PMID- 35164829 OWN - NLM STAT- MEDLINE DCOM- 20220310 LR - 20220311 IS - 1478-6362 (Electronic) IS - 1478-6354 (Print) IS - 1478-6354 (Linking) VI - 24 IP - 1 DP - 2022 Feb 14 TI - Tumor necrosis factor alpha neutralization attenuates immune checkpoint inhibitor-induced activation of intermediate monocytes in synovial fluid mononuclear cells from patients with inflammatory arthritis. PG - 43 LID - 10.1186/s13075-022-02737-6 [doi] LID - 43 AB - OBJECTIVE: During treatment with immune checkpoint inhibitors (ICI) such as the anti-PD-1 antibody pembrolizumab, half of patients with pre-existing inflammatory arthritis experience disease flares. The underlying immunological mechanisms have not been characterized. Here, we investigate the effect of pembrolizumab on cells involved in inflammation and destruction in the synovial joint and how immunosuppressive treatments affect the pembrolizumab-induced immune reactions. METHODS: We included synovial fluid mononuclear cells (SFMCs, n = 28) and peripheral blood mononuclear cells (PBMCs, n = 6) from patients with rheumatoid arthritis and peripheral spondyloarthritis and PBMCs from healthy controls (n = 6). Fibroblast-like synovial cells (FLSs) were grown from SFMCs. The in vitro effect of pembrolizumab was tested in SFMCs cultured for 48 h, FLS-PBMC co-cultures and in SFMCs cultured for 21 days (inflammatory osteoclastogenesis). Cells and supernatants were analyzed by ELISA, flow cytometry, and pro-inflammatory multiplex assay. Finally, the effect of the disease-modifying anti-rheumatic drugs (DMARDs) adalimumab (TNFalpha inhibitor), tocilizumab (IL-6R inhibitor), tofacitinib (JAK1/JAK3 inhibitor), and baricitinib (JAK1/JAK2 inhibitor) on pembrolizumab-induced immune reactions was tested. RESULTS: Pembrolizumab significantly increased monocyte chemoattractant protein-1 (MCP-1) production by arthritis SFMCs (P = 0.0031) but not by PBMCs from patients or healthy controls (P = 0.77 and P = 0.43). Pembrolizumab did not alter MMP-3 production in FLS-PBMC co-cultures (P = 0.76) or TRAP secretion in the inflammatory osteoclastogenesis model (P = 0.28). In SFMCs, pembrolizumab further increased the production of TNFalpha (P = 0.0110), IFNgamma (P = 0.0125), IL-12p70 (P = 0.0014), IL-10 (P = 0.0100), IL-13 (P = 0.0044), IL-2 (P = 0.0066), and IL-4 (P = 0.0008) but did not change the production of IL-6 (P = 0.1938) and IL-1 (P = 0.1022). The SFMCs treated with pembrolizumab showed an increased frequency of intermediate monocytes (P = 0.044), and the MCP-1 production increased only within the intermediate monocyte subset (P = 0.028). Lastly, adalimumab, baricitinib, and tofacitinib treatment were able to attenuate the pembrolizumab-induced MCP-1 production (P = 0.0004, P = 0.033, and P = 0.025, respectively), while this was not seen with tocilizumab treatment (P = 0.75). CONCLUSION: Pembrolizumab specifically activated intermediate monocytes and induced the production of several cytokines including TNFalpha but not IL-6. These findings indicate that flares in patients with pre-existing inflammatory arthritis involve monocyte activation and could be managed with TNFalpha neutralization. CI - (c) 2022. The Author(s). FAU - Sorensen, Anne Sofie AU - Sorensen AS AD - Department of Biomedicine, Aarhus University, Skou Building, DK-8000, Aarhus C, Denmark. FAU - Andersen, Morten Norgaard AU - Andersen MN AD - Department of Biomedicine, Aarhus University, Skou Building, DK-8000, Aarhus C, Denmark. AD - Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus N, Denmark. FAU - Juul-Madsen, Kristian AU - Juul-Madsen K AD - Department of Biomedicine, Aarhus University, Skou Building, DK-8000, Aarhus C, Denmark. FAU - Brokso, Amalie Dyrelund AU - Brokso AD AD - Department of Biomedicine, Aarhus University, Skou Building, DK-8000, Aarhus C, Denmark. FAU - Skejo, Caecilie AU - Skejo C AD - Department of Biomedicine, Aarhus University, Skou Building, DK-8000, Aarhus C, Denmark. FAU - Schmidt, Henrik AU - Schmidt H AD - Department of Oncology, Aarhus University Hospital, Aarhus N, Denmark. FAU - Vorup-Jensen, Thomas AU - Vorup-Jensen T AD - Department of Biomedicine, Aarhus University, Skou Building, DK-8000, Aarhus C, Denmark. FAU - Kragstrup, Tue Wenzel AU - Kragstrup TW AUID- ORCID: 0000-0002-6439-397X AD - Department of Biomedicine, Aarhus University, Skou Building, DK-8000, Aarhus C, Denmark. kragstrup@biomed.au.dk. AD - Department of Rheumatology, Aarhus University Hospital, Aarhus N, Denmark. kragstrup@biomed.au.dk. AD - Diagnostic Center, Silkeborg Regional Hospital, Silkeborg, Denmark. kragstrup@biomed.au.dk. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20220214 PL - England TA - Arthritis Res Ther JT - Arthritis research & therapy JID - 101154438 RN - 0 (Immune Checkpoint Inhibitors) RN - 0 (Tumor Necrosis Factor-alpha) SB - IM MH - *Arthritis, Rheumatoid MH - Cells, Cultured MH - Humans MH - Immune Checkpoint Inhibitors MH - Leukocytes, Mononuclear MH - Monocytes MH - *Synovial Fluid MH - Tumor Necrosis Factor-alpha/pharmacology PMC - PMC8842914 OTO - NOTNLM OT - Arthritis OT - Cytokine OT - Immunotherapy OT - Monocyte COIS- TWK has engaged in educational activities presenting in topics on immunology in rheumatic diseases receiving speaking fees from Pfizer, Bristol-Myers Squibb, Eli Lilly, Novartis, and UCB and has received a consultancy fee from Bristol-Myers Squibb. TWK is co-founder and clinical developer in iBiotech ApS developing diagnostic and therapeutic solutions for people with autoimmune diseases and cancer. TV-J taught in a training course for health care professionals on the side effects of ICIs and was paid an honorarium by Roche. The rest of the authors declare no potential conflicts of interest. EDAT- 2022/02/16 06:00 MHDA- 2022/03/11 06:00 PMCR- 2022/02/14 CRDT- 2022/02/15 05:31 PHST- 2021/08/16 00:00 [received] PHST- 2022/02/03 00:00 [accepted] PHST- 2022/02/15 05:31 [entrez] PHST- 2022/02/16 06:00 [pubmed] PHST- 2022/03/11 06:00 [medline] PHST- 2022/02/14 00:00 [pmc-release] AID - 10.1186/s13075-022-02737-6 [pii] AID - 2737 [pii] AID - 10.1186/s13075-022-02737-6 [doi] PST - epublish SO - Arthritis Res Ther. 2022 Feb 14;24(1):43. doi: 10.1186/s13075-022-02737-6.