Synovial Cytokine Expression in Predicting Response to Anti-TNF Therapy
Synovial Cytokine Expression in Predicting Response to Anti-TNF Therapy
Objectives: Clinical response to TNF-α blockade in the treatment of RA is heterogeneous. The study aims were to determine whether pre-treatment synovial cytokine expression predicted infliximab response and whether synovial changes after therapy correlated with response.
Methods: Fifty-one patients had arthroscopic biopsies of the knee joint prior to infliximab (3 mg/kg) treatment. Synovial tissue cell numbers (CD68 and CD3 positive) and cytokine expression (TNF-α, lymphotoxin-α, IL-1α, -β and receptor antagonist, and IL-6) pre-treatment was assessed using semi-quantitative immunohistochemistry. Changes in these parameters were assessed 16 weeks after infliximab in 32 patients who underwent repeat arthroscopic biopsy.
Results: Of the total patients, 47% (n = 24) achieved an ACR20 response; 53% (n = 27) did not. Baseline synovial TNF-α, IL-1α and -β expression did not differ between the two groups. No differences in baseline TNF-α levels were observed with ACR levels of response (ACR20 and ACR50/70 groups). Post-treatment biopsies (17 ACR responders, 15 ACR non-responders) revealed significant reductions in sub-lining layer TNF-α expression in both response and non-response groups with significant reduction in vascularity and membrane proliferation scores. The worst ACR non-responders (<20% CRP suppression) demonstrated no reduction in any of the parameters.
Conclusion: Pre-treatment synovial TNF-α or IL-1 expression does not predict TNF blockade response. Both ACR response and non-response was associated with reduction in synovial TNF-α-level expression. Suppression in TNF-α levels was not observed in the worst non-responders. The improvements (including in vascularity), independent of ACR clinical response, are compatible with the reduced structural damage documented in all groups of patients independent of response.
Pro-inflammatory cytokines, especially TNF-α and IL-1, are pivotal in the RA inflammatory cascade. Initial in vitro and subsequent in vivo studies demonstrated a hierarchical role of TNF-α in RA; development of TNF antagonist therapies with monoclonal antibodies or soluble receptor antagonists have been shown to dramatically suppress signs and symptoms of inflammation and prevent progression of structural damage in virtually all patients.
Despite the general effectiveness of anti-TNF-α therapies, a lack of response is evident in up to 40% of the patients treated with these agents. Few studies have investigated the underlying basis of anti-TNF-α resistance. Variable synovial cytokine expression and variable synovial tissue TNF-α levels with treatment have been observed; however, studies have generally comprised few patients and no clear explanation has emerged.
The principal aims of this study were to examine the heterogeneity of synovial cytokine (particularly TNF-α) expression, correlate this with the level of response to infliximab and observe whether non-response represented a subgroup of RA that was mediated independently of TNF-α. Our findings indicate that baseline cytokine expression is not predictive, and changes do not correlate with ACR response. Importantly, TNF-α expression was significantly reduced in both ACR response and non-response patients, consistent with structural data. However, complete failure to respond to TNF-blockade in the small minority may be associated with unchanged tissue TNF-α expression. These findings have implications both for the therapeutics of RA and for understanding disease mechanisms.
Abstract and Introduction
Abstract
Objectives: Clinical response to TNF-α blockade in the treatment of RA is heterogeneous. The study aims were to determine whether pre-treatment synovial cytokine expression predicted infliximab response and whether synovial changes after therapy correlated with response.
Methods: Fifty-one patients had arthroscopic biopsies of the knee joint prior to infliximab (3 mg/kg) treatment. Synovial tissue cell numbers (CD68 and CD3 positive) and cytokine expression (TNF-α, lymphotoxin-α, IL-1α, -β and receptor antagonist, and IL-6) pre-treatment was assessed using semi-quantitative immunohistochemistry. Changes in these parameters were assessed 16 weeks after infliximab in 32 patients who underwent repeat arthroscopic biopsy.
Results: Of the total patients, 47% (n = 24) achieved an ACR20 response; 53% (n = 27) did not. Baseline synovial TNF-α, IL-1α and -β expression did not differ between the two groups. No differences in baseline TNF-α levels were observed with ACR levels of response (ACR20 and ACR50/70 groups). Post-treatment biopsies (17 ACR responders, 15 ACR non-responders) revealed significant reductions in sub-lining layer TNF-α expression in both response and non-response groups with significant reduction in vascularity and membrane proliferation scores. The worst ACR non-responders (<20% CRP suppression) demonstrated no reduction in any of the parameters.
Conclusion: Pre-treatment synovial TNF-α or IL-1 expression does not predict TNF blockade response. Both ACR response and non-response was associated with reduction in synovial TNF-α-level expression. Suppression in TNF-α levels was not observed in the worst non-responders. The improvements (including in vascularity), independent of ACR clinical response, are compatible with the reduced structural damage documented in all groups of patients independent of response.
Introduction
Pro-inflammatory cytokines, especially TNF-α and IL-1, are pivotal in the RA inflammatory cascade. Initial in vitro and subsequent in vivo studies demonstrated a hierarchical role of TNF-α in RA; development of TNF antagonist therapies with monoclonal antibodies or soluble receptor antagonists have been shown to dramatically suppress signs and symptoms of inflammation and prevent progression of structural damage in virtually all patients.
Despite the general effectiveness of anti-TNF-α therapies, a lack of response is evident in up to 40% of the patients treated with these agents. Few studies have investigated the underlying basis of anti-TNF-α resistance. Variable synovial cytokine expression and variable synovial tissue TNF-α levels with treatment have been observed; however, studies have generally comprised few patients and no clear explanation has emerged.
The principal aims of this study were to examine the heterogeneity of synovial cytokine (particularly TNF-α) expression, correlate this with the level of response to infliximab and observe whether non-response represented a subgroup of RA that was mediated independently of TNF-α. Our findings indicate that baseline cytokine expression is not predictive, and changes do not correlate with ACR response. Importantly, TNF-α expression was significantly reduced in both ACR response and non-response patients, consistent with structural data. However, complete failure to respond to TNF-blockade in the small minority may be associated with unchanged tissue TNF-α expression. These findings have implications both for the therapeutics of RA and for understanding disease mechanisms.
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