OUTCOME MEASURES IN PsA: IMMUNOHISTOLOGY

1. OUTCOME MEASURES IN PsA: IMMUNOHISTOLOGY Oliver FitzGerald

2. Immunohistology: State of the Art • 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. • 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. 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:R569-80.

3. Synovial Histopathology in SpA, PsA and RA

4. Immunohistology: State of the Art • A number of studies have explored synovial changes in PsA following treatment intervention. • In an open study of treatment with methotrexate, 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. Expression of pro-inflammatory cytokines, most significantly IL-8, was reduced with methotrexate. • In further studies in the same group of patients, the molecular target of MTX was shown to be the nuclear orphan receptor NURR1 and was mediated through adenosine release. 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. Ralph JA, et al. Modulation of orphan nuclear receptor NURR1 expression by methotrexate in human inflammatory joint disease involves adenosine A2A receptor-mediated responses. J Immunol 2005;175:555-65.

5. Immunohistology: State of the Art • Synovial tissue and lesional skin biopsy specimens were obtained at baseline and 48 hours after treatment with Infliximab. • 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). • 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;63:769-73.

6. 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. • After 4 weeks, cell infiltrate was reduced in both skin and synovium. • 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. There was a trend toward reduced expression of vascular endothelial growth factor 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):R326-34.

7. Immunohistology: State of the Art • Synovial tissue biopsy samples were obtained at weeks 0, 12, and 52 following Etanercept therapy • Histologic synovitis was down-regulated, with a profound reduction in global cellular infiltration, T cells but not B cells. • The most prominent change was a reduction in the different macrophage subsets (CD68, CD163, MRP-8, and MRP-14), but this was not paralleled by a decrease in serum MRP-8/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. • 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. 2005 Dec;52(12):3898-909.

8. Psoriatic Arthritis Immunopathologic Mechanisms (PsAIM) • PSAIM has 21 members, both rheumatologists and dermatologists, from 13 different centers. • Established to further develop collaborative research in the fields of Ps and PsA skin and synovium. • 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.

9. Current Research Agenda • It has now been agreed that a prospective study should be undertaken to examine changes in tissue (skin and synovium) biomarkers at earlier time-points which should predict clinical responses to anti-TNF therapy in PsA. Biopsies of skin and synovium will be obtained at baseline and at 4 weeks and clinical responses will be determined at 12 weeks. • 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.