Soluble Interleukin-2 Receptor Research Articles

Real-life experience with rilonacept for the treatment of recurrent pericarditis

Abstract Background Rilonacept, a soluble Interleukin-1 (IL-1) receptor fusion protein that neutralizes IL-1α and IL-1β, has shown efficacy in symptom resolution, weaning of standard-of-care therapies, and reducing the frequency of recurrent pericarditis (RP) episodes in clinical trials. Purpose We aimed to review the efficacy, safety, and duration of treatment with Rilonacept reliance in managing RP in our practice. Methods We analyzed 22 patients with RP treated with Rilonacept, 55 [43-69] years, 11 (50%) females. We reviewed clinical characteristics and outcomes, including the time since initial diagnosis of pericarditis, the presence of pericardial effusion/thickening, the duration of Rilonacept treatment, the ability to wean off steroids, and the recurrence of pericarditis symptoms attempting discontinuation. Results The length of time from the initial diagnosis of pericarditis to Rilonacept initiation was 9 [4-32] months. Fifteen patients out of 22 (68%) had pericardial effusion, 3 (20%) with tamponade requiring pericardiocentesis. Median length of treatment with Rilonacept was 14 [6-23] months, with 17/22 (77%) of patients being treated for ≥ 6 months. All patients who were on steroids (14/22, 64%) were able to discontinue their usage 1 [1-9] months after starting Rilonacept. Of the seventeen who were treated for 6 months or more, 12 (70%) remained on Rilonacept 160 mg weekly at the most recent assessment, 3 (18%) continued treatment with Rilonacept 160 mg every 2 or 4 weeks, and 2 (12%) discontinued Rilonacept treatment after 6 and 50 months. Of the 12 patients who remained on weekly treatment after a period of 6 months, 8 (67%) required Rilonacept for symptom control, 1 (8%) had recurrent symptoms after treatment every 2 weeks, and the remaining 3 (25%) preferred to continue despite a lack of symptoms (Figure 1). Conclusions The efficacy of Rilonacept in treating patients with RP and the ability to stop steroid therapy in the real world is in line with the efficacy data from clinical trials.Figure 1

Non-linear relationship between soluble interleukin-2 receptor and prognosis of diffuse large B-cell lymphoma.

Despite an emphasis on the prognostic impact of serum soluble interleukin-2 receptor (sIL-2R) at diagnosis in patients with diffuse large B-cell lymphoma (DLBCL), whether the prognostic impact of elevated sIL-2R is linear remains unclear. To verify the presence of a non-linear association between sIL-2R level at diagnosis and overall survival (OS) in patients with newly diagnosed DLBCL, we conducted a multi-center, observational retrospective study. Among 488 analyzable patients, Cox proportional hazards modeling identified serum sIL-2R level at diagnosis as an independent predictor of OS. Multivariate Cox hazard modeling with restricted cubic spline model demonstrated that the relationship between serum sIL-2R level and OS was clearly non-linear (P for effect of sIL-2R = 0.002; P for non-linearity = 0.015). Mortality risk increased gradually as sIL-2R levels increased and plateaued at approximately 5,000 U/mL. Segmented regression analysis revealed that the trend in negative prognostic impact from a gradual increase in serum sIL-2R level changed significantly, with a breakpoint at approximately 2,000 U/mL. Multivariate receiver operating characteristic curves showed a significant improvement in prediction ability when serum sIL-2R level was added to the International Prognostic Index (IPI). Serum sIL-2R level at diagnosis was not only a prognostic factor, but also improved predictive accuracy for OS when incorporated with the IPI. However, the negative correlation between increasing sIL-2R and prognosis was non-linear.

Usefulness of the 3-hydroxykynurenine/kynurenic acid ratio as a diagnostic biomarker for diffuse larger B-cell lymphoma.

Reports have shown that the kynurenine pathway, one of the pathways by which tryptophan is metabolized, is activated in patients with diffuse large B-cell lymphoma (DLBCL). Activation of the kynurenine pathway triggers the production of various metabolites, such as kynurenine (Kyn), 3-hydroxykynurenine (3-HK), 3-hydroxyanthranilic acid (3-HAA), kynurenic acid (KA) and anthranilic acid (AA), which contribute to immune tolerance. The current study aimed to investigate the changes in metabolites of kynurenine pathway in DLBCL patients and evaluate their performance predicting DLBCL. Changes in metabolites of kynurenine pathway were examined using high-performance liquid chromatography in 35 DLBCL patients (age 61.2 ± 13.5 years) and 44 healthy controls (age 58.5 ± 12.5 years). DLBCL patients had significantly higher levels of 3-HK, AA, and 3-HAA but lower levels of Tryptophan (Trp) and KA compared to healthy controls. Given that the ratio of each metabolite represents the change in the Kyn pathway, the 3-HK/KA ratio was examined. Notably, DLBCL patients had a significantly higher 3-HK/KA ratio compared to healthy controls. In DLBCL, the area under the receiver operative characteristic (ROC) curve for 3-HK/KA (0.999) was higher than that for lactate dehydrogenase (0.885) and comparable to that for soluble interleukin-2 receptor (sIL-2R) (0.997). Based on ROC curve analysis, the 3-HK/KA ratio was found to be useful biomarker for the diagnosis of DLBCL. Our results suggest that the 3-HK/KA ratio is a clinically useful biomarker of DLBCL. Moreover, its combination with existing markers, such as sIL-2R, can improve its effectiveness of diagnosing DLBCL.

