Skip to main content
Canadian Medical Association Journal logoLink to Canadian Medical Association Journal
. 1980 Feb 23;122(4):405–415.

Remission-inducing drugs in rheumatoid arthritis.

T P Anastassiades
PMCID: PMC1801796  PMID: 6768438

Abstract

The administration of certain drugs to patients with established rheumatoid arthritis frequently results in improvement that is slow to appear but persists for long periods, even after the drug is discontinued. The three main drugs with this effect, whose efficacy and toxicity are reviewed in this paper, are gold salts, D-penicillamine and chloroquine. The cytotoxic agents used to treat rheumatoid arthritis, which likely have nonspecific anti-inflammatory actions and have serious long-term side effects, are also briefly reviewed. A new drug, levamisole, is currently being tested in patients with rheumatoid arthritis. It is suggested that the time for considering the introduction of a remission-inducing drug in patients with progressive rheumatoid arthritis is after an adequate trial of therapy with salicylates or other nonsteroidal anti-inflammatory agents, or both, and before the oral administration of steroids. It is difficult, however, on the basis of rigorous clinical comparisons, to recommend which of the three main remission-inducing drugs should be tried first, although gold salts have been used the most. Patients who have improved with 6 months of chrysotherapy may continue treatment for at least 3 years, during which time the frequency of mucocutaneous and renal toxic effects will steadily decrease. Some aspects of the medical economics of therapy with remission-inducing drugs for rheumatoid arthritis are discussed.

Full text

PDF
406

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Anastassiades T. P. The effect of cortisone on hexosamine metabolism in the rat. Biochim Biophys Acta. 1971 Jul 20;244(1):167–177. [PubMed] [Google Scholar]
  2. Anastassiades T., Dziewiatkowski D. The effect of cortisone on the metabolism of connective tissues in the rat. J Lab Clin Med. 1970 May;75(5):826–839. [PubMed] [Google Scholar]
  3. Assem E. S., Vickers M. R. Immunological response to penicillamine in penicillin-allergic patients and in normal subjects. Postgrad Med J. 1974 Aug;50 (Suppl 2):65–71. [PubMed] [Google Scholar]
  4. Bacon P. A., Tribe C. R., Mackenzie J. C., Verrier-Jones J., Cumming R. H., Amer B. Penicillamine nephropathy in rheumatoid arthritis. A clinical, pathological and immunological study. Q J Med. 1976 Oct;45(180):661–684. [PubMed] [Google Scholar]
  5. Berglöf F. E., Berglöf K., Walz D. T. Auranofin: an oral chrysotherapeutic agent for the treatment of rheumatoid arthritis. J Rheumatol. 1978 Spring;5(1):68–74. [PubMed] [Google Scholar]
  6. Bertrand J. J., Debeyre N., Kahn M. F., Ryckewaert A. La surveillance oculaire au cours des traitements prolongés par les antimalariques de synthèse. Résultats chez 237 malades suivis en moyenne pendant 4 ans. Presse Med. 1968 Nov 23;76(45):2139–2142. [PubMed] [Google Scholar]
  7. Bluhm G. B. The treatment of rheumatoid arthritis with gold. Semin Arthritis Rheum. 1975 Nov;5(2):147–166. doi: 10.1016/0049-0172(75)90003-7. [DOI] [PubMed] [Google Scholar]
