Cancer risks along the disease trajectory in antineutrophil cytoplasmic antibody associated vasculitis

Abstract

This review appraises the current literature on carcinogenic risks in anti-neutrophilic cytoplasmic autoantibody (ANCA) associated vasculitis (AAV). Patients with AAV are often at increased risk of developing non-melanoma skin carcinomas (NMSCs), haematological malignancies, bladder, breast, lung, prostate, and colorectal carcinomas. Reported cancer incidence in these patients ranged from 10 to 26%. Cancer risks at the time of diagnosis of AAV and disease outcomes along the trajectory of AAV that may lead to chronic kidney disease (CKD); dialysis and transplantation are summarized. Inherent carcinogenic risks as part of immunosuppressive treatment in AAV are further detailed with considerations on specific malignancy risks of therapeutic agents used. Challenges that contribute to malignancy risk include a high relapse rate of AAV and prolonged exposure to immunosuppressants. The incidence of malignancy increases significantly after 5 years of immunosuppressant exposure though risks in the earlier years have also been described. Following renal transplantation, there is limited information available on risk of malignancy. Thoughtful use of immunosuppressants, modification of lifestyle, and environmental factors, as well as adopting appropriate cancer screening will likely influence malignancy risk in individuals with AAV.

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References

  1. 1.

    Jennette JC, Falk RJ, Bacon PA, Basu N, Cid MC, Ferrario F et al (2013) 2012 revised international Chapel Hill consensus conference nomenclature of Vasculitides. Arthritis Rheum 65(1):1–11

    CAS  PubMed  Google Scholar 

  2. 2.

    McAdoo SP, Medjeral-Thomas N, Gopaluni S, Tanna A, Mansfield N, Galliford J, et al. Long-term follow-up of a combined rituximab and cyclophosphamide regimen in renal anti-neutrophil cytoplasm antibody-associated vasculitis. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. 2018;33(5):899

  3. 3.

    Yoo J, Ahn SS, Jung SM, Song JJ, Park YB, Lee SW. Cancer development in Korean patients with ANCA-associated vasculitis: a single centre study. Clin Exp Rheumatol. 2018;36 Suppl 111(2):73–7

  4. 4.

    Karras A, Pagnoux C, Haubitz M, Groot K, Puechal X, Tervaert JWC, Segelmark M, Guillevin L, Jayne D, European Vasculitis Society (2017) Randomised controlled trial of prolonged treatment in the remission phase of ANCA-associated vasculitis. Ann Rheum Dis 76(10):1662–1668

    CAS  PubMed  Google Scholar 

  5. 5.

    Thiel J, Troilo A, Salzer U, Schleyer T, Halmschlag K, Rizzi M, Frede N, Venhoff A, Voll RE, Venhoff N (2017) Rituximab as induction therapy in Eosinophilic Granulomatosis with Polyangiitis refractory to conventional immunosuppressive treatment: a 36-month follow-up analysis. J Allergy Clin Immunol Pract 5(6):1556–1563

    PubMed  Google Scholar 

  6. 6.

    van Daalen EE, Rizzo R, Kronbichler A, Wolterbeek R, Bruijn JA, Jayne DR, Bajema IM, Rahmattulla C (2017) Effect of rituximab on malignancy risk in patients with ANCA-associated vasculitis. Ann Rheum Dis 76(6):1064–1069

    PubMed  Google Scholar 

  7. 7.

    Sriskandarajah S, Bostad L, Myklebust TA, Moller B, Skrede S, Bjorneklett R (2017) Cancer in ANCA-associated glomerulonephritis: a registry-based cohort study. Int J Nephrol 2017:6013038

    PubMed  PubMed Central  Google Scholar 

  8. 8.

    Sanders JS, de Joode AA, De Sevaux RG, Broekroelofs J, Voskuyl AE, van Paassen P, et al. Extended versus standard azathioprine maintenance therapy in newly diagnosed proteinase-3 anti-neutrophil cytoplasmic antibody-associated vasculitis patients who remain cytoplasmic anti-neutrophil cytoplasmic antibody-positive after induction of remission: a randomized clinical trial. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. 2016;31(9):1453–9

  9. 9.

