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Drug-induced lupus

INTRODUCTION

Certain drugs may trigger an autoimmune response; most often, these drugs induce autoantibodies, which may occur in a significant number of patients, but most of these patients do not develop signs of an autoantibody-associated disease. In some patients, a clinical syndrome with features similar to systemic lupus erythematosus (SLE) may develop, which is termed drug-induced lupus. As examples, procainamide and anti-tumor necrosis factor (TNF) therapies often cause increased levels of antinuclear antibodies (ANA) in serum, yet few patients with these antibodies develop clinical symptoms such as rash, serositis, or arthritis suggesting drug-induced disease [1]. Drug-induced lupus has similarities to spontaneous SLE, but there are some differences in clinical and immunologic features and in the frequency of such features (table 1). (See 'Clinical manifestations' below.)

This topic will review causes, pathogenesis, clinical manifestations, diagnosis and approach to treatment of drug-induced lupus. The clinical manifestations, diagnosis, and treatment of idiopathic SLE in adults and in children are presented elsewhere. (See "Overview of the clinical manifestations of systemic lupus erythematosus in adults" and "Diagnosis and differential diagnosis of systemic lupus erythematosus in adults" and "Overview of the therapy and prognosis of systemic lupus erythematosus in adults" and "Systemic lupus erythematosus in children".)

EPIDEMIOLOGY

The demographic characteristics of drug-induced lupus largely depend upon the populations most likely to receive the relevant drugs. There are an estimated 15,000 to 30,000 cases of drug-induced lupus per year in the United States [2]. It is generally equally common in males and females, and more common in older people and white populations [2,3]. An exception is minocycline-induced lupus, which is mostly observed in young women treated for acne.

The risk for developing drug-induced lupus varies substantially between different medications, ranging from 15 to 20 percent of those taking procainamide, and 7 to 13 percent of those taking hydralazine, to as low as 2 per 1000 for those taking anti-tumor necrosis factor (TNF) agent, and 5 per 10,000 of those taking minocycline [2]. However, the relative incidence of drug-induced lupus from each of these agents will depend upon the extent to which they are prescribed; thus, procainamide- and hydralazine-induced lupus are relatively uncommon in clinical practice, given the infrequent use of these medications.

PATHOGENESIS

The mechanism or mechanisms involved in drug-induced lupus remain uncertain. However, various theories have been developed regarding the pathogenesis of drug-induced lupus [4]. Inherited differences in drug metabolism (eg, acetylator status) and immunogenetic characteristics are genetic factors that may influence the risk of developing disease. Potential disease mechanisms include:

                    

