Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Syndrome and the Rheumatologist

Abstract

Purpose of the Review

The purpose of the review is to summarise the various drugs used in rheumatology practice implicated in the causation of DRESS syndrome.

Recent Findings

The most commonly reported drugs are allopurinol, sulfasalazine and minocycline, which pose a very high risk for DRESS syndrome development, followed by strontium ranelate and dapsone. Other, less commonly reported, drugs include leflunomide, hydroxychloroquine, non-steroidal anti-inflammatory drugs, febuxostat, bosentan and solcitinib. Reaction to some drugs is strongly associated with certain HLA alleles, which may be used to screen patients at risk of serious toxicity.

Summary

DRESS syndrome is a serious reaction to many drugs used in rheumatic diseases, with a potentially fatal outcome and needs to be considered in any patient started on these medications who presents with a rash, fever and eosinophilia, sometimes with internal organ involvement.

This is a preview of subscription content, log in to check access.

Fig. 1
Fig. 2

References

Papers of particular interest, published recently, have been highlighted as: •• Of major importance

  1. 1.

    Shear NH, Spielberg SP. Anticonvulsant hypersensitivity syndrome. In vitro assessment of risk. J Clin Investig. 1988;82(6):1826.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  2. 2.

    Bocquet H, Bagot M, Roujeau J. Drug-induced pseudolymphoma and drug hypersensitivity syndrome (Drug Rash with Eosinophilia and Systemic Symptoms: DRESS). In Seminars in cutaneous medicine and surgery. 1996.

  3. 3.

    Peyriere H et al. Variability in the clinical pattern of cutaneous side‐effects of drugs with systemic symptoms: does a DRESS syndrome really exist? Br J Dermatol. 2006;155(2):422–8.

    CAS  Article  PubMed  Google Scholar 

  4. 4.

    Cacoub P, et al. The DRESS syndrome: a literature review. 2011.

  5. 5.

    Fiszenson‐Albala F et al. A 6‐month prospective survey of cutaneous drug reactions in a hospital setting. Br J Dermatol. 2003;149(5):1018–22.

    Article  PubMed  Google Scholar 

  6. 6.

    Muller P et al. Drug hypersensitivity syndrome in a West‐Indian population. Eur J Dermatol. 2003;13(5):478–81.

    PubMed  Google Scholar 

  7. 7.

    •• Kardaun S et al. Drug reaction with eosinophilia and systemic symptoms (DRESS): an original multisystem adverse drug reaction. Results from the prospective RegiSCAR study. Br J Dermatol. 2013;169(5):1071–80. This is a a large multinational prospective study over a 6 year period which used a standardised scoring system.

  8. 8.

    Agier M, et al. Risk Assessment of drug‐induced DRESS syndrome: a disproportionality analysis using French Pharmacovigilance Database. Br J Dermatol. 2016.

  9. 9.

    Dalbeth N, Stamp L. Allopurinol dosing in renal impairment: walking the tightrope between adequate urate lowering and adverse events. In Seminars in dialysis. Wiley Online Library; 2007.

  10. 10.

    Kinyó Á et al. Allopurinol is the most common cause of DRESS syndrome in Hungarian patients. Clin Translat Allergy. 2014;4(3):1.

    Google Scholar 

  11. 11.

    Funck-Brentano E et al. Therapeutic management of DRESS: a retrospective study of 38 cases. J Am Acad Dermatol. 2015;72(2):246–52.

    Article  Google Scholar 

  12. 12.

    Lin I-C et al. Liver injury in patients with DRESS: a clinical study of 72 cases. J Am Acad Dermatol. 2015;72(6):984–91.

    Article  PubMed  Google Scholar 

  13. 13.

    Ortonne N et al. Histopathology of drug rash with eosinophilia and systemic symptoms syndrome: a morphological and phenotypical study. Br J Dermatol. 2015;173(1):50–8.

    CAS  Article  PubMed  Google Scholar 

  14. 14.

    Renda F et al. Drug reaction with eosinophilia and systemic symptoms (DRESS): a national analysis of data from 10-year post-marketing surveillance. Drug Saf. 2015;38(12):1211–8.

    CAS  Article  PubMed  Google Scholar 

  15. 15.

    Ramasamy SN et al. Allopurinol hypersensitivity: a systematic review of all published cases, 1950–2012. Drug Saf. 2013;36(10):953–80.

    CAS  Article  PubMed  Google Scholar 

  16. 16.

