Clinical Rheumatology

, Volume 37, Issue 6, pp 1729–1735 | Cite as

Imatinib mesylate use in refractory eosinophilic granulomatosis with polyangiitis: a literature review and a case report

  • Tatiana V. Beketova
  • Mikhail Y. Volkov
  • Evgeniy A. Naryshkin
  • Tatiana M. Novoselova
  • Evgeniy L. Nasonov
Case Based Review


Recent advances in pharmacology have greatly expanded the drug repertoire for treatment of anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitis. Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare multisystemic disorder, a type of the ANCA-associated vasculitis. Important features of this disease are eosinophilia and anti-myeloperoxidase ANCA presence in around 30–70% of patients. Primary therapy of EGPA includes steroids and cytotoxic drugs, e.g., cyclophosphamide, azathioprine, or methotrexate. Nevertheless, some patients are refractory to this therapy. Alternative approaches include rituximab, mepolizumab, and intravenous immunoglobulin. Accumulating evidence highlight a new promising drug in EGPA therapy—imatinib mesylate (IM), tyrosine kinase inhibitor. This drug is a key pharmacological agent in treating various types of hematological malignancies and FIP1L1/PDGF-RA-positive hypereosinophilia. In this article, we present a case demonstrating successful treatment of EGPA with IM; we also discuss possible mechanisms of IM efficacy in EGPA treatment and future perspectives of this therapeutic approach.


Alternative therapeutical strategy ANCA-associated vasculitis Churg-Strauss syndrome Eosinophilic granulomatosis with polyangiitis Imatinib mesylate 


Compliance with ethical standards

Declaration of Helsinki

Our study complies with the Declaration of Helsinki; the approval for this study was not required in accordance with the policy of your institution; and the informed consent has been obtained from the patient.