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Literature review current through: Jul 2014. | This topic last updated: Oct 18, 2013.
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References
Top
  1. Olsen NJ. Drug-induced autoimmunity. Best Pract Res Clin Rheumatol 2004; 18:677.
  2. Borchers AT, Keen CL, Gershwin ME. Drug-induced lupus. Ann N Y Acad Sci 2007; 1108:166.
  3. Vasoo S. Drug-induced lupus: an update. Lupus 2006; 15:757.
  4. Rubin RL. Drug-induced lupus. Toxicology 2005; 209:135.
  5. Yung R, Richardson B. Drug-induced rheumatic syndromes. Bull Rheum Dis 2002; 51:1.
  6. Cameron HA, Ramsay LE. The lupus syndrome induced by hydralazine: a common complication with low dose treatment. Br Med J (Clin Res Ed) 1984; 289:410.
  7. Batchelor JR, Welsh KI, Tinoco RM, et al. Hydralazine-induced systemic lupus erythematosus: influence of HLA-DR and sex on susceptibility. Lancet 1980; 1:1107.
  8. Speirs C, Fielder AH, Chapel H, et al. Complement system protein C4 and susceptibility to hydralazine-induced systemic lupus erythematosus. Lancet 1989; 1:922.
  9. Jeffries M, Bruner G, Glenn S, et al. Sulpha allergy in lupus patients: a clinical perspective. Lupus 2008; 17:202.
  10. Gunnarsson I, Nordmark B, Hassan Bakri A, et al. Development of lupus-related side-effects in patients with early RA during sulphasalazine treatment-the role of IL-10 and HLA. Rheumatology (Oxford) 2000; 39:886.
  11. Adams LE, Mongey AB. Role of genetic factors in drug-related autoimmunity. Lupus 1994; 3:443.
  12. Dunphy J, Oliver M, Rands AL, et al. Antineutrophil cytoplasmic antibodies and HLA class II alleles in minocycline-induced lupus-like syndrome. Br J Dermatol 2000; 142:461.
  13. Hess E. Drug-related lupus. N Engl J Med 1988; 318:1460.
  14. Fritzler MJ. Drugs recently associated with lupus syndromes. Lupus 1994; 3:455.
  15. Grant DM, Mörike K, Eichelbaum M, Meyer UA. Acetylation pharmacogenetics. The slow acetylator phenotype is caused by decreased or absent arylamine N-acetyltransferase in human liver. J Clin Invest 1990; 85:968.
  16. Reidenberg MM, Drayer DE. Procainamide, N-acetylprocainamide, antinuclear antibody and systemic lupus erythematosus. Angiology 1986; 37:968.
  17. Stec GP, Lertora JJ, Atkinson AJ Jr, et al. Remission of procainamide-induced lupus erythematosus with N-acetylprocainamide therapy. Ann Intern Med 1979; 90:799.
  18. Reidenberg MM, Drayer DE, Lorenzo B, et al. Acetylation phenotypes and environmental chemical exposure of people with idiopathic systemic lupus erythematosus. Arthritis Rheum 1993; 36:971.
  19. Yung RL, Johnson KJ, Richardson BC. New concepts in the pathogenesis of drug-induced lupus. Lab Invest 1995; 73:746.
  20. Merola JF. Lupus-like syndromes related to drugs. In: Lupus erythematosus: Clinical evaluation and treatment, Schur PH, Massarotti E. (Eds), Springer, New York. in press.
  21. Totoritis MC, Tan EM, McNally EM, Rubin RL. Association of antibody to histone complex H2A-H2B with symptomatic procainamide-induced lupus. N Engl J Med 1988; 318:1431.
  22. Burlingame RW, Rubin RL. Drug-induced anti-histone autoantibodies display two patterns of reactivity with substructures of chromatin. J Clin Invest 1991; 88:680.
  23. Rubin RL, Bell SA, Burlingame RW. Autoantibodies associated with lupus induced by diverse drugs target a similar epitope in the (H2A-H2B)-DNA complex. J Clin Invest 1992; 90:165.
  24. Rubin RL, Burlingame RW, Arnott JE, et al. IgG but not other classes of anti-[(H2A-H2B)-DNA] is an early sign of procainamide-induced lupus. J Immunol 1995; 154:2483.
  25. Jiang X, Khursigara G, Rubin RL. Transformation of lupus-inducing drugs to cytotoxic products by activated neutrophils. Science 1994; 266:810.
