Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Complications of long-term therapy for ANCA-associated systemic vasculitis

Nature Reviews Nephrology volume 8, pages 523–532 (2012)Cite this article

Subjects

Abstract

The antineutrophil cytoplasmic antibody (ANCA)-associated systemic vasculitides (AASVs) include granulomatosis with polyangiitis and microscopic polyangiitis. These conditions are characterized by small-vessel inflammation and necrosis, predominantly in pulmonary and renal vascular beds. Untreated AASV has a poor prognosis, although the advent of effective immunosuppressive therapy (the mainstay of which remains cyclophosphamide with high-dose corticosteroids) has markedly improved patients' survival (78% at 5 years). Patients with AASV, however, continue to have an increased mortality compared to the general population. Mortality is greatest in the first year after diagnosis and remains consistently elevated in subsequent years. Patients with AASV also experience increased rates of infections, malignancies and cardiovascular events as compared to the general population. Current treatments for AASV, although effective in controlling the aggressive systemic disease, incur substantial long-term toxic effects. Long-term immunosuppressive therapy also has notable deleterious effects on bone health and fertility. The long-term safety profiles of biological therapies (such as rituximab) are yet to be evaluated in patients with AASV, but represent a promising treatment option. The challenge for the future is to develop specific therapies with improved safety profiles that can cure these diseases.

Key Points

  • Effective immunosuppressive therapy with cyclophosphamide and corticosteroids has markedly improved survival of patients with antineutrophil cytoplasmic antibody-associated systemic vasculitides (AASVs)

  • Patients with AASV should be informed of the potential risks associated with long-term immunosuppressive therapy

  • The risk of infection can be reduced by vaccination for influenza and pneumococcal species, use of topical antifungal agents and trimethoprim–sulfamethoxazole, together with regular monitoring for leukopenia

  • The substantial increase in risk of malignancy associated with cyclophosphamide therapy mandates lifelong surveillance for nonglomerular haematuria

  • Bone health and preservation of fertility must be addressed in all patients with AASVs

  • Assessments for cardiovascular disease and venous thromboembolism should form part of routine care for patients with AASVs

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

  1. Kallenberg, C. G. M. Pathogenesis of ANCA-associated vasculitis, an update. Clin. Rev. Allergy Immunol. 41, 224–231 (2011).

    Article  PubMed  Google Scholar 

  2. Reinhold-Keller, E., Herlyn, K., Wagner-Bastmeyer, R. & Gross, W. L. Stable incidence of primary systemic vasculitides over five years: results from the German vasculitis register. Arthritis Rheum. 53, 93–99 (2005).

    Article  PubMed  Google Scholar 

  3. Lane, S. E., Watts, R. & Scott, D. G. I. Epidemiology of systemic vasculitis. Curr. Rheumatol. Rep. 7, 270–275 (2005).

    Article  PubMed  Google Scholar 

  4. Harper, L. & Savage, C. O. ANCA-associated renal vasculitis at the end of the twentieth century—a disease of older patients. Rheumatology 44, 495–501 (2005).

    Article  CAS  PubMed  Google Scholar 

  5. Walton, E. W. Giant-cell granuloma of the respiratory tract (Wegeners granulomatosis). Br. Med. J. 2, 265–270 (1958).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Eriksson, P., Jacobsson, L., Lindell, A., Nilsson, J. A. & Skogh, T. Improved outcome in Wegener's granulomatosis and microscopic polyangiitis? A retrospective analysis of 95 cases in two cohorts. J. Int. Med. 265, 496–506 (2009).

    Article  CAS  Google Scholar 

  7. Stratta, P. et al. Improvement in relative survival of patients with vasculitis: study of 101 cases compared to the general population. Int. J. Immunopathol. Pharmacol. 21, 631–642 (2008).

    Article  CAS  PubMed  Google Scholar 

  8. Flossmann, O. et al. Long-term patient survival in ANCA-associated vasculitis. Ann. Rheum. Dis. 70, 488–494 (2011).

    Article  PubMed  Google Scholar 

  9. Holle, J. U. et al. Improved outcome in 445 patients with Wegener's granulomatosis in a German vasculitis center over four decades. Arthritis Rheum. 63, 257–266 (2011).

