Soluble Interleukin-2 Receptor Levels Research Articles

Overall survival and post-spontaneous regression relapse-free survival of patients with lymphoproliferative disorders associated with rheumatoid arthritis: a multi-center retrospective cohort study.

To clarify factors affecting 5-year survival rates and relapse rates after spontaneous regression (SR) of lymphoproliferative disorders (LPDs) in patients with rheumatoid arthritis (RA). This retrospective longitudinal study comprised 232 patients with RA diagnosed with LPDs between January 2000 and March 2017 at eight hospitals in Japan. The Kaplan-Meier method was used to analyze survival and the Cox proportional hazard model was applied to identify predictive factors. Among all patients, 1-, 2- and 5-year overall survival rates were 89.5%, 86.1%, and 78.2%, respectively. Multivariable analysis revealed four 5-year survival risk factors assessed at diagnosis: age above 70 years (p = .002), deep lymphadenopathy and/or more than one extranodal lesion (p = .008), Eastern Cooperative Oncology Group/Zubrod performance status of 2-4 (p = .004), and classic Hodgkin lymphoma (CHL) histology (p = .047). Among 143 patients who achieved SR, 2- and 5-year relapse rates were 14.2% and 24.9%, respectively. CHL histology (p = .003) and serum soluble interleukin-2 receptor levels exceeding 2000 IU/L (p = .014) were associated with post-SR relapse-free survival. Blood lymphocyte counts were significantly lower at relapse than at 3-6 months prior (p < .001). Assessment of the above risk factors and routine inspection of blood lymphocyte counts could aid in the care management of LPDs in RA.

Milky Ascites With Severe Peritonitis

View Large Image Figure ViewerDownload Hi-res image Download (PPT) Question: A 52-year-old woman who had undergone total hysterectomy and radiation therapy (RT) for cervical cancer 7 years earlier was referred for evaluation of severe pain throughout the abdomen. An abdominal computed tomography scan showed a large amount of ascites (Figure A) and thickening of the walls of the small intestine (mainly in the pelvis; Figure B) and the bladder (Figure C). A puncture sample of the ascites revealed milky fluid (Figure D) and exudate. Laboratory blood tests revealed a severe inflammatory reaction (C-reactive protein level, 260 mg/L; reference range, 0–1.4 mg/L) and elevated levels of tumor markers (carbohydrate antigen 125 level, 287 U/mL [reference range, ≤35 U/mL], and soluble IL-2 receptor level, 1211 U/mL [reference range, 122–496 U/mL]). No renal or liver damage was apparent, and no autoantibodies were detected. A whole-body computed tomography scan revealed no findings suggestive of any malignant tumors, such as space-occupying legions or enlarged lymph nodes. In addition, no remarkable findings were observed in blood and ascites cultures, such as acid-fast microorganisms or cytological abnormalities of ascites. Esophagogastroduodenoscopy showed no peptic ulcer, neoplastic regions, or inflammatory findings; however, the colonoscope could not pass through the sigmoid colon, probably because of RT-induced adhesions. In accordance with the diagnosis of peritonitis, the patient fasted and underwent treatment with anti-inflammatory agents, antibiotics, and diuretics. The abdominal ascites was diminished and other symptoms were relieved during treatment; however, abdominal pain and ascites recurred after treatment and persisted for several weeks. Such episodes recurred several times every few weeks. What are the possible causes of repeated milky ascites? See the Gastroenterology web site (www.gastrojournal.org) for more information on submitting your favorite image to Clinical Challenges and Images in GI.

A retrospective matched cohort single-center study evaluating outcomes of COVID-19 and the impact of immunomodulation on COVID-19-related cytokine release syndrome in solid organ transplant recipients.

