Search for: rheumatoid arthritis methotrexate autoimmune disease biomarker gene expression GWAS HLA genes non-HLA genes
| ID | PMID | Title | PublicationDate | abstract |
|---|---|---|---|---|
| 34148462 | Associations of loneliness and social isolation with physical and mental health among adol | 2021 Jul | AIMS: The present study investigates whether loneliness and social isolation are associated with poor physical and mental health among adolescents and young adults, and whether age and gender play a role in the associations of loneliness and social isolation with mental and physical health. METHODS: This study used cross-sectional self-report data from the 2017 Danish Health and Morbidity Surveys titled 'How are you?' (N = 19,890, M = 22.6 years). RESULTS: Logistic regression analyses showed that loneliness and social isolation were independently associated with poor physical and mental health. Loneliness was associated with increased odds of asthma, migraine, osteoarthritis, rheumatoid arthritis, hypertension, slipped disc/back pain, tinnitus, long-term mental illness, depressive symptomatology, anxiety symptomatology and alcohol problems. Social isolation was associated with decreased odds of having migraine, osteoarthritis and alcohol problems, and an increased risk of long-term mental illness and depressive symptomatology. Small age and gender differences were detected. CONCLUSIONS: In adolescents and young adults, loneliness and social isolation were associated with poor mental health and loneliness with poor physical health. These findings highlight the need for targeted prevention and intervention initiatives to alleviate loneliness and social isolation. | |
| 34119672 | Safety and immunological proof-of-concept following treatment with tolerance-inducing cell | 2021 Aug | In the past years, translational approaches have led to early-stage clinical trials assessing safety and efficacy of tolerance-inducing cell-based treatments in patients. This review aims to determine if tolerance-inducing cell-based therapies, including dendritic cells, regulatory T cells and mesenchymal stem cells, are safe in adult patients who underwent organ transplantation or in those with autoimmune diseases, including multiple sclerosis, diabetes mellitus type 1, Crohn's disease and rheumatoid arthritis. Immunological and clinical outcomes were reviewed, to provide evidence for proof-of-concept and efficacy. To summarize the current knowledge, a systematic review and meta-analysis were conducted. A total of 8906 records were reviewed by 2 independent assessors and 48 records were included in the final quantitative analysis. The overall frequency of serious adverse events was low: 0.018 (95% CI: 0.006-0.051). Immunological outcomes could not be assessed quantitatively because of heterogeneity in outcome assessments and description as well as lack of individual data. Most randomized controlled studies were at a medium risk of bias due to open-label treatment without masking of assessors and/or patients to the intervention. In conclusion, tolerance-inducing cell-based therapies are safe. We advocate for harmonization of study protocols of trials investigating cell-based therapies, adverse event reporting and systematic inclusion of immunological outcome measures in clinical trials evaluating tolerance-inducingcell-basedtreatment. Registration: PROSPERO, registration number CRD42020170557. | |
| 34048962 | Arrhythmia prevalence among patients with polymyositis-dermatomyositis in the United State | 2021 Sep | BACKGROUND: Systemic inflammation has been associated with atherosclerotic cardiovascular diseases (ASCVD) and arrhythmia occurrence in rheumatologic conditions such as rheumatoid arthritis. Polymyositis and dermatomyositis (PD) are rare rheumatologic conditions characterized by symmetrical proximal muscle weakness and, in the case of dermatomyositis, cutaneous eruption. Although there is literature associating PD with ASCVD, no population-level studies have analyzed arrhythmia risk in PD. OBJECTIVE: The purpose of this study was to assess the prevalence of arrhythmia and its subtypes by age and sex in patients with PD and to determine associations between arrhythmia and PD. METHODS: This retrospective cohort study included adults for whom hospitalizations had been recorded in the National Inpatient Sample database in the United States between 2016 and 2018. Patients with PD were matched (1:10) by age to patients without PD. Prevalence of arrhythmia was calculated in the 2 groups and compared