SpringerLink
Log in

Rheumatology (Arthritis and Myositis)

  • Chapter
  • First Online:
Managing Immunotherapy Related Organ Toxicities

  • 715 Accesses

Abstract

Rheumatic immune-related adverse events (irAEs) associated with immune checkpoint inhibitor (ICI) therapy in patients with cancer can be grouped into articular, muscular, granulomatous, vasculitic, and other systemic irAEs. In a large registry study, the two most prevalent types of rheumatic irAEs were articular (36% of cases) and muscular (34%) [1]; these two types are the focus of this chapter. The articular cluster is comprised of arthralgias and arthritis, and the muscular cluster is comprised of myalgias, myositis, and polymyalgia rheumatica (PMR)-like syndrome. Complete resolution of arthritic and myositis symptoms is expected in most patients after the discontinuation of ICI and often a course of treatment with immunosuppression. However, persistent inflammatory arthritis that requires prolonged DMARDs (disease-modifying antirheumatic drugs) has been reported.

Chapter debriefing: PowerPoint video presentation is provided at the end of the chapter.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 39.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 54.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free ship** worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Similar content being viewed by others

Abbreviations

ANA:

Anti-nuclear antibody

CK:

Creatine kinase

CRP:

C-reactive protein

CTCAE:

Common Terminology Criteria for Adverse Events

CTLA- 4:

Cytotoxic T-lymphocyte-associated protein 4

DMARD:

Disease-modifying antirheumatic drug

GCA:

Giant cell arteritis

ICI:

Immune checkpoint inhibitor

irAE:

Immune-related adverse events

PD-1:

Programmed cell death-protein1

PD-L1:

Programmed death-ligand 1

PMR:

Polymyalgia rheumatica

RA:

Rheumatoid arthritis

ReA:

Reactive arthritis

RS3PE:

Remitting seronegative symmetrical synovitis with pitting edema

References

  1. Ramos-Casals M, Lambotte O, Kostine M, Calabrese L, Suarez-Almazor M, Bingham C, Radstake TR, Baldini C, Schaeverbeke T, Gottenberg J-E. THU0649 phenotypic clusters of rheumatic/systemic immune-related adverse events induced by cancer immunotherapies (Immunocancer International Registry). BMJ Publishing Group Ltd; 2019.

    Book  Google Scholar 

  2. Calabrese LH, Calabrese C, Cappelli LC. Rheumatic immune-related adverse events from cancer immunotherapy. Nat Rev Rheumatol. 2018;14(10):569–79.

    Article  PubMed  Google Scholar 

  3. Robert C, Schachter J, Long GV, Arance A, Grob JJ, Mortier L, Daud A, Carlino MS, McNeil C, Lotem M, et al. Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med. 2015;372(26):2521–32.

    Article  CAS  PubMed  Google Scholar 

  4. Postow MA, Chesney J, Pavlick AC, Robert C, Grossmann K, McDermott D, Linette GP, Meyer N, Giguere JK, Agarwala SS, et al. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N Engl J Med. 2015;372(21):2006–17.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Buder-Bakhaya K, Benesova K, Schulz C, Anwar H, Dimitrakopoulou-Strauss A, Weber TF, Enk A, Lorenz HM, Hassel JC. Characterization of arthralgia induced by PD-1 antibody treatment in patients with metastasized cutaneous malignancies. Cancer Immunol Immunother. 2018;67(2):175–82.

    Article  CAS  PubMed  Google Scholar 

  6. Kostine M, Rouxel L, Barnetche T, Veillon R, Martin F, Dutriaux C, Dousset L, Pham-Ledard A, Prey S, Beylot-Barry M, et al. 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. 2018;77(3):393–8.

    Article  CAS  PubMed  Google Scholar 

  7. Pundole X, Abdel-Wahab N, Suarez-Almazor ME. Arthritis risk with immune checkpoint inhibitor therapy for cancer. Curr Opin Rheumatol. 2019;31(3):293–9.

