Abstract
(1) Background: Treatment of patients with rheumatoid arthritis (RA) with an anti-IL-6 receptor (anti-IL-6R) monoclonal antibody (tocilizumab) has been found to influence iron metabolism. The objective of the present study was to ascertain whether changes in iron metabolism induced by anti-IL-6R biologic therapy were independently associated with an increased infection risk. (2) Methods: A prospective longitudinal study of patients with RA treated with tocilizumab was conducted. RA patients treated with an antitumor necrosis factor α monoclonal antibody were also included as a control group. The primary outcome was occurrence of infection during the first 24 months of biologic therapy. (3) Results: A total of 15 patients were included, with a mean age of 51.0 ± 4,1 and 73.3% (n = 11) female. A multivariate survival regression model, adjusted for confounding factors, was fitted for each of the iron metabolism variables. Hazard ratios for being above the median of each parameter was considered. Transferrin saturation above the median value (>32.1%) was associated with a higher infection risk (HR 4.3; 95%CI 1.0–19.69; p = 0.05). Similarly, although non-significantly, higher serum iron was strongly associated with infection occurrence. (4) Conclusions: This study identified a probable association between infection risk and higher serum iron and transferrin saturation in patients with RA on anti-IL-6R biologic therapy. We suggest that both these parameters should be considered relevant contributing factors for infection occurrence in patients on anti-IL-6R therapy.
Highlights
Infection is a frequent complication during the natural clinical evolution of rheumatoid arthritis (RA), contributing to disease-associated morbidity and mortality [1]
(4) Conclusions: This study identified a probable association between infection risk and higher serum iron and transferrin saturation in patients with RA on anti-IL-6R biologic therapy
Three adaptive functions have been proposed for the hypoferremia of inflammation: inhibition of extracellular bacterial growth by sequestering available iron; protection from the toxicity caused by high levels of iron and heme released during tissue necrosis and erythrocyte destruction; and increased transferrin capacity to bind to iron released during infection and inflammation [6,8]
Summary
Infection is a frequent complication during the natural clinical evolution of rheumatoid arthritis (RA), contributing to disease-associated morbidity and mortality [1]. Age-adjusted mortality in RA might be increased about twofold when compared to the general population, and infectious diseases are one of the leading causes of death [2] This infection risk has been found to be influenced by several disease-related conditions, patient-associated comorbidities, and the immunomodulatory drugs used. IL-6 is a pleiotropic cytokine with a role in eliciting the acute-phase response in the liver, B-cell proliferation and antibody production, and T-cell differentiation and cytotoxicity [5] Chronic inflammatory states, such as the one present in RA, through increased levels of IL-6 and other cytokines, result in an increased transcription of the HAMP gene in the liver, which encodes hepcidin [6]. Three adaptive functions have been proposed for the hypoferremia of inflammation: inhibition of extracellular bacterial growth by sequestering available iron (considering that most infectious agents need to scavenge iron from the host to multiply); protection from the toxicity caused by high levels of iron and heme released during tissue necrosis and erythrocyte destruction; and increased transferrin capacity to bind to iron released during infection and inflammation [6,8]
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