by sex and age groups. Associations between PD and arrhythmia were determined after adjustment for common arrhythmia risk factors. RESULTS: From 107,001,355 hospitalizations, 32,085 adults with PD were matched to 320,850 controls. Patients with PD aged <70 years had a higher prevalence of arrhythmia and higher adjusted odds of arrhythmia compared with controls. This increased risk was only seen for supraventricular arrhythmias. Adults with PD had increased odds of in-hospital mortality if they had an arrhythmia diagnosis (odds ratio 3.3; 95% confidence interval 2.5-4.5; P <.001). CONCLUSION: We found a higher prevalence and odds of arrhythmias, particularly supraventricular arrhythmias, in young and middle-aged patients with PD compared with matched controls. Arrhythmias were associated with significant mortality among patients with PD. | |
| 33542676 | Simvastatin Inhibits CYR61 Expression in Orbital Fibroblasts in Graves' Ophthalmopathy thr | 2021 | Graves' ophthalmopathy (GO), which is characterized by orbital tissue inflammation, expansion, and fibrosis, is the ocular manifestation in 25% to 50% of patients with Graves' disease. As the pathology of GO is driven by autoimmune inflammation, many proinflammatory cytokines/chemokines, including TNF-α, IL-1β, IL-6, and CCL20, are crucial in the pathogenesis of GO to activate the orbital fibroblasts. Cysteine-rich protein 61 (CYR61), which is known to regulate cell proliferation, adhesion, and migration, plays a proinflammatory role in the pathogenesis of many inflammatory diseases, such as rheumatoid arthritis. CYR61 was considered a potential biomarker of GO in recent studies. Statins, which are cholesterol-lowering drugs, were found to reduce the risk of GO, probably through their anti-inflammatory and immunomodulatory effects. In this study, we established a link between CYR61 and statins in the pathogenesis and potential treatment for GO. Firstly, our data showed the overexpression of CYR61 in the orbital tissue (n = 4) and serum specimens (n = 6) obtained from the patients with inactive GO. CYR61 could induce the production of IL-6 and CCL20 in cultured GO orbital fibroblasts. The expression of CYR61 in cultured GO orbital fibroblasts was upregulated via TNF-α stimulation. Secondly, we pretreated cultured GO orbital fibroblasts using simvastatin, a statin, followed by TNF-α stimulation. The data revealed that simvastatin could inhibit TNF-α-induced CYR61 expression by modulating the activity of transcription factor FoxO3a. Our results provided insights into some cellular mechanisms that may explain the possible protective effects of simvastatin against the development of GO. | |
| 33527325 | Sjögren's Syndrome Associated with Chikungunya Infection: A Case Report. | 2021 Mar | Chikungunya virus (CHIKV) infection is caused by an arbovirus prevalent in various parts of the world. The virus can induce autoantibodies and rheumatic diseases, such as rheumatoid arthritis and spondylarthritis. However, until now, no case of Sjögren syndrome (SS) was described associated with CHIKV. In this article, we describe a 49-year-old female with polyarthralgia and a temporary rash on her trunk and arms. Her physical examination showed polyarthritis of her ankles and wrists. Serologies for CHIKV were interpreted as positive with IgM 6.5 (normal range < 0.8) and negative for IgG. Antinuclear antibodies were positive at a titer of 1:640 as well as anti-Ro/SS-A. The diagnosis of subacute CHIKV infection was determined. The Schirmer test, Rose Bengal, and salivary scintigraphy were positive and the diagnosis of SS was confirmed. She was treated with hydroxychloroquine, methotrexate, and a single dose of betamethasone depot. This is the first report on CHIKV associated with SS. Sequence analysis of the CHIKV proteome versus SS autoantigens showed an extensive peptide sharing between the virus and numerous SS autoantigens, thus supporting the hypothesis that autoimmune cross-reactivity might causally link CHIKV to SS. | |