    Article  CAS  PubMed  Google Scholar 

  8. Cappelli LC, Brahmer JR, Forde PM, Le DT, Lipson EJ, Naidoo J, Zheng L, Bingham CO 3rd, Shah AA. Clinical presentation of immune checkpoint inhibitor-induced inflammatory arthritis differs by immunotherapy regimen. Semin Arthritis Rheum. 2018;48(3):553–7.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Boutros C, Tarhini A, Routier E, Lambotte O, Ladurie FL, Carbonnel F, Izzeddine H, Marabelle A, Champiat S, Berdelou A, et al. Safety profiles of anti-CTLA-4 and anti-PD-1 antibodies alone and in combination. Nat Rev Clin Oncol. 2016;13(8):473–86.

    Article  CAS  PubMed  Google Scholar 

  10. Leipe J, Christ LA, Arnoldi AP, Mille E, Berger F, Heppt M, Goldscheider I, Kauffmann-Guerrero D, Huber RM, Dechant C, et al. Characteristics and treatment of new-onset arthritis after checkpoint inhibitor therapy. RMD Open. 2018;4(2):e000714.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Braaten TJ, Brahmer JR, Forde PM, Le D, Lipson EJ, Naidoo J, Schollenberger M, Zheng L, Bingham Iii CO, Shah AA, et al. Immune checkpoint inhibitor-induced inflammatory arthritis persists after immunotherapy cessation. Ann Rheum Dis. 2020;79(3):332–8.

    Article  CAS  PubMed  Google Scholar 

  12. Cappelli LC, Gutierrez AK, Baer AN, Albayda J, Manno RL, Haque U, Lipson EJ, Bleich KB, Shah AA, Naidoo J, et al. Inflammatory arthritis and sicca syndrome induced by nivolumab and ipilimumab. Ann Rheum Dis. 2017;76(1):43–50.

    Article  CAS  PubMed  Google Scholar 

  13. Sang T. Kim, Yanshuo Chu, Mercy Misoi, Maria E. Suarez-Almazor, Jean H. Tayar, Huifang Lu, Maryam Buni, Jordan Kramer, Emma Rodriguez, Zulekha Hussain, Sattva S. Neelapu, Jennifer Wang, Amishi Y. Shah, Nizar M. Tannir, Matthew T. Campbell, Don L. Gibbons, Tina Cascone, Charles Lu, George R. Blumenschein, Mehmet Altan, Bora Lim, Vincente Valero, Monica E. Loghin, Janet Tu, Shannon N. Westin, Aung Naing, Guillermo Garcia-Manero, Noha Abdel-Wahab, Hussein A. Tawbi, Patrick Hwu, Isabella C. Glitza Oliva, Michael A. Davies, Sapna P. Patel, Jun Zou, Andrew Futreal, Adi Diab, Linghua Wang & Roza Nurieva. Distinct molecular and immune hallmarks of inflammatory arthritis induced by immune checkpoint inhibitors for cancer therapy. Nature communications 13.1 (2022):1–19.

    Google Scholar 

  14. Albayda J, Dein E, Shah AA, Bingham CO 3rd, Cappelli L. Sonographic findings in inflammatory arthritis secondary to immune checkpoint inhibition: a case series. ACR Open Rheumatol. 2019;1(5):303–7.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Subedi A, Williams SG, Yao L, Maharjan S, Strauss J, Sharon E, Thomas A, Apolo AB, Gourh P, Hasni SA. Use of magnetic resonance imaging to identify immune checkpoint inhibitor–induced inflammatory arthritis. JAMA Netw Open. 2020;3(2):e200032.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Cappelli LC, Grieb SM, Shah AA, Bingham CO, Orbai A-M. Immune checkpoint inhibitor-induced inflammatory arthritis: a qualitative study identifying unmet patient needs and care gaps. BMC Rheumatol. 2020;4(1):1–10.

    Article  Google Scholar 

  17. Brahmer JR, Lacchetti C, Schneider BJ, Atkins MB, Brassil KJ, Caterino JM, Chau I, Ernstoff MS, Gardner JM, Ginex P, et al. 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. 2018;36(17):1714–68.

    Article  CAS  PubMed  Google Scholar 

  18. Thompson JA, Schneider BJ, Brahmer J, Andrews S, Armand P, Bhatia S, Budde LE, Costa L, Davies M, Dunnington D, et al. Management of immunotherapy-related toxicities, version 1.2019. J Natl Compr Cancer Netw. 2019;17(3):255–89.