    Robson J, Doll H, Suppiah R, Flossmann O, Harper L, Hoglund P et al (2015) Damage in the anca-associated vasculitides: long-term data from the European vasculitis study group (EUVAS) therapeutic trials. Ann Rheum Dis 74(1):177–184

    PubMed  Google Scholar 

  10. 10.

    Rahmattulla C, Berden AE, Wakker SC, Reinders ME, Hagen EC, Wolterbeek R, et al. Incidence of Malignancies in Patients With Antineutrophil Cytoplasmic Antibody-Associated Vasculitis Diagnosed Between 1991 and 2013. Arthritis Rheum (Hoboken, NJ). 2015;67(12):3270–3278

  11. 11.

    Alberici F, Smith RM, Jones RB, Roberts DM, Willcocks LC, Chaudhry A et al (2015) Long-term follow-up of patients who received repeat-dose rituximab as maintenance therapy for ANCA-associated vasculitis. Rheumatology (Oxford, England) 54(7):1153–1160

    CAS  Google Scholar 

  12. 12.

    McGregor JG, Hogan SL, Kotzen ES, Poulton CJ, Hu Y, Negrete-Lopez R et al (2015) Rituximab as an immunosuppressant in antineutrophil cytoplasmic antibody-associated vasculitis. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association 30(Suppl 1):i123–i131

    CAS  Google Scholar 

  13. 13.

    Faurschou M, Mellemkjaer L, Voss A, Keller KK, Hansen IT, Baslund B (2015) Prolonged risk of specific malignancies following cyclophosphamide therapy among patients with granulomatosis with polyangiitis. Rheumatology (Oxford, England) 54(8):1345–1350

    CAS  Google Scholar 

  14. 14.

    Guillevin L, Pagnoux C, Karras A, Khouatra C, Aumaitre O, Cohen P et al (2014) Rituximab versus azathioprine for maintenance in ANCA-associated vasculitis. N Engl J Med 371(19):1771–1780

    PubMed  Google Scholar 

  15. 15.

    Azar L, Springer J, Langford CA, Hoffman GS. Rituximab with or without a conventional maintenance agent in the treatment of relapsing granulomatosis with polyangiitis (Wegener's): a retrospective single-center study. Arthritis Rheum (Hoboken, NJ). 2014;66(10):2862–2870

  16. 16.

    Pendergraft WF 3rd, Cortazar FB, Wenger J, Murphy AP, Rhee EP, Laliberte KA et al (2014) Long-term maintenance therapy using rituximab-induced continuous B-cell depletion in patients with ANCA vasculitis. Clin J Am Soc Nephrol 9(4):736–744

    CAS  PubMed  PubMed Central  Google Scholar 

  17. 17.

    Calich AL, Puechal X, Pugnet G, London J, Terrier B, Charles P et al (2014) Rituximab for induction and maintenance therapy in granulomatosis with polyangiitis (Wegener's). Results of a single-center cohort study on 66 patients. J Autoimmun 50:135–141

    CAS  PubMed  Google Scholar 

  18. 18.

    Charles P, Neel A, Tieulie N, Hot A, Pugnet G, Decaux O et al (2014) Rituximab for induction and maintenance treatment of ANCA-associated vasculitides: a multicentre retrospective study on 80 patients. Rheumatology (Oxford, England) 53(3):532–539

    CAS  Google Scholar 

  19. 19.

    Smith RM, Jones RB, Guerry MJ, Laurino S, Catapano F, Chaudhry A, Smith KG, Jayne DR (2012) Rituximab for remission maintenance in relapsing antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Rheum 64(11):3760–3769

    CAS  PubMed  Google Scholar 

  20. 20.

    Pullerits R, Ljevak M, Vikgren J, Bokarewa M (2012) Off-trial evaluation of the B cell-targeting treatment in the refractory cases of antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis: long-term follow-up from a single Centre. Scand J Immunol 76(4):411–420

    CAS  PubMed  Google Scholar 

  21. 21.

    Harper L, Morgan MD, Walsh M, Hoglund P, Westman K, Flossmann O et al (2012) Pulse versus daily oral cyclophosphamide for induction of remission in ANCA-associated vasculitis: long-term follow-up. Ann Rheum Dis 71(6):955–960

    CAS  PubMed  Google Scholar 

  22. 22.

