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ID PMID Title PublicationDate abstract
32382031 Hypertension in rheumatic diseases: prevalence, awareness, treatment, and control rates ac 2021 May Hypertension is a major modifiable risk factor for cardiovascular disease. Autoimmune rheumatic diseases confer increased cardiovascular risk, which is at least partially mediated by traditional cardiovascular risk factors. We examined the prevalence, awareness, treatment, and control rates of hypertension in a large cohort of patients with rheumatic diseases. Consecutive patients attending the Rheumatology Οutpatient Clinics were studied. Hypertension was defined by both the 2018 European Society of Cardiology/European Society of Hypertension (ESC/ESH) guidelines and the 2017 American College of Cardiology/American Heart Association (ACC/AHA). In a total of 622 individuals, hypertension prevalence reached 54.5% according to the 2018 ESH/ESC guideline, with the highest rates observed in patients with osteoarthritis (69.6%), rheumatoid arthritis (60.9%), and psoriatic arthritis (57.8%). Among hypertensive individuals, 21.7% were unaware of high blood pressure levels, while 67.2% were treated. Only 48.6% of treated hypertensives reached the 2018 ESC/ESH treatment goals. Applying the 2017 ACC/AHA criteria would result in a substantial increase of hypertension prevalence (72.4%) for both genders and especially among younger individuals, accompanied by a dramatic drop in control rates among treated patients (16.7%). In conclusion, comorbid hypertension was highly prevalent in a large cohort of patients with rheumatic diseases according to ESH/ESC and especially, ACC/AHA guidelines. However, it remains underdiagnosed and undertreated in a significant portion, while control rates are far from optimal. Our findings highlight the importance of systematic screening and more aggressive treatment of hypertension among patients with rheumatic diseases.
32301444 The prophylactic effects of different Lactobacilli on collagen-induced arthritis in rats. 2020 Apr 1 Recent studies have shed light on the prophylactic effects of Lactobacilli on rheumatoid arthritis (RA). However, the modulatory mechanisms of Lactobacilli remain unclear. The current study evaluated different Lactobacillus species' ability to alleviate arthritis induced by collagen. Rats were intragastrically administered different lactobacilli cocktails two weeks before arthritis induction. The results revealed that the performance of Lactobacillus in relieving arthritis was different for some species. L. reuteri, L. casei, L. rhamnosus and L. fermentum attenuated RA through species-independent pathways that inhibited pro-inflammatory cytokines and anti-CII-antibodies; and through species-dependent immune regulation that was based on rebalancing the intestinal microbiota, and metabolites such as short-chain fatty acids. In particular, L. reuteri and L. casei weaken the Th1 immune response, while L. rhamnosus and L. fermentum impaired Th17 responses. Interestingly, L. plantarum did not alleviate arthritis although it did suppress Th1 and Th17 immune responses, while L. salivarius only delayed the onset of arthritis without influencing the immune response. In conclusion, Lactobacilli protect against collagen-induced-arthritis through both common and individual pathways.
32059381 Multifaceted Physiological Roles of Adiponectin in Inflammation and Diseases. 2020 Feb 12 Adiponectin is the richest adipokine in human plasma, and it is mainly secreted from white adipose tissue. Adiponectin circulates in blood as high-molecular, middle-molecular, and low-molecular weight isoforms. Numerous studies have demonstrated its insulin-sensitizing, anti-atherogenic, and anti-inflammatory effects. Additionally, decreased serum levels of adiponectin is associated with chronic inflammation of metabolic disorders including Type 2 diabetes, obesity, and atherosclerosis. However, recent studies showed that adiponectin could have pro-inflammatory roles in patients with autoimmune diseases. In particular, its high serum level was positively associated with inflammation severity and pathological progression in rheumatoid arthritis, chronic kidney disease, and inflammatory bowel disease. Thus, adiponectin seems to have both pro-inflammatory and anti-inflammatory effects. This indirectly indicates that adiponectin has different physiological roles according to an isoform and effector tissue. Knowledge on the specific functions of isoforms would help develop potential anti-inflammatory therapeutics to target specific adiponectin isoforms against metabolic disorders and autoimmune diseases. This review summarizes the current roles of adiponectin in metabolic disorders and autoimmune diseases.