    Article  CAS  Google Scholar 

  19. Puzanov I, Diab A, Abdallah K, Bingham CO 3rd, Brogdon C, Dadu R, Hamad L, Kim S, Lacouture ME, LeBoeuf NR, et al. Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group. J Immunother Cancer. 2017;5(1):95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Kostine M, Finckh A, Bingham CO, Visser K, Leipe J, Schulze-Koops H, Choy EH, Benesova K, Radstake TR, Cope AP. EULAR points to consider for the diagnosis and management of rheumatic immune-related adverse events due to cancer immunotherapy with checkpoint inhibitors. Ann Rheum Dis. 2021;80(1):36–48.

    Article  CAS  PubMed  Google Scholar 

  21. Kim ST, Tayar J, Suarez-Almazor M, Garcia S, Hwu P, Johnson DH, Uemura M, Diab A. Successful treatment of arthritis induced by checkpoint inhibitors with tocilizumab: a case series. Ann Rheum Dis. 2017;76(12):2061–4.

    Article  PubMed  Google Scholar 

  22. Tsukamoto H, Fujieda K, Miyashita A, Fukushima S, Ikeda T, Kubo Y, Senju S, Ihn H, Nishimura Y, Oshiumi H. Combined blockade of IL6 and PD-1/PD-L1 signaling abrogates mutual regulation of their immunosuppressive effects in the tumor microenvironment. Cancer Res. 2018;78(17):5011–22.

    Article  CAS  PubMed  Google Scholar 

  23. Cappelli LC, Bingham CO. Expert perspective: immune checkpoint inhibitors and rheumatologic complications. Arthritis Rheumatol. 2021;73(4):553–65.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Zhong H, Zhou J, Xu D, Zeng X. Rheumatic immune-related adverse events induced by immune checkpoint inhibitors. Asia Pac J Clin Oncol. 2021;17(3):178–85.

    Article  PubMed  Google Scholar 

  25. Belkhir R, Le Burel S, Lambotte O, Mouterde G, Pertuiset E, Dunogeant L, Marabelle A, Leary A, Voisin A, Mariette X. OP0004 Rheumatoid arthritis occuring after immune checkpoint inhibitors. BMJ Publishing Group Ltd; 2017.

    Book  Google Scholar 

  26. Jatwani K, Kaur H, Chugh K, Jatwani S. Nivolumab-induced psoriatic arthritis in a patient with advanced small cell lung cancer. J Clin Rheumatol. 2021;27(5):e162–3.

    Article  PubMed  Google Scholar 

  27. Nigro O, Pinotti G, Gueli R, Grigioni E, Santis M, Ceribelli A, Selmi C. Psoriatic arthritis induced by anti-PD1 and treated with apremilast: a case report and review of the literature. Immunotherapy. 2020;12(8):549–54.

    Article  CAS  PubMed  Google Scholar 

  28. Ghosh N, Tiongson MD, Stewart C, Chan KK, Jivanelli B, Cappelli L, Bass AR. Checkpoint inhibitor-associated arthritis: a systematic review of case reports and case series. J Clin Rheumatol. 2021;27(8):e317–22.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Weber JS, Hodi FS, Wolchok JD, Topalian SL, Schadendorf D, Larkin J, Sznol M, Long GV, Li H, Waxman IM: Safety profile of nivolumab monotherapy: a pooled analysis of patients with advanced melanoma. 2017.

    Google Scholar 

  30. Faje AT, Lawrence D, Flaherty K, Freedman C, Fadden R, Rubin K, Cohen J, Sullivan RJ. High-dose glucocorticoids for the treatment of ipilimumab-induced hypophysitis is associated with reduced survival in patients with melanoma. Cancer. 2018;124(18):3706–14.

    Article  CAS  PubMed  Google Scholar 

  31. Scott SC, Pennell NA. Early use of systemic corticosteroids in patients with advanced NSCLC treated with nivolumab. J Thorac Oncol. 2018;13(11):1771–5.

