Developing anti-inflammatory therapeutics for patients with osteoarthritis

Philp, Ashleigh M.; Davis, Edward T.; Jones, Simon W.

doi:10.1093/rheumatology/kew278

Cited by 64 publications

(76 citation statements)

References 140 publications

(155 reference statements)

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“…Indeed, clinical heterogeneity in OA pathogenesis is increasingly becoming recognized (17)(18)(19)(20). However, OA patients are not currently stratified for clinical trials based on synovitis or inflammatory biomarkers (21) because the mechanisms governing synovial inflammation in OA are not sufficiently understood. Clinical trials with antiinflammatory treatments in OA have so far been disappointing, which may Osteoarthritis (OA) is a leading cause of disability, globally.…”

Section: Introductionmentioning

confidence: 99%

Macrophage proliferation distinguishes 2 subgroups of knee osteoarthritis patients

Wood¹,

Leckenby²,

Reynolds³

et al. 2019

JCI Insight

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Section: Introductionmentioning

confidence: 99%

Macrophage proliferation distinguishes 2 subgroups of knee osteoarthritis patients

Wood¹,

Leckenby²,

Reynolds³

et al. 2019

JCI Insight

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“…Although OA patients share similar radiographic findings, OA is a heterogeneous disorder with diverse epidemiologic, structural, genetic, clinical, and pathologic risk factors/phenotypes . One consistent phenotype associated with worse clinical outcomes, including increased pain sensitization and accelerated joint damage, is joint inflammation, characterized by increased synovial tissue volume, vascularity, and proinflammatory signaling .…”

Section: Introductionmentioning

confidence: 99%

Multiparameter Analysis Identifies Heterogeneity in Knee Osteoarthritis Synovial Responses

Labinsky

Panipinto

et al. 2020

Arthritis & Rheumatology

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Objective Synovial membrane inflammation is common in osteoarthritis (OA) and increases cartilage injury. However, synovial fluid and histology studies suggest that OA inflammatory responses are not homogeneous. Greater understanding of these responses may provide new insights into OA disease mechanisms. We undertook this study to develop a novel multiparameter approach to phenotype synovial responses in knee OA. Methods Cell composition and soluble protein production were measured by flow cytometry and multiplex enzyme‐linked immunosorbent assay in synovium collected from OA patients undergoing knee replacement surgery (n = 35). Results Testing disaggregation conditions showed that aggressive digestion improved synovial cell yield and mesenchymal staining by flow cytometry, but it negatively impacted CD4+ T cell and CD56+ natural killer cell staining. Less aggressive digestion preserved these markers and showed highly variable T cell infiltration (range 0–43%; n = 32). Correlation analysis identified mesenchymal subpopulations associated with different nonmesenchymal populations, including macrophages and T cells (CD45+CD11b+HLA−DR+ myeloid cells with PDPN+CD73+CD90−CD34− mesenchymal cells [r = 0.65, P < 0.0001]; and CD45+CD3+ T cells with PDPN+CD73+CD90+CD34+ mesenchymal cells [r = 0.50, P = 0.003]). Interleukin‐6 (IL‐6) measured by flow cytometry strongly correlated with IL‐6 released by ex vivo culture of synovial tissue (r = 0.59, P = 0.0012) and was highest in mesenchymal cells coexpressing CD90 and CD34. IL‐6, IL‐8, complement factor D, and IL‐10 release correlated positively with tissue cellularity (P = 0.0042, P = 0.018, P = 0.0012, and P = 0.038, respectively). Additionally, increased CD8+ T cell numbers correlated with retinol binding protein 4 (P = 0.033). Finally, combining flow cytometry and multiplex data identified patient clusters with different types of inflammatory responses. Conclusion We used a novel approach to analyze OA synovium, identifying patient‐specific inflammatory clusters. Our findings indicate that phenotyping synovial inflammation may provide new insights into OA patient heterogeneity and biomarker development.

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“…Urinary CTX‐II and serum COMP levels have shown promise in longitudinal studies, correlating with incidence and progression of knee and hip osteoarthritis; however, these measures lack sufficient validation for clinical use . Recent studies have demonstrated the existence of local inflammation in FAI, suggesting that perhaps an inflammatory phenotype exists in FAI driving joint degradation, as has been proposed in osteoarthritis . The presence of systemic inflammation is not supported by this study, limiting the applicability of new anti‐inflammatory medications being studied in osteoarthritis .…”

Section: Discussionmentioning

confidence: 65%

“…36 The presence of systemic inflammation is not supported by this study, limiting the applicability of new anti-inflammatory medications being studied in osteoarthritis. 36 Therefore, it is unlikely that these drugs will be of benefit in the earlier condition of FAI. However, further research into other markers of systemic inflammation is required to validate this assumption.…”

Section: Systemic Inflammationmentioning

confidence: 71%

No Evidence of Systemic Inflammation in Symptomatic Patients With Femoroacetabular Impingement

Talks

Fernquest

Palmer

et al. 2019

Journal Orthopaedic Research

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Femoroacetabular impingement (FAI) is a common cause of hip pain and represents a major cause of early osteoarthritis. The role of systemic inflammation in pre‐arthritic hip conditions remains largely unknown and uninvestigated. Serum‐free light chains (sFLCs) are inflammatory markers produced by B cells. This study aimed to determine whether there was evidence of systemic inflammation in patients with FAI, defined by sFLCs, and whether this correlated with markers of disease severity. Participants for this study were recruited from a single center (Nuffield Orthopedic Center, Oxford) and were taking part in the Femoroacetabular Impingement Trial. The cohort comprised 115 individuals (38 male, 77 female, mean age 37 years): 57 individuals received surgical intervention and 58 received physiotherapy. All individuals provided patient‐reported outcome measures and serum samples at baseline and follow‐up 8 months post‐randomization. sFLC concentrations were measured in serum samples by immunoturbidimetry. At baseline, for all individuals, mean polyclonal sFLC concentrations were 30.36 mg/l (standard deviation [SD] 9.23). At follow‐up, the mean polyclonal sFLC concentrations were 31.68 mg/l (SD 9.61) in the surgical intervention cohort, and 29.48 mg/l (SD 7.85) in the physiotherapy intervention cohort. There was no significant correlation between sFLC concentrations and any of the patient reported outcome measures, or radiographic measures: average or maximum alpha angle, or center edge angle. In conclusion, in patients with symptomatic FAI there was no systemic inflammation, as defined by sFLC concentrations, and no correlation between sFLC concentrations and measures of disease severity. The lack of inflammation suggests FAI is a mechanical phenomenon. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 37:2189–2196, 2019

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Developing anti-inflammatory therapeutics for patients with osteoarthritis

Cited by 64 publications

References 140 publications

Macrophage proliferation distinguishes 2 subgroups of knee osteoarthritis patients

Macrophage proliferation distinguishes 2 subgroups of knee osteoarthritis patients

Multiparameter Analysis Identifies Heterogeneity in Knee Osteoarthritis Synovial Responses

No Evidence of Systemic Inflammation in Symptomatic Patients With Femoroacetabular Impingement

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