Presence of autoimmune disease affects not only risk but also survival in patients with B‐cell non‐Hodgkin lymphoma

Although autoimmune diseases (AIDs) are known to predispose to non‐Hodgkin lymphoma (NHL), their association with NHL prognosis has rarely been investigated. We examined associations between autoimmunity and B‐cell NHL onset by comparing AID history (determined by self‐report and medication review and supplemented by chart review where possible) among 435 adult B‐NHL patients in Hadassah‐Hebrew University Medical Center, diagnosed 2009‐2014, and 414 age‐and‐sex frequency‐matched controls. We examined AIDs as a whole, B‐ and T‐cell–mediated AIDs, and autoimmune thyroid diseases. Among cases, we used Kaplan‐Meier and Cox regression models to assess the association of AID with overall survival and relapse‐free survival, adjusting for prognostically important patient and disease characteristics such as Ki67% staining, International Prognostic Index, rituximab treatment, and histological subgroup. Autoimmune diseases were associated with B‐NHL (odds ratio [OR] = 1.95; 95% confidence interval (CI), 1.31‐2.92), especially AIDs mediated by B‐cell activation (OR = 5.20; CI, 1.90‐14.3), which were particularly associated with marginal zone lymphoma (OR = 19.3; CI, 4.59‐80.9). We found that time to relapse for all B‐NHL patients with AIDs was significantly shorter (mean of 49.21 mo [±3.22]) than among patients without AID (mean of 59.74 mo [±1.62]), adjusted hazard ratio [HRadj] = 1.69 (CI, 1.03‐2.79). Specifically, in patients with diffuse large B‐cell lymphoma, of whom 91.8% had received rituximab, a history of B‐cell–mediated AIDs was associated with shorter relapse‐free survival and overall survival, HRadj = 8.34 (CI, 3.01‐ 23.1) and HRadj = 3.83 (CI, 1.20‐12.3), respectively. Beyond confirming the well‐known association between AIDs and B‐NHL, we found that AID is an adverse prognostic factor in B‐cell lymphoma, associated with a shortened time to relapse, suggesting that there are specific therapeutic challenges in the subgroup of patients suffering from both these diseases. Further work is required to address mechanisms of resistance to standard treatment in the setting of AID‐associated B‐NHL. In the era of immunotherapy, these findings have particular relevance.This study was made possible by the generous support of the American people through the United States Agency for International Development (USAID)/MERC grant no. TA‐MOU‐11‐M31‐025. The contents are the responsibility of the authors and do not necessarily reflect the views of USAID or the United States Government; Israel Science Foundation (ISF) grant no. 877/10; and the Hadassah University Hospital Compensatory Fund. We thank Noemie Cohen for data entry

Two high-risk susceptibility loci at 6p25.3 and 14q32.13 for Waldenström macroglobulinemia

Waldenström macroglobulinemia (WM)/lymphoplasmacytic lymphoma (LPL) is a rare, chronic B-cell lymphoma with high heritability. We conduct a two-stage genome-wide association study of WM/LPL in 530 unrelated cases and 4362 controls of European ancestry and identify two high-risk loci associated with WM/LPL at 6p25.3 (rs116446171, near EXOC2 and IRF4; OR = 21.14, 95% CI: 14.40–31.03, P = 1.36 × 10 −54 ) and 14q32.13 (rs117410836, near TCL1; OR = 4.90, 95% CI: 3.45–6.96, P = 8.75 × 10 −19 ). Both risk alleles are observed at a low frequency among controls (~2–3%) and occur in excess in affected cases within families. In silico data suggest that rs116446171 may have functional importance, and in functional studies, we demonstrate increased reporter transcription and proliferation in cells transduced with the 6p25.3 risk allele. Although further studies are needed to fully elucidate underlying biological mechanisms, together these loci explain 4% of the familial risk and provide insights into genetic susceptibility to this malignancy. © 2018, The Author(s).Peer reviewe

Lipid trait variants and the risk of non-Hodgkin lymphoma subtypes : A Mendelian Randomization Study

