Can propylthiouracil induce autoimmune-related immunotoxicity?
Abstract
Introduction. The use of propylthiouracil can be associated with mild adverse reactions, but severe complications such as agranulocytosis and vasculitis can also be seen. Direct toxicity and immune-mediated induction of anti-neutrophile cytoplasmic antibodies have been described as possible mechanisms responsible for agranulocytosis. The majority of vasculitis is antimyeloperoxidase antibodies associated, but the exact mechanism for anti-neutrophile cytoplasmic antibodies-associated vasculitis as an adverse effect of propylthiouracil treatment is still unclear. Case report. We presented a 61-year-old female patient with Graves’ disease who experienced a fever and throat pain two weeks after propylthiouracil therapy was initiated. Agranulocytosis alongside basal left-sided pneumonia was noted. Propylthiouracil was discontinued, and the treatment with broad-spectrum antibiotics was started, as well as Lugol’s solution, methylprednisolone, and granulocyte-colony stimulating factor. Further course of treatment was complicated by the occurrence of a generalized erythematous-papillomatous rash. The patient was diagnosed with agranulocytosis and antimyeloperoxidase, anti-neutrophile cytoplasmic antibodies positive vasculitis as an adverse effect of propylthiouracil. Conclusion. Patients presenting with concomitant agranulocytosis and anti-neutrophile cytoplasmic antibodies-associated vasculitis as a complication of propylthiouracil therapy for Graves’ disease are rare in clinical practice. Prompt discontinuation of the antithyroid drug is of great importance to reduce damage to target organs. Similarities in the pathogenesis of both conditions could be the potential explanation for these two adverse events occurring at the same time, which points out the need for a deeper understanding of this topic.
References
1. Jacobs EM, Hartkamp A, Kaasjager HA. PTU-associated cutaneous vasculitis with ANCA anti-MPO and anti-PR3 antibodies. Neth J Med 2003; 61(9): 296‒9.
2. Sato H, Hattori M, Fujieda M, Sugihara S, Inomata H, Hoshi M, et al. High prevalence of antineutrophil cytoplasmic antibody positivity in childhood onset Graves' disease treated with propylthiouracil. J Clin Endocrinol Metab 2000; 85(11): 4270‒3.
3. Rodrigues R, Jorge PT. Vasculite leucocitoclástica: uma rara manifestação associada ao metimazol. Arq Bras Endocrinol Metab 2002; 46(6): 716‒9. (Portuguese)
4. Karincaoglu Y, Esrefoglu M, Aki T, Mizrak B. Propylthiouracil-induced vasculitic oral ulcers with anti-neutrophil cytoplasmic antibody. J Eur Acad Dermatol Venereol 2006; 20(1): 120‒2.
5. Aloush V, Litinsky I, Caspi D, Elkayam O. Propylthiouracil-induced autoimmune syndromes: Two distinct clinical presentations with different course and management. Semin Arthritis Rheum 2006; 36(1): 4–9.
6. Weetman AP. Non-thyroid autoantibodies in autoimmune thyroid disease. Best Pract Res Clin Endocrinol Metab 2005; 19(1): 17–32.
7. Vicente N, Cardoso L, Barros L, Carrilho F. Antithyroid Drug-Induced Agranulocytosis: State of the Art on Diagnosis and Management. Drugs RD 2017; 17(1): 91‒6.
8. Gao Y, Zhao MH. Review article: Drug-induced anti-neutrophil cytoplasmic antibody-associated vasculitis. Nephrology (Carlton) 2009; 14(1): 33‒41.
9. Wall AE, Weaver SM, Litt JS, Rae L. Propylthiouracil-Associated Leukocytoclastic Necrotizing Cutaneous Vasculitis: A Case Report and Review of the Literature. J Burn Care Res 2017; 38(3): e678‒85.
10. Wada N, Mukai M, Kohno M, Notoya A, Ito T, Yoshioka N. Prevalence of serum anti-myeloperoxidase antineutrophil cytoplasmic antibodies (MPO-ANCA) in patients with Graves' disease treated with propylthiouracil and thiamazole. Endocr J 2002; 49(3): 329‒34.
11. Slot MC, Links TP, Stegeman CA, Tervaert JW. Occurrence of antineutrophil cytoplasmic antibodies and associated vasculitis in patients with hyperthyroidism treated with antithyroid drugs: A long-term followup study. Arthritis Rheum 2005; 53(1): 108‒13.