Effects of Bacterial Lysates on TLRs/NF-κB Pathway, Immune Function, and Prognosis in Children with Pulmonary Infection Caused by Streptococcus pneumoniae

Background: Bacterial lysates, as immunomodulators, may play a role in regulating the host immune response. Objectives: This study aimed to investigate the effects of bacterial lysates OM85-BV in treating pulmonary infections caused by Streptococcus pneumoniae in children. Methods: A total of 120 children with S. pneumoniae pulmonary infection were divided into two groups: The control group and the OM85-BV group, with a 1: 1 ratio. The control group received intravenous mezlocillin at 100 mL/kg/d, while the OM85-BV group, in addition to mezlocillin, received OM85-BV orally at 3.5 mg per dose. The improvement of clinical symptoms and pulmonary function indexes—including respiratory rate, tidal volume, volume to peak expiratory flow as a proportion of exhaled volume, and time to peak tidal expiratory flow as a proportion of expiratory time—were compared. Additionally, levels of C-reactive protein (CRP), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), soluble interleukin-2 receptor (sIL-2R), T lymphocyte subsets, and immunoglobulins in serum were analyzed. Results: Compared to the control group, the OM85-BV group showed a significant decrease in respiratory rate and an increase in tidal volume, volume to peak expiratory flow, and time to peak tidal expiratory flow (P < 0.05 for all). The OM85-BV group also had significantly lower levels of serum inflammatory factors such as CRP, TNF-α, IL-6, and sIL-2R. In terms of immune function, the OM85-BV group showed increased levels of T lymphocyte subsets CD3+, CD4+, and CD4+/CD8+ ratios, with a decrease in CD8+, as well as elevated serum IgA and IgG levels. The total effective rate of treatment in the OM85-BV group was significantly higher than in the control group (P < 0.05). Conclusions: The addition of OM85-BV to the treatment of S. pneumoniae pulmonary infection in children significantly improves clinical symptoms, lung function, and immune function, while reducing the inflammatory response. OM85-BV appears to inhibit the activation of the toll-like receptors (TLRs) and nuclear factor kappa-B (NF-κB) pathway.

Relationship of cerebrospinal fluid and serum levels of SIL-2R, eNOS, and CD93 with the progression and prognosis of viral encephalitis in children

To investigate the relationship of cerebrospinal fluid and serum levels of soluble interleukin-2 receptor (SIL-2R), endothelial nitric oxide synthase (eNOS), and cluster of differentiation 93 (CD93) with the progression and prognosis of viral encephalitis (VE) in children. Prospectively, 102 children with VE admitted from January 2021 to January 2024 were selected as the VE group. The patients were divided into a mild subgroup (64 patients) and a severe subgroup (38 patients) according to disease progression. The patients were also divided into a good prognosis subgroup (29 patients) and a poor prognosis subgroup (73 patients) according to prognosis. A control group of 102 children with central nervous system diseases who were examined and found not to have VE during the same period was selected. The factors contributing to the poor prognosis of children with VE and the predictive value of SIL-2R, eNOS, and CD93 in cerebrospinal fluid and serum for the poor prognosis of children with VE were evaluated. Cerebrospinal fluid and serum SIL-2R, eNOS, and CD93 levels were significantly increased in the VE group, severe subgroup, and poor prognosis subgroup (P<0.05). Multivariate logistic regression analysis showed that high SIL-2R, eNOS, and CD93 levels in cerebrospinal fluid and serum were risk factors for poor prognosis in children with VE (P<0.05). Receiver operating characteristic curve analysis showed that the combination of cerebrospinal fluid SIL-2R, eNOS, and CD93 was superior to these individual indicators in prediction of poor prognosis in children with VE (P<0.05). Similarly, the combination of serum SIL-2R, eNOS, and CD93 was superior to these individual indicators in prediction of poor prognosis in children with VE (P<0.05). The cerebrospinal fluid and serum levels of SIL-2R, eNOS, and CD93 are significantly elevated in children with VE, and they are associated with VE progression and prognosis.

Diagnostic Value of sLR11 and sIL-2R in the Cerebrospinal Fluid for Malignant Central Nervous System Lymphoma.

Objective We previously reported that patients with acute leukemia and malignant lymphoma (ML) demonstrated significantly increased serum soluble LR11 (sLR11) levels compared to normal controls. Accurately diagnosing ML of the central nervous system (CNS ML) using cytology is frequently difficult. Therefore, we evaluated the use of cerebrospinal fluid (CSF) sLR11 and soluble interleukin-2 receptor (sIL-2R) as diagnostic and treatment response markers for CNS ML. Methods We retrospectively evaluated the CSF results for CNS ML using clinical data at our institution, and then analyzed the usefulness of sLR11 and sIL-2R in CSF for both the diagnosis and as surrogate markers that reflect the therapeutic effect. Patients We enrolled patients with CNS ML who received intrathecal anticancer drugs between 2017 and 2023. We analyzed the sLR11 and sIL-2R levels in CSF and cytological malignant grades. We studied 22 patients, including 17 with central nervous system (CNS) clinical conditions and five who received prevention treatment. Results The CSF sLR11 levels were significantly and positively correlated with CSF sIL-2R levels. The CSF sLR11 and sIL-2R levels in patients with CNS ML were significantly higher than those in the prevention group. A receiver operating characteristic (ROC) curve analysis showed the cut-off value of sLR11 for CNS invasion to be 21.7 ng/mL. Moreover, the chemotherapy-responder group demonstrated significantly decreased CSF sLR11 and sIL-2R levels after treatment. Conclusion CSF sLR11 and sIL-2R of CSF were found to be useful biomarkers for the diagnostic and treatment response evaluation in patients with CNS ML.

Diagnostic challenge: Combination of magnetic resonance imaging and serum soluble Interleukin-2 receptor in soft tissue non-hodgkin lymphoma

PurposeNon-Hodgkin lymphoma (NHL) sometimes occurs in soft tissue (referred to as soft tissue lymphoma or soft tissue NHL), often mimicking soft tissue tumors. Despite some clinical indicators, accurate diagnosis of soft tissue NHL before biopsy remains challenging. We investigated the diagnostic value of serum soluble interleukin-2 receptor (sIL-2R) levels and magnetic resonance imaging (MRI) as an initial tool to assess the likelihood of soft tissue NHL. MethodsWe analyzed 36 cases of pathologically proven soft tissue NHL initially suspected as soft tissue tumors alongside 48 control cases of soft tissue sarcoma or carcinoma. Patient medical charts and MRI scans were retrospectively reviewed and statistically analyzed, focusing on assessing the diagnostic efficacy of soft tissue NHL. ResultsThe diagnostic accuracy of soft tissue NHL combining the appearance of homogeneity on MRI (T2-weighted and/or short-time inversion recovery [STIR] images) and sIL-2R value (≧ 904 U/mL) yielded a sensitivity of 78 % and 86 %, and specificity of 83 % and 88 %, respectively. Meeting one or both criteria increased the sensitivity to a maximum of 92 %, albeit with a specificity of 71 %. When both criteria were met, sensitivity and specificity were 72 % and 100 %, respectively. ConclusionThe integrated approach of combining MRI and sIL-2R demonstrated excellent efficacy in predicting the diagnosis of soft tissue NHL, which was initially referred to as soft tissue tumor.