  8. Bourke B., Maini R. N., Griffits I. D., Scott J. T. Fatal marrow aplasia in patient on penicillamine. Lancet. 1976 Sep 4;1(7984):515–515. doi: 10.1016/s0140-6736(76)90804-7. [DOI] [PubMed] [Google Scholar]
  9. Brewerton D. D-Penicillamine. Br Med J. 1976 Dec 18;2(6050):1507–1507. doi: 10.1136/bmj.2.6050.1507-c. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Bucknall R. C., Dixon A St J., Glick E. N., Woodland J., Zutshi D. W. Myasthenia gravis associated with penicillamine treatment for rheumatoid arthritis. Br Med J. 1975 Mar 15;1(5958):600–602. doi: 10.1136/bmj.1.5958.600. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Burns R. P. Delayed onset of chloroquine retinopathy. N Engl J Med. 1966 Sep 29;275(13):693–696. doi: 10.1056/NEJM196609292751303. [DOI] [PubMed] [Google Scholar]
  12. Camus J. P., Crouzet J., Bach J. F., Homberg J. C. Autoantibodies in D-penicillamine treated rheumatoid arthritis. Agents Actions. 1976 Feb;6(1-3):351–354. doi: 10.1007/BF01972254. [DOI] [PubMed] [Google Scholar]
  13. Crouzet J., Camus J. P., Leca A. P., Guillien P., Lièvre J. A. Lupus induit par la D-pénicillamine au cours du traitement de la polyarthrite rhumatoïde. Deux observation et étude immunologique systématique au cours de ce traitment. Ann Med Interne (Paris) 1974 Jan;125(1):71–79. [PubMed] [Google Scholar]
  14. Currey H. L., Harris J., Mason R. M., Woodland J., Beveridge T., Roberts C. J., Vere D. W., Dixon A. S., Davies J., Owen-Smith B. Comparison of azathioprine, cyclophosphamide, and gold in treatment of rheumatoid arthritis. Br Med J. 1974 Sep 28;3(5934):763–766. doi: 10.1136/bmj.3.5934.763. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Cytotoxic drugs in treatment of nonmalignant diseases. Ann Intern Med. 1972 Apr;76(4):619–642. doi: 10.7326/0003-4819-76-4-619. [DOI] [PubMed] [Google Scholar]
  16. DALL J. L., KEANE J. A. Disturbances of pigmentation with chloroquine. Br Med J. 1959 May 30;1(5134):1387–1389. doi: 10.1136/bmj.1.5134.1387. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. DEUTSCH H. F., MORTON J. I. Dissociation of human serum macroglobulins. Science. 1957 Mar 29;125(3248):600–601. doi: 10.1126/science.125.3248.600. [DOI] [PubMed] [Google Scholar]
  18. Dahl M. G., Gregory M. M., Scheuer P. J. Liver damage due to methotrexate in patients with psoriasis. Br Med J. 1971 Mar 20;1(5750):625–630. doi: 10.1136/bmj.1.5750.625. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Desai S. N. Sudden gigantism of breasts: drug induced? Br J Plast Surg. 1973 Oct;26(4):371–372. doi: 10.1016/s0007-1226(73)90043-x. [DOI] [PubMed] [Google Scholar]
  20. Dixon A. J., Davies J., Dormandy T. L., Hamilton E. B., Holt P. J., Mason R. M., Thompson M., Weber J. C., Zutshi D. W. Synthetic D(-)penicillamine in rheumatoid arthritis. Double-blind controlled study of a high and low dosage regimen. Ann Rheum Dis. 1975 Oct;34(5):416–421. doi: 10.1136/ard.34.5.416. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Dwosh I. L., Stein H. B., Urowitz M. B., Smythe H. A., Hunter T., Ogryzlo M. A. Azathioprine in early rheumatoid arthritis. Comparison with gold and chloroquine. Arthritis Rheum. 1977 Mar;20(2):685–692. doi: 10.1002/art.1780200208. [DOI] [PubMed] [Google Scholar]
  22. Favreau M., Tannenbaum H., Lough J. Hepatic toxicity associated with gold therapy. Ann Intern Med. 1977 Dec;87(6):717–719. doi: 10.7326/0003-4819-87-6-717. [DOI] [PubMed] [Google Scholar]
  23. Folb P. I., Trounce J. R. Immunological aspects of candida infection complicating steroid and immunosuppressive drug therapy. Lancet. 1970 Nov 28;2(7683):1112–1114. doi: 10.1016/s0140-6736(70)92299-3. [DOI] [PubMed] [Google Scholar]
  24. Fraser T. N. Gold Treatment in Rheumatoid Arthritis. Ann Rheum Dis. 1945 Jun;4(4):71–75. doi: 10.1136/ard.4.4.71. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Furst D. E., Levine S., Srinivasan R., Metzger A. L., Bangert R., Paulus H. E. A double-blind trial of high versus conventional dosages of gold salts for rheumatoid arthritis. Arthritis Rheum. 1977 Nov-Dec;20(8):1473–1480. doi: 10.1002/art.1780200805. [DOI] [PubMed] [Google Scholar]
  26. Gerber R. C., Paulus H. E., Jennrich R. I., Lederer M., Bluestone R., Blahd W. H., Pearson C. M. Gold kinetics following aurothiomalate therapy: use of a whole-body radiation counter. J Lab Clin Med. 1974 May;83(5):778–789. [PubMed] [Google Scholar]
  27. Gerster J. C., de Kalbermatten A., de Peyer R., Toussaint M., Carrel J. Réactions toxiques aux sels d'or avec entérocolite grave chez un homme atteint d'une polyarthrite rhumatoïde. Schweiz Med Wochenschr. 1976 Nov 13;106(46):1606–1608. [PubMed] [Google Scholar]
  28. Girdwood R. H. Death after taking medicaments. Br Med J. 1974 Mar 16;1(5906):501–504. doi: 10.1136/bmj.1.5906.501. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Gottlieb N. L., Smith P. M., Smith E. M. Pharmacodynamics of 197Au and 195Au labeled aurothiomalate in blood. Correlation with course of rheumatoid arthritis, gold toxicity and gold excretion. Arthritis Rheum. 1974 Mar-Apr;17(2):171–183. doi: 10.1002/art.1780170211. [DOI] [PubMed] [Google Scholar]
  30. Gould P. W., McCormack P. L., Palmer D. G. Pulmonary damage associated with sodium aurothiomalate therapy. J Rheumatol. 1977 Autumn;4(3):252–260. [PubMed] [Google Scholar]
  31. Gumpel J. M. Deaths associated with gold treatment: a reassessment. Br Med J. 1978 Jan 28;1(6107):215–216. doi: 10.1136/bmj.1.6107.215. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Halla J. T., Hardin J. G., Linn J. E. Postinjection nonvasomotor reactions during chrysotherapy. Constitutional and rheumatic symptoms following injections of gold salts. Arthritis Rheum. 1977 Jul-Aug;20(6):1188–1191. doi: 10.1002/art.1780200605. [DOI] [PubMed] [Google Scholar]
  33. Harth M., Hickey J. P., Coulter W. K., Thompson J. M., Disney T. F. Gold-induced thrombocytopenia. J Rheumatol. 1978 Summer;5(2):165–172. [PubMed] [Google Scholar]
  34. Harth M. Serum gold levels during chrysotherapy with relation to urinary and fecal excretion. Clin Pharmacol Ther. 1974 Apr;15(4):354–360. doi: 10.1002/cpt1974154354. [DOI] [PubMed] [Google Scholar]
  35. Hill H. F. Selection of patients with rheumatoid arthritis to be treated with penicillamine, and their management. Curr Med Res Opin. 1974;2(9):573–580. doi: 10.1185/03007997409115260. [DOI] [PubMed] [Google Scholar]
  36. Hobbs H. E., Eadie S. P., Somerville F. OCULAR LESIONS AFTER TREATMENT WITH CHLOROQUINE. Br J Ophthalmol. 1961 Apr;45(4):284–297. doi: 10.1136/bjo.45.4.284. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Hunter T., Urowitz M. B., Gordon D. A., Smythe H. A., Ogryzlo M. A. Azathioprine in rheumatoid arthritis: a long-term follow-up study. Arthritis Rheum. 1975 Jan-Feb;18(1):15–20. doi: 10.1002/art.1780180103. [DOI] [PubMed] [Google Scholar]
  38. Hurd E. R. Immunosuppressive and antiinflammatory properties of cyclophosphamide, azathioprine and methotrexate. Arthritis Rheum. 1973 Jan-Feb;16(1):84–88. doi: 10.1002/art.1780160114. [DOI] [PubMed] [Google Scholar]
  39. Huskisson E. C., Gibson T. J., Balme H. W., Berry H., Burry H. C., Grahame R., Hart F. D., Henderson D. R., Wojtulewski J. A. Trial comparing D-penicillamine and gold in rheumatoid arthritis. Preliminary report. Ann Rheum Dis. 1974 Nov;33(6):532–535. doi: 10.1136/ard.33.6.532. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Hutter A. M., Jr, Bauman A. W., Frank I. N. Cyclophosphamide and severe hemorrhagic cystitis. N Y State J Med. 1969 Jan 15;69(2):305–309. [PubMed] [Google Scholar]
  41. Jaffe I. A. D-penicillamine. Bull Rheum Dis. 1977;28(6):948–952. [PubMed] [Google Scholar]
  42. Jaffe I. A. The technique of penicillamine administration in rheumatoid arthritis. Arthritis Rheum. 1975 Sep-Oct;18(5):513–514. doi: 10.1002/art.1780180515. [DOI] [PubMed] [Google Scholar]
  43. Kean W. F., Anastassiades T. P. Long term chrysotherapy: incidence of toxicity and efficacy during sequential time periods. Arthritis Rheum. 1979 May;22(5):495–501. doi: 10.1002/art.1780220509. [DOI] [PubMed] [Google Scholar]
  44. LAWRENCE J. S. Prevalence of rheumatoid arthritis. Ann Rheum Dis. 1961 Mar;20:11–17. doi: 10.1136/ard.20.1.11. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Liang M. H., Fries J. F. Containing costs in chronic disease: monitoring strategies in the gold therapy of rheumatoid arthritis. J Rheumatol. 1978 Fall;5(3):241–244. [PubMed] [Google Scholar]
  46. Lidsky M. D., Sharp J. T., Billings S. Double-blind study of cyclophosphamide in rheumatoid arthritis. Arthritis Rheum. 1973 Mar-Apr;16(2):148–153. doi: 10.1002/art.1780160203. [DOI] [PubMed] [Google Scholar]
  47. Lorber A., Atkins C. J., Chang C. C., Lee Y. B., Starrs J., Bovy R. A. Monitoring serum gold values to improve chrysotherapy in rheumatoid arthritis. Ann Rheum Dis. 1973 Mar;32(2):133–139. doi: 10.1136/ard.32.2.133. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Luukkainen R., Isomäki H., Kajander A. Effect of gold treatment on the progression of erosions in RA patients. Scand J Rheumatol. 1977;6(2):123–127. doi: 10.3109/03009747709095434. [DOI] [PubMed] [Google Scholar]
  49. MARKOWITZ H. A., MCGINLEY J. M. CHLOROQUINE POISONING IN A CHILD. JAMA. 1964 Sep 21;189:950–951. doi: 10.1001/jama.1964.03070120072023. [DOI] [PubMed] [Google Scholar]
  50. Mackenzie A. H. An appraisal of chloroquine. Arthritis Rheum. 1970 May-Jun;13(3):280–291. doi: 10.1002/art.1780130310. [DOI] [PubMed] [Google Scholar]
  51. Mascarenhas B. R., Granda J. L., Freyberg R. H. Gold metabolism in patients with rheumatoid arthritis treated with gold compounds--reinvestigated. Arthritis Rheum. 1972 Jul-Aug;15(4):391–402. doi: 10.1002/art.1780150410. [DOI] [PubMed] [Google Scholar]
  52. Mason M., Currey H. L., Barnes C. G., Dunne J. F., Hazleman B. L., Strickland I. D. Azathioprine in rheumatoid arthritis. Br Med J. 1969 Feb 15;1(5641):420–422. doi: 10.1136/bmj.1.5641.420. [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. McKenzie J. M. An initial report on a double-blind trial comparing small and large doses of gold in the treatment of rheumatoid disease. Rheumatol Rehabil. 1977 May;16(2):78–82. doi: 10.1093/rheumatology/16.2.78. [DOI] [PubMed] [Google Scholar]
  54. Mery C., Delrieu F., Ghozlan R., Saporta L., Simon F., Amor B., Menkes C. J., Delbarre F. Controlled trial of D-penicillamine in rheumatoid arthritis. Dose effect and the role of zinc. Scand J Rheumatol. 1976;5(4):241–247. doi: 10.3109/03009747609099913. [DOI] [PubMed] [Google Scholar]
  55. Miller D. G. Alkylating agents and human spermatogenesis. JAMA. 1971 Sep 20;217(12):1662–1665. doi: 10.1001/jama.217.12.1662. [DOI] [PubMed] [Google Scholar]
  56. Millingen K. S., Suerth E. Peripheral neuromyopathy following chloroquine therapy. Med J Aust. 1966 May 14;1(20):840–841. doi: 10.5694/j.1326-5377.1966.tb72878.x. [DOI] [PubMed] [Google Scholar]
  57. Mjolnerod O. K., Dommerud S. A., Rasmussen K., Gjeruldsen S. T. Congenital connective-tissue defect probably due to D-penicillamine treatment in pregnancy. Lancet. 1971 Apr 3;1(7701):673–675. doi: 10.1016/s0140-6736(71)92681-x. [DOI] [PubMed] [Google Scholar]
  58. Norton W. L., Lewis D. C., Ziff M. Electron-dense deposits following injection of gold sodium thiomalate and thiomalic acid. Arthritis Rheum. 1968 Jun;11(3):436–443. doi: 10.1002/art.1780110309. [DOI] [PubMed] [Google Scholar]
  59. PAGE F. Treatment of lupus erythematosus with mepacrine. Lancet. 1951 Oct 27;2(6687):755–758. doi: 10.1016/s0140-6736(51)91643-1. [DOI] [PubMed] [Google Scholar]
  60. POPERT A. J., MEIJERS K. A., SHARP J., BIER F. Chloroquine diphosphate in rheumatoid arthritis. A controlled trial. Ann Rheum Dis. 1961 Mar;20:18–35. doi: 10.1136/ard.20.1.18. [DOI] [PMC free article] [PubMed] [Google Scholar]
  61. Pass F., Goldfischer S., Sternlieb I., Scheinberg I. H. Elastosis perforans serpiginosa during penicillamine therapy for Wilson disease. Arch Dermatol. 1973 Nov;108(5):713–715. [PubMed] [Google Scholar]
  62. Percival S. P., Behrman J. Ophthalmological safety of chloroquine. Br J Ophthalmol. 1969 Feb;53(2):101–109. doi: 10.1136/bjo.53.2.101. [DOI] [PMC free article] [PubMed] [Google Scholar]
  63. Pirofsky B., Bardana E. J., Jr Immunosuppressive therapy in rheumatic disease. Med Clin North Am. 1977 Mar;61(2):419–437. doi: 10.1016/s0025-7125(16)31342-6. [DOI] [PubMed] [Google Scholar]
  64. Proceedings of the 42nd annual meeting of the American Rheumatism Association. A section of the Arthritis Foundation. June 1 & 2, 1978. New York City. Abstracts of papers presented. Arthritis Rheum. 1978 Jun;21(5):539–606. doi: 10.1002/art.1780210508. [DOI] [PMC free article] [PubMed] [Google Scholar]
  65. Reynolds M. D. Prevalence of rheumatic diseases as causes of disability and complaints by ambulatory patients. Arthritis Rheum. 1978 Apr;21(3):377–382. doi: 10.1002/art.1780210314. [DOI] [PubMed] [Google Scholar]
  66. Rubinstein H. M., Dietz A. A. Serum gold. II. Levels in rheumatoid arthritis. Ann Rheum Dis. 1973 Mar;32(2):128–132. doi: 10.1136/ard.32.2.128. [DOI] [PMC free article] [PubMed] [Google Scholar]
  67. Scheinberg I. H., Sternlieb I. Pregnancy in penicillamine-treated patients with Wilson's disease. N Engl J Med. 1975 Dec 18;293(25):1300–1302. doi: 10.1056/NEJM197512182932507. [DOI] [PubMed] [Google Scholar]
  68. Scheinman J. I., Stamler F. W. Cyclophosphamide and fatal varicella. J Pediatr. 1969 Jan;74(1):117–119. doi: 10.1016/s0022-3476(69)80018-1. [DOI] [PubMed] [Google Scholar]
  69. Schraeder P. L., Peters H. A., Dahl D. S. Polymyositis and penicillamine. Arch Neurol. 1972 Nov;27(5):456–457. doi: 10.1001/archneur.1972.00490170088013. [DOI] [PubMed] [Google Scholar]
  70. Schuermans Y. Letter: Levamisole in rheumatoid arthritis. Lancet. 1975 Jan 11;1(7898):111–111. doi: 10.1016/s0140-6736(75)91127-7. [DOI] [PubMed] [Google Scholar]
  71. Seidenfeld A. M., Smythe H. A., Ogryzlo M. A., Urowitz M. B., Dotten D. A. Acute leukemia in rheumatoid arthritis treated with cytotoxic agents. J Rheumatol. 1976 Sep;3(3):295–304. [PubMed] [Google Scholar]
  72. Sigler J. W., Bluhm G. B., Duncan H., Sharp J. T., Ensign D. C., McCrum W. R. Gold salts in the treatment of rheumatoid arthritis. A double-blind study. Ann Intern Med. 1974 Jan;80(1):21–26. doi: 10.7326/0003-4819-80-1-21. [DOI] [PubMed] [Google Scholar]
  73. Silvergleid A. J., Schrier S. L. Acute myelogenous leukemia in two patients treated with azathioprine for nonmalignant diseases. Am J Med. 1974 Dec;57(6):885–888. doi: 10.1016/0002-9343(74)90165-x. [DOI] [PubMed] [Google Scholar]
  74. Sternlieb I., Bennett B., Scheinberg I. H. D-penicillamine induced Goodpasture's syndrome in Wilson's disease. Ann Intern Med. 1975 May;82(5):673–676. doi: 10.7326/0003-4819-82-5-673. [DOI] [PubMed] [Google Scholar]
  75. Stevens J. E., Willoughby D. A. The anti-inflammatory effect of some immunosuppressive agents. J Pathol. 1969 Feb;97(2):367–373. doi: 10.1002/path.1710970223. [DOI] [PubMed] [Google Scholar]
  76. Tsang I. K., Patterson C. A., Stein H. B., Robinson H. S., Ford D. K. D-penicillamine in the treatment of rheumatoid arthritis. Arthritis Rheum. 1977 Mar;20(2):666–670. doi: 10.1002/art.1780200205. [DOI] [PubMed] [Google Scholar]
  77. WALSHE J. M. Disturbances of aminoacid metabolism following liver injury; a study by means of paper chromatography. Q J Med. 1953 Oct;22(88):483–505. [PubMed] [Google Scholar]
  78. Waine H., Baker F., Mettier S. R. CONTROLLED EVALUATION OF GOLD THERAPY IN RHEUMATOID ARTHRITIS. Calif Med. 1947 May;66(5):295–296. [PMC free article] [PubMed] [Google Scholar]
  79. Weiss A. S., Markenson J. A., Weiss M. S., Kammerer W. H. Toxicity of D-penicillamine in rheumatoid arthritis. A report of 63 patients including two with aplastic anemia and one with the nephrotic syndrome. Am J Med. 1978 Jan;64(1):114–120. doi: 10.1016/0002-9343(78)90186-9. [DOI] [PubMed] [Google Scholar]

Articles from Canadian Medical Association Journal are provided here courtesy of Canadian Medical Association

RESOURCES