31403345 Factors influencing physician decisions to discontinue treatment after onset of liver dysf 2020 Jul Objectives: Adverse drug reactions (ADRs) related to liver dysfunction are a common problem in patients with rheumatoid arthritis (RA) receiving iguratimod, but which patient subgroups go on to discontinue iguratimod treatment is unclear. A post-hoc analysis of a post-marketing surveillance study was performed to investigate factors influencing treatment continuation after the onset of liver dysfunction.Methods: Types of ADR were compared between patients in whom iguratimod treatment was discontinued or continued in accordance with the judgment of the patient's physician after the patient developed liver dysfunction as an ADR. Stepwise logistic regression analysis was also conducted to investigate factors associated with treatment discontinuation.Results: The multivariate analysis found that concomitant use of methotrexate (MTX) at >8 mg/week (vs. no use) was associated with a significantly lower risk of discontinuation (OR: 0.136; 95%CI: 0.030-0.620), and previous treatment with MTX (vs. no use) was associated with a significantly higher discontinuation risk (OR: 4.045; 95%CI: 1.098-14.908).Conclusion: Although concomitant use of MTX during iguratimod treatment does not appear to influence treatment discontinuation due to abnormal liver function, liver function tests are of importance to continued treatment in patients receiving iguratimod who have a history of MTX use.
32586461 Hand Infections Associated with Systemic Conditions. 2020 Aug Systemic conditions are associated with higher rates of hand and upper extremity infections, leading to more severe and atypical presentations. Understanding the unique problems associated with some of the most common systemic conditions, including human immunodeficiency virus, diabetes mellitus, and rheumatoid arthritis, can assist the hand surgeon in diagnosing and treating infection in these patients. This article reviews the most common presentation of hand infections for these patients and summarizes current approaches to the management of hand infections for patients with common immunocompromising conditions.
32035179 B cells in rheumatoid arthritis synovial tissues encode focused antibody repertoires that 2020 Mar Rheumatoid arthritis (RA) is characterized by the production of anti-citrullinated protein antibodies (ACPAs). To gain insights into the relationship between ACPA-expressing B cells in peripheral blood (PB) and synovial tissue (ST), we sequenced the B cell repertoire in paired PB and ST samples from five individuals with established, ACPA+ RA. Bioinformatics analysis of paired heavy- and light-chain sequences revealed clonally-related family members shared between PB and ST. ST-derived antibody repertoires exhibited reduced diversity and increased normalized clonal family size compared to PB-derived repertoires. Functional characterization showed that seven recombinant antibodies (rAbs) expressed from subject-derived sequences from both compartments bound citrullinated antigens and immune complexes (ICs) formed using one ST-derived rAb stimulated macrophage TNF-α production. Our findings demonstrate B cell trafficking between PB and ST in subjects with RA and ST repertoires include B cells that encode ACPA capable of forming ICs that stimulate cellular responses implicated in RA pathogenesis.
32153567 Key Components of the Complement Lectin Pathway Are Not Only Required for the Development 2020 The complement system plays an important role in the pathogenesis of rheumatoid arthritis (RA). Besides driving lectin pathway (LP) activation, the mannan-binding lectin (MBL)-associated serine proteases (MASPs) also play a key role in regulating the alternative pathway (AP). We evaluated the effects of N-acetylgalactosamine (GalNAc)-conjugated MASP-1 and MASP-2 duplexes in vitro and in mice with and without arthritis to examine whether knockdown of MASP-1 and MASP-2 expression affects the development of arthritis. GalNAc-siRNAs for MASP-1 and MASP-2 demonstrated robust silencing of MASP-1 or MASP-2 at pM concentrations in vitro. To evaluate the impact of silencing in arthritic mice, we used the collagen antibody-induced arthritis (CAIA) mouse model of RA. Mice were injected a 10 mg/kg dose of GalNAc-siRNAs 3x s.q. prior to the induction of CAIA. Liver gene expression was examined using qRT-PCR, and protein levels were confirmed in the circulation by sandwich immunoassays and Western blot. At day 10, CAIA mice separately treated with MASP-1 and MASP-2 duplexes had a specific reduction in expression of liver MASP-1 (70-95%, p < 0.05) and MASP-2 (90%, p < 0.05) mRNA, respectively. MASP-1-siRNA treatment resulted in a 95% reduction in levels of MASP-1 protein in circulation with no effect on MASP-2 levels and clinical disease activity (CDA). In mice injected with MASP-2 duplex, there was a significant (p < 0.05) 90% decrease in ex vivo C4b deposition on mannan, with nearly complete elimination of MASP-2 in the circulation. MASP-2 silencing initially significantly decreased CDA by 60% but subsequently changed to a 40% decrease vs. control. Unexpectedly, GalNAc-siRNA-mediated knockdown of MASP-1 and MASP-2 revealed a marked effect of these proteins on the transcription of FD under normal physiological conditions, whereas LPS-induced inflammatory conditions reversed this effect on FD levels. LPS is recognized by Toll-like receptor 4 (TLR4), we found MBL not only binds to TLR4 an interaction with a K(d) of 907 nM but also upregulated FD expression in differentiated adipocytes. We show that MASP-2 knockdown impairs the development of RA and that the interrelationship between proteins of the LP and the AP may extend to the transcriptional modulation of the FD gene.
