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

ID PMID Title PublicationDate abstract
32459025 Anti-inflammatory effect of omega unsaturated fatty acids and dialysable leucocyte extract 2020 Feb Rheumatoid arthritis is a disabling autoimmune disease with a high global prevalence. Treatment with disease-modifying anti-arthritic drugs (DIMARDs) has been routinely used with beneficial effects but with adverse long-term consequences; novel targeted biologics and small-molecule inhibitors are promising options. In this study, we investigated whether purified omega unsaturated fatty acids (ω-UFAs) and dialysable leukocyte extracts (DLEs) prevented the development of arthritis in a model of collagen-induced arthritis (CIA) in mice. We also investigated whether the transcription factor NF-κB and the NLRP3 inflammasome were involved in the process and whether their activity was modulated by treatment. The development of arthritis was evaluated for 84 days following treatment with nothing, dexamethasone, DLEs, docosahexaenoic acid, arachidonic acid, and oleic acid. Progression of CIA was monitored by evaluating clinical manifestations, inflammatory changes, and histological alterations in the pads' articular tissues. Both DLEs and ω-UFAs led to an almost complete inhibition of the inflammatory histopathology of CIA and this was concomitant with the inhibition of NF-kB and the inhibition of the activation of NLRP3. These data suggest that ω-UFAs and DLEs might have NF-κB as a common target and that they might be used as ancillary medicines in the treatment of arthritis.
33424810 Therapeutic Efficacy of a Trichinella Spiralis Paramyosin-Derived Peptide Modified With a 2020 Helminth-derived molecules have the ability to modulate the host immune system. Our previous study identified a tetradecapeptide derived from Trichinella spiralis paramyosin (Ts-pmy) that could bind to human complement component C9 to inhibit its polymerization, making the peptide a candidate therapeutic agent for complement-related immune disorders. Here, the peptide underwent an N-terminal modification with a membrane-targeting signal (a unique myristoylated peptide) to improve its therapeutic efficacy. We found that the modified peptide had a binding affinity to human C9 that was similar to that of the original peptide, as confirmed by microscale thermophoresis assays. The binding of the modified peptide to human C9 resulted in the inhibition of C9-related complement activation, as reflected by the decreased Zn(2+)-induced C9 polymerization and the decreased C9-dependent lysis of rabbit erythrocytes. In addition, the original and modified peptides could both bind to recombinant mouse C9 and inhibit the C9-dependent lysis of rabbit erythrocytes in normal mouse serum (NMS), which meant that the peptides could cross the species barrier to inhibit complement activity in mice. Further in vitro and in vivo analyses confirmed that the peptide modification increased the retention time of the peptide. Furthermore, intraarticular injection of the modified peptide markedly ameliorated knee swelling and joint damage in mice with antigen-induced arthritis (AIA), as assessed histologically. These results suggested that the Ts-pmy-derived peptide modified with a membrane-targeting signal was a reasonable candidate therapeutic agent for membrane attack complex (MAC)-related diseases [such as rheumatoid arthritis (RA)] and the study presented a new modification method to improve the potential therapeutic effects of the peptide.
33664837 Interstitial lung abnormalities a risk factor for rheumatoid arthritis interstitial lung d 2020 Dec ILA/ILD extension and subpleural ILA localisation are risk factors for disease progression in RA subjects. A semiquantitative method to assess ILA/ILD extent and to measure the fibrotic burden is feasible to accurately determine ILA progression. https://bit.ly/3mmMJk2.
33510984 Gastrointestinal Histoplasmosis as an Obstructing Ileocecal Mass. 2020 Dec 25 Histoplasmosis is a self-limiting and asymptomatic disease in immunocompetent individuals. Patients in an immunocompromised state are susceptible to disseminated disease. We present a case of a 60-year-old male with a history of psoriatic and rheumatoid arthritis treated with a tumor necrosis factor inhibitor (adalimumab), who presented with abdominal pain and was found to have gastrointestinal histoplasmosis as an obstructing ileocecal mass. Although gastrointestinal involvement is common in disseminating disease, symptomatic involvement is rare. This case presentation has implications in rheumatological patients on biologic medications.
