OUTCOME MEASURES IN OUTCOME MEASURES IN PsA: IMMUNOHISTOLOGYPsA: IMMUNOHISTOLOGY

Oliver FitzGeraldOliver FitzGerald

Immunohistology: State of the Immunohistology: State of the ArtArt• Kruithof et al recently compared synovial Kruithof et al recently compared synovial

immunohistologic features characterizing immunohistologic features characterizing rheumatoid arthritis (RA) and rheumatoid arthritis (RA) and spondyloarthropathy (SpA), including PsA. spondyloarthropathy (SpA), including PsA.

• Using a semi-quantitative scoring system, the Using a semi-quantitative scoring system, the authors identified a number of features authors identified a number of features characteristic of RA synovium. characteristic of RA synovium.

• In the PsA sub-group alone, increased vascularity In the PsA sub-group alone, increased vascularity and neutrophil numbers distinguished from RA. and neutrophil numbers distinguished from RA.

• The authors concluded that the synovitis in PsA, The authors concluded that the synovitis in PsA, both oligo- and polyarticular, resembles more both oligo- and polyarticular, resembles more SpA than RA.SpA than RA.

Kruithof E, et al. Kruithof E, et al. Synovial histopathology of psoriatic arthritis, both oligo- Synovial histopathology of psoriatic arthritis, both oligo- and polyarticular, resembles spondyloarthropathy more than it does and polyarticular, resembles spondyloarthropathy more than it does rheumatoid arthritis. Arthritis Res Ther 2005;7:R569-80.rheumatoid arthritis. Arthritis Res Ther 2005;7:R569-80.

Synovial Histopathology in Synovial Histopathology in SpA, PsA and RASpA, PsA and RA

SpA v RASpA v RA PsA v RAPsA v RAIncreased in Increased in SpA/PsASpA/PsA

VascularityVascularityNeutrophilsNeutrophilsCD163+ MCD163+ M

VascularityVascularityNeutrophilsNeutrophils

Increased in Increased in RARA

Lining layer Lining layer thicknessthicknessCD83+ dendritic CD83+ dendritic cellscellsCCP+CCP+MHC/HC gp-39+MHC/HC gp-39+

CCP+CCP+MHC/HC gp-MHC/HC gp-39+39+

Immunohistology: State of the Immunohistology: State of the ArtArt• A number of studies have explored synovial A number of studies have explored synovial

changes in PsA following treatment intervention. changes in PsA following treatment intervention. • In an open study of treatment with methotrexate, In an open study of treatment with methotrexate,

Kane et al. demonstrated significant reductions in Kane et al. demonstrated significant reductions in T cell and macrophage numbers but vascularity T cell and macrophage numbers but vascularity remained unchanged. Interestingly, adhesion remained unchanged. Interestingly, adhesion molecule expression was reduced suggesting less molecule expression was reduced suggesting less vascular endothelial activation. Expression of pro-vascular endothelial activation. Expression of pro-inflammatory cytokines, most significantly IL-8, inflammatory cytokines, most significantly IL-8, was reduced with methotrexate. was reduced with methotrexate.

• In further studies in the same group of patients, In further studies in the same group of patients, the molecular target of MTX was shown to be the the molecular target of MTX was shown to be the nuclear orphan receptor NURR1 and was mediated nuclear orphan receptor NURR1 and was mediated through adenosine releasethrough adenosine release. .

Kane D, et al. Reduction of synovial sublining layer inflammation and proinflammatory cytokine Kane D, et al. Reduction of synovial sublining layer inflammation and proinflammatory cytokine expression in psoriatic arthritis treated with methotrexate. Arthritis Rheum 2004;50:3286-95.expression in psoriatic arthritis treated with methotrexate. Arthritis Rheum 2004;50:3286-95.Ralph JA, et al. Modulation of orphan nuclear receptor NURR1 expression by methotrexate in human Ralph JA, et al. Modulation of orphan nuclear receptor NURR1 expression by methotrexate in human inflammatory joint disease involves adenosine A2A receptor-mediated responses. inflammatory joint disease involves adenosine A2A receptor-mediated responses. J Immunol J Immunol 2005;175:555-65.2005;175:555-65.

Immunohistology: State of the Immunohistology: State of the ArtArt• Synovial tissue and lesional skin biopsy specimens Synovial tissue and lesional skin biopsy specimens

were obtained at baseline and 48 hours after were obtained at baseline and 48 hours after treatment with Infliximab. treatment with Infliximab.

• A significant reduction in mean T cell numbers was A significant reduction in mean T cell numbers was found in both lesional epidermis ( p = 0.028) and found in both lesional epidermis ( p = 0.028) and synovial tissue (p = 0.043) after infliximab synovial tissue (p = 0.043) after infliximab treatment, but not after placebo. treatment, but not after placebo.

• Similarly, the number of macrophages in the synovial Similarly, the number of macrophages in the synovial sublining was significantly reduced (p = 0.043). sublining was significantly reduced (p = 0.043).