5117 Unusual Sarcoid Presentation as a Case of Hypercalcemia

Abstract Disclosure: M. Salim: None. A. Chauhan: None. S. Avula: None. A. Ahmed: None. K. Zekarias: None. Background: Hypercalcemia may arise from a variety of causes and can pose challenging diagnostic dilemma. Clinical Case: An 89-year-old male presented with worsening malaise related to persistent hypercalcemia. He reported productive cough, polyuria, polydipsia, generalized muscle weakness and weight loss. Physical exam was remarkable for upper and lower extremities weakness. Laboratory tests showed calcium 11.6 (8.8-10.2 mg/dL), phosphorus 2.8 mg/dL (2.5-4.5 mg/dL), albumin 4.2 g/dL (3.5-5.2 g/dL), parathyroid hormone (PTH) 10 pg/mL (15-65 pg/mL), parathyroid hormone-related protein (PTH-rp) 4.5 pmol/L (0.0-2.3 pmol/L), TSH 6.24 (0.30 - 4.20 uIU/mL), free T4 1.10 ng/dL (0.90-1.70 ng/dL), GFR 61 mL/min/1.73m2, 25 OH Vit D 31 ng/mL (20-75 ng/mL), vit D 1,25-dihydroxy 134 pg/mL (19.9-79.3 pg/mL), calcium urine/creatinine 0.54. Hypercalcemia was first noted 11 months before the visit with a level of 14.0 mg/dL (8.8-10.2 mg/dL), phosphorus 3.5 mg/dL, PTH 11, PTH-rp 1.4 pmol/L, 25 OH Vit D 62 ng/mL, Vit D 1,25-dihydroxy 90 pg/mL, angiotensin-1-converting enzyme 12 U/L (16-85 U/L), serum and urine electrophoresis showed no monoclonal gammopathy present, and tuberculosis interferon-gamma test negative. Autoimmune workup was unremarkable, except for weak positive anti-signal recognition particle (SRP) antibodies and anti-Mi-2 antibodies. CT chest/pelvis/abdomen demonstrated peripheral predominant reticular opacities suggestive of interstitial lung disease and no malignant findings. Treatment history included zoledronic acid 11 months before the visit. The patient was referred for a granulomatous disease workup.Upon one month follow-up, the hypercalcemia symptoms were worsening. Repeat calcium was 12.3 mg/dL and fungal serologies were negative. The patient was started on prednisone empirically. PET CT was ordered and revealed patchy inflamed musculature of extremities suspicious of dermatomyositis/polymyositis. Further labs showed unremarkable myomarker panel, u3-Hydroxy-3-Methylglutaryl Coenzyme A reductase (HMGCR) antibody, Anti-cN-1A antibody, ACE 53 U/L, creatine kinase 32 U/L (39-309 U/L), aldolase 5.4 U/L (1.2-7.6 U/L), soluble IL-2R 1,021 U/mL (137-838 U/mL), and lysozyme 3.89 ug/mL (&amp;lt;2.75 ug/mL). A muscle biopsy was done, which showed benign skeletal muscle with patchy myofiber atrophy, patchy interstitial fibrosis, and focal interstitial mild chronic inflammation with no evidence of sarcoid granulomas in the sample. One week lab follow-up post initiation of steroid showed calcium of 10.1 mg/dL and subsequently improvement in his overall labs. Working diagnosis of sarcoid myositis was made. Conclusion: This case report highlights the approach of diagnosing a rare case of hypercalcemia due to sarcoid myositis. In a highly clinical suspicious patient, PET CT scan might be a necessary modality for diagnosis. Presentation: 6/2/2024

Regulation of plasma soluble receptors of TNF and IL-1 in patients with COVID-19 differs from that observed in sepsis

IL-1α/β and TNF are closely linked to the pathology of severe COVID-19 and sepsis. The soluble forms of their receptors, functioning as decoy receptors, exhibit inhibitory effects. However, little is known about their regulation in severe bacterial and viral infections, which we aimed to investigate in this study. The circulating soluble receptors of TNF (sTNFR1 and sTNFR2) and IL-1α/β (sIL-1R1, sIL-1R2) were evaluated in the plasma of patients with COVID-19, severe bacterial infections, and sepsis and compared with healthy controls. Additionally, IL1R1, IL1R2, TNFRSF1A, and TNFRSF1B expression was evaluated at the single cell level in PBMCs derived from COVID-19 or sepsis patients. Plasma concentrations of sIL-1R1, sTNFR1, and sTNFR2 were significantly higher in COVID-19 patients compared to healthy subjects. Notably, sIL-1R1 levels were particularly elevated in ICU COVID-19 patients, and transcriptome analysis indicated heightened IL1R1 expression in PBMCs from severe COVID-19 patients. In severe bacterial infections, only sTNFR1 and sTNFR2 exhibited increased levels compared to healthy controls. Sepsis patients had decreased sIL-1R1 plasma concentrations but elevated sIL-1R2, sTNFR1, and sTNFR2 levels compared to healthy individuals, reflecting the heightened expression due to the increased numbers of monocytes present in sepsis. Finally, elevated concentrations of sIL-1R2, sTNFR1, and sTNFR2 were moderately associated with reduced 28-day survival in sepsis patients. Our study reveals distinct regulation of plasma concentrations of soluble IL-1 receptors in COVID-19 and sepsis. Moreover, soluble TNF receptors 1 and 2 consistently rise in all conditions and show a positive correlation with disease severity in sepsis.

JAK inhibitors inhibit angiogenesis by reducing VEGF production from rheumatoid arthritis-derived fibroblast-like synoviocytes.

JAK/STAT signaling inhibition exerts therapeutic effects on angiogenesis in rheumatoid arthritis (RA). However, whether the inhibitory effect differs among JAK inhibitors because of differing selectivity is unknown. Therefore, we compared the inhibitory effects of tofacitinib, baricitinib, peficitinib, upadacitinib, and filgotinib on angiogenesis. RA-derived fibroblast-like synoviocytes (RA-FLS) were seeded on type I collagen gel, and human umbilical vein endothelial cells (HUVECs) were directly added. The control and aforementioned JAK inhibitors were added to the medium, followed by stimulation with interleukin (IL)-6 and soluble IL-6 receptor (sIL-6R). Each JAK inhibitor's concentration was determined based on estimated blood concentrations. The vascular endothelial growth factor (VEGF) concentration was evaluated with an enzyme-linked immunosorbent assay using the medium from the first exchange. A migration assay was performed, and HUVEC migration was evaluated using CD31 fluorescence immunostaining. Hematoxylin-eosin staining showed that compared with the non-JAKi treatment group, the JAKi treatment group markedly degenerated in the sub-lining and deep lining, with decreased lymphocyte infiltration and neovascularization [Rooney's score subscale, non-JAKi vs JAKi (median, 6.5 vs 2.5, p = 0.005)]. In vitro, IL-6 and sIL-6R administration increased VEGF production from RA-FLS and promoted neovascularization in HUVECs, and JAK-inhibitor administration, which decreased VEGF production from RA-FLS and suppressed HUVEC migration, inhibited neovascularization in RA-FLS and HUVEC co-cultures. The JAK inhibitors suppressed IL-6-induced angiogenesis via decreased VEGF production and HUVEC migration in RA-FLS and HUVEC co-cultures. No significant differences were observed among the JAK inhibitors, whose anti-angiogenic effect may be an important mechanism for RA treatment. Key Points • JAK inhibitors inhibit angiogenesis in RA by reducing VEGF production from RA-derived fibroblast-like synoviocytes. • Our study provides new insights into RA treatment by elucidating the anti-angiogenic effect of JAK inhibitors.

Effect of targeted temperature management on systemic inflammatory responses after out-of-hospital cardiac arrest: A prospective cohort study.

Interleukin (IL)-6 is a major inflammatory cytokine that predicts mortality after out-of-hospital cardiac arrest (OHCA). Targeted temperature management (TTM) is associated with improved all-cause mortality in patients with OHCA. However, the effect of TTM on IL-6 production remains unclear. This study investigated whether TTM has additional anti-inflammatory effects after OHCA. This prospective cohort study included a total of 141 hospitalized patients with OHCA who were treated between January 2015 and June 2023. The study was conducted in the intensive care unit of China Medical University Hospital, Taichung. Postcardiac arrest care included TTM or the control approach (no TTM). The primary outcomes included the 90-day mortality rate and neurologic outcomes after OHCA. Differences between the TTM and control groups were examined using Student t test, chi-square test, and Kaplan-Meier survival curve analysis. Multivariate analysis of variance model was used to examine interaction effects. Plasma IL-6 and IL-6/soluble IL-6 receptor complex levels were measured at 6 and 24 hours after resuscitation. IL-6 and IL-6/soluble IL-6 receptor complex production was lower in the TTM group than in the control group (-50.0% vs +136.7%, P < .001; +26.3% vs +102.40%, P < .001, respectively). In addition, the 90-day mortality rate and poor neurologic outcomes were lower in the TTM group than in the control group (36.8% vs 63.0%, relative risk 0.39, 95% confidence interval 0.24-0.64, P < .001; 65.5% vs 81.5%, relative risk 0.80, 95% confidence interval 0.66-0.98, P = .04). TTM improves both the mortality rate and neurologic outcomes in patients resuscitated from OHCA, possibly by reducing IL-6-induced proinflammatory responses.

Serum soluble interleukin-2 receptor alpha may predict tubulointerstitial inflammatory cell infiltration and short-term disease progression in immunoglobin A nephropathy.

This study aims to explore the relationship between serum soluble interleukin-2 receptoralpha (sIL-2Rα) levels and histologic features in immunoglobin A nephropathy (IgAN), and evaluate its predicting values on disease progression and remission status. IgAN patients were included retrospectively. Lee classification, Oxford classification and histological scoring were evaluated. Patients' estimated filtration rate (eGFR) and proteinuria remission status were collected during 6-month follow-up. Logistic regression was used to determine the risk factors and predicting value. Receiver operating characteristic (ROC) curve were used to determine the predicting value for outcome. One hundred seventy-two subjects were included in this study. Individuals in moderate-to-severe tubulointerstitial inflammatory cell infiltration group manifested with significantly elevated serum sIL-2Rα levels than those in non-to-mild group. Serum sIL-2Rα levels were positively correlated with infiltration scores. Serum sIL-2Rα was an independent risk factor for moderate-to-severe inflammatory cell infiltration [sIL-2Rα: OR 1.29 (1.015-1.640, p = 0.038)]. ROC curve analysis regarding predictive value for moderate-to-severe inflammatory cell infiltration of sIL-2Rα suggested area under curve was 0.859 (0.801-0.918, p = 0.000) when sIL-2Rα combined with eGFR < 60mL/(min·1.73 m2), 24-h proteinuria excretion > 1.0g, and hemoglobin. It showed good sensitivity (71.6%) and specificity (87.6%). Additionally, sIL-2Rα levels at kidney biopsy were strong predictive factor for kidney function loss 6months after kidney biopsy [OR 4.161 (1.013-17.088, p = 0.048)]. High serum sIL-2Rα was significantly associated with serious inflammatory cell infiltration in IgAN, and it showed strong predictive value for disease prognosis. Serum sIL-2Rα could be a useful noninvasive biomarker to evaluate the extent of histological injury and disease prognosis in IgAN.

The Usefulness of Serum Interleukin-6 as a Predictor of Response to Atezolizumab plus Bevacizumab Combination Treatment in Hepatocellular Carcinoma

Introduction: In atezolizumab plus bevacizumab (Atezo/Bev) combination treatment, both drugs act on the immune system. Previously, we reported that immunological changes after Atezo/Bev administration for unresectable hepatocellular carcinoma (uHCC) revealed significant alterations in interleukin (IL)-6, soluble IL-2 receptor, tumor necrosis factor-alpha, and programmed cell death-1 levels. Among these variable factors, serum levels of IL-6 can be easily measured on a commercial basis. Therefore, this study aimed to investigate the utility of serum IL-6 as a predictor of tumor response to Atezo/Bev treatment for uHCC. Method: The study included 44 patients with HCC treated with Atezo/Bev. Blood samples were collected before and 3 weeks after treatment, and tumor response was assessed using contrast-enhanced computed tomography 6 weeks after treatment. Results: Significant changes in serum IL-6 levels were observed in patients treated with Atezo/Bev as first-line therapy but not in those treated with it as second-line or later-line therapy. In patients treated with Atezo/Bev as first-line therapy, serum IL-6 levels increased significantly after treatment in patients with a complete or partial response but not in patients with stable or progressive disease. Furthermore, compared to other tumor markers such as alpha-fetoprotein, Lens culinaris agglutinin-reactive fraction of alpha-fetoprotein, and des-gamma-carboxyprothrombin, serum IL-6 levels exhibited the highest sensitivity in predicting tumor response during the treatment period. Conclusion: In patients with uHCC treated with Atezo/Bev, serum IL-6 levels could serve as a potential predictor of tumor response. Elevated levels after treatment may indicate a favorable tumor response and prognosis.

Evaluation serum soluble interleukin 2 receptor with diagnosis and prognosis in canine solid tumour: 34 cases.

The soluble interleukin-2 receptor (sIL-2R) serve as a valuable biomarker for tumors in human patients, as its levels increase during the activation of T lymphocytes in clinical states such as inflammation, infection, and tumor. This study aimed to demonstrate that sIL-2R levels can be also elevated in dogs with tumors and evaluate its applicability as a diagnostic and prognostic factor in canine cancer patients. Serum was collected from 6 healthy dogs and 34 dogs with solid tumors. The concentration of sIL-2R was measured using a commercial enzyme-linked immunosorbent assay kit. The median sIL-2R concentration was significantly higher in dogs with solid masses than in healthy dogs (117.3 vs 68.33 pg/ml, p=0.016). The highest median sIL-2R concentration was found in dogs with malignant tumors, followed by those with benign tumors, and healthy dogs (119.6 vs 93.74 vs 68.33 pg/ml, respectively). In dogs with malignant tumors, the mortality rate was significantly higher in the group with high sIL-2R levels than in the group with low sIL-2R levels. Dogs with solid tumors, particularly those with malignant tumors, had higher concentrations of sIL-2R than healthy dogs. Among dogs with malignant tumors, a correlation between sIL-2R concentration and mortality rate was confirmed. Serum sIL-2R levels may be used to detect malignant tumors and serve as a prognostic factor in dogs with malignant tumors.

Systemic T-cell activation and IFN-γ activity in indeterminate severe hepatitis are reminiscent of hemophagocytic lymphohistiocytosis: Implications for T-cell– and IFN-γ–directed therapies

BackgroundSevere hepatitis cases in children are increasingly recognized, however, the exact etiology remains unknown in a significant proportion of patients. Cases of indeterminate severe hepatitis (iSH) may progress to indeterminate pediatric acute liver failure (iPALF), hence understanding the immunobiology is critical to preventing disease progression. Hemophagocytic lymphohistiocytosis (HLH) is a systemic hyperinflammatory disorder associated with T-cell and macrophage activation with liver injury. ObjectivesWe hypothesized a high proportion of patients with iSH demonstrate systemic T-cell activation similar to HLH prior to developing iPALF and that the degree of T-cell activation in iSH might correlate with outcomes. MethodsFrom 2019-2022, 14 patients with iSH and 7 patients with PALF of known, non-immune etiology were prospectively enrolled. We compared immune signatures of iSH, HLH, known PALF, and healthy controls. ResultsWe found that patients with iSH have increased CD8+ T-cell activation and high interferon-γ activity similar to HLH. The amplitude of CD8+ T-cell activation was predictive of iSH progression to iPALF. We also found that in patients with iSH, ferritin had only modest elevation. However, age-normalized plasma soluble interleukin-2 receptor (sIL-2R) to ferritin level ratio can distinguish iSH from known PALF and HLH. As a proof of concept, we report that in three patients with steroid refractory iSH, emapalumab, an IFN-γ blocking antibody used in combination with steroids, improved liver function and may have prevented progression to PALF. ConclusionsOur data suggests flow-based T-cell activation markers could help in early identification and risk stratification for targeted intervention in patients with iSH.

