Effect of adalimumab on neutrophil function in patients with rheumatoid arthritis.
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.
Capsoni
Franco
F
Department of Internal Medicine, Ospedale Maggiore Policlinico, IRCCS, University of Milan, Milan, Italy. franco.capsoni@unimi.it
Sarzi-Puttini
Piercarlo
P
Atzeni
Fabiola
F
Minonzio
Francesca
F
Bonara
Paola
P
Doria
Andrea
A
Carrabba
Mario
M
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
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
N Engl J Med. 1999 May 6;340(18):1398-405
10228190
Clin Sci (Lond). 1999 Sep;97(3):323-9
10464057
Arthritis Rheum. 2000 Jan;43(1):38-47
10643698
Mol Immunol. 1999 Sep-Oct;36(13-14):885-92
10698343
N Engl J Med. 2000 Mar 16;342(11):763-9
10717011
Indian J Pathol Microbiol. 1999 Jul;42(3):283-9
10862285
Arthritis Rheum. 2000 Jul;43(7):1488-95
10902750
Lancet. 2000 Jul 29;356(9227):385-90
10972371
N Engl J Med. 2000 Nov 30;343(22):1594-602
11096166
BioDrugs. 2001;15(4):251-9
11437690
Clin Immunol. 2002 Apr;103(1):13-21
11987981
Arthritis Rheum. 2003 Jan;48(1):35-45
12528101
J Rheumatol. 2003 Feb;30(2):232-7
12563673
Int J Immunopathol Pharmacol. 2001 Sep-Dec;14(3):161-167
12604017
Cell Immunol. 2002 Nov;220(1):20-9
12718936
Int Immunol. 2003 Aug;15(8):987-92
12882836
J Pathol. 2003 Sep;201(1):17-27
12950013
Blood. 1992 Feb 1;79(3):745-53
1370644
Shock. 2003 Oct;20(4):309-15
14501943
Arthritis Rheum. 2003 Nov;48(11):3013-22
14613261
J Leukoc Biol. 1992 Dec;52(6):630-6
1464735
Clin Exp Rheumatol. 2004 May-Jun;22(3):331-4
15144128
N Engl J Med. 2004 May 20;350(21):2167-79
15152062
J Clin Invest. 1991 Aug;88(2):546-52
1830891
Ann Rheum Dis. 1990 Nov;49(11):916-20
2256738
Leuk Lymphoma. 1991;4(5-6):335-41
27467665
Arthritis Rheum. 1988 Aug;31(8):1041-5
3136775
Arthritis Rheum. 1988 Mar;31(3):315-24
3358796
Scand J Clin Lab Invest Suppl. 1968;97:77-89
4179068
J Periodontal Res. 1994 Mar;29(2):127-37
8158501
J Cell Physiol. 1996 Jul;168(1):183-7
8647914
Arthritis Rheum. 1996 Jul;39(7):1077-81
8670314
Arthritis Rheum. 1996 Jul;39(7):1082-91
8670315
Arthritis Rheum. 1996 Feb;39(2):216-25
8849371
N Engl J Med. 1997 Jul 17;337(3):141-7
9219699
Immunol Today. 1997 Jul;18(7):320-4
9238834
Eur J Haematol. 1997 Sep;59(3):142-7
9310121
Inflammation. 1998 Oct;22(5):533-43
9793799
Inflamm Res. 1998 Oct;47 Suppl 3:S158-65
9831319
Mediators Inflamm. 1998;7(1):19-23
9839694