Lipid traits have been inconsistently linked to risk of non-Hodgkin lymphoma (NHL). We examined the association of genetically predicted lipid traits with risk of diffuse large B-cell lymphoma (DLBCL), chronic lymphocytic leukemia (CLL), follicular (FL) and marginal zone (MZL) lymphoma using Mendelian randomization (MR) analysis. Methods: Genome-wide association study data from the InterLymph Consortium were available for 2,661 DLBCLs, 2,179 CLLs, 2,142 FLs, 824 MZLs, and 6,221 controls. SNPs associated (P < 5 × 10-8) with high-density lipoprotein (HDL, n = 164), low-density lipoprotein (LDL, n = 137), total cholesterol (TC, n = 161), and triglycerides (TG, n = 123) were used as instrumental variables (IV), explaining 14.6%, 27.7%, 16.8%, and 12.8% of phenotypic variation, respectively. Associations between each lipid trait and NHL subtype were calculated using the MR inverse variance-weighted method, estimating odds ratios (OR) per standard deviation and 95% confidence intervals (CI). Results: HDL was positively associated with DLBCL (OR = 1.14; 95% CI, 1.00-1.30) and MZL (OR = 1.09; 95% CI, 1.01-1.18), while TG was inversely associated with MZL risk (OR = 0.90; 95% CI, 0.83-0.99), all at nominal significance (P < 0.05). A positive trend was observed for HDL with FL risk (OR = 1.08; 95% CI, 0.99-1.19; P = 0.087). No associations were noteworthy after adjusting for multiple testing. Conclusions: We did not find evidence of a clear or strong association of these lipid traits with the most common NHL subtypes. While these IVs have been previously linked to other cancers, our findings do not support any causal associations with these NHL subtypes. Impact: Our results suggest that prior reported inverse associations of lipid traits are not likely to be causal and could represent reverse causality or confounding

Correction: Distinct germline genetic susceptibility profiles identified for common non-Hodgkin lymphoma subtypes

Correction to: Leukemia https://doi.org/10.1038/s41375-022-01711-0, published online 22 October 202

Shared Medical and Environmental Risk Factors in Dry Eye Syndrome, Sjogren’s Syndrome, and B-Cell Non-Hodgkin Lymphoma: A Case-Control Study

Objectives. To assess whether there are shared exposures associated with Sjogren’s syndrome (SS), dry eye syndrome (DES), and B-cell non-Hodgkin lymphoma (B-NHL), in order to determine whether they are etiologically related. Methods. In a clinic-based case-control study, 702 participants (91 SS, 120 DES, 211 (age and sex frequency-matched) controls, and 280 B-NHL cases) were recruited and interviewed regarding exposures, medical history, and family history. Results. Female predominance was noted in SS (ratio 9.2 : 1). Eye dryness was severest in SS compared to DES and controls (P<0.001). Compared to controls, alcohol consumption was inversely associated with NHL, DES, and SS (odds ratio OR=0.47, 95% confidence interval (CI): 0.31-0.71; OR=0.54, 95% CI: 0.33-0.88; and OR=0.26, 95% CI: 0.14-0.49, respectively), while a previous history of infection requiring hospitalization was positively associated with all three conditions: NHL (OR=1.92; 95% CI: 1.23-2.99), DES (OR=3.29; 95% CI: 1.97-5.47), and SS (OR=4.74; 95% CI: 2.66-8.44). NHL patients were more likely to report first-degree relatives with hematologic cancer, while having first-degree relatives with an autoimmune disease (AID) was associated with SS (OR=5.25; 95% CI: 2.59-10.63) and DES (OR=3.55; 95% CI: 1.83-6.91) compared to controls. Conclusions. Some exposures are associated with all three conditions (such as an inverse association with alcohol consumption and a positive association with serious past infection), while a family history of AID appears to be shared by DES and SS, but not NHL subjects. Shared risk factors for all three conditions indicate possible mutual etiological pathways

Serological and hematological characteristics of Sjogren's syndrome and dry eye syndrome patients using a novel immune serology technique.

ObjectivesTo compare hematologic and serological parameters among patients with Sjogren's syndrome (SS), dry eye syndrome (DES) and controls, and validate a novel multiplex-serology method for identifying auto-antibodies in these populations.MethodsIn a clinic-based case-control study a total of 422 participants were recruited, including 91 with SS, 120 DES, and 211 controls (age and sex frequency-matched). We measured blood counts, anti-nuclear-antibodies (ANA), anti-SSA/SSB, anti-ribonucleoprotein (RNP), anti-double-stranded-DNA (DS-DNA), and rheumatoid factor (RF) using the "Immunodot" qualitative-ELISA assay. Immunoglobulins, C3 and C4 were measured by immune-fluorescence. Autoantibodies were also quantified with a newly-developed method using glutathione-S-transferase fusion proteins of SSA/Ro 52 and 60kD and SSB/La (multiplex-serology), measuring median fluorescence intensity (MFI).ResultsAmong DES patients, only 2% (95%CI: 0.36-6.3) had positive immune serology. SS patients had lower lymphocyte, hemoglobin and C3 levels but higher prevalence of RF, ANA, anti-SSA/B and higher IgG and MFI levels, compared to DES and controls (PConclusionsSerologic parameters distinguish SS from DES patients and controls. A newly-developed multiplex-serology technique may be useful to detect autoantibodies in large epidemiologic studies

SNP variations in IL10, TNFα and TNFAIP3 genes in patients with dry eye syndrome and Sjogren’s syndrome

Abstract Background Cytokines are known to be key players in dry eye syndrome (DES) and Sjogren’s syndrome (SS) pathogenesis. In this study we compared single nucleotide polymorphism (SNP) variations in genes encoding cytokine levels among SS and DES patients in Israel. Methods We recruited 180 subjects, 82 with SS and 98 with DES. Using a candidate gene approach and allele-specific PCR technique for genotyping, proportions of risk alleles in Tumor Necrosis Factor α (TNFα) (rs1800629), IinterLeukin-10 (IL-10) (rs1800896) and TNFAIP3 (rs2230926) SNPs were compared between study groups. Results Allelic distribution was found very similar to Caucasian (CEU – Utah residents with Northern and Western European roots) population distributions in these SNPs. While none of the SNPs’ variants were significantly associated with SS or DES in a recessive model, in an additive model the TNFα G risk allele was found higher among SS patients compared to DES (Homozygote-G: 84.2% vs. 70.8%; Heterozygote: 26.9% vs. 11.2%, respectively, p = 0.02). After adjustment for age, gender and ethnicity, these variants weren’t associated with SS. Genetic scoring reveals that SS patients are more likely to present variants of all three SNPs than DES subjects. Conclusions This is the first study evaluating these SNP variations among both patients with DES and patients with SS. We found the allelic distribution in each SNP to be very similar to that found in healthy Caucasian populations presented in the HapMap project. We found the TNFα allele significantly associated with DES for homozygotes, and associated with SS for heterozygotes in the additive model

Ethnic variation in medical and lifestyle risk factors for B cell non-Hodgkin lymphoma: A case-control study among Israelis and Palestinians

<div><p>Background</p><p>Risk factors for B-cell non-Hodgkin lymphoma (B-NHL) have not been assessed among Palestinian Arabs (PA) and Israeli Jews (IJ).</p><p>Methods</p><p>In a case-control study we investigated self-reported medical and lifestyle exposures, reporting odds ratios (ORs) and 95% confidence intervals [CIs], by ethnicity, for overall B-NHL and subtypes.</p><p>Results</p><p>We recruited 823 cases and 808 healthy controls. Among 307 PA/516 IJ B-NHL cases (mean age at diagnosis = 51 [±17] versus 60 [±15] years, respectively) subtype distributions differed, with diffuse large B-cell lymphoma (DLBCL) being prominent among PA (71%) compared to IJ (41%); follicular lymphoma (FL), was observed in 14% versus 28%, and marginal zone lymphoma, in 2% versus 14%, respectively. Overall B-NHL in both populations was associated with recreational sun exposure OR = 1.43 [CI:1.07–1.91], black hair-dye use OR = 1.70 [CI:1.00–2.87], hospitalization for infection OR = 1.68 [CI:1.34–2.11], and first-degree relative with hematopoietic cancer, OR = 1.69 [CI:1.16–2.48]. An inverse association was noted with alcohol use, OR = 0.46 [CI:0.34–0.62]. Subtype-specific exposures included smoking (FL, OR = 1.46 [CI:1.01–2.11]) and >monthly indoor pesticide use (DLBCL, OR = 2.01 [CI:1.35–3.00]). Associations observed for overall B-NHL in PA only included: gardening OR = 1.93 [CI:1.39–2.70]; history of herpes, mononucleosis, rubella, blood transfusion (OR>2.5, P<0.01 for all); while for IJ risk factors included growing fruits and vegetables, OR = 1.87 [CI:1.11–3.15]; and self-reported autoimmune diseases, OR = 1.99 [CI:1.34–2.95].</p><p>Conclusions</p><p>In these geographically proximate populations we found some unique risk factors for B-NHL. Heterogeneity in the observed associations by ethnicity could reflect differences in lifestyle, medical systems, and reporting patterns, while variations by histology infer specific etiologic factors for lymphoma subtypes.</p></div