| 33505716 | Familial Risks between Pernicious Anemia and Other Autoimmune Diseases in the Population o | 2021 | BACKGROUND: Pernicious anemia (PA) is an autoimmune disease (AID) which is caused by lack of vitamin B12 (cobalamin) due to its impaired uptake. PA is a multifactorial disease which is associated with a number of other AID comorbidities and which is manifested as part of autoimmune polyglandular syndrome. Due to the shortage of family studies on PA, we planned to address the problem by assessing familial risks for concordant PA between family members and for discordant PA in families of other AID patients. METHODS: We collected data on patients diagnosed with AIDs from the Swedish hospitals and family data from a population register. We calculated standardized incidence ratios (SIRs) in families for concordant and discordant risks. RESULTS: The number of PA patients in the offspring generation (for which the familial risk was calculated) was 7701; 278 (3.6%) patients had a family history of PA. The population prevalence of PA was 0.9/1000. The familial risk for PA was 3.88 when any first-degree relative was the proband, equal for men and women. The familial risk was two times higher between siblings than between offspring and parents which may be due to complex genetic background. Associations of PA with 14 discordant AIDs were significant; these included some AIDs that have previously been described as comorbidities in PA patients and several yet unreported associations, including rheumatoid arthritis and other AIDs. CONCLUSIONS: The familial risks for PA were high suggesting multifactorial genetic etiology. The results call for further population-level studies to unravel mechanisms of familial PA which may help to understand the etiology of this disease. | |
| 33443168 | Spinal and paraspinal inflammatory reactions after epidural steroid injection in a patient | 2021 Apr | BackgroundDisease-modifying anti-rheumatic drugs (DMARDs) are used in the management of rheumatoid arthritis (RA) and are classified as conventional DMARDs and biologic agents. A concern with DMARDs is the increased risk of infection after surgery. A practice advisory from the American Society of Anesthesiologists recommend alternatives to neuraxial injections in patients who are immunocompromized. We describe a patient who was on several DMARDs and developed inflammatory reactions in her bilateral paraspinal muscles and lumbar spine after an epidural steroid injection (ESI). CASE PRESENTATION: The patient was a 79-year-old woman; she was taking methotrexate, adalimumab and prednisone for her RA. She had a left L5-S1 paramedian ESI for her L5 radiculitis. After relief of her back and radicular pain for 5 weeks, she had an acute exacerbation of her back pain. MRI showed bilateral paraspinal fluid accumulations and enhancement in her ligamentum flavum. Cultures of the aspirated fluid and biopsy specimens were negative for fungal, aerobic and anaerobic organisms. A repeat MRI 2 months later showed diminution of the fluid collection but with a new fluid accumulation near the left L4-5 facet and left L4 pedicle. Repeat cultures and gram stain of the specimens taken from the pedicle and the paraspinal muscles were negative. The patient was followed by her rheumatologist and in the pain clinic until resolution of her symptoms. CONCLUSIONS: Several society guidelines recommend the continuation of methotrexate but stoppage of the biologic DMARDS before surgery. The occurrence of an intense inflammatory reaction after an ESI in our patient calls for additional research on the subject and shared decision-making between the pain physician, patient and rheumatologist especially in patients on several DMARDs. | |
| 34782452 | Exploring Family Planning, Parenting, and Sexual and Reproductive Health Care Experiences | 2022 Mar | OBJECTIVE: To explore family planning, parenting, and sexual and reproductive health (SRH) care needs and experiences of men with rheumatic diseases. METHODS: Men aged 18-45 years who were diagnosed with at least 1 rheumatic disease and used at least 1 antirheumatic drug were recruited from rheumatology clinics. Research coordinators engaged participants in semistructured phone interviews. A codebook was developed based on the interview transcripts and used to conduct an inductive thematic analysis. RESULTS: Participants ranged in age from 22 to 44 years (n = 20). Most were heterosexual and had at least 1 child. The most common disease diagnoses were spondyloarthritis, systemic lupus erythematosus, and rheumatoid arthritis. Four themes emerged from the interviews: (1) Men had family planning concerns, particularly related to the heritability of their diseases, their fertility, and potential effects of their medications on their offspring's health. (2) Men felt that fatigue, disability, and/or pain from their diseases either impaired or would impair their abilities to parent. (3) Men often did not discuss sexual dysfunction with their rheumatologists, even when they believed that it arose from their diseases or antirheumatic drugs. (4) Men rarely discussed any family planning, parenting, or SRH issues with their rheumatologists; gender discordance with rheumatologists did not affect men's comfort in discussing these issues. CONCLUSION: Men expressed concerns related to family planning, parenting, and SRH, which they rarely discussed with their rheumatologists. Our study suggests that some men's SRH information needs are incompletely addressed in the rheumatology clinical setting. | |
| 33966541 | Urine β-2-glycoprotein 1 as a biomarker for diagnosis of systemic lupus erythematosus. | 2021 Jul | OBJECTIVE: The need for a biomarker with robust sensitivity and specificity in diagnosing systemic lupus erythematosus (SLE) remains unmet. Compared with blood samples, urine samples are more easily collected; thus, we aimed to identify such a biomarker based on urinary proteomics which could distinguish patients with SLE from healthy controls (HCs). METHODS: Urine samples were collected from 76 SLE patients who visited rheumatology clinic in 2019 at Asan medical center and from 25 HCs. Urine proteins were analyzed using sequential windowed acquisition of all theoretical fragment ion spectra-mass spectrometry, and the candidate marker was confirmed by enzyme-linked immunosorbent assay (ELISA). Receiver operating characteristic curve analysis was used to determine the diagnostic value of the candidate biomarker. RESULTS: Of 1157 proteins quantified, 153 were differentially expressed in urine samples from HCs. Among them were previously known markers including α-1-acid glycoprotein 1, α-2-HS-glycoprotein, ceruloplasmin, and prostaglandin-H2 D-isomerase. Moreover, the amount of β-2 glycoprotein (APOH) was increased in the urine of patients with SLE. The ELISA results also showed the level of urine APOH was higher in patients with SLE than in HCs and patients with rheumatoid arthritis. Moreover, the level was not different between SLE patients with and without nephritis. The urine APOH had an area under the curve value of 0.946 at a cut-off value of 228.53 ng/mg (sensitivity 91.5%, specificity 92.0%) for the diagnosis of SLE. CONCLUSION: The results indicate that the urine APOH level can be an appropriate screening tool in a clinical setting when SLE is suspected. | |
| 33956259 | High endothelial venules (HEVs) in immunity, inflammation and cancer. | 2021 Nov | High endothelial venules (HEVs) are specialized blood vessels mediating lymphocyte trafficking to lymph nodes (LNs) and other secondary lymphoid organs. By supporting high levels of lymphocyte extravasation from the blood, HEVs play an essential role in lymphocyte recirculation and immune surveillance for foreign invaders (bacterial and viral infections) and alterations in the body's own cells (neoantigens in cancer). The HEV network expands during inflammation in immune-stimulated LNs and is profoundly remodeled in metastatic and tumor-draining LNs. HEV-like blood vessels expressing high levels of the HEV-specific sulfated MECA-79 antigens are induced in non-lymphoid tissues at sites of chronic inflammation in many human inflammatory and allergic diseases, including rheumatoid arthritis, Crohn's disease, allergic rhinitis and asthma. Such vessels are believed to contribute to the amplification and maintenance of chronic inflammation. MECA-79(+) tumor-associated HEVs (TA-HEVs) are frequently found in human tumors in CD3(+) T cell-rich areas or CD20(+) B-cell rich tertiary lymphoid structures (TLSs). TA-HEVs have been proposed to play important roles in lymphocyte entry into tumors, a process essential for successful antitumor immunity and lymphocyte-mediated cancer immunotherapy with immune checkpoint inhibitors, vaccines or adoptive T cell therapy. In this review, we highlight the phenotype and function of HEVs in homeostatic, inflamed and tumor-draining lymph nodes, and those of HEV-like blood vessels in chronic inflammatory diseases. Furthermore, we discuss the role and regulation of TA-HEVs in human cancer and mouse tumor models. | |
