Immunomodulatory effects of anti-tumor necrosis factor alpha therapy on synovium in spondylarthropathy: histologic findings in eight patients from an open-label pilot study

Abstract

Objective: To assess the effects of treatment with anti-tumor necrosis factor alpha (anti-TNFalpha) on synovial histology in patients with spondylarthropathy (SpA) in order to confirm the effect on peripheral synovitis and to investigate the immunologic mechanisms involved in anti-TNFalpha therapy.

Methods: Patients with treatment-resistant SpA were treated with infliximab (5 mg/kg) at weeks 0, 2, and 6 in an open-label pilot study. In 8 patients, synovial biopsy tissues obtained at baseline, week 2, and week 12 were used for histologic and immunohistochemical evaluation.

Results: In all 8 patients (3 with ankylosing spondylitis, 1 with undifferentiated SpA, and 4 with psoriatic arthritis), there was a clear clinical improvement in the peripheral arthritis after anti-TNFalpha therapy. Histologic analysis of the synovial biopsy tissues indicated that the synovial lining layer thickness tended to decrease, with a significant reduction of CD55+ synoviocytes, at week 12. In the sublining layer, vascularity was reduced at week 12, with a decreased endothelial expression of vascular cell adhesion molecule 1 but not intercellular adhesion molecule 1, platelet endothelial cell adhesion molecule 1, and E-selectin. Although at week 2 and week 12, the number of neutrophils and CD68+ macrophages in the sublining layer was decreased, the overall degree of inflammatory infiltration remained unchanged. This could be related to the lymphocyte infiltration since at week 12, only CD4+ cells (but not CD3+, CD45RO+, and CD8+ cells) tended to decrease, while CD20+ lymphocytes and plasma cells were clearly increased.

Conclusion: The reduction in lining layer thickness, vascularity, and infiltration with neutrophils and macrophages paralleled the beneficial effect of anti-TNFalpha therapy on peripheral synovitis in 8 patients with different subtypes of SpA. The adhesion molecule expression, T cell infiltration, and, most important, B cell infiltration seemed to contrast with previous observations in RA. Although these preliminary data need to be confirmed in a larger cohort, they suggest distinct immunomodulatory mechanisms of anti-TNFalpha in SpA.