Skip to main content

Advertisement

SpringerLink
Log in

Immune checkpoint inhibitor-induced musculoskeletal manifestations

  • Review
  • Published:
Rheumatology International Aims and scope Submit manuscript

Abstract

Immune checkpoint inhibitors (ICI) associate with a wide range of immune-related adverse events (Ir-AE), including musculoskeletal manifestations. We aimed at identifying all studies reporting musculoskeletal Ir-AE. An electronic (Medline, Scopus and Web of Science) search was performed using two sets of key words. The first set consisted of: arthritis, musculoskeletal, polymyalgia rheumatica and myositis. The second set consisted of: anti-PD-1, anti-PD-L1, anti-CTLA-4, ipilimumab, tremelimumab, pembrolizumab, nivolumab, atezolizumab, avelumab and durvalumab. We identified 3 prospective studies, 17 retrospective studies and 4 case series reporting 363 patients in total. Combined data from all three prospective studies provide a prevalence rate of 6.13%. Most patients were males (59.68%) and the vast majority (73%) were on programmed death-1 (PD-1)/programmed death ligand-1 (PD-L1) inhibitors. Most studies report a median time of ≤ 12 weeks from first ICI administration to symptom onset. The main clinical phenotypes reported were: (a) inflammatory arthritis (57.57%), (b) myositis (14.04%) and (c) polymyalgia rheumatica (PMR) (12.12%). A total of 256 patients required steroids (70.52%) and 67 patients (18.45%) were treated with DMARDs. Positive auto-antibodies and family history of any autoimmune disease were present in 18.48% and 19.04% of cases, respectively. Only a few patients (19%) had to discontinue treatment due to musculoskeletal Ir-AE. Two prospective studies show that significantly more patients with musculoskeletal Ir-AE exhibit a favorable oncologic response compared to patients not exhibiting such manifestations whereas retrospective studies show that 77.22% of patients with musculoskeletal Ir-AE have a good tumor response. One out of 15 patients treated with ICI will develop musculoskeletal Ir-AE; in most cases the severity of these manifestations is mild/moderate and usually ICI may be continued. Rheumatologists should familiarize with this new clinical entity and develop relevant therapeutic algorithms.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Pardoll DM (2012) The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 12:252–264

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Farhood B, Najafi M, Mortezaee K (2019) CD8 + cytotoxic T lymphocytes in cancer immunotherapy: a review. J Cell Physiol 234:8509–8521

    CAS  PubMed  Google Scholar 

  3. Tivol EA, Borriello F, Nicola Schweitzer A, Lynch WP, Bluestone JA, Sharpe AH (1995) Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4. Immunity 3:541–547

    CAS  PubMed  Google Scholar 

  4. Nishimura H, Nose M, Hiai H, Minato N, Honjo T (1999) Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor. Immunity 11(2):141–151

    CAS  PubMed  Google Scholar 

  5. Rotte A, Jin JY, Lemaire V (2018) Mechanistic overview of immune checkpoints to support the rational design of their combinations in cancer immunotherapy. Ann Oncol 29:71–83

    CAS  PubMed  Google Scholar 

  6. Park Y-J, Kuen D-S, Chung Y (2018) Future prospects of immune checkpoint blockade in cancer: from response prediction to overcoming resistance. Exp Mol Med 50:109

    PubMed Central  Google Scholar 

  7. Webb ES, Liu P, Baleeiro R, Lemoine NR, Yuan M, Wang Y-H (2018) Immune checkpoint inhibitors in cancer therapy. J Biomed Res 32:317–326

    PubMed  Google Scholar 

  8. Postow MA, Sidlow R, Hellmann MD (2018) Immune-related adverse events associated with immune checkpoint blockade. N Engl J Med 378:158–168

