Browse

Search for: rheumatoid arthritis    methotrexate    autoimmune disease    biomarker    gene expression    GWAS    HLA genes    non-HLA genes   

ID PMID Title PublicationDate abstract
34254681 Porphyromonas gingivalis survival skills: Immune evasion. 2021 Dec Periodontitis is a chronic inflammatory condition that destroys the tooth-supporting tissues and eventually leads to tooth loss. As one of the most prevalent oral conditions, periodontitis endangers the oral health of 70% of people throughout the world. Periodontitis is also related to various systemic diseases, such as diabetes mellitus, atherosclerosis, and rheumatoid arthritis, which not only has a great impact on population health status and the quality of life but also increases the social burden. Porphyromonas gingivalis (P. gingivalis) is a gram-negative oral anaerobic bacterium that plays a key role in the pathogenesis of periodontitis. Porphyromonas gingivalis can express various of virulence factors to overturn innate and adaptive immunities, which makes P. gingivalis survive and propagate in the host, destroy periodontal tissues, and have connection to systemic diseases. Porphyromonas gingivalis can invade into and survive in host tissues by destructing the gingival epithelial barrier, internalizing into the epithelial cells, and enhancing autophagy in epithelial cells. Deregulation of complement system, degradation of antibacterial peptides, and destruction of phagocyte functions facilitate the evasion of P. gingivalis. Porphyromonas gingivalis can also suppress adaptive immunity, which allows P. gingivalis to exist in the host tissues and cause the inflammatory response persistently. Here, we review studies devoted to understanding the strategies utilized by P. gingivalis to escape host immunity. Methods for impairing P. gingivalis immune evasion are also mentioned.
34143945 Mechanistic insights into 5-lipoxygenase inhibition by pyocyanin: a molecular docking and 2021 Jun 18 Pyocyanin, a redox-active phenazine pigment produced by Pseudomonas aeruginosa, inhibits 5-lipoxygenase (5-LOX) activity. However, whether pyocyanin can directly block the enzymatic activity by binding at the active site still remains a question because of its ability to produce superoxide radicals and H(2)O(2). With the objective of characterizing this mechanism, we carried out molecular docking and molecular dynamics simulations and performed Molecular Mechanics Poisson-Boltzmann surface area (MMPBSA) binding energy studies. The results of the study revealed that pyocyanin is dynamically stable at the active site of 5-LOX and its MMPBSA binding energy (-84.720 kJ/mol) is comparable to that of the 5-LOX standard inhibitor zileuton (-72.729 kJ/mol). Similar studies using three other phenazine derivatives - 1-hydroxyphenazine, phenazine-1-carboxylic acid and phenazine-1-carboxamide - also showed encouraging results. In light of this evidence, we postulate as a proof of concept that pyocyanin and these phenazine derivatives have the potential to inhibit 5-LOX activity by directly binding at the active site and blocking enzymatic catalysis of the substrate. Considering the potential of 5-LOX inhibitors in inflammatory diseases such as asthma and rheumatoid arthritis, the findings of this study open up the exploration of phenazine derivatives in structure-based drug design against 5-LOX. Communicated by Ramaswamy H. Sarma.
34033878 Beyond Lipoprotein(a) plasma measurements: Lipoprotein(a) and inflammation. 2021 Jul Genome wide association, epidemiological, and clinical studies have established high lipoprotein(a) [Lp(a)] as a causal risk factor for atherosclerotic cardiovascular disease (ASCVD). Lp(a) is an apoB100 containing lipoprotein covalently bound to apolipoprotein(a) [apo(a)], a glycoprotein. Plasma Lp(a) levels are to a large extent determined by genetics. Its link to cardiovascular disease (CVD) may be driven by its pro-inflammatory effects, of which its association with oxidized phospholipids (oxPL) bound to Lp(a) is the most studied. Various inflammatory conditions, such as rheumatoid arthritis (RA), systemic lupus erythematosus, acquired immunodeficiency syndrome, and chronic renal failure are associated with high Lp(a) levels. In cases of RA, high Lp(a) levels are reversed by interleukin-6 receptor (IL-6R) blockade by tocilizumab, suggesting a potential role for IL-6 in regulating Lp(a) plasma levels. Elevated levels of IL-6 and IL-6R polymorphisms are associated with CVD. Therapies aimed at lowering apo(a) and thereby reducing plasma Lp(a) levels are in clinical trials. Their results will determine if reductions in apo(a) and Lp(a) decrease cardiovascular outcomes. As we enter this new arena of available treatments, there is a need to improve our understanding of mechanisms. This review will focus on the role of Lp(a) in inflammation and CVD.