    Chung W-H, et al. Insights into the poor prognosis of allopurinol-induced severe cutaneous adverse reactions: the impact of renal insufficiency, high plasma levels of oxypurinol and granulysin. Ann Rheum Dis. 2014: p. annrheumdis-2014-205577.

  17. 17.

    Hung S-I et al. HLA-B* 5801 allele as a genetic marker for severe cutaneous adverse reactions caused by allopurinol. Proc Natl Acad Sci U S A. 2005;102(11):4134–9.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  18. 18.

    Gonçalo M et al. HLA-B* 58: 01 is a risk factor for allopurinol-induced DRESS and Stevens–Johnson syndrome/toxic epidermal necrolysis in a Portuguese population. Br J Dermatol. 2013;169(3):660–5.

    Article  PubMed  Google Scholar 

  19. 19.

    Eshki M et al. Twelve-year analysis of severe cases of drug reaction with eosinophilia and systemic symptoms: a cause of unpredictable multiorgan failure. Arch Dermatol. 2009;145(1):67–72.

    Article  PubMed  Google Scholar 

  20. 20.

    Day RO et al. Clinical pharmacokinetics and pharmacodynamics of allopurinol and oxypurinol. Clin Pharmacokinet. 2007;46(8):623–44.

    CAS  Article  PubMed  Google Scholar 

  21. 21.

    Elion GB, et al. Studies with allopurinol in patients with impaired renal function, in Purine Metabolism in Man-III. Springer; 1980. p. 263–267.

  22. 22.

    Chung W-H, et al. Oxypurinol-specific T cells possess preferential TCR clonotypes and express granulysin in allopurinol-induced severe cutaneous adverse reactions. J Investig Dermatol. 2015.

  23. 23.

    Jasmeen PK, et al. Sulfasalazine induced DRESS syndrome: a review of case reports. BJMMR. 2016;11(7).

  24. 24.

    Tanaka E et al. Adverse effects of sulfasalazine in patients with rheumatoid arthritis are associated with diplotype configuration at the N-acetyltransferase 2 gene. J Rheumatol. 2002;29(12):2492–9.

    CAS  PubMed  Google Scholar 

  25. 25.

    Yang F et al. HLA-B* 13: 01 is associated with salazosulfapyridine-induced drug rash with eosinophilia and systemic symptoms in Chinese Han population. Pharmacogenomics. 2014;15(11):1461–9.

    CAS  Article  PubMed  Google Scholar 

  26. 26.

    Brown RJ et al. Minocycline-induced drug hypersensitivity syndrome followed by multiple autoimmune sequelae. Arch Dermatol. 2009;145(1):63–6.

    Article  PubMed  PubMed Central  Google Scholar 

  27. 27.

    Shaughnessy KK et al. Minocycline-induced drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome with persistent myocarditis. J Am Acad Dermatol. 2010;62(2):315–8.

    CAS  Article  PubMed  Google Scholar 

  28. 28.

    Vinson AE et al. Drug rash, eosinophilia, and systemic symptoms syndrome: two pediatric cases demonstrating the range of severity in presentation—a case of vancomycin-induced drug hypersensitivity mimicking toxic shock syndrome and a milder case induced by minocycline. Pediatr Crit Care Med. 2010;11(4):e38–43.

    PubMed  Google Scholar 

  29. 29.

    Reginster J-Y et al. The position of strontium ranelate in today’s management of osteoporosis. Osteoporos Int. 2015;26(6):1667–71.

    CAS  Article  PubMed  Google Scholar 

  30. 30.

    Grosso A et al. Post-marketing assessment of the safety of strontium ranelate; a novel case-only approach to the early detection of adverse drug reactions. Br J Clin Pharmacol. 2008;66(5):689–94.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. 31.

    Cacoub P et al. Drug rash with eosinophilia and systemic symptoms (DRESS) in patients receiving strontium ranelate. Osteoporos Int. 2013;24(5):1751–7.

    CAS  Article  PubMed  Google Scholar 

  32. 32.

    Lee H, et al. Increased risk of strontium ranelate-related SJS/TEN is associated with HLA. Osteoporos Int. 2016;1–7.

  33. 33.

    Pinto B et al. Leflunomide-induced DRESS syndrome with renal involvement and vasculitis. Clin Rheumatol. 2013;32(5):689–93.

    Article  PubMed  Google Scholar 

  34. 34.

