Immune checkpoint inhibitor-induced musculoskeletal manifestations


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.

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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.

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Correspondence to Dimitrios Daoussis.

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Angelopoulou, F., Bogdanos, D., Dimitroulas, T. et al. Immune checkpoint inhibitor-induced musculoskeletal manifestations. Rheumatol Int (2020).

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  • Arthritis
  • Myositis
  • Polymyalgia rheumatica
  • Immunotherapy
  • Programmed death-1
  • Programmed death ligand-1
  • Cytotoxic T lymphocyte-associated antigen-4
  • Ipilimumab
  • Nivolumab
  • Rheumatic diseases
  • Autoimmune diseases
  • Fasciitis