Abstract
Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) refers to a group of potentially life-threatening autoimmune diseases. A recent development in this field is the recognition that certain drugs can induce AAV. Among these agents, the drug most often implicated in causing disease is the commonly used antithyroid agent propylthiouracil (PTU). This Review provides an update on PTU-induced AAV. Clinical characteristics of PTU-induced AAV are similar to that of primary AAV, but usually have a milder course and better prognosis, provided early cessation of the disease-causing drug. PTU-induced ANCAs usually react to several components of myeloid granules, which is helpful in differentiating PTU-induced AAV from primary AAV. Early cessation of PTU is crucial in the treatment of PTU-induced AAV. The duration of immunosuppressive therapy might be shorter than in primary AAV, depending on the severity of organ damage, and maintenance therapy is not always necessary.
Key Points
-
The antithyroid drug propylthiouracil (PTU) can induce antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis
-
The interaction between PTU and myeloperoxidase might contribute to the pathogenesis of PTU-induced vasculitis
-
PTU-induced ANCAs usually react to several components of myeloid granules
-
Compared with primary ANCA-associated vasculitis, PTU-induced vasculitis usually has a mild course and good prognosis, provided early cessation of the disease-causing drug
-
The duration of immunosuppressive therapy for PTU-induced vasculitis might be shorter than in primary ANCA-associated vasculitis, depending on the severity of organ damage, and maintenance therapy might not be necessary
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
£139.00 per year
only £11.58 per issue
Buy this article
- Purchase on SpringerLink
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Jennette, J. C. & Falk, R. J. Small-vessel vasculitis. N. Engl. J. Med. 337, 1512–1523 (1997).
Hagen, E. C. et al. Diagnostic value of standardized assays for anti-neutrophil cytoplasmic antibodies in idiopathic systemic vasculitis. EC/BCR Project for ANCA Assay Standardization. Kidney Int. 53, 743–753 (1998).
Falk, R. J., Terrell, R. S., Charles, L. A. & Jennette, J. C. Anti-neutrophil cytoplasmic autoantibodies induce neutrophils to degranulate and produce oxygen radicals in vitro. Proc. Natl Acad. Sci. USA 87, 4115–4119 (1990).
Charles, L. A., Caldas, M. L., Falk, R. J., Terrell, R. S. & Jennette, J. C. Antibodies against granule proteins activate neutrophils in vitro. J. Leukoc. Biol. 50, 539–546 (1991).
Xiao, H. et al. Antineutrophil cytoplasmic autoantibodies specific for myeloperoxidase cause glomerulonephritis and vasculitis in mice. J. Clin. Invest. 110, 955–963 (2002).
Schreiber, A., Xiao, H., Falk, R. J. & Jennette, J. C. Bone marrow-derived cells are sufficient and necessary targets to mediate glomerulonephritis and vasculitis induced by anti-myeloperoxidase antibodies. J. Am. Soc. Nephrol. 17, 3355–3364 (2006).
Little, M. A. et al. Antineutrophil cytoplasm antibodies directed against myeloperoxidase augment leukocyte-microvascular interactions in vivo. Blood 106, 2050–2058 (2005).
Jayne, D. R. et al. Randomized trial of plasma exchange or high-dosage methylprednisolone as adjunctive therapy for severe renal vasculitis. J. Am. Soc. Nephrol. 18, 2180–2188 (2007).
de Lind van Wijngaarden, R. A. et al. Chances of renal recovery for dialysis-dependent ANCA-associated glomerulonephritis. J. Am. Soc. Nephrol. 18, 2189–2197 (2007).
Birck, R., Schmitt, W. H., Kaelsch, I. A. & van der Woude, F. J. Serial ANCA determinations for monitoring disease activity in patients with ANCA-associated vasculitis: systematic review. Am. J. Kidney Dis. 47, 15–23 (2006).
Finkielman, J. D. et al. Antiproteinase 3 antineutrophil cytoplasmic antibodies and disease activity in Wegener granulomatosis. Ann. Intern. Med. 147, 611–619 (2007).
Chen, M. & Kallenberg, C. G. The environment, geoepidemiology and ANCA-associated vasculitides. Autoimmun. Rev. 9, A293–A298 (2010).
Chen, M. & Kallenberg, C. G. ANCA-associated vasculitides—advances in pathogenesis and treatment. Nat. Rev. Rheumatol. 6, 653–664 (2010).
Wiik, A. Clinical and laboratory characteristics of drug-induced vasculitic syndromes. Arthritis Res. Ther. 7, 191–192 (2005).