    CAS  PubMed  Google Scholar 

  9. Spain L, Diem S, Larkin J (2016) Management of toxicities of immune checkpoint inhibitors. Cancer Treat Rev 44:51–60

    CAS  PubMed  Google Scholar 

  10. Daoussis D, Kraniotis P, Filippopoulou A, Argiriadi R, Theodoraki S, Makatsoris T, Koutras A, Kehagias I, Papachristou DJ, Solomou A, Haralabos Kalofonos S-NL (2020) MRI study of immune checkpoint inhibitor–induced musculoskeletal manifestations. Myofasciitis is the prominent imaging finding. Rheumatology (Oxford) 59:1041–1050

    CAS  Google Scholar 

  11. Kostine M, Rouxel L, Barnetche T, Veillon R, Martin F, Dutriaux C et al (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 77:393–398

    CAS  PubMed  Google Scholar 

  12. Narváez J, Nolla JM, García X, del Muro J, Lluch JAN, Domingo-Domenech E et al (2018) Rheumatic immune-related adverse events in patients on anti-PD-1 inhibitors: fasciitis with myositis syndrome as a new complication of immunotherapy. Autoimmun Rev 17:1040–1045

    PubMed  Google Scholar 

  13. Kostine M, Truchetet M-E, Schaeverbeke T (2019) Clinical characteristics of rheumatic syndromes associated with checkpoint inhibitors therapy. Rheumatology 58:vii68–vii74

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Kostine M, Finckh A, Bingham CO, Visser K, Leipe J, Schulze-Koops H et al (2020) 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. https://doi.org/10.1136/annrheumdis-2020-217139

    Article  PubMed  Google Scholar 

  15. Daoussis D, Melissaropoulos K, Dimitroulas T, Andreadis H, Christopoulou A, Douganiotis G et al (2020) Immune checkpoint inhibitor-induced musculoskeletal manifestations. A multicentre prospective study. Mediterr J Rheumatol 31:239

    PubMed  PubMed Central  Google Scholar 

  16. 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 Rheumatol 71:468–475

    CAS  PubMed  Google Scholar 

  17. 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 82:34–44

    PubMed  Google Scholar 

  18. Lidar M, Giat E, Garelick D, Horowitz Y, Amital H, Steinberg-Silman Y et al (2018) Rheumatic manifestations among cancer patients treated with immune checkpoint inhibitors. Autoimmun Rev 17:284–289

    CAS  PubMed  Google Scholar 

  19. Cappelli LC, Gutierrez AK, Baer AN, Albayda J, Manno RL, Haque U et al (2017) Inflammatory arthritis and sicca syndrome induced by nivolumab and ipilimumab. Ann Rheum Dis 76:43–50

    CAS  PubMed  Google Scholar 

  20. Belkhir R, Le Burel S, Dunogeant L, Marabelle A, Hollebecque A, Besse B et al (2017) Rheumatoid arthritis and polymyalgia rheumatica occurring after immune checkpoint inhibitor treatment. Ann Rheum Dis 76:1747–1750

    CAS  PubMed  Google Scholar 

  21. Mooradian MJ, Nasrallah M, Gainor JF, Reynolds KL, Cohen JV, Lawrence DP et al (2019) Musculoskeletal rheumatic complications of immune checkpoint inhibitor therapy: a single center experience. Semin Arthritis Rheum 48:1127–1132

    CAS  PubMed  Google Scholar 

  22. Smith MH, Bass AR (2019) Arthritis after cancer immunotherapy: symptom duration and treatment response. Arthritis Care Res 71:362–366

    CAS  Google Scholar 

  23. 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 48:736–740

    CAS  PubMed  Google Scholar 

  24. Lee J, Graham A, Sion A (2019) Evaluation of arthralgias in adult oncology patients receiving immune checkpoint inhibitors. J Oncol Pharm Pract 25:1867–1872

    CAS  PubMed  Google Scholar 

  25. Cappelli LC, Brahmer JR, Forde PM, Le DT, Lipson EJ, Naidoo J et al (2018) Clinical presentation of immune checkpoint inhibitor-induced inflammatory arthritis differs by immunotherapy regimen. Semin Arthritis Rheum 48:553–557