34019264 Interstitial Lung Disease Associated with Connective Tissue Diseases. 2021 Pulmonary manifestations of connective tissue diseases (CTD) carry high morbidity and potential mortality, and the most serious pulmonary type is interstitial lung disease (ILD). Identifying and promptly intervening CTD-ILD with immune suppressor therapy will change the natural course of the disease resulting in survival improvement. Compared to idiopathic pulmonary fibrosis, the most common presentation of idiopathic interstitial pneumonia (IIP), CTD-ILD carries a better prognosis due to the response to immune suppressor therapy. Nonspecific interstitial pneumonia (NSIP) is the most common type of CTD-ILD that is different from the fibrotic classical presentation of IPF, known as usual interstitial pneumonia (UIP). An exception is rheumatoid arthritis that presents more frequently with UIP type. Occasionally, IPF may not have typical radiographic features of UIP, and a full assessment to differentiate IPF from CTD-ILD is necessary, including the intervention of a multidisciplinary team and the histopathology. Interstitial pneumonia with autoimmune features (IPAF) shows promising advantages to identify patients with ILD who have some features of a CTD without a defined autoimmune disease and who may benefit from immune suppressors. A composition of clinical, serological, and morphologic features in patients presenting with ILD will fulfill criteria for IPAF. In summary, the early recognition and treatment of CTD-ILD, differentiation from IPF-UIP, and identification of patients with IPAF fulfill the assessment by the clinician for an optimal care.
33923792 Lymphopenia, Lymphopenia-Induced Proliferation, and Autoimmunity. 2021 Apr 16 Immune homeostasis is a tightly regulated system that is critical for defense against invasion by foreign pathogens and protection from self-reactivity for the survival of an individual. How the defects in this system might result in autoimmunity is discussed in this review. Reduced lymphocyte number, termed lymphopenia, can mediate lymphopenia-induced proliferation (LIP) to maintain peripheral lymphocyte numbers. LIP not only occurs in normal physiological conditions but also correlates with autoimmunity. Of note, lymphopenia is also a typical marker of immune aging, consistent with the fact that not only the autoimmunity increases in the elderly, but also autoimmune diseases (ADs) show characteristics of immune aging. Here, we discuss the types and rates of LIP in normal and autoimmune conditions, as well as the coronavirus disease 2019 in the context of LIP. Importantly, although the causative role of LIP has been demonstrated in the development of type 1 diabetes and rheumatoid arthritis, a two-hit model has suggested that the factors other than lymphopenia are required to mediate the loss of control over homeostasis to result in ADs. Interestingly, these factors may be, if not totally, related to the function/number of regulatory T cells which are key modulators to protect from self-reactivity. In this review, we summarize the important roles of lymphopenia/LIP and the Treg cells in various autoimmune conditions, thereby highlighting them as key therapeutic targets for autoimmunity treatments.
33889087 Sos1 Modulates Extracellular Matrix Synthesis, Proliferation, and Migration in Fibroblasts 2021 Non-reversible fibrosis is common in various diseases such as chronic renal failure, liver cirrhosis, chronic pancreatitis, pulmonary fibrosis, rheumatoid arthritis and atherosclerosis. Transforming growth factor beta 1 (TGF-β1) is involved in virtually all types of fibrosis. We previously described the involvement of Ras GTPase isoforms in the regulation of TGF-β1-induced fibrosis. The guanine nucleotide exchange factor Son of Sevenless (Sos) is the main Ras activator, but the role of the ubiquitously expressed Sos1 in the development of fibrosis has not been studied. For this purpose, we isolated and cultured Sos1 knock-out (KO) mouse embryonic fibroblasts, the main extracellular matrix proteins (ECM)-producing cells, and we analyzed ECM synthesis, cell proliferation and migration in the absence of Sos1, as well as the role of the main Sos1-Ras effectors, Erk1/2 and Akt, in these processes. The absence of Sos1 increases collagen I expression (through the PI3K-Akt signaling pathway), total collagen proteins, and slightly increases fibronectin expression; Sos1 regulates fibroblast proliferation through both PI3K-Akt and Raf-Erk pathways, and Sos1-PI3K-Akt signaling regulates fibroblast migration. These study shows that Sos1 regulates ECM synthesis and migration (through Ras-PI3K-Akt) and proliferation (through Ras-PI3K-Akt and Ras-Raf-Erk) in fibroblasts, and describe for the first time the role of the Sos1-Ras signaling axis in the regulation of cellular processes involved in the development of fibrosis.
31533152 High Medium-Term Survivorship of Cruciate-Retaining Total Knee Arthroplasties (110 Knees) 2021 Mar The main purpose of this article is to evaluate the clinical outcomes and survivorship of cruciate-retaining (CR) knee arthroplasties for valgus deformity. This article is retrospective consecutive series of 110 valgus knees using CR implants with a minimum 2-year follow-up. Deformity correction was achieved using stepwise sequential soft tissue releases (iliotibial band, popliteus tendon, lateral collateral release through sliver femoral condylar osteotomy). Demographic data, range of movement, and degrees of deformity were collected. The Oxford Knee Score (OKS) was used as patients' reported outcome measure at final follow-up. One-hundred and four patients (110 knees) were included (87 females/17 males) with mean age of 68.7 years. Primary diagnosis was osteoarthritis in 85 patients and rheumatoid arthritis in 19 patients. Mean follow-up was 5.5 years (median: 5 years; range: 2-14 years). Preoperative valgus deformity was measured radiographically using the mechanical tibiofemoral angle with a mean 18.6° (standard deviation [SD]: 7.5; range: 11-38°). At final follow-up, mechanical tibiofemoral angle was 3.8° (SD: 1.97; range: 2-8°). A p-value was <0.0001 and mean OKS was 42 (SD: 5.4; range: 36-48) suggesting satisfactory patients' reported outcomes with no implant revision for any cause. CR implants for valgus knees using staged soft tissue releases including sliver condylar osteotomy had excellent medium-term survivorship and satisfactory patient reported outcome measures. The Level of Evidence for this study is IV.
33300326 Chronic cancer and non-cancer pain and opioid-induced hyperalgesia share common mechanisms 2021 Feb Neuroinflammation, a peculiar form of inflammation that occurs in response to noxious stimuli in peripheral and central nervous system (CNS), consists in altered vascular permeability followed by leukocyte recruitment and activation in the inflamed tissue, release of inflammatory mediators including cytokines and chemokines, and finally in the activation of microglia and astrocytes in the spinal cord and CNS. This phenomenon mediates and even worsen the inflammatory pain in many painful states and is responsible for central sensitization leading to pain chronicity. We describe the major neuroinflammatory mechanisms shared by cancer and non-cancer pain. Particular attention is given to two different chronic inflammatory painful diseases such as the complex regional pain syndrome and the rheumatoid arthritis as prototypes of neuroinflammatory diseases (gliopathies). In addition, we describe the complexity of tumor microenvironment, their main cellular components (tumor cells, tumor infiltrating leukocytes and sensory neurons) and their reciprocal interactions that characterize different forms and intensity of cancer pain. We also hypothesize that one type of cancer pain, the breakthrough pain, can be attributable to receptor-mediated interaction of opioids with tumor cells and intratumoral leukocytes. Surprisingly, long-term opioid treatment shares the same neuroinflammatory potential responsible for the chronicity of both cancer and non-cancer pain; thus, resulting in paradoxical worsening rather than relieving pain. This paradox has upset the world of pain therapy, with neuroinflammation now being a main target of emerging therapies.
31971014 Review of total hip arthroplasty in patients younger than 30 years: mid- to long-term resu 2021 Jul BACKGROUND: Data on the outcome of THA in patients under the age of 30 years is sparse. There is a perceived reluctance to offer surgery to young patients on the basis of potential early failure of the implant. The aim of this study was to review clinical and radiological outcomes of THA in patients under the age of 30 years in a high-volume specialist arthroplasty unit. METHODS: A retrospective review of patients between 1989 and 2009 was undertaken. 95 patients (118 THAs) were identified but 17 patients were excluded for lack of clinical records or for follow-up under 5 years. Clinical records were reviewed for demographics, underlying pathology, details of operation and failures. Radiographs were reviewed for evidence of loosening and wear of the components. Functional assessment was carried out using the modified Hip disability and Osteoarthritis Outcome Score, Oxford Hip Score and EQ-5D-5L. RESULTS: Mean age was 25 (16-30) years and 65% patients were females. The most common underlying pathologies were development dysplasia of the hip (29%) and juvenile rheumatoid arthritis (25%). Mean follow-up was 12.6 (5-24) years, during which 19 patients (25%) were revised. The majority of the revisions were for aseptic loosening of the acetabular component. CONCLUSIONS: Surgeons are cautious when considering THA in very young patients despite the significant documented improvement in function and quality of life after THA. This study reports on the mid- to long-term results of THA which will be valuable when advising young patients on the prospects of revision surgery at the time of primary THA.
34816222 Health and Gender Inequalities of the COVID-19 Pandemic: Adverse Impacts on Women's Health 2021 In this paper we discuss the nexus of health and gender inequalities associated with the COVID-19 pandemic and highlight its adverse impacts on women's health, welfare and social standing. The COVID-19 pandemic has exposed the link between socio-economic inequalities and health outcomes, especially in the area of rheumatic and musculoskeletal (RMDs) diseases. Women are more adversely affected by RMDs diseases compared to men. Epidemiological research carried out over several decades has demonstrated the presence of clear gender patterns in the manifestation of musculoskeletal diseases, including osteoarthritis (OA), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), systemic sclerosis (SS) and osteoporosis (OP). The public health measures that have been adopted to curb the spread of Sars-COV-2 are expected to have a particularly detrimental impact on women in the long term precisely because of the nexus between health outcomes and socio-economic structures. Moreover, the prioritization of urgent care will further compound this effect. COVID-19 has created a condition of ontological insecurity that is becoming increasingly manifested through various chronic diseases and associated comorbidities. RMDs and their impact on mobility and the ability of individuals to be independent, happy and mobile is a key public health challenge in the post-COVID-19 reality and a key part of the ongoing pandemic. There is an urgent need to engage with policymakers to publicize and prioritize this problem and develop viable solutions to address it.
34593238 Targeting cytokines and immune checkpoints in atherosclerosis with monoclonal antibodies. 2021 Oct Over the past fifteen years, treatments using monoclonal antibodies specifically targeting cytokines have been developed to treat chronic inflammatory diseases, including rheumatoid arthritis or psoriasis, both associated with increased cardiovascular risk. The cardiovascular impact of these therapies allows us to validate the clinical relevance of the knowledge acquired from experimental studies about the role of cytokines in atherosclerosis. Several clinical studies have confirmed the protective effects of anti-TNFα and anti-IL-6R monoclonal antibodies against athero-thrombotic cardiovascular risk in patients with chronic inflammatory diseases. Yet, caution is needed since anti-TNFα treatment can aggravate chronic heart failure. More recently, the CANTOS study showed for the first time that an anti-inflammatory treatment using anti-IL-1β monoclonal antibody in coronary artery disease patients significantly reduced cardiovascular events. The effects of IL-23/IL-17 axis blockade on cardiovascular risk in patients with psoriasis or arthritis remain controversial. Several monoclonal antibodies targeting costimulatory molecules have also been developed, a direct way to confirm their involvement in atherothrombotic cardiovascular diseases. Blocking the CD28(-)CD80/86 axis with Abatacept has been shown to reduce cardiovascular risk. In contrast, the treatment of cancer patients with antibodies blocking immune checkpoint inhibitory receptors, such as CTLA-4, PD1, or PDL1, could worsen the risk of atherothrombotic events. In the future, cardiologists will be increasingly solicited to assess the cardiovascular risk of patients suffering from chronic inflammatory diseases or cancer and participate in choosing the most appropriate treatment. At the same time, immunomodulatory approaches directly targeting cardiovascular diseases will be developed as a complement to the usual treatment strategies.