Aloush, V., Litinsky, I., Caspi, D. & Elkayam, O. Propylthiouracil-induced autoimmune syndromes: two distinct clinical presentations with different course and management. Semin. Arthritis Rheum. 36, 4–9 (2006).
Pillinger, M. H. & Staud, R. Propylthiouracil and antineutrophil cytoplasmic antibody associated vasculitis: the detective finds a clue. Semin. Arthritis Rheum. 36, 1–3 (2006).
Bonaci-Nikolic, B., Nikolic, M. M., Andrejevic, S., Zoric, S. & Bukilica, M. Antineutrophil cytoplasmic antibody (ANCA)-associated autoimmune diseases induced by antithyroid drugs: comparison with idiopathic ANCA vasculitides. Arthritis Res. Ther. 7, R1072–R1081 (2005).
Wiik, A. Drug-induced vasculitis. Curr. Opin. Rheumatol. 20, 35–39 (2008).
Dolman, K. M. et al. Vasculitis and antineutrophil cytoplasmic autoantibodies associated with propylthiouracil therapy. Lancet 342, 651–652 (1993).
Gao, Y. et al. The prevalence and target antigens of antithyroid drugs induced antineutrophil cytoplasmic antibodies (ANCA) in Chinese patients with hyperthyroidism. Endocr. Res. 30, 205–213 (2004).
Zhao, M. H., Chen, M., Gao, Y. & Wang, H. Y. Propylthiouracil-induced anti-neutrophil cytoplasmic antibody-associated vasculitis. Kidney Int. 69, 1477–1481 (2006).
Hori, Y. et al. Antineutrophil cytoplasmic autoantibody-positive crescentic glomerulonephritis associated with thiamazole therapy. Nephron 74, 734–735 (1996).
Kawachi, Y., Nukaga, H., Hoshino, M., Iwata, M. & Otsuka, F. ANCA-associated vasculitis and lupus-like syndrome caused by methimazole. Clin. Exp. Dermatol. 20, 345–347 (1995).
Nässberger, L., Johansson, A. C., Björck, S. & Sjöholm, A. G. Antibodies to neutrophil granulocyte myeloperoxidase and elastase: autoimmune responses in glomerulonephritis due to hydralazine treatment. J. Intern. Med. 229, 261–265 (1991).
Almroth, G., Eneström, S., Hed, J., Samuelsson, I. & Sjöström, P. Autoantibodies to leucocyte antigens in hydralazine-associated nephritis. J. Intern. Med. 231, 37–42 (1992).
Stokes, M. B. et al. Development of glomerulonephritis during anti-TNF-α therapy for rheumatoid arthritis. Nephrol. Dial. Transplant. 20, 1400–1406 (2005).
De Bandt, M. & Saint-Marcoux, B. Tumour necrosis factor α blockade and the risk of vasculitis. Ann. Rheum. Dis. 65, 1534–1535 (2006).
Simms, R., Kipgen, D., Dahill, S., Marshall, D. & Rodger, R. S. ANCA-associated renal vasculitis following anti-tumor necrosis factor α therapy. Am. J. Kidney Dis. 51, e11–e14 (2008).
Salerno, S. M. et al. Sulfasalazine pulmonary toxicity in ulcerative colitis mimicking clinical features of Wegener's granulomatosis. Chest 110, 556–559 (1996).
Denissen, N. H., Peters, J. G., Masereeuw, R. & Barrera, P. Can sulfasalazine therapy induce or exacerbate Wegener's granulomatosis? Scand. J. Rheumatol. 37, 72–74 (2008).
Bienaimé, F. et al. D-Penicillamine-induced ANCA-associated crescentic glomerulonephritis in Wilson disease. Am. J. Kidney Dis. 50, 821–825 (2007).
Locke, I. C., Worrall, J. G., Leaker, B., Black, C. M. & Cambridge, G. Autoantibodies to myeloperoxidase in systemic sclerosis. J. Rheumatol. 24, 86–89 (1997).
Sethi, S., Sahani, M. & Oei, L. S. ANCA-positive crescentic glomerulonephritis associated with minocycline therapy. Am. J. Kidney Dis. 42, E27–E31 (2003).
Cooper, D. S. Antithyroid drugs. N. Engl. J. Med. 352, 905–917 (2005).
Gao, Y. & Zhao, M. H. Review article: drug-induced anti-neutrophil cytoplasmic antibody-associated vasculitis. Nephrology (Carlton) 14, 33–41 (2009).
Kimura, S. & Ikeda-Saito, M. Human myeloperoxidase and thyroid peroxidase, two enzymes with separate and distinct physiological functions, are evolutionarily related members of the same gene family. Proteins 3, 113–120 (1988).
Nakamura, H. et al. Comparison of methimazole and propylthiouracil in patients with hyperthyroidism caused by Graves' disease. J. Clin. Endocrinol. Metab. 92, 2157–2162 (2007).
Bilu Martin, D., Deng, A., Gaspari, A. & Pearson, F. Perinuclear antineutrophil cytoplasmic antibody-associated vasculitis in a patient with Graves' disease treated with methimazole. Skinmed 5, 302–305 (2006).
Tsai, M. H., Chang, Y. L., Wu, V. C., Chang, C. C. & Huang, T. S. Methimazole-induced pulmonary hemorrhage associated with antimyeloperoxidase-antineutrophil cytoplasmic antibody: a case report. J. Formos. Med. Assoc. 100, 772–775 (2001).
D'Cruz, D. et al. Antineutrophil cytoplasmic antibody-positive crescentic glomerulonephritis associated with anti-thyroid drug treatment. Br. J. Rheumatol. 34, 1090–1091 (1995).
Calañas-Continente, A. et al. Necrotizing glomerulonephritis and pulmonary hemorrhage associated with carbimazole therapy. Thyroid 15, 286–288 (2005).
Gumà, M. et al. Frequency of antineutrophil cytoplasmic antibody in Graves' disease patients treated with methimazole. J. Clin. Endocrinol. Metab. 88, 2141–2146 (2003).
Wada, N. et al. Prevalence of serum anti-myeloperoxidase antineutrophil cytoplasmic antibodies (MPO-ANCA) in patients with Graves' disease treated with propylthiouracil and thiamazole. Endocr. J. 49, 329–334 (2002).
Huang, C. N., Hsu, T. C., Chou, H. H. & Tsay, G. J. Prevalence of perinuclear antineutrophil cytoplasmic antibody in patients with Graves' disease treated with propylthiouracil or methimazole in Taiwan. J. Formos. Med. Assoc. 103, 274–279 (2004).
Slot, M. C., Links, T. P., Stegeman, C. A. & Tervaert, J. W. Occurrence of antineutrophil cytoplasmic antibodies and associated vasculitis in patients with hyperthyroidism treated with antithyroid drugs: a long-term followup study. Arthritis Rheum. 53, 108–113 (2005).
Stankus, S. J. & Johnson, N. T. Propylthiouracil-induced hypersensitivity vasculitis presenting as respiratory failure. Chest 102, 1595–1596 (1992).
Yazisiz, V., Ongüt, G., Terzioglu, E. & Karayalçin, U. Clinical importance of antineutrophil cytoplasmic antibody positivity during propylthiouracil treatment. Int. J. Clin. Pract. 64, 19–24 (2010).
Fujieda, M., Hattori, M., Kurayama, H. & Koitabashi, Y. Members and Coworkers of the Japanese Society for Pediatric Nephrology. Clinical features and outcomes in children with antineutrophil cytoplasmic autoantibody-positive glomerulonephritis associated with propylthiouracil treatment. J. Am. Soc. Nephrol. 13, 437–445 (2002).
Sera, N. et al. Treatment with propylthiouracil is associated with appearance of antineutrophil cytoplasmic antibodies in some patients with Graves' disease. Thyroid 10, 595–599 (2000).
Harper, L. et al. Propylthiouracil and carbimazole associated-antineutrophil cytoplasmic antibodies (ANCA) in patients with Graves' disease. Clin. Endocrinol. (Oxf.) 60, 671–675 (2004).
Noh, J. Y. et al. Clinical characteristics of myeloperoxidase antineutrophil cytoplasmic antibody-associated vasculitis caused by antithyroid drugs. J. Clin. Endocrinol. Metab. 94, 2806–2811 (2009).
Cin, M. O. et al. Prevalence and clinical significance of antineutrophil cytoplasmic antibody in Graves' patients treated with propylthiouracil. Int. J. Clin. Pract. 63, 299–302 (2009).
Lee, E. et al. Inactivation of peroxidases of rat bone marrow by repeated administration of propylthiouracil is accompanied by a change in the heme structure. Biochem. Pharmacol. 37, 2151–2153 (1988).
Lee, E., Miki, Y., Hosokawa, M., Sayo, H. & Kariya, K. Oxidative metabolism of propylthiouracil by peroxidases from rat bone marrow. Xenobiotica 18, 1135–1142 (1988).
Zhang, A. H., Chen, M., Gao, Y., Zhao, M. H. & Wang, H. Y. Inhibition of oxidation activity of myeloperoxidase (MPO) by propylthiouracil (PTU) and anti-MPO antibodies from patients with PTU-induced vasculitis. Clin. Immunol. 122, 187–193 (2007).
Jiang, X., Khursigara, G. & Rubin, R. L. Transformation of lupus-inducing drugs to cytotoxic products by activated neutrophils. Science 266, 810–813 (1994).
von Schmiedeberg, S., Goebel, C., Gleichmann, E. & Uetrecht, J. Neutrophils and drug metabolism. Science 268, 585–586 (1995).
Gunton, J. E., 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. 142, 587 (2000).
Gao, Y. et al. The target antigens of antineutrophil cytoplasmic antibodies (ANCA) induced by propylthiouracil. Int. Immunopharmacol. 7, 55–60 (2007).
Ye, H., Gao, Y., Guo, X. H. & Zhao, M. H. Titre and affinity of propylthiouracil-induced anti-myeloperoxidase antibodies are closely associated with the development of clinical vasculitis. Clin. Exp. Immunol. 142, 116–119 (2005).
Gao, Y. et al. Follow-up of avidity and titre of anti-myeloperoxidase antibodies in sera from patients with propylthiouracil-induced vasculitis. Clin. Endocrinol. (Oxf.) 66, 543–547 (2007).
Fujieda, M. et al. Epitope analysis of myeloperoxidase-specific antineutrophil cytoplasmic autoantibodies (MPO-ANCA) in childhood onset Graves' disease treated with propylthiouracil. Clin. Nephrol. 63, 437–445 (2005).
Yu, F., Zhao, M. H., Zhang, Y. K., Zhang, Y. & Wang, H. Y. Anti-endothelial cell antibodies (AECA) in patients with propylthiouracil (PTU)-induced ANCA positive vasculitis are associated with disease activity. Clin. Exp. Immunol. 139, 569–574 (2005).
Herlin, T., Birkebaek, N. H., Wolthers, O. D., Heegaard, N. H. & Wiik, A. Anti-neutrophil cytoplasmic autoantibody (ANCA) profiles in propylthiouracil-induced lupus-like manifestations in monozygotic triplets with hyperthyroidism. Scand. J. Rheumatol. 31, 46–49 (2002).
Yu, F. et al. Clinical and pathological features of renal involvement in propylthiouracil-associated ANCA-positive vasculitis. Am. J. Kidney Dis. 49, 607–614 (2007).
Chen, Y. X. et al. Propylthiouracil-induced antineutrophil cytoplasmic antibody (ANCA)-associated renal vasculitis versus primary ANCA-associated renal vasculitis: a comparative study. J. Rheumatol. 39, 558–563 (2012).
Chen, Y. X. et al. Propylthiouracil-associated antineutrophil cytoplasmic autoantibody-positive vasculitis: retrospective study of 19 cases. J. Rheumatol. 34, 2451–2456 (2007).
Schur, P. H. IgG subclasses—a review. Ann. Allergy 58, 89–96 (1987).
Gao, Y., Ye, H., Yu, F., Guo, X. H. & Zhao, M. H. Anti-myeloperoxidase IgG subclass distribution and avidity in sera from patients with propylthiouracil-induced antineutrophil cytoplasmic antibodies associated vasculitis. Clin. Immunol. 117, 87–93 (2005).
Aalberse, R. C., van der Gaag, R. & van Leeuwen, J. Serologic aspects of IgG4 antibodies. I. Prolonged immunization results in an IgG4-restricted response. J. Immunol. 130, 722–726 (1983).
Ye, H., Zhao, M. H., Gao, Y., Guo, X. H. & Wang, H. Y. Antimyeloperoxidase antibodies in sera from patients with propylthiouracil-induced vasculitis might recognize restricted epitopes on myeloperoxidase molecule. Clin. Exp. Immunol. 138, 179–182 (2004).
Yung, R. L. & Richardson, B. C. Drug-induced lupus. Rheum. Dis. Clin. North Am. 20, 61–85 (1994).
Bilge, N. S., Kasifoglu, T. & Korkmaz, C. PTU-induced ANCA-positive vasculitis: an innocent or a life-threatening adverse effect? Rheumatol. Int. http://dx.doi.org/10.1007/s00296-011-2280-5.
Flendrie, M. et al. Dermatological conditions during TNF-α-blocking therapy in patients with rheumatoid arthritis: a prospective study. Arthritis Res. Ther. 7, R666–R676 (2005).
Doyle, M. K. & Cuellar, M. L. Drug-induced vasculitis. Expert Opin. Drug Saf. 2, 401–409 (2003).
Vasoo, S. Drug-induced lupus: an update. Lupus 15, 757–761 (2006).
Sheen, Y. S., Chu, C. Y. & Yu, H. S. Antineutrophil cytoplasmic antibody-positive cutaneous leukocytoclastic vasculitis associated with propylthiouracil therapy. Arch. Dermatol. 142, 879–880 (2006).
Merkel, P. A. Drug-induced vasculitis. Rheum. Dis. Clin. North Am. 27, 849–862 (2001).
Maguchi, S., Fukuda, S., Chida, E. & Terayama, Y. Myeloperoxidase-antineutrophil cytoplasmic antibody-associated sensorineural hearing loss. Auris Nasus Larynx 28, S103–S106 (2001).
Sano, M., Kitahara, N. & Kunikata, R. Progressive bilateral sensorineural hearing loss induced by an antithyroid drug. ORL J. Otorhinolaryngol. Relat. Spec. 66, 281–285 (2004).
Colakovski, H. & Lorber, D. L. Propylthiouracil-induced perinuclear-staining antineutrophil cytoplasmic autoantibody-positive vasculitis in conjunction with pericarditis. Endocr. Pract. 7, 37–39 (2001).
Darben, T., Savige, J., Prentice, R., Paspaliaris, B. & Chick, J. Pyoderma gangrenosum with secondary pyarthrosis following propylthiouracil. Australas. J. Dermatol. 40, 144–146 (1999).
Hong, S. B. & Lee, M. H. A case of propylthiouracil-induced pyoderma gangrenosum associated with antineutrophil cytoplasmic antibody. Dermatology 208, 339–341 (2004).
Vanek, C. & Samuels, M. H. Central nervous system vasculitis caused by propylthiouracil therapy: a case report and literature review. Thyroid 15, 80–84 (2005).
Abe, T. et al. Cerebral pachyleptomeningitis associated with MPO-ANCA induced by PTU therapy. Intern. Med. 46, 247–250 (2007).
Ishii, R. et al. A long-term follow-up of serum myeloperoxidase antineutrophil cytoplasmic antibodies (MPO-ANCA) in patients with Graves disease treated with propylthiouracil. Endocr. J. 57, 73–79 (2010).
Morais, P. et al. Antineutrophil cytoplasmic antibody (ANCA)-positive cutaneous leukocytoclastic vasculitis induced by propylthiouracil confirmed by positive patch test: a case report and review of the literature. Cutan. Ocul. Toxicol. 30, 147–153 (2011).
Irani, F., Elkambergy, H., Naraharisetty, K. & Jamal, R. Propylthiouracil-induced leucocytoclastic vasculitis with pulmonary hemorrhage treated with plasmapheresis. Am. J. Med. Sci. 337, 470–472 (2009).
Dhillon, S. S. et al. Diffuse alveolar hemorrhage and pulmonary capillaritis due to propylthiouracil. Chest 116, 1485–1488 (1999).
Jennette, J. C. et al. Nomenclature of systemic vasculitides. Proposal of an international consensus conference. Arthritis Rheum. 37, 187–192 (1994).
Radic, M., Martinovic Kaliterna, D. & Radic, J. Drug-induced vasculitis: a clinical and pathological review. Neth. J. Med. 70, 12–17 (2012).
Cuellar, M. L. Drug-induced vasculitis. Curr. Rheumatol. Rep. 4, 55–59 (2002).
Gao, Y. et al. Long-term outcomes of patients with propylthiouracil-induced anti-neutrophil cytoplasmic auto-antibody-associated vasculitis. Rheumatology (Oxford) 47, 1515–1520 (2008).
Acknowledgements
Our studies discussed in this Review were supported by a grant from the Chinese 973 project (No. 2012CB517702) and two grants from the National Natural Science Fund (No. 30972733 and No. 81021004).
Author information
Authors and Affiliations
Contributions
M. Chen and Y. Gao researched data to include in the article and made a substantial contribution to discussion of content for the article. M. Chen and M.-H. Zhao wrote the article. M. Chen, X.-H. Guo and M.-H. Zhao reviewed and edited the manuscript before submission.
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Rights and permissions
About this article
Cite this article
Chen, M., Gao, Y., Guo, XH. et al. Propylthiouracil-induced antineutrophil cytoplasmic antibody-associated vasculitis. Nat Rev Nephrol 8, 476–483 (2012). https://doi.org/10.1038/nrneph.2012.108
Published:
Issue Date:
DOI: https://doi.org/10.1038/nrneph.2012.108