Salmonella septicemia in rheumatoid arthritis patients receiving anti-tumor necrosis factor therapy: association with decreased interferon-gamma production and Toll-like receptor 4 expression.
OBJECTIVE
Patients treated with antibodies to tumor necrosis factor alpha (TNFalpha) have an increased susceptibility to intracellular infections. We describe 2 patients with rheumatoid arthritis (RA) who developed Salmonella septicemia during anti-TNF treatment. The aim of this study was to identify the mechanisms involved in the increased susceptibility of anti-TNF-treated patients to intracellular microorganisms.


METHODS
We evaluated an additional 6 RA patients receiving anti-TNF antibodies, 5 RA patients not receiving anti-TNF therapy, and 6 age- and sex-matched healthy volunteers. The in vitro production of cytokines (interleukin-1beta [IL-1beta], IL-6, interferon-gamma [IFNgamma], and IL-10) upon bacterial stimulation of whole blood and the expression of Toll-like receptor 4 (TLR-4) on dendritic cells from RA patients treated with infliximab, RA patients not treated with infliximab, and healthy controls were compared.


RESULTS
Stimulation with heat-killed Salmonella typhimurium or Candida albicans led to a significantly decreased production of IFNgamma, but not to a decreased production of IL-10, IL-beta, or IL-6, in anti-TNF-treated RA patients compared with RA patients who were not receiving anti-TNF antibodies and compared with healthy controls. TNF-blocking treatment ex vivo significantly inhibited TLR-4 expression on dendritic cells from RA patients and healthy controls.


CONCLUSIONS
Since recognition of microorganisms by TLR-4 and activation of phagocytes by IFNgamma are essential mechanisms for the defense against intracellular and fungal pathogens, we propose that this pathway is crucial for the increased susceptibility to these microorganisms in patients receiving anti-TNF therapy.
Netea
Mihai G
MG
University Medical Center St. Radboud, and Nijmegen University Center for Infectious Diseases, Nijmegen, The Netherlands.
Radstake
Timothy
T
Joosten
Leo A
LA
van der Meer
Jos W M
JW
Barrera
Pilar
P
Kullberg
Bart Jan
BJ
D000328:Adult; D000911:Antibodies, Monoclonal / Q000009:adverse effects; D018501:Antirheumatic Agents / Q000009:adverse effects; D001172:Arthritis, Rheumatoid / Q000150:complications / Q000188:drug therapy* / Q000276:immunology; D016207:Cytokines / Q000097:blood; D003713:Dendritic Cells / Q000737:chemistry / Q000187:drug effects / Q000276:immunology; D005260:Female; D006801:Humans; D016867:Immunocompromised Host; D000069285:Infliximab; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D008297:Male; D008562:Membrane Glycoproteins / Q000032:analysis / Q000276:immunology; D008875:Middle Aged; D011956:Receptors, Cell Surface / Q000032:analysis / Q000276:immunology; D012480:Salmonella Infections / Q000150:complications* / Q000276:immunology; D019779:Salmonella enterica; D018805:Sepsis / Q000276:immunology / Q000382:microbiology*; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*
D000911:Antibodies, Monoclonal; D018501:Antirheumatic Agents; D016207:Cytokines; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha; D000069285:Infliximab