title: Effect of adalimumab on neutrophil function in patients with rheumatoid arthritis.
abstract: Neutrophils are known to be targets for the biological activity of tumour necrosis factor (TNF)-alpha in the pathogenesis of rheumatoid arthritis (RA). Therefore, these cells may be among the targets of anti-TNF-alpha therapy. In this study we evaluated the effect of therapy with adalimumab (a fully human anti-TNF-alpha mAb; dosage: 40 mg subcutaneously every other week) on certain phenotypic and functional aspects of neutrophils obtained from 10 selected patients with RA and 20 healthy control individuals. Peripheral blood neutrophils were obtained at baseline and during anti-TNF-alpha therapy (2, 6 and 12 weeks after the first administration of adalimumab). All patients had been receiving a stable regimen of hydroxychloroquine, methotrexate and prednisone for at least 3 months before and during the study. Baseline neutrophil chemotaxis was significantly decreased in RA patients when compared with control individuals (P < 0.001). Two weeks after the first administration of adalimumab, chemotactic activity was completely restored, with no differences noted between patients and control individuals; these normal values were confirmed 6 and 12 weeks after the start of anti-TNF-alpha therapy. Phagocytic activity and CD11b membrane expression on neutrophils were similar between RA patients and control individuals; no modifications were observed during TNF-alpha neutralization. The production of reactive oxygen species, both in resting and PMA (phorbol 12-myristate 13-acetate)-stimulated cells, was significantly higher in RA patients at baseline (P < 0.05) and was unmodified by anti-TNF-alpha mAb. Finally, we showed that the activation antigen CD69, which was absent on control neutrophils, was significantly expressed on neutrophils from RA patients at baseline (P < 0.001, versus control individuals); however, the molecule was barely detectable on cells obtained from RA patients during adalimumab therapy. Because CD69 potentially plays a role in the pathogenesis of arthritis, our findings suggest that neutrophils are among the targets of anti-TNF-alpha activity in RA and may provide an insight into a new and interesting mechanism of action of anti-TNF-alpha mAbs in the control of inflammatory arthritis.
authors.affiliation: Department of Internal Medicine, Ospedale Maggiore Policlinico, IRCCS, University of Milan, Milan, Italy. franco.capsoni@unimi.it
authors.forename: Franco
authors.initials: F
authors.lastname: Capsoni
authors.forename: Piercarlo
authors.initials: P
authors.lastname: Sarzi-Puttini
authors.forename: Fabiola
authors.initials: F
authors.lastname: Atzeni
authors.forename: Francesca
authors.initials: F
authors.lastname: Minonzio
authors.forename: Paola
authors.initials: P
authors.lastname: Bonara
authors.forename: Andrea
authors.initials: A
authors.lastname: Doria
authors.forename: Mario
authors.initials: M
authors.lastname: Carrabba
mesh_terms: D000068879:Adalimumab; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000494:pharmacology* / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D015703:Antigens, CD / Q000096:biosynthesis / Q000235:genetics; D000945:Antigens, Differentiation, T-Lymphocyte / Q000096:biosynthesis / Q000235:genetics; D018501:Antirheumatic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001172:Arthritis, Rheumatoid / Q000097:blood / Q000188:drug therapy*; D001327:Autoimmune Diseases / Q000097:blood / Q000188:drug therapy*; D015415:Biomarkers; D039481:CD11b Antigen / Q000096:biosynthesis / Q000235:genetics; D002478:Cells, Cultured / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D002630:Chemotactic Factors / Q000494:pharmacology; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D016130:Immunophenotyping; D037181:Lectins, C-Type; D008163:Luminescent Measurements; D008297:Male; D008875:Middle Aged; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D009504:Neutrophils / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D010587:Phagocytosis / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*; D015054:Zymosan / Q000494:pharmacology; D000099192:CD69 Antigens
chemical_list: D000068879:Adalimumab; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D018501:Antirheumatic Agents; D015415:Biomarkers; D039481:CD11b Antigen; D002630:Chemotactic Factors; D037181:Lectins, C-Type; D009240:N-Formylmethionine Leucyl-Phenylalanine; D017382:Reactive Oxygen Species; D013755:Tetradecanoylphorbol Acetate; D014409:Tumor Necrosis Factor-alpha; D015054:Zymosan; D000099192:CD69 Antigens
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