Diagnostic value of soluble Interleukin-2 receptor in patients suffering neurosarcoidosis: A systematic review.

Neurosarcoidosis is an inflammatory granulomatous disease. Up to 25% of occult sarcoidosis affecting the nervous system are only detected by autopsy. In addition, in recent years the suspicion arose that the soluble Interleukin-2 Receptor (sIL-2R) might be useful in differentiating between neurosarcoidosis and neurosarcoidosis-like diseases such as neurotuberculosis, multiple sclerosis, or cerebral lymphoma. Therefore, we aimed to systematically review randomized controlled trials (RCT), observational studies, and case-control studies evaluating sIL-2R levels in neurosarcoidosis patients. For this systematic review, a comprehensive literature search of electronic databases including EMBASE, The Web Of Science, The Cochrane Library, MEDLINE, and Google Scholar was conducted. The search was limited to the English language and publication date up to January 08th, 2024. As part of the search strategy conducted, 6 articles met the inclusion criteria. Two independent reviewers extracted the relevant data from each article. In addition, 2 independent reviewers assessed the quality of each study using the Newcastle-Ottawa Scale (NOS). We included 6 studies comprising 98 patients suffering from neurosarcoidosis, 525 non-sarcoidosis patients, and 118 healthy controls. Included studies were published between 2010 and 2023. Cerebrospinal fluid (CSF) sIL-2R levels differed significantly between neurosarcoidosis patients and multiple sclerosis, vasculitis, and healthy controls whereas serum sIL-2R levels did not reveal sufficient discriminative power. sIL-2R index was able to discriminate neurosarcoidosis from neurotuberculosis, bacterial/viral meningitis, and healthy controls. In this systematic review, we found indications that sIL-2R may be a useful biomarker for the diagnosis of neurosarcoidosis. To determine an additional diagnostic value of sIL-2R, large prospective studies are needed that not only examine absolute sIL-2R levels in serum or CSF but also the dynamic changes as well as the implications of renal function on sIL-2R levels.

Low echogenicity of Hashimoto's disease could be useful in detecting early phase of thyroid lymphomas, especially diffuse large B cell lymphomas

BackgroundHashimoto's disease, characterized by low echogenicity on ultrasonography, is associated with thyroid lymphomas. Most thyroid lymphomas are diffuse large B cell lymphomas (DLBCLs) and mucosa-associated lymphoid tissue (MALT) lymphomas. DLBCLs have a worse prognosis than MALT lymphomas. This study aimed to evaluate the early signs, especially the low echogenicity, of Hashimoto's disease and thyroid lymphomas. MethodsThis retrospective cohort study was conducted at Noguchi Thyroid Clinic and Hospital Foundation. A total of 9008 cases were operated on between 2008 and 2016, of which 162 had operated with suspected thyroid lymphoma, because of low echogenicity and aspiration biopsy cytology. The final diagnosis revealed 28 Hashimoto's disease, 134 thyroid lymphomas (91 MALT lymphomas and 43 DLBCLs). The primary outcomes were clinicopathological characteristics including low echogenicity of the thyroid. Early signs of thyroid lymphomas, especially DLBCLs were also investigated. ResultsAge, echo pattern, echogenicity anti-thyroid peroxidase antibody (TPOAb) and lactate dehydrogenase (LDH) were significantly different between Hashimoto's disease and thyroid lymphomas. Echogenicity, echo pattern and age were significant early signs of thyroid lymphomas. Age, echogenicity, soluble interleukin-2 receptor (IL2R), lactate dehydrogenase (LDH), and the neutrophil-to-lymphocyte ratio were significantly different between MALT lymphomas and DLBCLs. Echogenicity, and IL2R were significant early signs of DLBCL. The ROC analysis of low echogenicity for thyroid lymphomas compared to Hashimoto's disease revealed that Area Under the Curve (AUC) was 0.80 and the ROC analysis for DLBCL compared to Hashimoto's disease and MALT lymphoma revealed that the AUC was 0.73. ConclusionsLow echogenicity of Hashimoto's disease could be a useful early sign of thyroid lymphomas, especially DLBCL. Data availabilityThe data that supports the findings of this study are available in the supplementary material of this article.

Clinical Characteristics Analysis of EBV-associated Hemophagocytic Lymphohistiocytosis Patients with Acute Kidney Injury

To analyze the clinical characteristics of patients with Epstein-Barr virus(EBV)-associated hemophagocytic lymphohistiocytosis(HLH) with acute kidney injury(AKI). EBV-HLH patients who were hospitalized in our hospital from January 2014 to December 2020 were collected, and their clinical characteristics, treatment, concurrent acute kidney injury and prognosis were retrospectively analyzed. In this study, the incidence of AKI complicated by EBV-HLH was 65.5%, and the 28-day mortality rate was 15.3%. Compared with non-AKI group, patients in the AKI group had higher levels of bilirubin, lactate dehydrogenase, creatinine, urea nitrogen, and β2-microglobulin（β2-MG）, poorer coagulation, and lower soluble IL-2 receptor （sCD25）. Patients in the AKI group had a higher proportion of chemotherapy, transplantation, mechanical ventilation, and the application of vasoactive medications, and were hospitalized for longer periods of time, with higher in-hospital mortality rates and 28-day mortality rates. Patients in the AKI group were analyzed in subgroups according to the Kidney Disease Improving Global Outcomes （KDIGO）classification, and the levels of leukocytes, bilirubin, albumin, creatinine, urea nitrogen, β2-MG, activated partial thromboplastin time （APTT）, and prothrombin time activity （PTA）were more responsive to the severity of the patient's condition. KDIGO grade 2 and 3 had higher proportions of receiving transplants, diuretics, organ support (mechanical ventilation, application of vasoactive medications, and renal replacement therapy), and admissions to the intensive care unit （ICU）, and with higher in-hospital mortality rates and 28-day mortality rates. Regression analysis found that creatinine, β2-MG, APTT, transplantation, and chemotherapy were independent risk factors for the development of AKI; the application of vasoactive drugs was both an independent risk factor for the development of AKI and for death at 28 days; and chemotherapy, length of hospitalization, and HGB and fibrinogen levels were protective factors for death at 28 days. AKI in EBV-HLH has high incidence and high rate of progression to severe disease and death, early attention should be given and strengthened in order to carry out early treatment and improve the prognosis of patients.

Pathway-Based Mendelian Randomization for Pre-Infection IL-6 Levels Highlights Its Role in Coronavirus Disease.

Interleukin 6 (IL-6) levels at hospital admission have been suggested for disease prognosis, and IL-6 antagonists have been suggested for the treatment of patients with severe COVID-19. However, less is known about the relationship between pre-COVID-19 IL-6 levels and the risk of severe COVID-19. To fill in this gap, here we extensively investigated the association of genetically instrumented IL-6 pathway components with the risk of severe COVID-19. We used a two-sample Mendelian randomization study design and retrieved genetic instruments for blood biomarkers of IL-6 activation, including IL-6, soluble IL-6 receptor, IL-6 signal transducer, and CRP, from respective large available GWASs. To establish associations of these instruments with COVID-19 outcomes, we used data from the Host Genetics Initiative and GenOMICC studies. Our analyses revealed inverse associations of genetically instrumented levels of IL-6 and its soluble receptor with the risk of developing severe disease (OR = 0.60 and 0.94, respectively). They also demonstrated a positive association of severe disease with the soluble signal transducer level (OR = 1.13). Only IL-6 associations with severe COVID-19 outcomes reached the significance threshold corrected for multiple testing (p < 0.003; with COVID-19 hospitalization and critical illness). These potential causal relationships for pre-COVID-19 IL-6 levels with the risk of developing severe symptoms provide opportunities for further evaluation of these factors as prognostic/preventive markers of severe COVID-19. Further studies will need to clarify whether the higher risk for a severe disease course with lower baseline IL-6 levels may also extend to other infectious diseases.

Impact of Interleukin-6 Activation and Arthritis on Epidermal Growth Factor Receptor (EGFR) Activation in Sensory Neurons and the Spinal Cord.

In tumor cells, interleukin-6 (IL-6) signaling can lead to activation of the epidermal growth factor receptor (EGFR), which prolongs Stat3 activation. In the present experiments, we tested the hypothesis that IL-6 signaling activates EGFR signaling in peripheral and spinal nociception and examined whether EGFR localization and activation coincide with pain-related behaviors in arthritis. In vivo in anesthetized rats, spinal application of the EGFR receptor blocker gefitinib reduced the responses of spinal cord neurons to noxious joint stimulation, but only after spinal pretreatment with IL-6 and soluble IL-6 receptor. Using Western blots, we found that IL-6-induced Stat3 activation was reduced by gefitinib in microglial cells of the BV2 cell line, but not in cultured DRG neurons. Immunohistochemistry showed EGFR localization in most DRG neurons from normal rats, but significant downregulation in the acute and most painful arthritis phase. In the spinal cord of mice, EGFR was highly activated mainly in the chronic phase of inflammation, with localization in neurons. These data suggest that spinal IL-6 signaling may activate spinal EGFR signaling. Downregulation of EGFR in DRG neurons in acute arthritis may limit nociception, but pronounced delayed activation of EGFR in the spinal cord may be involved in chronic inflammatory pain.