OUTCOME MEASURES IN PsA: TISSUE ANALYSIS Oliver FitzGerald

OMERACT 2004 Immunohistology at 38% Immunohistology at 38% Maintained on Research agenda Maintained on Research agenda OMERACT 2006 OMERACT 2006 Outer outer circle Outer outer circle Maintained on Research agenda Maintained on Research agenda

Immunohistology: State of the Art Kruithof et al recently compared synovial immunohistologic features characterizing rheumatoid arthritis (RA) and spondyloarthropathy (SpA), including PsA. Kruithof et al recently compared synovial immunohistologic features characterizing rheumatoid arthritis (RA) and spondyloarthropathy (SpA), including PsA. Using a semi-quantitative scoring system, the authors identified a number of features characteristic of RA synovium. Using a semi-quantitative scoring system, the authors identified a number of features characteristic of RA synovium. In the PsA sub-group alone, increased vascularity and neutrophil numbers distinguished from RA. In the PsA sub-group alone, increased vascularity and neutrophil numbers distinguished from RA. The authors concluded that the synovitis in PsA, both oligo- and polyarticular, resembles more SpA than RA. The authors concluded that the synovitis in PsA, both oligo- and polyarticular, resembles more SpA than RA. Kruithof E, et al. Synovial histopathology of psoriatic arthritis, both oligo- and polyarticular, resembles spondyloarthropathy more than it does rheumatoid arthritis. Arthritis Res Ther 2005;7:R

Synovial Histopathology in SpA, PsA and RA SpA v RA PsA v RA Increased in SpA/PsA VascularityNeutrophils CD163+ M  VascularityNeutrophils Increased in RA Lining layer thickness CD83+ dendritic cells CCP+ MHC/HC gp-39+ CCP+

Immunohistology: State of the Art A number of studies have explored synovial changes in PsA following treatment intervention. A number of studies have explored synovial changes in PsA following treatment intervention. In an open study of treatment with methotrexate (n=11), Kane et al. demonstrated significant reductions in T cell and macrophage numbers but vascularity remained unchanged. In an open study of treatment with methotrexate (n=11), Kane et al. demonstrated significant reductions in T cell and macrophage numbers but vascularity remained unchanged. Interestingly, adhesion molecule expression was reduced suggesting less vascular endothelial activation. Interestingly, adhesion molecule expression was reduced suggesting less vascular endothelial activation. Gene expression of pro-inflammatory cytokines, most significantly IL-8, was reduced with methotrexate. Gene expression of pro-inflammatory cytokines, most significantly IL-8, was reduced with methotrexate. Kane D, et al. Reduction of synovial sublining layer inflammation and proinflammatory cytokine expression in psoriatic arthritis treated with methotrexate. Arthritis Rheum 2004;50:

Immunohistology: State of the Art Synovial tissue and lesional skin biopsy specimens were obtained at baseline and 48 hours after treatment with Infliximab (n=6) or placebo (n=6). Synovial tissue and lesional skin biopsy specimens were obtained at baseline and 48 hours after treatment with Infliximab (n=6) or placebo (n=6). A significant reduction in mean T cell numbers was found in both lesional epidermis ( p = 0.028) and synovial tissue (p = 0.043) after infliximab treatment, but not after placebo. A significant reduction in mean T cell numbers was found in both lesional epidermis ( p = 0.028) and synovial tissue (p = 0.043) after infliximab treatment, but not after placebo. Similarly, the number of macrophages in the synovial sublining was significantly reduced (p = 0.043). Similarly, the number of macrophages in the synovial sublining was significantly reduced (p = 0.043). The changes in cell numbers could not be explained by induction of apoptosis at the site of inflammation. The changes in cell numbers could not be explained by induction of apoptosis at the site of inflammation. Goedkoop AY, et al. Early effects of tumour necrosis factor alpha blockade on skin and synovial tissue in patients with active psoriasis and psoriatic arthritis. Ann Rheum Dis 2004;63:

Immunohistology: State of the Art Skin biopsies from a target psoriatic plaque and synovial tissue biopsies from a target joint were taken before and at week 4 of Infliximab therapy (n=11). Skin biopsies from a target psoriatic plaque and synovial tissue biopsies from a target joint were taken before and at week 4 of Infliximab therapy (n=11). After 4 weeks, cell infiltrate was reduced in both skin and synovium but synovial changes were not significant. After 4 weeks, cell infiltrate was reduced in both skin and synovium but synovial changes were not significant. There was a significant reduction in the number of blood vessels in dermis and synovium at week 4. There was a significant reduction in the number of blood vessels in dermis and synovium at week 4. A significant reduction in the expression of alphavbeta3 integrin, a marker of neovascularization, and in adhesion molecules was also found. A significant reduction in the expression of alphavbeta3 integrin, a marker of neovascularization, and in adhesion molecules was also found. There was a trend toward reduced expression of vascular endothelial growth factor (VEGF) in both skin and synovium. There was a trend toward reduced expression of vascular endothelial growth factor (VEGF) in both skin and synovium. Goedkoop AY, et al. Deactivation of endothelium and reduction in angiogenesis in psoriatic skin and synovium by low dose infliximab therapy in combination with stable methotrexate therapy: a prospective single-centre study. Arthritis Res Ther. 2004;6(4):R