    Parajuli S et al. Leflunomide induced DRESS syndrome: a case report. Nepal J Dermatol, Venereol Leprol. 2012;10(1):46–8.

    Google Scholar 

  35. 35.

    Shastri V et al. Severe cutaneous adverse drug reaction to leflunomide: a report of five cases. Indian Journal of Dermatology. Venereol Leprol. 2006;72(4):286.

    Article  Google Scholar 

  36. 36.

    Uppal M, Rai R, Srinivas C. Leflunomide induced drug rash and hepatotoxicity. Indian J Dermatol. 2004;49(03):154.

    Google Scholar 

  37. 37.

    Do‐Pham G et al. Drug reaction with eosinophilia and systemic symptoms and severe involvement of digestive tract: description of two cases. Br J Dermatol. 2011;165(1):207–9.

    Article  PubMed  Google Scholar 

  38. 38.

    Grabar PB et al. Genetic polymorphism of CYP1A2 and the toxicity of leflunomide treatment in rheumatoid arthritis patients. Eur J Clin Pharmacol. 2008;64(9):871–6.

    Article  Google Scholar 

  39. 39.

    Grabar PB et al. Dihydroorotate dehydrogenase polymorphism influences the toxicity of leflunomide treatment in patients with rheumatoid arthritis. Ann Rheum Dis. 2009;68(8):1367–8.

    CAS  Article  PubMed  Google Scholar 

  40. 40.

    Wiese MD et al. Polymorphisms in cytochrome P450 2C19 enzyme and cessation of leflunomide in patients with rheumatoid arthritis. Arthritis Res Ther. 2012;14(4):1.

    Article  Google Scholar 

  41. 41.

    Hopkins AM et al. Genetic polymorphism of CYP1A2 but not total or free teriflunomide concentrations is associated with leflunomide cessation in rheumatoid arthritis. Br J Clin Pharmacol. 2016;81(1):113–23.

    CAS  Article  PubMed  Google Scholar 

  42. 42.

    Zhang F-R et al. HLA-B* 13: 01 and the dapsone hypersensitivity syndrome. N Engl J Med. 2013;369(17):1620–8.

    CAS  Article  PubMed  Google Scholar 

  43. 43.

    Zhu YI, Stiller MJ. Dapsone and sulfones in dermatology: overview and update. J Am Acad Dermatol. 2001;45(3):420–34.

    CAS  Article  PubMed  Google Scholar 

  44. 44.

    Lorenz M, Wozel G, Schmitt J. Hypersensitivity reactions to dapsone: a systematic review. Acta Derm Venereol. 2012;92(2):194–199III.

    Article  PubMed  Google Scholar 

  45. 45.

    Tian W et al. Dapsone hypersensitivity syndrome among leprosy patients in China. Lepr Rev. 2012;83(4):370–7.

    PubMed  Google Scholar 

  46. 46.

    Sheen Y-S et al. Dapsone hypersensitivity syndrome in non-leprosy patients: a retrospective study of its incidence in a tertiary referral center in Taiwan. J Dermatol Treat. 2009;20(6):340–3.

    CAS  Article  Google Scholar 

  47. 47.

    Allanore Y et al. Bosentan-induced drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome. J Rheumatol. 2010;37(5):1077–8.

    Article  PubMed  Google Scholar 

  48. 48.

    Nagai Y et al. Drug eruption due to bosentan in a patient with systemic sclerosis. Mod Rheumatol. 2006;16(3):188–90.

    Article  PubMed  Google Scholar 

  49. 49.

    Romano A et al. Delayed hypersensitivity to bosentan. Allergy. 2009;64(3):499–501.

    CAS  Article  PubMed  Google Scholar 

  50. 50.

    Kretzmann BR, Fang MA. Hydroxychloroquine-induced DRESS Syndrome. Proc UCLA Healthcare. 2011;15.

  51. 51.

    Volpe A et al. Hydroxychloroquine-induced DRESS syndrome. Clin Rheumatol. 2008;27(4):537–9.

    Article  PubMed  Google Scholar 

  52. 52.

    Nam YH et al. Drug reaction with eosinophilia and systemic symptoms syndrome is not uncommon and shows better clinical outcome than generally recognised. Allergol Immunopathol (Madr). 2015;43(1):19–24.

    CAS  Article  Google Scholar 

  53. 53.

    Um SJ et al. Clinical features of drug-induced hypersensitivity syndrome in 38 patients. J Investig Allergol Clin Immunol. 2010;20(7):556–62.

