Synovial fluid leukocyte apoptosis is inhibited in patients with very early rheumatoid arthritis

Abstract

Synovial leukocyte apoptosis is inhibited in established rheumatoid arthritis (RA). In contrast, high levels of leukocyte apoptosis are seen in self-limiting crystal arthritis. The phase in the development of RA at which the inhibition of leukocyte apoptosis is first apparent, and the relationship between leukocyte apoptosis in early RA and other early arthritides, has not been defined. We measured synovial fluid leukocyte apoptosis in very early arthritis and related this to clinical outcome. Synovial fluid was obtained at presentation from 81 patients with synovitis of < or = 3 months duration. The percentages of apoptotic neutrophils and lymphocytes were assessed on cytospin preparations. Patients were assigned to diagnostic groups after 18 months follow-up. The relationship between leukocyte apoptosis and patient outcome was assessed. Patients with early RA had significantly lower levels of neutrophil apoptosis than patients who developed non-RA persistent arthritis and those with a resolving disease course. Similarly, lymphocyte apoptosis was absent in patients with early RA whereas it was seen in patients with other early arthritides. The inhibition of synovial fluid leukocyte apoptosis in the earliest clinically apparent phase of RA distinguishes this from other early arthritides. The mechanisms for this inhibition may relate to the high levels of anti-apoptotic cytokines found in the early rheumatoid joint (e.g. IL-2, IL-4, IL-15 GMCSF, GCSF). It is likely that this process contributes to an accumulation of leukocytes in the early rheumatoid lesion and is involved in the development of the microenvironment required for persistent RA.

Figure 1

Apoptotic lymphocytes and neutrophils in synovial fluid cytospin preparations from patients with very early inflammatory arthritis. (a) An apoptotic lymphocyte (dashed arrow). (b) An apoptotic lymphocyte (dashed arrow) and apoptotic neutrophil (solid arrow). (c) Four apoptotic neutrophils (solid arrows).

Figure 2

Synovial fluid neutrophil and lymphocyte apoptosis in patients with very early inflammatory arthritis. (a) Synovial fluid neutrophil apoptosis at clinical presentation in patients with very early inflammatory arthritis divided according to outcome. (b) Synovial fluid lymphocyte apoptosis at clinical presentation in patients with very early inflammatory arthritis divided according to outcome. (c) Maximum synovial fluid neutrophil apoptosis observed in each patient with very early inflammatory arthritis; patients divided according to outcome. (d) Maximum synovial fluid lymphocyte apoptosis in each patient with very early inflammatory arthritis; patients divided according to outcome. (e) Synovial fluid neutrophil apoptosis over time in all samples obtained from patients with very early inflammatory arthritis that eventually persisted divided according to outcome (open circles = non-RA persistent synovitis; closed circles = RA). (f) Synovial fluid lymphocyte apoptosis over time in all samples obtained from patients with very early inflammatory arthritis that eventually persisted divided according to outcome (open circles = non-RA persistent synovitis; closed circles = RA). Comparisons were made using the Mann-Whitney test. RA, rheumatoid arthritis.