This retrospective matched cohort study describes 30 solid organ transplant (SOT) patients with Coronavirus Disease 2019 (COVID‐19) matched 1:2 to 60 non‐SOT patients (control group) based on age, body mass index (BMI), and comorbidities (hypertension and diabetes mellitus with hemoglobin A1c > 8.0%). The SOT group had a higher proportion of cardiovascular disease (P < .05). During the index hospitalization, there were no significant differences with regard to disease severity or critical care needs (mechanical intubation, vasopressors, and renal replacement therapy). At 28 days, 4 (13%) patients died in the SOT group and 8 (13%) patients died in the control group (P = 1.0). Nineteen patients received tocilizumab in the SOT group compared to 29 patients in the control group. Among these patients, interleukin‐6 (IL‐6) and soluble interleukin‐2 receptor (sIL2R) levels increased after tocilizumab and interleukin‐10 (IL‐10) levels decreased after tocilizumab. Overall, SOT patients had comparable mortality to non‐SOT patients, although numerically more SOT patients received tocilizumab (63% vs 48%) and steroids (37% vs 20%). Larger, multi‐center studies are needed to ascertain these findings. Lastly, the complex cytokine release syndrome in COVID‐19 remains an area of intense research and the analysis of key interleukin levels (IL‐6, IL‐10, and sIL2R) in this study contributes to the understanding of this process.

Interleukin 6 trans-signaling is a critical driver of lung allograft fibrosis.

Histopathologic examination of lungs afflicted by chronic lung allograft dysfunction (CLAD) consistently shows both mononuclear cell (MNC) inflammation and mesenchymal cell (MC) fibroproliferation. We hypothesize that interleukin 6 (IL-6) trans-signaling may be a critical mediator of MNC-MC crosstalk and necessary for the pathogenesis of CLAD. Bronchoalveolar lavage (BAL) fluid obtained after the diagnosis of CLAD has approximately twofold higher IL-6 and soluble IL-6 receptor (sIL-6R) levels compared to matched pre-CLAD samples. Human BAL-derived MCs do not respond to treatment with IL-6 alone but have rapid and prolonged JAK2-mediated STAT3Tyr705 phosphorylation when exposed to the combination of IL-6 and sIL-6R. STAT3 phosphorylation within MCs upregulates numerous genes causing increased invasion and fibrotic differentiation. MNC, a key source of both IL-6 and sIL-6R, produce minimal amounts of these proteins at baseline but significantly upregulate production when cocultured with MCs. Finally, the use of an IL-6 deficient recipient in a murine orthotopic transplant model of CLAD reduces allograft fibrosis by over 50%. Taken together these results support a mechanism where infiltrating MNCs are stimulated by resident MCs to release large quantities of IL-6 and sIL-6R which then feedback onto the MCs to increase invasion and fibrotic differentiation.

Cessation of methotrexate and a small intestinal resection provide a good clinical course for a patient with a jejunum perforation induced by a methotrexate-associated lymphoproliferative disorder: a case report

BackgroundMethotrexate (MTX) is a frequently used drug in the treatment of rheumatoid arthritis (RA), but occurrences of lymphoproliferative disorders (LPD) have been reported in patients undergoing an MTX regimen. Almost half of the patients with methotrexate-associated lymphoproliferative disorders (MTX-LPD) have extranodal lesions; moreover, although extremely rare, digestive tract perforations resulting from the extranodal lesions of MTX-LPD have also been reported.Case presentationWe describe the case of an 81-year-old woman with RA who had been prescribed MTX at 6 mg per week for the past 11 years. She was admitted to our hospital with occasional abdominal pain and was first diagnosed with enteritis. Her abdominal pain did not improve, and a computed tomography scan showed abdominal effusion and free air in the abdominal cavity. She was diagnosed with a digestive tract perforation and underwent emergency surgery. The perforation site was identified in the jejunum, and she underwent small intestinal resection around the perforated region. The pathological findings showed an ulcer in the jejunum and infiltration of large atypical lymphocytes around the perforated region. An immunohistochemical examination revealed the expression of a cluster of differentiation 20 and latent membrane protein 1. Considering the patient’s history of RA treated with MTX, she was diagnosed as having Epstein–Barr virus (EBV)-related MTX-LPD with a histological diagnosis of EBVMCU. MTX was discontinued after the surgery, and her soluble interleukin-2 receptor (sIL-2R) levels had returned to normal 1 year later. She has had a good course for the 2 years since surgery and remains asymptomatic with no recurrence of MTX-LPD, as confirmed by the sIL-2R levels.ConclusionWe experienced a rare case of the jejunum perforation induced by MTX-LPD. Since only a few cases have been reported of a patient with small intestinal perforation induced by MTX-LPD, further research is necessary to evaluate the clinicopathological features of MTX-LPD. The patient had disease remission after surgery and by discontinuing MTX treatment; our case did not require chemotherapy. EBV-positive patients, especially those with a pathological presentation of EBVMCU, could have a higher likelihood of remission, which could have been a factor in the present case.