    Holle JU, Gross WL, Latza U, Nolle B, Ambrosch P, Heller M et al (2011) Improved outcome in 445 patients with Wegener's granulomatosis in a German vasculitis center over four decades. Arthritis Rheum 63(1):257–266

    PubMed  Google Scholar 

  23. 23.

    Heijl C, Harper L, Flossmann O, Stucker I, Scott DG, Watts RA et al (2011) 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(8):1415–1421

    CAS  PubMed  Google Scholar 

  24. 24.

    Silva F, Seo P, Schroeder DR, Stone JH, Merkel PA, Hoffman GS, Spiera R, Sebastian JK, Davis JC Jr, St Clair EW, Allen NB, McCune W, Ytterberg SR, Specks U, Wegener's Granulomatosis Etanercept Trial Research Group (2011) Solid malignancies among etanercept-treated patients with granulomatosis with polyangiitis (Wegener's): long-term followup of a multicenter longitudinal cohort. Arthritis Rheum 63(8):2495–2503

    PubMed  PubMed Central  Google Scholar 

  25. 25.

    Jones RB, Tervaert JW, Hauser T, Luqmani R, Morgan MD, Peh CA, Savage CO, Segelmark M, Tesar V, van Paassen P, Walsh D, Walsh M, Westman K, Jayne DR, European Vasculitis Study Group (2010) Rituximab versus cyclophosphamide in ANCA-associated renal vasculitis. N Engl J Med 363(3):211–220

    CAS  PubMed  Google Scholar 

  26. 26.

    Stone JH, Merkel PA, Spiera R, Seo P, Langford CA, Hoffman GS, Kallenberg CG, St Clair EW, Turkiewicz A, Tchao NK, Webber L, Ding L, Sejismundo LP, Mieras K, Weitzenkamp D, Ikle D, Seyfert-Margolis V, Mueller M, Brunetta P, Allen NB, Fervenza FC, Geetha D, Keogh KA, Kissin EY, Monach PA, Peikert T, Stegeman C, Ytterberg SR, Specks U, RAVE-ITN Research Group (2010) Rituximab versus cyclophosphamide for ANCA-associated vasculitis. N Engl J Med 363(3):221–232

    CAS  PubMed  PubMed Central  Google Scholar 

  27. 27.

    Faurschou M, Sorensen IJ, Mellemkjaer L, Loft AG, Thomsen BS, Tvede N, Baslund B (2008) Malignancies in Wegener's granulomatosis: incidence and relation to cyclophosphamide therapy in a cohort of 293 patients. J Rheumatol 35(1):100–105

    CAS  PubMed  Google Scholar 

  28. 28.

    Pagnoux C, Mahr A, Hamidou MA, Boffa JJ, Ruivard M, Ducroix JP, Kyndt X, Lifermann F, Papo T, Lambert M, le Noach J, Khellaf M, Merrien D, Puéchal X, Vinzio S, Cohen P, Mouthon L, Cordier JF, Guillevin L, French Vasculitis Study Group (2008) Azathioprine or methotrexate maintenance for ANCA-associated vasculitis. N Engl J Med 359(26):2790–2803

    CAS  PubMed  Google Scholar 

  29. 29.

    Westman KW, Bygren PG, Olsson H, Ranstam J, Wieslander J (1998) Relapse rate, renal survival, and cancer morbidity in patients with Wegener's granulomatosis or microscopic polyangiitis with renal involvement. J Am Soc Nephrol 9(5):842–852

    CAS  PubMed  Google Scholar 

  30. 30.

    Hoffman GS, Kerr GS, Leavitt RY, Hallahan CW, Lebovics RS, Travis WD, Rottem M, Fauci AS (1992) Wegener granulomatosis: an analysis of 158 patients. Ann Intern Med 116(6):488–498

    CAS  PubMed  Google Scholar 

  31. 31.

    Knight A, Askling J, Ekbom A (2002) Cancer incidence in a population-based cohort of patients with Wegener's granulomatosis. Int J Cancer 100(1):82–85

    CAS  PubMed  Google Scholar 

  32. 32.

    Lam KY, Law SY, Chan KW, Yuen MC (1998) Glomerulonephritis associated with basaloid squamous cell carcinoma of the oesophagus. A possible unusual paraneoplastic syndrome. Scand J Urol Nephrol 32(1):61–63

    CAS  PubMed  Google Scholar 

  33. 33.