| 33882635 | Efficacy and safety of hydroxychloroquine in osteoarthritis: a systematic review and meta- | 2022 Jan | BACKGROUND/AIMS: Conventional disease-modifying anti-rheumatic drugs have been trialed in osteoarthritis (OA). Hydroxychloroquine (HCQ), which has shown its effectiveness in rheumatoid arthritis, has been trialed for the treatment of OA; however, its efficacy and safety remain unclear. This systematic review and meta-analysis evaluate efficacy and safety of HCQ for the treatment of OA. METHODS: MEDLINE, EMBASE, and Cochrane Central were searched from inception through June 2020. Two reviewers independently screened for randomized controlled trials (RCTs) comparing HCQ with placebo or other active-comparators for the treatment of knee, hand, or hip OA, extracted data, and performed Cochrane risk of bias assessments. RESULTS: Six RCTs, four in hand OA, two in knee OA, consisting of 842 patients (436 in HCQ arm, 406 in control arm) were included. RCTs were conducted between 2012 and 2020, one each at UK, Netherlands, Germany, Italy, Iran, and Egypt; follow-up period ranged 24 to 52 weeks. High-quality evidence showed no clinically important pain reduction with HCQ compared to placebo/active-control in hand OA (standardized mean difference [SMD], 0.14; 95% confidence interval [CI], -0.20 to 0.48). Effect on pain reduction in knee and hand OA was small and non-significant (SMD, -0.09; 95% CI, -0.44 to 0.25). High-quality evidence showed no improvement in dysfunction with HCQ compared to placebo in hand OA patients (SMD, 0.08; 95% CI, -0.23 to 0.40). Effect on dysfunction improvement in knee and hand OA was modest and statistically non-significant (SMD, -0.20; 95% CI,-0.57 to 0.18). No improvement in quality of life was observed in hand OA. CONCLUSION: HCQ has no benefit in reducing pain and improving physical function in hand or knee OA patients. | |
| 33808759 | Anti-Inflammatory Effects of a Polyphenol, Catechin-7,4'-O-Digallate, from Woodfordia unif | 2021 Mar 19 | Inflammation is a defense mechanism that protects the body from infections. However, chronic inflammation causes damage to body tissues. Thus, controlling inflammation and investigating anti-inflammatory mechanisms are keys to preventing and treating inflammatory diseases, such as sepsis and rheumatoid arthritis. In continuation with our work related to the discovery of bioactive natural products, a polyphenol, catechin-7,4'-O-digallate (CDG), was isolated from Woodfordia uniflora, which has been used as a sedative and remedy for skin infections in the Dhofar region of Oman. Thus far, no study has reported the anti-inflammatory compounds derived from W. uniflora and the mechanisms underlying their action. To investigate the effects of CDG on the regulation of inflammation, we measured the reduction in nitric oxide (NO) production following CDG treatment in immortalized mouse Kupffer cells (ImKCs). CDG treatment inhibited NO production through the downregulation of inducible nitric oxide synthase expression in lipopolysaccharide (LPS)-stimulated ImKCs. The anti-inflammatory effects of CDG were mediated via the inhibition of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation, an important inflammatory-response-associated signaling pathway. Moreover, CDG treatment has regulated the expression of pro-inflammatory cytokines, such as IL-6 and IL-1β. These results suggested the anti-inflammatory action of CDG in LPS-stimulated ImKCs. | |
| 33789440 | New Therapeutic Approaches Using Hydrogen Sulfide Donors in Inflammation and Immune Respon | 2021 Aug 10 | Significance: Inflammation and immune response are associated with many pathological disorders, including rheumatoid arthritis, lupus, heart failure, and cancer(s). In recent times, important roles of hydrogen sulfide (H(2)S) have been evidenced by researchers in inflammatory responses, as well as immunomodulatory effects in several disease models. Recent Advances: Numerous biological targets, including cytochrome c oxidase, various kinases, enzymes involved in epigenetic changes, transcription factors, namely nuclear factor kappa B and nuclear factor erythroid 2-related factor 2, and several membrane ion channels, are shown to be sensitive to H(2)S and have been widely investigated in various preclinical models. Critical Issues: A complete understanding of the effects of H(2)S in inflammatory and immune response is vital in the development of novel H(2)S generating therapeutics. In this review, the biological effects and pharmacological properties of H(2)S in inflammation and immune response are addressed. The review also covers some of the novel H(2)S releasing prodrugs developed in recent years as tools to study this fascinating molecule. Future Directions: H(2)S plays important roles in inflammation and immunity-related processes. Future researches are needed to further assess the immunomodulatory effects of H(2)S and to assist in the design of more efficient H(2)S carrier systems, or drug formulations, for the management of immune-related conditions in humans. Antioxid. Redox Signal. 35, 341-356. | |