Four Biomarkers Linked to Activation of Cluster of Differentiation 8-Positive Lymphocytes Predict Clinical Outcomes in Pediatric Acute Liver Failure.

Immune dysregulation contributes to the pathogenesis of pediatric acute liver failure (PALF). Our aim was to identify immune activation markers (IAMs) in PALF that are associated with a distinct clinical phenotype and outcome. Among 47 PALF study participants, 12 IAMs collected ≤6days after enrollment were measured by flow cytometry and IMMULITE assay on blood natural killer and cluster of differentiation 8-positive (CD8+ ) lymphocytes and subjected to unsupervised hierarchical analyses. A derivation cohort using 4 of 12 IAMs which were available in all participants (percent perforin-positive and percent granzyme-positive CD8 cells, absolute number of CD8 cells, soluble interleukin-2 receptor level) were sufficient to define high (n=10), medium (n=15), and low IAM (n=22) cohorts. High IAM was more frequent among those with indeterminate etiology than those with defined diagnoses (80% versus 20%, P<0.001). High IAM was associated with higher peak serum total bilirubin levels than low IAM (median peak 21.7 versus 4.8mg/dL, P<0.001) and peak coma grades. The 21-day outcomes differed between groups, with liver transplantation more frequent in high IAM participants (62.5%) than those with medium (28.2%) or low IAM (4.8%) (P=0.002); no deaths were reported. In an independent validation cohort (n=71) enrolled in a prior study, segregation of IAM groups by etiology, initial biochemistries, and short-term outcomes was similar, although not statistically significant. High serum aminotransferases, total bilirubin levels, and leukopenia at study entry predicted a high immune activation profile. Four circulating T-lymphocyte activation markers identify a subgroup of PALF participants with evidence of immune activation associated with a distinct clinical phenotype and liver transplantation; these biomarkers may identify PALF participants eligible for future clinical trials of early targeted immunosuppression.

Massive splenomegaly due to splenic marginal zone B‐cell lymphoma

A 73-year-old man presented with an abdominal mass that gradually swells over 3months. He denied any subjective symptoms. Physical examination revealed massive enlargement of the spleen-the spleen had crossed the midline and its lower margin extended into the lower abdomen.

Prolonged, Continuous Treatment of Hairy Cell Leukemia Patients With Recombinant Interferon-α2a