    Article  PubMed  Google Scholar 

  10. Bosch, X., Guilabert, A., Espinosa, G. & Mirapeix, E. Treatment of antineutrophil cytoplasmic antibody-associated vasculitis—a systematic reviw. JAMA 298, 655–669 (2007).

    Article  CAS  PubMed  Google Scholar 

  11. Mukhtyar, C. et al. EULAR recommendations for the management of primary small and medium vessel vasculitis. Ann. Rheum. Dis. 68, 310–317 (2009).

    Article  CAS  PubMed  Google Scholar 

  12. Lapraik, C. et al. BSR and BHPR guidelines for the management of adults with ANCA associated vasculitis. Rheumatology 46, 1615–1616 (2007).

    Article  CAS  PubMed  Google Scholar 

  13. Mukhtyar, C. et al. Outcomes from studies of antineutrophil cytoplasm antibody associated vasculitis: a systematic review by the European League Against Rheumatism systemic vasculitis task force. Ann. Rheum. Dis. 67, 1004–1010 (2008).

    Article  CAS  PubMed  Google Scholar 

  14. Schäcke, H., Döcke, W.-D. & Asadullah, K. Mechanisms involved in the side effects of glucocorticoids. Pharmacol. Ther. 96, 23–43 (2002).

    Article  PubMed  Google Scholar 

  15. Turnbull, J. & Harper, L. Adverse effects of therapy for ANCA-associated vasculitis. Best Pract. Res. Clin. Rheumatol. 23, 391–401 (2009).

    Article  PubMed  Google Scholar 

  16. Hamour, S., Salama, A. D. & Pusey, C. D. Management of ANCA-associated vasculitis: Current trends and future prospects. Ther. Clin. Risk Manag. 6, 253–264 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. de Groot, K. et al. DRW for EUVAS. Randomized trial of cyclophosphamide versus methotrexate for induction of remission in non-renal ANCA-associated vasculitis. Arthritis Rheum. 48, S660–S660 (2003).

    Article  CAS  Google Scholar 

  18. Casian, A. & Jayne, D. Plasma exchange in the treatment of Wegener's granulomatosis, microscopic polyangiitis, Churg-Strauss syndrome and renal limited vasculitis. Curr. Opin. Rheumatol. 23, 12–17 (2011).

    Article  PubMed  Google Scholar 

  19. Stegmayr, B. et al. World apheresis registry 2003–2007 data. Transfus. Apher. Sci. 39, 247–254 (2008).

    Article  CAS  PubMed  Google Scholar 

  20. Rufino Hernandez, M. et al. Patients treated with plasmapheresis: a case review from University Hospital of the Canary Islands. Nefrologia 31, 415–434 (2011).

    PubMed  Google Scholar 

  21. Ei-Ghariani, K. & Unsworth, D. J. Therapeutic apheresis—plasmapheresis. Clin. Med. 6, 343–347 (2006).

    Article  Google Scholar 

  22. Wood, L. & Jacobs, P. The effect of serial therapeutic plasmapheresis on platelet count, coagulation factors, plasma immunoglobulin, and complement levels. J. Clin. Apher. 3, 124–128 (1986).

    Article  CAS  PubMed  Google Scholar 

  23. Metzler, C. et al. Elevated relapse rate under oral methotrexate versus leflunomide for maintenance of remission in Wegener's gyranulomatosis. Rheumatology 46, 1087–1091 (2007).

    Article  CAS  PubMed  Google Scholar 

  24. Berden, A. et al. Long-term renal outcome of patients enrolled in the CYCAZAREM trial. Clin. Exp. Immunol. 164, 51 (2011).

    Google Scholar 

  25. Jayne, D. et al. A randomized trial of maintenance therapy for vasculitis associated with antineutrophil cytoplasmic autoantibodies. N. Engl. J. Med. 349, 36–44 (2003).

    Article  CAS  PubMed  Google Scholar 

  26. Langford, C. A., Talar-Williams, C., Barron, K. S. & Sneller, M. C. Use of a cyclophosphamide-induction methotrexate-maintenance regimen for the treatment of Wegener's granulomatosis: extended follow-up and rate of relapse. Am. J. Med. 114, 463–469 (2003).

    Article  CAS  PubMed  Google Scholar 

  27. Chakravarty, K. et al. BSR/BHPR guideline for disease-modifying anti-rheumatic drug (DMARD) therapy in consultation with the British association of dermatologists. Rheumatology 47, 924–925 (2008).