31586131 Correction: Complete remission of seronegative rheumatoid arthritis following haplo-identi 2020 May An amendment to this paper has been published and can be accessed via a link at the top of the paper.
33166704 [Methotrexate: How long between administration and conception?]. 2021 Feb In women of childbearing age, methotrexate is prescribed in many indications other than cancer, either chronically (psoriasis, rheumatoid arthritis, IBD, etc.) or occasionally (ectopic pregnancies). The time given to these patients to consider pregnancy is currently subject to great variability depending on the sources. Analysis of the available objective evidence suggests that it is not justified to unnecessarily lengthen this period, and that conceiving the menstrual cycle following stopping methotrexate is quite possible.
32972155 Metal complexes in medicine and pharmacy - the past and the present III. 2020 Summer Bioactive metal complexes represent a promising and rapidly evolving area of pharmacotherapy. After the first part of our survey on metallopharmaceuticals dealing with antimicrobial activity of metal complexes and their application in diagnostics and the second part dedicated to anticancer properties of these compounds, this third and last part of the review focuses on several other applications of metals in therapy (mainly on the therapy of rheumatoid arthritis, some mental diseases, diabetes, as well as on chelation therapy). Following a brief account of the historical development of clinical use of the respective category of drugs, their chemical properties, toxicity, clinical applications and mechanism of action are discussed. The aim of this brief survey is to provide basic outline of the area of metallopharmacy, aimed at specialists in pharmacy and chemistry as well as at the general educated public.
32076877 Correction to: Development of Methotrexate and Minocycline Loaded Nanoparticles for the Ef 2020 Feb 19 Typesetting error occurred and author corrections to the numbering of figures and captions at the proofing stage were not incorporated in the published article.
32993688 Correction to: Guizhi-Shaoyao-Zhimu decoction attenuates rheumatoid arthritis partially by 2020 Sep 29 An amendment to this paper has been published and can be accessed via the original article.
32796044 Contrasting contributions of TNF from distinct cellular sources in arthritis. 2020 Nov OBJECTIVES: Neutralisation of tumour necrosis factor (TNF) is widely used as a therapy for rheumatoid arthritis (RA). However, this therapy is only effective in less than a half of patients and is associated with several side effects. We hypothesised that TNF may possess non-redundant protective and immunomodulatory functions in vivo that cannot be blocked without a cost. The present work aimed to identify cellular sources of protective and pathogenic TNF, and its molecular forms during autoimmune arthritis. METHODS: Mice lacking TNF expression by distinct cell types, such as myeloid cells and T or B lymphocytes, were subjected to collagen-induced arthritis (CIA) and collagen antibody-induced arthritis. Mice lacking soluble TNF production were also employed. The severity and incidence of the disease, as well as humoral and cellular responses were assessed. RESULTS: Myeloid cell-derived TNF contributes to both induction and pathogenesis of autoimmune arthritis. Conversely, T cell-derived TNF is protective during the induction phase of arthritis via limiting of interleukin-12 production by dendritic cells and by subsequent control of autoreactive memory T cell development, but is dispensable during the effector phase of arthritis. B cell-derived TNF mediates severity of CIA via control of pathogenic autoantibody production. CONCLUSIONS: Distinct TNF-producing cell types may modulate disease development through different mechanisms, suggesting that in arthritis TNF ablation from restricted cellular sources, such as myeloid cells, while preserving protective TNF functions from other cell types may be superior to pan-anti-TNF therapy.