Immunohistology: State of the Art Synovial tissue biopsy samples were obtained in 20 SpA patients, 6 with PsA, at weeks 0, 12, and 52 following Etanercept therapy Synovial tissue biopsy samples were obtained in 20 SpA patients, 6 with PsA, at weeks 0, 12, and 52 following Etanercept therapy Histologic synovitis was down-regulated, with a profound reduction in global cellular infiltration, including T cells and macrophages but not B cells. Histologic synovitis was down-regulated, with a profound reduction in global cellular infiltration, including T cells and macrophages but not B cells. The most prominent change was a reduction in the different macrophage subsets (CD68, CD163, MRP-8, and MRP-14) The most prominent change was a reduction in the different macrophage subsets (CD68, CD163, MRP-8, and MRP-14) Structural changes included normalization of lining layer hyperplasia and a moderate reduction in vascularity. No effect on the microarchitecture of lymphoid aggregates was observed. Structural changes included normalization of lining layer hyperplasia and a moderate reduction in vascularity. No effect on the microarchitecture of lymphoid aggregates was observed. In terms of matrix degradation, synovial expression of MMP-3 and MMP-9 was down-modulated in correlation with a rapid and profound decrease in serum MMP-3. In terms of matrix degradation, synovial expression of MMP-3 and MMP-9 was down-modulated in correlation with a rapid and profound decrease in serum MMP-3. Kruithof et al. Immunomodulatory effects of etanercept on peripheral joint synovitis in the spondylarthropathies. Arthritis Rheum Dec;52(12):

Psoriatic Arthritis Immunopathogenic Mechanisms (PsAIM) PSAIM has 21 members, both rheumatologists and dermatologists, from 13 different centers. PSAIM has 21 members, both rheumatologists and dermatologists, from 13 different centers. Established to further develop collaborative research in the fields of Ps/PsA skin and synovial tissue analysis. Established to further develop collaborative research in the fields of Ps/PsA skin and synovial tissue analysis. An initial inventory has been completed which has documented what archival material is available for future study. An initial inventory has been completed which has documented what archival material is available for future study. Under the leadership of D. Baeten, archival material from 52 spondyloarthropathy patients, including 16 with psoriatic arthritis, has been examined for markers of treatment response (Arthritis Rheum; in press). Analysis showed that changes in synovial macrophage subsets, PMN, and MMP3 expression best reflected clinical response to treatment after 12 weeks. Under the leadership of D. Baeten, archival material from 52 spondyloarthropathy patients, including 16 with psoriatic arthritis, has been examined for markers of treatment response (Arthritis Rheum; in press). Analysis showed that changes in synovial macrophage subsets, PMN, and MMP3 expression best reflected clinical response to treatment after 12 weeks.

Current Research Agenda It has now been agreed that a prospective study should be undertaken (Amsterdam): It has now been agreed that a prospective study should be undertaken (Amsterdam): –Biopsies of skin and synovium will be obtained at baseline and at 4 weeks following anti-TNF therapy or placebo. This will help to identify marker(s) which best distinguish active treatment from placebo. –Patients clinical responses will be determined at 12 weeks and tissue (skin and synovium) biomarkers which best predict clinical responses will be ascertained. In 2 other open studies with anakinra (n=12) and etanercept (n=15), clinical responses, immunohistological and MRI changes are being compared at baseline and 12 weeks (Dublin). In 2 other open studies with anakinra (n=12) and etanercept (n=15), clinical responses, immunohistological and MRI changes are being compared at baseline and 12 weeks (Dublin).

Anakinra (IL-1ra) in PsA Moderate clinical responses (6/11 meet PsARC) Moderate clinical responses (6/11 meet PsARC) Little/no change in SQ MRI synovitis score Little/no change in SQ MRI synovitis score No change or worsening in CD68, CD3 or vascularity (DIA) No change or worsening in CD68, CD3 or vascularity (DIA) Compared to clinical measures, is IH assessment more objective?

Tissue Analysis: Summary Evidence IH features of PsA can be distinguished from RA (vascularity; neutrophils) IH features of PsA can be distinguished from RA (vascularity; neutrophils) Effective treatment is accompanied by a reduction in synovial cellularity (CD3; CD68) and of vascular activation Effective treatment is accompanied by a reduction in synovial cellularity (CD3; CD68) and of vascular activation Should proof-of-concept studies and phase 1 clinical trials include assessment of synovium by both MRI and immunohistology?

Psoriatic Arthritis Immunopathogenic Mechanisms (PsAIM) Tissue Analysis New Technologies e.g. proteomics Psoriasis Psoriatic Arthritis Serum and Synovial Biomarkers Genetics