  1. 1.
    Comarmond C, Pagnoux C, Khellaf M, Cordier JF, Hamidou M, Viallard JF, Maurier F, Jouneau S, Bienvenu B, Puéchal X, Aumaître O, Guenno GL, Quellec AL, Cevallos R, Fain O, Godeau B, Seror R, Dunogué B, Mahr A, Guilpain P, Cohen P, Aouba A, Mouthon L, Guillevin L, for the French Vasculitis Study Group (2013) Eosinophilic granulomatosis with polyangiitis (Churg-Strauss): clinical characteristics and long-term followup of the 383 patients enrolled in the French Vasculitis Study Group cohort. Arthritis Rheum 65(1):270–281. CrossRefPubMedGoogle Scholar
  2. 2.
    Groh M, Pagnoux C, Baldini C, Bel E, Bottero P, Cottin V, Dalhoff K, Dunogué B, Gross W, Holle J, Humbert M, Jayne D, Jennette JC, Lazor R, Mahr A, Merkel PA, Mouthon L, Sinico RA, Specks U, Vaglio A, Wechsler ME, Cordier JF, Guillevin L (2015) Eosinophilic granulomatosis with polyangiitis (Churg-Strauss) (EGPA) Consensus Task Force recommendations for evaluation and management. Eur J Intern Med 26(7):545–553. CrossRefPubMedGoogle Scholar
  3. 3.
    Mohammad AJ, Hot A, Arndt F, Moosig F, Guerry M-J, Amudala N, Smith R, Sivasothy P, Guillevin L, Merkel PA, Jayne DRW (2016) Rituximab for the treatment of eosinophilic granulomatosis with polyangiitis (Churg–Strauss). Ann Rheum Dis 75(2):396–401. CrossRefPubMedGoogle Scholar
  4. 4.
    Jachiet M, Samson M, Cottin V, Kahn JE, Le Guenno G, Bonniaud P et al (2016) Anti-IgE monoclonal antibody (omalizumab) in refractory and relapsing eosinophilic granulomatosis with polyangiitis (Churg-Strauss): data on seventeen patients. Arthritis Rheumatol 68(9):2274–2282. CrossRefPubMedGoogle Scholar
  5. 5.
    Detoraki A, Di Capua L, Varricchi G, Genovese A, Marone G, Spadaro G (2016) Omalizumab in patients with eosinophilic granulomatosis with polyangiitis: a 36-month follow-up study. J Asthma 53(2):201–206. CrossRefPubMedGoogle Scholar
  6. 6.
    Aguirre-Valencia D, Posso-Osorio I, Bravo JC, Bonilla-Abadía F, Tobón GJ, Cañas CA (2017) Sequential rituximab and omalizumab for the treatment of eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome). Clin Rheumatol 36(9):2159–2162. CrossRefPubMedGoogle Scholar
  7. 7.
    Metzgeroth G, Walz C, Erben P, Popp H, Schmitt-Graeff A, Haferlach C, Fabarius A, Schnittger S, Grimwade D, Cross NCP, Hehlmann R, Hochhaus A, Reiter A (2008) Safety and efficacy of imatinib in chronic eosinophilic leukaemia and hypereosinophilic syndrome—a phase-II study. Br J Haematol 143(5):707–715. CrossRefPubMedGoogle Scholar
  8. 8.
    Azizi G, Mirshafiey A (2013) Imatinib mesylate: an innovation in treatment of autoimmune diseases. Recent Pat Inflamm Allergy Drug Discov 7(3):259–267. CrossRefPubMedGoogle Scholar
  9. 9.
    Wallace E, Gewin L (2013) Imatinib: novel treatment of immune-mediated kidney injury. J Am Soc Nephrol 24(5):694–701. CrossRefPubMedGoogle Scholar
  10. 10.
    Paniagua RT, Sharpe O, Ho PP, Chan SM, Chang A, Higgins JP, Tomooka BH, Thomas FM, Song JJ, Goodman SB, Lee DM, Genovese MC, Utz PJ, Steinman L, Robinson WH (2006) Selective tyrosine kinase inhibition by imatinib mesylate for the treatment of autoimmune arthritis. J Clin Invest 116(10):2633–2642. CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Josselin-Mahr L, Werbrouck-Chiraux A, Garderet L, Cabane J (2014) Efficacy of imatinib mesylate in a case of Churg–Strauss syndrome: evidence for the pathogenic role of a tyrosine kinase? Rheumatology 53(2):378–379. CrossRefPubMedGoogle Scholar
  12. 12.
    Erre GL, Pardini S, Cuccuru L, Taras L, Passiu G (2015) Is there a role for imatinib mesylate in the treatment of eosinophilic granulomatosis with polyangiitis? Jt Bone Spine 82(1):72–73. CrossRefGoogle Scholar
  13. 13.
    Klaeger S, Heinzlmeir S, Wilhelm M, Polzer H, Vick B, Koenig PA, et al. (2017) The target landscape of clinical kinase drugs. Science 358:eaan4368.
  14. 14.
    Buchdunger E, Cioffi CL, Law N, Stover D, Ohno-Jones S, Druker BJ, Lydon NB (2000) Abl protein-tyrosine kinase inhibitor STI571 inhibits in vitro signal transduction mediated by c-kit and platelet-derived growth factor receptors. J Pharmacol Exp Ther 295(1):139–145PubMedGoogle Scholar