    Article  PubMed  Google Scholar 

  32. Abdel-Wahab N, Suarez-Almazor ME. Frequency and distribution of various rheumatic disorders associated with checkpoint inhibitor therapy. Rheumatology. 2019;58(Supplement_7):vii40–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Ramos-Casals M, Lambotte O, Kostine M, Calabrese L, Suarez-Almazor M, Bingham C, Radstake TR, Baldini C, Schaeverbeke T, Gottenberg J-E. Thu0628 immune-related adverse events induced by cancer immunotherapies. Big data analysis of 13,051 cases (Immunocancer international registry). BMJ Publishing Group Ltd; 2019.

    Google Scholar 

  34. Anquetil C, Salem J-E, Lebrun-Vignes B, Johnson DB, Mammen AL, Stenzel W, Léonard-Louis S, Benveniste O, Moslehi JJ, Allenbach Y. Immune checkpoint inhibitor–associated myositis: expanding the spectrum of cardiac complications of the immunotherapy revolution. Circulation. 2018;138(7):743–5.

    Article  PubMed  Google Scholar 

  35. Aldrich J, Pundole X, Tummala S, Palaskas N, Andersen CR, Shoukier M, Abdel-Wahab N, Deswal A, Suarez-Almazor ME. Inflammatory myositis in cancer patients receiving immune checkpoint inhibitors. Arthritis Rheumatol. 2021;73(5):866–74.

    Article  CAS  PubMed  Google Scholar 

  36. Shah M, Tayar JH, Abdel-Wahab N, Suarez-Almazor ME. Myositis as an adverse event of immune checkpoint blockade for cancer therapy. In: Seminars in arthritis and rheumatism: 2019. Elsevier; 2019. p. 736–40.

    Google Scholar 

  37. Kostine M, Truchetet M-E, Schaeverbeke T. Clinical characteristics of rheumatic syndromes associated with checkpoint inhibitors therapy. Rheumatology. 2019;58(Supplement_7):vii68–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Ramos-Casals M, Brahmer JR, Callahan MK, Flores-Chávez A, Keegan N, Khamashta MA, Lambotte O, Mariette X, Prat A, Suárez-Almazor ME. Immune-related adverse events of checkpoint inhibitors. Nat Rev Dis Primers. 2020;6(1):1–21.

    Article  Google Scholar 

  39. Moreira A, Loquai C, Pföhler C, Kähler KC, Knauss S, Heppt MV, Gutzmer R, Dimitriou F, Meier F, Mitzel-Rink H. Myositis and neuromuscular side-effects induced by immune checkpoint inhibitors. Eur J Cancer. 2019;106:12–23.

    Article  CAS  PubMed  Google Scholar 

  40. Messer A, Drozd B, Glitza IC, Lu H, Patel AB. Dermatomyositis associated with nivolumab therapy for melanoma: a case report and review of the literature. Dermatol Online J. 2020;26(8):13030/qt4c21b068.

    PubMed  Google Scholar 

  41. Bilen MA, Subudhi SK, Gao J, Tannir NM, Tu S-M, Sharma P. Acute rhabdomyolysis with severe polymyositis following ipilimumab-nivolumab treatment in a cancer patient with elevated anti-striated muscle antibody. J Immunother Cancer. 2016;4(1):1–5.

    Article  Google Scholar 

  42. Fazel M, Jedlowski PM. Severe myositis, myocarditis, and myasthenia gravis with elevated anti-striated muscle antibody following single dose of ipilimumab-nivolumab therapy in a patient with metastatic melanoma. Case Rep Immunol. 2019;2019:2539493.

    Google Scholar 

  43. Suarez-Almazor ME, Calabrese LH. Rheumatic diseases and syndromes induced by cancer immunotherapy: a handbook for diagnosis and management. Springer Nature; 2020.

    Google Scholar 

  44. Mooradian MJ, Nasrallah M, Gainor JF, Reynolds KL, Cohen JV, Lawrence DP, Miloslavsky EM, Kohler MJ, Sullivan RJ, Schoenfeld SR. Musculoskeletal rheumatic complications of immune checkpoint inhibitor therapy: a single center experience. In: Seminars in arthritis and rheumatism: 2019. Elsevier; 2019. p. 1127–32.