    Article  CAS  PubMed  Google Scholar 

  28. Newman, W. G. et al. A pragmatic randomized controlled trial of thiopurine methyltransferase genotyping prior to azathioprine treatment: the TARGET study. Pharmacogenomics 12, 815–826 (2011).

    Article  CAS  PubMed  Google Scholar 

  29. Hiemstra, T. F. et al. Mycophenolate mofetil vs azathioprine for remission maintenance in antineutrophil cytoplasmic antibody-associated vasculitis a randomzed controlled trial. JAMA 304, 2381–2388 (2010).

    Article  CAS  PubMed  Google Scholar 

  30. Jones, R. B. et al. Rituximab versus cyclophosphamide in ANCA-associated renal vasculitis. N. Engl. J. Med. 363, 211–220 (2010).

    Article  CAS  PubMed  Google Scholar 

  31. Stone, J. H. et al. Rituximab versus cyclophosphamide for ANCA-associated vasculitis. N. Engl. J. Med. 363, 221–232 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Helena, M. et al. Hypogammaglobulinaemia and infections following RTX therapy for systemic vasculitis and SLE. Clin. Exp. Immunol. 164, 59–60 (2011).

    Google Scholar 

  33. Buch, M. H. et al. Updated consensus statement on the use of rituximab in patients with rheumatoid arthritis. Ann. Rheum. Dis. 70, 909–920 (2011).

    Article  CAS  PubMed  Google Scholar 

  34. Bukhari, M. et al. BSR and BHPR guidelines on the use of rituximab in rheumatoid arthritis. Rheumatology 50, 2311–2313 (2011).

    Article  PubMed  Google Scholar 

  35. Tesfa, D. et al. Late-onset neutropenia following rituximab therapy in rheumatic diseases: association with B lymphocyte depletion and infections. Arthritis Rheum. 63, 2209–2214 (2011).

    Article  CAS  PubMed  Google Scholar 

  36. Tesfa, D. & Palmblad, J. Late-onset neutropenia following rituximab therapy: incidence, clinical features and possible mechanisms. Expert Rev. Hematol. 4, 619–625 (2011).

    Article  CAS  PubMed  Google Scholar 

  37. Morgan, M. D., Drayson, M. T., Savage, C. O. S. & Harper, L. Addition of infliximab to standard therapy for ANCA-associated vasculitis. Nephron Clin. Pract. 117, C89–C97 (2011).

    Article  CAS  PubMed  Google Scholar 

  38. Stone, J. H. et al. Etanercept plus standard therapy for Wegener's granulomatosis. N. Engl. J. Med. 352, 351–361 (2005).

    Article  CAS  Google Scholar 

  39. Booth, A. D. et al. Outcome of ANCA-associated renal vasculitis: a 5-year retrospective study. Am. J. Kidney Dis. 41, 776–784 (2003).

    Article  PubMed  Google Scholar 

  40. Little, M. A. et al. Early mortality in systemic vasculitis: relative contribution of adverse events and active vasculitis. Ann. Rheum. Dis. 69, 1036–1043 (2010).

    Article  PubMed  Google Scholar 

  41. Villa-Forte, A. et al. Substitution of methotrexate for cyclophosphamide in Wegener granulomatosis—a 12-year single-practice experience. Medicine 86, 269–277 (2007).

    Article  CAS  PubMed  Google Scholar 

  42. Hellmich, B., Schanbel, A. & Gross, W. L. Granulocyte colony-stimulating factor treatment for cyclophosphamide-induced severe neutropenia in Wegener's granulomatosis. Arthritis Rheum. 42, 1752–1756 (1999).

    Article  CAS  PubMed  Google Scholar 

  43. Charlier, C. et al. Risk factors for major infections in Wegener granulomatosis: analysis of 113 patients. Ann. Rheum. Dis. 68, 658–663 (2009).

    Article  CAS  PubMed  Google Scholar 

  44. Reinhold-Keller, E. et al. An interdisciplinary approach to the care of patients with Wegener's granulomatosis—long-term outcome in 155 patients. Arthritis Rheum. 43, 1021–1032 (2000).