34301319 Differential impacts of TNFα inhibitors on the transcriptome of Th cells. 2021 Jul 23 BACKGROUND: Targeting TNFα is beneficial in many autoimmune and inflammatory diseases, including rheumatoid arthritis. However, the response to each of the existing TNFα inhibitors (TNFis) can be patient- and/or disease-dependent. In addition, TNFis can induce the production of type 1 interferons (IFNs), which contribute to their non-infection side effects, such as pustular psoriasis. Thus far, the molecular mechanisms mediating the drug-specific effects of TNFis and their induction of type 1 IFNs are not fully understood. METHODS: Peripheral blood mononuclear cells (PBMCs) were collected from healthy donors and stimulated in vitro with anti-CD3 and anti-CD28 in the absence or presence of adalimumab, etanercept, or certolizumab. Th cells were isolated from the stimulated PBMCs, and their RNA was subjected to RNA-seq and quantitative polymerase chain reaction. RESULTS: Adalimumab and etanercept, which contain Fc, but not certolizumab, which does not contain Fc, inhibited the expression of several effector cytokines by Th cells within anti-CD3/anti-CD28-stimulated PBMCs. Transcriptomic analyses further showed that adalimumab, but not certolizumab, reciprocally induced type 1 IFN signals and the expression of CD96 and SIRPG in Th cells. The unique effects of adalimumab were not due to preferential neutralization of soluble TNFα but instead were mediated by several distinct mechanisms independent or dependent of Fc-facilitated physical interaction between Th cells and CD14+ monocytes. CONCLUSIONS: TNFis can have drug-specific effects on the transcriptional profile of Th cells.
34196507 Associations Between Safety of Certolizumab Pegol, Disease Activity, and Patient Character 2021 Aug OBJECTIVE: To investigate the impact of baseline and time-varying factors on the risk of serious adverse events (SAEs) in patients during long-term certolizumab pegol (CZP) treatment. METHODS: Safety data were pooled across 34 CZP clinical trials in rheumatoid arthritis (RA), axial spondyloarthritis (axSpA), psoriatic arthritis (PsA), and plaque psoriasis (PSO). Cox proportional hazards modeling was used to investigate the association of baseline patient characteristics with risk of serious infectious events (SIEs), malignancies, and major adverse cardiac events (MACEs). Cox modeling for recurrent events assessed the impact of time-varying body mass index (BMI), systemic corticosteroid (CS) use, and disease activity on SIE risk in RA and SAE risk in PSO. RESULTS: Data were pooled from 8747 CZP-treated patients across indications. Cox models reported a 44% increase in SIE risk associated with a baseline BMI of 35 kg/m(2) or more versus a baseline BMI of 18.5 kg/m(2) to less than 25 kg/m(2) . Baseline systemic CS use, age of 65 years or more, and disease duration of 10 years or longer also increased SIE risk. Older age was the only identified risk factor for malignancies. The risk of MACEs increased 107% for BMI of 35 kg/m(2) or more versus BMI of 18.5 kg/m(2) to less than 25 kg/m(2) and increased 51% for men versus women. Higher disease activity, older age, systemic CS use, BMI of 35 kg/m(2) or more, and baseline comorbidities were SIE risk factors in RA. Age and systemic CS use were risk factors for SAEs in PSO. CONCLUSION: Age, BMI, systemic CS use, and disease activity were identified as SIE risk factors in CZP-treated patients. Risk of malignancies was greater in older patients, whereas obesity and male sex were MACE risk factors.
