369 LEVAMISOLE IN RHEUMATOID ARTHRITIS

SIR,-Conflicting results have been reported in the use of levamisole in rheumatoid arthritis.’2 K’ass et al.reported promising results in the treatment of juvenile rheumatoid arthritis by immunopotentiation with transfer factor, and it is possible that levamisole’s effects in rheumatoid arthritis may also be explained by its immune-stimulating action. Castor and we have shown that hyaluronic acid production by human synovial cells in culture may be used as a sensitive measure of inflammatory responses: addition of inflammatory cells (leucocytes) to fibroblast cultures induced a significant increase of hyaluronic-acid production by the fibroblasts.4 Antiinflammatory drugs decreased hyaluronic-acid production by fibroblast cultures and inhibited overproduction induced by addition of leucocytes.5 We have now studied the effect of levamisole on hyaluronicacid production by cultured synovial cells (see table): addition EFFECT OF LEVAMISOLE ON HYALURONIC-ACID PRODUCED BY CULTURED

HUMAN SYNOVIAL FIBROBLASTS

proposed oral doses, an appropriate concentration of levamisole in the synovial membrane is reached only after a period of accumulation, and its clinical effect may therefore be delayed. Arthritis Research Unit, Departments of Physical Medicine, Rheumatology, and Chemical Pathology, Rockah (Hadassah) and Ichilov Hospitals, and Tel-Aviv University Medical School, Israel.

M. YARON I. YARON M. HERZBERG

LEUCOCYTOTOXIC EFFECT OF LEVAMISOLE

SIR,-Levamisole, an antihelminthic drug, attracted considerable interest when its stimulatory capacity was demonstrated. 12 It is now being subjected to extensive clinical trials in a variety of disorders in which immunological impairment is postulated.3-s We should like to draw attention to a serious adverse reaction in patients on long-term levamisole. Among our 48 patients with rheumatic diseases (rheumatoid arthritis, ankylosing spondylitis, Reiter’s syndrome, psoriatic arthritis, and sarcoidosis) receiving levamisole (150 mg daily for 4 weeks and 150 mg 3 times a week thereafter) 2 patients developed severe leucopenia. Both developed leucocyteagglutinating antibodies (see table),6 which could be demonDETAILS OF PATIENTS WITH LEUCOCYTOPENIA

period of additives with the cultures was the last 2 days of a 7-day growth cycle. t Ftbroblast tnoculum=0.5xx 106 cells. Individual values are the mean of several ’ "Interaction"

determinations.

oflevamisole to a "non-rheumatoid" fibroblast strain (derived from the synovium of a patient operated on for a meniscus tear), in doses of 10 Ilg, 50 Ilg, and 200 Ilglml medium, induced a dose-dependent fall in hyaluronic-acid production by cultured fibroblasts, but it had no effect on cell proliferation or appearance. Addition of leucocytes (from peripheral blood of a healthy person) to a "rheumatoid" fibroblast strain (derived from the synovium of a patient with rheumatoid arthritis), induced a 400% increase in the hyaluronic-acid synthesis. Overproduction of hyaluronic acid induced by addition of frozen/thawed leucocytes was inhibited by levamisole (200

g/mi medium). These observations suggest that the beneficial effects of levamisole in rheumatoid arthritis and other inflammatory ioint diseases may not be due only to its action on the immune system. Our results suggest that at some concentrations levamisole may inhibit pathological accumulation of hyaluronic acid in the inflamed joint, acting in the same way as anti-inflammatory drugs. It is possible that, with previously 1 Schuermans, Y. Lancet, 1975, i,

111. 2 Dinai, Y., Pras, M. ibid, 1975, ii, 556. Kass. E, Frøland, S. S., Natvig, J. B.,

Blichfeldt, P., Høyeraal, H. M. ibid. 1974, i, 627. 4 Yaron, M, Castor, C. W. Arth. Rheum. 1969, 12, 365. 5 Yaron, M., Yaron, I., Allaouf, D. Ann. rheum. Dis. 1971, 613.

strated only when patients’ serum containing levamisole was added to leucocyte suspensions from normal donors. Levamisole alone, patients’ serum alone, and normal serum to which levamisole was added did not evoke agglutination of normal

leucocytes. In view of these findings it seems that the leucocytotoxic effect of long-term administration of levamisole is due to an immunological mechanism. Whether this effect is unique for levamisole or represents a general adverse reaction of any immunostimulatory therapy is unknown. Among our patients we could not demonstrate any new formation of other autoantibodies (rheumatoid factor, antinuclear antibodies, antimitochon-

drial antibodies, antithyroid antibodies, &c.). We suggest that clinical trials of immunostimulatory agents, particularly levamisole, should be undertaken only if a very close control of the patients can be guaranteed. University of Basel, Department of Rheumatology, CH-4055 Basel, Switzerland.

1. 2. 3. 4. 5. 6.

M. ROSENTHAL U. TRABERT W. MüLLER

Renoux, G., Renoux, M. J. Immun. 1972, 109, 761. Renoux, G., Renoux, M. Infect. Immunity, 1973, 8, 544. Biniaminov, M., Ramot, B. Lancet, 1975, i, 464. Symoens, J., Brugmans, J. Br. med. J. 1974, iv, 592. Rosenthal, M., Trabert, U., Müller, W. Scand. J. Rheumatol. (in the press). Müller, W., Zäch, G. A. m Handbuch der Inneren Medizin (edited by L. Mohr and R. Staehelin). Berlin, 1974.

Letter: Levamisole in rheumatoid arthritis.

369 LEVAMISOLE IN RHEUMATOID ARTHRITIS SIR,-Conflicting results have been reported in the use of levamisole in rheumatoid arthritis.’2 K’ass et al.re...
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