• The changes in cell numbers could not be explained The changes in cell numbers could not be explained by induction of apoptosis at the site of by induction of apoptosis at the site of inflammation inflammation ..

Goedkoop AY, et al. Early effects of tumour necrosis factor alpha blockade on skin and 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. synovial tissue in patients with active psoriasis and psoriatic arthritis. Ann Rheum Dis Ann Rheum Dis 2004;63:769-73.2004;63:769-73.

Immunohistology: State of the Immunohistology: State of the ArtArt

• Skin biopsies from a target psoriatic plaque and Skin biopsies from a target psoriatic plaque and synovial tissue biopsies from a target joint were synovial tissue biopsies from a target joint were taken before and at week 4 of Infliximab therapy.taken before and at week 4 of Infliximab therapy.

• After 4 weeks, cell infiltrate was reduced in both After 4 weeks, cell infiltrate was reduced in both skin and synovium. skin and synovium.

• There was a significant reduction in the number of There was a significant reduction in the number of blood vessels in dermis and synovium at week 4. A blood vessels in dermis and synovium at week 4. A significant reduction in the expression of significant reduction in the expression of alphavbeta3 integrin, a marker of alphavbeta3 integrin, a marker of neovascularization, and in adhesion molecules was neovascularization, and in adhesion molecules was also found. There was a trend toward reduced also found. There was a trend toward reduced expression of vascular endothelial growth factor in expression of vascular endothelial growth factor in both skin and synovium. 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):R326-34.

Immunohistology: State of the Immunohistology: State of the ArtArt• Synovial tissue biopsy samples were obtained at weeks Synovial tissue biopsy samples were obtained at weeks 0, 12, and 52 following Etanercept therapy0, 12, and 52 following Etanercept therapy

• Histologic synovitis was down-regulated, with a Histologic synovitis was down-regulated, with a profound reduction in global cellular infiltration, T cells profound reduction in global cellular infiltration, T cells but not B cells.but not B cells.

• The most prominent change was a reduction in the The most prominent change was a reduction in the different macrophage subsets (CD68, CD163, MRP-8, different macrophage subsets (CD68, CD163, MRP-8, and MRP-14), but this was not paralleled by a decrease and MRP-14), but this was not paralleled by a decrease in serum MRP-8/MRP-14. in serum MRP-8/MRP-14.

• Structural changes included normalization of lining Structural changes included normalization of lining layer hyperplasia and a moderate reduction in layer hyperplasia and a moderate reduction in vascularity. No effect on the microarchitecture of vascularity. No effect on the microarchitecture of lymphoid aggregates was observed. lymphoid aggregates was observed.

• In terms of matrix degradation, synovial expression of In terms of matrix degradation, synovial expression of MMP-3 and MMP-9 was down-modulated in correlation MMP-3 and MMP-9 was down-modulated in correlation with a rapid and profound decrease in serum MMP-3. 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. 2005 Dec;52(12):3898-909.

Psoriatic Arthritis Psoriatic Arthritis Immunopathologic Mechanisms Immunopathologic Mechanisms (PsAIM)(PsAIM)• PSAIM has 21 members, both rheumatologists and PSAIM has 21 members, both rheumatologists and

dermatologists, from 13 different centers. dermatologists, from 13 different centers. • Established to further develop collaborative research Established to further develop collaborative research

in the fields of Ps and PsA skin and synovium. in the fields of Ps and PsA skin and synovium. • An initial inventory has been completed which has An initial inventory has been completed which has

documented what archival material is available for documented what archival material is available for future study. Under the leadership of D. Baeten, future study. Under the leadership of D. Baeten, archival material from 52 spondyloarthropathy archival material from 52 spondyloarthropathy patients, including 16 with psoriatic arthritis, has patients, including 16 with psoriatic arthritis, has been examined for markers of treatment response been examined for markers of treatment response (Arthritis Rheum; in press). Analysis showed that (Arthritis Rheum; in press). Analysis showed that changes in synovial macrophage subsets, PMN, and changes in synovial macrophage subsets, PMN, and MMP3 expression best reflected clinical response to MMP3 expression best reflected clinical response to treatment after 12 weeks. treatment after 12 weeks.

Current Research AgendaCurrent Research Agenda• It has now been agreed that a prospective It has now been agreed that a prospective

study should be undertaken to examine study should be undertaken to examine changes in tissue (skin and synovium) changes in tissue (skin and synovium) biomarkers at earlier time-points which should biomarkers at earlier time-points which should predict clinical responses to anti-TNF therapy predict clinical responses to anti-TNF therapy in PsA. Biopsies of skin and synovium will be in PsA. Biopsies of skin and synovium will be obtained at baseline and at 4 weeks and obtained at baseline and at 4 weeks and clinical responses will be determined at 12 clinical responses will be determined at 12 weeks.weeks.

• In 2 other open studies with anakinra (n=12) In 2 other open studies with anakinra (n=12) and etanercept (n=15), clinical responses, and etanercept (n=15), clinical responses, immunohistological and MRI changes are immunohistological and MRI changes are being compared at baseline and 12 weeks.being compared at baseline and 12 weeks.