    Shang W, Ning Y, Xu X, Li M, Guo S, Han M, Zeng R, Ge S, Xu G (2015) Incidence of Cancer in ANCA-associated Vasculitis: a meta-analysis of observational studies. PLoS One 10(5):e0126016

    PubMed  PubMed Central  Google Scholar 

  34. 34.

    Knight A, Askling J, Granath F, Sparen P, Ekbom A (2004) Urinary bladder cancer in Wegener's granulomatosis: risks and relation to cyclophosphamide. Ann Rheum Dis 63(10):1307–1311

    CAS  PubMed  PubMed Central  Google Scholar 

  35. 35.

    Mahr A, Heijl C, Le Guenno G, Faurschou M (2013) ANCA-associated vasculitis and malignancy: current evidence for cause and consequence relationships. Best Pract Res Clin Rheumatol 27(1):45–56

    PubMed  Google Scholar 

  36. 36.

    Lowrance WT, Ordonez J, Udaltsova N, Russo P, Go AS (2014) CKD and the risk of incident cancer. J Am Soc Nephrol 25(10):2327–2334

    CAS  PubMed  PubMed Central  Google Scholar 

  37. 37.

    Wong G, Hayen A, Chapman JR, Webster AC, Wang JJ, Mitchell P, Craig JC (2009) Association of CKD and cancer risk in older people. J Am Soc Nephrol 20(6):1341–1350

    CAS  PubMed  PubMed Central  Google Scholar 

  38. 38.

    Christensson A, Savage C, Sjoberg DD, Cronin AM, O'Brien MF, Lowrance W, Nilsson PM, Vickers AJ, Russo P, Lilja H (2013) Association of cancer with moderately impaired renal function at baseline in a large, representative, population-based cohort followed for up to 30 years. Int J Cancer 133(6):1452–1458

    CAS  PubMed  PubMed Central  Google Scholar 

  39. 39.

    Schollmeyer P, Bozkurt F (1988) The immune status of the uremic patient: hemodialysis vs CAPD. Clin Nephrol 30(Suppl 1):S37–S40

    PubMed  Google Scholar 

  40. 40.

    Malachi T, Zevin D, Gafter U, Chagnac A, Slor H, Levi J (1993) DNA repair and recovery of RNA synthesis in uremic patients. Kidney Int 44(2):385–389

    CAS  PubMed  Google Scholar 

  41. 41.

    Maisonneuve P, Agodoa L, Gellert R, Stewart JH, Buccianti G, Lowenfels AB et al (1999) Cancer in patients on dialysis for end-stage renal disease: an international collaborative study. Lancet (London, England) 354(9173):93–99

    CAS  Google Scholar 

  42. 42.

    Nachman PH, Segelmark M, Westman K, Hogan SL, Satterly KK, Jennette JC, Falk R (1999) Recurrent ANCA-associated small vessel vasculitis after transplantation: a pooled analysis. Kidney Int 56(4):1544–1550

    CAS  PubMed  Google Scholar 

  43. 43.

    Cattran DCFJ, Cook HT, Liu ZH, Fervenza FC, Mezzano SA, Floege J, Nachman PH, Gipson DS, Praga M, Glassock RJ (2012) Kidney disease: improving global outcomes (KDIGO) glomerulonephritis work group. KDIGO clinical practice guideline for glomerulonephritis

  44. 44.

    Gopaluni S, Smith RM, Lewin M, McAlear CA, Mynard K, Jones RB, Specks U, Merkel PA, Jayne DR, RITAZAREM Investigators (2017) Rituximab versus azathioprine as therapy for maintenance of remission for anti-neutrophil cytoplasm antibody-associated vasculitis (RITAZAREM): study protocol for a randomized controlled trial. Trials. 18(1):112

    PubMed  PubMed Central  Google Scholar 

  45. 45.

    Kempen JH, Gangaputra S, Daniel E, Levy-Clarke GA, Nussenblatt RB, Rosenbaum JT et al (2008) Long-term risk of malignancy among patients treated with immunosuppressive agents for ocular inflammation: a critical assessment of the evidence. Am J Ophthalmol 146(6):802–12.e1

    CAS  PubMed  PubMed Central  Google Scholar 

  46. 46.