AbstractInterferons are not curative in hairy cell leukemia (HCL), and retreatment is necessary in most patients whose therapy is stopped. In an attempt to maintain or improve responses, we administered recombinant interferon-α2a (rlFN-α2a) continuously to patients with HCL who initially responded to this therapy. Of 53 evaluable patients enrolled in this study, 32 have received rlFN-α2a continuously for a median of 5 years. Patients received 3 million units of rlFN-α2a subcutaneously (SC) daily for 6 months, followed, in responding patients, by the same dose three times weekly. Twenty-one patients (40%) discontinued IFN after a median of 29 months, seven of whom developed resistant disease in association with anti-IFN antibodies. Treatment produced high response rates: complete response plus partial response (CR + PR) = 40 of 53 (76%), CR + PR + minor response (MR) = 43 of 53 (82%), with no differences in response rates between patients with and without splenectomy. Sixteen patients who had MR at 18 months had PR with prolonged treatment, nine of whom had a significant further reduction in the hairy cell infiltrate in the bone marrow (BM). The median granulocyte and platelet counts have continued to increase and the median serum soluble interleukin-2 receptor (slL-2R) level has continued to decrease with prolonged treatment. Two patients developed erythrocytosis that may be treatment related, but no other new toxicities were noted with prolonged treatment. We conclude that prolonged, continuous rlFN-α2a treatment has acceptable toxicity, is not associated with late development of IFN resistance, and results in continued hematologic improvement with time on treatment. This is a US government work. There are no restrictions on its use.

Ruxolitinib-ECP combination treatment for refractory severe chronic graft-versus-host disease.

Glucocorticoid-refractory (SR) chronic (c) graft-versus-host disease (GVHD) is a multisystem immunological disease and the leading cause of non-relapse mortality (NRM) in patients surviving longer than 2 years after allogeneic hematopoietic cell transplantation. Both ruxolitinib (RUX) and extracorporeal photopheresis (ECP) have shown activity for SR-cGVHD which motivated us to treat refractory cGHVD patients with the RUX-ECP combination. In this retrospective survey, 23 patients received RUX-ECP as salvage therapy for SR-cGVHD. The best response (CR or PR) at any time point during treatment was 74% (17/23) including 9% (2/23) CR and 65% (15/23) PR. The 24-months-survival was 75% (CI 56.0-94.1). Newly diagnosed cytopenia occurred in 22% (5/23) and CMV reactivation was observed in 26% (6/23) of the patients. Serum levels of soluble interleukin-2 receptor (sIL-2R) correlated with response. Our retrospective analysis shows that the RUX-ECP combination is safe and has activity in a fraction of patients with SR-cGVHD, which needs validation in a prospective trial.

Mogamulizumab for adult T-cell leukemia-lymphoma: a multicenter prospective observational study

AbstractMonitoring of Immune Responses Following Mogamulizumab-Containing Treatment in Patients with Adult T-Cell Leukemia-Lymphoma (ATL) (MIMOGA) is a multicenter prospective observational study to establish the most effective and safe treatment strategy using mogamulizumab for ATL patients (UMIN000008696). Mogamulizumab-naive patients were enrolled (n = 102), of whom 101 received mogamulizumab-containing treatment (68 acute, 18 lymphoma, 12 chronic, and 3 smoldering subtypes). At enrollment, there was a significant inverse correlation between serum soluble interleukin-2 receptor (sIL-2R) levels and percentages of Tax-specific cytotoxic T lymphocytes (Tax-CTLs) in the entire lymphocyte population or in the CD8+ T cell subset, but there was not a correlation with cytomegalovirus pp65–specific cytotoxic T lymphocytes (CMV-CTLs). The overall response rate was 65%, and median progression-free survival and overall survival (OS) were 7.4 and 16.0 months, respectively. A higher percentage of Tax-CTLs, but not CMV-CTLs, within the entire lymphocyte population or in the CD8+ T cell subset was significantly associated with longer survival. Multivariate analysis identified the clinical subtype (acute or lymphoma type), a higher sIL-2R level, and a lower percentage of CD2−CD19+ B cells in peripheral blood mononuclear cells as significant independent unfavorable prognostic factors for OS. This indicates that a higher percentage of B cells might reflect some aspect of a favorable immune status leading to a good outcome with mogamulizumab treatment. In conclusion, the MIMOGA study has demonstrated that mogamulizumab exerts clinically meaningful antitumor activity in ATL. The patient's immunological status before mogamulizumab was significantly associated with treatment outcome. Further time series immunological analyses, in addition to comprehensive genomic analyses, are warranted.

Abatacept Use Is Associated with Steroid Dose Reduction and Improvement in Fatigue and CD4-Dysregulation in CVID Patients with Interstitial Lung Disease

Interstitial lung disease (ILD) represents a severe clinical manifestation of systemic immune dysregulation in patients with common variable immunodeficiency (CVID). Its treatment often requires systemic immunosuppression beyond corticosteroids. To assess the safety and efficacy of abatacept in patients with CVID and ILD. Ten patients with confirmed diagnosis ofCVIDand ILD were included in a single-center, prospective, open-label, nonrandomized trial. Abatacept was administered subcutaneously at a dose of 125 mg/wk for 12 months. Abatacept was a safe treatment for ILD in CVID except for 1 case of bronchopulmonary aspergillosis. One additional patient terminated the trial prematurely because of recurrent bronchitis. Five of 8 patients treated per protocol benefited from the treatment according to American ThoracicSociety/European Respiratory Society criteria. The primary end point of the study was met because single breath diffusing capacity of the lung for carbon monoxide was stable (62.5%) or improved (37.5%) in all patients treated per protocol. Although nodules (71%) and ground-glass opacities (57%) improved in most patients, other computed tomographypathologies were less responsive. Quality of life improved in 87.5% and fatigue in 57% of patients. Abatacept treatment was associated with significant improvement in CD4 T-cell dysregulation, signified by a decrease in serum soluble IL-2 receptor levels and of proliferating Ki67+ CD4 T cells, and a recovery of total lymphocytes, CD4+ T cells, and naive CD4 T cells. Abatacept may represent a treatment option for CVID-associated ILD. This pilot study demonstrated a good safety profile, steroid-sparing effect, positive immune modulation, and overall positive treatment response especially in quality of life. Larger controlled studies are needed to confirm these findings.

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.

SIL-2R levels predict the spontaneous remission in sarcoidosis

BackgroundSarcoidosis is associated with a wide range of disease outcomes including spontaneous remission and progressive courses. It is necessary to identify patients with spontaneous remission without corticosteroid treatment. This study aimed to identify the markers for predicting spontaneous remission in patients with sarcoidosis. Methods453 patients diagnosed with sarcoidosis at the Shanghai Pulmonary Hospital between Jan 2013 and Aug 2017 and were followed-up for more than 2 years were enrolled. Patients were divided into spontaneous remission group and non-remission group. Differences of variables between groups were analyzed by chi-square test or unpaired Student's t-test. The cumulative spontaneous remission rate was analyzed using the Kaplan-Meier method. ResultsOf the 173 patients (stage I/II/III/IV, 53/110/6/4) without medication, 117 (67.6%) achieved spontaneous remission. The serum level of soluble interleukin-2 (IL-2) receptor (sIL-2R) and the ratio of CD4/CD8 was significantly lower and CD8+ T cell was significantly higher in spontaneous remission group when compared with non-remission group (P < 0.001, P = 0.042 and P = 0.048). Multivariate logistic regression model showed sIL-2R level was an independent predictor of spontaneous remission (P = 0.021). In stage I subgroup, a cut-off value of 1129.5U/ml was obtained from the ROC curve, which yielded a sensitivity of 50% and a specificity of 94.4%. In stage II subgroup, a cut-off value of 1026.5U/ml was obtained with a sensitivity of 66.7% and a specificity of 68.7%. ConclusionThis study provided useful information that sIL-2R level could be used as a maker for spontaneous remission in determining the treatment strategies for patients with pulmonary sarcoidosis.

Ocular sarcoidosis: clinical experience and recent pathogenetic and therapeutic advancements

PurposeTo describe the ocular manifestations in a cohort of patients with systemic sarcoidosis (SS). Recent advances in the pathophysiology, diagnosis, and therapy of SS are also discussed.MethodsData from 115 Italian patients diagnosed between 2005 and 2016 were retrospectively reviewed. All but the first 17 patients underwent a comprehensive ophthalmologic examination. The diagnosis was based on clinical features, the demonstration of non-caseating granulomas in biopsies from involved organs, and multiple imaging techniques. Data on broncho-alveolar lavage fluid analysis, calcemia, calciuria, serum angiotensin-converting enzyme levels and soluble interleukin-2 receptor levels were retrieved when available.ResultsOcular involvement, detected in 33 patients (28.7%), was bilateral in 29 (87.9%) and the presenting feature in 13 (39.4%). Anterior uveitis was diagnosed in 12 patients (36.4%), Löfgren syndrome and uveoparotid fever in one patient each (3%), intermediate uveitis in 3 patients (9.1%), posterior uveitis in 7 (21.2%), and panuveitis in 9 (27.3%). First-line therapy consisted of corticosteroids, administered as eyedrops (10 patients), sub-Tenon’s injections (1 patient), intravitreal implants (9 patients), or systemically (23 patients). Second-line therapy consisted of steroid-sparing immunosuppressants, including methotrexate (10 patients) and azathioprine (10 patients). Based on pathogenetic indications that tumor necrosis factor (TNF)-α is a central mediator of granuloma formation, adalimumab, targeting TNF-α, was employed in 6 patients as a third-line agent for severe/refractory chronic sarcoidosis.ConclusionUveitis of protean type, onset, duration, and course remains the most frequent ocular manifestation of SS. Diagnostic and therapeutic advancements have remarkably improved the overall visual prognosis. An ophthalmologist should be a constant component in the multidisciplinary approach to the treatment of this often challenging but intriguing disease.

Tocilizumab Treatment for Cytokine Release Syndrome in Hospitalized Patients With Coronavirus Disease 2019: Survival and Clinical Outcomes

BackgroundTocilizumab, an IL-6 receptor antagonist, can be used to treat cytokine release syndrome (CRS), with observed improvements in a coronavirus disease 2019 (COVID-19) case series.Research QuestionThe goal of this study was to determine if tocilizumab benefits patients hospitalized with COVID-19.Study Design and MethodsThis observational study of consecutive COVID-19 patients hospitalized between March 10, 2020, and March 31, 2020, and followed up through April 21, 2020, was conducted by chart review. Patients were treated with tocilizumab using an algorithm that targeted CRS. Survival and mechanical ventilation (MV) outcomes were reported for 14 days and stratified according to disease severity designated at admission (severe, ≥ 3 L supplemental oxygen to maintain oxygen saturation > 93%). For tocilizumab-treated patients, pre/post analyses of clinical response, biomarkers, and safety outcomes were assessed. Post hoc survival analyses were conducted for race/ethnicity.ResultsAmong the 239 patients, median age was 64 years; 36% and 19% were black and Hispanic, respectively. Hospital census increased exponentially, yet MV census did not. Severe disease was associated with lower survival (78% vs 93%; P < .001), greater proportion requiring MV (44% vs 5%; P < .001), and longer median MV days (5.5 vs 1.0; P = .003). Tocilizumab-treated patients (n = 153 [64%]) comprised 90% of those with severe disease; 44% of patients with nonsevere disease received tocilizumab for evolving CRS. Tocilizumab-treated patients with severe disease had higher admission levels of high-sensitivity C-reactive protein (120 vs 71 mg/L; P < .001) and received tocilizumab sooner (2 vs 3 days; P < .001), but their survival was similar to that of patients with nonsevere disease (83% vs 91%; P = .11). For tocilizumab-treated patients requiring MV, survival was 75% (95% CI, 64-89). Following tocilizumab treatment, few adverse events occurred, and oxygenation and inflammatory biomarkers (eg, high-sensitivity C-reactive protein, IL-6) improved; however, D-dimer and soluble IL-2 receptor (also termed CD25) levels increased significantly. Survival in black and Hispanic patients, after controlling for age, was significantly higher than in white patients (log-rank test, P = .002).InterpretationA treatment algorithm that included tocilizumab to target CRS may influence MV and survival outcomes. In tocilizumab-treated patients, oxygenation and inflammatory biomarkers improved, with higher than expected survival. Randomized trials must confirm these findings.

Soluble interleukin-2 receptor (sIL-2r) level is a limited test for the diagnosis of adult secondary hemophagocytic lymphohistiocytosis.

Soluble interleukin-2 receptor (sIL-2r) level is used as a diagnostic tool in hemophagocytic lymphohistiocytosis (HLH). However, evidence supporting its use among adults is inadequate. We conducted a retrospective study to assess the performance characteristics of sIL-2r for the diagnosis of adult HLH. One hundred thirty-two adults with sIL-2r levels sent for evaluation of HLH over a ten-year period were included. Sixty-five (49%) met criteria for HLH. Mean sIL-2r was significantly higher among patients with HLH relative to all patients without HLH (12942U/ml vs. 6308U/mL, P=.00311). However, when comparing mean sIL-2r in the HLH group to those in the non-HLH group with primary diagnoses of hematologic malignancy (8911U/mL), sepsis (7127U/mL), and rheumatologic disease (4624U/mL), no significant differences were found (P=.241, P=.178, and P=.0607, respectively). There was only weak correlation between sIL-2r and diagnosis of HLH (r=.253). The standard cutoff sIL-2r>2400 U/ml yielded a sensitivity of 89.2% and specificity of 38.8%. The area under the curve for the corresponding receiver-operator curve was 0.691, consistent with a poor discriminating ability for the diagnosis of HLH. sIL-2r is a limited test for the diagnosis of adult secondary HLH, and its role in this setting should be reevaluated.

Pretreatment serum soluble interleukin-2 receptor level predicts survival in patients with newly diagnosed follicular lymphoma

This retrospective, multicenter observational study investigated the prognostic value of pretreatment serum soluble interleukin-2 receptor (sIL-2R) level for outcomes of newly diagnosed follicular lymphoma (FL) grade 1-3a who required treatment at diagnosis. A total of 628 patients were recorded, and 502 of these were eligible for analysis. Patients were divided into four quartiles, based on their serum sIL-2R levels as follows: Q1 (sIL-2R < 520 IU/mL), Q2 (520 ≤ sIL-2R < 1030 IU/mL), Q3 (1030 ≤ sIL-2R < 2530 IU/mL) and Q4 (sIL-2R ≥ 2530 IU/mL). Using a multivariable Cox proportional-hazards model, we showed the adjusted probability of overall survival (OS) decreased with increasing serum sIL-2R levels (p for trend = .007). Similar trends were observed for disease-specific survival (DSS) and progression-free survival (PFS). In conclusion, pretreatment serum sIL-2R levels significantly and dose-dependently associate with worse outcomes (OS, DSS and PFS) of patients with newly diagnosed FL.

Prevalence of atrial FDG uptake and association with atrial arrhythmias in patients with cardiac sarcoidosis

BackgroundThere is increasing evidence that a proportion of patients with cardiac sarcoidosis (CS) have atrial arrhythmias (AA). Although 18F-fluorodeoxy-glucose (FDG) uptake in the ventricle on positron emission tomography/computed tomography (PET/CT) is well studied, FDG uptake in the atrium has not been elucidated in detail. ObjectivesTo evaluate FDG uptake in the atrium and its relationship with AA in patients with CS. MethodsWe retrospectively investigated 62 CS patients. All patients underwent echocardiography and PET/CT. Serum angiotensin converting enzyme (ACE) and soluble IL-2 receptor (sIL-2R) levels, plasma N-terminal pro–brain natriuretic peptide (NT-proBNP) concentrations were also evaluated. ECG, Holter monitoring and device interrogations were used to detect AA. ResultsOf the studied population, 25 patients (40.3%) had AA, of which 2 patients had atrial tachycardia (AT) and 23 patients had atrial fibrillation (AF). Eighteen patients with AA had atrial FDG uptake on PET/CT, whereas 14 patients without AA had atrial FDG uptake (72.0% vs 37.8%, P = 0.017). Multivariate analysis revealed a significant association between AA and age (odds ratio [OR]: 1.15; 95% confidence interval [CI]: 1.01–1.31, P = 0.040), atrial FDG uptake (odds ratio [OR]: 7.23; 95% confidence interval [CI]: 1.91–27.36, P = 0.004), and left atrial diameter (OR: 1.08; 95% CI: 1.01–1.16, P = 0.027). Meanwhile, gender, serum ACE and BNP levels, and left ventricular ejection fraction were not associated with AA. ConclusionsAtrial FDG uptake was common in patients with CS and strongly associated with AA.