| 33610375 | A clinical audit of pneumococcal vaccination among patients with autoimmune rheumatic dise | 2021 Mar 12 | INTRODUCTION: Patients with autoimmune rheumatic diseases (ARDs) are at increased risk for pneumococcal infections and should be vaccinated against Streptococcus pneumoniae. Data on the rates of pneumococcal vaccination among patients with ARDs in Southern Europe are scarce. Here, we estimate the pneumococcal vaccination rate in patients living in Greece with ARDs, explore the patients' awareness regarding vaccination, and try to recognize factors that influence the vaccine uptake. METHODS: Between October 2015 and September 2016, a structured questionnaire was provided to all consecutive patients with ARDs attending one outpatient clinic of our department. The survey included parameters concerning patients' demographics, underlying ARD and immunosuppressive medications, other comorbidities, vaccine type, knowledge about infection risk and necessity of vaccination. Univariate and multivariate analyses were performed to study any association of these factors with the vaccination uptake. RESULTS: Overall, 395 patients with ARDs (30.13% aged >65 years and 78.99% female) participated in our survey. The most frequent ARD was rheumatoid arthritis (43.04%); 40.51% of patients were receiving biologic agents and 44.56% steroids. Pneumococcal vaccination rate was 49.37%, while 45.06% of patients have been vaccinated during the last five years and only 8.21% of them had a second pneumococcal vaccine, as per national guidelines. The decision of vaccination was significantly influenced by the patient's age (>65 years) (p < 0.001) and the complete awareness of reasons for being vaccinated (p < 0.001), but not by presence of comorbidities, the type of ARD or administration of a biologic agent. The main reason for no vaccination was that it was not suggested by the caring physician (82.50%). CONCLUSIONS: In our cohort of patients with ARDs the pneumococcal vaccination was suboptimal. Better understanding of the significance of vaccination by the patient and suggestion for vaccination by the caring physician will improve vaccination uptake and optimize the clinical benefits among patients with ARDs. | |
| 33597943 | Recombinant Adiponectin Induces the Production of Pro-Inflammatory Chemokines and Cytokine | 2020 | Adiponectin is an adipokine with a modulatory role in metabolism and exerting both anti- and pro-inflammatory effects. Levels of adiponectin are increased in serum and synovial fluid from patients with rheumatoid arthritis (RA). Adiponectin is able to stimulate the production of different pro-inflammatory factors from peripheral blood mononuclear cells (PBMCs) and fibroblast-like synoviocytes (FLS) from subjects with established RA. As increased circulating adiponectin levels are a risk factor for future development of RA in subjects with obesity, we hypothesize that adiponectin is implicated in the development of RA at an early stage by initiating the pro-inflammatory processes associated with the disease pathogenesis. Therefore, we aimed to determine if adiponectin is able to induce pro-inflammatory responses in cells involved in the pathogenesis of RA, but collected from subjects without any known inflammatory disease. PBMCs and FLS were obtained from non-inflamed subjects and stimulated with 5 μg/ml human recombinant adiponectin. Supernatants collected after 48 h were analyzed for the production of 13 chemokines and 12 cytokines using multiplex assay and ELISA. Adiponectin significantly stimulated the production of CXCL1, CXCL5, and interleukin (IL)-6 in both PBMCs and FLS, whereas it induced CCL20, CCL4, CCL3, CCL17, tumor necrosis factor (TNF), granulocyte-macrophage colony-stimulating factor and IL-10 only in PBMCs, and CXCL8, CXCL10, CCL5, CCL11, and CCL2 only in FLS. Pre-stimulation with TNF of FLS from non-inflamed subjects did not significantly enhance the release of most pro-inflammatory factors compared to adiponectin alone. Our findings indicate that PBMCs and FLS from non-inflamed subjects react to adiponectin stimulation with the secretion of several pro-inflammatory chemokines and cytokines. These results suggest that adiponectin is able to initiate pro-inflammatory responses in cells from non-inflamed subjects and support the hypothesis that adiponectin is implicated in the early phases of RA pathogenesis. | |