    Kuschal C, Thoms KM, Schubert S, Schafer A, Boeckmann L, Schon MP et al (2012) Skin cancer in organ transplant recipients: effects of immunosuppressive medications on DNA repair. Exp Dermatol 21(1):2–6

    CAS  PubMed  Google Scholar 

  47. 47.

    Talar-Williams C, Hijazi YM, Walther MM, Linehan WM, Hallahan CW, Lubensky I, Kerr GS, Hoffman GS, Fauci AS, Sneller MC (1996) Cyclophosphamide-induced cystitis and bladder cancer in patients with Wegener granulomatosis. Ann Intern Med 124(5):477–484

    CAS  PubMed  Google Scholar 

  48. 48.

    de Groot K, Harper L, Jayne DR, Flores Suarez LF, Gregorini G, Gross WL, Luqmani R, Pusey CD, Rasmussen N, Sinico RA, Tesar V, Vanhille P, Westman K, Savage CO, EUVAS (European Vasculitis Study Group) (2009) Pulse versus daily oral cyclophosphamide for induction of remission in antineutrophil cytoplasmic antibody-associated vasculitis: a randomized trial. Ann Intern Med 150(10):670–680

    PubMed  Google Scholar 

  49. 49.

    Booth A, Harper L, Hammad T, Bacon P, Griffith M, Levy J, Savage C, Pusey C, Jayne D (2004) Prospective study of TNFalpha blockade with infliximab in anti-neutrophil cytoplasmic antibody-associated systemic vasculitis. J Am Soc Nephrol 15(3):717–721

    CAS  PubMed  Google Scholar 

  50. 50.

    Rhee RL, Hogan SL, Poulton CJ, McGregor JA, Landis JR, Falk RJ, et al. Trends in Long-Term Outcomes Among Patients With Antineutrophil Cytoplasmic Antibody-Associated Vasculitis With Renal Disease. Arthritis Rheum (Hoboken, NJ). 2016;68(7):1711–1720

  51. 51.

    Vamvakas S, Bahner U, Heidland A (1998) Cancer in end-stage renal disease: potential factors involved -editorial. Am J Nephrol 18(2):89–95

    CAS  PubMed  Google Scholar 

  52. 52.

    Hibberd AD, Trevillian PR, Wlodarczyk JH, Kemp DG, Stein AM, Gillies AH, Heer MK, Sheil AG (2013) Effect of immunosuppression for primary renal disease on the risk of cancer in subsequent renal transplantation: a population-based retrospective cohort study. Transplantation. 95(1):122–127

    CAS  PubMed  Google Scholar 

  53. 53.

    Australia & New Zealand Dialysis and Trasnplant Registry: ANZDATA 41st Annual Report2018. https://www.anzdata.org.au/wpcontent/uploads/2018/11/c07_transplant_2017_v1.0_20181220.pdf

  54. 54.

    Tanriover B, Jaikaransingh V, MacConmara MP, Parekh JR, Levea SL, Ariyamuthu VK, Zhang S, Gao A, Ayvaci MU, Sandikci B, Rajora N, Ahmed V, Lu CY, Mohan S, Vazquez MA (2016) Acute rejection rates and graft outcomes according to induction regimen among recipients of kidneys from deceased donors treated with Tacrolimus and Mycophenolate. Clin J Am Soc Nephrol 11(9):1650–1661

    CAS  PubMed  PubMed Central  Google Scholar 

  55. 55.

    Heaf JG, Hansen A, Laier GH (2018) Quantification of cancer risk in glomerulonephritis. BMC Nephrol 19(1):27

    PubMed  PubMed Central  Google Scholar 

  56. 56.

    Tessmer MS, Flaherty KT (2017) AACR Cancer Progress report 2017: harnessing research discoveries to save lives. Clin Cancer Res 23(18):5325

    PubMed  Google Scholar 

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Correspondence to Alfred K. Lam or Tien K. Khoo.

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Thet, Z., Lam, A.K., Ranganathan, D. et al. Cancer risks along the disease trajectory in antineutrophil cytoplasmic antibody associated vasculitis. Clin Rheumatol 39, 2501–2513 (2020). https://doi.org/10.1007/s10067-020-05055-x

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Keywords

  • ANCA
  • Cancer
  • Glomerular nephritis
  • Malignancy
  • Vasculitis