Dual role of IL6 mediated by mesenchymal stromal cell signaling to joint macrophages in osteoarthritis

Purpose: Osteoarthritis (OA) is a joint disease affecting > 5 million Canadians and patients have limited palliative and joint-replacement surgical options. Stromal cell therapy is emerging as a compelling treatment for OA. Our group led the first-in-Canada Ph1/2 trial with bone marrow mesenchymal stromal cells (BM-MSCs) in OA patients successfully; and significant improvements in patient outcomes were observed. This was accompanied with reduction in pro-inflammatory monocytes/macrophages (MΦs) in the synovial fluid (SF), suggestive of a clinical MSC anti-inflammatory effect. Understanding mechanism of action of MSCs in OA will enable effective donor MSC screening, and generation of more efficient engineered MSCs. While IL6 is a known pro-inflammatory mediator in the joint, and anti-IL6 therapeutics have been effective in treatment of Rheumatoid Arthritis, blocking single pro-inflammatory cytokines has been less effective in OA. This leads us to believe that IL6 might have complex roles. Indeed, MSCs-induced polarization of macrophages to inflammation resolving subtypes via IL6 signaling. This effect is not well studied in an OA joint where high levels of IL6 may have pro-inflammatory effects. We hypothesize that IL-6, which is known as pro-inflammatory mediator in OA is mediating anti-inflammatory function of MSCs through signaling via membrane-bound, but not soluble receptors. Methods: We co-cultured peripheral blood-derived MΦs with OA BM-MSCs in the presence of early and late SF from OA patients; or in the presence of IL6 antibody. Polarization of MΦs were assessed by analysis of surface markers and IL10 secretion. Levels of IL6 soluble IL6 receptor (sIL6R) were measured by ELISA. Results: Preliminary quantification of BM- MSC from OA patients revealed high IL6 secretion is associated with positive patient-reported outcomes. IL6 antibody abrogated MSCs-induced anti-inflammatory polarization of MΦs as shown by reduction of CD163 and CD206, suggesting a key role for IL6 in MSC anti-inflammatory effects on MΦs. Paradoxically, IL6 levels were increased in SF from late stage OA, whereas levels of sIL6R were comparable in early and late OA-SF. Further, the effect of MSCs on anti-inflammatory polarization of MΦs was attenuated in the presence of late OA-SF compared to early OA-SF. This could be due to enhanced IL6 trans-signaling (mediated by sIL6R) in late-stage OA SF expected to occur at the expense of reduced IL6 classical pathway (mediated by membrane bound IL6 receptor, mIL6R). To discriminate between classical vs. trans-signalling, we are using soluble gp130, a non-signaling decoy receptor which complexes IL6-sIL6R. Our preliminary result showed that sgp130 treatment enhanced the expression of CD163 in MΦs exposed to pooled OA SF. The classical IL6 pathway will be studied specifically by silencing mIL6R in MΦs using siRNA Conclusions: MSCs exert their anti-inflammatory action in OA, at least partly through polarization of MΦs to anti-inflammatory phenotype mediated by IL6. The ratio of IL6 signaling through trans-vs. classical signaling pathways is an important arbiter of MSC-modulation of joint inflammation.

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.