  26. Yung R, Powers D, Johnson K, et al. Mechanisms of drug-induced lupus. II. T cells overexpressing lymphocyte function-associated antigen 1 become autoreactive and cause a lupuslike disease in syngeneic mice. J Clin Invest 1996; 97:2866.
  27. Lu Q, Kaplan M, Ray D, et al. Demethylation of ITGAL (CD11a) regulatory sequences in systemic lupus erythematosus. Arthritis Rheum 2002; 46:1282.
  28. Deng C, Lu Q, Zhang Z, et al. Hydralazine may induce autoimmunity by inhibiting extracellular signal-regulated kinase pathway signaling. Arthritis Rheum 2003; 48:746.
  29. McKinnon RA, Nebert DW. Possible role of cytochromes P450 in lupus erythematosus and related disorders. Lupus 1994; 3:473.
  30. Kretz-Rommel A, Duncan SR, Rubin RL. Autoimmunity caused by disruption of central T cell tolerance. A murine model of drug-induced lupus. J Clin Invest 1997; 99:1888.
  31. Kretz-Rommel A, Rubin RL. A metabolite of the lupus-inducing drug procainamide prevents anergy induction in T cell clones. J Immunol 1997; 158:4465.
  32. De Bandt M. Lessons for lupus from tumour necrosis factor blockade. Lupus 2006; 15:762.
  33. Eriksson C, Engstrand S, Sundqvist KG, Rantapää-Dahlqvist S. Autoantibody formation in patients with rheumatoid arthritis treated with anti-TNF alpha. Ann Rheum Dis 2005; 64:403.
  34. Love LA. New environmental agents associated with lupus-like disorders. Lupus 1994; 3:467.
  35. Shakoor N, Michalska M, Harris CA, Block JA. Drug-induced systemic lupus erythematosus associated with etanercept therapy. Lancet 2002; 359:579.
  36. De Rycke L, Kruithof E, Van Damme N, et al. Antinuclear antibodies following infliximab treatment in patients with rheumatoid arthritis or spondylarthropathy. Arthritis Rheum 2003; 48:1015.
  37. Ioannou Y, Isenberg DA. Current evidence for the induction of autoimmune rheumatic manifestations by cytokine therapy. Arthritis Rheum 2000; 43:1431.
  38. Crowson AN, Magro CM. Diltiazem and subacute cutaneous lupus erythematosus-like lesions. N Engl J Med 1995; 333:1429.
  39. Atzeni F, Turiel M, Capsoni F, et al. Autoimmunity and anti-TNF-alpha agents. Ann N Y Acad Sci 2005; 1051:559.
  40. Haraoui B, Keystone E. Musculoskeletal manifestations and autoimmune diseases related to new biologic agents. Curr Opin Rheumatol 2006; 18:96.
  41. De Rycke L, Baeten D, Kruithof E, et al. The effect of TNFalpha blockade on the antinuclear antibody profile in patients with chronic arthritis: biological and clinical implications. Lupus 2005; 14:931.
  42. Laversuch CJ, Collins DA, Charles PJ, Bourke BE. Sulphasalazine-induced autoimmune abnormalities in patients with rheumatic disease. Br J Rheumatol 1995; 34:435.
  43. Berning SE, Iseman MD. Rifamycin-induced lupus syndrome. Lancet 1997; 349:1521.
  44. Callen JP, Hughes AP, Kulp-Shorten C. Subacute cutaneous lupus erythematosus induced or exacerbated by terbinafine: a report of 5 cases. Arch Dermatol 2001; 137:1196.
  45. Sheikhzadeh A, Schäfer U, Schnabel A. Drug-induced lupus erythematosus by amiodarone. Arch Intern Med 2002; 162:834.
  46. Spiera RF, Berman RS, Werner AJ, Spiera H. Ticlopidine-induced lupus: a report of 4 cases. Arch Intern Med 2002; 162:2240.
  47. Chen M, Crowson AN, Woofter M, et al. Docetaxel (taxotere) induced subacute cutaneous lupus erythematosus: report of 4 cases. J Rheumatol 2004; 31:818.
  48. Mor A, Pillinger MH, Wortmann RL, Mitnick HJ. Drug-induced arthritic and connective tissue disorders. Semin Arthritis Rheum 2008; 38:249.
  49. Chang RS, Cole AJ. Lamotrigine-induced lupus-like syndrome: a case report and literature review. Am J Ther 2014; 21:e85.
  50. Grönhagen CM, Fored CM, Linder M, et al. Subacute cutaneous lupus erythematosus and its association with drugs: a population-based matched case-control study of 234 patients in Sweden. Br J Dermatol 2012; 167:296.
  51. Callen JP. Drug-induced cutaneous lupus erythematosus, a distinct syndrome that is frequently unrecognized. J Am Acad Dermatol 2001; 45:315.
  52. Srivastava M, Rencic A, Diglio G, et al. Drug-induced, Ro/SSA-positive cutaneous lupus erythematosus. Arch Dermatol 2003; 139:45.
  53. Noël B. Lupus erythematosus and other autoimmune diseases related to statin therapy: a systematic review. J Eur Acad Dermatol Venereol 2007; 21:17.
  54. Cemil BC, Atas H, Canpolat F, et al. Infliximab-induced discoid lupus erythematosus. Lupus 2013; 22:515.
  55. Yoshimasu T, Hiroi A, Uede K, Furukawa F. Discoid lupus erythematosus (DLE)-like lesion induced by uracil-tegafur (UFT). Eur J Dermatol 2001; 11:54.
  56. Shapiro KS, Pinn VW, Harrington JT, Levey AS. Immune complex glomerulonephritis in hydralazine-induced SLE. Am J Kidney Dis 1984; 3:270.
  57. Short AK, Lockwood CM. Antigen specificity in hydralazine associated ANCA positive systemic vasculitis. QJM 1995; 88:775.
  58. Gough A, Chapman S, Wagstaff K, et al. Minocycline induced autoimmune hepatitis and systemic lupus erythematosus-like syndrome. BMJ 1996; 312:169.
  59. Elkayam O, Levartovsky D, Brautbar C, et al. Clinical and immunological study of 7 patients with minocycline-induced autoimmune phenomena. Am J Med 1998; 105:484.
  60. Sturkenboom MC, Meier CR, Jick H, Stricker BH. Minocycline and lupuslike syndrome in acne patients. Arch Intern Med 1999; 159:493.
  61. Lawson TM, Amos N, Bulgen D, Williams BD. Minocycline-induced lupus: clinical features and response to rechallenge. Rheumatology (Oxford) 2001; 40:329.
  62. Margolis DJ, Hoffstad O, Bilker W. Association or lack of association between tetracycline class antibiotics used for acne vulgaris and lupus erythematosus. Br J Dermatol 2007; 157:540.
  63. Schlienger RG, Bircher AJ, Meier CR. Minocycline-induced lupus. A systematic review. Dermatology 2000; 200:223.
  64. El-Hallak M, Giani T, Yeniay BS, et al. Chronic minocycline-induced autoimmunity in children. J Pediatr 2008; 153:314.
  65. Callen JP. Drug-induced subacute cutaneous lupus erythematosus. Lupus 2010; 19:1107.
  66. Nässberger L, Johansson AC, Björck S, Sjöholm AG. Antibodies to neutrophil granulocyte myeloperoxidase and elastase: autoimmune responses in glomerulonephritis due to hydralazine treatment. J Intern Med 1991; 229:261.
  67. Cambridge G, Wallace H, Bernstein RM, Leaker B. Autoantibodies to myeloperoxidase in idiopathic and drug-induced systemic lupus erythematosus and vasculitis. Br J Rheumatol 1994; 33:109.
  68. Sen D, Isenberg DA. Antineutrophil cytoplasmic autoantibodies in systemic lupus erythematosus. Lupus 2003; 12:651.
  69. Nässberger L, Sjöholm AG, Jonsson H, et al. Autoantibodies against neutrophil cytoplasm components in systemic lupus erythematosus and in hydralazine-induced lupus. Clin Exp Immunol 1990; 81:380.
  70. Sethi S, Sahani M, Oei LS. ANCA-positive crescentic glomerulonephritis associated with minocycline therapy. Am J Kidney Dis 2003; 42:E27.
  71. Bonaci-Nikolic B, Nikolic MM, Andrejevic S, et al. Antineutrophil cytoplasmic antibody (ANCA)-associated autoimmune diseases induced by antithyroid drugs: comparison with idiopathic ANCA vasculitides. Arthritis Res Ther 2005; 7:R1072.
  72. Sarzi-Puttini P, Atzeni F, Capsoni F, et al. Drug-induced lupus erythematosus. Autoimmunity 2005; 38:507.
  73. Miller FW, Hess EV, Clauw DJ, et al. Approaches for identifying and defining environmentally associated rheumatic disorders. Arthritis Rheum 2000; 43:243.
  74. Marzano AV, Lazzari R, Polloni I, et al. Drug-induced subacute cutaneous lupus erythematosus: evidence for differences from its idiopathic counterpart. Br J Dermatol 2011; 165:335.
  75. Mongey A-B, Hess EV. Drug-induced disease. In: Systemic Lupus Erythematosus, Fifth edition, Lahita RG, Tsokos G, Buyon J, Koike T. (Eds), Academic Press, London 2011. p.599-627.