Clinical Rheumatology

, Volume 37, Issue 9, pp 2579–2584 | Cite as

Vasculitis associated with immune checkpoint inhibitors—a systematic review

  • Anisha DaxiniEmail author
  • Keri Cronin
  • Antoine G. Sreih
Case Based Review


Recent experimental and genetic studies have implicated the role of programmed cell death protein 1 (PD-1), programmed cell death protein-ligand 1 (PDL-1), and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) in the pathogenesis of medium and large vessel vasculitis. This study sought to evaluate the occurrence and nature of vasculitis associated with cancer treatment using immune checkpoint inhibition (anti-PD-1, anti-PDL-1, and anti-CTLA4). A systematic review of the medical literature was conducted by searching all available clinical data up to February 2018 in several databases and search engines including Cochrane Library, Embase, Google Scholar, Medline, Scopus, Web of Science, and Searches included the following FDA-approved anti-PD1 (nivolumab and pembrolizumab), anti-PDL1 (atezolizumab, avelumab, and durvalumab), and anti-CTLA4 (ipilimumab). The vasculitis cases were compiled and classified based on the 2012 revised Chapel Hill Consensus Conference nomenclature. The clinical feature of the vasculitis cases and their relationship to immune checkpoint inhibition was assessed. There were 53 cases of vasculitis of which 20 were confirmed. The main reported type of vasculitis was large vessel vasculitis and vasculitis of the central and peripheral nervous system. All cases resolved with either holding the immune checkpoint inhibitors and/or administering glucocorticoids. No death related to vasculitis was reported. Vasculitis, namely large vessel and vasculitis of the nervous system, is associated with immune checkpoint inhibition. Results of this study add to the growing evidence regarding the relationship between immune checkpoints and vasculitis and suggest that the pathway may be a therapeutic target.


CTLA-4 Immune checkpoint inhibitors PD-1 PDL-1 Vasculitis 


Compliance with ethical standards

The manuscript does not contain clinical studies or patient data information.




  1. 1.
    Yang Y (2015) Cancer immunotherapy harnessing the immune system to battle cancer. J Clin Invest 125:3335–3337CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Amos SM, Duong CP, Westwood JA, Ritchie DS, Junghans RP, Darcy PK et al (2011) Autoimmunity associated with immunotherapy of cancer. Blood 118:499–509CrossRefPubMedGoogle Scholar
  3. 3.
    Caspi RR (2008) Immunotherapy of autoimmunity and cancer: the penalty for success. Nat Rev Immunol 8:970–976CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Abdel-Wahab N, Shah M, Suarez-Almazor ME (2016) Adverse events associated with immune checkpoint blockade in patients with cancer: a systematic review of case reports. PLoS One 11:e0160221CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Postow MA, Sidlow R, Hellmann MD (2018) Immune-related adverse events associated with immune checkpoint blockade. N Engl J Med 378:158–168CrossRefPubMedGoogle Scholar
  6. 6.
    Zhang H, Watanabe R, Berry GJ, Vaglio A, Liao YJ, Warrington KJ, Goronzy JJ, Weyand CM (2017) Immunoinhibitory checkpoint deficiency in medium and large vessel vasculitis. Proc Natl Acad Sci U S A 114:E970–EE79CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Jennette JC (2013) Overview of the 2012 revised International Chapel Hill Consensus Conference nomenclature of vasculitides. Clin Exp Nephrol 17:603–606CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Hersh EM, O’Day SJ, Powderly J, Khan KD, Pavlick AC, Cranmer LD et al (2011) A phase II multicenter study of ipilimumab with or without dacarbazine in chemotherapy-naive patients with advanced melanoma. Investig New Drugs 29:489–498CrossRefGoogle Scholar
  9. 9.
    Minor DR, Bunker SR, Doyle J (2013) Lymphocytic vasculitis of the uterus in a patient with melanoma receiving ipilimumab. J Clin Oncol 31:e356CrossRefPubMedGoogle Scholar
  10. 10.
    Goldstein BL, Gedmintas L, Todd DJ (2014) Drug-associated polymyalgia rheumatica/giant cell arteritis occurring in two patients after treatment with ipilimumab, an antagonist of ctla-4. Arthritis Rheumatol 66:768–769CrossRefPubMedGoogle Scholar
  11. 11.
    Manusow JS, Khoja L, Pesin N, Joshua AM, Mandelcorn ED (2014) Retinal vasculitis and ocular vitreous metastasis following complete response to PD-1 inhibition in a patient with metastatic cutaneous melanoma. J Immunother Cancer 2:41CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Pinkston O FB, Wang B (2016) Type and frequency of immune-related adverse reactions in patients treated with pembrolizumab (keytruda), a monoclonal antibody directed against PD-1, in advanced melanoma at a single institutionGoogle Scholar
  13. 13.
    Liao B, Wang W, Hammack J, Mauermann M (2016) Vasculitic neuropathy in the setting of nivolumab therapy for metastatic mesothelioma. Ann Neurol 80:M279Google Scholar
  14. 14.
    Aya F, Ruiz-Esquide V, Viladot M, Font C, Prieto-Gonzalez S, Prat A et al (2017) Vasculitic neuropathy induced by pembrolizumab. Ann Oncol 28:433–434PubMedGoogle Scholar
  15. 15.
    van den Brom RR, Abdulahad WH, Rutgers A, Kroesen BJ, Roozendaal C, de Groot DJ et al (2016) Rapid granulomatosis with polyangiitis induced by immune checkpoint inhibition. Rheumatology (Oxford) 55:1143–1145CrossRefGoogle Scholar
  16. 16.
    Bender C, Dimitrakopoulou-Strauss A, Enk A, Hassel JC (2016) Safety of the PD-1 antibody pembrolizumab in patients with high-grade adverse events under ipilimumab treatment. Ann Oncol 27:1353–1354CrossRefPubMedGoogle Scholar
  17. 17.
    Khoja L, Maurice C, Chappell M, MacMillan L, Al-Habeeb AS, Al-Faraidy N et al (2016) Eosinophilic fasciitis and acute encephalopathy toxicity from pembrolizumab treatment of a patient with metastatic melanoma. Cancer Immunol Res 4:175–178CrossRefPubMedGoogle Scholar
  18. 18.
    Arellano K, Mosley JC 3rd, Moore DC (2018) Case report of ipilimumab-induced diffuse, nonnecrotizing granulomatous lymphadenitis and granulomatous vasculitis. J Pharm Pract 31:227–229CrossRefPubMedGoogle Scholar
  19. 19.
    Roy AK, Tathireddy HR, Roy M (2017) Aftermath of induced inflammation: acute periaortitis due to nivolumab therapy. BMJ Case Rep:2017Google Scholar
  20. 20.
    Kao JC, Liao B, Markovic SN, Klein CJ, Naddaf E, Staff NP et al (2017) Neurological complications associated with anti-programmed death 1 (PD-1) antibodies. JAMA Neurol 74:1216–1222CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Cappelli LC, Shah AA, Bingham CO 3rd (2017) Immune-related adverse effects of cancer immunotherapy—implications for rheumatology. Rheum Dis Clin N Am 43:65–78CrossRefGoogle Scholar
  22. 22.
    Laubli H, Hench J, Stanczak M, Heijnen I, Papachristofilou A, Frank S et al (2017) Cerebral vasculitis mimicking intracranial metastatic progression of lung cancer during PD-1 blockade. J Immunother Cancer 5:46CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Le Burel S, Champiat S, Mateus C, Marabelle A, Michot JM, Robert C et al (2017) Prevalence of immune-related systemic adverse events in patients treated with anti-programmed cell death 1/anti-programmed cell death-ligand 1 agents: a single-centre pharmacovigilance database analysis. Eur J Cancer 82:34–44CrossRefPubMedGoogle Scholar
  24. 24.
    Ban BH CJ, Graham RM (2017) Rheumatology case report immune-related aortitis associated with ipilimumab. The Rheumatologist 2017Google Scholar
  25. 25.
    Sun R, Danlos FX, Ammari S, Louvel G, Dhermain F, Champiat S, Lambotte O, Deutsch E (2017) Anti-PD-1 vasculitis of the central nervous system or radionecrosis? J Immunother Cancer 5:96CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Padda A, Schiopu E, Sovich J, Ma V, Alva A, Fecher L (2018) Ipilimumab induced digital vasculitis. J Immunother Cancer 6:12CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Jennette JC, Falk RJ, Bacon PA, Basu N, Cid MC, Ferrario F, Flores-Suarez LF, Gross WL, Guillevin L, Hagen EC, Hoffman GS, Jayne DR, Kallenberg CGM, Lamprecht P, Langford CA, Luqmani RA, Mahr AD, Matteson EL, Merkel PA, Ozen S, Pusey CD, Rasmussen N, Rees AJ, Scott DGI, Specks U, Stone JH, Takahashi K, Watts RA (2013) 2012 revised International Chapel Hill Consensus Conference nomenclature of vasculitides. Arthritis Rheum 65:1–11CrossRefPubMedGoogle Scholar
  28. 28.
    Watanabe R, Zhang H, Berry G, Goronzy JJ, Weyand CM (2017) Immune checkpoint dysfunction in large and medium vessel vasculitis. Am J Physiol Heart Circ Physiol 312:H1052–H1H59CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Watson AM, Prasad KM, Klei L, Wood JA, Yolken RH, Gur RC et al (2013) Persistent infection with neurotropic herpes viruses and cognitive impairment. Psychol Med 43:1023–1031CrossRefPubMedGoogle Scholar
  30. 30.
    Chun JK, Kang DW, Yoo BW, Shin JS, Kim DS (2010) Programmed death-1 (PD-1) gene polymorphisms lodged in the genetic predispositions of Kawasaki Disease. Eur J Pediatr 169:181–185CrossRefPubMedGoogle Scholar
  31. 31.
    Sakthivel P, Giscombe R, Ramanujam R, Lefvert AK (2009) Polymorphisms in PDCD1 gene are not associated with Wegener’s granulomatosis. Rheumatol Int 29:1247–1250CrossRefPubMedGoogle Scholar
  32. 32.
    Giscombe R, Wang X, Huang D, Lefvert AK (2002) Coding sequence 1 and promoter single nucleotide polymorphisms in the CTLA-4 gene in Wegener’s granulomatosis. J Rheumatol 29:950–953PubMedGoogle Scholar
  33. 33.
    Kamesh L, Heward JM, Williams JM, Gough SC, Chavele KM, Salama A et al (2009) CT60 and +49 polymorphisms of CTLA 4 are associated with ANCA-positive small vessel vasculitis. Rheumatology (Oxford) 48:1502–1505CrossRefGoogle Scholar
  34. 34.
    Meng Q, Guo H, Hou S, Jiang Z, Kijlstra A, Yang P (2011) Lack of an association of PD-1 and its ligand genes with Behcet’s disease in a Chinese Han population. PLoS One 6:e25345CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Direskeneli H, Tuna-Erdogan E, Gunduz F, Bandurska-Luque A, Alparslan B, Kebe M et al (2012) PDCD1 polymorphisms are not associated with Takayasu’s arteritis in Turkey. Clin Exp Rheumatol 30:S11–S14PubMedGoogle Scholar
  36. 36.
    Veitch D, Tsai T, Watson S, Joshua F (2014) Paraneoplastic polyarteritis nodosa with cerebral masses: case report and literature review. Int J Rheum Dis 17:805–809CrossRefPubMedGoogle Scholar
  37. 37.
    Anastasakis A, Dick AD, Damato EM, Spry PG, Majid MA (2011) Cancer-associated retinopathy presenting as retinal vasculitis with a negative ERG suggestive of on-bipolar cell pathway dysfunction. Doc Ophthalmol 123:59–63CrossRefPubMedGoogle Scholar
  38. 38.
    Okada M, Suzuki K, Hidaka T, Shinohara T, Takada K, Nakajima M et al (2002) Polyarteritis associated with hypopharyngeal carcinoma. Intern Med 41:892–895CrossRefPubMedGoogle Scholar

Copyright information

© International League of Associations for Rheumatology (ILAR) 2018

Authors and Affiliations

  1. 1.Department of Internal MedicineMercy Nazareth HospitalPhiladelphiaUSA
  2. 2.Division of RheumatologyUniversity of PennsylvaniaPhiladelphiaUSA

Personalised recommendations