    PubMed  PubMed Central  Google Scholar 

  26. Buder-Bakhaya K, Benesova K, Schulz C, Anwar H, Dimitrakopoulou-Strauss A, Weber TF et al (2018) Characterization of arthralgia induced by PD-1 antibody treatment in patients with metastasized cutaneous malignancies. Cancer Immunol Immunother 67:175–182

    CAS  PubMed  Google Scholar 

  27. Mitchell EL, Lau PKH, Khoo C, Liew D, Leung J, Liu B et al (2018) Rheumatic immune-related adverse events secondary to anti-programmed death-1 antibodies and preliminary analysis on the impact of corticosteroids on anti-tumour response: a case series. Eur J Cancer 105:88–102

    CAS  PubMed  Google Scholar 

  28. Zimmer L, Goldinger SM, Hofmann L, Loquai C, Ugurel S, Thomas I et al (2016) Neurological, respiratory, musculoskeletal, cardiac and ocular side-effects of anti-PD-1 therapy. Eur J Cancer 60:210–225

    CAS  PubMed  Google Scholar 

  29. Moreira A, Loquai C, Pföhler C, Kähler KC, Knauss S, Heppt MV et al (2019) Myositis and neuromuscular side-effects induced by immune checkpoint inhibitors. Eur J Cancer 106:12–23

    CAS  PubMed  Google Scholar 

  30. 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:e000412

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Leipe J, Christ LA, Arnoldi AP, Mille E, Berger F, Heppt M et al (2018) Characteristics and treatment of new-onset arthritis after checkpoint inhibitor therapy. RMD Open 4(2):e000714. https://doi.org/10.1136/rmdopen-2018-000714

    Article  PubMed  PubMed Central  Google Scholar 

  32. Liew DFL, Leung JLY, Liu B, Cebon J, Frauman AG, Buchanan RRC (2019) Association of good oncological response to therapy with the development of rheumatic immune-related adverse events following PD-1 inhibitor therapy. Int J Rheum Dis 22:297–302

    CAS  PubMed  Google Scholar 

  33. 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 47:907–910

    CAS  PubMed  Google Scholar 

  34. Goldstein BL, Gedmintas L, Todd DJ (2014) Concise communication. Arthritis Rheumatol 66:768–769

    PubMed  Google Scholar 

  35. Chan MMK, Kefford RF, Carlino M, Clements A, Manoliosz N (2015) Arthritis and tenosynovitis associated with the anti-PD1 antibody pembrolizumab in metastatic melanoma case presentation case 1. J Immunother 38:37–39

    CAS  PubMed  Google Scholar 

  36. Garel B, Kramkimel N, Trouvin AP, Frantz C, Dupin N (2017) Pembrolizumab-induced polymyalgia rheumatica in two patients with metastatic melanoma. Jt Bone Spine 84:233–234

    Google Scholar 

  37. Weinstock C, Singh H, Maher VE, Kim G, Pazdur R (2017) FDA analysis of patients with baseline autoimmune diseases treated with PD-1/PD-L1 immunotherapy agents. J Clin Oncol 35:3018–3018

    Google Scholar 

  38. Tison A, Quéré G, Misery L, Funck-Brentano E, Danlos FX, Routier E et al (2019) Safety and Efficacy of Immune Checkpoint Inhibitors in Patients With Cancer and Preexisting Autoimmune Disease: A Nationwide Multicenter Cohort Study. Arthritis Rheumatol 71:2100–2111

    CAS  PubMed  Google Scholar 

  39. Kehl KL, Yang S, Awad MM, Palmer N, Kohane IS, Schrag D (2019) Pre-existing autoimmune disease and the risk of immune-related adverse events among patients receiving checkpoint inhibitors for cancer. Cancer Immunol Immunother 68:917–926

