Neutrophil Migration and Production of Reactive Oxygen Species During Treatment with a Fully Human Anti-Tumor Necrosis Factor-a Monoclonal Antibody in Patients with Rheumatoid Arthritis

ALFONS A. den BROEDER, GEERT J.A. WANTEN, WIM J.G. OYEN, TON NABER, PIET L.C.M. van RIEL, and PILAR BARRERA

ABSTRACT.

Objective. To evaluate the effects of therapy with a fully human anti-tumor necrosis factor (TNF)-a monoclonal antibody on the production of superoxide and other reactive oxygen species (ROS) and on the migration capacity of neutrophils in patients with rheumatoid arthritis (RA).

Methods. A total of 29 patients with active RA and 25 healthy controls participated. Assessments were performed at baseline and 2 weeks after the first administration of anti-TNF-a. The production of ROS was studied in unstimulated conditions and after stimulation of receptor dependent (serum treated zymosan, STZ) and receptor independent (phorbol mystrate acetate, PMA) pathways by luminol enhanced chemiluminescence. As well, the PMA induced burst production of superoxide was measured using the cytochrome-c reduction assay. Potential changes in neutrophil migration to joints were assessed by scintigraphy with autologous leukocytes.

Results. Baseline production of ROS (both spontaneously and after STZ stimulation) and superoxide and the ex vivo chemotaxis were similar in RA patients (n = 25) and controls (n = 25) and remained unchanged after administration of anti-TNF-a. The production of ROS after PMA stimulation was slightly higher in patients than in controls (p = 0.04) and this difference disappeared 2 weeks after the first dose of anti-TNF-a (p < 0.05). The scintigraphic study showed that a single dose of anti-TNF-a, but not placebo, markedly decreased the influx of leukocytes to inflamed joints.

Conclusion. In patients with RA, anti-TNF-a therapy rapidly decreases the influx of leukocytes into inflamed joints but does not impair neutrophil chemotaxis and production of ROS. (J Rheumatol 2003;30:232-7)

Key Indexing Terms:

ANTI-TUMOR NECROSIS FACTOR-a
RHEUMATOID ARTHRITIS
ADALIMUMAB
NEUTROPHIL MIGRATION
PMN
REACTIVE OXYGEN SPECIES

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From the Departments of Rheumatology, Gastroenterology, and Nuclear Imaging, University Medical Center Nijmegen, Nijmegen, The Netherlands.

A.A. den Broeder, MD, PhD; P.L.C.M. van Riel, MD, PhD, Professor in Rheumatology; P. Barrera, MD, PhD, Department of Rheumatology; G.J.A. Wanten, MD; T. Naber, MD, PhD, Department of Gastroenterology; W.J.G. Oyen, MD, PhD, Department of Nuclear Imaging.

Address reprint requests to Dr. A.A. den Broeder, Department of Rheumatology, University Medical Center Nijmegen, PO Box 9101, 6500 HB Nijmegen, The Netherlands. E-mail: A.denbroeder@aig.azn.nl

Submitted August 13, 2001; revision accepted August 12, 2002.

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