Soluble Interleukin-2 Receptor Levels Research Articles

Methotrexate-associated Lymphoproliferative Disorder of the Small Intestine

A 66-year-old woman with psoriatic arthritis was referred to our department for lower abdominal pain. She had been treated with methotrexate (MTX) for more than 12 years. Laboratory tests revealed iron deficiency anemia with a hemoglobin level of 8.7 g/dL and a slightly increased soluble interleukin-2 receptor level (638 U/mL; normal range, 145–519 U/mL). Abdominal enhanced computed tomography examination detected thickening of the wall of the distal ileum (Figure A), which was surrounded by swollen lymph nodes.

Serum level of soluble interleukin 6 receptor is a useful biomarker for identification of treatment-resistant major depressive disorder.

AimA substantial proportion of major depressive disorder patients are treatment‐resistant to antidepressant therapy, who require augmentation drugs, or other treatments including electroconvulsive therapy or transcranial magnetic stimulation. Identifying treatment‐resistant major depressive disorder patients before the actual administration of antidepressant is, however, often difficult. Accordingly, the serum biomarker to identify treatment‐resistant patients will be helpful in clinical settings. This study aims to clarify the appropriate biomarkers for identification of treatment‐resistant major depressive disorder.MethodGiven that immune‐inflammatory processes are involved in the pathogenesis of major depressive disorder, it is possible that certain cytokine‐related molecules could serve as clinically useful biomarkers of treatment‐resistant major depressive disorder patients. In this study, we measured serum levels of tumor necrosis factor‐α, interleukin 6, and soluble interleukin 6 receptor after major depressive disorder patients underwent antidepressant therapy.ResultsThe serum level of soluble interleukin 6 receptor, but not interleukin 6 or tumor necrosis factor‐α, was significantly higher in treatment‐resistant major depressive disorder patients than in remitted patients, suggesting that serum soluble interleukin 6 receptor could be a good biomarker of treatment‐resistant major depressive disorder. Receiver operating characteristic analysis confirmed that serum soluble interleukin‐6 receptor level measurement was useful for identification of treatment‐resistant major depressive disorder patients. Multiple regression analysis using the serum levels of the aforementioned cytokines as explanatory variables and the Quick Inventory of Depressive Symptomatology‐Self Report score (QIDS‐SR16) as a target variable showed that only serum soluble interleukin‐6 receptor level could explain the severity of major depressive disorder.ConclusionBased on these results, we recommend measurement of serum soluble interleukin‐6 receptor level to discriminate treatment‐resistant major depressive disorder patients. High serum soluble interleukin‐6 receptor level is associated with the pathogenesis of treatment‐resistant major depressive disorder, suggesting the involvement of the interleukin 6 trans‐signaling system in onset of treatment‐resistant major depressive disorder.

Pseudo-inflammatory manifestations of choroidal lymphoma resembling Vogt-Koyanagi-Harada disease: case report based on multimodal imaging

BackgroundHematologic malignancies occasionally cause serous retinal detachment (SRD); however, its pathogenesis remains unclear. Here we present the imaging characteristics of metastatic choroidal lymphoma masquerading as Vogt-Koyanagi-Harada (VKH) disease.Case presentationA 45-year-old Japanese woman was referred to our clinic because of bilateral SRD with blurred vision. Fluorescein angiography revealed multiple pinpoint leakage followed by pooling OU. Enhanced depth imaging optical coherence tomography showed marked choroidal thickening OU. Laser speckle flowgraphy detected choroidal circulation impairment OU. Although these results totally agreed with the inflammatory manifestations of acute VKH disease, indocyanine green angiography demonstrated various sizes of sharply marginated hypofluorescent lesions that seemed atypical for the finding of VKH disease, i.e., vaguely marginated hypofluorescent small dots. Cerebrospinal fluid pleocytosis was not detected. Blood tests revealed leukocytosis together with elevation of lactate dehydrogenase and soluble interleukin-2 receptor levels. Corticosteroid pulse therapy did not improve any ocular findings. Bone marrow biopsy was then performed, leading to a definite diagnosis of diffuse large B-cell lymphoma. After starting systemic chemotherapy, both SRD and choroidal thickening resolved rapidly with visual recovery. However, choroidal hypoperfusion persisted, which contrasted distinctly with the inflammatory pattern of VKH disease, i.e., the restoration of choroidal blood flow in parallel with normalization of choroidal thickness.ConclusionsOur detailed multimodal observations highlighted the differential imaging features of choroidal lymphoma despite close resemblance to VKH disease especially at the initial stage. Impaired circulation in the thickened choroid marked the pseudo-inflammatory pathogenesis of SRD due to choroidal involvement with neoplastic, but not inflammatory cells.

Cytotoxic Tph-like cells are involved in persistent tissue damage in IgG4-related disease

Objectives The aim of this study was to determine pathological features of T peripheral helper (Tph)-like (PD-1+CXCR5−CD4+ T) cells in IgG4-related disease (IgG4-RD). Methods Tph-like cells in the blood and submandibular glands (SMGs) from IgG4-RD patients were analyzed by flow cytometry. Correlations between level of a Tph-like cell subset and clinical parameters of IgG4-RD were investigated. The cytotoxic capacity of Tph-like cells was also examined. Expression profiles of a molecule related to a Tph-like cell subset in IgG4-RD SMGs were assessed by immunohistochemistry. Results Tph-like cells from IgG4-RD patients highly expressed a fractalkine receptor, CX3CR1. Percentages of circulating CX3CR1+ Tph-like cells were significantly correlated with clinical parameters including IgG4-RD Responder Index, number of involved organs, and serum level of soluble IL-2 receptor. CX3CR1+ Tph-like cells abundantly possessed cytotoxic T lymphocyte-related molecules such as granzyme A, perforin, and G protein-coupled receptor 56. Functional assays revealed their cytotoxic potential against vascular endothelial cells and ductal epithelial cells. Immunohistochemistry showed that fractalkine was markedly expressed in vascular endothelial cells and ductal epithelial cells in IgG4-RD SMGs. Conclusion CX3CR1+ Tph-like cells are thought to contribute to persistent tissue injury in IgG4-RD and are a potential clinical marker and/or therapeutic target for inhibiting progression of IgG4-RD.

Hemophagocytic lymphohistiocytosis complicating invasive pneumococcal disease: a pediatric case report

BackgroundHemophagocytic lymphohistiocytosis (HLH) is an infrequent but life-threatening disease due to excessive immune activation. Secondary HLH can be triggered by infections, autoimmune diseases, and malignant diseases. Streptococcus pneumoniae is a pathogenic bacterium responsible for invasive pneumococcal disease (IPD) such as meningitis and bacteremia. Although the pneumococcal conjugate vaccine (PCV) has led to reductions in IPD incidence, cases of IPD caused by serotypes not included in PCV are increasing. There are few reports of secondary HLH caused by IPD in previously healthy children. We herein report a rare case of a previously healthy boy with secondary HLH complicating IPD of serotype 23A, which is not included in the pneumococcal 13-valent conjugate vaccine (PCV-13).Case presentationAn 11-month-old boy who had received three doses of PCV-13 was hospitalized with prolonged fever, bilateral otitis media, neutropenia and elevated C-reactive protein (CRP) levels. Blood culture on admission revealed S. pneumoniae, leading to a diagnosis of IPD. HLH was diagnosed based on a prolonged fever, neutropenia, anemia, hepatosplenomegaly, hemophagocytosis in the bone marrow, and elevated serum levels of triglycerides, ferritin, and soluble interleukin-2 receptor. He received broad-spectrum antibiotics and intravenous immunoglobulins for IPD and high-dose steroid pulse therapy and cyclosporine A for HLH; thereafter, his fever resolved, and laboratory findings improved. The serotype of the isolated S. pneumoniae was 23A, which is not included in PCV-13.ConclusionsIt is important to consider secondary HLH as a complication of IPD cases with febrile cytopenia or hepatosplenomegaly, and appropriate treatment for HLH should be started without delay.

Evaluation of interleukin-18 and soluble interleukin-2 receptor serum levels in patients with alopecia areata: an Egyptian study

Background Alopecia areata (AA) is a chronic inflammatory disorder of hair follicle cycling characterized by nonscarring hair loss. Interleukin-18 (IL-18) is a proinflammatory cytokine that was implicated in various inflammatory and autoimmune skin diseases, including AA. IL-2 initiates and develops the immune response through binding to interleukin-2 receptor (IL-2R) on T cells. Levels of soluble IL-2R (sIL-2R) may be estimated as a sign of T-cell activation in serum of patients having many disorders involving aberrant immune activation, including AA. Objective To estimate of the serum levels of IL-18 and sIL-2R as immunological factors in patients with AA and to test the correlation between these serum levels and disease severity. Patients and methods A total of 46 patients with AA and 40 age-matched and sex-matched healthy individuals as controls were included. All participants were subjected to thorough history taking, full general examination, and detailed dermatological examination for diagnosis of cases and determination of extent of the lesions. The severity of AA was graded as mild (three or less patches of alopecia with a widest diameter of 3 cm or less or the disease limited to the eyelashes and eyebrows) or severe (existence of more than three patches of alopecia or a patch >3 cm at the widest diameter or alopecia totalis or alopecia universalis). Estimation of serum levels of IL-18 and sIL-2R was done by enzyme-linked immunosorbent assay. Results Serum IL-18 was significantly higher in patients with AA compared with the controls. Serum sIL-2R was nonsignificantly increased among patients with AA than the controls. Patients with severe disease had significantly higher serum IL-18 and nonsignificantly higher serum sIL-2R compared with patients with mild disease. Conclusion AA is associated with elevation of serum IL-18 and sIL-2R, and their levels increase with the increase in the severity of the disease. The exact role of serum IL-18 and sIL-2R in AA should be investigated in future studies.

The significance of serum levels of soluble interleukin-2 receptor in patients undergoing maintenance hemodialysis

Background Elevated serum levels of sIL-2R are commonly observed in patients undergoing maintenance hemodialysis (MHD). However, the clinical implications in these subjects are unclear. This study is aimed to assess the significance of elevated sIL-2R levels in MHD patients. Methods A total of 382 MHD patients were followed-up from September 2016 to December 2019. Patients were divided into two groups: high sIL-2R, with sIL-2R levels ≥2-fold of the upper limit of normal (710 U/ml); and low sIL-2R, with sIL-2R levels < 2-fold the upper limit of normal. The relationships between sIL-2R levels and other clinical parameters, as well as patient prognosis were both assessed. Results The median concentration of sIL-2R was 1268 U/mL. A total of 372 (97.38%) patients exhibited sIL-2R levels higher than the upper limit of the normal range. Multiple linear regression analysis revealed that monocyte count (β = 0.1571, p = 0.01), and β2-MG (β = 0.2635, p < 0.0001), hemoglobin (β = −0.1610, p = 0.001), SCr (β = −0.3471, p < 0.0001), and HDL-C (β = −0.1091, p = 0.029) levels were independent factors influencing serum concentrations of sIL-2R. High sIL-2R was significantly correlated with non-cardiovascular-related mortality (OR 2.97 [95% CI 1.59–5.56; p = 0.001), of which 39 (82.98%) were attributed to infection and/or cancer. Conclusions Elevated sIL-2R is prevalent in MHD patients and related with several unfavorable parameters. sIL-2R appears to have no ability to predict cardiovascular mortality, which accounts for approximately one-half of all deaths. However, sIL-2R may be beneficial in predicting noncardiovascular mortality.

Clinicopathological significance of CD79a expression in classic Hodgkin lymphoma.

Classic Hodgkin lymphoma (CHL) is a lymphoid neoplasia characterized by the presence of large tumor cells, referred to as Hodgkin and Reed-Sternberg (HRS) cells, originating from B-cells in an inflammatory background. As the clinical significance of B-cell markers has yet to be fully elucidated, this study aimed to clarify the clinicopathological significance of CD79a in 55 patients with CHL. They were immunohistochemically divided into two groups, comprising of 20 CD79a-positive and 35 CD79a-negative patients. There was no significant correlation between CD79a and CD20 expression (rs = 0.125, P = 0.362). CD79a-positive patients were significantly older at onset (P = 0.011). There was no significant correlation between CD79a-positivity and clinical stage (P = 0.203), mediastinal involvement (P = 0.399), extranodal involvement (P = 0.749), or laboratory findings, including serum levels of lactate dehydrogenase (P = 1) and soluble interleukin-2 receptor (P = 0.251). There were significant differences in overall survival (OS) (P = 0.005) and progression-free survival (PFS) (P = 0.007) between CD79a-positive and CD79a-negative patients (5-year OS: 64.6% and 90.5%; 5-year PFS: 44.0% and 76.6%, respectively). Five patients in whom the majority (> 80%) of HRS cells expressed CD79a consisted of 4 males and 1 female aged between 52 and 81 years; 4 of them were in a limited clinical stage. We concluded that CD79a-positive CHL may have unique clinicopathological features.

Serum Levels of Interleukin-8 and Soluble Interleukin-6 Receptor in Patients with Stage-I Multiple Myeloma: A Case-Control Study.

Objective:Multiple myeloma (MM) remains an incurable disease that needs better recognition and further research. Previous studies elucidated the interaction between myeloma cells and showed the necessity of bone marrow stromal cells for the initiation and progression of MM. Many chemokines and their receptors including interleukin-8 (IL-8) and soluble interleukin-6 receptor (sIL-6R) play important roles in this interaction. The main purpose of this study is evaluating the serum level of IL-8 and sIL-6R on stage-I of MM patients and healthy controls. Methods:Serum samples from 30 stage-I MM patients (13 males and 17 females) and 30 healthy subjects as controls (13 males and 17 females) were examined in this study. The protein concentrations of serum IL-8 and sIL-6R were assessed by enzyme-linked immunosorbent assay (ELISA). Results:The mean level of IL-8 and sIL-6R were significantly elevated in stage-I MM. The mean levels of IL-8 were 1246.57±279.22 ng/ml in stage-I MM and 902.53± 294.61 ng/ml in controls (P<0.001). The mean levels of sIL-6R were 5.39±1.38 ng/ml and 4.1±1.14 ng/ml in stage-I MM and controls, respectively (P<0.001). The mean levels of IL-8 were 1342.18±193.4 ng/ml in patient females and 859± 278.2ng/ml in control females (P <0.001). The mean levels of sIL-6R were 5.21±1.55 ng/ml and 3.91±1.22 ng/ml in patient females and control females, respectively (P=0.01). The mean level of sIL-6R in patient males and control males were 5.63±1.43 ng/ml and 4.34±1.04 ng/ml, respectively (P=0.01). A significant correlation (Pearson’s correlation = 0.45, P=0.008) was observed in the population of females (patients and controls). Conclusion:The results of study suggest the possible involvement of IL-8 and the sIL-6R at stage-I MM and can better characterize the role of chemokines and their receptors in the disease process, especially in the early stages.

Characteristics of 68 patients with clinically proven sarcoidosis based on the Japan Society of Sarcoidosis and Other Granulomatous Disorders 2015 criteria.

The presence of histologically evident epithelioid granuloma is required for the diagnosis of sarcoidosis worldwide. The Japan Society of Sarcoidosis and Other Granulomatous Disorders 2015 diagnostic criteria (JSSOG 2015 criteria) includes "clinically proven diagnosis" (involvement of at least 2 of 3 systems confirmed solely by clinical assessment) because of the frequency of sarcoidosis with ocular, cardiac, and respiratory involvement in Japan and the difficulty of obtaining specimens. Here, we describe in detail the clinical presentation of clinically diagnosed sarcoidosis. We enrolled 68 consecutive patients with clinically diagnosed sarcoidosis (12 men, 56 women) based on the JSSOG 2015 criteria who were treated at Jichi Medical University between December 2018 and January 2000. We analyzed age at diagnosis, organ involvement, and laboratory findings. Age at diagnosis was unimodal in women. Ocular, splenic, cardiac, and skin involvement, and hypercalcemia were observed in 95.6%, 8.8%, 7.4%, 5.9%, and 35.0% of patients, respectively. High serum lysozyme and soluble interleukin-2 receptor (sIL-2R) levels, bilateral hilar lymphadenopathy on chest radiography, high-grade atrioventricular block or fatal ventricular arrhythmia, and bundle branch block were found in 18.8%, 48.3%, 95.6%, 5.0%, and 10.0% of patients, respectively. The age-specific distribution of clinically diagnosed sarcoidosis was similar to histologically diagnosed sarcoidosis in women, as previously reported. Rates of elevated serum lysozyme and sIL-2R levels were lower in this study than previously reported in histologically diagnosed patients in Japan.

Interim Serum Soluble Interleukin-2 Receptor Levels Are Strongly Associated with Prognosis in Newly Diagnosis DLBCL Patients

&lt;Background&gt; Serum soluble interleukin-2 receptor (sIL2R) levels are often measured to evaluate the state of lymphoma. The serum sIL2R level at diagnosis has been reported to be correlated with the prognosis of diffuse large B cell lymphoma (DLBCL) patients treated with the R-CHOP regimen. However, it is unclear whether interim sIL2R levels are associated with prognosis in DLBCL. Here, we analyzed the prognostic impact of interim serum sIL2R levels in DLBCL. &lt;Patients and Methods&gt; We retrospectively examined data for DLBCL patients who started receiving chemotherapy at the Japanese Red Cross Society Kyoto Daini Hospital between January 2012 and December 2018. All of the patients received R-CHOP-like regimens (rituximab plus pirarubicin or adriamycin, cyclophosphamide, vincristine, and prednisolone). The interim sIL2R level (I-IL2R) was defined as the value measured after the third chemotherapy cycle. I-IL2R levels of &gt;700 U/ml were regarded as positive. The primary endpoints of this study were progression-free survival (PFS) and overall survival (OS). The unadjusted probabilities of PFS and OS were estimated using the Kaplan-Meier method. The log-rank test and multivariate Cox regression analysis were used to assess the prognostic value of each clinical variable. &lt;Results&gt; In total, 102 patients were enrolled. The patients' median age was 73.5 years (range, 35-88), 58 patients (56.9%) were male, and 52 (51.0%) had poor revised International Prognostic Index scores. The median follow-up time was 25.2 months (range, 3.7-88.6). Twenty-three patients (22.5%) were I-IL2R-positive (&gt;700 U/ml). Univariate analysis revealed that I-IL2R-positivity was associated with a poor prognosis. The 3-y PFS rates of the I-IL2R-negative (&lt;700 U/ml) and I- IL2R-positive (&gt;700 U/ml) patients were 60.4% (95% confidence interval [95%CI], 46.2-71.9) and 37.5% (95%CI, 15.7-59.4; p&lt;0.001, log-rank test), respectively, and their 3-y OS rates were 82.2% (95%CI, 69.7-89.9) and 37.4% (95%CI, 13.8-61.4; p&lt;0.001, log-rank test), respectively. Multivariate analysis confirmed that the I-IL2R level is independently associated with prognosis. &lt;Conclusion&gt; The I-IL2R level of &gt;700 U/ml patients had poor prognosis. The I-IL2R level can be used to predict the outcomes of DLBCL patients. IL2R levels should be measured during chemotherapy, and I-IL2R-positive patients could be targeted with high-dose or novel therapies. As this study was based on a retrospective analysis and involved a small cohort and a limited follow-up period, further studies are needed to confirm the prognostic impact of I-IL2R. Figure Disclosures No relevant conflicts of interest to declare.

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.

Natural Killer Cell Function Tests by Flowcytometry-Based Cytotoxicity and IFN-γ Production for the Diagnosis of Adult Hemophagocytic Lymphohistiocytosis.

Although natural killer (NK) cell function is a hallmark of hemophagocytic lymphohistiocytosis (HLH), there is no standard method or data on its diagnostic value in adults. Thus, we performed a single-center retrospective study of 119 adult patients with suspected HLH. NK cell function was determined using both flowcytometry-based NK-cytotoxicity test (NK-cytotoxicity) and NK cell activity test for interferon-gamma (NKA-IFNγ). NK cell phenotype and serum cytokine levels were also tested. Fifty (42.0%) HLH patients showed significantly reduced NK cell function compared to 69 non-HLH patients by both NK-cytotoxicity and NKA-IFNγ (p < 0.001 and p = 0.020, respectively). Agreement between NK-cytotoxicity and NKA-IFNγ was 88.0% in HLH patients and 58.0% in non-HLH patients. NK-cytotoxicity and NKA-IFNγ assays predicted HLH with sensitivities of 96.0% and 92.0%, respectively. The combination of NKA-IFNγ and ferritin (>10,000 µg/L) was helpful for ruling out HLH, with a specificity of 94.2%. Decreased NK-cytotoxicity was associated with increased soluble IL-2 receptor levels and decreased CD56dim NK cells. Decreased NKA-IFNγ was associated with decreased serum cytokine levels. We suggest that both NK-cytotoxicity and NKA-IFNγ could be used for diagnosis of HLH. Further studies are needed to validate the diagnostic and prognostic value of NK cell function tests.

Pathological assessment of the lymph node biopsies for lymphadenopathy in rheumatoid arthritis

Objectives: To assess the incidence of reactive lymph node hyperplasia (RLH) and the diagnostic characteristics that can help differentiate it from lymphoproliferative disorders (LPD) in patients with rheumatoid arthritis (RA).Methods: Data on patient characteristic from 32 consecutive RA patients with lymphadenopathy at a single medical center over a 6-year period were collected and analyzed to determine whether any of these characteristics can differentiated RLH from LPD.Results: LPD including methotrexate (MTX) - associated LPD (MTX-LPD) and RLH were diagnosed in 19 and 10 patients, respectively. Conclusive diagnosis was not reached in the remaining three cases and they were regarded as grey-zone cases. Age, levels of lactate dehydrogenase (LDH) and soluble interleukin-2 receptor (sIL-2R), as well as maximum standardized uptake value (SUVmax), were significantly higher in LPD than in RLH patients. The diagnosis cut-off values for these parameters were 66 year, 169 U/L, 899 U/mL and 8.18, respectively, based on the receiver operating characteristics curve analysis for both RLH and LPD.Conclusions: About one-third of patients with RA who presented with lymphadenopathy had reactive lymph node enlargement. Older age and higher levels of LDH, sIL-2R, and SUVmax are more associated with LPD than should be considered when deciding to perform a biopsy.

Progress in Allogeneic Hematopoietic Cell Transplantation in Adult T-Cell Leukemia-Lymphoma.

The prognosis of aggressive adult T-cell leukemia-lymphoma (ATL) remains poor because of frequent infections and drug resistance. Dose-intensified chemotherapy followed by autologous stem cell transplantation failed to improve the prognosis of patients with ATL; however, we first revealed that allogeneic hematopoietic cell transplantation (allo-HCT) might improve their prognosis. We showed that reduced-intensity stem cell transplantation using peripheral blood was feasible for elderly patients. Further, the prognosis of patients in remission, who receive cord blood transplantation, has been recently improved and is equivalent to that of patients who receive transplants from other stem cell sources. As for the timing of HCT, the patients who underwent transplantation early showed better outcomes than those who underwent transplantation late. Based on the analysis of patients with aggressive ATL, including those who received transplants, we identified five prognostic factors for poor outcomes: acute-type ATL, poor performance status, high soluble interleukin-2 receptor levels, hypercalcemia, and high C-reactive protein level. Next, we developed a new prognostic index: the modified ATL-PI. The overall survival (OS) rates were significantly higher in patients who underwent allo-HCT than those who did not in the intermediate and high-risk groups stratified using the modified ATL-PI. Two new anti-cancer agents, mogamulizumab and lenalidomide, were recently approved for ATL patients in Japan. They are expected to induce longer survival in ATL patients when administered along with transplantation. However, a retrospective analysis that the risk of severe, acute, and corticosteroid-refractory graft-versus-host disease was higher in patients who received mogamulizumab before allo-HCT, and that mogamulizumab might increase the transplant-related mortality (TRM) rates and decrease the OS rates compared to those of patients who did not receive mogamulizumab. However, our recent study showed that administration of mogamulizumab before allo-HCT tended to improve the survival of patients with ATL. In conclusion, allo-HCT procedures for patients with aggressive ATL have considerably progressed and have helped improve the prognosis of these patients; however, many concerns still remain to be resolved. Further development of allo-HCT by using new molecular targeting agents is required for the improvement of cure rates in patients with ATL.

Biomarkers of Systemic Lupus Erythematosus and Systemic Sclerosis diseases activity in a sample of Egyptian patients :Soluble Intercellular Adhesion Molecule-1 and Soluble Interleukin-2 Receptor, Case Control Study

Systemic Lupus Erythematosus (SLE) and systemic sclerosis (SSc) are systemic inflammatory autoimmune disorders characterized by a large spectrum of clinical and laboratory features. The aim of the present study was to investigate the possible use of serum level of soluble intercellular adhesion molecule-1(sICAM-1) and soluble interleukin-2 receptor (sIL-2Ra) as biomarkers for monitoring of SLE and SSc disease activity. Moreover, it aimed to compare the specificity and sensitivity as well as cut-off value of both biomarkers in a sample of Egyptian patients. 50 SLE patients, 30 SSc patients and 60 age and sex matched healthy controls were enrolled in our study. sICAM-1and sIL-2Ra were measured in serum samples obtained from all participants. In addition to Erythosedimentation rate (ESR), complete blood count (CBC), Antineuclearantibodies (ANA) estimation, disease activity of both diseases were also assessed. sICAM-1and sIL-2Ra levels were higher in SLE and SSc patients versus control. Both parameters are correlated with each other as well as the activity parameters. A cut-off levels of 455.59 (ng/ml) &amp;2525935 (pg/ml) in both SLE &amp; SSs respectively was observed with the highest specificity and sensitivity. It could be concluded that sICAM-1 and sIL-2Ra are noninvasive biomarkers for SLE and SSc that could play a pathophysiologic role in development and progression of both diseases. Moreover, sICAM-1 and sIL-2Ra are correlated with the disease activity at cut-off values of 455.59 (ng/ml) &amp; 2525935(pg/ml) respectively.

Fulminant hepatitis and elevated levels of sIL-2R in thyroid storm.

SummaryWe report the case of a 48-year-old man with thyroid storm associated with fulminant hepatitis and elevated levels of soluble interleukin-2 receptor (sIL-2R). Fatigue, low-grade fever, shortness of breath, and weight loss developed over several months. The patient was admitted to the hospital because of tachycardia-induced heart failure and liver dysfunction. Graves’ disease with heart failure was diagnosed. He was treated with methimazole, inorganic iodide, and a β-blocker. On the day after admission, he became unconscious with a high fever and was transferred to the intensive care unit. Cardiogenic shock with atrial flutter was treated with intra-aortic balloon pumping and cardioversion. Hyperthyroidism decreased over 10 days, but hepatic failure developed. He was diagnosed with thyroid storm accompanied by fulminant hepatitis. Laboratory investigations revealed elevated levels of sIL-2R (9770 U/mL). The fulminant hepatitis was refractory to plasma exchange and plasma filtration with dialysis, and no donors for liver transplantation were available. He died of hemoperitoneum and gastrointestinal hemorrhage due to fulminant hepatitis 62 days after admission. Elevated circulating levels of sIL-2R might be a marker of poor prognosis in thyroid storm with fulminant hepatitis.Learning points: The prognosis of thyroid storm when fulminant hepatitis occurs is poor.Liver transplantation is the preferred treatment for fulminant hepatitis induced by thyroid storm refractory to plasma exchange.Elevated levels of soluble interleukin-2 receptor might be a marker of poor prognosis in patients with thyroid storm.

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.

Impact of serum levels of IL-18 and soluble IL-2 receptor on the clinical outcome of patients with diffuse large B-cell lymphoma treated with R-CHOP regimen.

Aim & methods:To assess the impact of pretreatment serum levels of IL-18 and soluble IL-2 receptor (sIL-2R) on the clinical outcome of patients with diffuse large B-cell lymphoma treated with an R-CHOP protocol. Total 73 patients were included.Results:Elevated serum IL-18 (using mean as cutoff) was associated with numerically lower complete remission, and 3-year disease-free survival rates; however, the difference was not statistically significant. Nevertheless, the 3-year overall survival rates were significantly more favorable for the lower serum level group. Correspondingly, the complete remission, 3-year disease-free survival and overall survival rates for patients with low pretreatment sIL-2R levels were significantly better than individuals with higher levels.Conclusion:There is a growing body of evidence supporting the utility of pretreatment serum levels of sIL-2R and IL-18 as prognostic factors in diffuse large B-cell lymphoma patients.

Utility of serum ferritin and soluble interleukin-2 receptor as markers of disease activity in childhood systemic lupus erythematosus.

ObjectiveTo assess the usefulness of serum ferritin and soluble interleukin-2 receptor (sIL-2r) levels as markers of disease activity in childhood systemic lupus erythematosus (cSLE) and their role in screen for subclinical macrophage activation syndrome (MAS).Patients and methodsThis is a cross-sectional analysis of prospectively collected data. Consecutive children who met the Systemic Lupus International Collaborating Clinics (SLICC) criteria were enrolled between June 2015 and June 2017. All patients interviewed and assessed for disease activity using SLE disease activity index (SLEDAI). Biochemical and serological tests including markers of disease activity and MAS were measured by standard laboratory procedure.ResultsA total of 31 (25 female; 6 male) consecutive cSLE patients with a mean age of 10.6 (±3.2) years were included. The most frequent manifestations were mucocutaneous and musculoskeletal (84%) followed by hematological (64.5%) then renal involvement (58%). Twenty-two patients had active disease (SLEDAI ≥ 4), with a mean of 9.8. Mean serum ferritin and sIL-2r were 555 (±1860) and 2789 (±1299) respectively. Both correlated significantly with leucocyte, platelet count, transferrin, C3 and SLEDAI (p < 0.05). Additionally, sIL-2r had positive correlation with ANA, ds-DNA and C4. Both ferritin and sIL-2r had weak correlation with ESR, but no correlation with CRP. Twelve patients had a recent infection. However, they were comparable to patients without infection with regard to all clinical and laboratory features. Three patients had MAS proved by bone marrow aspiration.ConclusionMeasurement of serum ferritin and sIL-2r might help in assessing disease activity of cSLE. Both might be good screening markers for MAS in cSLE. A larger prospective study is required to allow more definitive conclusions.