    CAS  PubMed  Google Scholar 

  54. 54.

    Mayer MD et al. Pharmacokinetics and pharmacodynamics of febuxostat, a new non-purine selective inhibitor of xanthine oxidase in subjects with renal impairment. Am J Ther. 2005;12(1):22–34.

    Article  PubMed  Google Scholar 

  55. 55.

    Schumacher HR et al. Effects of febuxostat versus allopurinol and placebo in reducing serum urate in subjects with hyperuricemia and gout: a 28-week, phase III, randomized, double-blind, parallel-group trial. Arthritis Care Res. 2008;59(11):1540–8.

    CAS  Article  Google Scholar 

  56. 56.

    Becker MA et al. Febuxostat compared with allopurinol in patients with hyperuricemia and gout. N Engl J Med. 2005;353(23):2450–61.

    CAS  Article  PubMed  Google Scholar 

  57. 57.

    Chou HY et al. Febuxostat-associated drug reaction with eosinophilia and systemic symptoms (DRESS). J Clin Pharm Ther. 2015;40(6):689–92.

    Article  PubMed  Google Scholar 

  58. 58.

    Tausche A-K, Reuss-Borst M, Koch U. Urate lowering therapy with febuxostat in daily practice—a multicentre, open-label, prospective observational study. Int J Rheumatol. 2014;2014.

  59. 59.

    van Vollenhoven R et al. DRESS syndrome and reversible liver function abnormalities in patients with systemic lupus erythematosus treated with the highly selective JAK-1 inhibitor GSK2586184. Lupus. 2015;0961203315573347.

  60. 60.

    Kahl L, et al. Safety, tolerability, efficacy and pharmacodynamics of the selective JAK1 inhibitor GSK2586184 in patients with systemic lupus erythematosus. Lupus. 2016;0961203316640910.

  61. 61.

    Ludbrook V et al. Investigation of selective JAK1 inhibitor GSK2586184 for the treatment of psoriasis in a randomized placebo-controlled phase IIa study. Br J Dermatol. 2016;174(5):985–95.

    CAS  Article  PubMed  Google Scholar 

  62. 62.

    Chi MH et al. Histopathological analysis and clinical correlation of drug reaction with eosinophilia and systemic symptoms (DRESS). Br J Dermatol. 2014;170(4):866–73.

    Article  PubMed  Google Scholar 

  63. 63.

    Vahid B. What caused diffuse alveolar hemorrhage in a patient with gout? J Respir Dis. 2006;27(10):441.

    Google Scholar 

  64. 64.

    Wi JO et al. A case of DRESS syndrome accompanied by leukocytoclastic vasculitis. Korean J Asthma Allergy Clin Immunol. 2010;30(4):320–4.

    Google Scholar 

  65. 65.

    Gaha M et al. DRESS syndrome: cerebral vasculitic-like presentation. Neuroradiology. 2015;57(10):1015–21.

    Article  PubMed  Google Scholar 

  66. 66.

    Sola D et al. DRESS syndrome with cerebral vasculitis. Intern Med. 2013;52(12):1403–5.

    Article  PubMed  Google Scholar 

  67. 67.

    Schrijvers R et al. Pathogenesis and diagnosis of delayed-type drug hypersensitivity reactions, from bedside to bench and back. Clin Translat Allergy. 2015;5(1):1.

    Article  Google Scholar 

  68. 68.

    Pichler WJ et al. Drug hypersensitivity: how drugs stimulate T cells via pharmacological interaction with immune receptors. Int Arch Allergy Immunol. 2015;168(1):13–24.

    CAS  Article  PubMed  Google Scholar 

  69. 69.

    Tohyama M et al. Association of human herpesvirus 6 reactivation with the flaring and severity of drug-induced hypersensitivity syndrome. Br J Dermatol. 2007;157(5):934–40.

    CAS  Article  PubMed  Google Scholar 

  70. 70.

    Picard D et al. Drug reaction with eosinophilia and systemic symptoms (DRESS): a multiorgan antiviral T cell response. Sci Transl Med. 2010;2(46):46ra62-46ra62.

    Article  Google Scholar 

  71. 71.

    Torres M, Mayorga C, Blanca M. Nonimmediate allergic reactions induced by drugs: pathogenesis and diagnostic tests. J Investig Allergol Clin Immunol. 2009;19(2):80–90.

