Abstract
Blockade of tumour necrosis factor (TNF) is an effective treatment in rheumatoid arthritis (RA), but both non-responders and partial responders are quite frequent. This suggests that other pro-inflammatory cytokines may be of importance in the pathogenesis of RA and as possible targets for therapy. In this study we investigated the effect of TNF blockade (infliximab) on the synovial expression of IL-15 in RA in relation to different cell types and expression of other cytokines, to elucidate whether or not IL-15 is a possible target for therapy, independently of TNF blockade. Two arthroscopies with multiple biopsies were performed on nine patients with RA and knee-joint synovitis before and after three infusions of infliximab (3 mg/kg). Synovial biopsies were analysed with immunohistochemistry for expression of IL-15, TNF, IL-1α, IL-1ß and IFN-γ, and for the cell surface markers CD3, CD68 and CD163. Stained synovial biopsy sections were evaluated by computerized image analysis. IL-15 expression was detected in all synovial biopsies taken at baseline. After infliximab therapy, the expression of IL-15 was increased in four patients and reduced in five. Synovial expression of IL-15 was not correlated with any CD marker or with the presence of any other cytokine. Synovial cellularity was decreased after 8 to 10 weeks of treatment with a significant reduction of the CD68-positive synovial cells, whereas no significant change was seen in the number of CD3-positive T cells and CD163-expressing macrophages. The number of TNF-producing cells in the synovial tissue at baseline was correlated with a good response to therapy. Thus, in this study the synovial expression of IL-15 in RA was not consistently influenced by TNF blockade, being apparently independent of TNF expression in the synovium. Consequently, we propose that IL-15 should remain as a therapeutic target in RA, regardless of the response to TNF blockade.
Highlights
Blockade of tumour necrosis factor (TNF) in active rheumatoid arthritis (RA) is effective in reducing disease activity [1] and in stopping joint destruction [2]
These findings suggest that an IL-15-dependent pro-inflammatory feedback loop may be created in the inflamed synovium, in which IL-15 stimulates the production of TNF, IFN-γ and IL-17, which in ACR = American College of Rheumatology; DAS28 = Disease Activity Score counted on 28 joints; IFN = interferon; IL = interleukin; mAb = monoclonal antibody; RA = rheumatoid arthritis; TNF = tumour necrosis factor
Semi-quantitative analysis was performed for tumour necrosis factor (TNF; mAb1 and mAb11) and IFN-γ, for which a semi-quantitative four-point scale was used: 0 = no positive cells, 1 = 1 to positive cells, 2 = to 100 positive cells, and 3 = more than 100 positive cells. bA computerized image analysis was performed for IL-1a, IL-1ß IL-15 neutralizing antibody and IL-15 non-neutralizing antibody; values are median percentages of the stained tissue area, with ranges in parenthesis
Summary
Blockade of tumour necrosis factor (TNF) in active rheumatoid arthritis (RA) is effective in reducing disease activity [1] and in stopping joint destruction [2] Both non-responders and partial responders to TNF blockade are frequent [1], indicating a considerable influence of other pro-inflammatory cytokines beside TNF in perpetuating inflammation in RA. IL-15 may contribute to an increased production of the pro-inflammatory cytokines TNF, IFN-γ and IL-17 in T cells [7] Taken together, these findings suggest that an IL-15-dependent pro-inflammatory feedback loop may be created in the inflamed synovium, in which IL-15 stimulates the production of TNF, IFN-γ and IL-17, which in ACR = American College of Rheumatology; DAS28 = Disease Activity Score counted on 28 joints; IFN = interferon; IL = interleukin; mAb = monoclonal antibody; RA = rheumatoid arthritis; TNF = tumour necrosis factor
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