Dasari, Harika

ImportanceAnthracyclines increase the risk for congestive heart failure (CHF); however, long-term cumulative incidence and risk factors for CHF after anthracycline therapy are not well defined in population-based studies.ObjectiveTo compare the long-term cumulative incidence of CHF in patients with breast cancer or lymphoma treated with anthracycline therapy compared with healthy controls from the same community.Design, Setting, and ParticipantsThis retrospective population-based case-control study included data from the Rochester Epidemiology Project. Participants included residents of Olmsted County, Minnesota, diagnosed with breast cancer or lymphoma from January 1985 through December 2010 matched for age, sex, and comorbidities with healthy controls, with a final ratio of 1 case to 1.5 controls. Statistical analysis was performed between July 2017 and February 2022.ExposuresCancer treatment and CHF risk factors.Main Outcomes and MeasuresThe main outcome was new-onset CHF, as defined by the modified Framingham criteria. Cox proportional hazards regression was used to estimate hazard ratios (HRs) to compare the risk of CHF in participants with cancer vs controls, adjusted for age, sex, diabetes, hypertension, hyperlipidemia, coronary artery disease, obesity, and smoking history.ResultsA total of 2196 individuals were included, with 812 patients with cancer and 1384 participants without cancer. The mean (SD) age was 52.62 (14.56) years and 1704 participants (78%) were female. Median (IQR) follow-up was 8.6 (5.2-13.4) years in the case group vs 12.5 (8.7-17.5) years in the control group. Overall, patients with cancer had higher risk of CHF compared with the control cohort even after adjusting for age, sex, diabetes, hypertension, coronary artery disease, hyperlipidemia, obesity, and smoking status (HR, 2.86 [95% CI, 1.90-4.32]; P < .001). After adjusting for the same variables, CHF risk was greater for patients with cancer receiving anthracycline (HR, 3.25 [95% CI, 2.11-5.00]; P < .001) and was attenuated and lost statistical significance for patients with cancer not receiving anthracyclines (HR, 1.78 [95% CI, 0.83-3.81]; P = .14). Higher cumulative incidence for patients treated with anthracyclines vs comparator cohort was observed at 1 year (1.81% vs 0.09%), 5 years (2.91% vs 0.79%), 10 years (5.36% vs 1.74%), 15 years (7.42% vs 3.18%), and 20 years (10.75% vs 4.98%) (P < .001). There were no significant differences in risk of CHF for patients receiving anthracycline at a dose of less than 180 mg/m2 compared with those at a dose of 180 to 250 mg/m2 (HR, 0.54 [95% CI, 0.19-1.51]) or at a dose of more than 250 mg/m2 (HR, 1.23 [95% CI, 0.52-2.91]). At diagnosis, age was an independent risk factor associated with CHF (HR per 10 years, 2.77 [95% CI, 1.99-3.86]; P < .001).Conclusions and RelevanceIn this retrospective population-based case-control study, anthracyclines were associated with an increased risk of CHF early during follow-up, and the increased risk persisted over time. The cumulative incidence of CHF in patients with breast cancer or lymphoma treated with anthracyclines at 15 years was more than 2-fold that of the control group.

Abstract Background Acute respiratory exacerbations in idiopathic pulmonary fibrosis (IPF), often triggered by infection, are life threatening events characterized by rapid deterioration of lung function and associated with poor prognosis. Since microbial antigens modulate immunity by activating different pattern recognition receptors (PRR) expressed by innate immune cells (including B-cells), we sought to investigate how the activation of human B-cells through PRR stimulation by different microbial (CpG and β-glucan) and non-microbial (Mitochondrial DAMPs; MTDs) antigens resulted in the release of an inflammatory/fibrotic milieu that contributed to the pathogenesis of fibrosis in patients with IPF. Results Our results show that an inflammatory milieu is induced by stimulating circulating B-cells with both noninfectious (MTDs) and infectious antigens (CpG and β-glucan) commonly found in bacteria and fungi. Moreover, we show that the inflammatory milieu produced was specific to the inducing antigen, and that the microbial antigens (CpG and β-glucan) triggered distinct signaling pathways in B-cells. Specifically, CpG induced mTOR-activation while β-glucan was mTOR-independent and activated Src and p38. Furthermore, our results also show that B-cell aggregates are present within fibrotic areas of the lung in IPF patients and activated B-cells induce fibroblast migration, which was modified by antifibrotics (nintedanib and pirfenidone). Conclusion Our results highlight the potential contribution of activated B-cells through PRRs to the proinflammatory and profibrotic milieu seen in patients with idiopathic pulmonary fibrosis.

Abstract We hypothesize that B-lymphocytes are conducive to the pathogenesis of idiopathic pulmonary fibrosis (IPF), a progressive and fatal interstitial lung disease. B-lymphocytes aggregate in the lungs of IPF patients to form tertiary lymphoid follicles. How these follicles are formed and their role in the pathogenesis of IPF is not known. Hence, we sought to characterize how the activation of B-lymphocytes from IPF patients may contribute to the disease. Methods IPF patients defined by ATS guidelines were identified and recruited under local IRB #14-004714. B-lymphocytes were then isolated by negative selection. Cytokines and immunoglobulins from plasma or B-lymphocyte supernatants were measured by ELISA and signaling pathways were elucidated from whole-cell lysates by immunoblotting. Our results show that B-lymphocyte aggregates are present within fibrotic areas of the lung of IPF patients and that activated B-lymphocytes induce fibroblast migration. This effect was abrogated by nintedanib inhibition of B-lymphocyte activation. Furthermore, microbial antigen (β-glucan and CpG) activation of B-lymphocytes through pattern recognition receptors (PRRs; TLR9 and Dectin-1) contributed to the proinflammatory and profibrotic milieu seen in IPF patients. Stimulation of TLR9 and Dectin-1 resulted in activation of mTOR-dependent and -independent pathways, respectively. Rapamycin decreased TLR9 signaling, but not Dectin-1 mediated pathways. Nintedanib abrogated B-cell activation, IgM production, and the profibrotic milieu by interfering with both the mTOR-dependent and -independent pathways. In conclusion, our findings implicate activated B-lymphocytes in IPF pathogenesis highlighting the role of PRRs in this disease.

Abstract B-cell activation is increasingly linked to numerous fibrotic lung diseases, and it is well known that aggregates of lymphocytes form in the lung of many of these patients. Activation of B-cells by pattern recognition receptors (PRRs) drives the release of inflammatory cytokines, chemokines, and metalloproteases important in the pathophysiology of pulmonary fibrosis. However, the specific mechanisms of B-cell activation in patients with idiopathic pulmonary fibrosis (IPF) are poorly understood. Herein, we have demonstrated that B-cell activation by microbial antigens contributes to the inflammatory and profibrotic milieu seen in patients with IPF. B-cell stimulation by CpG and β-glucan via PRRs resulted in activation of mTOR-dependent and independent pathways. Moreover, we showed that the B-cell–secreted inflammatory milieu is specific to the inducing antigen and causes differential fibroblast migration and activation. B-cell responses to infectious agents and subsequent B-cell–mediated fibroblast activation are modifiable by antifibrotics, but each seems to exert a specific and different effect. These results suggest that, upon PRR activation by microbial antigens, B-cells can contribute to the inflammatory and fibrotic changes seen in patients with IPF, and antifibrotics are able to at least partially reverse these responses.