32826932 Acidosis induces synovial fibroblasts to release vascular endothelial growth factor via ac 2021 Mar Acid-sensitive ion channel 1a (ASIC1a) is a member of the extracellular H+ activated cation channel family. Studies have shown that tissue acidification contributes to the formation of microvessels in rheumatoid arthritis (RA) synovial tissue, but its underlying mechanisms remain unclear. The purpose of this study was to investigate the role of tissue acidification in microvascular formation of arthritic synovial tissue and the effect of ASIC1a on vascular endothelial growth factor (VEGF) release from arthritic synovial tissue. Our results indicate that ASIC1a expression, VEGF expression, and microvessel density (MVD) are elevated in RA synovial tissue and adjuvant arthritis (AA) rat synovial tissue. When AA rats were treated with ASIC1a-specific blocker psalmotoxin-1 (PcTx-1), the expression of ASIC1a, VEGF expression, and MVD were all reduced. Acidification of RA synovial fibroblasts (RASF) can promote the release of VEGF. PcTx-1 and ASIC1a-short hairpin RNA can inhibit acid-induced release of VEGF. In addition, the ASIC1a overexpression vector can promote acid-induced VEGF release. This indicates that extracellular acidification induces the release of VEGF by RASF via ASIC1a. These findings suggest that blocking ASIC1a mediates the release of VEGF from synoviocytes may provide a potential therapeutic strategy for RA therapy.
32991425 Traditional therapies of Zhuang medicine improve pain and joint dysfunction of patients in 2020 Sep 25 BACKGROUND: Rheumatoid arthritis (RA) is a common chronic inflammatory autoimmune disease, which can lead to joint destruction, dysfunction, finally deformity. Currently, Western medicine treats it with disease-modifying antireheumatic drugs, NSAIDs, glucocorticoid, biological agents, etc, which can induce adverse drug reactions. And now, as an important mean of treating RA, Zhuang medicine has been widely used in clinics, and has achieved significant efficacy. METHODS AND ANALYSIS: The following databases will be searched for relevant information before July 2020: PubMed, Embase, Cochrane Library, Web of Science, and China National Knowledge Infrastructure. MAJOR RESULTS: levels of C-reactive protein, erythrocyte sedimentation rate, Rheumatoid factor. Secondary results: morning stiffness time, range of motion, arthralgia, joint tenderness index, joint swelling index, total effective rate, adverse event. Data will be collected independently by 2 researchers, and the risk of bias in meta analysis will be evaluated according to "Cochrane Handbook for Systematic Reviews of Interventions". All data analysis will be conducted using Review Manager V.5.3. and Stata V.12.0. RESULTS: The curative effect and safety of traditional therapies of Zhuang Medicine treatment for RA patients will be evaluated systematically. CONCLUSION: The systematic review of this study will summarize the currently published evidence of traditional therapies of Zhuang Medicine treatment for RA to further guide its promotion and application.Open Science Framework (OSF) registration number: https://osf.io/c4xv3/.
