Higher sIL-2R Levels Research Articles

Аутоантитела, иммуноглобулины и цитокиновый профиль у пациентов с болезнью Грейвса и эндокринной офтальмопатией

BACKGROUND : Graves' Orbitopathy (GO) — also known as Thyroid Eye Disease (TED) — is an autoimmune condition in the modern sense. It is closely associated with autoimmune thyroid diseases. Cytokine-mediated mechanisms play a critical part in immunopathogenesis of autoimmune thyroid diseases including GO. Investigating cytokine profiles as well as antibodies to tissue-specific antigens is essential for explaining GO pathogenesis and developing future therapeutic strategies. AIMS : The study examines serum levels of cytokines, autoantibodies and immunoglobulins IgG and IgG4 as mediators of autoimmune inflammation in patients with GO and Graves' Disease (GD). MATERIALS AND METHODS : The study included 52 patients (104 orbits) aged 25-70 years (mean age 48,8±12,3) in the active phase of GO and GD verified with the international diagnostic standards. These patients did not get any treatment for GO before. The control group consisted of 14 individuals (28 orbits) aged 30-68 years without known autoimmune disease. Serum levels of IgG, IgG4,TNFα, IL-1α, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-17A, IL-13, sIL-6R, sTNFα- RI и TNFα- R2 IL-2R, TGFβ1, TGF β3, antibodies to TSH-receptor, free T4, free T3 and TSH were measured. A diagnostic ultrasound exam of thyroid gland, multislice computed tomography (MSCT) / magnetic resonance imaging (MRI) of orbits were performed. RESULTS : Mean duration of GO prior to being admitted to the centre was 8,8±1,5 months (range: 1 — 48 months). According to the degree of thyrotoxicosis compensation: 24 patients were clinically euthyroid, TSH 3,3±0,7 mU/L, free T4 11,9±0,59 pmol/L, free T3 3,97±0,1 pmol/L; 28 patients were considered to have subclinical thyrotoxicosis: TSH 0,03±0,01 mU/L, free T4 14,2±1,0 pmol/L, free T3 5,77±0,49 pmol/L. Serum levels of sTNFα-R2 (p=0,041, p≤0,05), sIL-2R (p=0,020, p≤0,05), TGFβ1 (p=0,000, p≤0,001) were significantly higher in patients with GO compared to the control group. Serum levels of sTNFRα2 (p=0,038, p 5%). CONCLUSION : High levels of soluble cytokine receptors sTNFα-R2 and sIL-2R and cytokine TGFβ1 in patients with long-standing untreated GO and GD being euthyroid or having subclinical thyrotoxicosis indicate activation of regulatory T cells aimed at suppressing autoimmune processes. High concentration level of IgG4 in IgG and cytokine TGFβ1 can determine the development of fibrotic changes in the orbital tissues. A decrease in the concentration of cytokine TGFβ1 can indicate an unfavorable course of the disease GO.

Serum Soluble Interleukin-2 Receptor Does Not Differentiate Complex Regional Pain Syndrome from Other Pain Conditions in a Tertiary Referral Setting.

Previously, we showed that serum soluble interleukin-2 receptor (sIL-2R) levels, a marker for T-cell activation, were higher in complex regional pain syndrome (CRPS) patients than in healthy controls, suggesting pathogenic T-cell activation in CRPS. Additionally, sIL-2R levels discriminated well between CRPS and healthy controls with a high sensitivity (90%) and specificity (89.5%), suggesting a possible role for sIL-2R in the diagnosis of CRPS. In order to further validate this marker in the diagnostic workup of CRPS, we conducted this prospective cohort study in which we determined sIL-2R levels in patients that were referred to our tertiary referral center with a suspicion of CRPS in a limb, and subsequently compared sIL-2R levels between the patients that were diagnosed with CRPS (CRPS group) and those who were not (no CRPS group). A group of anonymous blood bank donors were used as a healthy control group. Furthermore, we explored the relationship between sIL-2R and CRPS disease severity using the CRPS severity score. Median sIL-2R levels of both the CRPS group (2809.0 pg/ml; Q3-Q1: 3913.0-1589.0) and no CRPS group (3654.0 pg/ml; Q3-Q1: 4429.0-2095.5) were significantly higher than that of the control group (1515.0 pg/ml; Q3-Q1: 1880.0-1150.0): CRPS vs. controls, p < .001; no CRPS vs. controls, p < 0.001. Serum sIL-2R levels did not differ significantly between the CRPS and no CRPS group. A statistically significant negative correlation was observed between sIL-2R levels and the CRPS severity score (rs = −0.468, p = 0.024). Our results confirm our previous findings of higher sIL-2R levels in CRPS patients than in healthy controls. We further showed that serum sIL-2R cannot differentiate between CRPS and other pain conditions of a limb in a tertiary referral setting. Interestingly, a negative correlation was found between sIL-2R and CRPS disease severity; this finding warrants further research into the relationship between sIL-2R and CRPS disease severity.

Prognostic significance of plasma IL-2 and sIL-2R\u03b1 in patients with first-ever ischaemic stroke

BackgroundAn imbalance between circulating neuroprotective and neurotoxic T cell subsets leads to poor prognosis in acute ischaemic stroke (AIS). Preclinical studies have indicated that the soluble form of the interleukin-2 receptor α (sIL-2Rα)-IL-2 complex regulates T cell differentiation. However, the association between sIL-2Rα levels and AIS remains unclear.MethodsA total of 201 first-ever AIS patients within 24 h after stroke onset and 76 control subjects were recruited. The National Institutes of Health Stroke Scale (NIHSS) score and 3-month functional outcome (modified Rankin Scale [mRS] score) at admission were assessed. Plasma sIL-2Rα and IL-2 levels at admission were measured. Prognostic significance was identified by using univariate and multivariate logistic regression analyses.ResultsPatients with poor functional outcomes at 3 months had significantly higher levels of sIL-2Rα and lower levels of IL-2 than patients with good outcomes. Moreover, sIL-2Rα levels showed a strong positive correlation with NIHSS and mRS scores (p < 0.0001), whereas IL-2 levels were negatively correlated with mRS scores (p < 0.01). Univariate analyses showed that higher sIL-2Rα and IL-2 levels were associated with an increased and reduced risk of unfavourable outcomes, respectively. After adjusting for confounding variables, the sIL-2Rα level remained independently associated with an increased risk of an unfavourable outcome, and adding sIL-2Rα levels to the conventional risk factor model significantly improved risk reclassification (net reclassification improvement 17.56%, p = 0.003; integrated discrimination improvement 5.78%, p = 0.0003).ConclusionssIL-2Rα levels represent a novel, independent prognostic marker that can improve the currently used risk stratification of AIS patients. Our findings also highlight that elevated plasma sIL-2Rα and IL-2 levels manifested opposite correlations with functional outcome, underlining the importance of IL-2/IL-2R autocrine loops in AIS.

Value of serum soluble interleukin-2 receptor as a diagnostic and predictive biomarker in sarcoidosis

ABSTRACT Background Differentiating between interstitial lung diseases (ILD) is challenging. Serum soluble interleukin 2 receptor (sIL-2R) is used as a diagnostic marker in sarcoidosis, but its diagnostic value has not yet been studied in other ILDs like Idiopathic Pulmonary Fibrosis (IPF) or Hypersensitivity Pneumonitis (HP). Also, the prognostic value of sIL-2R in sarcoidosis remains unknown. Methods This retrospective cohort study included 121 patients with sarcoidosis, 35 with cHP, 62 with IPF (idiopathic pulmonary fibrosis) and 70 healthy controls. Serum sIL-2R levels were determined at diagnosis. Follow-up data were available for patients with chronic sarcoidosis (n = 64) and patients with non-chronic sarcoidosis (n = 29). Results Patients with sarcoidosis had higher sIL-2R levels (median 5418 pg/mL) than patients with cHP (median 4015 pg/mL, P = 0.002) and IPF (median 4192 pg/mL, P = 0.034). No differences were found between patients with cHP and IPF. Logistic regression revealed that sIL-2R at diagnosis is a significant predictor of the development of chronic sarcoidosis (OR = 2.1, P = 0.032). Conclusion High levels of sIL-2R are suggestive of sarcoidosis, although a broad overlap exists in sIL-2R levels across sarcoidosis, cHP, and IPF. High levels of sIL-2R might serve as a prognostic biomarker for chronicity.

Elevated Serum Soluble Interleukin-2 Receptor Level Is a Useful Prognostic Factor for Disease-Specific Overall Survival in Patients with Newly Diagnosed Follicular Lymphoma before Initiation of Treatment

Introduction: Serum soluble interleukin-2 receptor (sIL-2R) is recognized as a tumor-related biomarker of malignant lymphomas, including follicular lymphoma (FL). The objective of this study is to assess the prognostic significance of pretreatment serum sIL-2R level for disease-specific overall survival (DSS) in patients with FL. Methods: We retrospectively analyzed medical records of our 10 individual institutions to identify all patients (pts) ≥ 18 years old with newly diagnosed FL between 01/01/2008 and 12/31/2018. Only pts with FL grade 1-3b, confirmed at pathological review, were included. Pts with histological transformation at diagnosis were excluded. Serum sIL-2R was determined by sandwich enzyme-linked immunosorbent assay. Clinical characteristics, therapies, response, relapse patterns and follow up status were collected and analyzed in the cohort. DSS was defined from the time of initial diagnosis to death due to lymphoma or last follow up. DSS was analyzed according to Kaplan Meier method and differences between subgroups were compared with log-rank test. Multivariate cox regression analysis was used to investigate associations of sIL-2R, FL International Prognostic Index (FLIPI) and progression or relapse within 24 months after diagnosis (POD24) with DSS. Serum levels of sIL-2R was measured before initiation of treatment and the data on the nearest date of the diagnostic biopsy within six months was adopted. Results: We recorded 565 pts and 535 pts of them with pretreatment serum sIL-2R levels available were included in the analysis with median age 64 years (range: 30-90) and 305 females (57%). Clinical characteristics are summarized in Table 1. The median of the serum sIL-2R level was 896 IU/mL (range: 145 - 23800). We decided an optimal cutoff value of 1800 IU/mL by using receiver operating characteristic (ROC) analysis, which showed it was 1830 IU/mL (AUC : 0.76, 95%CI : 0.67 - 0.84). Various poor prognostic indicators, such as bulky mass, increased LDH, ≥5 nodal lesions, poor performance status (PS), bone marrow invasion, FLIPI and FLIPI-2 high-risk, decreased Hb, advanced disease, high tumor burden, increased β2MG and existence of B symptoms, were strongly associated with high serum sIL-2R level (≥1800 IU/mL), and high sIL-2R level correlated with POD24 (P&lt;0.001, Chi-squared test). The estimated 10-year DSS rate was 87.2% with a median follow up duration of 4.4 years. In pts with POD24 (96 pts, 18%), DSS was significantly worse than those with non-POD24; 64.3% vs 93.0% (P&lt;0.001) and rituximab maintenance did not improve DSS in both groups (P=0.85 and 0.98, respectively). In patients with sIL-2R level of ≥1800 (high sIL-2R, 378 pts, 71%), DSS was significantly worse than those with sIL-2R level of &lt;1800 IU/mL (low sIL-2R, 157 pts, 29%); 68.2% vs 96.0% (P&lt;0.001), respectively (Figure 1). Multivariate analyses employing sex, PS, sIL-2R, FLIPI and POD24 demonstrated that high sIL-2R was an independent prognostic factor for DSS (HR : 2.88, 95% CI : 1.15-7.21, P&lt;0.05). Regardless of POD24 status, pts with high sIL-2R had significantly worse DSS than those with low sIL-2R; 44.6% vs 91.5% in pts with POD24 (P&lt;0.05) and 82.6% vs 96.8% in pts without POD24 (P&lt;0.001), respectively. Among pts treated with rituximab plus anthracycline-containing chemotherapy as the 1st line regimen (222 pts, 41%), pts with high sIL-2R had significantly worse DSS than those with low sIL-2R; 68.1% vs 97.2% (P&lt;0.001). Among pts treated with rituximab-bendamustine as the 1st line regimen (48 pts, 9%), there was no significant difference between high and low sIL-2R populations (P=0.2), however, among pts treated with bendamustine-containing regimen at least once in their life time (180 pts, 34%), there was significant difference between them; 63.1% vs 87.8% (P&lt;0.05). Even in pts achieving complete metabolic response after 1st line treatment (178 pts, 33%), high pretreatment sIL-2R level was a significant factor affecting poor DSS; 75.9% vs 94.3% (P&lt;0.05). Conclusions: High sIL-2R level ( ≥1800 IU/mL) is a significant and independent adverse prognostic factor for DSS in pts with newly diagnosed FL. This study provides us useful information to predict population with worse DSS before initiation of treatment. Disclosures Nozaki: Chugai: Honoraria; Celgene: Honoraria. Kida:Eisai Co., Ltd: Honoraria. Kosugi:Novartis Pharma Co.: Honoraria; Bristol-Myers Squibb Co.: Honoraria; Eisai Co., Ltd: Honoraria; Takeda Pharmaceutical Company Limited: Honoraria; Kyowa Kirin Co., Ltd: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria; ONO PHARMACEUTICAL CO., LTD.: Honoraria; NIPPON SHINYAKU CO.,LTD.: Honoraria; Janssen Pharmaceutical K.K.: Honoraria; Celgene K.K.: Honoraria; Pfizer Inc.: Honoraria. Shibayama:Astellas, Teijin, MSD, Shionogi, Eisai, Sumitomo Dainippon, Taiho, Nippon Shinyaku: Research Funding; Celgene, Chugai, Eisai, AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Takeda, Novartis, Janssen, Chugai, Eisai, Mundi Pharma, Ono, Otsuka, Kyowa Kirin, Sumitomo Dainippon, AstraZeneca, Avvie, DaiichiSankyo, Fujimoto, Nippon Shinyaku, Sanofi, Bristol-Myers Squibb, Pfizer: Honoraria.

Transplant-related complications are impediments to the success of allogeneic hematopoietic stem cell transplantation for adult T cell leukemia patients in non-complete remission.

Outcomes of allogeneic hematopoietic stem cell transplantation (allo-HSCT) for patients with adult T cell leukemia/lymphoma (ATL) are not satisfactory, particularly in patients in non-complete remission at transplantation (Pt-non-CR). We conducted a regional retrospective study in the ATL endemic area of Okinawa, Japan. Of 62 ATL patients, 21 received allo-HSCT in CR and 41 in non-CR. The 3-year overall survival (3yOS) rate and median survival time for the whole cohort was 25.6% and 7.7 months, respectively. The 3yOS of Pt-non-CR was significantly lower than that of patients in CR (Pt-CR) (16.8% vs. 43.6%, P = 0.005). Transplant-related mortality (TRM) was significantly higher in Pt-non-CR than in Pt-CR (46.3% vs. 15.7%, P = 0.025), while there was no significant difference in disease-associated mortality (DAM) between Pt-non-CR and Pt-CR. Multivariable analysis for Pt-non-CR revealed that poor performance status (poor-PS) and higher sIL-2R level (high sIL-2R) adversely affected OS. Poor-PS was associated with higher TRM, but not with higher DAM in Pt-non-CR. High sIL-2R did not affect TRM or DAM in Pt-non-CR. Overall, high TRM rates rather than DAM contribute to the poor outcomes of Pt-non-CR, suggesting that not only disease control but also management of transplant-related complications is required for allo-HSCT in ATL patients.

Soluble Interleukin-2 Receptor Level at Diagnosis Predicts Prognosis of Patients With Follicular Lymphoma Irrespective of Initial Management Strategy.

Although various prognostic indices for follicular lymphoma (FL) have been proposed, they are designed specifically for patients requiring immediate therapy. We aimed to develop a new simple prognostic tool applicable for all patients with FL at diagnosis. We retrospectively analyzed various clinical, pathological, and laboratory data, including soluble interleukin-2 receptor (sIL2R), from 140 patients with FL from two centers for their impact on prognosis. This study analyzed the impact of soluble interleukin-2 receptor (sIL2R) in order to develop a new simple prognostic tool applicable for all patients with FL at diagnosis. The initial management of these patients was watchful waiting (n=48) or immediate treatment (n=92). Event-free survival at 24 months predicted overall survival. When categorized into three groups according to the sIL2R levels at diagnosis, a very high sIL2R level identified about 20% of patients with a distinctively worse survival compared to the others. sIL2R is a very effective biomarker that can be easily applied in routine practice to predict survival for all patients with FL at diagnosis irrespective of initial management approach.

Elevated serum soluble interleukin-2 receptor levels increase malignancy-related risk in patients on chronic hemodialysis.

Patients on chronic hemodialysis (HD) have an increased incidence of malignancy due to decreased immunity. Soluble interleukin-2 receptor (sIL-2R), as an immunomodulator, seemed to have an effect in the process of malignancy. In this study, we aimed to evaluate the clinical significance of increased sIL-2R in the course of malignancy among HD patients. Patients who undergoing chronic hemodialysis were followed for 24months. Risk factors for malignancy events and malignancy-related mortality during the 2-year follow-up period were investigated among various clinicopathological variables. Of the 363 patients included in this research, 47 patients (12.95%) had a prior history of treated malignancy. During the 2-year follow-up period, malignancy events were detected in 15 (4.12%) patients. Sixty-seven patients died during the study period, of which nine patients (13.43%) were died of malignancy. Malignancy events reduced 2-year mortality significantly (log-rank = 23.02, P < 0.0001). Both high sIL-2R levels ( ≥ 2-fold upper limit of the normal value) (OR 6.6, P = 0.006) and a prior history of treated malignancy (OR 4.12, P = 0.018)were identified by multivariate logistic analysis as independent determinants for malignancy events. However, only the levels of sIL-2R (used as a continuous variable) had the significantly predictive effect on malignancy events and malignancy-related mortality in the following 2years. Elevated sIL-2R levels was commonly seen in serum of HD patients. And this elevated level increased the risk of malignancy. Aside from its role as a biomarker, sIL-2R may also exert biological effects in the course of malignancy.

PS1324 GENETIC SIMILARITY BETWEEN WALDENSTRÖM MACROGLOBULINEMIA AND IGG-TYPE LYMPHOPLASMACYTIC LYMPHOMA. TARGETED NEXT-GENERATION SEQUENCING RESULTS OF FORMALIN-FIXED PARAFFIN EMBEDDED SAMPLES

Background: Follicular lymphoma (FL), the most frequent type of indolent non Hodgkin lymphoma, exhibits a heterogeneous clinical behavior. Predictive biological variables are eagerly sought, in an effort to better anticipate outcomes for each individual patient. Cytokines are small proteins involved in cell signaling and immune regulation. The levels of soluble interleukin 2 receptor (sIL-2R), interleukin 6 (IL-6), and tumor necrosis factor (TNF) have been correlated with tumor burden and prognosis in solid tumors and some lymphomas. High sIL-2R has been associated with shorter progression-free survival (PFS) in FL, but the impact of the levels of IL-6 and TNF is not known in this disease specifically. Aims: To determine the prognostic significance of the serum levels of sIL-2R, IL-6 and TNF in patients with newly diagnosed FL. Methods: We identified 300 patients (132 males/168 females; median age: 60 years) diagnosed with FL at our institution between January 2002 and December 2017 who had available information about serum cytokine levels (sIL-2R, IL-6 and TNF), determined by ELISA, before the initiation of frontline treatment. Baseline patient and disease characteristics, type of frontline treatment, PFS and overall survival (OS) were assessed retrospectively and compared between patients with normal vs. elevated levels (above the upper normal limit) of each one of the three evaluated cytokines. Results: Baseline characteristics, treatment, response, PFS and OS data are detailed in the table. Patients with elevated IL-6 or TNF levels were older and those with elevated IL-6 had a worse performance status and higher rate of B symptoms. An advanced stage was more frequently seen in patients with any elevated cytokine, while secondary extranodal involvement, and specifically, bone marrow involvement, was more frequent if either sIL-2R or TNF were raised. Patients with any elevated cytokine were more likely to have elevated LDH or β2-microglobulin (β2m) levels or a high-risk FLIPI score. A Ki67 index >30% was more frequently seen among patients with high TNF levels. Patients requiring frontline treatment with R-CHOP showed higher levels of any one of the 3 evaluated cytokines, while those who were not treated or received single-agent rituximab were more likely to have normal levels. The complete response (CR) rate was higher for patients with normal levels of sIL-2R and TNF. Median PFS was 10 years for treated patients in the entire series. 10-year PFS was significantly lower for patients with high levels of either sIL-2R, IL-6 or TNF. Similarly, patients who had elevated levels of any one of the 3 evaluated cytokines had a lower 10-year OS. However, in a multivariate analysis including FLIPI score, β2m and cytokine levels, only FLIPI and β2m retained statistical significance for PFS and OS.Summary/Conclusion: FL patients with elevated levels of cytokines are more symptomatic and have a higher tumor burden. Despite being treated more aggressively, they are less likely to achieve a CR after treatment or to maintain it after 2 years. PFS and OS are also significantly shorter in patients with elevated cytokine levels compared to those with normal levels. Determination of serum cytokine levels is simple and could become an additional factor informing about response to treatment, early progression, and survival.

High Level of Serum Soluble Interleukin-2 Receptor Is Associated With Poor Survival in Patients With First Relapsed or Refractory Peripheral T-Cell Lymphoma, Not Otherwise Specified: A Retrospective Study

BackgroundPatients with relapsed or refractory peripheral T-cell lymphoma, not otherwise specified (R/R-PTCL-NOS) usually have short survival with conventional salvage chemotherapies. Prediction of poor survival in patients who undergo conventional salvage chemotherapies might help identify candidates for novel therapies that have been recently available for R/R-PTCL-NOS. However, no prognostic marker other than the second-line International Prognostic Index (sIPI) has been reported. We aimed to investigate the prognostic value of serum soluble interleukin-2 receptor (sIL-2R) level in patients with R/R-PTCL-NOS. Patients and MethodsWe retrospectively analyzed 37 patients with R/R-PTCL-NOS who underwent salvage chemotherapy. Serum sIL-2R level was measured within a week before salvage chemotherapy initiation. We determined the cutoff level of serum sIL-2R as 4.03 times the upper limit of normal by using receiver operating characteristic curve analysis. ResultsThe 3-year overall survival (3yOS) was 5.2% and 37.5% in high sIL-2R and low sIL-2R groups, respectively (P = .005). In multivariate analysis, high sIL-2R level was independently associated with lower 3yOS (hazard ratio, 2.30; 95% confidence interval, 1.04-5.11; P = .040). In subgroup analysis, high sIL-2R level did not affect 3yOS in patients with high-risk sIPI (NA [not available] vs. 7.1%; P = .354), but was significantly associated with poor 3yOS in patients with low-risk sIPI (NA vs. 60.0%; P = .037). ConclusionSerum sIL-2R is a useful prognostic marker for patients with R/R-PTCL-NOS. In particular, high sIL-2R level can identify groups of patients with low-risk sIPI who have poor prognosis. Our results suggest that novel therapeutic approaches might be necessary for patients with high-risk sIPI and/or high sIL-2R level.

Hemophagocytic lymphohistiocytosis followed by an episode of peritoneal dialysis associated peritonitis: a case report

BackgroundHemophagocytic lymphohistiocytosis (HLH) is characterized by excessive activation of the immune system due to infection, autoimmune diseases, or malignancy. As an aggressive and life-threatening clinical syndrome, HLH secondary to peritoneal dialysis associated peritonitis (PDAP) has never been reported.Case presentationA 34-year-old female peritoneal dialysis (PD) patient was hospitalized for fever, progressively multi-organ damage (including cytopenias, abnormalities of coagulation and liver enzyme) after an episode of organism-specific peritonitis. She was refractory to the broad-spectrum antimicrobial agent. Further tests found hemophagocytosis on the bone marrow examination, and extremely high level of sIL2-R and impaired activity of NK cell. The diagnosis of HLH was eventually established. After HLH-specific therapy, this patient recovered and discharged.ConclusionsThe present case suggests that clinicians should to be aware of HLH in those patients apparently suspected with refractory or relapsing peritonitis, especially those accompanied with persist fever, hyperferritinemia, and cytopenias. HLH-specific therapy and supportive care should be applied without delay.

Prognostic impact of serum soluble interleukin-2 receptor level at diagnosis in elderly patients with diffuse large B-cell lymphoma treated with R-CHOP

Diffuse large B-cell lymphoma (DLBCL) is a clinically heterogeneous disease. To evaluate the clinical relevance of the serum soluble interleukin-2 receptor (sIL-2R) level, we retrospectively analyzed 178 patients aged ≥60 years who were newly diagnosed with DLBCL. We determined the cutoff value of the sIL-2R level to be 1280 U/mL using the area under the receiver operating characteristic curve. The high sIL-2R group exhibited significantly inferior 5-year progression-free survival (PFS) (36.2% vs. 86.1%, p < .001) and 5-year overall survival (OS) (49.7% s. 83.8%, p < .001) than the low sIL-2R group. Multivariate analysis revealed that a high sIL-2R level was a significant prognostic factor for PFS and OS (hazard ratio [HR]: 5.65, p < .001 and HR: 2.99, p = .001, respectively). This study showed that measurement of the sIL-2R level at diagnosis is clinically beneficial for identifying elderly patients with DLBCL who have a poor prognosis.

The Role of Soluble Interleukin-2 Receptor (sIL-2r) in Diagnosis of Adult Hemophagocytic Lymphohistiocytosis (HLH): A Single Center Retrospective Study

Purpose: Serum soluble interleukin-2 receptor (sIL-2r) is considered an important disease marker in hemophagocytic lymphohistiocytosis (HLH). High levels of sIL2r are indicative of T-cell activation, and sIL2r > 2400 U/mL was 93% sensitive and 100% specific for pediatric HLH in the HLH-2004 diagnostic criteria. [1] There are no published data on its performance characteristics in adults and very limited data in children. [2] We conducted a retrospective study to examine the diagnostic sensitivity and specificity of sIL-2r in diagnosing HPS/HLH, to assess how it varies with disease severity, determine its prognostic significance and ability to discriminate between subgroups of HPS/HLH.Methods: Retrospective data was collected on adult patients with at least one sIL-2r level at Vancouver General Hospital in Vancouver, Canada between March 2012 and April 2017. Patients were subdivided into HLH and non-HLH groups. Sensitivity, specificity, prognosis associated with sIL-2r >10,000U/ml, utility as a marker of disease activity and mean sIL-2r between subgroups of HLH were evaluated. Non-HLH patients did not have convincing evidence to suggest HLH and did not receive HLH-specific therapy. Serum sIL-2r levels were enzyme-linked immunosorbent assay (ELISA; Siemens IMMULITE Immunoassay platform, adult reference range 241-846 U/ml).Results: 81 patients were included, 41 with HLH and 40 with an alternate diagnosis (non-HLH). Non-HLH diagnoses included sepsis, histiocyte disorders, multiple transfusions, liver disease, cardiac disease, autoimmune disease/vasculitis, and other inflammatory diseases. The sensitivity of sIL-2r >2400 U/ml was 93% (95% CI 0.79 - 0.98) and specificity 63% (95% CI 0.46 - 0.77). Specificity improved to 93% (95% CI 0.79 - 0.98) with a threshold of sIL-2r >10,000U/ml. Based on ROC curves, sIL2r is a good diagnostic test (AUC of 0.86) with a threshold that optimizes sensitivity and specificity of 2785U/ml and ferritin is a fair test (AUC 0.78) with an optimal threshold of 5775 ug/L. Similar to ferritin, sIL-2r levels correlated with disease activity in seven HLH patients that had multiple sIL-2r levels drawn during their disease course. Within the HLH group, sIL-2r >10,000U/ml was not associated with worse prognosis. Higher sIL-2r levels were seen in malignancy associated HLH (MAHS) as compared to infection associated HLH (IAHS) and macrophage activation syndrome (MAS).Conclusion: sIL-2r >2,400U/ml is a sensitive test for diagnosis of adult HPS/HLH and has utility in monitoring disease activity. At higher levels (sIL-2r >10,000U/ml), this biomarker loses sensitivity but gains specificity in diagnosing HPS/HLH. Higher sIL-2r levels may indicate MAHS when the underlying etiology is unclear. In adults, secondary HPS/HLH is much more common than primary HLH, and all patients in this study were presumed to be secondary. The defining features of secondary HPS/HLH are pathologic immune activation and hypercytokinemia leading to end organ damage. SIL-2r is elevated in numerous conditions associated with T-cell activation and inflammation, such as lymphoma and autoimmune lymphoproliferative syndrome (ALPS), and larger prospective studies of adults with these and other conditions are needed to better define the specificity of increased sIL-2r for HPS/HLH. Since adult secondary HPS/HLH is increasingly diagnosed and treated in many centers, diagnostic criteria for adult secondary HPS/HLH should incorporate markers of hypercytokinemia and immune activation.

High level of soluble interleukin-2 receptor in serum predicts treatment resistance and poor progression-free survival in multiple myeloma.

The IL-2/IL-2 receptor (IL-2R) system plays a central role in maintaining normal T cell immunity, and its disturbance is associated with several hematologic disorders. Studies have found in several types of lymphoma that abnormal amounts of soluble IL-2R (sIL-2R) may result in imbalance of the IL-2/IL-2R system and hence of the T cell immunoregulation. Whether the level of sIL-2R in blood could predict treatment outcomes or not needs to be investigated in multiple myeloma (MM) patients. The level of sIL-2R in serum was measured using enzyme-linked immunosorbent assay (ELISA) in 81 patients with newly diagnosed MM. Twenty-six patients (32.1%) were treated with bortezomib-based regimens and 55patients (67.9%) received old drugs-based regimens. The mean concentration of sIL-2R for myeloma patients was 8.51ng/ml, significantly higher than that of healthy controls (0.56ng/ml, p<0.0001). The best cutoff value for sIL-2R in predicting high risk for disease progression is 6.049ng/ml with an area under curve (AUC) of 0.665 (p=0.013). Thirty-six patients (44.4%) were classified as higher sIL-2R level group (>6.049ng/ml), and 45 patients (55.6%) as lower group (≤6.049ng/ml). The overall response rate (ORR) was 60.0% in lower sIL-2R level group, and 41.7% in higher level group (p=0.156). The median progression-free survival (PFS) and overall survival (OS) was 12months (range, 2.0-65months) and 20months (range, 2.0-118months), respectively. In a multivariate survival analysis, including Eastern Cooperative Oncology Group performance status score, treatment response, and sIL-2R level, it was found that all these three parameters were significantly independent prognostic factors for PFS (p=0.032, 0.016, and 0.043, respectively), but none factors maintained their value in predicting OS. Subgroup analysis revealed that high level of sIL-2R is correlated with significantly inferior PFS in patients treated with bortezomib-based regimens (p=0.004). Serum sIL-2R level is an independent prognostic factor for PFS, indicating novel drugs targeting the imbalance of IL-2/IL-2R system may be a promising strategy in MM.

Clinical utility of soluble interleukin-2 receptor in hemophagocytic syndromes: a systematic scoping review.

The serum-soluble interleukin-2 receptor (sIL-2r) level is considered an important diagnostic test and disease marker in hemophagocytic syndromes/hemophagocytic lymphohistiocytosis (HPS/HLH). However, this cytokine receptor is rarely measured in clinical practice and has been excluded from recent diagnostic/classification criteria such as the HScore and macrophage activation syndrome (MAS) 16. We performed a systematic scoping review of 64 articles (1975-2016) examining the clinical utility of sIL-2r in HPS/HLH. Twenty-two articles describe sIL-2r as a sensitive diagnostic marker for HLH, but only three distinct datasets actually address sensitivity. The original HLH-2004 Guidelines reported sensitivity of 93% and specificity of 100% for sIL-2r≥2400, based on a pediatric dataset (n=152) which is published for the first time in this review. Two pediatric studies reported sensitivity of 89% for sIL-2r≥2400 in diagnosis of MAS complicating juvenile idiopathic arthritis (JIA) (n=27) and 88% for secondary HLH in acute liver failure (n=9). Twenty articles described sIL-2r as a dynamic marker of disease activity that falls with response to treatment, and 15 described high initial sIL-2r levels >10,000U/mL as a poor prognostic marker. The ability of sIL-2r to distinguish between subtypes of HPS/HLH was inconsistent. This review confirms the importance of soluble IL-2r as a diagnostic and disease marker in HPS/HLH, but also reveals the need for more primary data about its performance characteristics, particularly in adults. More emphasis should be made in including this simple, inexpensive test in clinical practice and studies of HPS/HLH.

The clinical value of serum soluble interleukin-2 receptor in pulmonary sarcoidosis.

Background: Sarcoidosis is a multi-system granulomatous disease in which T-helper type 1 cytokines play a key role. We evaluated the clinical value of serum soluble interleukin-2 receptor (sIL-2R) as a marker of disease activity and prognosis in sarcoidosis. Methods: This study included 67 patients who were newly diagnosed with sarcoidosis from 2006 to 2012 at our department. The clinical and follow-up data were retrospectively collected from their medical records. Results: The mean (±SD) age of the patients was 53.9±15.4 years; 41 patients were women and were significantly older than men. Serum angiotensin-converting enzyme had a mean value of 15.3±6.1 U/L and a positive rate of 10.4%. Serum sIL-2R had mean level of 818.8±453.1 U/mL and a positive rate of 45.9%. Moreover, the sIL-2R level of patients who had lung parenchymal lesions was significantly higher than that of patients who had no lung parenchymal lesions. Fifty-two patients who had no medications were followed up at our hospital for a median period of 37 months (range, 0-107 months). Patients who demonstrated chest imaging evidence of exacerbation (n = 8) tended to have higher sIL-2R levels than those who remained stable. Conclusion: Serum sIL-2R may have a role as a diagnostic and prognostic marker in pulmonary sarcoidosis. (Sarcoidosis Vasc Diffuse Lung Dis 2017; 34: 41-47).

Prognostic value of the soluble interleukin-2 receptor level after patients with follicular lymphoma achieve a response to R-CHOP

ABSTRACTObjectives: Follicular lymphoma (FL) is a clinically and biologically heterogeneous disease. Therefore, it is important to identify factors that can predict its clinical outcome.Methods: We retrospectively evaluated the usefulness of soluble interleukin-2 receptor (sIL-2R) levels after R-CHOP (posttreatment sIL-2R) in 72 patients with newly diagnosed FL who had either a complete response (CR) or partial response. With the use of a recursive partitioning analysis, we determined the cut-off values of post- and pretreatment sIL-2R levels that were associated with disease progression, which corresponded to 486.5 and 5405 U/mL, respectively.Results: The high posttreatment sIL-2R group showed a significantly inferior progression-free survival (PFS) compared to the low posttreatment sIL-2R group in all patients (3-year PFS 52.6% vs. 77.4%, P = 0.003), and in patients with CR (3-year PFS 57.1% vs. 82.1%, P = 0.034). Although a multivariate analysis showed that pretreatment sIL-2R, but not posttreatment sIL-2R, was an independently significant predictive factor for disease progression, among patients with low pretreatment sIL-2R levels, those with high posttreatment sIL-2R levels tended to have inferior PFS. There was a significant trend in PFS among the high pretreatment sIL-2R group, the low pre- and high posttreatment sIL-2R group, and the low pre- and low posttreatment sIL-2R group (P < 0.001).Conclusion: Among patients with a low pretreatment sIL-2R level who exhibited a positive response to R-CHOP, the posttreatment sIL-2R level may help to identify those with a poor prognosis.

O2-8-5 - Possible stimulatory immune checkpoint molecules releasing allows adult T-cell leukemia/lymphoma development

The interleukin (IL)-2 receptor α chain (IL-2Rα, CD25) and CD30 are cell membrane proteins expressed on activated T-cell. High levels of soluble cytokine receptors, soluble IL-2Rα (sIL-2R) and soluble CD30 (sCD30) are detected in the serum of patients with adult T-cell leukemia/lymphoma (ATL), which is a highly aggressive leukemia/lymphoma caused by human T-cell leukemia virus type 1 (HTLV-1) (Nishioka C, Takemoto S, et al. 2005; Porunkuna R, Takemoto S, et al. 2014). Freshly isolated leukemic cells from acute type ATL patients express little CD30 on the surface, and predominantly produce sCD30 (Pornkuna R, Nishioka C, and Takemoto S. 2014). We here investigated whether plasma sCD30 is associated with risk of ATL in a nested case-control study within a cohort of HTLV-1 carriers (Takemoto S, et al. 2015). We compared sCD30 levels between 11 cases (i.e., HTLV-1 carriers who later progressed to ATL) and 22 age-, sex- and institution-matched control HTLV-1 carriers (i.e., those with no progression). The sIL-2R and sCD30 concentrations at baseline were significantly higher in cases than in controls (P = 0.009 and P<0.001, respectively). In the univariate logistic regression analysis, a higher sIL-2R (≥546.5 U/mL) or sCD30 (≥30.2 U/mL) was significantly associated with ATL development. Among cases, sIL-2R and sCD30 concentrations tended to increase at the time of diagnosis of aggressive-type ATL, but the concentrations were stable in those developing the smoldering-type. High levels of sIL-2R probably down-regulate the proliferative capability of T cells that encounter tumor cells, and proliferating ATL cells are thought to release sCD30, and excess sCD30 may block CD30L on normal activated T cells and myeloid cells, protecting CD30+ ATL cells from apoptosis. Accordingly, high levels of sIL-2R and sCD30 suggest that impaired tumor surveillance leads to the survival of ATL cells. The interleukin (IL)-2 receptor α chain (IL-2Rα, CD25) and CD30 are cell membrane proteins expressed on activated T-cell. High levels of soluble cytokine receptors, soluble IL-2Rα (sIL-2R) and soluble CD30 (sCD30) are detected in the serum of patients with adult T-cell leukemia/lymphoma (ATL), which is a highly aggressive leukemia/lymphoma caused by human T-cell leukemia virus type 1 (HTLV-1) (Nishioka C, Takemoto S, et al. 2005; Porunkuna R, Takemoto S, et al. 2014). Freshly isolated leukemic cells from acute type ATL patients express little CD30 on the surface, and predominantly produce sCD30 (Pornkuna R, Nishioka C, and Takemoto S. 2014). We here investigated whether plasma sCD30 is associated with risk of ATL in a nested case-control study within a cohort of HTLV-1 carriers (Takemoto S, et al. 2015). We compared sCD30 levels between 11 cases (i.e., HTLV-1 carriers who later progressed to ATL) and 22 age-, sex- and institution-matched control HTLV-1 carriers (i.e., those with no progression). The sIL-2R and sCD30 concentrations at baseline were significantly higher in cases than in controls (P = 0.009 and P<0.001, respectively). In the univariate logistic regression analysis, a higher sIL-2R (≥546.5 U/mL) or sCD30 (≥30.2 U/mL) was significantly associated with ATL development. Among cases, sIL-2R and sCD30 concentrations tended to increase at the time of diagnosis of aggressive-type ATL, but the concentrations were stable in those developing the smoldering-type. High levels of sIL-2R probably down-regulate the proliferative capability of T cells that encounter tumor cells, and proliferating ATL cells are thought to release sCD30, and excess sCD30 may block CD30L on normal activated T cells and myeloid cells, protecting CD30+ ATL cells from apoptosis. Accordingly, high levels of sIL-2R and sCD30 suggest that impaired tumor surveillance leads to the survival of ATL cells.

High Level of Soluble Interleukin-2 Receptor in Serum Predicts Treatment Resistance and Poor Progression Free Survival in Multiple Myeloma

Background: The IL-2/IL-2 receptor (IL-2R) system plays a central role in maintaining normal T cell immunity, and its disturbance is associated with several hematologic disorders. Studies have found in several types of lymphoma that abnormal amounts of soluble IL-2R (sIL-2R) may result in imbalance of the IL-2/IL-2R system and hence of the T cell immunoregulation. Whether the level of sIL-2R in blood could predict treatment response and survival outcomes or not needs to be investigated in multiple myeloma (MM) patients.Methods: The level of sIL-2R in serum was measured using enzyme-linked immunosorbent assay (ELISA) in 81 patients with newly diagnosed MM. 26 patients (32.1%) were treated with bortezomib-based regimens and 55 patients (67.9%) received old drugs-based regimens.Results: The mean concentration of sIL-2R for myeloma patients was 8.51ng/ml, significantly higher than that of healthy controls (0.56ng/ml, p<0.0001). The best cutoff value for sIL-2R in predicting high risk for disease progression is 6.049ng/ml with an area under curve (AUC) of 0.665 (p = 0.013). 36 patients (44.4%) were classified as higher sIL-2R level group (>6.049ng/ml), and 45 patients (55.6%) as lower group (=<6.049ng/ml). The overall response rate (ORR) was 60.0% in lower sIL-2R level group, higher than that in higher level group (41.7%, p=0.156). The 3-year progression free survival (PFS) and overall survival (OS) rate was 16% and 64%, respectively. In a multivariate survival analysis including ECOG performance status score, treatment response, and sIL-2R level, it was found that all these three parameters were significantly independent prognostic factors for PFS (p=0.032, 0.016, and 0.043, respectively), but none factors maintained their value in predicting OS. Subgroup analysis revealed that high level of sIL-2R correlated with significantly inferior PFS in patients treated with bortezomib-based regimens (p=0.004).Conclusions: Serum sIL-2R level is a valuable biomarker for predicting treatment response and an independent prognostic factor for PFS, indicating novel drugs targeting the imbalance of IL-2/IL-2R system may be a promising strategy in MM. DisclosuresNo relevant conflicts of interest to declare.

Opportunistic Infections in Patients with HTLV-1 Infection.

As an acquired immunodeficiency, human immunodeficiency virus (HIV) infection is primarily responsible for opportunistic infections in infected patients. However, opportunistic infections also occur in individuals with human T cell lymphotrophic virus type 1 (HTLV-1) infection. Here, we report opportunistic infections in two Japanese HTLV-1-seropositive patients. The first patient was a 67-year-old male, who had cytomegalovirus infection associated with esophagogastritis and terminal ileitis. The patient was HTLV-1-positive and was diagnosed with smoldering adult T cell leukemia (ATL). High levels of serum soluble IL-2 receptor (sIL-2R; 4,304 U/mL) and an increased percentage of CD4+CD25+ T cells (75.5%) in peripheral blood were also detected. The second patient was a 78-year-old female, a known asymptomatic HTLV-1 carrier, who presented with persistent herpes zoster, followed by Pneumocystis jirovecii pneumonia. Disease progression of smoldering ATL along opportunistic infections was observed with very high levels of serum sIL-2R (14,058 U/mL) and an increased percentage of CD4+CD25+ T cells (87.2%) in peripheral blood. In patients with suspected opportunistic infections, both HTLV-1 and HIV should be considered. In HTLV-1-positive patients, an increase in the CD4+CD25+ T cell subset may have its value as a prognostic marker.