33078630 Current treatment options and safety considerations when treating adult-onset Still's dise 2020 Dec INTRODUCTION: Adult onset Still disease (AOSD) is a rare systemic inflammatory condition. The clinical spectrum of this disease ranges from self-limiting forms with mild symptoms to life-threatening cases. Glucocorticoids and non-steroidal anti-inflammatory drugs (NSAIDs) represent the first line of therapy for AOSD, with add-on therapy with second-line drug reserved to steroid-dependent patients and in life-threatening cases. Currently, early treatment with conventional disease modifying anti-rheumatic drugs (DMARDs) and biologic agents blocking causal cytokines is advocated in patients with severe and recalcitrant clinical manifestations. AREAS COVERED: This review analyzes the available controlled evidence and observational data regarding the efficacy and safety of conventional and biological pharmacological agents in the treatment of AOSD. EXPERT OPINION: Non-steroidal anti-inflammatory drugs (NSAIDs) and glucocorticoids are effective in controlling clinical manifestations in the majority of AOSD patients. Conventional DMARDs can be 20 effective in some severe and steroid-dependent cases of AOSD; however, anti-cytokine agents represent an effective and overall more suitable alternative in this specific subset of patients. IL-1 and IL-6 blockade are effective in treating systemic and articular inflammation of AOSD patients. IL-1 blockade also has an excellent safety profile and therefore represent the first choice of biologic treatment in this clinical scenario.
32013725 Adult macrophage activation syndrome-haemophagocytic lymphohistiocytosis: 'of plasma excha 2020 Mar OBJECTIVE: In the context of systemic autoimmunity, that is systemic lupus erythematosus (SLE) or adult-onset Still's disease (AOSD), secondary haemophagocytic lymphohistiocytosis (HLH; also referred to as macrophage activation syndrome (MAS) or more recently MAS-HLH) is a rare and potentially life-threatening complication. Pathophysiological hallmarks are aberrant macrophage and T cell hyperactivation and a systemic cytokine flare, which generate a sepsis-like, tissue-damaging, cytopenic phenotype. Unfortunately, for adult MAS-HLH we lack standardized treatment protocols that go beyond high-dose corticosteroids. Consequently, outcome data are scarce on steroid refractory cases. Aside from protocols based on treatment with calcineurin inhibitors, etoposide, cyclophosphamide and anti-IL-1, favourable outcomes have been reported with the use of intravenous immunoglobulin (IvIG) and plasma exchange (PE). METHODS: Here we report a retrospective series of steroid refractory MAS-HLH, the associated therapeutic regimes and outcomes. RESULTS: In this single-centre experience, 6/8 steroid refractory patients survived (median follow-up: 54.4 (interquartile range: 23.3-113.3) weeks). All were initially treated with PE, which induced partial response in 5/8 patients. Yet, all patients required escalation of immunosuppressive therapies. One case of MAS-HLH in new-onset AOSD had to be escalated to etoposide, whereas most SLE-associated MAS-HLH patients responded well to cyclophosphamide. Relapses occurred in 2/8 cases. CONCLUSION: Together, early use of PE is at most a supportive measure, not a promising monotherapy of adult MAS-HLH. In refractory cases, conventional cytoreductive therapies (i.e. cyclophosphamide and etoposide) constitute potent and reliable rescue approaches, whereas IvIG, anti-thymoglobulin, and biologic agents appear to be less effective.
31864144 Evaluation of salivary gland fat fraction values in patients with primary Sjögren's syndr 2020 Feb PURPOSE: To explore the role of salivary fat fraction (FF) values in evaluating patients with primary Sjögren's syndrome (pSS). MATERIAL AND METHOD: A total of 28 patients with pSS, ten patients with suspected pSS, and 28 volunteers were enrolled. The FF values of the parotid and submandibular glands were generated from mDIXON Quant. A one-way analysis of variance was used to compare the FF values among the groups. A receiver-operating characteristic analysis was applied to assess the diagnostic performance of the parotid and submandibular FF values in distinguishing patients with pSS from non-pSS subjects. In particular, we focused on distinguishing patients with grade 0 pSS from those with suspected pSS. RESULTS: The parotid and submandibular mean FF value of patients with pSS was significantly higher than that of healthy volunteers. The submandibular mean FF value of patients with pSS was higher than those suspected ones. Submandibular FF value performed better than parotid FF value in differentiating patients with pSS from those non-pSS subjects (area under the curve [AUC] = 0.927 vs. 0.734), patients with pSS from patients with suspected pSS (AUC = 0.907 vs. 0.725). This value also performed better at distinguishing patients with grade 0 pSS from those patients with suspected pSS (AUC = 0.925 vs. 0.783). CONCLUSIONS: The salivary gland FF value, especially the submandibular gland FF value, distinguished patients with pSS from those patients with suspected pSS and healthy volunteers.