32419304 Efficacy and Safety of PF-06651600 (Ritlecitinib), a Novel JAK3/TEC Inhibitor, in Patients 2020 Oct OBJECTIVE: To evaluate the efficacy and safety of PF-06651600 (ritlecitinib), an irreversible inhibitor of JAK3 and the tyrosine kinase expressed in hepatocellular carcinoma (TEC) kinase family, in comparison with placebo in patients with rheumatoid arthritis (RA). METHODS: An 8-week, phase II, double-blind, parallel-group study was conducted. Seventy patients who were seropositive for anti-citrullinated protein antibodies and/or rheumatoid factor were randomized 3:2 to receive oral PF-06651600 (200 mg once daily) or placebo for 8 weeks. Eligible patients had an inadequate response to methotrexate, and the study design allowed up to 50% of patients to have previously received 1 tumor necrosis factor inhibitor that was inadequately effective and/or not tolerated. The primary end point was change from baseline in the Simplified Disease Activity Index (SDAI) score at week 8, assessed by Bayesian analysis using an informative prior distribution for placebo response. RESULTS: Mean change from baseline in the SDAI score at week 8 was greater in the PF-06651600 group (-26.1 [95% credible interval -29.7, -22.4]) than in the placebo group (-16.8 [95% credible interval -20.9, -12.7]; P < 0.001). Most adverse events (AEs) were mild in severity, and no treatment-related serious AEs, severe AEs, or deaths were reported. The most common classes of AE were infections and infestations as well as skin and subcutaneous tissue disorders; there was 1 mild case of herpes simplex in the PF-06651600 group that was considered to be treatment related, which resolved within 3 days without study treatment discontinuation or antiviral therapy. CONCLUSION: Treatment with the oral JAK3/TEC inhibitor PF-06651600 (200 mg once daily) was associated with significant improvements in RA disease activity and was generally well-tolerated in this small 8-week study.
31199570 Validity and Reliability of Screening Measures for Depression and Anxiety Disorders in Rhe 2020 Aug OBJECTIVE: To test the validity and reliability of screening instruments for depression and anxiety in rheumatoid arthritis (RA). METHODS: Participants with RA completed the Patient Health Questionnaire (PHQ-2 or PHQ-9), the Patient Reported Outcomes Measurement Information System depression short form 8a and anxiety short form 8a, the Hospital Anxiety and Depression Scale anxiety score (HADS-A) and depression score (HADS-D), the Overall Anxiety Severity and Impairment Scale, the Generalized Anxiety Disorder 2- and 7-item scales, and the Kessler-6 scale. Clinical depression and anxiety disorders were confirmed using the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Axis I Disorders (SCID-1) research version. We reported sensitivity, specificity, positive predictive value, and negative predictive value using SCID-1 diagnoses as the criterion standard. Test-retest reliability was assessed with the intraclass correlation coefficient. RESULTS: Of 150 participants, 11.3% had SCID-1-diagnosed depression, 7.3% had SCID-1-diagnosed generalized anxiety disorder, and 19.3% had any SCID-1-diagnosed anxiety disorder. For depression, sensitivity ranged from HADS-D (cut point 11; 35%) to PHQ-2 (88%) and PHQ-9 (87%). Specificity ranged from PHQ-9 (77%) and PHQ-2 (84%) to HADS-D (cut point 11; 94%). Positive predictive value ranged from 30% to 43%. Negative predictive value ranged from 92% to 98%. For generalized anxiety disorder, sensitivity ranged from HADS-A (cut point 11; 45%) to HADS-A (cut point 8; 91%). Specificity ranged from 81% to 89% for all measures except the HADS-A (cut point 8; 63%). Intraclass correlation coefficient estimates ranging from 0.69 to 0.88 confirmed good test-retest reliability. CONCLUSION: Depression screening instruments had good diagnostic performance; anxiety instruments were more variable. Identified depression and anxiety require clinical confirmation.
