Soluble interleukin-6 receptor in the COVID-19 cytokine storm syndrome.

Data suggest that interleukin (IL)-6 blockade could reduce mortality in severe COVID-19, yet IL-6 is only modestly elevated in most patients. Chen et al. describe the role of soluble interleukin-6 receptor (sIL-6R) in IL-6 trans-signaling and how understanding the IL-6:sIL-6R axis might help define and treat COVID-19 cytokine storm syndrome.

99mTechnetium- or Cy7-Labeled Fab(Tocilizumab) as Potential Multiple Myeloma Imaging Agents.

BACKGROUND: Multiple Myeloma (MM) is a malignant hematologic disorder and the second most common blood cancer. Interleukin-6 (IL-6) has been identified as a crucial factor for the proliferation and survival of MM cells and the overexpression of IL-6 receptor is being studied as a molecular target for therapeutic and diagnostic use in myelomas and other comorbidities. Tocilizumab is a humanized monoclonal antibody that binds IL-6R. OBJECTIVE: We aim to label and evaluate Fab(Tocilizumab) with 99mTechnetium or Cy7 as potential MM imaging agents. METHODS: IL-6R distribution was analyzed by Laser Confocal Microscopy (LCM) in MM cell lines. Fab(Tocilizumab) was produced by the digestion of Tocilizumab with papain for 24h at 37°C, derivatized with NHS-HYNIC-Tfa and radiolabeled with 99mTc. Radiochemical stability and in vitro cell assays were evaluated. Biodistribution and SPECT/CT were performed. Also, Fab(Tocilizumab) was labeled with Cy7 for in vivo fluorescence imaging up to 72h. RESULTS: LCM analysis demonstrates IL-6R distribution on MM cell lines. Incubation with papain resulted in complete digestion of Tocilizumab and exhibited a good purity and homogeneity. Radiolabeling with 99mTc via NHS-HYNIC-Tfa was found to be fast, easy, reproducible and stable, revealing high radiochemical purity and without interfering with IL-6R recognition. Biodistribution and SPECT/CT studies showed a quick blood clearance and significant kidney and MM engrafted tumor uptake. Cy7-Fab(Tocilizumab) fluorescent imaging allowed MM1S tumor identification up to 72h p.i. CONCLUSION: These new molecular imaging agents could potentially be used in the clinical setting for staging and follow-up of MM through radioactive whole-body IL-6R expression visualization in vivo. The fluorescent version could be used for tissue sample evaluation and to guide surgical excision, if necessary.

Systemic lupus erythematosus is associated with impaired autophagic degradation via interleukin-6 in macrophages.

Systemic lupus erythematosus (SLE) is an autoimmune disease associated with dysregulated interleukin (IL)-6 and autophagy. Although such disturbances are increasingly recognized in patients with SLE and animal models of the disease, little is known about the specific role of IL-6 and autophagy in SLE macrophages. Here, we investigated alterations in the IL-6 axis and autophagy in macrophages derived from patients with SLE and determined whether IL-6 modulates autophagy using human macrophage models. Serum IL-6 detected by ELISA was higher in SLE patients (n = 19) than in normal controls (n = 19, p < 0.001). Levels of the IL-6 receptor (IL-6R) and autophagic markers LC3B and p62 in SLE and normal macrophages were assessed by real-time PCR, western blotting, and immunofluorescence. Compared with normal macrophages, SLE macrophages not only overexpressed IL-6Rs but also exhibited impaired autophagic degradation as evidenced by elevated levels of LC3B and p62. In vitro analyses using macrophage models revealed that prolonged exposure to exogenous recombinant human IL-6 induced a marked impairment of autophagic degradation indicated by elevated levels of LC3B and p62 in both primary macrophages and transformed macrophages. Pretreatment with tocilizumab, a humanized anti-IL-6R monoclonal antibody, restored autophagic degradation and reversed p62 accumulation in a paracrine manner in macrophages. These findings demonstrate that SLE involves IL-6-induced impairment of autophagic degradation through augmentation of IL-6R in human macrophages.

Biosensing Cytokine IL-6: A Comparative Analysis of Natural and Synthetic Receptors.

Cytokines are a family of proteins which play a major role in the regulation of the immune system and the development of several diseases, from rheumatoid arthritis to cancer and, more recently, COVID-19. Therefore, many efforts are currently being developed to improve therapy and diagnosis, as well as to produce inhibitory drugs and biosensors for a rapid, minimally invasive, and effective detection. In this regard, even more efficient cytokine receptors are under investigation. In this paper we analyze a set of IL-6 cytokine receptors, investigating their topological features by means of a theoretical approach. Our results suggest a topological indicator that may help in the identification of those receptors having the highest complementarity with the protein, a feature expected to ensure a stable binding. Furthermore, we propose and discuss the use of these receptors in an idealized experimental setup.

YKL-40 levels are associated with disease severity and prognosis of viral pneumonia, but not available in bacterial pneumonia in children.

BACKGROUND: Viral pneumonia is the main type of community-acquired pneumonia (CAP) in children. YKL-40, a chitinase-like protein, is regarded as a biomarker of the degree of inflammation. METHODS: Children who were diagnosed with CAP, including viral pneumonia, bacterial pneumonia, and dual infection, were included in the cohort study. The pathogenic diagnosis depended on PCR and immunoassay test. YKL-40 levels were examined twice by enzyme-linked immunoassay (ELISA). RESULTS: Serum YKL-40 levels were higher in patients with pneumonia than in healthy controls. The admission levels of YKL-40 in serum and Bronchoalveolar lavage (BALFs) indicated a positive correlation with the serum levels of C-reactive protein and other inflammatory cytokines (IL-6 and TNF-α). The disease severity have no correlation with the admission serum levels of YKL-40. Meanwhile, reductions in YKL-40 levels from initial admission levels to day 5 post-admission were correlated with disease severity. The multiple logistic analysis indicated the decreased extent of serum YKL-40 level as an independent prognostic predictor of severe cases in patients with viral pneumonia. CONCLUSIONS: Reductions in serum YKL-40 levels on day 5 after receiving therapy is a possible prognostic biomarker for children with viral pneumonia.

A pilot study to profile salivary angiogenic factors to detect head and neck cancers.

BACKGROUND: Early diagnosis of head and neck squamous cell carcinoma (HNSCCs) is an appealing way to increase survival rates in these patients as well as to improve quality of life post-surgery. Angiogenesis is a hallmark of tumor initiation and progression. We have investigated a panel of angiogenic factors in saliva samples collected from HNSCC patients and controls using the Bio-Plex ProTM assays. METHODS: We have identified a panel of five angiogenic proteins (sEGFR, HGF, sHER2, sIL-6Ra and PECAM-1) to be elevated in the saliva samples collected from HNSCC patients (n = 58) compared to a control cohort (n = 8 smokers and n = 30 non-smokers). RESULTS: High positive correlations were observed between the following sets of salivary proteins; sEGFR:sHER2, sEGFR:HGF, sEGFR:sIL-6Rα, sHER2:HGF and sHER2:sIL6Ra. A moderate positive correlation was seen between FGF-basic and sEGFR. CONCLUSION: We have shown that angiogenic factor levels in saliva can be used as a potential diagnostic biomarker panel in HNSCC.

The regulatory role of IL-6R in hepatitis B-associated fibrosis and cirrhosis.

This study investigated the expression and regulation of IL-6R in hepatitis B-associated moderate hepatic fibrosis and cirrhosis. Liver tissues, peripheral blood monocytes (PBMs) and serum were collected from 26 hepatitis B patients with liver fibrosis and 35 hepatitis B patients with liver cirrhosis. The levels of Il-6r mRNA expression in these samples were examined by quantitative real-time PCR and IL-6R protein levels were analyzed by western blot and ELISA. MiRNAs that regulate IL-6R expression were predicted by bioinformatics analysis, and validated by dual luciferase reporter assay. Compared with the hepatic fibrosis group, IL-6R was significantly upregulated at both mRNA and protein levels in liver tissues, PBMs and serum samples from the hepatic cirrhosis group (P<0.05). The 3'UTR of Il-6r mRNA was predicted to contain a miR-30b binding site and IL-6R was identified as a possible target of miR-30b. MiR-30b expression was significantly downregulated in samples from hepatic cirrhosis patients compared with hepatic fibrosis patients (P<0.05). In conclusion, IL-6R was upregulated while miR-30b was decreased in patients with liver cirrhosis. The miR-30 can directly regulate the expression of IL-6R.

The regulatory role of IL-6R in hepatitis B-associated fibrosis and cirrhosis

This study investigated the expression and regulation of IL-6R in hepatitis B-associated moderate hepatic fibrosis and cirrhosis. Liver tissues, peripheral blood monocytes (PBMs) and serum were collected from 26 hepatitis B patients with liver fibrosis and 35 hepatitis B patients with liver cirrhosis. The levels of Il-6r mRNA expression in these samples were examined by quantitative real-time PCR and IL-6R protein levels were analyzed by western blot and ELISA. MiRNAs that regulate IL-6R expression were predicted by bioinformatics analysis, and validated by dual luciferase reporter assay. Compared with the hepatic fibrosis group, IL-6R was significantly upregulated at both mRNA and protein levels in liver tissues, PBMs and serum samples from the hepatic cirrhosis group (P<0.05). The 3′UTR of Il-6r mRNA was predicted to contain a miR-30b binding site and IL-6R was identified as a possible target of miR-30b. MiR-30b expression was significantly downregulated in samples from hepatic cirrhosis patients compared with hepatic fibrosis patients (P<0.05). In conclusion, IL-6R was upregulated while miR-30b was decreased in patients with liver cirrhosis. The miR-30 can directly regulate the expression of IL-6R.

Associations Between Delirium and Preoperative Cerebrospinal Fluid C-Reactive Protein, Interleukin-6, and Interleukin-6 Receptor in Individuals with Acute Hip Fracture.

OBJECTIVES: To examine whether delirium in individuals with hip fracture is associated with high C-reactive protein (CRP), interleukin-6 (IL-6), and soluble IL-6 receptor (sIL-6R) levels in the cerebrospinal fluid (CSF). DESIGN: Prospective cohort study. SETTING: Two university hospitals in Oslo, Norway, and Edinburgh, United Kingdom. PARTICIPANTS: Individuals admitted with acute hip fracture (N = 151). MEASUREMENTS: Participants were assessed for delirium pre- and postoperatively using the Confusion Assessment Method. Prefracture cognitive impairment was detected using the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE). Serum was collected preoperatively and CSF just before the onset of spinal anesthesia. Cytokine levels in serum and CSF samples were determined using an enzyme-linked immunosorbent assay. Student t-tests or Mann-Whitney U-tests were used for between-group comparisons. Spearman rho was used for correlations. RESULTS: Sixty participants had prior cognitive impairment (IQCODE score ≥3.44). Delirium was diagnosed in 46 participants (77%) with prior cognitive impairment and 25 (29%) without. In participants without prior cognitive impairment, CSF CRP levels were higher in participants with delirium (median 0.05 µg/mL, interquartile range (IQR) 0.02-0.12 µg/mL) than in those without delirium (median 0.01 µg/mL, IQR 0.00-0.06 µg/mL) (P = .01); there were no differences in participants with prior cognitive impairment. In secondary analyses, in participants with prior cognitive impairment, the concentration of CSF sIL-6R was higher in those participants who developed delirium than in the other subgroups, but this difference was not statistically significant. Serum levels of CRP, IL-6, and sIL-6R were not different according to delirium in participants with or without prefracture cognitive impairment. CONCLUSION: High CSF levels of CRP and sIL-6R may be associated with delirium. Different pathophysiological mechanisms may operate in different subgroups, notably in relation to the presence of prior cognitive impairment.

Reduced corticosteroid-binding globulin cleavage in active rheumatoid arthritis.

OBJECTIVE: Corticosteroid-binding globulin (CBG), the cortisol transport protein, is cleaved from high-affinity (haCBG) to low-affinity (laCBG) CBG at sites of inflammation releasing bioavailable, anti-inflammatory cortisol. Rheumatoid arthritis (RA) is a glucocorticoid-responsive disorder, with paradoxically normal cortisol levels despite elevated inflammatory mediators. Our objective was to determine whether CBG cleavage relates to RA disease activity. We hypothesized that impaired CBG cleavage may limit delivery of free cortisol to inflamed joints in RA. DESIGN: Prospective, cross-sectional observational study. SETTING AND PARTICIPANTS: Fifty-three patients with RA recruited from a Rheumatology outpatient clinic at a tertiary referral centre in Adelaide, Australia, and 73 healthy controls. MEASUREMENTS: Total CBG, haCBG and laCBG, total, free and salivary cortisol, inflammatory markers including interleukin-6 soluble receptor (IL-6sR) and macrophage migration inhibitory factor and clinical measures of disease activity. RESULTS: Among patients with RA, a wide range of disease activity scores was observed (DAS28: range 1·2-6·4). laCBG was lower in patients with RA (mean ± SEM); 153 ± 9, compared with healthy controls; 191 ± 8 nmol/l, P = 0·003. Levels of total and haCBG were higher in patients with more severe RA disease activity. Free and total cortisol, free cortisol:IL-6sR ratio and total cortisol:IL-6sR ratio correlated negatively with disease activity. CONCLUSIONS: These results suggest that patients with RA have reduced CBG cleavage compared to healthy controls and that cleavage is reduced further with higher RA disease activity. Hence, impaired CBG-mediated delivery of endogenous cortisol may perpetuate chronic inflammation in RA.

Prognostic value of interleukin-6 and interleukin-6 receptor in organ-confined clear-cell renal cell carcinoma: a 5-year conditional cancer-specific survival analysis.

BACKGROUND: Interleukin-6 (IL-6) is the major cytokine that induces transcriptional acute and chronic inflammation responses, and was recently incorporated as a recurrence prognostication signature for localised clear-cell renal cell carcinoma (ccRCC). As the prognostic efficacy of initial risk factors may ebb during long-term practice, we aim to report conditional cancer-specific survival (CCSS) of RCC patients and evaluate the impact of IL-6 as well as its receptor (IL-6R) to offer more relevant prognostic information accounting for elapsing time. METHODS: We enrolled 180 histologically proven localised ccRCC patients who underwent nephrectomy between 2001 and 2004 with available pathologic information. Five-year CCSS was determined and stratified by future prognostic factors. Constant Cox regression analysis and Harrell's concordance index were used to indicate the predictive accuracy of established models. RESULTS: The 5-year CCSS of organ-confined ccRCC patients with both IL-6- and IL-6R-positive expression was 52% at year 2 after surgery, which was close to locally advanced patients (48%, P=0.564) and was significantly poorer than organ-confined patients with IL-6- or IL-6R-negative expression (89%, P<0.001). Multivariate analyses proved IL-6 and IL-6R as independent predictors after adjusting for demographic factors. Concordance index of pT-IL-6-IL-6R risk stratification was markedly higher compared with the stage, size, grade and necrosis prognostic model (0.724 vs 0.669, P=0.002) or UCLA Integrated Staging System (0.724 vs 0.642, P=0.007) in organ-confined ccRCC population during the first 5 years. CONCLUSIONS: Combined IL-6 and IL-6R coexpression emerges as an independent early-stage immunologic prognostic factor for organ-confined ccRCC patients.

Meta-Analysis of Cytokines and Chemokines in Suicidality: Distinguishing Suicidal Versus Nonsuicidal Patients.

BACKGROUND: Major psychiatric disorders are associated with inflammation. Aberrant cytokine and chemokine levels have been associated with psychiatric disorders and suicidal behavior. We performed a meta-analysis of cytokine and chemokine levels in patients with versus without suicidality and patients with suicidality versus healthy controls. METHODS: We identified articles by searching MEDLINE, PsycINFO, and Thomson Reuters Web of Knowledge databases and the reference lists of identified studies. RESULTS: Study inclusion criteria were met by 18 studies comprising 583 patients with suicidality, 315 patients without suicidality, and 845 healthy control subjects. Levels of interleukin (IL)-1ß and IL-6 were significantly increased in blood and postmortem brain samples of patients with suicidality compared with both patients without suicidality and healthy control subjects (p < .05 for each). In vitro IL-2 production by peripheral blood mononuclear cells was significantly decreased in patients with suicidality compared with both patients without suicidality and healthy controls (p < .01 for each). Cerebrospinal fluid levels of IL-8 were significantly decreased in patients with suicidality versus control subjects (p < .05). CONCLUSIONS: We found evidence for aberrant cytokine levels in blood, cerebrospinal fluid, and postmortem brain samples of patients with suicidality. Levels of IL-1ß and IL-6 were most robustly associated with suicidality, and these cytokines may help distinguish suicidal from nonsuicidal patients. Rigorously designed longitudinal studies are needed to evaluate these associations further.

Effects of obesity on the association between long-term sleep apnea treatment and changes in interleukin-6 levels: the Icelandic Sleep Apnea Cohort.

The aim of this study was to evaluate changes in interleukin (IL)-6 and soluble IL-6 receptor levels in obstructive sleep apnea patients and assess the role of positive airway pressure treatment and obesity on these changes. A total of 309 newly diagnosed subjects with sleep apnea from the Icelandic Sleep Apnea Cohort were referred for treatment and reassessed at a 2-year follow-up. Full treatment was defined objectively as use ≥ 4 h day(-1) and ≥ 20 days month(-1). At the 2-year follow-up, there were 177 full users, 44 partial users and 88 non-users. The mean change in biomarker levels from baseline to the 2-year follow-up was assessed in a primary model that included adjustment for baseline biomarker levels, baseline body mass index and change in body mass index, as well as after adjustment for numerous relevant covariates. No significant overall difference in IL-6 level change was found among full, partial and non-users. However, in severely obese patients (body mass index ≥ 35), a significant increase in IL-6 levels during the 2-year period was found in partial and non-users, compared to no change in full users. Results were attenuated in a smaller propensity score matched subsample, although similar trends were observed. No differences were found in soluble IL-6 receptor levels between full users and non-users, after adjustment for confounders. In conclusion, among untreated obese sleep apnea patients, IL-6 levels increase substantially during 2 years, while adherence to positive airway pressure treatment may prevent further increases in this inflammatory biomarker.

The effect of IL-17 on the production of proinflammatory cytokines and matrix metalloproteinase-1 by human periodontal ligament fibroblasts.

OBJECTIVES: To investigate the effects of IL-17 on IL-6, IL-1ß, and matrix metalloproteinase (MMP-1) production, and to compare the MMP-1 production between the individual and combined effects of IL-1ß and IL-6 in human periodontal ligament fibroblasts (HPDLF). MATERIALS AND METHODS: Human periodontal ligament fibroblasts were cultured with IL-17 for 0.5, 1, 4, 24, 48, and 72 h, and were cultured with IL-1ß, IL-6/sIL-6R, or a combination of IL-1ß and IL-6/sIL-6R for 24 h. To measure the mRNA levels of IL-6, IL-1ß, and MMP-1, total RNA was extracted from the cultured HPDLF, and a real-time PCR analysis was performed. The protein levels of IL-6, IL-1ß, and MMP-1 in supernatants were measured using enzyme-linked immunosorbent assays (ELISAs). RESULTS: IL-17 significantly increased the expression of IL-6 and MMP-1 mRNA and protein, while IL-17 transiently increased the expression of IL-1ß mRNA. The combination of IL-1ß and IL-6/sIL-6R induced significantly higher levels of MMP-1 protein than IL-1ß alone. CONCLUSIONS: IL-17 upregulated the production of IL-6 and MMP-1 sequentially in HPDLF. IL-6/sIL-6R may enhance the effects of IL-1ß on MMP-1 production. The present results suggest that IL-17 induces MMP-1 production not only directly, but also indirectly by promoting IL-6 production, thus resulting in the degradation of collagens in the PDL.

Expression of monocyte subsets and angiogenic markers in relation to carotid plaque neovascularization in patients with pre-existing coronary artery disease and carotid stenosis.

AIM: To characterize blood monocyte subsets in patients with different degrees of carotid atherosclerosis and pathological carotid plaque neovascularization. METHODS: Assessment of carotid plaque neovascularization using contrast ultrasonography and flow cytometric quantification of monocyte subsets and their receptors involved in inflammation, angiogenesis, and tissue repair was done in 40 patients with carotid stenosis ≥ 50% and CAD (CS > 50), 40 patients with carotid stenosis < 50% and documented CAD (CS < 50), 40 hypercholesterolaemic controls (HC group), and 40 normocholesterolaemic controls (NC). RESULTS: CS > 50 and CS < 50 groups had increased counts of Mon1 ('classical' CD14++ CD16-CCR2 + cells) compared to HCs (P = 0.03, and P = 0.009). Mon3 ('non-classical' CD14 + CD16++ CCR2- cells) were only increased in CS < 50 compared with HCs (P < 0.01). Both CS>50 and CS < 50 groups showed increased expression of proinflammatory interleukin-6 receptor on Mon1 and Mon2 ('intermediate' CD14++ CD16 + CCR2+ cells); TLR4, proangiogenic Tie2 on all subsets (P < 0.01 for all). In multivariate regression analysis only high Mon1 count was a significant predictor of carotid stenosis (P = 0.04) and intima-media thickness (P = 0.02). In multivariate regression analysis only the Mon1 subset was significantly associated with severe, grade 2 neovascularization (P = 0.034). CONCLUSION: In this pilot study classical monocytes (Mon1) represent the only monocyte subset predictive of the severity of carotid and systemic atherosclerosis, such as carotid intima-media thickness, degree of carotid stenosis, and presence of carotid intraplaque neovascularization.

Biological markers in cord blood for prediction of bronchopulmonary dysplasia in premature infants.

OBJECTIVE: The current study aims to determine the contents of biological markers in cord blood and to investigate their feasibility as the predictive indices of bronchopulmonary dysplasia (BPD) in premature infants. MATERIALS AND METHODS: Cord blood was collected from 134 premature infants that had birth weight < or = 1500 g and gestational age (GA) < or = 32 weeks at the time of birth. The contents of IL-6, IL-6R, Sgp130, and MMP-9 were determined. Infants' clinical data, as well as their mothers' placental pathological data were also collected. Infants with BPD constituted the BPD group, whereas those without BPD comprised the non-BPD (NBPD) group. Differences in the contents of the biological markers between the groups were analyzed to investigate the correlations of these markers with BPD, and then biological markers that can serve as the predictive factors of BPD were defined. RESULTS: GA was negatively correlated with BPD. IL-6, IL-6R, and Sgp130 in the BPD group was higher than those in the NBPD group, whereas MMP-9 in the BPD group was lower than that in the NBPD group. IL-6 was positively correlated with BPD and therefore had a predictive effect on BPD. Sgp130 had a collinear correlation with IL-6, which had a predictive effect on BPD as well. When GA was < 30 weeks and IL-6 was > 46.125 pg/ml, the sensitivity, specificity, and area under curve were 1, 0.59, and 0.849, respectively, indicating a good predictive effect on BPD. CONCLUSION: IL-6 and Sgp130 can serve as the independent predictive cytokines of BPD.

Pro-inflammatory cytokine associated with somatic and pain symptoms in depression.

BACKGROUND: More than two-thirds of depressed patients complain of somatic and pain symptoms, which are frequently regarded as a psychological reaction. Although there is a growing body of evidence showing that depression is related to immune abnormalities, few studies have investigated the association between inflammatory cytokines and somatic/pain symptoms. METHOD: Patients with depressive disorder but without any medical disorders, and age/gender/body mass index (BMI)-matched healthy subjects were enrolled. All the subjects completed the self-rating scales of the Beck Depression Inventory-II and the Depression and Somatic Symptoms Scale, which was comprised of depressive, somatic, and pain subscales. Pro-inflammatory cytokines, including C-reactive protein (CRP), interleukin-2 receptor (sIL-2R), soluble interleukin 6 receptor (sIL-6R), soluble TNF-receptors (sTNF-R), soluble P-selectin (sP-selectin), monocyte chemotactic protein-1 (MCP-1), and adiponectin, were assessed by enzyme-linked immunosorbent assays. RESULTS: In all, 109 patients with depressive disorder and 126 normal controls were enrolled. The patients with depressive disorder had significantly more severe depression, somatic and pain symptoms (all p<0.001), and higher levels of sIL-2R (p<0.0001), sTNF-R (p<0.001), and sP-selectin (p=0.005) than the normal control group. Using multivariate regression analysis with controlling of age, gender, BMI, and other pro-inflammatory cytokines, sIL-2R was the most significant predictor for depressive symptoms (p<0.0001); with further controlling of severity of depressive symptom, sP-selectin was the only predictor for somatic (p=0.002) and pain (p=0.059) symptoms. CONCLUSION: The elevated sP-selectin associated with somatic symptoms in depression, may indicate early micro-vascular changes occur subtly, and provide neurobiological evidence for somatic and pain symptom in depression.

Tocilizumab: a review of its use in the treatment of juvenile idiopathic arthritis.

Tocilizumab (RoActemra(®); Actemra(®)) is a recombinant humanized monoclonal antibody that acts as an interleukin-6 receptor antagonist. Both in the US and EU, tocilizumab has been approved for the treatment of two subtypes of juvenile idiopathic arthritis (JIA), namely systemic JIA (sJIA) and polyarticular JIA (pJIA), in patients aged ≥2 years. These approvals are based on favorable results from two randomized, double-blind, placebo-controlled, multinational, phase III trials in which patients aged 2-17 years with active sJIA (TENDER) or pJIA (CHERISH) received an intravenous dose of tocilizumab based on bodyweight every 2 or 4 weeks, respectively. Tocilizumab met the primary endpoint in both of these ongoing, multi-part studies. That is, in TENDER, significantly more tocilizumab recipients than placebo recipients achieved a JIA American College of Rheumatology (ACR) 30 response plus absence of fever, as assessed at the end of a 12-week double-blind treatment period, while in CHERISH, significantly fewer tocilizumab recipients than placebo recipients experienced a JIA ACR 30 flare during a 24-week double-blind withdrawal period (all patients had previously received open-label tocilizumab in a 16-week lead-in phase). Tocilizumab was generally well tolerated in the TENDER trial. Infections (e.g. upper respiratory tract infection and pharyngitis or nasopharyngitis) accounted for just over one-third of all reported adverse events in this trial; tocilizumab-treated patients appeared to have an approximately 11 % risk of a serious infection per year of treatment. Clinical laboratory abnormalities included neutropenia and elevated aminotransferase levels. The tolerability profile of tocilizumab in CHERISH was generally consistent with that of the drug in TENDER.

Role of interleukin-6, its receptor and soluble gp130 in chronic lung disease of prematurity.

BACKGROUND: Interleukin-6 (IL-6) signalling involves the interplay between IL-6, soluble IL-6 receptor (sIL-6R) and soluble gp130 (sgp130). IL-6 activity is modulated by the soluble receptors to produce both pro- and anti-inflammatory effects in human diseases and animal models. The expression and functional activity of these molecules in lungs of preterm ventilated infants is unknown. OBJECTIVES: We investigated this pathway in preterm infants who were at risk of developing chronic lung disease of prematurity (CLD). METHODS: Cytokines and soluble receptors were measured in bronchoalveolar lavage fluid (BALF) from ventilated preterm infants ≤32 weeks of gestation who did or did not develop CLD. B9 cells, which specifically proliferate to IL-6, were used to assess BALF IL-6 functional activity. RESULTS: Inflammatory cells, IL-8 and monocyte chemotactic protein-1 were increased in BALF from the CLD group when compared to the No CLD group (p < 0.05). BALF IL-6 and sIL-6R were similar in both groups. In contrast, BALF sgp130 and sgp130/sIL-6R were greater in the CLD group when compared to the No CLD group (p = 0.01 and p = 0.02, respectively). However, the increased BALF sgp130 did not appear to modulate the BALF IL-6 functional activity. CONCLUSION: Lung inflammation was observed in the CLD group. Increased BALF sgp130 was noted in the CLD group but it did not appear to modulate the pulmonary IL-6 bioactivity. Further research is needed to investigate the potential modulatory activity of sgp130 in the preterm lung.