33193369 Frailty in Rheumatic Diseases. 2020 Frailty is a syndrome characterized by the decline in the physiologic reserve and function of several systems, leading to increased vulnerability and adverse health outcomes. While common in the elderly, recent studies have underlined the higher prevalence of frailty in chronic diseases, independent of age. The pathophysiological mechanisms that contribute to frailty have not been completely understood, although significant progresses have recently been made. In this context, chronic inflammation is likely to play a pivotal role, both directly and indirectly through other systems, such as the musculoskeletal, endocrine, and neurological systems. Rheumatic diseases are characterized by chronic inflammation and accumulation of deficits during time. Therefore, studies have recently started to explore the link between frailty and rheumatic diseases, and in this review, we report what has been described so far. Frailty is dynamic and potentially reversible with 8.3%-17.9% of older adults spontaneously improving their frailty status over time. Muscle strength is likely the most significant influencing factor which could be improved with training thus pointing at the need to maintain physical activity. Not surprisingly, frailty is more prevalent in patients affected by rheumatic diseases than in healthy controls, regardless of age and is associated with high disease activity to affect the clinical outcomes, largely due to chronic inflammation. More importantly, the treatment of the underlying condition may prevent frailty. Scales to assess frailty in patients affected by rheumatic diseases have been proposed, but larger casuistries are needed to validate disease-specific indexes, which could allow more accurate prognostic estimates than demographic and disease-related variables alone. Frail patients can be more vulnerable and more difficult to treat, due to the risk of side effects, therefore frailty should be taken into account in clinical decisions. Clinical trials addressing frailty could identify patients who are less likely to tolerate potentially toxic medications and might benefit from more conservative regimens. In conclusion, the implementation of the concept of frailty in rheumatology will allow a better understanding of the patient global health, a finest risk stratification and a more individualized management strategy.
32990361 Maintenance of Sustained Low Disease Activity or Remission in Patients With Rheumatoid Art 2020 Oct OBJECTIVE: The purpose of this study was to evaluate maintenance of remission/low disease activity (LDA) in patients with rheumatoid arthritis (RA) who achieved remission/LDA with etanercept (ETN) plus a conventional synthetic disease-modifying antirheumatic drug (csDMARD) and to compare patients who discontinued csDMARD to receive ETN monotherapy (Mono) with those remaining on combination therapy (Combo). METHODS: Patients from the Corrona RA registry between October 1, 2001, and August 31, 2017, were eligible. The index date for the Mono cohort was the csDMARD discontinuation date; the index visit for the Combo cohort was estimated from time between ETN initiation and csDMARD discontinuation in the Mono cohort. The main outcome calculated was maintenance of remission/LDA. Patients were censored if they switched to or added a biologic DMARD, discontinued ETN, when a csDMARD was reintroduced (Mono), or if methotrexate increased more than 5 mg/d (Combo). Trimming was used to balance demographic and clinical characteristics between groups. Cox regression models were adjusted for the remaining differences across groups. RESULTS: We identified 182 Mono and 403 Combo patients; 120 Mono and 207 Combo patients remained after trimming. Most patients (approximately 80%) were biologic medication-naive before initiating ETN. At 24 months postindex, modeled percentages of patients remaining in remission/LDA were 75% for Mono and 86% for Combo (overall adjusted P = 0.057). More patients were censored for therapy change in Mono than in Combo groups (37% versus 5%), largely due to reintroduction of csDMARDs in the Mono group. CONCLUSION: Many patients with RA who achieved remission/LDA on combination therapy maintained remission/LDA with ETN monotherapy for 2 years after csDMARD discontinuation. ETN monotherapy may be a viable option for patients who discontinue csDMARDs after achieving LDA/remission.
32751547 Slower Elimination of Tofacitinib in Acute Renal Failure Rat Models: Contribution of Hepat 2020 Jul 30 Tofacitinib is a Jak inhibitor developed as a treatment for rheumatoid arthritis. Tofacitinib is metabolized mainly through hepatic CYP3A1/2, followed by CYP2C11. Rheumatoid arthritis tends to increase renal toxicity due to drugs used for long-term treatment. In this study, pharmacokinetic changes of tofacitinib were evaluated in rats with gentamicin (G-ARF) and cisplatin-induced acute renal failure (C-ARF). The time-averaged total body clearance (CL) of tofacitinib in G-ARF and C-ARF rats after 1-min intravenous infusion of 10 mg/kg was significantly decreased by 37.7 and 62.3%, respectively, compared to in control rats. This seems to be because the time-averaged renal clearance (CL(R)) was significantly lower by 69.5 and 98.6%, respectively, due to decreased creatinine clearance (CL(CR)). In addition, the time-averaged nonrenal clearance (CL(NR)) was also significantly lower by 33.2 and 57.4%, respectively, due to reduction in the hepatic CYP3A1/2 and CYP2C11 subfamily in G-ARF and C-ARF rats. After oral administration of tofacitinib (20 mg/kg) to G-ARF and C-ARF rats, both CL(R) and CL(NR) were also significantly decreased. In conclusion, an increase in area under plasma concentration-time curves from time zero to time infinity (AUC) of tofacitinib in G-ARF and C-ARF rats was due to the significantly slower elimination of tofacitinib contributed by slower hepatic metabolism and urinary excretion of the drug.
32609496 Localization of Therapeutic Fab-CHP Conjugates to Sites of Denatured Collagen for the Trea 2020 Aug 19 Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation in synovial joints and protease-induced cartilage degradation. Current biologic treatments for RA can effectively reduce symptoms, primarily by neutralizing the proinflammatory cytokine TNFα; however, continued, indiscriminate overinhibition of inflammatory factors can significantly weaken the host immune system, leading to opportunistic infections and interrupting treatment. We hypothesize that localizing anti-TNFα therapeutics to denatured collagen (dCol) present at arthritic joints, via conjugation with collagen-hybridizing peptides (CHPs), will reduce off-site antigen binding and maintain local immunosuppression. We isolated the antigen-binding fragment of the clinically approved anti-TNFα therapeutic infliximab (iFab) and prepared iFab-CHP conjugates via lysine-based conjugation with an SMCC linker. After successful conjugation, confirmed by LC-MS, the binding affinity of iFab-CHP was characterized by ELISA-like assays, which showed comparable antigen binding relative to infliximab, comparable dCol binding relative to CHP, and the hybrid ability to bind both dCol and TNFα simultaneously. We further demonstrated localization of Fab-CHP to areas of high dCol in vivo and promising therapeutic efficacy, assessed by histological staining (Safranin-O and H&E), in a pilot mouse study.
32341806 Metabolic Targets for Treatment of Autoimmune Diseases. 2020 There is a considerable unmet demand for safe and efficacious medications in the realm of autoimmune and inflammatory diseases. The fate of the immune cells is precisely governed by control of various metabolic processes such as mitochondrial oxidative phosphorylation, glycolysis, fatty acid synthesis, beta-oxidation, amino acid metabolism, and several others including the pentose phosphate pathway, which is a unique source of metabolites for cell proliferation and maintenance of a reducing environment. These pathways are tightly regulated by the cytokines, growth factors, availability of the nutrients and host-microbe interaction. Exploring the immunometabolic pathways that govern the fate of cells of the innate and adaptive immune system, during various stages of activation, proliferation, differentiation and effector response, is crucial for new development of new treatment targets. Identifying the pathway connections and key enzymes will help us to target the dysregulated inflammation in autoimmune diseases. The mechanistic target of rapamycin (mTOR) pathway is increasingly recognized as one of the key drivers of proinflammatory responses in autoimmune diseases. In this review, we provide an update on the current understanding of the metabolic signatures noted within different immune cells of many different autoimmune diseases with a focus on selecting pathways and specific metabolites as targets for treatment.
32189120 Rheumatological care in rural areas : The Rheuma-Bus project 2018. 2021 Feb OBJECTIVE: To explore the medical care of individuals in rural areas during a public health awareness project on musculoskeletal disorders (MSD). METHODS: A tour bus was adapted to accommodate rheumatological consultations at widely accessible sites in 16 towns, providing individual medical advice with respect to MSD. The participating rheumatologists assessed the nature (e.g. inflammatory/non inflammatory), extent and duration of MSD and, where possible, made a tentative diagnosis and gave further advice on the course of action. In addition, age, sex and pre-existing care were recorded. All individuals were asked to assess their own severity of pain using a numeric ordinal scale from "no" (0) to "extreme" (10). RESULTS: A total of 647 individuals visited the service. Median current pain intensity was 5 (interquartile range [IQR] 3-6), mean 4.9 (standard deviation [SD] 2.3). Osteoarthritis was suspected in 381 clients (59.6%), inflammatory rheumatic disease in 247 (38.7%), and in 104 (16.3%) other diseases. 307 (50%) were treated by a GP, 95 (15.5%) were under orthopaedic care, 204 (33.2%) under rheumatological care and 81 (13.1%) under supervision of other specialists. 104 clients (17%) had never consulted a physician for their MSD symptoms before. 27 (4.2%) of all the clients had a newly detected inflammatory rheumatic disease and 62 (9.6%) patients with suspected inflammatory rheumatic disease were not under previous rheumatological care. CONCLUSION: The findings showed that there is still a lot of negligence in awareness and knowledge of rheumatic diseases, at least in rural areas.
31989787 Outreach to Promote Management of Cardiovascular Risk in Primary Care Among Patients With 2020 Mar OBJECTIVE: Rheumatoid arthritis (RA) confers a 1.5- to 2.0-fold increased risk of cardiovascular disease (CVD). A prior multifaceted quality improvement approach to improving CVD preventive care increased CVD risk factor assessments, but there was no significant effect on the management of risk factors. We tested the impact of adding a proactive outreach strategy promoting primary care treatment of CVD risk factors among patients with RA through their rheumatology practice. METHODS: Through electronic health record searches, we identified patients with RA who were potential candidates for hypertension treatment initiation or intensification, statin therapy, or a smoking-cessation intervention. A nonclinician care manager contacted patients by phone and mail on behalf of the rheumatologists, provided information about the identified risk factor(s), recommend follow-up with primary care physicians (PCPs), sent correspondence to PCPs, and followed up with patients to see what actions had been taken. We measured preventive cardiology quality indicators and compared preintervention and intervention time periods using interrupted time series methods. RESULTS: During the 6-month intervention period, the proportion of patients prescribed at least moderate-intensity statin treatment for primary prevention rose from 18.4% to 23.8%. The rate of increase was 1.06% greater per month than during the preceding period (P < 0.001). Rates of increase in hypertension diagnosis and control improved more rapidly during this phase (P < 0.001 for each) and reversed preceding negative trends. CONCLUSION: Implementing proactive nonclinician outreach to encourage primary care-based treatment of CVD risk factors was associated with increases in statin prescribing and in hypertension diagnosis and control. Smoking was not affected.