31580188 Suppression of joint destruction with subcutaneous tocilizumab for Japanese patients with 2020 Sep Objectives: To investigate the efficacy of suppressing joint destruction with subcutaneous tocilizumab (TCZ-SC) for Japanese rheumatoid arthritis (RA) patients in the real-world clinical setting.Methods: This 1-year prospective, multicenter study included 110 RA patients in whom TCZ-SC was newly initiated. Primary endpoint was the change from baseline in vdH-modified total Sharp score (mTSS) at week 52. Structural remission was defined as yearly mTSS of 0.5 or less. Disease activity was evaluated using the disease activity score (DAS28-ESR) and clinical disease activity index (CDAI).Results: At baseline, the patients' mean age was 58.6 years, and the mean disease duration was 10.6 years. The proportion of patients who were naïve for biologics was 44.5%, and 64.5% concomitantly received methotrexate. The yearly mTSS showed significant improvement from 9.41 before TCZ-SC initiation to -0.15 after 52 weeks. The structural remission rate was 76.1%. After 52 weeks, the DAS28-ESR and CDAI remission rates were 52% and 21%, respectively. Although the previous usage of biologics and baseline disease activity significantly affected the clinical remission, no factors with significant effects on structural remission were identified.Conclusion: These findings support the efficacy of TCZ-SC in suppressing disease activity as well as joint destruction over a 1-year period.
32916134 Rare Oral Presentation of a Mycophenolate Mofetil-Related Other Iatrogenic Immunodeficienc 2021 Feb Oral manifestations of side effects of medications, such as methotrexate (MTX) for management of rheumatoid arthritis (RA) and mycophenolate mofetil (MMF) for solid organ transplant (SOT), are very rare. The known side effects include entities called other iatrogenic immunodeficiency-associated lymphoproliferative disorders (OIIA-LPD) due to immunosuppression caused by these medications. While there has been an increased incidence of oral cavity LPD reported in the literature associated with MTX, oral presentations that involve MMF are rare. This case report will detail a 74-year-old man with scleroderma treated with MMF who developed Epstein-Barr virus + polymorphic B-cell lymphoproliferative disorder in the right maxillary gingiva presenting as osteonecrosis of the jaw (ONJ). His oral presentation was successfully treated with a combination of surgery and MMF dosage reduction with an oral presentation free of disease at 6 months follow-up. This is the first known case report of an oral manifestation of MMF-related OIIA-LPD.
32271918 A novel monoclonal antibody cross-reactive with both human and mouse α9 integrin useful f 2020 Sep 1 This study introduces a novel monoclonal anti-α9 integrin antibody (MA9-413) with human variable regions, isolated by phage display technology. MA9-413 specifically binds to both human and mouse α9 integrin by recognizing a conserved loop region designated as L1 (amino acids 104-122 of human α9 integrin). MA9-413 inhibits human and mouse α9 integrin-dependent cell adhesion to ligands and suppresses synovial inflammation and osteoclast activation in a mouse model of arthritis. This is the first monoclonal anti-α9 integrin antibody that can react with and functionally inhibit both human and mouse α9 integrin. MA9-413 allows data acquisition both in animal and human pharmacological studies without resorting to surrogate antibodies. Since MA9-413 showed certain therapeutic effects in the mouse arthritis model, it can be considered as a useful therapy against rheumatoid arthritis and other α9 integrin-associated diseases.
32363539 Role of folate-conjugated glycol-chitosan nanoparticles in modulating the activated macrop 2020 Aug Activated macrophages are the primary targets in rheumatoid arthritis (RA) management. So, we report efficacious, dual-functional Methotrexate (MTX) loaded folate-conjugated pH-responsive glycol-chitosan nanoparticles (MFGCN) prepared by nano-precipitation and zero-order cross-linking reaction for targeting inflamed arthritic tissue. Physical characterization by DLS, SEM and TEM indicated a spherical, smooth morphology with a diameter ~ 300 nm. (1)H NMR and FTIR indicated folic acid conjugation to GC by zero-order cross-linkers. In vitro release kinetics in PBS showed pH-responsive and sustained release behaviour of MFGCN. Enhanced cellular uptake and cytotoxicity of MFGCN in LPS(+)RAW and activated peritoneal macrophages (Mϕ) were observed when compared to LPS(-)RAW cells. MFGCN-induced mitochondrial membrane potential (MMP) perturbations indicated apoptosis. Oxidative stress was evident by significant increase in ROS and RNS, 4 h post incubation with MFGCN. Negligible hemolysis by FGCN and MFGCN on rat RBC's indicated biocompatibility. In vivo biodistribution of MFGCN in adjuvant-induced arthritis (AIA) rats indicated RA targetability. Prolonged blood circulation coupled with higher concentrations of (99m)Tc-MFGCN at the arthritic site was observed post 24 h of injection. The gamma scintigraphic image confirmed accumulation of radiolabelled MFGCN in arthritic paw when compared to the non-inflamed paw, confirming the selective uptake of (99m)Tc-MFGCN by folate-overexpressing macrophages in the arthritic synovium thereby proving its targeted efficacy and theranostic potential. In AIA rats, MFGCN lowers arthritic signs, improves antioxidant response and decreases pro-inflammatory cytokines, suggesting its potential in targeting activated macrophages of synovium. Graphical abstract.
33169933 Effect of radiographic disease severity in high-resolution quantitative computed tomograph 2021 Jan AIM: Bone erosions are the hallmark of rheumatoid arthritis (RA). High-resolution peripheral quantitative computed tomography (HR-pQCT) enables 3-dimensional visualization of arthritic bone erosions at a high resolution. However, the degree of erosive disease could influence the reliability of HR-pQCT evaluation. We aim to assess the intra- and inter-reader variability of identification of erosions in the metacarpophalangeal (MCP) joints using HR-pQCT in healthy controls and patients with RA, stratified according to van der Heijde-modified Sharp Score (HSS) of radiographic erosions. METHOD: We analyzed HR-pQCT images from 78 patients with RA and 25 healthy controls. Patients were allocated to one of three groups of mild, moderate or severe disease according to HSS of MCP joints 2 and 3. Total HR-pQCT scans were analyzed twice in random order by three experienced readers, blinded to group distribution. The number of cortical interruptions and their classification as either erosions or cysts according to predefined criteria were recorded. Intraclass correlation coefficients (ICC) for cortical interruptions, erosions and cysts were calculated for each group using a 2-way random-effects model for inter-reader ICC and a 2-way mixed-effects model for intra-reader ICC. RESULTS: The intra- and inter-reader ICC were good to moderate for cortical interruptions and moderate for erosions throughout disease severity groups. The ICCs for the identification of cysts decreased with increasing degree of erosive disease. CONCLUSION: The detection of cortical interruptions is only minimally affected by the degree of erosive damage, whereas the distinction between erosions and cysts is more complex in patients with extensive erosive disease.
31981609 Genetics and evolution of tuberculosis pathogenesis: New perspectives and approaches. 2020 Jul Tuberculosis is the most lethal infectious disease globally, but the vast majority of people who are exposed to the primary causative pathogen, Mycobacterium tuberculosis (MTB), do not develop active disease. Most people do, however, show signs of infection that remain throughout their lifetimes. In this review, we develop a framework that describes several possible transitions from pathogen exposure to TB disease and reflect on the genetics studies to address many of these. The evidence strongly supports a human genetic component for both infection and active disease, but many of the existing studies, including some of our own, do not clearly delineate what transition(s) is being explicitly examined. This can make interpretation difficult in terms of why only some people develop active disease. Nonetheless, both linkage peaks and associations with either active disease or latent infection have been identified. For transition to active disease, pathways defined as active TB altered T and B cell signaling in rheumatoid arthritis and T helper cell differentiation are significantly associated. Pathways that affect transition from exposure to infection are less clear-cut, as studies of this phenotype are less common, and a primary response, if it exists, is not yet well defined. Lastly, we discuss the role that interaction between the MTB lineage and human genetics can play in TB disease, especially severity. Severity of TB is at present the only way to study putative co-evolution between MTB and humans as it is impossible in the absence of disease to know the MTB lineage(s) to which an individual has been exposed. In addition, even though severity has been defined in multiple heterogeneous ways, it appears that MTB-human co-evolution may shape pathogenicity. Further analysis of co-evolution, requiring careful analysis of paired samples, may be the best way to completely assess the genetic basis of TB.
31602572 Comparative Efficacy and Safety of Peficitinib 25, 50, 100, and 150 mg in Patients with Ac 2020 Jan BACKGROUND AND OBJECTIVE: Peficitinib, a JAK3-selective inhibitor that blocks the signal transduction and then suppresses immune responses, has been developed for the treatment of patients with moderate to severe active rheumatoid arthritis (RA). We assessed the relative efficacy and safety of once-daily administration of peficitinib (a JAK3-selective inhibitor) 25 mg, 50 mg, 100 mg, and 150 mg in patients with active RA. METHODS: A Bayesian network meta-analysis was conducted to combine direct and indirect evidence from eligible randomized controlled trials (RCTs). The literature search was performed up to May 2019 using MEDLINE, Embase, and the Cochrane Controlled Trials Register. RESULTS: Three RCTs involving 948 patients met the inclusion criteria. There were ten pairwise comparisons, including five direct comparisons and five interventions. The American College of Rheumatology 20% (ACR20) response rate was significantly higher in the peficitinib 150-mg group than in the placebo group (odds ratio (OR): 3.61; 95% credible interval (CrI): 2.35-5.57). Similarly, the ACR20 response rate was significantly higher in the peficitinib 100-mg group than in the placebo group (OR: 2.33, 95% CrI: 1.51-3.56). The peficitinib 50-mg group had a significantly higher ACR20 response rate than the placebo group. However, the ACR20 response rate was not significantly higher in the peficitinib 25-mg group than in the placebo group. The ranking probability based on the surface under the cumulative ranking curve (SUCRA) indicated that peficitinib 150 mg was likely to achieve the best ACR20 response rate (SUCRA = 0.995), followed by peficitinib 100 mg (SUCRA = 0.696), peficitinib 50 mg (SUCRA = 0.558), peficitinib 25 mg (SUCRA = 0.153), and placebo (SUCRA = 0.098). The ACR50 and ACR70 response rates showed a similar distribution pattern to the ACR20 response rate. The difference in the number of patients with adverse events (AEs) among the intervention groups was not statistically significant. CONCLUSIONS: Peficitinib 50, 100, and 150 mg once daily was effective in treating active RA, without causing a significant risk for AEs.
32769150 Risk factors for hospital admissions related to COVID-19 in patients with autoimmune infla 2020 Nov OBJECTIVES: To describe patients with autoimmune inflammatory rheumatic diseases (AIRD) who had COVID-19 disease; to compare patients who required hospital admission with those who did not and assess risk factors for hospital admission related to COVID-19. METHODS: An observational longitudinal study was conducted during the pandemic peak of severe acute respiratory syndrome coronavirus 2 (1 March 2020 to 24 April). All patients attended at the rheumatology outpatient clinic of a tertiary hospital in Madrid, Spain with a medical diagnosis of AIRD and with symptomatic COVID-19 were included. The main outcome was hospital admission related to COVID-19. The covariates were sociodemographic, clinical and treatments. We ran a multivariable logistic regression model to assess risk factors for the hospital admission. RESULTS: The study population included 123 patients with AIRD and COVID-19. Of these, 54 patients required hospital admission related to COVID-19. The mean age on admission was 69.7 (15.7) years, and the median time from onset of symptoms to hospital admission was 5 (3-10) days. The median length of stay was 9 (6-14) days. A total of 12 patients died (22%) during admission. Compared with outpatients, the factors independently associated with hospital admission were older age (OR: 1.08; p=0.00) and autoimmune systemic condition (vs chronic inflammatory arthritis) (OR: 3.55; p=0.01). No statistically significant findings for exposure to disease-modifying antirheumatic drugs were found in the final model. CONCLUSION: Our results suggest that age and having a systemic autoimmune condition increased the risk of hospital admission, whereas disease-modifying antirheumatic drugs were not associated with hospital admission.
33378180 Development of Orally Efficacious Allosteric Inhibitors of TNFα via Fragment-Based Drug D 2021 Jan 14 Tumor necrosis factor α (TNFα) is a soluble cytokine that is directly involved in systemic inflammation through the regulation of the intracellular NF-κB and MAPK signaling pathways. The development of biologic drugs that inhibit TNFα has led to improved clinical outcomes for patients with rheumatoid arthritis and other chronic autoimmune diseases; however, TNFα has proven to be difficult to drug with small molecules. Herein, we present a two-phase, fragment-based drug discovery (FBDD) effort in which we first identified isoquinoline fragments that disrupt TNFα ligand-receptor binding through an allosteric desymmetrization mechanism as observed in high-resolution crystal structures. The second phase of discovery focused on the de novo design and optimization of fragments with improved binding efficiency and drug-like properties. The 3-indolinone-based lead presented here displays oral, in vivo efficacy in a mouse glucose-6-phosphate isomerase (GPI)-induced paw swelling model comparable to that seen with a TNFα antibody.