    Article  CAS  PubMed  Google Scholar 

  45. Hoffman, G. S. et al. Wegener granulomatosis—an analysis of 158 patients. Ann. Intern. Med. 116, 488–498 (1992).

    Article  CAS  PubMed  Google Scholar 

  46. Jones, R. B., Walsh, M., Jayne, D. R. W. & European Vasculitis Study, G. Two-year follow-up results from a randomized trial of RTX versus CyP for ANCA-associated renal vasculitis: RITUXVAS. Clin. Exp. Immunol. 164, 57–58 (2011).

    Article  CAS  Google Scholar 

  47. Oren, S. et al. Vaccination against influenza in patients with rheumatoid arthritis: the effect of rituximab on the humoral response. Ann. Rheum. Dis. 67, 937–941 (2008).

    Article  CAS  PubMed  Google Scholar 

  48. Bingham, C. O. et al. Immunization responses in rheumatoid arthritis patients treated with rituximab results from a controlled clinical trial. Arthritis Rheum. 62, 64–74 (2010).

    Article  CAS  PubMed  Google Scholar 

  49. Stassen, P. M., Sanders, J.-S. F., Kallenberg, C. G. M. & Stegeman, C. A. Influenza vaccination does not result in an increase in relapses in patients with ANCA-associated vasculitis. Nephrol. Dial. Transplant. 23, 654–658 (2008).

    Article  PubMed  Google Scholar 

  50. Holvast, A. et al. Wegener's granulomatosis patients show an adequate antibody response to influenza vaccination. Ann. Rheum. Dis. 68, 873–878 (2009).

    Article  CAS  PubMed  Google Scholar 

  51. van Assen, S. et al. EULAR recommendations for vaccination in adult patients with autoimmune inflammatory rheumatic diseases. Ann. Rheum. Dis. 70, 414–422 (2011).

    Article  CAS  PubMed  Google Scholar 

  52. Koselj-Kajtna, M., Koselj, M., Rott, T., Kandus, A. & Bren, A. Infectious complications of immunosuppressive treatment for anti-neutrophil cytoplasm antibody-related vasculitis. Transplant. Proc. 34, 3001–3002 (2002).

    Article  CAS  PubMed  Google Scholar 

  53. Laudien, M. et al. Nasal carriage of Staphylococcus aureus and endonasal activity in Wegener's granulomatosis as compared to rheumatoid arthritis and chronic rhinosinusitis with nasal polyps. Clin. Exp. Rheumatol. 28, S51–S55 (2010).

    Google Scholar 

  54. van Rijen, M., Bonten, M., Wenzel, R. & Kluytmans, J. Mupirocin ointment for preventing Staphylococcus aureus infections in nasal carriers. Cochrane Database of Systematic Reviews, Issue 3. Art. No.: CD006216. http://dx.doi.org/10.1002/14651858.CD006216.pub2.

  55. Moosig, F., Holle, J. U. & Gross, W. L. Value of anti-infective chemoprophylaxis in primary systemic vasculitis: what is the evidence? Arthritis Res. Ther. 11, 1–11 (2009).

    Article  CAS  Google Scholar 

  56. Stegeman, C. A., Tervaert, J. W. C., deJong, P. E. & Kallenberg, C. G. M. Trimethoprim-sulfamethoxazole (co-trimoxazole) for the prevention of relapses of Wegener's granulomatosis. N. Engl. J. Med. 335, 16–20 (1996).

    Article  CAS  PubMed  Google Scholar 

  57. Ognibene, F. P. et al. Pneumocystis-carinii pneumonia—a major complication of immunosuppressive therapy in patients with wegeners granulomatosis. Am. J. Respir. Crit. Care Med. 151, 795–799 (1995).

    CAS  PubMed  Google Scholar 

  58. Ward, M. M. & Donald, F. Pneumocystis carinii pneumonia in patients with connective tissue diseases—the role of hospital experience in diagnosis and mortality. Arthritis Rheum. 42, 780–789 (1999).

    Article  CAS  PubMed  Google Scholar 

  59. Falagas, M. E., Manta, K. G., Betsi, G. I. & Pappas, G. Infection-related morbidity and mortality in patients with connective tissue diseases: a systematic review. Clin. Rheumatol. 26, 663–670 (2007).