| 33340765 | In vitro display evolution of IL-6R-binding unnatural peptides ribosomally initiated and | 2021 Jan 8 | The interaction of the multifunctional cytokine interleukin (IL)-6 and its receptor (IL-6R) is involved in various diseases, including not only autoimmune diseases such as rheumatoid arthritis but also cancer and cytokine storms in coronavirus disease 2019 (COVID-19). In this study, systematic evolution of ligands by exponential enrichment (SELEX) against human IL-6R from mRNA-displayed unnatural peptide library ribosomally initiated and cyclized with m-(chloromethyl)benzoic acid (mClPh) incorporated by genetic code expansion (sense suppression) was performed using the PURE (Protein synthesis Using Recombinant Elements) system. A novel 13-mer unnatural mClPh-cyclized peptide that binds to the extracellular domain of IL-6R was discovered from an extremely diverse random peptide library. In vitro affinity maturation of IL-6R-binding unnatural mClPh-cyclized peptide from focused libraries was performed, identifying two IL-6R-binding unnatural mClPh-cyclized peptides by next-generation sequencing. Because cyclization can increase the protease resistance of peptides, novel IL-6R-binding mClPh-cyclized peptides discovered in this study have the potential to be used for a variety of research, therapeutic, and diagnostic applications involving IL-6/IL-6R signaling. | |
| 33222113 | Evaluation of Adherence and Persistence Differences Between Adalimumab Citrate-Free and Ci | 2021 Mar | INTRODUCTION: Our aim was to evaluate patient adherence and persistence with citrate-free adalimumab (ADA-CF), introduced in 2018 to reduce injection-site pain, compared with citrate-containing adalimumab (ADA-C). METHODS: This was a retrospective cohort study using a US claims database (IBM(®) MarketScan(®) Commercial and Medicare Supplemental Claims Database) from February 2018 to January 2020. Patients at least 18 years of age who were naïve to adalimumab 6 months before the index date (date of first adalimumab claim) and with at least 12 months of continuous medical and pharmacy coverage were eligible for the study. Adherence was assessed by determining the proportion of days covered (PDC) and the percentage of patients with PDC ≥ 80% during the 12-month follow-up period. Persistence was evaluated by measuring the rate of discontinuation and days to discontinuation (i.e., time on treatment) from the index date over the 12-month follow-up period. Continuous adherence outcomes (PDC) were evaluated using linear regression models. Binary adherence outcomes (PDC ≥ 80%) were assessed using logistic regression models. Kaplan-Meier analysis and Cox proportional hazards models were used to assess persistence outcomes. RESULTS: There were 2195 and 1005 patients in the ADA-CF and ADA-C cohorts, respectively, with most using adalimumab for rheumatoid arthritis (ADA-CF 29.7%, ADA-C 27.2%) and psoriasis (ADA-CF 24.5%, ADA-C 31.9%). Significantly greater adherence was achieved with ADA-CF compared with ADA-C (mean PDC [standard deviation] 0.68 [0.30] vs 0.61 [0.32], P < 0.0001). A significantly greater percentage of patients receiving ADA-CF (47.2%) vs ADA-C (39.6%) had PDC ≥ 80% (P < 0.0001). The discontinuation rate was significantly lower for the ADA-CF cohort (46.4%) compared with ADA-C (55.9%, P < 0.0001), resulting in a 27% lower likelihood of discontinuation during the 12-month follow-up period (hazard ratio 0.73; 95% confidence interval 0.66, 0.82; P < 0.0001) and longer time on treatment (260 vs 232 days, P < 0.0001). CONCLUSION: Adherence and persistence are significantly improved with ADA-CF compared with ADA-C. | |
| 33103259 | Recent advances in the design of choline kinase α inhibitors and the molecular basis of t | 2021 Mar | Upregulated choline metabolism, characterized by an increase in phosphocholine (PCho), is a hallmark of oncogenesis and tumor progression. Choline kinase (ChoK), the enzyme responsible for PCho synthesis, has consequently become a promising drug target for cancer therapy and as such a significant number of ChoK inhibitors have been developed over the last few decades. More recently, due to the role of this enzyme in other pathologies, ChoK inhibitors have also been used in new therapeutic approaches against malaria and rheumatoid arthritis. Here, we review research results in the field of ChoKα inhibitors from their synthesis to the molecular basis of their binding mode. Strategies for the development of inhibitors and their selectivity on ChoKα over ChoKβ, the plasticity of the choline-binding site, the discovery of new exploitable binding sites, and the allosteric properties of this enzyme are highlighted. The outcomes summarized in this review will be a useful guide to develop new multifunctional potent drugs for the treatment of various human diseases. | |