33850845 Macrophage regulator of G-protein signaling 12 contributes to inflammatory pain hypersensi 2021 Mar BACKGROUND: Pain is a predominant symptom in rheumatoid arthritis (RA) patients that results from joint inflammation and is augmented by central sensitization. Regulator of G-protein signaling 12 (RGS12) is the largest protein in the RGS protein family and plays a key role in the development of inflammation. This study investigated the regulation of RGS12 in inflammatory pain and explored the underlying mechanisms and potential RA pain targets. METHODS: Macrophage-specific RGS12-deficient (LysM-Cre(+);RGS12(fl/fl)) mice were generated by mating RGS12(fl/fl) mice with LysM-Cre(+) transgenic mice. Collagen antibody-induced arthritis (CAIA) models were induced in LysM-Cre(+);RGS12(fl/fl) mice by the administration of a cocktail of five monoclonal antibodies and LPS. Mouse nociception was examined using the von Frey and heat plate tests. Primary macrophages and RAW264.7 cells were used to analyze the regulatory function and mechanism of RGS12 in vitro. The expression and function of RGS12 and COX2 (cyclooxygenase 2) were determined by real-time PCR, ELISA, and luciferase assays. RESULTS: Ablation of RGS12 in macrophages decreased pain-related phenotypes, such as paw swelling, the clinical score, and the inflammatory score, in the CAIA model. LysM-Cre(+);RGS12(fl/fl) mice displayed increased resistance to thermal and mechanical stimulation from day 3 to day 9 during CAIA, indicating the inhibition of inflammatory pain. Overexpression of COX2 and PGE2 in macrophages enhanced RGS12 expression, and PGE2 regulated RGS12 expression through the G-protein-coupled receptors EP2 and EP4. Furthermore, RGS12 or the RGS12 PTB domain strengthened the transcriptional regulation of COX2 by NF-κB, whereas inhibiting NF-κB suppressed RGS12-mediated regulation of COX2 in macrophages. CONCLUSIONS: Our results demonstrate that the deletion of RGS12 in macrophages attenuates inflammatory pain, which is likely due to impaired regulation of the COX2/PGE2 signaling pathway.
34881269 Patients With IBD Receiving Methotrexate Are at Higher Risk of Liver Injury Compared With 2021 Background: Methotrexate is well-known in treating inflammatory bowel disease (IBD), rheumatoid arthritis (RA), psoriasis (Ps), and psoriatic arthritis (PsA). Several reports have indicated a higher incidence of methotrexate (MTX)-related liver adverse events in patients with IBD. We aim to investigate the risk of liver injury in patients with IBD and those with non-IBD diseases treated with MTX. Methods: We searched PubMed, Embase, and the Cochrane Library for articles that reported liver adverse events in patients with IBD, RA, and Ps/PsA, receiving MTX therapy. Additional articles were obtained by screening the references of recent meta-analysis and reviews. Raw data from included articles were pooled to calculate the cumulative incidence of total liver injury (TLI), MTX discontinuation (MTX-D), and liver fibrosis (LF). RR (relative risk) was calculated to compare the difference between patients with IBD and those with non-IBD diseases. Results: A total of 326 articles with 128,876 patients were included. The patients with IBD had higher incidence of TLI [11.2 vs. 9.2%; relative risk (RR) = 1.22; P = 0.224] and MTX-D (2.6 vs. 1.8%; RR, 1.48; P = 0.089) than patients with non-IBD diseases. Due to the publication bias, trim-and-fill was performed. Afterwards, the patients with IBD showed significantly higher risk of TLI (11.2 vs. 3%; RR = 3.76; p < 0.001), MTX-D (3.3 vs. 0.7%; RR = 5; p < 0.001) and LF (3.1 vs. 0.1%; RR = 38.62; P = 0.001) compared with patients with non-IBD diseases. Conclusion: IBD is associated with a higher risk of MTX-related liver injury. The mechanism of MTX-induced hepatotoxicity might be different in IBD and non-IBD diseases, and needs to be verified in future research.