    Article  PubMed  Google Scholar 

  60. Guillevin, L. et al. A prospective, multicenter, randomized trial comparing steroids and pulse cyclophosphamide versus steroids and oral cyclophosphamide in the treatment of generalized Wegener's granulomatosis. Arthritis Rheum. 40, 2187–2198 (1997).

    Article  CAS  PubMed  Google Scholar 

  61. Sowden, E. & Carmichael, A. J. Autoimmune inflammatory disorders, systemic corticosteroids and pneumocystis pneumonia: a strategy for prevention. BMC Infect. Dis. 4, 1–6 (2004).

    Article  CAS  Google Scholar 

  62. Marcotte, H. et al. Pneumocystis carinii infection in transgenic B cell-deficient mice. J. Infect. Dis. 173, 1034–1037 (1996).

    Article  CAS  PubMed  Google Scholar 

  63. Hugle, B. et al. Pneumocystis jiroveci pneumonia following rituximab treatment in Wegener's granulomatosis. Arthritis Care Res. 62, 1661–1664 (2010).

    Article  Google Scholar 

  64. Wung, P. K. et al. Herpes zoster in immunocompromised patients: incidence, timing, and risk factors. Am. J. Med. 118, 1416 (2005).

    Article  PubMed  Google Scholar 

  65. Wung, P. K. et al. Risk factors for herpes zoster in immunocompromised patients: experience from the Wegener's granulomatosis etanercept trial. Arthritis Rheum. 52, S648–S649 (2005).

    Google Scholar 

  66. Evens, A. M. et al. Rituximab-associated hepatitis B virus (HBV) reactivation in lymphoproliferative diseases: meta-analysis and examination of FDA safety reports. Ann. Oncol. 22, 1170–1180 (2011).

    Article  CAS  PubMed  Google Scholar 

  67. Ghrenassia, E., Mekinian, A., Rouaghe, S., Ganne, N. & Fain, O. Reactivation of resolved hepatitis B during rituximab therapy for rheumatoid arthritis. Joint Bone Spine 79, 100–101 (2012).

    Article  PubMed  Google Scholar 

  68. Pyrpasopoulou, A. et al. Reactivation of chronic hepatitis B virus infection following rituximab administration for rheumatoid arthritis. Rheumatol. Int. 31, 403–404 (2011).

    Article  PubMed  Google Scholar 

  69. Molloy, E. S. PML and rheumatology: the contribution of disease and drugs. Clev. Clin. J. Med. 78 (Suppl. 2), S28–S32 (2011).

    Article  Google Scholar 

  70. Clifford, D. B. et al. Rituximab-associated progressive multifocal leukoencephalopathy in rheumatoid arthritis. Arch. Neurol. 68, 1156–1164 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  71. Molloy, E. S. & Calabrese, L. H. Progressive multifocal leukoencephalopathy associated with immunosuppressive therapy in rheumatic diseases: evolving role of biologic therapies. Arthritis Rheum. doi:10.1002/art.34468 (2012).

  72. Bharat, A. et al. Incidence and risk factors for progressive multifocal leukoencephalopathy among patients with selected rheumatic diseases. Arthritis Care Res. 64, 612–615 (2012).

    Article  CAS  Google Scholar 

  73. Knight, A. M., Ekbom, A. & Askling, J. Cancer risk in a population based cohort of patients with Wegener's granulomatosis. Arthritis Rheum. 44, S332–S332 (2001).

    Google Scholar 

  74. Westman, K. W. A., Bygren, P. G., Olsson, H., Ranstam, J. & Wieslander, J. Relapse rate, renal survival, and cancer morbidity in patients with Wegener's granulomatosis or microscopic polyangiitis with renal involvement. J. Am. Soc. Nephrol. 9, 842–852 (1998).

    CAS  PubMed  Google Scholar 

  75. Faurschou, M. et al. Malignancies in Wegener's granulomatosis: Incidence and relation to cyclophosphamide therapy in a cohort of 293 patients. J. Rheumatol. 35, 100–105 (2008).

    CAS  PubMed  Google Scholar 

  76. Heijl, C. et al. Incidence of malignancy in patients treated for antineutrophil cytoplasm antibody-associated vasculitis: follow-up data from European Vasculitis Study Group clinical trials. Ann. Rheum. Dis. 70, 1415–1421 (2011).

