Paper of the Week: sCD28, sCD80, sCTLA-4, and sBTLA Are Promising Markers in Diagnostic and Therapeutic Approaches for Aseptic Loosening and Periprosthetic Joint Infection

Jubel J.M., Randau T. M., Becker-Gotot J., Scheidt S., Wimmer M. D., Kohlhof H., Burger C., Wirtz D. C., Schildberg F. A.

Front Immunol. 2021 Aug 6; 12: 687065.
doi: 10.3389/fimmu.2021.687065

Summary by Diana Fernández-Rodríguez, MD

Aseptic loosening, peri-implant fractures, and prosthetic joint infection (PJI) are the most frequently described complications after arthroplasty.1–3 Macrophage-mediated osteolysis is a key element of both septic and aseptic loosening.3,4 Because of this, the role of the immune system and associated immunoregulatory molecules is a current area of interest in joint arthroplasty research.5–7 In this study, Jubel et al. (2021) compared the qualitative and quantitative composition of soluble immunoregulatory molecules in joint aspirates of patients with prior knee or hip replacement with or without aseptic loosening or PJI.

The study authors prospectively enrolled 99 consecutive patients who underwent joint aspirates for diagnostic or therapeutic procedures. Patients were classified in 4 groups: control (CO) patients with native joints (no prosthesis and no signs of infection, n=13); patients with fixed total joint arthroplasty (TJA, no signs of infection or aseptic loosening, n=23); patients with aseptic loosening (referred to as aseptic implant failure in this study, [AIF], n=24); and patients with PJI (n=39). There were 64 knee joints and 35 hip joints in the study. The Musculoskeletal Infection Society (MSIS) criteria was used to identify patients with PJI and AIF.8 Fourteen soluble molecules were measured using Imuno-Oncology Checkpoint 14-plex ProcartaPlex™ bead-based assays. 

This study found that the lowest immunoregulatory molecule concentrations were generally found in the joints of the CO group, followed by TJA joints. The highest concentrations were generally found in PJI joints. The joints of AIF patients had higher concentrations of sBTLA compared to CO and TJA patients. Similar trends were observed in PJI patients, who had higher concentrations of sCTLA-4, sIDO, sBTLA, sCD28, and sCD27 compared to CO and TJA patients. Lower concentration of sCD80 was observed in CO patients, compared to TJA, AIF, and PJI patients. Secondary analysis comparing immunoregulatory molecule concentrations between hip and knee joints within each group only revealed a statistically significant difference in sLAG-3 concentrations within PJI patients; the authors did not report whether the knee or hip joint had the higher concentration of sLAG-3. Within each group, no differences were observed for the tested markers between patients with and without diabetes mellitus (n=23, 17 in the PJI group), or rheumatoid arthritis (n=10).   

Soluble immunoregulatory molecules are promising biomarkers that need to be studied thoroughly. The authors of this study acknowledged that their findings should be validated in larger, multi-center studies and across more diverse patient cohorts. The mechanism of action for some of the molecules tested is not yet known, limiting their applications in current therapeutic and diagnostic development. Importantly, this study encourages a multi-disciplinary clinical and research network for the development of synovial and/or serum biomarkers, as well as, novel therapies.

References

  1. Izakovicova P, Borens O, Trampuz A. Periprosthetic joint infection: current concepts and outlook. EFORT open Rev. 2019;4(7):482-494. doi:10.1302/2058-5241.4.180092
  2. Del Pozo JL, Patel R. Clinical practice. Infection associated with prosthetic joints. N Engl J Med. 2009;361(8):787-794. doi:10.1056/NEJMcp0905029
  3. Landgraeber S, Jäger M, Jacobs JJ, Hallab NJ. The pathology of orthopedic implant failure is mediated by innate immune system cytokines. Mediators Inflamm. 2014;2014:185150. doi:10.1155/2014/185150
  4. Yang F, Wu W, Cao L, et al. Pathways of macrophage apoptosis within the interface membrane in aseptic loosening of prostheses. Biomaterials. 2011;32(35):9159-9167. doi:10.1016/j.biomaterials.2011.08.039
  5. Wang Q, Zhang J, Tu H, et al. Soluble immune checkpoint-related proteins as predictors of tumor recurrence, survival, and T cell phenotypes in clear cell renal cell carcinoma patients. J Immunother cancer. 2019;7(1):334. doi:10.1186/s40425-019-0810-y
  6. Chakrabarti R, Kapse B, Mukherjee G. Soluble immune checkpoint molecules: Serum markers for cancer diagnosis and prognosis. Cancer reports (Hoboken, NJ). 2019;2(4):e1160. doi:10.1002/cnr2.1160
  7. Zhou L, Li X, Huang X, Chen L, Gu L, Huang Y. Soluble programmed death-1 is a useful indicator for inflammatory and fibrosis severity in chronic hepatitis B. J Viral Hepat. 2019;26(7):795-802. doi:10.1111/jvh.13055
  8. Schwarz EM, Parvizi J, Gehrke T, et al. 2018 International Consensus Meeting on Musculoskeletal Infection: Research Priorities from the General Assembly Questions. J Orthop Res Off Publ Orthop Res Soc. 2019;37(5):997-1006. doi:10.1002/jor.24293

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