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Table 1 Overview of immunohistopathological data obtained from small proof-of-concept studies using synovial biopsies in RA

From: Is there a role of synovial biopsy in drug development?

Drug

Timing of biopsies

Key finding

Reference

DMARDs/anti-TNF/experimental

2–16 weeks

Number of CD68+ macrophages in sublining synovial layer is a good biomarker of therapeutic response.

[76–79]

Methotrexate

16 weeks

Decrease in the numbers of inflammatory cells, including CD3+ and CD8+ T cells, CD38+ plasma cells, CD68+ macrophages (lining layer), inflammatory and destructive mediators (Ki67, IL-1β, TNF-α, E-selectin, ICAM-1, VCAM-1, MMP-1). Responders displayed a reduction in the expression of all ICAM-1, VCAM-1, TNF-α and IL-1 β.

[80, 81]

Methotrexate

12 weeks

No change in synovial hyperplasia, lymphoplasmocytic infiltrate, CD68+ macrophages, CD3+ T cells and CD138+ plasma cells

[50]

Leflunomide

16 weeks

Decrease in the numbers CD68+ macrophages (sublining), inflammatory and destructive mediators (ICAM-1, VCAM-1, MMP-1). Responders displayed a reduction in the expression of ICAM-1, VCAM-1 and TNF-α.

[81]

Prednisolone

24 h

Decrease in the expression of TNF-α (lining and sublining), IL-8 (lining), as well as reduced synovial fluid IL-8 levels. Change in TNF-α correlated with clinical response to, and subsequent relapse after therapy

[82]

Prednisolone

2 weeks

Reduction in the number of sublining synovial macrophages, a trend toward decreased infiltration by CD4+ T cells, CD38+ plasma cells, and CD55+ fibroblast-like synoviocytes

[76]

Infliximab (3 mg/kg)

48 h/4 weeks

Reduced number of CD68+ intimal macrophages after 48 h, a trend to decreased amount of CD38+ plasma cells, CD3+ T cells, sublining CD68+ macrophages after 48 h/4 weeks. Decreased numbers of CD3+, CD38+ and both intinal and sublining CD68+ cells were observed in clinical responders after 4 weeks.

[23]

Infliximab (10 mg/kg)

2 weeks

Reduction in the numbers of infiltrating synovial CD3+ T cells, CD22+ B cells, CD68+ macrophages and in the expression of IL-8, MCP-1 and TNF-α. High levels of synovial TNF-α prior to treatment may predict responsiveness to therapy.

[83, 84]

Rituximab

4 weeks

Incomplete depletion of CD22+ B cells, no correlation with the change in DAS28.

[62]

Rituximab

4 weeks

16 weeks

CD19+ B cells significantly but incompletely decreased at 4 weeks, with further reduction at 16 weeks in some patients. Decrease in CD68+ macrophages at 4 and 16 weeks, CD3+ T cells decreased at 16 weeks. The reduction of CD138+ plasma cells predicted clinical improvement at 24 weeks.

[64]

Rituximab

12 weeks

Depletion of CD20+ B cells, trend to decrease in CD68+ macrophages. No correlations between changes in CD20+ or CD68+ and changes in the DAS28. Positivity for circulating IgM ACPA, in combination with a high infiltration of CD79a + B cells is a predictor of clinical outcome after rituximab.

[51, 65]

Tocilizumab

12 weeks

Decrease in synovial hyperplasia, lymphoplasmocytic infiltrate, CD68+ macrophages, CD3+ T cells and CD138+ plasma cells

[50]

Anakinra + pegsunercept

4 weeks

52 weeks

Decrease in number of CD3+ T cells and TGFβ expression as biomarker therapeutic response at weeks 4 and 52 of combination therapy. Baseline CD3+ and sublining CD68+ infiltration, VEGF and TGFβ expression were predictive of subsequent structural outcome at 6 or 12 months.

[19]

CCR1 antagonist

2 weeks

Reduction in overall cellularity, number of CD4+ and CD8+ T cells, CD68+ macrophages and the number of CCR1+ cells.

[22]

RecIL-10

12 weeks

No significant change in number of inflammatory cells or in the scores for the expression of cytokines.

[85]

IL-1 receptor antagonist

24 weeks

Reduction in intimal and sublining CD68+ macrophages and CD3+ lymphocytes.

[86]

Anti-CCL2 antibody

6 weeks

No immunohistologic changes.

[66]

C5aR-antagonis

4 weeks

No immunohistologic changes.

[67]

IFN-β (18/36/54 million IU/week)

4 weeks

12 weeks

Decrease in number of CD3+ T cells at 4 weeks and CD38+ plasma cells at 12 weeks along with changes of several inflammatory and destructive molecules (e.g. MMP-1, IL-6 or IL-1β).

[87]

IFN-β (6.6/132 μg/week)

24 weeks

No changes in synovial tissue infiltrates.

[68]