Manganese in the Therapy of Disseminated Lupus Erythematosus Bg PAULD. REDLEAF On the basis of a reported relationship between manganese depletion and the hydralazine syndrome, the possible therapeutic role of this metal in systemic lupus erythematosus was studied. hlanganese glycerophosphate was administered to six patients with the latter disease without favorable effects, suggesting that the hydralazine syndrome and systemic lupus erythematosus have different pathogenic mechanisms. Super le base del reportate relation inter le depletion de manganese e le syndrome de hydralazina, le possibile rolo therapeutic de iste metallo in systemic lupus erythematose esseva studiate. Glvcerophosphato de manganese esseva administrate a sex patientes con le morbo mentionate. Le absentia de effectos favorabile suggere que le syndrome de hydralazina e systemic lupus erythematose es governate per differente mechanismos pathogenic. T HE SYNDROME which sometimes develops following the use of hydralazine resembles spontaneous lupus erythematosus in many respects.’ For this reason recent studies implicating manganese depletion as an etiologic factor in hydralazine disease are of considerable interest.2 Hydralazine chelates several trace metals. When given to cockerels, perosis, a disease produced by manganese deficiency,” results. Perosis can be prevented by the simultaneous administration of manganese citrate.‘ Manganese glycerophosphate prevents the convulsions which normally follow hydralazine administration in rats,2 whereas several other trace metals are ineffective. Furthermore, the glomerular “wire-loop” lesions of hydralazine disease in dogs are prevented by the concomitant administration of manganese.‘ In human patients manganese inhibits the in vitro formation of the l u p s erythematosus cell; in contrast, copper, cobalt, zinc and iron do not show this effecte2 Finally, symptomatic benefit in two patients with spontaneous lupus erythematosus given manganous ion has been reported.’ These findings prompted the following clinical evaluation of manganese therapy in oiir patients with lupus erythematosus. METHODSAND CASESELECTION The author attempted to see all patients with lupus erythematosus on the adult medicine wards and out-patient clinics of the University of Minnesota Hospitals during the period from September, 1956 through April, 1357. All patients with the clinical diagnosis of disseminated lupus erythematosus, substantiated by positive L.E. clot preparations, were ~ ~~~ From the Department of Medicine, Uniuersity of Minnesota Hospitals, Minneapolis, Mhn. The uuthor wishes to express his nppreciution for the encouragement offered b y Dr. C . J. Watson and Dr. Louis Tobian, ns well us for the cooperution of the staff of the Department of Medicine in making the prescnt study possible. This inves$igation was undertaken during the tenure of a post-doctoral fellowship of the National Heurt Institute of the Nuticmul Institutes of Health, Public Health Seruice. 112 hfANGANESE I N DISSEMINATED LUPUS ERYTHEMATOSUS 113 included in this study. One patient died one week after hospitalization, and therapy in this case could not be evaluated. Two patients considered to have rheumatoid arthritis, despite positive clot tests,’ were not included. The small number of patients available precluded a double-blind investigation. TO enable us to include subjective responses in our evaluation, a placebo was administered initially for a period of about two weeks. Thereafter manganese glycerophosphate was given as a capsule in the suggested dose of 300 mg. three times daily after meals,’ for a period of at least seven weeks. Ambulatory patients were examined at intervals of two or three weeks, and appropriate laboratory studies, including hemoglobin determination, white blood counts and differentials, erythrocyte sedimentation rates, serum albumin and globulin, and L.E. clot tests, were obtained. Five female patients and one male patient completed the course of manganese therapy. Their ages ranged from 26 to 55 years. The disease had been present from two to nine years. Arthralgia, fever, asthenia, pleurisy or skin lesions were present in all when manganese therapy was started. Four patients were receiving prednisone or hydrocortisone, which was continued at the same dosage during the administration of manganese. RESULTS There was no evidence of benefit, either subjectively or on physical examination, as a result of manganese therapy. Erythrocyte sedimentation rates remained elevated with remarkably little fluctuation. Anemia and leukopenia, when present, persisted. Serum proteins were unchanged. L.E. clot tests remained positive in all patients throughout therapy. DISCUSSION Evaluation of therapy of a disease as uncommon as lupus erythematosus is made more difficult by the occurrence of spontaneous fluctuations or re- missions. In six consecutive patients, none the less, evidence of benefit was lacking with doses of manganese previously reported adequateS5While this may not exclude possible value in some cases, analysis of the present results reveals less than one chance in twenty that as many as 40 per cent of patients with lupus might be expected to respond. In a recent study6 manganese was found to be ineffective in the treatment of rheumatoid arthritis. The disparity between our results and those of Comens raise the possibility that the pathogenesis of spontaneous lupus erythematosus and of hydralazine disease may differ fundamentally, despite their similar clinical manifestations. SUMMARY Because of its favorable effect in hydralazine disease, manganese therapy was evaluated in six consecutive patients with disseminated lupus erythematosus. In no patient was there subjective or objective evidence of benefit. This small series was statistically adequate to assure the likelihood that a majority of patients with lupus erythematosus will not respond to manganese. Our results suggest that the pathogenetic mechanism of lupus erythematosus, which is still unknown, may differ from that of clinically similar hydralazine disease. 114 PAUL D. REDLEAF REFERENCES 1. Morrow, J. D., Schroeder, H. A. and Perry, H. M., Jr.: Studies on the control of hypertension by Hyphex. 11. Toxic reactions and side effects. Circidation 8:829, 1953. 2. Comens, P.: Manganese depletion as an etiological factor in hydralazine disease. Am. J. Med. 20:944, 1956. 3. Wilgus, H. S., Jr., Norris, L. C. and Heuser, G. F.: The role of certain inorganic elements in the cause and prevention of perosis. Science 84:252, 1936. 4. Slocumb, C. H.: Rheumatic complaints during chronic hypercortisonism and syndromes during withdrawal of cortisone in rheumatic patients. Proc. Staff Meet. Mayo Clinic 28.455, 1953. 5. Comens, P.: Personal communication. 6. Bepler, C. R. and Rogers, F. R.: A double blind study using manganese against placebo in rheumatoid arthritis. Am. J. Med. Sc. 234:459, 1957. P ~ i r D. l Redleof, M.D., Ireland Army Hospital, Fort Knox, &j.