34705051 A bio-what? Medical companions' perceptions towards biosimilars and information needs in r 2021 Oct 27 Patient perceptions influence biosimilar uptake in non-mandatory transitions. Companions (support people) are often actively involved in the patient's medical journey and are likely to have unique perceptions of biosimilars, which may shape patient attitudes. This study explores the congruence between patient and companion perceptions towards biosimilars and their information needs. Patients taking bio-originators for rheumatic diseases (59% for rheumatoid arthritis) and their companions received an explanation about biosimilars. Participants (N = 78) completed questionnaires assessing their familiarity with biosimilars, perceptions, concerns, and benefits of being accompanied. Contingency tables and paired sample t-tests were used to explore differences in familiarity, confidence in knowledge, and perceptions. Intra-class correlation coefficients were calculated to assess the degree of congruence for perceptions towards biosimilars. Companions were significantly less familiar with biosimilars (p = 0.014, Cramer's V = 0.28) and reported lower confidence in their knowledge (p = 0.006, Cohen's d = 0.47) than patients. Companions and patients had moderate to good congruency for perceptions toward confidence in biosimilar use and safety, efficacy, and side-effect expectations (intra-class correlation coefficients ranging from 0.75 to 0.81). Companions and patients were most concerned about safety and effectiveness. Companions also reported concerns about cost savings driving the transition, while patients had concerns about uncertainty and testing. Patients reported the ability for discussion, improved understanding, and validation as benefits of being accompanied. Companions and patients have similar levels of perceptions and expectations towards biosimilars but report some unique information needs. Future educational interventions should involve companions and address their concerns to help improve biosimilar acceptance.
34278373 Investigating Pleiotropy Between Depression and Autoimmune Diseases Using the UK Biobank. 2021 Jun BACKGROUND: Epidemiological studies report increased comorbidity between depression and autoimmune diseases. The role of shared genetic influences in the observed comorbidity is unclear. We investigated the evidence for pleiotropy between these traits in the UK Biobank (UKB). METHODS: We defined autoimmune and depression cases using hospital episode statistics, self-reported conditions and medications, and mental health questionnaires. Pairwise comparisons of depression prevalence between autoimmune cases and controls, and vice versa, were performed. Cross-trait polygenic risk score (PRS) analyses tested for pleiotropy, i.e., whether PRSs for depression could predict autoimmune disease status, and vice versa. RESULTS: We identified 28,479 cases of autoimmune diseases (pooling across 14 traits) and 324,074 autoimmune controls, and 65,075 cases of depression and 232,552 depression controls. The prevalence of depression was significantly higher in autoimmune cases than in controls, and similarly, the prevalence of autoimmune disease was higher in depression cases than in controls. PRSs for myasthenia gravis and psoriasis were significantly higher in depression cases than in controls (p < 5.2 × 10(-5), R (2) ≤ 0.04%). PRSs for depression were significantly higher in inflammatory bowel disease, psoriasis, psoriatic arthritis, rheumatoid arthritis, and type 1 diabetes cases than in controls (p < 5.8 × 10(-5), R (2) range = 0.06%-0.27%), and lower in celiac disease cases than in controls (p < 5.4 × 10(-7), R (2) range = 0.11%-0.15%). CONCLUSIONS: Consistent with the literature, depression was more common in individuals with autoimmune diseases than in controls, and vice versa. PRSs showed some evidence for involvement of shared genetic factors, but the modest R (2) values suggest that shared genetic architecture accounts for a small proportion of the increased risk across traits.
34011076 Mutation analysis of the TNFAIP3 in A20 haploinsufficiency: A case report. 2021 May 21 INTRODUCTION: Haploinsufficiency of A20 (HA20) is a novel genetic disease presented by Zhou et al in 2016. A20 is a protein encoded by TNFAIP3. Loss-of-function mutation in TNFAIP3 will trigger a new autoinflammatory disease: HA20. HA20-affected patients may develop a wide range of clinical manifestations, such as Behcet disease, rheumatoid arthritis, rheumatic fever, juvenile idiopathic arthritis, and systemic lupus erythematosus. HA20 is rarely reported, thus remaining far from thoroughly understood. Sixty-one cases of HA20 have been reported worldwide, among which 29 cases were diagnosed with Behcet disease ultimately. Moreover, 3 cases have been reported in China, which was the first report of HA20 characterized by Behcet disease. A comprehensive understanding of the pathogenic genes of HA20 could help us apply targeted therapy as soon as possible to improve patients' survival rates. PATIENT CONCERNS: A 2-year-old 3-month-old child was presented to our hospital with recurrent infectious enteritis and stomatitis. DIAGNOSIS: Genetic mutations were detected immediately, and a novel pathogenic mutation was found in TNFAIP3. A heterozygous mutation (c.436-437deTC) located at TNFAIP3 was confirmed. The present research indicated that the TNFAIP3 mutation of c.436-437deTC (p.L147Qfs∗7) accounted for familial Behcet-like autoinflammatory syndrome in the child suffering from HA20, while no variation in this locus was found in her parents. INTERVENTIONS: Symptomatic treatments including oral administration of prednisone (12.5 mg/d) and iron supplement were performed, and repeated infection was no longer observed in the child. Pain and activity limitation was found in the knee joints. The treatment regimen was adjusted to oral prednisone (12.5 mg/dose, 2 doses/d) and subcutaneous injection of rhTNFR:Fc (12.5 mg/week).Outcomes: At the last follow-up, the limbs' activities were normal, the inflammatory indicators were reduced or within the normal range. The prednisone dose was reduced to 7.5 mg/d, while the dose of rhTNFR:Fc was not changed. CONCLUSION: We have identified a novel pathogenic HA20 mutation. In this article, 1 case was analyzed in-depth in terms of clinical manifestations of the patient and new sources of such a novel disease, which might improve our understanding of this disease.
33671473 Sarcopenia in Inflammatory Bowel Disease: A Narrative Overview. 2021 Feb 17 Malnutrition is a common condition encountered in patients with inflammatory bowel disease (IBD) and is often associated with sarcopenia (the reduction of muscle mass and strength) which is an ever-growing consideration in chronic diseases. Recent data suggest the prevalence of sarcopenia is 52% and 37% in Crohn's disease and ulcerative colitis, respectively, however it is challenging to fully appreciate the prevalence of sarcopenia in IBD. Sarcopenia is an important consideration in the management of IBD, including the impact on quality of life, prognostication, and treatment such as surgical interventions, biologics and immunomodulators. There is evolving research in many chronic inflammatory states, such as chronic liver disease and rheumatoid arthritis, whereby interventions have begun to be developed to counteract sarcopenia. The purpose of this review is to evaluate the current literature regarding the impact of sarcopenia in the management of IBD, from mechanistic drivers through to assessment and management.
35096568 Knockdown of NAA25 Suppresses Breast Cancer Progression by Regulating Apoptosis and Cell C 2021 NAA25 gene variants were reported as risk factors for type 1 diabetes, rheumatoid arthritis and acute arterial stroke. But it's unknown whether it could contribute to breast cancer. We identified rs11066150 in lncHSAT164, which contributes to breast cancer, in our earlier genome-wide long non-coding RNA association study on Han Chinese women. However, rs11066150 A/G variant is also located in NAA25 intron. Based on the public database, such as TCGA and Curtis dataset, NAA25 gene is highly expressed in breast cancer tissues and this result has also been proved in our samples and cell lines through RT-qPCR and western blot analysis. To better understand the function of NAA25 in breast cancer, we knocked down the expression of NAA25 in breast cancer cell lines, FACS was used to detect cell apoptosis and cell cycle and colony formation assay was used to detect cell proliferation. We found that NAA25-deficient cells could increase cell apoptosis, delay G2/M phase cell and decrease cell clone formation. RNA sequencing was then applied to analyze the molecular profiles of NAA25-deficient cells, and compared to the control group, NAA25 knockdown could activate apoptosis-related pathways, reduce the activation of tumor-associated signaling pathways and decrease immune response-associated pathways. Additionally, RT-qPCR was employed to validate these results. Taken together, our results revealed that NAA25 was highly expressed in breast cancer, and NAA25 knockdown might serve as a therapeutic target in breast cancer.