the possible relationship between the chronic discoid and the systemic varieties. As a nitrobensene derivative, chioromycetin is capable of producing allergic reactions and in this manner may selectively interfere with myeloid maturation. This is a possible explanation for the leukopenia and neutropenia encountered in our cases. CONCLUSION5 1. Four patients out of fourteen treated for chronic discoid lupus erythematosus with chloromycetin developed leukopenia. 2. This adverse reaction was noted in four out of seven females treated and in none of the seven males.

6 204 THE JOURNAL OF INVESTIGATIVE DERMATOLOGY 3. The white blood count has returned to normal in two of the patients when the drug was discontinued; in the other two the leukopenia has remained irreversible at the time of writing. 4. The leukopenia was not dependent on the total dosage of chloromycetin administered. 5. Of five hundred patients treated for various dermatoses with peroral chloromycetin and in eightysix of which there was an adequate hematologic followup, leukopenia was noted only in the four cases of chronic discoid lupus crythematosus. 6. Five patients showed improvement of the chronic discoid lupus erythcmatosus while under chloromycetin treatment, four developed new lesions or showed increased activity of preexisting lesions, and five remained unchanged. REFERENCES 1. RABINSON, H. M.: Chioramphenicol (Chloromycetin) in the Treatment of chronic discoid lupus erythematosus. J. Invest. Dermat. 14: , JoHNSoN, S. A. M., MEYER, 0. 0., BEOWN, J. W., AND RASMUSSEN, A. F., JR.: Failure of chloramphenicol (chloromycetin) in the treatment of three cases of lupus erythematosus disseminatus. J. Invest. Dermat. 14: , HonciNs, J. C.: Subacute disseminated lupus erythematosus: Remission after treatment with chloramphenicol. Arch. Dermat. & Syph. 63: , Coaan.&, F. E.: Discussion of Hopkins, J. C., ibid. 5. (a) V0LINI, I. F., SCHWARTZ, 5. 0., CREENSPAN, I., EHRLICH, L., CONNER, J. A., AND FELSENFELD, 0.: Hemapohtic changes during chioromycetin administration. J. Lab. & Clin. Med. 34: , (b) VOLINI, I. F., CREENSPAN, I., EHHLICH, L., CONNER, J. A., FELSENFELD, 0., AND SCHWARTZ, 5. 0.: Hemopoitic changes during administration of chloramphenicol. J. A. M. A., 142: , GILL, P. F.: Agranulocytopenis following "chloromycetin": Report of two cases. Med. J. Australia 1: , RICH, M. L., RITTERHOFF, R. J., AND HOFFMAN, R. J.: Afatal case of aplastic anaemia following chlornmphenicol (chloromycetin) therapy. Ann. Tnt. Med. 33: , BINAOLI, C., CARCASSI, V., AND PIEASTcT, C.: Central and peripheral hematological picture in normal and pathological subjects treated with high doses of synthetic chloramphenicol. Rass. Med. Sarda, Cagliari 52: 56, 1950; Abst. J. A. M. A. 146: 874, RAISTEICK, H.: Chloromycetin: Its structure and synthesis. Nature 163: