Drug Safety

, Volume 23, Issue 4, pp 279–293 | Cite as

Drug-Induced Rheumatic Disorders

Incidence, Prevention and Management
  • Pascale VergneEmail author
  • Phillipe Bertin
  • Christine Bonnet
  • Claire Scotto
  • Richard Trèves
Review Article


The purpose of this article is to review the causes, the clinical manifestations and the management of the more frequent drug-induced rheumatic disorders. These include: (i) articular and periarticular manifestations induced by fluoroquinolones, nonsteroidal anti-inflammatory drugs, injections of corticosteroids, and retinoids; (ii) multisystemic manifestations such as drug-induced lupus and arthritis induced by vaccination, Bacillus Calmette-Guérin therapy and cytokines; (iii) drug-induced disorders of bone metabolism (corticosteroid-induced osteoporosis, drug-induced osteomalacia and osteonecrosis); and (iv) iatrogenic complex regional pain syndromes. Disorders caused by nonpharmacological and rarely used treatments have been deliberately excluded.

Knowledge of these drug-induced clinical symptoms or syndromes allows an earlier diagnosis and treatment, and earlier drug withdrawal if necessary. With the introduction of new medications such as the recombinant cytokines and antiretroviral treatments, the number of drug-induced rheumatic disorders is likely to increase.


Bone Mineral Density Systemic Lupus Erythematosus Complex Regional Pain Syndrome Etidronate Human Leucocyte Antigen 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    Hooper DC, Wolfson JS. Fluoroquinolone antimicrobial agents. N Engl J Med 1991; 324: 384–94PubMedCrossRefGoogle Scholar
  2. 2.
    Halkin H. Adverse effects of the fluoroquinolones. Rev Infect Dis 1988; 10Suppl. 1: S258–S261PubMedCrossRefGoogle Scholar
  3. 3.
    Arcieri G, Griffith E, Gurenwaldt G, et al. Ciprofloxacine: an update on clinical experience. Am J Med 1987; 82: 381–6PubMedGoogle Scholar
  4. 4.
    Lafon M. Tendinopathies et fluoroquinolones. Concours Med 1993; 115: 819–25Google Scholar
  5. 5.
    Lanoux P, Legin C, Reksa A, et al. Effets secondaires des fluoroquinolones. Etude rétrospective sur l’année 1992. Sem Hôp Paris 1993; 69: 1273–6Google Scholar
  6. 6.
    Gough A, Kasali O, Sigler R, et al. Quinolone arthropathy. Acute toxicity to immature articular cartilage. Toxicol Pathol 1992; 20(3): 436–50PubMedCrossRefGoogle Scholar
  7. 7.
    Pertuiset E, Lenoir G, Jehanne M, et al. Tolérance articulaire de la péfloxacine et de l’ofloxacine chez les enfants et adolescents atteints de mucoviscidose. Rev Rheum 1989; 56: 735–40Google Scholar
  8. 8.
    Stahlmann R, Förster C, Van Sickle D. Quinolones in children. Are concerns over arthropathy justified? Drug Saf 1993; 9(6): 397–403PubMedCrossRefGoogle Scholar
  9. 9.
    Chysky V, Kapila K, Hullman R. Safety of ciprofloxacin in children: world wide clinical experience based on compassionate use. Emphasis on joint evaluation. Infection 1991; 19: 329–32CrossRefGoogle Scholar
  10. 10.
    Pradhan K, Arora N, Jena A, et al. Safety of ciprofloxacin therapy in children: magnetic resonance images, body fluid levels of fluoride and linear growth. Acta Paediatr 1995; 84: 555–60PubMedCrossRefGoogle Scholar
  11. 11.
    Zabraniecki L, Negrier I, Vergne P, et al. Fluoroquinolone induced tendinopathy: report of 6 cases. J Rheumatol 1996; 23: 516–20PubMedGoogle Scholar
  12. 12.
    Chaslerie A, Bannwarth B, Landreau JM, et al. Ruptures tendineuses et fluoroquinolones: un effet indésirable de classe. Rev Rheum 1992; 59: 297–8Google Scholar
  13. 13.
    Koeger AC, Chaibi P, Roger B, et al. Apport de l’IRM dans les complications tendineuses des fluoroquinolones [abstract]. Rev Rheum 1993; 60: 752Google Scholar
  14. 14.
    Ronningen H, Langeland N. Indomethacin treatment in osteoarthritis of hip joint. Does the treatment interfere with the natural course of the disease. Acta Orthop Scand 1979; 50: 169–74PubMedCrossRefGoogle Scholar
  15. 15.
    Rashad S, Revell P, Hemingway A, et al. Effect of non steroidal anti-inflammatory drugs on the course of osteoarthritis. Lancet 1989; II: 519–22CrossRefGoogle Scholar
  16. 16.
    Watson M. Femoral-head height loss: a study of the relative significance of some of its determinants in hip degeneration. Rheumatol Rehabil 1976; 15: 264–9PubMedCrossRefGoogle Scholar
  17. 17.
    Loyau G. Anti-inflammatoires non stéroïdiens et cartilage. In: Le cartilage articulaire: dégénérescence et possibilités de réparation. Paris: MSD, Sidem, 1984: 145–60Google Scholar
  18. 18.
    Lequesne M, Ray G. La coxopathie destructrice rapide idiopathique. Etude étiologique prospective de 27 cas. Rev Rhum 1989; 56: 115–9PubMedGoogle Scholar
  19. 19.
    Brandt KD, Palmoski MJ. Effects of salicylates and other nonsteroidal anti-inflammatory drugs on articular cartilage. Am J Med 1984; 13: 65–9CrossRefGoogle Scholar
  20. 20.
    Palmoski MJ, Brandt KD. Effects of some nonsteroidal antiinflammatory drugs on proteoglycan metabolism and organization in canine articular cartilage. Arthritis Rheum 1980; 23: 1010–20PubMedCrossRefGoogle Scholar
  21. 21.
    Palmoski MJ, Brandt KD. Effects of salicylate and indomethacin on glycosaminoglycan and prostaglandin E2 synthesis in intact canine knee cartilage ex vivo. Arthritis Rheum 1984; 27: 398–403PubMedCrossRefGoogle Scholar
  22. 22.
    Del Favero A. Dangers of long-term use of NSAIDs in osteoarthritis. In: Aronson JK, Van Boxtel CJ, editors. Side effects of drugs annual. 18th ed. Amsterdam: Elsevier, 1994: 87–8Google Scholar
  23. 23.
    Ito A, Nose T, Takahashi S, et al. Cyclooxygenase inhibitors augment the production of pro-matrix metalloproteinase 9 (progelatinase B) in rabbit articular chondrocytes. FEBS Lett 1995; 360: 75–9PubMedCrossRefGoogle Scholar
  24. 24.
    Jolly W, Whittem T, Jolly A, et al. The dose-related effects of phenylbutazone and a methylprednisolone acetate formulation (Depo-medrol) on cultured explants of equine carpal articular cartilage. J Vet Pharmacol Ther 1995; 18: 429–37PubMedCrossRefGoogle Scholar
  25. 25.
    Erill S. Corticotrophins and corticosteroids. In: Aronson JK, Van Boxtel CJ, editors. Side effects of drugs annual. 18th ed. Amsterdam: Elsevier, 1994: 391Google Scholar
  26. 26.
    Parikh J, Houpt J, Jacobs S, et al. Charcot’s arthropathy of the shoulder following intraarticular corticosteroid injection. J Rheumatol 1993; 20: 885–7PubMedGoogle Scholar
  27. 27.
    Verschure PJ, Van Der Kraan PM, Vitters EL, et al. Stimulation of proteoglycan synthesis by triamcinolone acetonide and insulin-like growth factor 1 in normal and arthritic murine articular cartilage. J Rheumatol 1994; 21: 920–6PubMedGoogle Scholar
  28. 28.
    Roberts W, Babcock E, Breitbach S, et al. Corticosteroid injection in rheumatoid arthritis does not increase rate of total joint arthroplasty. J Rheumatol 1996; 23(6): 1001–4PubMedGoogle Scholar
  29. 29.
    Pelletier JP, DiBattista J, Raynauld J, et al. The in vivo effects of intraarticular corticosteroid injections on cartilage lesions, stromelysin, interleukin-1, and oncogene protein synthesis in experimental osteoarthritis. Lab Invest 1995; 72(5): 578–88PubMedGoogle Scholar
  30. 30.
    Caldwell JR. Intra-articular corticosteroids. Drugs 1996; 52(4): 507–14PubMedCrossRefGoogle Scholar
  31. 31.
    Owen DS. Aspiration and injection of joints and soft tissues. In: Kelley WN, Harris ED, Ruddy S, et al., editors. Textbook of rheumatology, 4th ed. Philadelphia: Saunders Company, 1993: 545–61Google Scholar
  32. 32.
    Kaplan G, Haettich B. Rheumatological symptoms due to retinoids. Baillière’s Clin Rheumatol 1991; 5(1): 77–97CrossRefGoogle Scholar
  33. 33.
    Frame B, Jackson CE, Reynolds WA, et al. Hypercalcemia and skeletal effects in chronic hypervitaminosis A. Ann Intern Med 1974; 80: 44PubMedGoogle Scholar
  34. 34.
    Freyria A, Ronzière M, Boutillon M, et al. Effects of retinoic acid on protein synthesis by foetal bovine chondrocytes in high-density culture: down-regulation of the glucose-regulated protein, GRP-78, and type II collagen. Biochem J 1995; 305: 391–6PubMedGoogle Scholar
  35. 35.
    Kelley WN, Schumacher HR. Gout. In: Kelley WN, Harris ED, Ruddy S, et al., editors. Textbook of rheumatology, 4th ed. Philadelphia: Saunders Company, 1993: 1291–336Google Scholar
  36. 36.
    Bannwarth B. The drug-induced rheumatisms. Rev Rheum 1996; 63(10): 639–47Google Scholar
  37. 37.
    Scott JT. Drug-induced gout. Baillieres Clin Rheumatol 1991; 5(1): 39–60PubMedCrossRefGoogle Scholar
  38. 38.
    Burack DA, Griffith BP, Thompson ME, et al. Hyperuricemia and gout among heart transplant recipients receiving cyclosporine. Am J Med 1992; 92: 141–6PubMedCrossRefGoogle Scholar
  39. 39.
    Le Goff P, Saraux A. Induced lupus. Rev Rheum 1999; 66(1): 40–5Google Scholar
  40. 40.
    Fritzler MJ. Drugs recently associated with lupus syndromes. Lupus 1994; 3: 455–9PubMedCrossRefGoogle Scholar
  41. 41.
    Yung RL, Richardson BC. Drug-induced lupus. Rheum Dis Clin North Am 1994; 20: 61–85PubMedGoogle Scholar
  42. 42.
    Burlingame RW. The clinical utility of antihistone antibodies. Autoantibodies reactive with chromatin in systemic lupus erythematosus and drug-induced lupus. Clin Lab Med 1997; 17: 367–78PubMedGoogle Scholar
  43. 43.
    Rubin RL, Bell SA, Burlingame RW. Autoantibodies associated with lupus induced by diverse drugs target a similar epitope in the (H2A-H2B)-DNA complexe. J Clin Invest 1992; 90: 165–73PubMedCrossRefGoogle Scholar
  44. 44.
    Drouvalakis KA, Buchanan RBC. Phospholipid specificity of autoimmune and drug-induced lupus anticoagulants; association of phosphatidylethanolamine reactivity with thrombosis in autoimmune disease. J Rheumatol 1998; 25: 290–5PubMedGoogle Scholar
  45. 45.
    Masson C, Chevailler A, Pascaretti C, et al. Minocycline related lupus. J Rheumatol 1996; 23: 2160–1PubMedGoogle Scholar
  46. 46.
    Yung RL, Johnson KJ, Richardson BC. New concepts in the pathogenesis of drug-induced lupus. Lab Invest 1995; 73(6): 746–59PubMedGoogle Scholar
  47. 47.
    Tingle AJ, Allen M, Petty RE, et al. Rubella-associated arthritis. 1. Comparative study of joint manifestations associated with natural rubella infection and RA 27/3 rubella immunisation. Ann Rheum Dis 1986; 45: 606–12CrossRefGoogle Scholar
  48. 48.
    Weibel RE, Benor DE. Chronic arthropathy and musculoskeletal symptoms associated with rubella vaccines. Arthritis Rheum 1996; 39(9): 1529–34PubMedCrossRefGoogle Scholar
  49. 49.
    Ray P, Black MD, Shinefield H, et al. Risk of chronic arthropathy among women after rubella vaccination. JAMA 1997; 278(7): 551–6PubMedCrossRefGoogle Scholar
  50. 50.
    Tingle AJ, Mitchell LA, Grace M, et al. Randomised double-bind placebo-controlled study on adverse effects of rubella immunisation in seronegative women. Lancet 1997; 349(3): 1277–81PubMedCrossRefGoogle Scholar
  51. 51.
    Gross K, Combe C, Kruger K, et al. Arthritis after hepatitis B vaccination: report of three cases. Scand J Rheumatol 1995; 24: 50–2PubMedCrossRefGoogle Scholar
  52. 52.
    Vautier G, Carty JE. Acute sero-positive rheumatoid arthritis occurring after hepatitis B vaccination. Br J Rheumatol 1994; 33: 991–8PubMedCrossRefGoogle Scholar
  53. 53.
    Vinceneux P, Pouchot J, Lemaitre F, et al. Vaccinations et rhumatismes. In: Kahn MF, Kuntz D, Dryll A, et al, editors. Actualités rhumatologiques. Paris: Expansion Scientifique Française, 1996: 28–44Google Scholar
  54. 54.
    Maillefert JF, Sibilia J, Toussirot E, et al. Arthropathies après vaccin contre l’hépatite B. Rev Rheum 1998; 65Suppl. 5: S246–S247Google Scholar
  55. 55.
    Pope JE, Stevens A, Howson W, et al. The development of rheumatoid arthritis after recombinant hepatitis B vaccination. J Rheumatol 1998; 25: 1687–93PubMedGoogle Scholar
  56. 56.
    Buchs N, Chevrel G, Miossec P. Bacillus Calmette-Guérin induced aseptic arthritis: an experimental model of reactive arthritis. J Rheumatol 1998; 25(9): 1662–4PubMedGoogle Scholar
  57. 57.
    Pancaldi P, Van Linthoudt D, Alborino D, et al. Reiter’s syndrome after intravesical bacillus Calmette-Guérin treatment for superficial bladder carcinoma. Br J Rheumatol 1993; 32: 1096–8PubMedCrossRefGoogle Scholar
  58. 58.
    Torisu M, Miyahara T, Shinohara N, et al. A new side effect of BCG immunotherapy: BCG-induced arthritis in man. Cancer Immunol Immunother 1978; 5: 77–83CrossRefGoogle Scholar
  59. 59.
    Pichert G, Jost LM, Zobeli L, et al. Thyroiditis after treatment with interleukin-2 and interferon alpha-2a. Br J Cancer 1990; 62: 100–4PubMedCrossRefGoogle Scholar
  60. 60.
    Rönnblom LE, Alm GV, Öberg KE. Autoimmunity after alpha-interferon therapy for malignant carcinoid tumors. Ann Intern Med 1991; 115: 178–83PubMedGoogle Scholar
  61. 61.
    Jumbou O, Berthelot JM, French N, et al. Polyarthritis during interferon alpha therapy: 3 cases and review of the literature. Eur J Dermatol 1995; 5: 581–4Google Scholar
  62. 62.
    Chazerain P, Meyer O, Ribard P. Trois cas de polyarthrite survenant au cours d’un traitement par interféron-alpha recombinant. Rev Rheum 1992; 59(5): 303–9Google Scholar
  63. 63.
    O’Connell PG, Gerber LH, DiGiovanna JJ, et al. Arthritis in patients with psoriasis treated with gamma-interferon. J Rheumatol 1992; 19: 80–2PubMedGoogle Scholar
  64. 64.
    Massarotti EM, Liu NY, Mier J, et al. Chronic inflammatory arthritis after treatment with high-dose interleukin-2 for malignancy. Am J Med 1992; 92: 693–7PubMedCrossRefGoogle Scholar
  65. 65.
    Vidarsson B, Geirsson AJ, Onundarson PT. Reactivation of rheumatoid arthritis and development of leukocytoclastic vasculitis in a patient receiving granulocyte colony-stimulating factor for Felty’s syndrome. Am J Med 1995; 98: 589–91PubMedCrossRefGoogle Scholar
  66. 66.
    De Vries EGE, Willemse PHB, Biesma B, et al. Flare-up of rheumatoid arthritis during GM-CSF treatment after chemotherapy. Lancet 1991; 338: 517–8PubMedCrossRefGoogle Scholar
  67. 67.
    Sambrook PN. Corticosteroid induced osteoporosis. J Rheumatol 1996; 23Suppl. 45: S19–S22Google Scholar
  68. 68.
    Gronowicz G, McCarthy MB. Glucocorticoids inhibit the attachment of osteoblasts to bone extracellular matrix proteins and decrease β-1 integrin levels. Endocrinology 1995; 136: 598–608PubMedCrossRefGoogle Scholar
  69. 69.
    American College of Rheumatology task force on osteoporosis guidelines. Recommendations for the prevention and treatment of glucocorticoid-induced osteoporosis. Arthritis Rheum 1996; 39 (11): 1791–801Google Scholar
  70. 70.
    Jones G, Sambrook PN. Drug-induced disorders of bone metabolism. Drug Saf 1994; 10(6): 480–9PubMedCrossRefGoogle Scholar
  71. 71.
    Cosman F, Nieves J, Herbert J, et al. High-dose glucocorticoids in multiple sclerosis patients exert direct effects on the kidney and skeleton. J Bone Miner Res 1994; 9: 1097–105PubMedCrossRefGoogle Scholar
  72. 72.
    Zaqqa D, Jackson RD. Diagnosis and treatment of glucocorticoid-induced osteoporosis. Cleve Clin J Med 1999; 66(4): 221–30PubMedGoogle Scholar
  73. 73.
    Saag KG, Emkey RD, Gruber B, et al. Alendronate for the management of glucocorticoid-induced osteoporosis: results of the multicenter U.S. study [abstract]. Arthritis Rheum 1997; 40: S136Google Scholar
  74. 74.
    Hall GM, Daniels M, Doyle DV, et al. The effect of hormone replacement therapy on bone mass in rheumatoid arthritis patients treated with or without steroids. Arthritis Rheum 1994; 37: 1499–505PubMedCrossRefGoogle Scholar
  75. 75.
    Reid IR, Wattie DJ, Evans MC, et al. Testosterone therapy in glucocorticoid-treated men. Arch Intern Med 1996; 156: 1173–7PubMedCrossRefGoogle Scholar
  76. 76.
    Lems WF, Jacobs JW, Bijlsma JW, et al. Is addition of sodium fluoride to cyclical etidronate beneficial in the treatment of corticosteroid-induced osteoporosis? Ann Rheum Dis 1997; 56: 357–63PubMedCrossRefGoogle Scholar
  77. 77.
    Rizzoli R, Chevalley T, Slosman DO, et al. Sodium monofluorophosphate increases vertebral bone mineral density in patients with corticosteroid-induced osteoporosis. Osteoporos Int 1995; 5: 39–46PubMedCrossRefGoogle Scholar
  78. 78.
    Adachi JD, Bensen WG, Brown J, et al. Intermittent etidronate therapy to prevent corticosteroid-induced osteoporosis. N Engl J Med 1997; 337: 382–7PubMedCrossRefGoogle Scholar
  79. 79.
    Cortet B, Hachulla E, Barton I, et al. Evaluation of the efficacy of etidronate therapy in preventing glucocorticoid-induced bone loss in patients with inflammatory rheumatic diseases. Rev Rheum 1999; 66(4): 214–9Google Scholar
  80. 80.
    Hahn TJ, Hendin BA, Scharp CR, et al. Serum 25-hydroxycalciferol levels and bone mass in children on chronic anticonvulsant therapy. N Engl J Med 1975; 292: 550–4CrossRefGoogle Scholar
  81. 81.
    Weinstein RS, Bryce GF, Sappington LJ, et al. Decreased serum ionized calcium and normal vitamin D metabolite levels with anticonvulsant drug treatment. J Clin Endocrinol Metab 1984; 58: 1003–9PubMedCrossRefGoogle Scholar
  82. 82.
    Perry W, Erooga MA, Brown J, et al. Calcium metabolism during rifampicine and isoniazid therapy for tuberculosis. J R Soc Med 1982; 75: 533–6PubMedGoogle Scholar
  83. 83.
    Woodson GC. An interesting case of osteomalacia due to antacid use associated with stainable bone aluminiumin a patient with normal renal function. Bone 1998; 22: 695–8PubMedCrossRefGoogle Scholar
  84. 84.
    Jowsey J, Riggs BL, Kelly PJ, et al. The treatment of osteoporosis with disodium ethane-1-hydroxy-1, 1-diphosphonate. J Lab Clin Med 1971; 78: 574–84PubMedGoogle Scholar
  85. 85.
    Boyce BF, Smith L, Fogelman I, et al. Focal osteomalacia due to low dose diphosphonate therapy in Paget’s disease. Lancet 1984; I: 821–4CrossRefGoogle Scholar
  86. 86.
    Miller P, Watts NB, Licata AA, et al. Cyclic etidronate in the treatment of postmenopausal osteoporosis: efficacy and safety after seven years of treatment. Am J Med 1997; 103: 468–76PubMedCrossRefGoogle Scholar
  87. 87.
    Fleisch H. Bisphosphonates: mechanisms of action. Endocrin Rev 1998; 19: 80–100CrossRefGoogle Scholar
  88. 88.
    Schnitzler CM, Solomon L. Histomorphometric analysis of a calcaneal stress fracture: a possible complication of fluoride therapy for osteoporosis. Bone 1986; 7: 193–8PubMedCrossRefGoogle Scholar
  89. 89.
    Steinberg ME, Steinberg DR. Osteonecrosis. In: Kelley WN, Harris ED, Ruddy S, et al., editors. Textbook of rheumatology, 4th ed. Philadelphia: Saunders Company, 1993: 1628–50Google Scholar
  90. 90.
    Ficat RP, Arlet J. In: Hungerford DS, editor. Ischemia and necrosis of the bone. Baltimore: Williams & Wilkins, 1980: 131–71Google Scholar
  91. 91.
    Kenzora JE, Glimcher MJ. Accumulative cell stress: the multifactorial etiology of idiopathic osteonecrosis. Orthop Clin North Am 1985; 16: 667–70Google Scholar
  92. 92.
    Cruess RL. Osteonecrosis of bone: current concepts as to etiology and pathogenesis. Clin Orthop 1978; 130: 151–5Google Scholar
  93. 93.
    Good AE, Green RA, Zarafonetis CJ. Rheumatic symptoms during tuberculosis therapy. Ann Intern Med 1965; 63: 800–7PubMedGoogle Scholar
  94. 94.
    Lequesne M, Moghtader R. L’algodystrophie de l’isoniazide et de l’éthionamide. Rev Rheum 1966; 33: 727–34Google Scholar
  95. 95.
    Zabraniecki L, Doub A, Mularczyk M, et al. Frozen shoulder: a new delayed complication of protease inhibitors therapy. Rev Rheum 1998; 65: 72–4Google Scholar
  96. 96.
    Léone J, Béguinot I, Dehlinger V, et al. Adhesive capsulitis of the shoulder induced by protease inhibitor therapy. Three new cases. Rev Rheum 1998; 65: 800–1Google Scholar

Copyright information

© Adis International Limited 2000

Authors and Affiliations

  • Pascale Vergne
    • 1
    Email author
  • Phillipe Bertin
    • 1
  • Christine Bonnet
    • 1
  • Claire Scotto
    • 1
  • Richard Trèves
    • 1
  1. 1.Department of RheumatologyCHU DupuytrenLimoges CedexFrance

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