Hipersensibilidade a drogas: um alerta em pacientes portadores de doenças autoimunes
Drug hypersensitivity: an alert in patients with autoimmune diseases
Mateus Rios; Luiz Rocha; Gladys Queiroz; Filipe W. Sarinho; Renata Vasconcelos; Almerinda Maria Rego; Emanuel Sarinho
Resumo
Objetivo: Avaliar a hipersensibilidade a medicamentos em pacientes com o diagnóstico de doenças autoimunes. Métodos: Estudo clínico, analítico, do tipo caso-controle. Foram selecionadas 35 mulheres com doenças autoimunes e 35 sem esse diagnóstico que participaram do protocolo de pesquisa sobre antecedentes de hipersensibilidade a drogas. Resultados: As pacientes apresentavam idade variando de 16 a 66 anos, com a mediana semelhante nos dois grupos. A doença autoimune mais prevalente foi o lupus eritematoso sistêmico, 24/35 (68,5%). A proporção de hipersensibilidade a medicamentos, nas pacientes com doenças autoimunes, foi de 14/35 (40%), e apenas 2/35 (5,7%) no grupo controle (p = 0,0029). As reações de hipersensibilidade do tipo tardia foram as mais frequentes, e na maioria dos casos precederam o diagnóstico de doença autoimune em um total de cinco pacientes, sendo que destas cinco, duas apresentaram síndrome de Stevens Johnson, duas exantema maculopapular, e uma eritema fixo pigmentar. O grupo de drogas mais envolvido foi os anti-inflamatórios não esteroides, seguidos pelos anticonvulsivantes. Conclusão: Hipersensibilidade a medicamentos foi mais frequente em pacientes portadoras de doenças autoimunes, e pode preceder o diagnóstico, especialmente se for do tipo tardia. Estudos adicionais multicêntricos para verificar uma eventual associação de hipersensibilidade a medicamentos e doenças autoimunes são necessários.
Palavras-chave
Abstract
Objective: To evaluate drug hypersensitivity in patients with autoimmune diseases. Methods: In this clinical, analytical, casecontrol study, we selected 35 women with autoimmune diseases and 35 women without this diagnosis to participate in this research protocol on history of drug hypersensitivity. Results: Patients’ age ranged from 16 to 66 years with similar median in both groups. The most prevalent autoimmune disease was systemic lupus erythematosus, in 24/35 (68.5%) patients. The proportion of drug hypersensitivity was 14/35 (40%) in the autoimmune disease group and only 2/35 (5.7%) in the control group (p = 0.0029). Delayed hypersensitivity reactions were most frequent and preceded the diagnosis of autoimmune disease in five patients, including two with Stevens-Johnson syndrome, two with maculopapular rash and one with fixed pigmented erythema. The most frequently involved group of drugs was nonsteroidal anti-inflammatory drugs, followed by anticonvulsants. Conclusion: Drug hypersensitivity was more common in patients with autoimmune diseases and may precede the diagnosis, especially in delayed-type. Additional multicenter studies are required to evaluate a possible association of drug hypersensitivity to autoimmune diseases.
Keywords
References
1. Ensina LF, Fernandes FR, Gesu GD, Malaman MF, Chavarria ML, Bernd LAG. Reações de hipersensibilidade a medicamentos. Rev Bras Alerg Imunopatol. 2009;32:42-6.
2. Kowalski ML, Makowska JS, Blanca M, Bavbek S, Bochenek G, Bousquet J, et al. Hypersensitivity to nonsteroidal anti-inflammatory drugs(NSAIDs) – classification, diagnosis and management: review of the EAACI\ENDA and GA2LEN\HANNA. Allergy. 2011;66:818‑29.
3. Demoly P, Adkinson NF, Brockow K, Castells M, Chiriac AM, Greenberger PA, et al. International Consensus on drug allergy. Allergy. 2014;69:420-37.
4. Aota N, Shiohara T. Viral connection between drug rashe and autoimmune diseases: How autoimmune responses are generated after resolution of drug rashes. Autoimmun Rev. 2008; 8:488-94.
5. Moroni L, Bianchi I, Lleo A. Geoepidemiology, gender and autoimmune disease. Autoimmun Rev. 2012;11:386-92.
6. Chiou C, Chumg WH, Hung SI, Hong HS. Pulminant type I diabetes mellitus caused by drug hypersensitivity syndrome with humam herpesvirus 6 infection. J Am Acad Dermatol. 2006;54:14-7.
7. Shiohara T, Inaoka M, Kano Y. Drug-induced hypersensitivity syndrome (DIHS): a reactivation induced by a complex interplay among herpesviruses and antiviral and antidrug immune responses. Allergol Int. 2006;55(1):1-8.
8. Kano Y, Hirahara K, Sakuma K, Shiohara T. Several herpesviruses can reactivate in a severe drug-induced multiorgan reaction in the same sequential order as in graft-versus-host disease. Br J Dermatol. 2006;155:301-6.
9. Hochberg MC. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 1997;40(9):1725.
10. Fries JF, Hunder GG, Bloch DA, Michel BA, Arend WP, Colabrese LH, et al. The American College of Rheumatology 1990 criteria for the classification of vasculitis. Summary. Arthritis Rheum. 1990;33:1135‑6.
11. Van Den Hoogen F, Khanna D, Fransen J, Johnson SR, Baron M, Tyndall A, et al. 2013 classification criteria for systemic sclerosis: an American College of Rheumatology/European League against Rheumatism collaborative initiative. Arthritis Rheum. 2013;65(11):2737-47.
12. Aletaha D, Neogi T, Silman AJ, Funovits J, Felson DT, Bingham CO, et al. 2010 Rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheum. 2010 Sep;62(9):2569-81.
13. Lichtenstein GR, Hanauer SB, Sandborn WJ. Manegement of Crohn`s diseases in adults. Am J Gastroenterol. 2009;104(2):465‑83.
14. Chiou CC, Chung WH, Hung SI, Yang LC, Hong HS, et al. Fulminant type 1 diabetes mellitus caused by drug hypersensitivity syndrome with human herpesvirus 6 infection. J Am Acad Dermatol. 2006;54(2):S14-17.
15. Aota N, Hirahara K, Kano Y, Fukuoka T, Yamada A, Shiohara T. Systemic lupus erythematosus presenting with Kikuchi-Fujimoto's disease as a long-term sequel of drug-induced hypersensitivity syndrome. A possible role of Epstein-Barr virus reactivation. Dermatology. 2009;218(3):275-7.
16. Kano Y, Sakuma K, Shiohara T. Sclerodermoid graft-versus-host disease-like lesions occurring after drug-induced hypersensitivity syndrome. Br J Dermatol. 2007;156(5):1083-4.
17. Shiohara T, Kano Y. A complex interaction between drug allergy and viral infection. Clin Rev Allergy Immunol. 2007;33(1-2):124‑33.
18. Saraya T , Mikoshiba M, Kamiyama H, Yoshizumi M, Tsuchida S, Tsukagoshi H, et al. Evidence for reactivation of human herpesvirus 6 in generalized lymphadenopathy in a patient with drug-induced hypersensitivity syndrome. J Clin Microbiol. 2013; 51(6):1979‑82.
19. Yagami A, Yoshikawa T, Asano Y, Kote S, Shiohara T, Matsunaga K. Drug-induced hypersensitivity syndrome due to mexiletine hydrochloride associated with reactivation of human herpesvirus 7. Dermatology. 2006;213(4):341-4.
20. Asano Y, Kagawa H, Shiohara T. Cytomegalovirus disease during severe drug eruptions: report of 2 cases and retrospective study of 18 patients with drug-induced hypersensitivity syndrome. Arch Dermatol. 2009;145(9):1030-6.
21. Kano T, Horie C, Inaoka M, Tadashi I, Mizukawa Y, Shiohara T. Herpes Zoster in patients with drug-induced hypersensitivity syndrome DRESS. Acta Derm Venereol. 2012;92:193-220.
22. Hirahara K, Kano Y, Ishida T, Shiohara T. Diffuse large B-cell lymphoma as a sequela of Stevens-Johnson syndrome associated with an increased Epstein-Barr virus load. Eur J Dermatol. 2012;22(1):144-5.
23. Kanetaka Y, Kano Y, Hirahara K, Kurata M, Shiohara T. Relationship between cytomegalovirus reactivation and dermatomyositis. Eur J Dermatol. 2011;21(2):248-53.
24. Sabatini A, Bombardueri S, Miqliorini P. Autoantibodies from patients with systemic lupus erythematous bind a shared sequence of Smd and Epstein-Barr vírus encoded nuclear antigen EBNA 1. Eur J Immunol. 1993;23:1146-52.
25. James JA, Kaufman KM, Farris AD, Taylor-Albert E, Lehman TJA, Harley JB. An increased prevalence of Epstein Barr virus infection in young patients suggests a possible etiology for systemic lupus erythematosus. J Clin Invest. 1997;100:3019-26.
26. Sundar K, Jacques S, Gottlieb P, Villars R, Benito ME, Taylor DK, Spatz LA. Expression of the Epstein-Barr virus nuclear antigen-1 (EBNA-1) in the mouse can elicit the production of anti-dsDNA and anti-Sm antibodies. J Autoimmun. 2004;23:127-40.
27. Kukreja A, Cost G, Marker J, Zhang C, Sun Z, Lin-Su K, et al. Multiple immuneregulatory defects in type 1 diabetes. J Clin Invest. 2002;109:131-40.
28. Balandina A, Lecart S, Dartevelle P, Saoudi A, Berrih-Aknin. Functional defect of regulatory CD4CD25 T cells in the thymus of patients whith autoimmune myasthenia gravis. Blood. 2005;105:735‑41.
29. Viglietta V, Baecher-Allan C, Weiner HL, Hafler DA. Loss of functional suppression by CD4CD25 regulatory T cells in patients with multiple sclerosis. J Exp Med. 2004;199:971-9.
30. Takahashi R, Kano Y, Yamazaki Y, Kimishima M, Mizukawa Y, Shiohara T. Defective T cells in patients with severe drug eruptions: timing of the dysfunction is associated with the pathological phenotype and outcome. J Immunol. 2009;182:8071-9.
Submitted date:
05/26/2018
Accepted date:
04/08/2019
