Non-Hodgkin's lymphoma in a woman with adult-onset Still's disease: a case report

INTRODUCTION: Adult onset Still's disease is a chronic multisystemic inflammatory disorder characterized by high spiking fever, polyarthralgia and rash. Lymphadenopathy is a prominent feature of adult onset Still's disease and is seen in about 65% of patients. Searching the medical literature using the MEDLINE database from January 1966 through November 2007 we could only find two reported cases of adult onset Still's disease that had progressed to lymphoma. CASE PRESENTATION: We describe a woman who was diagnosed with adult onset Still's disease and developed lymphoma 10 months after the onset of her symptoms. She initially presented with fever and arthritis of the knees, ankles and shoulders, along with a nonpruritic skin rash, myalgia and weight loss. On physical examination she was found to have several enlarged anterior cervical lymph nodes and left posterior auricular lymph nodes all of which were non-tender, immobile and rubbery. Excisional biopsy of the cervical lymph nodes was negative for malignancy. Bone marrow biopsy was also negative for malignancy. She was treated with prednisone. She remained in good health until she presented 10 months later with low back pain, dyspnea and weight loss. Work up revealed malignant lymphoma. She was treated with chemotherapy and was doing well until she presented with abdominal pain. Work up revealed a cirrhotic liver and ascites. She then passed away from hepatorenal syndrome 13 years after the diagnosis of lymphoma. To our knowledge, this is the third reported case of such an occurrence. CONCLUSION: Although the association between adult onset Still's disease and lymphoma has been rarely reported, careful screening for this malignancy in patients suspected to have adult onset Still's disease is warranted

Multi -ancestry genome-wide association analyses identify novel genetic mechanisms in rheumatoid arthritis.

Rheumatoid arthritis (RA) is a highly heritable complex disease with unknown etiology. Multi-ancestry genetic research of RA promises to improve power to detect genetic signals, fine-mapping resolution and performances of polygenic risk scores (PRS). Here, we present a large-scale genome-wide association study (GWAS) of RA, which includes 276,020 samples from five ancestral groups. We conducted a multi-ancestry meta-analysis and identified 124 loci (P < 5 × 10−8), of which 34 are novel. Candidate genes at the novel loci suggest essential roles of the immune system (for example, TNIP2 and TNFRSF11A) and joint tissues (for example, WISP1) in RA etiology. Multi-ancestry fine-mapping identified putatively causal variants with biological insights (for example, LEF1). Moreover, PRS based on multi-ancestry GWAS outperformed PRS based on single-ancestry GWAS and had comparable performance between populations of European and East Asian ancestries. Our study provides several insights into the etiology of RA and improves the genetic predictability of RA.We thank the Director of Health Malaysia for supporting the work described in the South Asian (SAS) population: the Malaysian Epidemiological Investigation of Rheumatoid Arthritis (MyEIRA) study. The MyEIRA study was funded by grants from Ministry of Health Malaysia (NMRR-08-820-1975) and the Swedish National Research Council (DNR-348-2009-6468). The GENRA study and the CARDERA genetics cohort genotyping were funded by Versus Arthritis (grant reference 19739 to I.C.S.). The Nurses’ Health Study (NHS cohort) is funded by the National Institutes of Health (NIH) (R01 AR049880, UM1 CA186107, R01 CA49449, U01 CA176726 and R01 CA67262). The Swedish EIRA study was supported by the Swedish Research Council (to L.K., L.P. and L.A.). S.S. was in part supported by the Mochida Memorial Foundation for Medical and Pharmaceutical Research, Kanae Foundation for the Promotion of Medical Science, Astellas Foundation for Research on Metabolic Disorders, JCR Grant for Promoting Basic Rheumatology, and Manabe Scholarship Grant for Allergic and Rheumatic Diseases. I.C.S. is funded by the National Institute for Health and Care Research (NIHR) Advanced Research Fellowship (grant reference NIHR300826). The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. K.A.S. is supported by the Sherman Family Chair in Genomic Medicine and by a Canadian Institutes for Health Research Foundation Grant (FDN 148457) and grants from the Ontario Research Fund (RE-09-090) and Canadian Foundation for Innovation (33374). S.-C.B. is supported by the Basic Science Research Program through the NRF funded by the Ministry of Education (NRF-2021R1A6A1A03038899). R.P.K. and J.C.E. are funded by NIH (UL1 TR003096). C.M.L. is partly funded by the NIHR Maudsley Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London. T. Arayssi was partially supported by the National Priorities Research Program (grant 4-344-3-105 from the Qatar National Research Fund, a member of Qatar Foundation). M. Kerick and J.M. are funded by Rheumatology Cooperative Research Thematic Network program RD16/0012/0013 from the Instituto de Salud Carlos III (Spanish Ministry of Science and Innovation). Y.O. is funded by JSPS KAKENHI (19H01021 and 20K21834), AMED (JP21km0405211, JP21ek0109413, JP21ek0410075, JP21gm4010006 and JP21km0405217), JST Moonshot R&D (JPMJMS2021 and JPMJMS2024), Takeda Science Foundation, and the Bioinformatics Initiative of Osaka University Graduate School of Medicine. Y. Kochi is funded by grants from Nanken-Kyoten, TMDU and Medical Research Center Initiative for High Depth Omics. S.R. is supported by UH2AR067677, U01HG009379, R01AR063759 and U01HG012009

Global, regional, and national life expectancy, all-cause mortality, and cause-specific mortality for 249 causes of death, 1980-2015 : a systematic analysis for the Global Burden of Disease Study 2015

Background Improving survival and extending the longevity of life for all populations requires timely, robust evidence on local mortality levels and trends. The Global Burden of Disease 2015 Study (GBD 2015) provides a comprehensive assessment of all-cause and cause-specific mortality for 249 causes in 195 countries and territories from 1980 to 2015. These results informed an in-depth investigation of observed and expected mortality patterns based on sociodemographic measures. Methods We estimated all-cause mortality by age, sex, geography, and year using an improved analytical approach originally developed for GBD 2013 and GBD 2010. Improvements included refinements to the estimation of child and adult mortality and corresponding uncertainty, parameter selection for under-5 mortality synthesis by spatiotemporal Gaussian process regression, and sibling history data processing. We also expanded the database of vital registration, survey, and census data to 14 294 geography-year datapoints. For GBD 2015, eight causes, including Ebola virus disease, were added to the previous GBD cause list for mortality. We used six modelling approaches to assess cause-specific mortality, with the Cause of Death Ensemble Model (CODEm) generating estimates for most causes. We used a series of novel analyses to systematically quantify the drivers of trends in mortality across geographies. First, we assessed observed and expected levels and trends of cause-specific mortality as they relate to the Socio-demographic Index (SDI), a summary indicator derived from measures of income per capita, educational attainment, and fertility. Second, we examined factors affecting total mortality patterns through a series of counterfactual scenarios, testing the magnitude by which population growth, population age structures, and epidemiological changes contributed to shifts in mortality. Finally, we attributed changes in life expectancy to changes in cause of death. We documented each step of the GBD 2015 estimation processes, as well as data sources, in accordance with Guidelines for Accurate and Transparent Health Estimates Reporting (GATHER). Findings Globally, life expectancy from birth increased from 61.7 years (95% uncertainty interval 61.4-61.9) in 1980 to 71.8 years (71.5-72.2) in 2015. Several countries in sub-Saharan Africa had very large gains in life expectancy from 2005 to 2015, rebounding from an era of exceedingly high loss of life due to HIV/AIDS. At the same time, many geographies saw life expectancy stagnate or decline, particularly for men and in countries with rising mortality from war or interpersonal violence. From 2005 to 2015, male life expectancy in Syria dropped by 11.3 years (3.7-17.4), to 62.6 years (56.5-70.2). Total deaths increased by 4.1% (2.6-5.6) from 2005 to 2015, rising to 55.8 million (54.9 million to 56.6 million) in 2015, but age-standardised death rates fell by 17.0% (15.8-18.1) during this time, underscoring changes in population growth and shifts in global age structures. The result was similar for non-communicable diseases (NCDs), with total deaths from these causes increasing by 14.1% (12.6-16.0) to 39.8 million (39.2 million to 40.5 million) in 2015, whereas age-standardised rates decreased by 13.1% (11.9-14.3). Globally, this mortality pattern emerged for several NCDs, including several types of cancer, ischaemic heart disease, cirrhosis, and Alzheimer's disease and other dementias. By contrast, both total deaths and age-standardised death rates due to communicable, maternal, neonatal, and nutritional conditions significantly declined from 2005 to 2015, gains largely attributable to decreases in mortality rates due to HIV/AIDS (42.1%, 39.1-44.6), malaria (43.1%, 34.7-51.8), neonatal preterm birth complications (29.8%, 24.8-34.9), and maternal disorders (29.1%, 19.3-37.1). Progress was slower for several causes, such as lower respiratory infections and nutritional deficiencies, whereas deaths increased for others, including dengue and drug use disorders. Age-standardised death rates due to injuries significantly declined from 2005 to 2015, yet interpersonal violence and war claimed increasingly more lives in some regions, particularly in the Middle East. In 2015, rotaviral enteritis (rotavirus) was the leading cause of under-5 deaths due to diarrhoea (146 000 deaths, 118 000-183 000) and pneumococcal pneumonia was the leading cause of under-5 deaths due to lower respiratory infections (393 000 deaths, 228 000-532 000), although pathogen-specific mortality varied by region. Globally, the effects of population growth, ageing, and changes in age-standardised death rates substantially differed by cause. Our analyses on the expected associations between cause-specific mortality and SDI show the regular shifts in cause of death composition and population age structure with rising SDI. Country patterns of premature mortality (measured as years of life lost [YLLs]) and how they differ from the level expected on the basis of SDI alone revealed distinct but highly heterogeneous patterns by region and country or territory. Ischaemic heart disease, stroke, and diabetes were among the leading causes of YLLs in most regions, but in many cases, intraregional results sharply diverged for ratios of observed and expected YLLs based on SDI. Communicable, maternal, neonatal, and nutritional diseases caused the most YLLs throughout sub-Saharan Africa, with observed YLLs far exceeding expected YLLs for countries in which malaria or HIV/AIDS remained the leading causes of early death. Interpretation At the global scale, age-specific mortality has steadily improved over the past 35 years; this pattern of general progress continued in the past decade. Progress has been faster in most countries than expected on the basis of development measured by the SDI. Against this background of progress, some countries have seen falls in life expectancy, and age-standardised death rates for some causes are increasing. Despite progress in reducing age-standardised death rates, population growth and ageing mean that the number of deaths from most non-communicable causes are increasing in most countries, putting increased demands on health systems. Copyright (C) The Author(s). Published by Elsevier Ltd.Peer reviewe

Epstein-Barr virus DNA modulates regulatory T-cell programming in addition to enhancing interleukin-17A production via Toll-like receptor 9.

Infection with the Epstein-Barr virus (EBV) has been associated with several autoimmune diseases including rheumatoid arthritis (RA). We have previously reported that DNA from this virus enhances production of the pro-autoimmune interleukin 17A (IL-17A) in mice. In this study we assessed the effect of EBV DNA on regulatory T cell programming and examined whether it mediated its effects via Toll-like receptor 9 (TLR9) in mice; moreover, we evaluated whether EBV DNA in humans had similar effects to those seen in mice. For this purpose, we assessed the linearity of the correlation between EBV DNA and IL-17A levels in RA subjects and matched controls. A modulatory effect for the viral DNA was observed for regulatory T cell markers with an inhibitory effect observed for CTLA4 expression in the EBV DNA-treated mice. To examine whether TLR9 mediated the detection of EBV DNA and enhancement of IL-17A production, mouse peripheral blood mononuclear cells were treated with the DNA in the presence or absence of the TLR9 inhibitor ODN 2088. Subsequently, IL-17A production from these cells was assessed. Treatment with the TLR9 inhibitor resulted in a significant decrease in IL-17A production indicating that TLR9 is involved in this pathway. In human subjects, examining the linearity of the correlation between EBV DNA and IL-17A levels in RA subjects showed a propensity for linearity that was not observed in controls. Our data thus indicates that EBV DNA itself acts as a modulator of the Th17 compartment as well as that of regulatory T cell mechanisms. The involvement of TLR9 in the EBV DNA-triggered induction of IL-17A suggests therapeutic targeting of this endosomal receptor in EBV positive subjects with an autoimmune flare-up or possibly for prophylactic purposes

Average serum levels of IL-17A in RA patients and non-RA controls.

<p>Serum was collected from 24 RA patients and 24 non-RA controls. IL-17A levels were then assessed by ELISA. * indicates p<0.05 compared to controls.</p