    Article  CAS  PubMed  Google Scholar 

  77. Le Guenno, G. et al. Incidence and predictors of urotoxic adverse events in cyclophosphamide-treated patients with systemic necrotizing vasculitides. Arthritis Rheum. 63, 1435–1445 (2011).

    Article  CAS  PubMed  Google Scholar 

  78. Knight, A., Askling, J., Granath, F., Sparen, P. & Ekbom, A. Urinary bladder cancer in Wegener's granulomatosis: risks and relation to cyclophosphamide. Ann. Rheum. Dis. 63, 1307–1311 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Nath, R. et al. High risk of human papillomavirus type 16 infections and of development of cervical squamous Intraepithelial lesions in systemic lupus erythematosus patients. Arthritis Rheum. 57, 619–625 (2007).

    Article  CAS  PubMed  Google Scholar 

  80. Pankhurst, T., Savage, C. O. S., Gordon, C. & Harper, L. Malignancy is increased in ANCA-associated vasculitis. Rheumatology 43, 1532–1535 (2004).

    Article  CAS  PubMed  Google Scholar 

  81. Faurschou, M. et al. Cancer preceding Wegeners granulomatosis: a casecontrol study. Rheumatology 48, 421–424 (2009).

    Article  PubMed  Google Scholar 

  82. den Uyl, D., Bultink, I. E. M. & Lems, W. F. Advances in glucocorticoid-induced osteoporosis. Curr. Rheumatol. Rep. 13, 233–240 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Weinstein, R. S. Glucocorticoid-induced bone disease. N. Engl. J. Med. 365, 62–70 (2011).

    Article  CAS  PubMed  Google Scholar 

  84. Boomsma, M. M. et al. Prevalence of reduced bone mineral density in patients with antineutrophil cytoplasmic antibody associated vasculitis and the role of immunosuppressive therapy: a cross-sectional study. Osteoporos. Int. 13, 74–82 (2002).

    Article  CAS  PubMed  Google Scholar 

  85. Boling, E. P. Secondary osteoporosis: underlying disease and the risk for glucocorticoid-induced osteoporosis. Clin. Ther. 26, 1–14 (2004).

    Article  CAS  PubMed  Google Scholar 

  86. Compston, J. et al. Guidelines for the diagnosis and management of osteoporosis in postmenopausal women and men from the age of 50 years in the UK. Maturitas 62, 105–108 (2009).

    Article  CAS  PubMed  Google Scholar 

  87. Rodrigues Pereira, R. M., de Carvalho, J. F. & Canalis, E. Glucocorticoid-induced osteoporosis in rheumatic diseases. Clinics 65, 1197–1205 (2010).

    Article  Google Scholar 

  88. Tang, B. M. P., Eslick, G. D., Nowson, C., Smith, C. & Bensoussan, A. Use of calcium or calcium in combination with vitamin D supplementation to prevent fractures and bone loss in people aged 50 years and older: a meta-analysis. Lancet 370, 657–666 (2007).

    Article  CAS  PubMed  Google Scholar 

  89. Grossman, J. M. et al. American college of rheumatology recommendations for the prevention and treatment of glucocorticoid-induced osteoporosis. Arthritis Care Res. 62, 1515–1526 (2010).

    Article  Google Scholar 

  90. Adachi, J. D. et al. Two-year effects of alendronate on bone mineral density and vertebral fracture in patients receiving glucocorticoids—a randomized, double-blind, placebo-controlled extension trial. Arthritis Rheum. 44, 202–211 (2001).

    Article  CAS  PubMed  Google Scholar 

  91. Reid, D. M. et al. Zoledronic acid and risedronate in the prevention and treatment of glucocorticoid-induced osteoporosis (HORIZON): a multicentre, double-blind, double-dummy, randomised controlled trial. Lancet 373, 1253–1263 (2009).

    Article  CAS  PubMed  Google Scholar 

  92. Netelenbos, J. C., Geusens, P. P., Ypma, G. & Buijs, S. J. E. Adherence and profile of non-persistence in patients treated for osteoporosis—a large-scale, long-term retrospective study in the Netherlands. Osteoporos. Int. 22, 1537–1546 (2011).

    Article  CAS  PubMed  Google Scholar 

  93. Landfeldt, E., Ström, O., Robbins, S. & Borgström, F. Adherence to treatment of primary osteoporosis and its association to fractures—the Swedish Adherence Register Analysis (SARA). Osteoporos. Int. 29, 433–443 (2012).