| 32981005 | Coronavirus disease 2019 (COVID-19) in patients with systemic autoimmune diseases or vascu | 2021 Feb | Coronavirus disease 2019 (COVID-19) has transformed into a worldwide challenge, since its outbreak in December 2019. Generally, patients with underlying medical conditions are at a higher risk of complications and fatality of pneumonias. Whether patients with systemic autoimmune diseases or vasculitides, are at increased risk for serious complications associated with COVID-19, is not established yet. Computed tomography (CT) has been employed as a diagnostic tool in the evaluation of patients with clinical suspicion of severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) infection with a reported sensitivity of higher than reverse transcription polymerase chain reaction (RT-PCR) test. Multifocal bilateral ground-glass opacities (GGOs) with peripheral and posterior distribution and subsequent superimposition of consolidations are considered the main imaging features of the disease in chest CT. However, chest CT images of underlying rheumatologic or autoimmune diseases or vasculitides, such as systemic sclerosis, systemic lupus erythematosus, rheumatoid arthritis, Behçet disease, and granulomatosis with polyangiitis, especially those with extensive lung involvement can overshadow or obliterate features of COVID-19. In addition, CT findings of such diseases may resemble manifestations of COVID-19 (such as ground glass opacities with or without superimposed consolidation), making the diagnosis of viral infections, more challenging on imaging. Comparing the imaging findings with prior studies (if available) for any interval change is the most helpful approach. Otherwise, the diagnosis of COVID-19 in such patients must be cautiously made according to the clinical context and laboratory results, considering a very high clinical index of suspicion on imaging. | |
| 32853526 | The Ubiquitin System and A20: Implications in Health and Disease. | 2021 Jan | Inflammation is triggered by stimulation of innate sensors that recognize pathogens, chemical and physical irritants, and damaged cells subsequently initiating a well-orchestrated adaptive immune response. Immune cell activation is a strictly regulated and self-resolving process supported by an array of negative feedback mechanisms to sustain tissue homeostasis. The disruption of these regulatory pathways forms the basis of chronic inflammatory diseases, including periodontitis. Ubiquitination, a covalent posttranslational modification of target proteins with ubiquitin, has a profound effect on the stability and activity of its substrates, thereby regulating the immune system at molecular and cellular levels. Through the cooperative actions of E3 ubiquitin ligases and deubiquitinases, ubiquitin modifications are implicated in several biological processes, including proteasomal degradation, transcriptional regulation, regulation of protein-protein interactions, endocytosis, autophagy, DNA repair, and cell cycle regulation. A20 (tumor necrosis factor α-induced protein 3 or TNFAIP3) is a ubiquitin-editing enzyme that mainly functions as an endogenous regulator of inflammation through termination of nuclear factor (NF)-κB activation as part of a negative feedback loop. A20 interacts with substrates that reside downstream of immune sensors, including Toll-like receptors, nucleotide-binding oligomerization domain-containing receptors, lymphocyte receptors, and cytokine receptors. Due to its pleiotropic functions as a ubiquitin binding protein, deubiquitinase and ubiquitin ligase, and its versatile role in various signaling pathways, aberrant A20 levels are associated with numerous conditions such as rheumatoid arthritis, diabetes, systemic lupus erythematosus, inflammatory bowel disease, psoriasis, Sjögren syndrome, coronary artery disease, multiple sclerosis, cystic fibrosis, asthma, cancer, neurological disorders, and aging-related sequelae. Similarly, A20 has recently been implicated as an essential regulator of inflammation in the oral cavity. This review presents information on the ubiquitin system and regulation of NF-κB by ubiquitination using A20 as a representative molecule and highlights how the dysregulation of this system can lead to several immune pathologies, including oral cavity-related disorders mainly focusing on periodontitis. |