    Google Scholar 

  45. Touat M, Maisonobe T, Knauss S, Salem OBH, Hervier B, Auré K, Szwebel T-A, Kramkimel N, Lethrosne C, Bruch J-F. Immune checkpoint inhibitor-related myositis and myocarditis in patients with cancer. Neurology. 2018;91(10):e985–94.

    Article  CAS  PubMed  Google Scholar 

  46. Mammen AL, Rajan A, Pak K, Lehky T, Casciola-Rosen L, Donahue RN, Lepone LM, Zekeridou A, Pittock SJ, Hassan R. Pre-existing antiacetylcholine receptor autoantibodies and B cell lymphopaenia are associated with the development of myositis in patients with thymoma treated with avelumab, an immune checkpoint inhibitor targeting programmed death-ligand 1. Ann Rheum Dis. 2019;78(1):150–2.

    Article  CAS  PubMed  Google Scholar 

  47. Pourhassan HZ, Tryon D, Schaeffer B, Mirshahidi H, Wong J. Autoimmune rhabdomyolysis and a multiorgan display of PD-1 inhibitor induced immune related adverse events during treatment of metastatic melanoma. Exp Hematol Oncol. 2019;8(1):1–6.

    Article  Google Scholar 

  48. Johnson DB, Balko JM, Compton ML, Chalkias S, Gorham J, Xu Y, Hicks M, Puzanov I, Alexander MR, Bloomer TL. Fulminant myocarditis with combination immune checkpoint blockade. N Engl J Med. 2016;375(18):1749–55.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  49. Le Burel S, Champiat S, Mateus C, Marabelle A, Michot J-M, Robert C, Belkhir R, Soria J-C, Laghouati S, Voisin A-L. 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. 2017;82:34–44.

    Article  PubMed  CAS  Google Scholar 

  50. Calabrese C, Cappelli LC, Kostine M, Kirchner E, Braaten T, Calabrese L. Polymyalgia rheumatica-like syndrome from checkpoint inhibitor therapy: case series and systematic review of the literature. RMD Open. 2019;5(1):e000906.

    Article  PubMed  PubMed Central  Google Scholar 

  51. Goldstein BL, Gedmintas L, Todd DJ. Drug-associated polymyalgia rheumatica/giant cell arteritis occurring in two patients after treatment with ipilimumab, an antagonist of ctla-4. Arthritis Rheumatol. 2014;66(3):768–9.

    Article  PubMed  Google Scholar 

  52. Calabrese C, Kirchner E, Kontzias A, Velcheti V, Calabrese L. Rheumatic immune-related adverse events of checkpoint therapy for cancer: case series of a new nosological entity. RMD Open. 2017;3(1):e000412.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Salvarani C, Cantini F, Boiardi L, Hunder GG. Polymyalgia rheumatica and giant-cell arteritis. N Engl J Med. 2002;347(4):261–71.

    Article  PubMed  Google Scholar 

Download references

Conflict of Interest

None of the authors have any conflicts of interest to disclose.

Author information

Authors and Affiliations

  1. Division of Internal Medicine, Department of General Internal Medicine, Section of Rheumatology and Clinical Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Sang T. Kim, Savannah Bowman & Huifang Lu

  2. Department of Internal Medicine, Baylor College of Medicine, Houston, TX, USA

    Savannah Bowman

Authors
  1. Sang T. Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Savannah Bowman
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Huifang Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Huifang Lu .

Editor information

Editors and Affiliations

  1. Division of Internal Medicine, Department of Gastroenterology Hepatology & Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Yinghong Wang

Electronic Supplementary Material

Data 15.1

(PPTX 66273 kb)

Rights and permissions

Reprints and permissions

Copyright information

© 2022 The Author(s), under exclusive license to Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Kim, S.T., Bowman, S., Lu, H. (2022). Rheumatology (Arthritis and Myositis). In: Wang, Y. (eds) Managing Immunotherapy Related Organ Toxicities. Springer, Cham. https://doi.org/10.1007/978-3-031-00241-0_15

Download citation

  • DOI: https://doi.org/10.1007/978-3-031-00241-0_15

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-031-00240-3

  • Online ISBN: 978-3-031-00241-0

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation