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.

Fibromyalgia among University Students: A Vulnerable Population.

Background: Fibromyalgia (FM), a complex musculoskeletal disorder, can affect individuals from different genders having different genetic and psychosocial backgrounds. The prevalence of FM depends specifically on the age, gender, and level of stress of the individual. Since the university student body tackles high levels of academic and non-academic stress, we aimed to assess the prevalence and characteristics of FM among such a vulnerable population. Methods: A survey was sent to participants from two major English-speaking private universities in Lebanon; the American University of Beirut (AUB) and the Lebanese American University (LAU). The survey included the modified American College of Rheumatology (ACR) 2016 criteria, the widespread pain index (WPI), the symptoms severity score (SSS), and the duration of presence of such FM symptoms. In addition, the survey evaluated the presence of other specific musculoskeletal disorders among participants. Nevertheless, a 12-item general healthy questionnaire (GHQ-12) was used to assess the presence of anxiety, depression, social dysfunction, and loss of confidence among participants. Results: The survey was sent to a total of 2178 students with 184 complete responses (8.45% response rate). The prevalence of FM among the respondents was 13.6%. Students with FM had a significant personal history of a musculoskeletal disorder other than FM and a significant family history of musculoskeletal disorders. The mean SSS score of the target population, including those with FM and those without FM, was 4.5. Patients with FM were significantly in distress and highly symptomatic as measured by GHQ-12 (Unadjusted OR 3.23 [95% CI 1.32-7.95]). Conclusion: Fibromyalgia seems to be prevalent among university students; in particular, those with other musculoskeletal disorders, those with a family history of musculoskeletal disorders, and those with severe depression and anxiety.

COVID-19 and antiphospholipid antibodies: A position statement and management guidance from AntiPhospholipid Syndrome Alliance for Clinical Trials and InternatiOnal Networking (APS ACTION).

Coronavirus disease 2019 (COVID-19) is associated with a high rate of thrombosis. Prolonged activated partial thromboplastin times (aPTT) and antiphospholipid antibodies (aPL) are reported in COVID-19 patients. The majority of publications have not reported whether patients develop clinically relevant persistent aPL, and the clinical significance of new aPL-positivity in COVID-19 is currently unknown. However, the reports of aPL-positivity in COVID-19 raised the question whether common mechanisms exist in the pathogenesis of COVID-19 and antiphospholipid syndrome (APS). In both conditions, thrombotic microangiopathy resulting in microvascular injury and thrombosis is hypothesized to occur through multiple pathways, including endothelial damage, complement activation, and release of neutrophil extracellular traps (NETosis). APS-ACTION, an international APS research network, created a COVID-19 working group that reviewed common mechanisms, positive aPL tests in COVID-19 patients, and implications of COVID-19 infection for patients with known aPL positivity or APS, with the goals of proposing guidance for clinical management and monitoring of aPL-positive COVID-19 patients. This guidance also serves as a call and focus for clinical and basic scientific research.

Dimensionality reduction reveals fine-scale structure in the Japanese population with consequences for polygenic risk prediction.

The diversity in our genome is crucial to understanding the demographic history of worldwide populations. However, we have yet to know whether subtle genetic differences within a population can be disentangled, or whether they have an impact on complex traits. Here we apply dimensionality reduction methods (PCA, t-SNE, PCA-t-SNE, UMAP, and PCA-UMAP) to biobank-derived genomic data of a Japanese population (n = 169,719). Dimensionality reduction reveals fine-scale population structure, conspicuously differentiating adjacent insular subpopulations. We further enluciate the demographic landscape of these Japanese subpopulations using population genetics analyses. Finally, we perform phenome-wide polygenic risk score (PRS) analyses on 67 complex traits. Differences in PRS between the deconvoluted subpopulations are not always concordant with those in the observed phenotypes, suggesting that the PRS differences might reflect biases from the uncorrected structure, in a trait-dependent manner. This study suggests that such an uncorrected structure can be a potential pitfall in the clinical application of PRS.

SuPAR, an emerging biomarker in kidney and inflammatory diseases.

Soluble urokinase plasminogen activator receptor (suPAR) is a circulating form of a physiological and pathophysiological important cell surface receptor, implicated in inflammation. Recent studies showed that suPAR is a promising biomarker, useful for diagnosis, assessment and prognosis of several diseases. This review summarises the majority of preliminary studies and analyses the significance and the clinical application of suPAR in various clinical conditions. SuPAR seems to have a significant value in the diagnosis as well as prognosis of many diseases; nonetheless, it merits large-scale studies to set cut-off values that help physicians in following up their patients and accordingly tailor their treatment plans.

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.

A Multinational Arab Genome-Wide Association Study Identifies New Genetic Associations for Rheumatoid Arthritis.

OBJECTIVE: Genetic factors underlying susceptibility to rheumatoid arthritis (RA) in Arab populations are largely unknown. This genome-wide association study (GWAS) was undertaken to explore the generalizability of previously reported RA loci to Arab subjects and to discover new Arab-specific genetic loci. METHODS: The Genetics of Rheumatoid Arthritis in Some Arab States Study was designed to examine the genetics and clinical features of RA patients from Jordan, the Kingdom of Saudi Arabia, Lebanon, Qatar, and the United Arab Emirates. In total, >7 million single-nucleotide polymorphisms (SNPs) were tested for association with RA overall and with seropositive or seronegative RA in 511 RA cases and 352 healthy controls. In addition, replication of 15 signals was attempted in 283 RA cases and 221 healthy controls. A genetic risk score of 68 known RA SNPs was also examined in this study population. RESULTS: Three loci (HLA region, intergenic 5q13, and 17p13 at SMTNL2/GGT6) reached genome-wide significance in the analyses of association with RA and with seropositive RA, and for all 3 loci, evidence of independent replication was demonstrated. Consistent with the findings in European and East Asian populations, the association of RA with HLA-DRB1 amino acid position 11 conferred the strongest effect (P = 4.8 × 10-16 ), and a weighted genetic risk score of previously associated RA loci was found to be associated with RA (P = 3.41 × 10-5 ) and with seropositive RA (P = 1.48 × 10-6 ) in this population. In addition, 2 novel associations specific to Arab populations were found at the 5q13 and 17p13 loci. CONCLUSION: This first RA GWAS in Arab populations confirms that established HLA-region and known RA risk alleles contribute strongly to the risk and severity of disease in some Arab groups, suggesting that the genetic architecture of RA is similar across ethnic groups. Moreover, this study identified 2 novel RA risk loci in Arabs, offering further population-specific insights into the pathophysiology of RA.

Salmonella enteritidis bacteremia with septic arthritis of the sacroiliac joint in a patient with systemic lupus erythematosus: case report and review of the literature.

An 18-year-old female presented with a ten days history of high grade fever, chills and pain of the left sacroiliac joint. The patient has systemic lupus erythematosus (SLE) and is on chronic immunosuppressive therapy (steroids, antimalarial and antimetabolites). Imaging of the left sacroiliac joint revealed inflammation. Blood cultures and an aspirate of a small gluteal abscess that she developed later grew Salmonella enteritidis resistant to nalidixic acid. The patient was treated conservatively with eight weeks of IV ceftriaxone and is currently asymptomatic. First case of SLE with this complication to be reported from Lebanon and treated conservatively, this communication deserved publishing together with a literature review.

Rheumatoid granuloma of the cervix and vagina: a challenging diagnosis and treatment.

BACKGROUND: Granulomas of the female genital tract are rare and usually occur after operative procedures. CASE: A patient with rheumatoid arthritis presented with vaginal discharge and bleeding with ulcerative, red, friable lesions of the cervix, which extended to the bladder floor and the right upper vaginal wall. Cervical biopsy was highly suggestive of rheumatoid nodules. This prompted revision of the diagnosis of tuberculosis, which was suspected several months earlier when pulmonary and renal lesions were noted. The cervico-vaginal lesions did not respond to local steroid treatment and improved when the systemic steroid dose was increased; however, they recurred on tapering the dose. CONCLUSION: Rheumatoid nodules can occur in the genital tract, which poses diagnostic and treatment challenges.

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.

An overview of familial Mediterranean fever with emphasis on pyrin and colchicine.

Familial Mediterranean fever (FMF) is the earliest known autoinflammatory disease, characterized by symptoms such as arthritis, peritonitis, pleuritis, erysipelas-like erythema, and most importantly amyloidosis. This disease is very common in populations of the Mediterranean area, and due to its high carrier frequency and occurrence rate in these populations, it has been the focus of much research work. Such research has allowed greater insights into the genetics of FMF, leading to the discovery of the responsible gene in 1997 and the determination of mutations and their effect on the phenotype of patients, as well as the interactions and roles of the pyrin protein, which seems to have various roles in regulation of innate immunity, inflammation, and apoptosis. Colchicine has been used as preventive treatment since 1972, and recent studies have allowed the determination of its mode of action.

Viral infections and antiphospholipid antibodies.

OBJECTIVE: To study the relationship between viral infections and the induction of antiphospholipid (aPL) antibodies. METHODS: We reviewed the medical literature from 1968 until 2000 using MEDLINE and the key words virus, infection, antiphospholipid, and anticardiolipin. RESULTS: Anticardiolipin antibodies and/or lupus anticoagulant were associated with a number of viral infections, including hepatitis C virus, human immunodeficiency virus, cytomegalovirus, varicella zoster, Epstein-Barr virus, adenovirus, and parvovirus B. In many instances, the presence of these antibodies was associated with thrombosis. CONCLUSION: The clinical significance of finding aPL antibodies in patients with viral infections remains unknown. In some patients, these antibodies may be transient and disappear within 2 or 3 months. In other susceptible individuals, they may persist and raise the question of whether infections may trigger the development of aPL antibodies in autoimmune diseases.