  15. 15.
    Winger JA, Hantschel O, Superti-Furga G, Kuriyan J (2009) The structure of the leukemia drug imatinib bound to human quinone reductase 2 (NQO2). BMC Struct Biol 9(1):1–12. CrossRefGoogle Scholar
  16. 16.
    Kälsch AI, Soboletzki M, Schmitt WH, Van Der Woude FJ, Hochhaus A, Yard BA et al (2008) Imatinib mesylate, a new kid on the block for the treatment of anti-neutrophil cytoplasmic autoantibodies-associated vasculitis? Clin Exp Immunol 151(3):391–398. CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Seggewiss R, Loré K, Greiner E, Magnusson MK, Price DA, Douek DC, Dunbar CE, Wiestner A (2005) Imatinib inhibits T-cell receptor-mediated T-cell proliferation and activation in a dose-dependent manner. Blood 105(6):2473–2479. CrossRefPubMedGoogle Scholar
  18. 18.
    Chen J, Schmitt A, Chen B, Rojewski M, Ringhoffer M, Von Harsdorf S et al (2007) Imatinib impairs CD8+ T lymphocytes specifically directed against the leukemia-associated antigen RHAMM/CD168 in vitro. Cancer Immunol Immunother 56(6):849–861. CrossRefPubMedGoogle Scholar
  19. 19.
    Dewar AL, Cambareri AC, Zannettino ACW, Miller BL, Doherty KV, Hughes TP, Lyons AB (2005) Macrophage colony-stimulating factor receptor c-fms is a novel target of imatinib. Blood 105(8):3127–3132. CrossRefPubMedGoogle Scholar
  20. 20.
    Ohashi A, Kinoshita K, Isozaki K, Nishida T, Shinomura Y, Kitamura Y, Hirota S (2004) Different inhibitory effect of imatinib on phosphorylation of mitogen-activated protein kinase and Akt and on proliferation in cells expressing different types of mutant platelet-derived growth factor receptor-alpha. Int J Cancer 111(3):317–321. CrossRefPubMedGoogle Scholar
  21. 21.
    Hellmich B, Ehlers S, Csernok E, Gross WL (2003) Update on the pathogenesis of Churg-Strauss syndrome. Clin Exp Rheumatol 21(Suppl 32):S69–77Google Scholar
  22. 22.
    Terrier B, Bièche I, Maisonobe T, Laurendeau I, Rosenzwajg M, Kahn J-E, et al. (2010) IL-25: a cytokine linking eosinophils and adaptive immunity in Churg-Strauss syndrome. Blood 116(22):4523–4531.
  23. 23.
    Suzuki N, Sasaki N, Utsumi Y, Nagashima H, Nakamura Y, Yamashita M, Yamauchi K, Sawai T (2013) Effects of imatinib mesylate on pulmonary allergic vasculitis in a murine model. Int J Rheum Dis 16(4):455–462. CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Tapper EB, Knowles D, Heffron T, Lawrence EC, Csete M (2009) Portopulmonary hypertension: imatinib as a novel treatment and the Emory experience with this condition. Transplant Proc 41(5):1969–1971. CrossRefPubMedGoogle Scholar
  25. 25.
    Lozano E, Segarra M, García-Martínez A, Hernández-Rodríguez J, Cid MC (2008) Imatinib mesylate inhibits in vitro and ex vivo biological responses related to vascular occlusion in giant cell arteritis. Ann Rheum Dis 67(11):1581–1588. CrossRefPubMedGoogle Scholar
  26. 26.
    Gągało I, Rusiecka I, Kocić I (2015) Tyrosine kinase inhibitor as a new therapy for ischemic stroke and other neurologic diseases: is there any hope for a better outcome? Curr Neuropharmacol 13(6):836–844. CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Emmi G, Silvestri E, Marconi R, Carrai V, Fanelli T, Zucchini P, Marasca R, Vannucchi AM, Emmi L, Prisco D, Vaglio A (2015) First report of FIP1L1-PDGFRα-positive eosinophilic granulomatosis with polyangiitis. Rheumatol (United Kingdom) 54(9):1751–1753. Google Scholar
  28. 28.
    Terabe F, Kitano M, Kawai M, Kuwahara Y, Hirano T, Arimitsu J, Hagihara K, Shima Y, Narazaki M, Tanaka T, Kawase I, Sano H, Ogata A (2009) Imatinib mesylate inhibited rat adjuvant arthritis and PDGF-dependent growth of synovial fibroblast via interference with the Akt signaling pathway. Mod Rheumatol 19(5):522–529. CrossRefPubMedGoogle Scholar
  29. 29.
    Aono Y, Nishioka Y, Inayama M, Ugai M, Kishi J, Uehara H, Izumi K, Sone S (2005) Imatinib as a novel antifibrotic agent in bleomycin-induced pulmonary fibrosis in mice. Am J Respir Crit Care Med 171(11):1279–1285. CrossRefPubMedGoogle Scholar
  30. 30.
    van Steensel L, Paridaens D, Schrijver B, Dingjan GM, van Daele PLA, Martin van Hagen P et al (2009) Imatinib mesylate and AMN107 inhibit PDGF-signaling in orbital fibroblasts: a potential treatment for Graves’ ophthalmopathy. Invest Ophthalmol Vis Sci 50(7):3091–3098. CrossRefPubMedGoogle Scholar
  31. 31.
    Wang S (2005) Imatinib mesylate blocks a non-Smad TGF- pathway and reduces renal fibrogenesis in vivo. FASEB J 19(1):1–11. CrossRefPubMedGoogle Scholar
  32. 32.
    Shiha GE, Abu-Elsaad NM, Zalata KR, Ibrahim TM (2014) Tracking anti-fibrotic pathways of nilotinib and imatinib in experimentally induced liver fibrosis: an insight. Clin Exp Pharmacol Physiol 41(10):788–797. CrossRefPubMedGoogle Scholar
  33. 33.
    Spiera RF, Gordon JK, Mersten J, Magro C, Mehta M, Wildman H et al (2010) Imatinib mesylate (Gleevec) in the treatment of diffuse cutaneous systemic sclerosis: results of a one year, phase IIa, single arm, open label clinical trial. Arthritis Rheum 62:2193. Google Scholar
  34. 34.
    Akhmetshina A, Venalis P, Dees C, Busch N, Zwerina J, Schett G, Distler O, Distler JHW (2009) Treatment with imatinib prevents fibrosis in different preclinical models of systemic sclerosis and induces regression of established fibrosis. Arthritis Rheum 60(1):219–224. CrossRefPubMedGoogle Scholar
  35. 35.
    Kuo WL, Yu MC, Lee JF, Tsai CN, Chen TC, Chen MF (2012) Imatinib mesylate improves liver regeneration and attenuates liver fibrogenesis in CCL 4-treated mice. J Gastrointest Surg 16(2):361–369. CrossRefPubMedGoogle Scholar
  36. 36.
    Elmholdt TR, Buus NH, Ramsing M, Olesen AB (2013) Antifibrotic effect after low-dose imatinib mesylate treatment in patients with nephrogenic systemic fibrosis: an open-label non-randomized, uncontrolled clinical trial. J Eur Acad Dermatol Venereol 27(6):779–784. CrossRefPubMedGoogle Scholar
  37. 37.
    Bournia VK, Evangelou K, Sfikakis PP (2013) Therapeutic inhibition of tyrosine kinases in systemic sclerosis: a review of published experience on the first 108 patients treated with Imatinib. Semin Arthritis Rheum 42(4):377–390. CrossRefPubMedGoogle Scholar
  38. 38.
    Guo L, Chen XX, Gu YY, Zou HJ, Ye S (2012) Low-dose imatinib in the treatment of severe systemic sclerosis: a case series of six Chinese patients and literature review. Clin Rheumatol 31(9):1395–1400. CrossRefPubMedGoogle Scholar
  39. 39.
    Horton JA, Chung EJ, Hudak KE, Sowers A, Thetford A, White AO, Mitchell JB, Citrin DE (2013) Inhibition of radiation-induced skin fibrosis with imatinib. Int J Radiat Biol 89(3):162–170. CrossRefPubMedGoogle Scholar
  40. 40.
    Daniels CE, Lasky JA, Limper AH, Mieras K, Gabor E, Schroeder DR, Imatinib-IPF Study Investigators (2010) Imatinib treatment for idiopathic pulmonary fibrosis: randomized placebo-controlled trial results. Am J Respir Crit Care Med 181(6):604–610. CrossRefPubMedGoogle Scholar
  41. 41.
    Prey S, Ezzedine K, Doussau A, Grandoulier AS, Barcat D, Chatelus E, Diot E, Durant C, Hachulla E, de Korwin-Krokowski JD, Kostrzewa E, Quemeneur T, Paul C, Schaeverbeke T, Seneschal J, Solanilla A, Sparsa A, Bouchet S, Lepreux S, Mahon FX, Chene G, Taïeb A (2012) Imatinib mesylate in scleroderma-associated diffuse skin fibrosis: a phase II multicentre randomized double-blinded controlled trial. Br J Dermatol 167(5):1138–1144. CrossRefPubMedGoogle Scholar
  42. 42.
    Savikko J, Rintala JM, Rintala SE, Koskinen PK, von Willebrand E (2011) Early short-term imatinib treatment is sufficient to prevent the development of chronic allograft nephropathy. Nephrol Dial Transplant 26(9):3026–3032. CrossRefPubMedGoogle Scholar
  43. 43.
    Zoja C, Corna D, Rottoli D, Zanchi C, Abbate M, Remuzzi G (2006) Imatinib ameliorates renal disease and survival in murine lupus autoimmune disease. Kidney Int 70(1):97–103. CrossRefPubMedGoogle Scholar
  44. 44.
    Sadanaga A, Nakashima H, Masutani K, Miyake K, Shimizu S, Igawa T, Sugiyama N, Niiro H, Hirakata H, Harada M (2005) Amelioration of autoimmune nephritis by imatinib in MRL/lpr mice. Arthritis Rheum 52(12):3987–3996. CrossRefPubMedGoogle Scholar
  45. 45.
    Hudkins KL, Gilbertson DG, Carling M, Taneda S, Hughes SD, Holdren MS, Palmer TE, Topouzis S, Haran AC, Feldhaus AL, Alpers CE (2004) Exogenous PDGF-D is a potent mesangial cell mitogen and causes a severe mesangial proliferative glomerulopathy. J Am Soc Nephrol 15(2):286–298. CrossRefPubMedGoogle Scholar
  46. 46.
    Taneda S, Hudkins KL, Cui Y, Farr AG, Alpers CE, Segerer S (2003) Growth factor expression in a murine model of cryoglobulinemia. Kidney Int 63(2):576–590. CrossRefPubMedGoogle Scholar
  47. 47.
    Iyoda M, Hudkins KL, Becker-Herman S, Wietecha TA, Banas MC, Guo S, Meyer-Bahlburg A, Kowalewska J, Liu G, Ziegler SF, Rawlings DJ, Alpers CE (2009) Imatinib suppresses cryoglobulinemia and secondary membranoproliferative glomerulonephritis. J Am Soc Nephrol 20(1):68–77. CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Agosti V, Corbacioglu S, Ehlers I, Waskow C, Sommer G, Berrozpe G, Kissel H, Tucker CM, Manova K, Moore MAS, Rodewald HR, Besmer P (2004) Critical role for Kit-mediated Src kinase but not PI 3-kinase signaling in pro T and pro B cell development. J Exp Med 199(6):867–878. CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Lam QLK, Lo CKC, Zheng BJ, Ko KH, Osmond DG, Wu GE, Rottapel R, Lu L (2007) Impaired V(D)J recombination and increased apoptosis among B cell precursors in the bone marrow of c-Abl-deficient mice. Int Immunol 19(3):267–276. CrossRefPubMedGoogle Scholar
  50. 50.
    Wallace E, Fogo AB, Schulman G (2012) Imatinib therapy for non-infection-related type II cryoglobulinemia with membranoproliferative glomerulonephritis. Am J Kidney Dis 59(1):122–125. CrossRefPubMedGoogle Scholar
  51. 51.
    Scheinfeld N (2006) Imatinib mesylate and dermatology part 2: a review of the cutaneous side effects of imatinib mesylate. Vol. 5, J Drugs Dermat: JDD. p. 228–31Google Scholar
  52. 52.
    Mumprecht S, Matter M, Pavelic V, Ochsenbein AF (2006) Imatinib mesylate selectively impairs expansion of memory cytotoxic T cells without affecting the control of primary viral infections. Blood 108(10):3406–3413. CrossRefPubMedGoogle Scholar
  53. 53.
    Napier RJ, Rafi W, Cheruvu M, Powell KR, Zaunbrecher MA, Bornmann W, Salgame P, Shinnick TM, Kalman D (2011) Imatinib-sensitive tyrosine kinases regulate mycobacterial pathogenesis and represent therapeutic targets against tuberculosis. Cell Host Microbe 10(5):475–485. CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Müller AMS, Martens UM, Hofmann SC, Bruckner-Tuderman L, Mertelsmann R, Lübbert M (2006) Imatinib mesylate as a novel treatment option for hypereosinophilic syndrome: two case reports and a comprehensive review of the literature. Ann Hematol 85(1):1–16. CrossRefPubMedGoogle Scholar
  55. 55.
    Baccarani M, Cilloni D, Rondoni M, Ottaviani E, Messa F, Merante S, Tiribelli M, Buccisano F, Testoni N, Gottardi E, de Vivo A, Giugliano E, Iacobucci I, Paolini S, Soverini S, Rosti G, Rancati F, Astolfi C, Pane F, Saglio G, Martinelli G (2007) The efficacy of imatinib mesylate in patients with FIP1L1-PDGFRα-positive hypereosinophilic syndrome. Results of a multicenter prospective study. Haematologica 92(9):1173–1179. CrossRefPubMedGoogle Scholar
  56. 56.
    Khoury P, Desmond R, Pabon A, Holland-Thomas N, Ware JM, Arthur DC, Kurlander R, Fay MP, Maric I, Klion AD (2016) Clinical features predict responsiveness to imatinib in platelet-derived growth factor receptor-alpha-negative hypereosinophilic syndrome. Allergy Eur J Allergy Clin Immunol 71(6):803–810. CrossRefGoogle Scholar
  57. 57.
    Helbig G (2016) Imatinib mesylate for unmutated hypereosinophilic syndromes: does it work? Eur J Intern Med 32:e19–e20. CrossRefPubMedGoogle Scholar

Copyright information

© International League of Associations for Rheumatology (ILAR) 2018

Authors and Affiliations

  1. 1.Department of Autoimmune Disorders in Rheumatic DiseasesV.A. Nasonova Research Institute of RheumatologyMoscowRussian Federation
  2. 2.Department of Rheumaorthopedics and RehabilitationV.A. Nasonova Research Institute of RheumatologyMoscowRussian Federation
  3. 3.Department of Vascular Problems in Rheumatic DiseasesV.A. Nasonova Research Institute of RheumatologyMoscowRussian Federation

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