    Article  Google Scholar 

  94. Newman, E. D. et al. Glucocorticoid-induced osteoporosis program (GIOP): a novel, comprehensive, and highly successful care program with improved outcomes at 1 year. Osteoporos. Int. 17, 1428–1434 (2006).

    Article  CAS  PubMed  Google Scholar 

  95. Dooley, M. A. & Nair, R. Therapy insight: preserving fertility in cyclophosphamide-treated patients with rheumatic disease. Nat. Clin. Pract. Rheumatol. 4, 250–257 (2008).

    Article  CAS  PubMed  Google Scholar 

  96. Schmidt, K. L. T. et al. Assisted reproduction in male cancer survivors: fertility treatment and outcome in 67 couples. Human Reprod. 19, 2806–2810 (2004).

    Article  Google Scholar 

  97. Boumpas, D. T. et al. Risk for sustained amenorrhea in patients with systemic lupus-erythematosus receiving intermittent pulse cyclophosphamide therapy. Ann. Intern. Med. 119, 366–369 (1993).

    Article  CAS  PubMed  Google Scholar 

  98. Seo, P. et al. Damage caused by Wegener's granulomatosis and its treatment—prospective data from the Wegener's granulomatosis Etanercept trial (WGET). Arthritis Rheum. 52, 2168–2178 (2005).

    Article  CAS  PubMed  Google Scholar 

  99. Mok, C. C., Lau, C. S. & Wong, R. W. S. Risk factors for ovarian failure in patients with systemic lupus erythematosus receiving cyclophosphamide therapy. Arthritis Rheum. 41, 831–837 (1998).

    Article  CAS  PubMed  Google Scholar 

  100. Shim, L., Eslick, G. D., Simring, A. A., Murray, H. & Weltman, M. D. The effects of azathioprine on birth outcomes in women with inflammatory bowel disease (IBD). J. Crohns Colitis 5, 234–238 (2011).

    Article  PubMed  Google Scholar 

  101. Langagergaard, V., Pedersen, L., Gislum, M., Norgard, B. & Sorensen, H. T. Birth outcome in women treated with azathioprine or mercaptopurine during pregnancy: a Danish nationwide cohort study. Aliment. Pharmacol. Ther. 25, 73–81 (2007).

    Article  CAS  PubMed  Google Scholar 

  102. Royal College of Physicians, The Royal College of Radiologists, Royal College of Obstetricians and Gynaecologists. The effects of cancer treatment on reproductive functions: guidance on management. Report of a Working Party. Royal College of Obstetricians and Gynaecologists [online], (2007).

  103. Suppiah, R. et al. A model to predict cardiovascular events in patients with newly diagnosed Wegener's granulomatosis and microscopic polyangiitis. Arthritis Care Res. 63, 588–596 (2011).

    Article  Google Scholar 

  104. Morgan, M. D. et al. Increased incidence of cardiovascular events in patients with antineutrophil cytoplasmic antibody-associated vasculitides a matched-pair cohort study. Arthritis Rheum. 60, 3493–3500 (2009).

    Article  PubMed  Google Scholar 

  105. Wung, P. K. et al. Effects of glucocorticoids on weight change during the treatment of Wegener's granulomatosis. Arthritis Rheum. 59, 746–753 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  106. Merkel, P. A. et al. Brief communication: high incidence of venous thrombotic events among patients with Wegener granulomatosis: the Wegener's clinical occurrence of thrombosis (WeCLOT) study. Ann. Intern. Med. 142, 620–626 (2005).

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Infection & Immunity, University of Birmingham Medical School, Edgbaston, B15 2TT, Birmingham, UK

    Nadezhda Wall & Lorraine Harper

Authors
  1. Nadezhda Wall
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Lorraine Harper
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Both authors contributed equally to researching data for the article, writing the manuscript, discussions of the content and review or editing of the article before submission.

Corresponding author

Correspondence to Lorraine Harper.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wall, N., Harper, L. Complications of long-term therapy for ANCA-associated systemic vasculitis. Nat Rev Nephrol 8, 523–532 (2012). https://doi.org/10.1038/nrneph.2012.107

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrneph.2012.107

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing