Skip to main content

Multinational Association of Supportive Care in Cancer (MASCC) 2020 clinical practice recommendations for the management of immune-mediated cardiovascular, rheumatic, and renal toxicities from checkpoint inhibitors

Abstract

Immune checkpoint inhibitors (ICIs) have emerged as the newest pillar of cancer treatment. Immune-mediated toxicities, stemming from increased activity within the T cell lineage, range from asymptomatic or mild complications to those that are fulminant and potentially fatal. Although they are of variable occurrence, cardiovascular, rheumatic, and renal immune-mediated toxicities are among the most serious of these adverse events. We present MASCC recommendations with respect to the workup and management of cardiovascular, rheumatic, and renal immune-mediated toxicities with a focus on presentations that require treatment with immunomodulating agents.

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

Fig. 1

References

  1. Ribas A, Wolchok JD (2018) Cancer immunotherapy using checkpoint blockade. Science 359(63982):1350–1355. https://doi.org/10.1126/science.aar4060

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  2. Johnson DB, Chandra S, Sosman JA (2018) Immune checkpoint inhibitor toxicity in 2018. JAMA 320(16):1702–1703. https://doi.org/10.1001/jama.2018.13995

    Article  PubMed  Google Scholar 

  3. Postow MA, Sidlow R, Hellmann MD (2018) Immune-related adverse events associated with immune checkpoint blockade. N Engl J Med 378(2):158–168. https://doi.org/10.1056/NEJMra1703481

    CAS  Article  PubMed  Google Scholar 

  4. Wang DY, Salem JE, Cohen JV, Chandra S, Menzer C, Ye F, Zhao S, Das S, Beckermann KE, Ha L, Rathmell WK, Ancell KK, Balko JM, Bowman C, Davis EJ, Chism DD, Horn L, Long GV, Carlino MS, Lebrun-Vignes B, Eroglu Z, Hassel JC, Menzies AM, Sosman JA, Sullivan RJ, Moslehi JJ, Johnson DB (2018) Fatal toxic effects associated with immune checkpoint inhibitors: a systematic review and meta-analysis. JAMA Oncol 4(12):1721–1728. https://doi.org/10.1001/jamaoncol.2018.3923

    Article  PubMed  PubMed Central  Google Scholar 

  5. Moslehi JJ, Salem JE, Sosman JA, Lebrun-Vignes B, Johnson DB (2018) Increased reporting of fatal immune checkpoint inhibitor-associated myocarditis. Lancet 391(10124):933. https://doi.org/10.1016/S0140-6736(18)30533-6

    Article  PubMed  PubMed Central  Google Scholar 

  6. Johnson DB, Balko JM, Compton ML, Chalkias S, Gorham J, Xu Y, Hicks M, Puzanov I, Alexander MR, Bloomer TL, Becker JR, Slosky DA, Phillips EJ, Pilkinton MA, Craig-Owens L, Kola N, Plautz G, Reshef DS, Deutsch JS, Deering RP, Olenchock BA, Lichtman AH, Roden DM, Seidman CE, Koralnik IJ, Seidman JG, Hoffman RD, Taube JM, Diaz LA Jr, Anders RA, Sosman JA, Moslehi JJ (2016) Fulminant myocarditis with combination immune checkpoint blockade. N Engl J Med 375(18):1749–1755. https://doi.org/10.1056/NEJMoa1609214

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  7. Mahmood SS, Fradley MG, Cohen JV, Nohria A, Reynolds KL, Heinzerling LM, Sullivan RJ, Damrongwatanasuk R, Chen CL, Gupta D, Kirchberger MC, Awadalla M, Hassan MZO, Moslehi JJ, Shah SP, Ganatra S, Thavendiranathan P, Lawrence DP, Groarke JD, Neilan TG (2018) Myocarditis in patients treated with immune checkpoint inhibitors. J Am Coll Cardiol 71(16):1755–1764. https://doi.org/10.1016/j.jacc.2018.02.037

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  8. Escudier M, Cautela J, Malissen N, Ancedy Y, Orabona M, Pinto J, Monestier S, Grob JJ, Scemama U, Jacquier A, Lalevee N, Barraud J, Peyrol M, Laine M, Bonello L, Paganelli F, Cohen A, Barlesi F, Ederhy S, Thuny F (2017) Clinical features, management, and outcomes of immune checkpoint inhibitor-related cardiotoxicity. Circulation 136(21):2085–2087. https://doi.org/10.1161/CIRCULATIONAHA.117.030571

    Article  PubMed  Google Scholar 

  9. Salem JE, Manouchehri A, Moey M, Lebrun-Vignes B, Bastarache L, Pariente A, Gobert A, Spano JP, Balko JM, Bonaca MP, Roden DM, Johnson DB, Moslehi JJ (2018) Cardiovascular toxicities associated with immune checkpoint inhibitors: an observational, retrospective, pharmacovigilance study. Lancet Oncol 19(12):1579–1589. https://doi.org/10.1016/S1470-2045(18)30608-9

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  10. Okazaki T, Tanaka Y, Nishio R, Mitsuiye T, Mizoguchi A, Wang J, Ishida M, Hiai H, Matsumori A, Minato N, Honjo T (2003) Autoantibodies against cardiac troponin I are responsible for dilated cardiomyopathy in PD-1-deficient mice. Nat Med 9(12):1477–1483. https://doi.org/10.1038/nm955

    CAS  Article  PubMed  Google Scholar 

  11. Nishimura H, Okazaki T, Tanaka Y, Nakatani K, Hara M, Matsumori A, Sasayama S, Mizoguchi A, Hiai H, Minato N, Honjo T (2001) Autoimmune dilated cardiomyopathy in PD-1 receptor-deficient mice. Science 291(5502):319–322. https://doi.org/10.1126/science.291.5502.319.

    CAS  Article  PubMed  Google Scholar 

  12. Tarrio ML, Grabie N, Bu DX, Sharpe AH, Lichtman AH (2012) PD-1 protects against inflammation and myocyte damage in T cell-mediated myocarditis. J Immunol 188(10):4876–4884. https://doi.org/10.4049/jimmunol.1200389

    CAS  Article  PubMed  Google Scholar 

  13. Grabie N, Gotsman I, DaCosta R, Pang H, Stavrakis G, Butte MJ, Keir ME, Freeman GJ, Sharpe AH, Lichtman AH (2007) Endothelial programmed death-1 ligand 1 (PD-L1) regulates CD8+ T-cell mediated injury in the heart. Circulation 116(18):2062–2071. https://doi.org/10.1161/CIRCULATIONAHA.107.709360

    CAS  Article  PubMed  Google Scholar 

  14. Gotsman I, Grabie N, Dacosta R, Sukhova G, Sharpe A, Lichtman AH (2007) Proatherogenic immune responses are regulated by the PD-1/PD-L pathway in mice. J Clin Invest 117(10):2974–2982. https://doi.org/10.1172/JCI31344

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  15. Bu DX, Tarrio M, Maganto-Garcia E, Stavrakis G, Tajima G, Lederer J, Jarolim P, Freeman GJ, Sharpe AH, Lichtman AH (2011) Impairment of the programmed cell death-1 pathway increases atherosclerotic lesion development and inflammation. Arterioscler Thromb Vasc Biol 31(5):1100–1107. https://doi.org/10.1161/ATVBAHA.111.224709

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  16. Reuben A, Petaccia de Macedo M, McQuade J, Joon A, Ren Z, Calderone T, Conner B, Wani K, Cooper ZA, Tawbi H, Tetzlaff MT, Padera RF, Durand JB, Lazar AJ, Wargo JA, Davies MA (2017) Comparative immunologic characterization of autoimmune giant cell myocarditis with ipilimumab. Oncoimmunology 6(12):e1361097. https://doi.org/10.1080/2162402X.2017.1361097

    Article  PubMed  PubMed Central  Google Scholar 

  17. Johnson DB, Sullivan RJ, Ott PA, Carlino MS, Khushalani NI, Ye F, Guminski A, Puzanov I, Lawrence DP, Buchbinder EI, Mudigonda T, Spencer K, Bender C, Lee J, Kaufman HL, Menzies AM, Hassel JC, Mehnert JM, Sosman JA, Long GV, Clark J (2016) Ipilimumab therapy in patients with advanced melanoma and preexisting autoimmune disorders. JAMA Oncol 2(2):234–240. https://doi.org/10.1001/jamaoncol.2015.4368

    Article  PubMed  Google Scholar 

  18. Menzies AM, Johnson DB, Ramanujam S, Atkinson VG, Wong ANM, Park JJ, McQuade JL, Shoushtari AN, Tsai KK, Eroglu Z, Klein O, Hassel JC, Sosman JA, Guminski A, Sullivan RJ, Ribas A, Carlino MS, Davies MA, Sandhu SK, Long GV (2017) Anti-PD-1 therapy in patients with advanced melanoma and preexisting autoimmune disorders or major toxicity with ipilimumab. Ann Oncol 28(2):368–376. https://doi.org/10.1093/annonc/mdw443

    CAS  Article  PubMed  Google Scholar 

  19. Awadalla M, Golden DLA, Mahmood SS, Alvi RM, Mercaldo ND, Hassan MZO, Banerji D, Rokicki A, Mulligan C, Murphy SPT, Jones-O’Connor M, Cohen JV, Heinzerling LM, Armanious M, Sullivan RJ, Damrongwatanasuk R, Chen CL, Gupta D, Kirchberger MC, Moslehi JJ, Shah SP, Ganatra S, Thavendiranathan P, Rizvi MA, Sahni G, Lyon AR, Tocchetti CG, Mercurio V, Thuny F, Ederhy S, Mahmoudi M, Lawrence DP, Groarke JD, Nohria A, Fradley MG, Reynolds KL, Neilan TG (2019) Influenza vaccination and myocarditis among patients receiving immune checkpoint inhibitors. J Immunother Cancer 7(1):53. https://doi.org/10.1186/s40425-019-0535-y

    Article  PubMed  PubMed Central  Google Scholar 

  20. Weber JS, Hodi FS, Wolchok JD, Topalian SL, Schadendorf D, Larkin J, Sznol M, Long GV, Li H, Waxman IM, Jiang J, Robert C (2017) Safety profile of nivolumab monotherapy: a pooled analysis of patients with advanced melanoma. J Clin Oncol 35(7):785–792. https://doi.org/10.1200/JCO.2015.66.1389

    CAS  Article  PubMed  Google Scholar 

  21. Anquetil C, Salem JE, Lebrun-Vignes B, Johnson DB, Mammen AL, Stenzel W, Léonard-Louis S, Benveniste O, Moslehi JJ, Allenbach Y (2018) Immune checkpoint inhibitor-associated myositis. Circulation 138(7):743–745. https://doi.org/10.1161/CIRCULATIONAHA.118.035898

    Article  PubMed  Google Scholar 

  22. Norwood TG, Westbrook BC, Johnson DB, Litovsky SH, Terry NL, McKee SB, Gertler AS, Moslehi JJ, Conry RM (2017) Smoldering myocarditis following immune checkpoint blockade. J Immunother Cancer 5(1):91. https://doi.org/10.1186/s40425-017-0296-4

    Article  PubMed  PubMed Central  Google Scholar 

  23. Wang DY, Okoye GD, Neilan TG, Johnson DB, Moslehi JJ (2017) Cardiovascular toxicities associated with cancer immunotherapies. Curr Cardiol Rep 19(3):21. https://doi.org/10.1007/s11886-017-0835-0

    Article  PubMed  Google Scholar 

  24. Brahmer JR, Lacchetti C, Schneider BJ, Atkins MB, Brassil KJ, Caterino JM, Chau I, Ernstoff MS, Gardner JM, Ginex P, Hallmeyer S, Holter Chakrabarty J, Leighl NB, Mammen JS, McDermott DF, Naing A, Nastoupil LJ, Phillips T, Porter LD, Puzanov I, Reichner CA, Santomasso BD, Seigel C, Spira A, Suarez-Almazor ME, Wang Y, Weber JS, Wolchok JD, Thompson JA, National Comprehensive Cancer Network (2018) Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol 36(17):1714–1768. https://doi.org/10.1200/JCO.2017.77.6385

    CAS  Article  PubMed  Google Scholar 

  25. Sarocchi M, Grossi F, Arboscello E, Bellodi A, Genova C, Dal Bello MG, Rijavec E, Barletta G, Rossi G, Biello F, Ghigliotti G, Canepa M, Mussap M, Brunelli C, Spallarossa P (2018) Serial troponin for early detection of nivolumab cardiotoxicity in advanced non-small cell lung cancer patients. Oncologist 23(8):936–942. https://doi.org/10.1634/theoncologist.2017-0452

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  26. Lee Chuy K, Oikonomou EK, Postow MA, Callahan MK, Chapman PB, Shoushtari AN, Neilan TG, Fradley MG, Ramanathan LV, Wolchok JD, Steingart RM, Gupta D (2019) Myocarditis surveillance in patients with advanced melanoma on combination immune checkpoint inhibitor therapy: the Memorial Sloan Kettering Cancer Center experience. Oncologist 24(5):e196–e197. https://doi.org/10.1634/theoncologist.2019-0040

    Article  PubMed  PubMed Central  Google Scholar 

  27. Friedrich MG, Sechtem U, Schulz-Menger J, Holmvang G, Alakija P, Cooper LT, White JA, Abdel-Aty H, Gutberlet M, Prasad S, Aletras A, Laissy JP, Paterson I, Filipchuk NG, Kumar A, Pauschinger M, Liu P, International Consensus Group on Cardiovascular Magnetic Resonance in Myocarditis (2009) Cardiovascular magnetic resonance in myocarditis: a JACC White Paper. J Am Coll Cardiol 53(17):1475–1487. https://doi.org/10.1016/j.jacc.2009.02.007

    Article  PubMed  PubMed Central  Google Scholar 

  28. Gräni C, Eichhorn C, Bière L, Murthy VL, Agarwal V, Kaneko K, Cuddy S, Aghayev A, Steigner M, Blankstein R, Jerosch-Herold M, Kwong RY (2017) Prognostic value of cardiac magnetic resonance tissue characterization in risk stratifying patients with suspected myocarditis. J Am Coll Cardiol 70(16):1964–1976. https://doi.org/10.1016/j.jacc.2017.08.050

    Article  PubMed  PubMed Central  Google Scholar 

  29. Aquaro GD, Perfetti M, Camastra G, Monti L, Dellegrottaglie S, Moro C, Pepe A, Todiere G, Lanzillo C, Scatteia A, Di Roma M, Pontone G, Perazzolo Marra M, Barison A, Di Bella G, Cardiac Magnetic Resonance Working Group of the Italian Society of Cardiology (2017) Cardiac MR with late gadolinium enhancement in acute myocarditis with preserved systolic function: ITAMY Study. J Am Coll Cardiol 70(16):1977–1987. https://doi.org/10.1016/j.jacc.2017.08.044

    Article  PubMed  Google Scholar 

  30. Cooper LT, Baughman KL, Feldman AM, Frustaci A, Jessup M, Kuhl U, Levine GN, Narula J, Starling RC, Towbin J, Virmani R (2007) The role of endomyocardial biopsy in the management of cardiovascular disease: a scientific statement from the American Heart Association, the American College of Cardiology, and the European Society of Cardiology. Endorsed by the Heart Failure Society of America and the Heart Failure Association of the European Society of Cardiology. J Am Coll Cardiol 50(19):1914–1931. https://doi.org/10.1016/j.jacc.2007.09.008.

    Article  PubMed  Google Scholar 

  31. Leone O, Veinot JP, Angelini A, Baandrup UT, Basso C, Berry G, Bruneval P, Burke M, Butany J, Calabrese F, d’Amati G, Edwards WD, Fallon JT, Fishbein MC, Gallagher PJ, Halushka MK, McManus B, Pucci A, Rodriguez ER, Saffitz JE, Sheppard MN, Steenbergen C, Stone JR, Tan C, Thiene G, van der Wal AC, Winters GL (2012) 2011 consensus statement on endomyocardial biopsy from the Association for European Cardiovascular Pathology and the Society for Cardiovascular Pathology. Cardiovasc Pathol 21(4):245–274. https://doi.org/10.1016/j.carpath.2011.10.001

    Article  PubMed  Google Scholar 

  32. Mahmood SS, Chen CL, Shapnik N, Krishnan U, Singh HS, Makker V (2018) Myocarditis with tremelimumab plus durvalumab combination therapy for endometrial cancer: a case report. Gynecol Oncol Rep 25:74–77. https://doi.org/10.1016/j.gore.2018.05.014

    Article  PubMed  PubMed Central  Google Scholar 

  33. Agrawal N, Khunger A, Vachhani P, Colvin TA, Hattoum A, Spangenthal E, Curtis AB, Dy GK, Ernstoff MS, Puzanov I (2019) Cardiac toxicity associated with immune checkpoint inhibitors: case series and review of the literature. Case Rep Oncol 12(1):260–276. https://doi.org/10.1159/000498985

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  34. Jain V, Mohebtash M, Rodrigo ME, Ruiz G, Atkins MB, Barac A (2018) Autoimmune myocarditis caused by immune checkpoint inhibitors treated with antithymocyte globulin. J Immunother 41(7):332–335. https://doi.org/10.1097/CJI.0000000000000239

    Article  PubMed  Google Scholar 

  35. Rota E, Varese P, Agosti S, Celli L, Ghiglione E, Pappalardo I, Zaccone G, Paglia A, Morelli N (2019) Concomitant myasthenia gravis, myositis, myocarditis and polyneuropathy, induced by immune-checkpoint inhibitors: a life-threatening continuum of neuromuscular and cardiac toxicity. ENeurologicalSci 14:4–5. https://doi.org/10.1016/j.ensci.2018.11.023

    Article  PubMed  Google Scholar 

  36. Imai R, Ono M, Nishimura N, Suzuki K, Komiyama N, Tamura T (2019) Fulminant myocarditis caused by an immune checkpoint inhibitor: a case report with pathologic findings. J Thorac Oncol 14(2):e36–e38. https://doi.org/10.1016/j.jtho.2018.10.156

    Article  PubMed  Google Scholar 

  37. Hodi FS, Chiarion-Sileni V, Gonzalez R, Grob JJ, Rutkowski P, Cowey CL, Lao CD, Schadendorf D, Wagstaff J, Dummer R, Ferrucci PF, Smylie M, Hill A, Hogg D, Marquez-Rodas I, Jiang J, Rizzo J, Larkin J, Wolchok JD (2018) Nivolumab plus ipilimumab or nivolumab alone versus ipilimumab alone in advanced melanoma (CheckMate 067): 4-year outcomes of a multicentre, randomised, phase 3 trial. Lancet Oncol 19(11):1480–1492. https://doi.org/10.1016/S1470-2045(18)30700-9

    CAS  Article  PubMed  Google Scholar 

  38. Shoushtari AN, Friedman CF, Navid-Azarbaijani P, Postow MA, Callahan MK, Momtaz P, Panageas KS, Wolchok JD, Chapman PB (2018) Measuring toxic effects and time to treatment failure for nivolumab plus ipilimumab in melanoma. JAMA Oncol 4(1):98–101. https://doi.org/10.1001/jamaoncol.2017.2391

    Article  PubMed  Google Scholar 

  39. Schadendorf D, Hodi FS, Robert C, Weber JS, Margolin K, Hamid O, Patt D, Chen TT, Berman DM, Wolchok JD (2015) Pooled analysis of long-term survival data from phase II and phase III trials of ipilimumab in unresectable or metastatic melanoma. J Clin Oncol 33(17):1889–1894. https://doi.org/10.1200/JCO.2014.56.2736

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  40. Pollack MH, Betof A, Dearden H, Rapazzo K, Valentine I, Brohl AS, Ancell KK, Long GV, Menzies AM, Eroglu Z, Johnson DB, Shoushtari AN (2018) Safety of resuming anti-PD-1 in patients with immune-related adverse events (irAEs) during combined anti-CTLA-4 and anti-PD1 in metastatic melanoma. Ann Oncol 29(1):250–255. https://doi.org/10.1093/annonc/mdx642

    CAS  Article  PubMed  Google Scholar 

  41. Abdel-Rahman O, Eltobgy M, Oweira H, Giryes A, Tekbas A, Decker M (2017) Immune-related musculoskeletal toxicities among cancer patients treated with immune checkpoint inhibitors: a systematic review. Immunotherapy 9(14):1175–1183. https://doi.org/10.2217/imt-2017-0108

    CAS  Article  PubMed  Google Scholar 

  42. Baxi S, Yang A, Gennarelli RL, Khan N, Wang Z, Boyce L, Korenstein D (2018) Immune-related adverse events for anti-PD-1 and anti-PD-L1 drugs: systematic review and meta-analysis. BMJ 360:k793. https://doi.org/10.1136/bmj.k793

    Article  PubMed  PubMed Central  Google Scholar 

  43. Cappelli LC, Gutierrez AK, Bingham CO 3rd, Shah AA (2017) Rheumatic and musculoskeletal immune-related adverse events due to immune checkpoint inhibitors: a systematic review of the literature. Arthritis Care Res 69(11):1751–1763. https://doi.org/10.1002/acr.23177

    Article  Google Scholar 

  44. Moseley KF, Naidoo J, Bingham CO, Carducci MA, Forde PM, Gibney GT, Lipson EJ, Shah AA, Sharfman WH, Cappelli LC (2018) Immune-related adverse events with immune checkpoint inhibitors affecting the skeleton: a seminal case series. J Immunother Cancer 6(1):104. https://doi.org/10.1186/s40425-018-0417-8

    Article  PubMed  PubMed Central  Google Scholar 

  45. Cancer Care Ontario. Immune checkpoint inhibitor toxicity management clinical practice guideline (Version 1. 2018) [Available from: https://www.cancercareontario.ca/en/guidelines-advice/types-of-cancer/52976. Accessed August 30, 2019.

  46. Abdel-Wahab N, Bingham COI, Suarez-Almazor ME (2019) Musculoskeletal and rheumatologic toxicities. In: Earstoff MS, Puzanov I, Robert C, Daib A, Hersey P (eds) SITC’s Guide to Managing Immunotherapy Toxicity. Demos Medical Publishing - Springer Publishing, New York, pp 171–184

    Google Scholar 

  47. Haanen J, Carbonnel F, Robert C, Kerr KM, Peters S, Larkin J, Jordan K, ESMO Guidelines Committee (2017) Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 28(suppl_4):iv119–iv142. https://doi.org/10.1093/annonc/mdx225

    CAS  Article  PubMed  Google Scholar 

  48. Puzanov I, Diab A, Abdallah K, Bingham CO 3rd, Brogdon C, Dadu R, Hamad L, Kim S, Lacouture ME, LeBoeuf NR, Lenihan D, Onofrei C, Shannon V, Sharma R, Silk AW, Skondra D, Suarez-Almazor ME, Wang Y, Wiley K, Kaufman HL, Ernstoff MS (2017) Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group. J Immunother Cancer 5(1):95. https://doi.org/10.1186/s40425-017-0300-z

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  49. Thompson JA, Schneider BJ, Brahmer J, Andrews S, Armand P, Bhatia S, Budde LE, Costa L, Davies M, Dunnington D, Ernstoff MS, Frigault M, Hoffner B, Hoimes CJ, Lacouture M, Locke F, Lunning M, Mohindra NA, Naidoo J, Olszanski AJ, Oluwole O, Patel SP, Reddy S, Ryder M, Santomasso B, Shofer S, Sosman JA, Wahidi M, Wang Y, Johnson-Chilla A, Scavone JL (2019) Management of immunotherapy-related toxicities, Version 1.2019. J Natl Compr Cancer Netw 17(3):255–289. https://doi.org/10.6004/jnccn.2019.0013

    CAS  Article  Google Scholar 

  50. 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(7):e0160221. https://doi.org/10.1371/journal.pone.0160221

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  51. Champiat S, Lambotte O, Barreau E, Belkhir R, Berdelou A, Carbonnel F, Cauquil C, Chanson P, Collins M, Durrbach A, Ederhy S, Feuillet S, François H, Lazarovici J, Le Pavec J, De Martin E, Mateus C, Michot JM, Samuel D, Soria JC, Robert C, Eggermont A, Marabelle A (2016) Management of immune checkpoint blockade dysimmune toxicities: a collaborative position paper. Ann Oncol 27(4):559–574. https://doi.org/10.1093/annonc/mdv623

    CAS  Article  PubMed  Google Scholar 

  52. Buder-Bakhaya K, Benesova K, Schulz C, Anwar H, Dimitrakopoulou-Strauss A, Weber TF, Enk A, Lorenz HM, Hassel JC (2018) Characterization of arthralgia induced by PD-1 antibody treatment in patients with metastasized cutaneous malignancies. Cancer Immunol Immunother 67(2):175–182. https://doi.org/10.1007/s00262-017-2069-9

    CAS  Article  PubMed  Google Scholar 

  53. Le Burel S, Champiat S, Mateus C, Marabelle A, Michot JM, Robert C, Belkhir R, Soria JC, Laghouati S, Voisin AL, Fain O, Mékinian A, Coutte L, Szwebel TA, Dunogeant L, Lioger B, Luxembourger C, Mariette X, Lambotte O (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 82:34–44. https://doi.org/10.1016/j.ejca.2017.05.032

    CAS  Article  PubMed  Google Scholar 

  54. Lidar M, Giat E, Garelick D, Horowitz Y, Amital H, Steinberg-Silman Y, Schachter J, Shapira-Frommer R, Markel G (2018) Rheumatic manifestations among cancer patients treated with immune checkpoint inhibitors. Autoimmun Rev 17(3):284–289. https://doi.org/10.1016/j.autrev.2018.01.003

    CAS  Article  PubMed  Google Scholar 

  55. Richter MD, Crowson C, Kottschade LA, Finnes HD, Markovic SN, Thanarajasingam U (2019) Rheumatic syndromes associated with immune checkpoint inhibitors: a single-center cohort of sixty-one patients. Arthritis Rheum 71(3):468–475. https://doi.org/10.1002/art.40745

    CAS  Article  Google Scholar 

  56. Kostine M, Rouxel L, Barnetche T, Veillon R, Martin F, Dutriaux C, Dousset L, Pham-Ledard A, Prey S, Beylot-Barry M, Daste A, Gross-Goupil M, Lallier J, Ravaud A, Forcade E, Bannwarth B, Truchetet ME, Richez C, Mehsen N, Schaeverbeke T, FHU ACRONIM (2018) Rheumatic disorders associated with immune checkpoint inhibitors in patients with cancer-clinical aspects and relationship with tumour response: a single-centre prospective cohort study. Ann Rheum Dis 77(3):393–398. https://doi.org/10.1136/annrheumdis-2017-212257

    CAS  Article  PubMed  Google Scholar 

  57. Calabrese C, Kirchner E, Kontzias K, Velcheti V, Calabrese LH (2017) Rheumatic immune-related adverse events of checkpoint therapy for cancer: case series of a new nosological entity. RMD Open 3(1):e000412. https://doi.org/10.1136/rmdopen-2016-000412

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  58. Belkhir R, Burel SL, Dunogeant L, Marabelle A, Hollebecque A, Besse B, Leary A, Voisin AL, Pontoizeau C, Coutte L, Pertuiset E, Mouterde G, Fain O, Lambotte O, Mariette X (2017) Rheumatoid arthritis and polymyalgia rheumatica occurring after immune checkpoint inhibitor treatment. Ann Rheum Dis 76(10):1747–1750. https://doi.org/10.1136/annrheumdis-2017-211216

    CAS  Article  PubMed  Google Scholar 

  59. Kuswanto WF, MacFarlane LA, Gedmintas L, Mulloy A, Choueiri TK, Bermas BL (2018) Rheumatologic symptoms in oncologic patients on PD-1 inhibitors. Semin Arthritis Rheum 47(6):907–910. https://doi.org/10.1016/j.semarthrit.2017.10.018

    CAS  Article  PubMed  Google Scholar 

  60. Mitchell EL, Lau PK, Khoo C, Liew D, Leung J, Liu B et al (2018) Management of rheumatological immune related adverse events in melanoma patients treated with anti-programmed cell death (PD) 1 antibodies. Pigment Cell Melanoma Res 31(1):190. https://doi.org/10.1111/pcmr.12656

    Article  Google Scholar 

  61. Abdel-Wahab N, Suarez-Almazor ME (2019) Frequency and distribution of various rheumatic disorders associated with checkpoint inhibitor therapy. Rheumatology (Oxford) 58(Suppl 7):vii40–vii48. https://doi.org/10.1093/rheumatology/kez297

    CAS  Article  Google Scholar 

  62. Abdel-Wahab N, Tayar JH, Diab A, Kim ST, Lu H, Suarez-Almazor ME (2017) Inflammatory arthritis induced by the use of checkpoint inhibitors for immunotherapy of cancer. J Immunother Cancer 5(2):215

    Google Scholar 

  63. Pundole X, Abdel-Wahab N, Suarez-Almazor ME (2019) Arthritis risk with immune checkpoint inhibitor therapy for cancer. Curr Opin Rheumatol 31(3):293–299. https://doi.org/10.1097/BOR.0000000000000601

    CAS  Article  PubMed  Google Scholar 

  64. Cappelli LC, Brahmer JR, Forde PM, Le DT, Lipson EJ, Naidoo J, Zheng L, Bingham CO 3rd, Shah AA (2018) Clinical presentation of immune checkpoint inhibitor-induced inflammatory arthritis differs by immunotherapy regimen. Semin Arthritis Rheum 48(3):553–557. https://doi.org/10.1016/j.semarthrit.2018.02.011

    Article  PubMed  PubMed Central  Google Scholar 

  65. Cappelli LC, Gutierrez AK, Baer AN, Albayda J, Manno RL, Haque U, Lipson EJ, Bleich KB, Shah AA, Naidoo J, Brahmer JR, Le D, Bingham CO 3rd (2017) Inflammatory arthritis and sicca syndrome induced by nivolumab and ipilimumab. Ann Rheum Dis 76(1):43–50. https://doi.org/10.1136/annrheumdis-2016-209595

    CAS  Article  PubMed  Google Scholar 

  66. Aletaha D, Neogi T, Silman AJ, Funovits J, Felson DT, Bingham CO 3rd, Birnbaum NS, Burmester GR, Bykerk VP, Cohen MD, Combe B, Costenbader KH, Dougados M, Emery P, Ferraccioli G, Hazes JM, Hobbs K, Huizinga TW, Kavanaugh A, Kay J, Kvien TK, Laing T, Mease P, Ménard HA, Moreland LW, Naden RL, Pincus T, Smolen JS, Stanislawska-Biernat E, Symmons D, Tak PP, Upchurch KS, Vencovsky J, Wolfe F, Hawker G (2010) 2010 Rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Ann Rheum Dis 69(9):1580–1588. https://doi.org/10.1136/ard.2010.138461

    Article  PubMed  Google Scholar 

  67. Calabrese C, Cappelli LC, Kostine M, Kirchner E, Braaten T, Calabrese L (2019) Polymyalgia rheumatica-like syndrome from checkpoint inhibitor therapy: case series and systematic review of the literature. RMD Open 5(1):e000906. https://doi.org/10.1136/rmdopen-2019-000906

    Article  PubMed  PubMed Central  Google Scholar 

  68. Dasgupta B, Cimmino MA, Maradit-Kremers H, Schmidt WA, Schirmer M, Salvarani C, Bachta A, Dejaco C, Duftner C, Jensen HS, Duhaut P, Poór G, Kaposi NP, Mandl P, Balint PV, Schmidt Z, Iagnocco A, Nannini C, Cantini F, Macchioni P, Pipitone N, Amo MD, Espígol-Frigolé G, Cid MC, Martínez-Taboada VM, Nordborg E, Direskeneli H, Aydin SZ, Ahmed K, Hazleman B, Silverman B, Pease C, Wakefield RJ, Luqmani R, Abril A, Michet CJ, Marcus R, Gonter NJ, Maz M, Carter RE, Crowson CS, Matteson EL (2012) 2012 Provisional classification criteria for polymyalgia rheumatica: a European League Against Rheumatism/American College of Rheumatology collaborative initiative. Ann Rheum Dis 71(4):484–492. https://doi.org/10.1136/annrheumdis-2011-200329

    Article  PubMed  Google Scholar 

  69. Daxini A, Cronin K, Sreih AG (2018) Vasculitis associated with immune checkpoint inhibitors-a systematic review. Clin Rheumatol 37(9):2579–2584. https://doi.org/10.1007/s10067-018-4177-0

    Article  PubMed  Google Scholar 

  70. 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 Rheum 66(3):768–769. https://doi.org/10.1002/art.38282

    Article  Google Scholar 

  71. Pundole X, Shah M, Abdel-Wahab N, Suarez-Almazor EM (2017) Immune checkpoint inhibitors and inflammatory myopathies: data from the US Food and Drug Administration Adverse Event Reporting System. Arthritis Rheum 69(10):1192–1193

    Google Scholar 

  72. Shah M, Tayar JH, Abdel-Wahab N, Suarez-Almazor ME (2019) Myositis as an adverse event of immune checkpoint blockade for cancer therapy. Semin Arthritis Rheum 48(4):736–740. https://doi.org/10.1016/j.semarthrit.2018.05.006

    CAS  Article  PubMed  Google Scholar 

  73. Liewluck T, Kao JC, Mauermann ML (2018) PD-1 inhibitor-associated myopathies: emerging immune-mediated myopathies. J Immunother 41(4):208–211. https://doi.org/10.1097/CJI.0000000000000196

    CAS  Article  PubMed  Google Scholar 

  74. Moreira A, Loquai C, Pfohler C, Kahler KC, Knauss S, Heppt MV, Gutzmer R, Dimitriou F, Meier F, Mitzel-Rink H, Schuler G, Terheyden P, Thoms KM, Türk M, Dummer R, Zimmer L, Schröder R, Heinzerling L (2019) Myositis and neuromuscular side-effects induced by immune checkpoint inhibitors. Eur J Cancer 106:12–23. https://doi.org/10.1016/j.ejca.2018.09.033

    CAS  Article  PubMed  Google Scholar 

  75. Kang KH, Grubb W, Sawlani K, Gibson MK, Hoimes CJ, Rogers LR, Lavertu P, Yao M (2018) Immune checkpoint-mediated myositis and myasthenia gravis: a case report and review of evaluation and management. Am J Otolaryngol 39(5):642–645. https://doi.org/10.1016/j.amjoto.2018.06.003

    Article  PubMed  Google Scholar 

  76. Mohn N, Suhs KW, Gingele S, Angela Y, Stangel M, Gutzmer R, Satzger I, Skripuletz T (2019) Acute progressive neuropathy-myositis-myasthenia-like syndrome associated with immune-checkpoint inhibitor therapy in patients with metastatic melanoma. Melanoma Res 29(4):435–440. https://doi.org/10.1097/CMR.0000000000000598

    CAS  Article  PubMed  Google Scholar 

  77. Suzuki S, Ishikawa N, Konoeda F, Seki N, Fukushima S, Takahashi K, Uhara H, Hasegawa Y, Inomata S, Otani Y, Yokota K, Hirose T, Tanaka R, Suzuki N, Matsui M (2017) Nivolumab-related myasthenia gravis with myositis and myocarditis in Japan. Neurology 89(11):1127–1134. https://doi.org/10.1212/WNL.0000000000004359

    CAS  Article  PubMed  Google Scholar 

  78. Starke A, Lindenmeyer MT, Segerer S, Neusser MA, Rusi B, Schmid DM, Cohen CD, Wüthrich RP, Fehr T, Waeckerle-Men Y (2010) Renal tubular PD-L1 (CD274) suppresses alloreactive human T-cell responses. Kidney Int 78(1):38–47. https://doi.org/10.1038/ki.2010.97

    CAS  Article  PubMed  Google Scholar 

  79. Cortazar FB, Marrone KA, Troxell ML, Ralto KM, Hoenig MP, Brahmer JR, Le DT, Lipson EJ, Glezerman IG, Wolchok J, Cornell LD, Feldman P, Stokes MB, Zapata SA, Hodi FS, Ott PA, Yamashita M, Leaf DE (2016) Clinicopathological features of acute kidney injury associated with immune checkpoint inhibitors. Kidney Int 90(3):638–647. https://doi.org/10.1016/j.kint.2016.04.008

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  80. Abdel-Rahman O, Fouad M (2016) A network meta-analysis of the risk of immune-related renal toxicity in cancer patients treated with immune checkpoint inhibitors. Immunotherapy. 8(5):665–674. https://doi.org/10.2217/imt-2015-0020

    CAS  Article  PubMed  Google Scholar 

  81. Shirali AC, Perazella MA, Gettinger S (2016) Association of Acute Interstitial Nephritis With Programmed Cell Death 1 Inhibitor Therapy in Lung Cancer Patients. Am J Kidney Dis 68(2):287–291. https://doi.org/10.1053/j.ajkd.2016.02.057

    CAS  Article  PubMed  Google Scholar 

  82. Izzedine H, Mathian A, Champiat S, Picard C, Mateus C, Routier E, Varga A, Malka D, Leary A, Michels J, Michot JM, Marabelle A, Lambotte O, Amoura Z, Soria JC, Kaaki S, Quellard N, Goujon JM, Brocheriou I (2019) Renal toxicities associated with pembrolizumab. Clin Kidney J 12(1):81–88. https://doi.org/10.1093/ckj/sfy100

    CAS  Article  PubMed  Google Scholar 

  83. Mamlouk O, Selamet U, Machado S, Abdelrahim M, Glass WF, Tchakarov A, Gaber L, Lahoti A, Workeneh B, Chen S, Lin J, Abdel-Wahab N, Tayar J, Lu H, Suarez-Almazor M, Tannir N, Yee C, Diab A, Abudayyeh A (2019) Nephrotoxicity of immune checkpoint inhibitors beyond tubulointerstitial nephritis: single-center experience. J Immunother Cancer 7(1):2. https://doi.org/10.1186/s40425-018-0478-8

    Article  PubMed  PubMed Central  Google Scholar 

  84. Glezerman IG, Latcha S, Jaimes EA (2018) Renal immune related adverse events in patients treated with PD-1 inhibitors: an emerging complication of immunotherapy. J Am Soc Nephrol 29:44

    Google Scholar 

  85. Cortazar FB, Kibbelaar ZA, Glezerman IG, Abudayyeh A, Mamlouk O, Motwani SS, Murakami N, Herrmann SM, Manohar S, Shirali AC, Kitchlu A, Shirazian S, Assal A, Vijayan A, Renaghan AD, Ortiz-Melo DI, Rangarajan S, Malik AB, Hogan JJ, Dinh AR, Shin DS, Marrone KA, Mithani Z, Johnson DB, Hosseini A, Uprety D, Sharma S, Gupta S, Reynolds KL, Sise ME, Leaf DE (2020) Clinical features and outcomes of immune checkpoint inhibitor-associated AKI: a multicenter study. J Am Soc Nephrol 31(2):435–446. https://doi.org/10.1681/ASN.2019070676

    CAS  Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

Professor BL Rapoport is supported by supported by the Cancer Association of South Africa (CANSA) and the National Research Foundation (NRF) of South Africa. Dr. I. Glezerman is supported by the NIH/NCI (Cancer Center Support Grant P30 CA008748).

Author information

Authors and Affiliations

Authors

Contributions

All of the authors contributed equally to the conceptualization of the manuscript; MES-A, XP, NA-W, DBJ, IG, and TC shared sections on rheumatic immune-related adverse events equally, while BLR and DBJ provided clinical input and BLR, DBJ, and RA editorial oversight. All of the authors provided critical appraisal of the manuscript and approve of its submission.

Corresponding author

Correspondence to Bernardo L. Rapoport.

Ethics declarations

Conflict of interest

AW, XP, AB, RA, JC, TC, PG, DG RAG, and VRS have no conflict of interest to declare. MD reports grants from Novartis, other (SAB) from Neoleukin Therapeutics, personal fees from Partner Therapeutics, personal fees from Tillotts Pharma, and grants from Genentech, outside the submitted work. MG reports consultant work with Bristol Myers Squibb (BMS), and AstraZeneca, outside the submitted work. IG reports other (Stock Ownership) from Pfizer Inc., and personal fees from CytomX Inc., outside the submitted work. DBJ reports other (advisory board) from Array Biopharma, grants and other (advisory board) from BMS, other (advisory board) from Jansen, grants from Incyte, other (advisory board) from Merck, and other (advisory board) from Novartis, outside the submitted work. In addition, DBJ has a patent co-inventor on use of CTLA-4 agonist for IAEs pending. BLR reports personal fees and other (advisory board) from Merck and Co.; grants, personal fees, and other (advisory board) from BMS; grants, personal fees, and other (advisory board) from Roche South Africa; and personal fees and other (advisory board) from AstraZeneca, during the conduct of the study. MSA reports personal fees from Gilead, grants from Pfizer, and personal fees from Abbvie, outside the submitted work.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Suarez-Almazor, M.E., Pundole, X., Abdel-Wahab, N. et al. Multinational Association of Supportive Care in Cancer (MASCC) 2020 clinical practice recommendations for the management of immune-mediated cardiovascular, rheumatic, and renal toxicities from checkpoint inhibitors. Support Care Cancer 28, 6159–6173 (2020). https://doi.org/10.1007/s00520-020-05710-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00520-020-05710-8

Keywords

  • Arthralgia
  • Arthritis
  • Cardiomyopathy
  • Corticosteroids
  • Myocarditis
  • Myositis
  • Immunomodulation agents
  • Other immunosuppressive agents
  • Polymyalgia