    CAS  PubMed  Google Scholar 

  72. 72.

    Ogawa K et al. Identification of thymus and activation-regulated chemokine (TARC/CCL17) as a potential marker for early indication of disease and prediction of disease activity in drug-induced hypersensitivity syndrome (DIHS)/drug rash with eosinophilia and systemic symptoms (DRESS). J Dermatol Sci. 2013;69(1):38–43.

    CAS  Article  PubMed  Google Scholar 

  73. 73.

    Hari Y et al. T cell involvement in cutaneous drug eruptions. Clin Exp Allergy: J Br Soc Allergy Clin Immunol. 2001;31(9):1398–408.

    CAS  Article  Google Scholar 

  74. 74.

    Ye YM, et al. Drug-specific CD4+ T-cell immune responses are responsible for antituberculosis drug-induced maculopapular exanthema and DRESS. Br J Dermatol. 2016.

  75. 75.

    Pavlos R et al. T cell-mediated hypersensitivity reactions to drugs. Annu Rev Med. 2015;66:439.

    CAS  Article  PubMed  Google Scholar 

  76. 76.

    Nguyen DV et al. Validation of a rapid test for HLA-B* 58: 01/57: 01 allele screening to detect individuals at risk for drug-induced hypersensitivity. Pharmacogenomics. 2016;17(5):473–80.

    CAS  Article  PubMed  Google Scholar 

  77. 77.

    Su S-C, Chung W-H, Hung S-I. Digging up the human genome: current progress in deciphering adverse drug reactions. BioMed Res Int. 2014;2014.

  78. 78.

    Yun J et al. Oxypurinol directly and immediately activates the drug-specific T cells via the preferential use of HLA-B* 58: 01. J Immunol. 2014;192(7):2984–93.

    CAS  Article  PubMed  Google Scholar 

  79. 79.

    Cardoso CS, Vieira AM, Oliveira AP. DRESS syndrome: a case report and literature review. BMJ Case Rep. 2011;2011.

  80. 80.

    Shalom R et al. Allopurinol-induced recurrent DRESS syndrome: pathophysiology and treatment. Ren Fail. 2008;30(3):327–9.

    CAS  Article  PubMed  Google Scholar 

  81. 81.

    Yang DC, Chang CM. Allopurinol-induced drug reaction with Eosinophilia and systemic symptoms syndrome with recurrence. J Am Geriatr Soc. 2010;58(10):2043–4.

    Article  PubMed  Google Scholar 

  82. 82.

    Hiransuthikul A, et al. Drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms (DIHS/DRESS): 11 years retrospective study in Thailand. Allergol Int. 2016.

  83. 83.

    Avancini J et al. Drug reaction with eosinophilia and systemic symptoms/drug-induced hypersensitivity syndrome: clinical features of 27 patients. Clin Exp Dermatol. 2015;40(8):851–9.

    CAS  Article  PubMed  Google Scholar 

  84. 84.

    Díaz-Molina V, Tirado-Sánchez A, Ponce-Olivera R. Clinical, aetiological and therapeutic findings in Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) syndrome, four years experience in a third-level Mexican hospital. Revista Médica del Hospital General de México; 2015.

  85. 85.

    Kano Y et al. Virus reactivation and intravenous immunoglobulin (IVIG) therapy of drug-induced hypersensitivity syndrome. Toxicology. 2005;209(2):165–7.

    CAS  Article  PubMed  Google Scholar 

  86. 86.

    Alexander T et al. Severe DRESS syndrome managed with therapeutic plasma exchange. Pediatrics. 2013;131(3):e945–9.

    Article  PubMed  Google Scholar 

  87. 87.

    Kirchhof MG, Wong A, Dutz JP. Cyclosporine treatment of drug-induced hypersensitivity Syndrome. JAMA Dermatol. 2016.

Download references

Author information

Affiliations

Authors

Corresponding author

Correspondence to Marwan H. Adwan.

Ethics declarations

Conflict of Interest

The author declares no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

This article is part of the Topical Collection on Orphan Diseases

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Adwan, M.H. Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Syndrome and the Rheumatologist. Curr Rheumatol Rep 19, 3 (2017). https://doi.org/10.1007/s11926-017-0626-z

Download citation

Keywords

  • DRESS syndrome
  • Eosinophilia
  • Hypersensitivity
  • Toxicity
  • Idiosynchratic
  • Allopurinol
  • Minocycline
  • Sulfasalazine