Higher levels of VEGF-A and TNFα in patients with immune checkpoint inhibitor-induced inflammatory arthritis
Abstract Background Immune checkpoint inhibitors (ICI), a type of cancer immunotherapy, can cause side effects including inflammatory arthritis (ICI-IA). Previous studies of ICI-IA do not include a thorough characterization of associated immune responses to provide potential targets for treatment. W...
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BMC
2025-04-01
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| Series: | Arthritis Research & Therapy |
| Online Access: | https://doi.org/10.1186/s13075-025-03546-3 |
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| author | Elise F. Gray-Gaillard Ami A. Shah Clifton O. Bingham III Jennifer H. Elisseeff Joseph Murray Julie Brahmer Patrick Forde Valsamo Anagnostou Jennifer Mammen Laura C. Cappelli |
| author_facet | Elise F. Gray-Gaillard Ami A. Shah Clifton O. Bingham III Jennifer H. Elisseeff Joseph Murray Julie Brahmer Patrick Forde Valsamo Anagnostou Jennifer Mammen Laura C. Cappelli |
| author_sort | Elise F. Gray-Gaillard |
| collection | DOAJ |
| description | Abstract Background Immune checkpoint inhibitors (ICI), a type of cancer immunotherapy, can cause side effects including inflammatory arthritis (ICI-IA). Previous studies of ICI-IA do not include a thorough characterization of associated immune responses to provide potential targets for treatment. We aimed to identify cytokines uniquely increased in ICI-IA and determine correlations with IA severity and persistence. Methods We evaluated patients diagnosed with ICI-IA by a rheumatologist (n = 80); control serum was obtained from ICI-treated cancer patients without any diagnosed irAEs (n = 17) or diagnosed with an unrelated irAE (n = 19). Serum was assayed to quantify 9 cytokine levels (IFN-γ, IL-4, IL-6, IL-10, IL-12p70, IL-1α, TNF-α, IL-17a, VEGF-A) using MSD U-PLEX assay. Mann-Whitney U tests were performed to evaluate differences in cytokine levels between control and ICI-IA groups. The Kruskal-Wallis test and multivariable ordinal logistic regression were used to determine difference in cytokine levels between patients of differing disease activity. Results VEGF-A and TNFα were significantly elevated in patients with ICI-IA compared to ICI-controls; results persisted when restricting analyses to patients not treated with immunosuppressants at the time of sampling. ICI-IA patients were stratified by IA severity using CDAI score; there was significantly higher VEGF-A in those with higher disease activity. Ordinal logistic regression showed higher levels of IL-6 and VEGF-A were associated with higher disease activity. Conclusion Elevated levels of VEGF-A and TNFα are associated with ICI-IA. There was also higher IL-6 and VEGF-A among those with higher disease activity when controlling for confounding. These cytokines could be used as biomarkers of ICI-IA severity and present therapeutic targets. |
| format | Article |
| id | doaj-art-7712cbec73a34714a5a94d5bced15db9 |
| institution | DOAJ |
| issn | 1478-6362 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | BMC |
| record_format | Article |
| series | Arthritis Research & Therapy |
| spelling | doaj-art-7712cbec73a34714a5a94d5bced15db92025-08-20T03:07:43ZengBMCArthritis Research & Therapy1478-63622025-04-012711810.1186/s13075-025-03546-3Higher levels of VEGF-A and TNFα in patients with immune checkpoint inhibitor-induced inflammatory arthritisElise F. Gray-Gaillard0Ami A. Shah1Clifton O. Bingham III2Jennifer H. Elisseeff3Joseph Murray4Julie Brahmer5Patrick Forde6Valsamo Anagnostou7Jennifer Mammen8Laura C. Cappelli9Johns Hopkins School of Medicine, Bloomberg Kimmel Institute for Cancer ImmunotherapyDivision of Rheumatology, Johns Hopkins School of MedicineDivision of Rheumatology, Johns Hopkins School of MedicineJohns Hopkins School of Medicine, Bloomberg Kimmel Institute for Cancer ImmunotherapyJohns Hopkins School of Medicine, Bloomberg Kimmel Institute for Cancer ImmunotherapyJohns Hopkins School of Medicine, Bloomberg Kimmel Institute for Cancer ImmunotherapyJohns Hopkins School of Medicine, Bloomberg Kimmel Institute for Cancer ImmunotherapyJohns Hopkins School of Medicine, Bloomberg Kimmel Institute for Cancer ImmunotherapyDivision of Endocrinology, Johns Hopkins School of MedicineDivision of Rheumatology, Johns Hopkins School of MedicineAbstract Background Immune checkpoint inhibitors (ICI), a type of cancer immunotherapy, can cause side effects including inflammatory arthritis (ICI-IA). Previous studies of ICI-IA do not include a thorough characterization of associated immune responses to provide potential targets for treatment. We aimed to identify cytokines uniquely increased in ICI-IA and determine correlations with IA severity and persistence. Methods We evaluated patients diagnosed with ICI-IA by a rheumatologist (n = 80); control serum was obtained from ICI-treated cancer patients without any diagnosed irAEs (n = 17) or diagnosed with an unrelated irAE (n = 19). Serum was assayed to quantify 9 cytokine levels (IFN-γ, IL-4, IL-6, IL-10, IL-12p70, IL-1α, TNF-α, IL-17a, VEGF-A) using MSD U-PLEX assay. Mann-Whitney U tests were performed to evaluate differences in cytokine levels between control and ICI-IA groups. The Kruskal-Wallis test and multivariable ordinal logistic regression were used to determine difference in cytokine levels between patients of differing disease activity. Results VEGF-A and TNFα were significantly elevated in patients with ICI-IA compared to ICI-controls; results persisted when restricting analyses to patients not treated with immunosuppressants at the time of sampling. ICI-IA patients were stratified by IA severity using CDAI score; there was significantly higher VEGF-A in those with higher disease activity. Ordinal logistic regression showed higher levels of IL-6 and VEGF-A were associated with higher disease activity. Conclusion Elevated levels of VEGF-A and TNFα are associated with ICI-IA. There was also higher IL-6 and VEGF-A among those with higher disease activity when controlling for confounding. These cytokines could be used as biomarkers of ICI-IA severity and present therapeutic targets.https://doi.org/10.1186/s13075-025-03546-3 |
| spellingShingle | Elise F. Gray-Gaillard Ami A. Shah Clifton O. Bingham III Jennifer H. Elisseeff Joseph Murray Julie Brahmer Patrick Forde Valsamo Anagnostou Jennifer Mammen Laura C. Cappelli Higher levels of VEGF-A and TNFα in patients with immune checkpoint inhibitor-induced inflammatory arthritis Arthritis Research & Therapy |
| title | Higher levels of VEGF-A and TNFα in patients with immune checkpoint inhibitor-induced inflammatory arthritis |
| title_full | Higher levels of VEGF-A and TNFα in patients with immune checkpoint inhibitor-induced inflammatory arthritis |
| title_fullStr | Higher levels of VEGF-A and TNFα in patients with immune checkpoint inhibitor-induced inflammatory arthritis |
| title_full_unstemmed | Higher levels of VEGF-A and TNFα in patients with immune checkpoint inhibitor-induced inflammatory arthritis |
| title_short | Higher levels of VEGF-A and TNFα in patients with immune checkpoint inhibitor-induced inflammatory arthritis |
| title_sort | higher levels of vegf a and tnfα in patients with immune checkpoint inhibitor induced inflammatory arthritis |
| url | https://doi.org/10.1186/s13075-025-03546-3 |
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