12. Fujieda M, Hattori M, Kurayama H, Koitabashi Y. Clinical features and outcomes in children with antineutrophil cytoplasmic autoantibody-positive glomerulonephritis associated with propylthiouracil treatment. J Am Soc Nephrol 2002; 13(2): 437‒45.
13. Harper L, Chin L, Daykin J, Allahabadia A, Heward J, Gough SC, et al. Propylthiouracil and carbimazole associated-antineutrophil cytoplasmic antibodies (ANCA) in patients with Graves' disease. Clin Endocrinol (Oxf) 2004; 60(6): 671‒5.
14. Criado PR, Grizzo Peres Martins AC, Gaviolli CF, Alavi A. Propylthiouracil- induced vasculitis with antineutrophil cytoplasmic antibody. Int J Low Extrem Wounds 2015; 14(2): 187‒91.
15. Noh JY, Asari T, Hamada N, Makino F, Ishikawa N, Abe Y, et al. Frequency of appearance of myeloperoxidase-antineutrophil cytoplasmic antibody (MPO-ANCA) in Graves' disease patients treated with propylthiouracil and the relationship between MPO-ANCA and clinical manifestations. Clin Endocrinol (Oxf) 2001; 54(5): 651‒4.
16. Otsuka S, Kinebuchi A, Tabata H, Yamakage A, Yamazaki S. Myeloperoxidase-antineutrophil cytoplasmic antibody-associated vasculitis following propylthiouracil therapy. Br J Dermatol 2000; 142(4): 828‒30.
17. Nakamura H, Miyauchi A, Miyawaki N, Imagawa J. Analysis of 754 cases of antithyroid drug-induced agranulocytosis over 30 years in Japan. J Clin Endocrinol Metab 2013; 98(12): 4776‒83.
18. Franklyn JA, Boelaert K. Thyrotoxicosis. Lancet 2012; 379(9821): 1155‒66.
19. Watanabe N, Narimatsu H, Noh JY, Yamaguchi T, Kobayashi K, Kami M, et al. Antithyroid drug-induced hematopoietic damage: a retrospective cohort study of agranulocytosis and pancytopenia involving 50,385 patients with Graves' disease. J Clin Endocrinol Metab 2012; 97(1): E49‒53.
20. Kobayashi S, Noh JY, Mukasa K, Kunii Y, Watanabe N, Matsumoto M, et al. Characteristics of agranulocytosis as an adverse effect of antithyroid drugs in the second or later course of treatment. Thyroid 2014; 24(5): 796‒801.
21. Mutharasan P, Oatis W, Kwaan H, Molitch M. Delayed anithyroid drug-induced agranulocytosis. Endocr Pract 2012; 18(4): e69‒72.
22. Andrès E, Zimmer J, Affenberger S, Federici L, Alt M, Maloisel F. Idiosyncratic drug-induced agranulocytosis: Update of an old disorder. Eur J Intern Med 2006; 17(8): 529‒35.
23. Fibbe WE, Claas FH, Van der Star-Dijkstra W, Schaafsma MR, Meyboom RH, Falkenburg JH. Agranulocytosis induced by propylthiouracil: evidence of a drug dependent antibody reacting with granulocytes, monocytes and haematopoietic progenitor cells. Br J Haematol 1986; 64(2): 363‒73.
24. Wall JR, Fang SL, Kuroki T, Ingbar SH, Braverman LE. In vitro immunoreactivity to propylthiouracil, methimazole, and carbimazole in patients with Graves' disease: a possible cause of antithyroid drug-induced agranulocytosis. J Clin Endocrinol Metab 1984; 58(5): 868‒72.
25. Csernok E, Ernst M, Schmitt W, Bainton DF, Gross WL. Activated neutrophils express proteinase 3 on their plasma membrane in vitro and in vivo. Clin Exp Immunol 1994; 95(2): 244‒50.
26. Owen CA, Campbell MA, Sannes PL, Boukedes SS, Campbell EJ. Cell surface-bound elastase and cathepsin G on human neutrophils: a novel, non-oxidative mechanism by which neutrophils focus and preserve catalytic activity of serine proteinases. J Cell Biol 1995; 131(3): 775‒89.
27. Yang J, Zhu YJ, Zhong JJ, Zhang J, Weng WW, et al. Characteristics of Antithyroid Drug-Induced Agranulocytosis in Patients with Hyperthyroidism: A Retrospective Analysis of 114 Cases in a Single Institution in China Involving 9690 Patients Referred for Radioiodine Treatment Over 15 Years. Thyroid 2016; 26(5): 627‒33.
28. Sheng WH, Hung CC, Chen YC, Fang CT, Hsieh SM, Chang SC, et al. Antithyroid-drug-induced agranulocytosis complicated by life-threatening infections. QJM 1999; 92(8): 455‒61.
29. Alexander EK, Larsen PR. High dose of (131)I therapy for the treatment of hyperthyroidism caused by Graves' disease. J Clin Endocrinol Metab 2002; 87(3): 1073‒7.
30. Fiorentino DF. Cutaneous vasculitis. J Am Acad Dermatol 2003; 48(3): 311‒40.
31. Sera N, Yokoyama N, Abe Y, Ide A, Usa T, Tominaga T, et al. Antineutrophil Cytoplasmic Antibody-associated Vasculitis Complicating Graves' Disease: Report of Two Adult Cases. Acta Med Nagasaki 2000; 45(1‒2): 33‒6.
32. Gunton JE, Stiel J, Clifton-Bligh P, Wilmshurst E, McElduff A. Prevalence of positive anti-neutrophil cytoplasmic antibody (ANCA) in patients receiving anti-thyroid medication. Eur J Endocrinol 2000; 142(6): 587.
33. Gao Y, Zhao MH, Guo XH, Xin G, Gao Y, Wang HY. The prevalence and target antigens of antithyroid drugs induced antineutrophil cytoplasmic antibodies (ANCA) in Chinese patients with hyperthyroidism. Endocr Res 2004; 30(2): 205‒13.
34. Jiang X, Khursigara G, Rubin RL. Transformation of lupus-inducing drugs to cytotoxic products by activated neutrophils. Science 1994; 266(5186): 810‒3.
35. Ye H, Gao Y, Guo XH, Zhao MH. Titre and affinity of propylthiouracil-induced anti-myeloperoxidase antibodies are closely associated with the development of clinical vasculitis. Clin Exp Immunol 2005; 142(1): 116‒9.
36. Yang J, Yao LP, Dong MJ, Xu Q, Zhang J, Weng WW, et al. Clinical Characteristics and Outcomes of Propylthiouracil-Induced Antineutrophil Cytoplasmic Antibody-Associated Vasculitis in Patients with Graves' Disease: A Median 38-Month Retrospective Cohort Study from a Single Institution in China. Thyroid 2017; 27(12): 1469‒74.
37. Bilge NS, Kaşifoğlu T, Korkmaz C. PTU-induced ANCA-positive vasculitis: an innocent or a life-threatening adverse effect? Rheumatol Int 2013; 33(1): 117‒20.
38. Tanaka R, Shimojima Y, Moteki H, Kishida D, Ueno KI, Sekijima Y. Propylthiouracil-induced Otitis Media with Antineutrophil Cytoplasmic Antibody-associated Vasculitis. Intern Med 2018; 57(20): 3029‒33.
39. Flendrie M, Vissers WH, Creemers MC, de Jong EM, van de Kerkhof PC, van Riel PL. Dermatological conditions during TNF-alpha-blocking therapy in patients with rheumatoid arthritis: a prospective study. Arthritis Res Ther 2005; 7(3): R666‒76.
40. Vasoo S. Drug-induced lupus: an update. Lupus 2006; 15(11): 757‒61.
41. Sheen YS, Chu CY, Yu HS. Antineutrophil cytoplasmic antibody-positive cutaneous leukocytoclastic vasculitis associated with propylthiouracil therapy. Arch Dermatol 2006; 142(7): 879‒80.
42. Khurshid I, Sher J. Disseminated intravascular coagulation and vasculitis during propylthiouracil therapy. Postgrad Med J 2000; 76(893): 185‒6.
43. Gao Y, Chen M, Ye H, Yu F, Guo XH, Zhao MH. Long-term outcomes of patients with propylthiouracil-induced anti-neutrophil cytoplasmic auto-antibody-associated vasculitis. Rheumatology (Oxford) 2008; 47(10): 1515‒20.
44. Erem C, Ersoz HO, Karti SS, Ukinç K, Hacihasanoglu A, Değer O, et al. Blood coagulation and fibrinolysis in patients with hyperthyroidism. J Endocrinol Invest 2002; 25(4): 345‒50.