Interleukin-1 beta inhibition improves hemoglobin levels, reduces anemia incidence
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Inflammation inhibition through the interleukin-1 beta/interleukin-6 signaling pathway reduced incidence of anemia and improved hemoglobin levels among patients with anemia, according to results of an exploratory analysis of randomized trial data published in Annals of Internal Medicine.
“Underlying chronic inflammation has been associated with the development of anemia,” Mounica Vallurupalli, MD, hematology-oncology fellow at Dana-Farber/Partners Cancer Center, told Healio. “The mechanisms by which this occurs are complex but involve the activation of inflammatory pathways and cytokines that lead to impaired red cell production, decreased red cell survival or resistance to erythropoietin.”
“Importantly, cytokines in the [interleukin-1 beta] and interleukin-6 axis have been implicated in the pathogenesis of anemia of chronic inflammation,” she added. “Many disease processes, as well as normal aging, may be the byproduct or contributors to progressive underlying inflammatory signaling. Our study helped to highlight a role for suppression of the [interleukin-1 beta] axis in mitigating anemia incidence in individuals with chronic inflammation.”
Vallurupalli and colleagues analyzed 8,683 participants in the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS) without anemia at trial entry and 1,303 participants with prevalent anemia at trial entry to determine whether interleukin-1 beta inhibition with canakinumab (Ilaris, Novartis) reduces incident anemia and improves hemoglobin levels among those with prevalent anemia.
Participants in CANTOS had been randomly assigned to receive canakinumab dosed at 50 mg, 150 mg or 300 mg subcutaneously once every 3 months (no baseline anemia, n = 5,796; baseline anemia, n = 870) or placebo (no baseline anemia, n = 2,887; baseline anemia, n = 433).
Those without baseline anemia tended to be younger (median age, 61 years vs. 65 years) and were less likely to be women (24.8% vs. 31.8%) than those with baseline anemia. Median hemoglobin level was 145 g/L among those with no anemia at baseline and 119 g/L among those with anemia at baseline.
Incident anemia, defined as hemoglobin levels of less than 130 g/L in men or less than 120 g/L in women, served as the study’s primary endpoint.
Results showed incidence of anemia increased with rising baseline levels of high-sensitivity C-reactive protein. In addition, both interleukin-6 and high-sensitivity C-reactive protein decreased among those receiving canakinumab vs. placebo.
After median follow-up 3.7 years, those without baseline anemia in the canakinumab groups had significantly less incident anemia than placebo recipients (HR = 0.84; 95% CI, 0.77-0.93).
Compared with placebo, researchers reported HRs for incident anemia of 0.83 (95% CI, 0.73-0.94) for the 50 mg canakinumab group, 0.84 (95% CI, 0.75-0.95) for the 150 mg group, and 0.85 (95% CI, 0.75-0.96) for the 300 mg group.
They observed the greatest benefits of interleukin-1 inhibition on incident anemia among participants with the most robust anti-inammatory response. This was corroborated in formal mediation analyses.
Among those with baseline anemia, canakinumab increased mean hemoglobin levels by 11.3 g/L (P < 0.001) compared with placebo after 2 years of treatment.
Canakinumab increased the risk for infection and appeared associated with mild cases of thrombocytopenia and neutropenia, none of which was grade 3 or higher, researchers wrote.
“Our study demonstrated that the use of canakinumab in a population with chronic inflammation was associated with a decreased incidence of anemia, particularly in those who had the most robust reduction in inflammation as measured by reduction in high-sensitivity [C-reactive protein],” Vallurupalli said. “The initial study was not designed to evaluate anemia as a primary outcome; thus, we cannot make any claims about the use of [interleukin-1 beta] inhibition as a potential therapy for anemia of chronic inflammation. However, our study provides additional impetus for future randomized controlled trials targeting the [interleukin-1 beta] signaling axis to develop new therapies for anemia of chronic inflammation.”
Mediation analysis based on randomized trials can help to explain the mechanisms by which treatments might lead to intended outcomes, A. Russell Localio, PhD, emeritus associate professor of biostatistics at Perelman School of Medicine at University of Pennsylvania, and colleagues wrote in a related article.
“Careful attention to assumptions and control of confounding are essential,” Localio and colleagues wrote. “When properly performed, however, a mediation analysis can produce helpful clinical and mechanistic insights.”– by John DeRosier
For more information:
Mounica Vallurupalli, MD, can be reached at mvallurupalli@bwh.harvard.edu.
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Localio AR, et al. Ann Intern Med. 2020;doi:10.7326/M20-0887.
Vallurupalli M, et al. Ann Intern Med. 2020;doi:10.7326/M19-2945.
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