    CAS  PubMed  Google Scholar 

  40. Johnson DB, Sullivan RJ, Ott PA, Carlino MS, Khushalani NI, Ye F et al (2016) Ipilimumab therapy in patients with advanced melanoma and preexisting autoimmune disorders. JAMA Oncol 2:234–240

    PubMed  Google Scholar 

  41. Gutzmer R, Koop A, Meier F, Hassel JC, Terheyden P, Zimmer L et al (2017) Programmed cell death protein-1 (PD-1) inhibitor therapy in patients with advanced melanoma and preexisting autoimmunity or ipilimumab-triggered autoimmunity. Eur J Cancer 75:24–32

    CAS  PubMed  Google Scholar 

  42. Danlos FX, Voisin AL, Dyevre V, Michot JM, Routier E, Taillade L et al (2018) Safety and efficacy of anti-programmed death 1 antibodies in patients with cancer and pre-existing autoimmune or inflammatory disease. Eur J Cancer 91:21–29

    CAS  PubMed  Google Scholar 

  43. Menzies AM, Johnson DB, Ramanujam S, Atkinson VG, Wong ANM, Park JJ et al (2017) Anti-PD-1 therapy in patients with advanced melanoma and preexisting autoimmune disorders or major toxicity with ipilimumab. Ann Oncol 28:368–376

    CAS  PubMed  Google Scholar 

  44. Leonardi GC, Gainor JF, Altan M, Kravets S, Dahlberg SE, Gedmintas L et al (2018) Safety of programmed death-1 pathway inhibitors among patients with non-small-cell lung cancer and preexisting autoimmune disorders. J Clin Oncol 36:1905–1912

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Lee B, Wong A, Kee D, Neeson P, Shackleton M, McArthur G et al (2016) The use of ipilimumab in patients with rheumatoid arthritis and metastatic melanoma. Ann Oncol 27:1174–1177

    CAS  PubMed  Google Scholar 

  46. Ruiz-Bañobre J, Pérez-Pampín E, García-González J, Gómez-Caamaño A, Barón-Duarte FJ, López-López R et al (2017) Development of psoriatic arthritis during nivolumab therapy for metastatic non-small cell lung cancer, clinical outcome analysis and review of the literature. Lung Cancer 108:217–221

    PubMed  Google Scholar 

  47. Kyi C, Carvajal RD, Wolchok JD, Postow MA (2014) Ipilimumab in patients with melanoma and autoimmune disease. J Immunother Cancer 14(2):35

    Google Scholar 

  48. Roberts J, Smylie M, Walker J, Basappa NS, Chu Q, Kolinsky M et al (2019) Hydroxychloroquine is a safe and effective steroid-sparing agent for immune checkpoint inhibitor-induced inflammatory arthritis. Clin Rheumatol 38:1513–1519

    PubMed  Google Scholar 

  49. Roberts J, Ennis D, Hudson M, Ye C, Saltman A, Rottapel R et al (2020) Rheumatic immune-related adverse events associated with cancer immunotherapy: a nationwide multi-center cohort. Autoimmun Rev 19:102595

    CAS  PubMed  Google Scholar 

  50. Liu Y, Jaquith JM, Mccarthy-Fruin K, Zhu X, Zhou X, Li Y et al (2020) Immune checkpoint inhibitor-induced inflammatory arthritis: a novel clinical entity with striking similarities to seronegative rheumatoid arthritis. Clin Rheumatol. https://doi.org/10.1007/s10067-020-05162-9

    Article  PubMed  PubMed Central  Google Scholar 

  51. Allenbach Y, Anquetil C, Manouchehri A, Benveniste O, Lambotte O, Lebrun-Vignes B et al (2020) Immune checkpoint inhibitor-induced myositis, the earliest and most lethal complication among rheumatic and musculoskeletal toxicities. Autoimmun Rev 19:102586

    CAS  PubMed  Google Scholar 

  52. Nguyen T, Maria ATJ, Ladhari C, Palassin P, Quantin X, Lesage C et al (2020) Rheumatic disorders associated with immune checkpoint inhibitors: What about myositis? An analysis of the WHO’s adverse drug reactions database. Ann Rheum Dis. https://doi.org/10.1136/annrheumdis-2020-217018

    Article  PubMed  Google Scholar 

  53. Matas-García A, Milisenda JC, Selva-O’Callaghan A, Prieto-González S, Padrosa J, Cabrera C et al (2020) Emerging PD-1 and PD-1L inhibitors-associated myopathy with a characteristic histopathological pattern. Autoimmun Rev 19:102455

    PubMed  Google Scholar 

  54. Martin de Fremont G, Belkhir R, Henry J, Voisin AL, Lambotte O, Besson FL et al (2020) Features of polymyalgia rheumatic-like syndrome after immune checkpoint inhibitor therapy. Ann Rheum Dis. https://doi.org/10.1136/annrheumdis-2020-217225

    Article  PubMed  Google Scholar 

  55. Van Der Geest KSM, Sandovici M, Rutgers A, Hiltermann TJN, Oosting SF, Slart RHJA et al (2020) Imaging in immune checkpoint inhibitor-induced polymyalgia rheumatica. Ann Rheum Dis. https://doi.org/10.1136/annrheumdis-2020-217381

    Article  PubMed  Google Scholar 

  56. Murray-Brown W, Wilsdon TD, Weedon H, Proudman S, Sukumaran S, Klebe S et al (2020) Nivolumab-induced synovitis is characterized by florid T cell infiltration and rapid resolution with synovial biopsy-guided therapy. J Immunother cancer. https://doi.org/10.1136/jitc-2019-000281

    Article  PubMed  PubMed Central  Google Scholar 

  57. Moura CA, Moura CG (2020) Severe polymyalgia-like symptoms secondary to anti-PD1 therapy successfully managed without discontinuing checkpoint inhibitor. Ann Rheum Dis. https://doi.org/10.1136/annrheumdis-2020-217605

    Article  PubMed  Google Scholar 

  58. Braaten TJ, Brahmer JR, Forde PM, Le D, Lipson EJ, Naidoo J et al (2019) Checkpoint inhibitor-induced inflammatory arthritis persists after immunotherapy cessation. Ann Rheum Dis 79:332–338

    PubMed  Google Scholar 

Download references

Funding

This study was not funded by any source.

Author information

Authors and Affiliations

  1. Department of Rheumatology, Patras University Hospital, University of Patras Medical School, Patras, Greece

    Foteini Angelopoulou & Dimitrios Daoussis

  2. Department of Rheumatology, Faculty of Medicine, School of Health Sciences, University of Thessaly, 41 110, Larissa, Greece

    Dimitrios Bogdanos & Lazaros Sakkas

  3. 4th Department of Internal Medicine Hippokration Hospital, Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece

    Theodoros Dimitroulas

Authors
  1. Foteini Angelopoulou
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Dimitrios Bogdanos
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Theodoros Dimitroulas
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Lazaros Sakkas
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Dimitrios Daoussis
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

FA performed the literature search, extracted data from the retrieved articles, analyzed the data and assisted in manuscript drafting. DB, TD and LS assisted in the design of the study, data analysis and manuscript drafting. DD conceived the idea and designed the study, extracted data from the retrieved articles, analyzed the data and drafted the manuscript. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

Corresponding author

Correspondence to Dimitrios Daoussis.

Ethics declarations

Conflict of interest

The authors declare no conflict of interest.

Additional information

Publisher's Note

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

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 49 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Angelopoulou, F., Bogdanos, D., Dimitroulas, T. et al. Immune checkpoint inhibitor-induced musculoskeletal manifestations. Rheumatol Int 41, 33–42 (2021). https://doi.org/10.1007/s00296-020-04665-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00296-020-04665-7

Keywords

Search

Navigation