Browse

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

ID PMID Title PublicationDate abstract
34780075 The role of the cholinergic anti-inflammatory pathway in autoimmune rheumatic diseases. 2021 Oct The cholinergic anti-inflammatory pathway (CAP) is a classic neuroimmune pathway, consisting of the vagus nerve, acetylcholine (ACh)-the pivotal neurotransmitter of the vagus nerve-and its receptors. This pathway can activate and regulate the activities of immune cells, inhibit cell proliferation and differentiation, as well as suppress cytokine release, thereby playing an anti-inflammatory role, and widely involved in the occurrence and development of various diseases; recent studies have demonstrated that the CAP may be a new target for the treatment of autoimmune rheumatic diseases. In this review, we will summarize the latest progress with the view of figuring out the role of the cholinergic pathway and how it interacts with inflammatory reactions in several autoimmune rheumatic diseases, and many advances are results from a wide range of experiments performed in vitro and in vivo.
34780107 Effectiveness and cost-effectiveness of longstanding exercise therapy versus usual care in 2022 Jan OBJECTIVES: Research on effectiveness and cost-effectiveness of longstanding exercise therapy in patients with axial SpondyloArthritis (axSpA) or Rheumatoid Arthritis (RA) is scarce, and mainly concerned patients with a relatively favorable health status. We aim to evaluate the effectiveness and cost-effectiveness of longstanding exercise therapy compared to usual care in the subgroup of patients with axSpA or RA and severe limitations in functioning. METHODS: In two separate, parallel randomized controlled trials the effectiveness and cost-effectiveness of longstanding, active exercise therapy (52 weeks) compared with usual care (1:1) will be evaluated. The longstanding, active exercise therapy will focus on improving individual limitations in daily activities and participation and will be given by a trained physical therapist in the vicinity of the participant. For each diagnosis, 215 patients with severe limitations in activities and participation will be included. Assessments are performed at baseline, 12, 26, and 52 weeks. The primary outcome measure of effectiveness is the individual level of functioning (activities and participation), as measured with the Patient-Specific Complaints instrument at 52 weeks. For cost-effectiveness analyses, the EuroQol (EQ-5D-5L) and questionnaires on healthcare use and productivity will be administered. The economic evaluation will be a cost-utility analysis from a societal perspective. After 52 weeks, the patients in the usual care group are offered longstanding, active exercise therapy as well. Follow-up assessments are done at 104, 156, and 208 weeks. CONCLUSION: The results of these studies will provide insights in the effectiveness and cost-effectiveness of longstanding exercise therapy in the subgroup of axSpA and RA patients with severe functional limitations.
34131243 Susceptibility of cyclin-dependent kinase inhibitor 1-deficient mice to rheumatoid arthrit 2021 Jun 15 We recently reported that cyclin-dependent kinase inhibitor 1 (p21) deficiency induces osteoarthritis susceptibility. Here, we determined the mechanism underlying the effect of p21 in synovial and cartilage tissues in RA. The knee joints of p21-knockout (p21(-/-)) (n = 16) and wild type C57BL/6 (p21(+/+)) mice (n = 16) served as in vivo models of collagen antibody-induced arthritis (CAIA). Arthritis severity was evaluated by immunological and histological analyses. The response of p21 small-interfering RNA (siRNA)-treated human RA FLSs (n = 5 per group) to interleukin (IL)-1β stimulation was determined in vitro. Arthritis scores were higher in p21(-/-) mice than in p21(+/+) mice. More severe synovitis, earlier loss of Safranin-O staining, and cartilage destruction were observed in p21(-/-) mice compared to p21(+/+) mice. p21(-/-) mice expressed higher levels of IL-1β, TNF-α, F4/80, CD86, p-IKKα/β, and matrix metalloproteinases (MMPs) in cartilage and synovial tissues via IL-1β-induced NF-kB signaling. IL-1β stimulation significantly increased IL-6, IL-8, and MMP expression, and enhanced IKKα/β and IκBα phosphorylation in human FLSs. p21-deficient CAIA mice are susceptible to RA phenotype alterations, including joint cartilage destruction and severe synovitis. Therefore, p21 may have a regulatory role in inflammatory cytokine production including IL-1β, IL-6, and TNF-α.
34686479 Two-dose COVID-19 vaccination and possible arthritis flare among patients with rheumatoid 2022 Apr OBJECTIVES: To investigate the relationship between COVID-19 full vaccination (two completed doses) and possible arthritis flare. METHODS: Patients with rheumatoid arthritis (RA) were identified from population-based electronic medical records with vaccination linkage and categorised into BNT162b2 (mRNA vaccine), CoronaVac (inactive virus vaccine) and non-vaccinated groups. The risk of possible arthritis flare after vaccination was compared using a propensity-weighted cohort study design. We defined possible arthritis flare as hospitalisation and outpatient consultation related to RA or reactive arthritis, based on diagnosis records during the episode. Weekly prescriptions of rheumatic drugs since the launch of COVID-19 vaccination programme were compared to complement the findings from a diagnosis-based analysis. RESULTS: Among 5493 patients with RA (BNT162b2: 653; CoronaVac: 671; non-vaccinated: 4169), propensity-scored weighted Poisson regression showed no significant association between arthritis flare and COVID-19 vaccination ((BNT162b2: adjusted incidence rate ratio 0.86, 95% Confidence Interval 0.73 to 1.01); CoronaVac: 0.87 (0.74 to 1.02)). The distribution of weekly rheumatic drug prescriptions showed no significant differences among the three groups since the launch of the mass vaccination programme (all p values >0.1 from Kruskal-Wallis test). CONCLUSIONS: Current evidence does not support that full vaccination of mRNA or inactivated virus COVID-19 vaccines is associated with possible arthritis flare.
32743706 Immune checkpoint inhibitor-induced musculoskeletal manifestations. 2021 Jan Immune checkpoint inhibitors (ICI) associate with a wide range of immune-related adverse events (Ir-AE), including musculoskeletal manifestations. We aimed at identifying all studies reporting musculoskeletal Ir-AE. An electronic (Medline, Scopus and Web of Science) search was performed using two sets of key words. The first set consisted of: arthritis, musculoskeletal, polymyalgia rheumatica and myositis. The second set consisted of: anti-PD-1, anti-PD-L1, anti-CTLA-4, ipilimumab, tremelimumab, pembrolizumab, nivolumab, atezolizumab, avelumab and durvalumab. We identified 3 prospective studies, 17 retrospective studies and 4 case series reporting 363 patients in total. Combined data from all three prospective studies provide a prevalence rate of 6.13%. Most patients were males (59.68%) and the vast majority (73%) were on programmed death-1 (PD-1)/programmed death ligand-1 (PD-L1) inhibitors. Most studies report a median time of ≤ 12 weeks from first ICI administration to symptom onset. The main clinical phenotypes reported were: (a) inflammatory arthritis (57.57%), (b) myositis (14.04%) and (c) polymyalgia rheumatica (PMR) (12.12%). A total of 256 patients required steroids (70.52%) and 67 patients (18.45%) were treated with DMARDs. Positive auto-antibodies and family history of any autoimmune disease were present in 18.48% and 19.04% of cases, respectively. Only a few patients (19%) had to discontinue treatment due to musculoskeletal Ir-AE. Two prospective studies show that significantly more patients with musculoskeletal Ir-AE exhibit a favorable oncologic response compared to patients not exhibiting such manifestations whereas retrospective studies show that 77.22% of patients with musculoskeletal Ir-AE have a good tumor response. One out of 15 patients treated with ICI will develop musculoskeletal Ir-AE; in most cases the severity of these manifestations is mild/moderate and usually ICI may be continued. Rheumatologists should familiarize with this new clinical entity and develop relevant therapeutic algorithms.
33476818 Novel insights into macrophage diversity in rheumatoid arthritis synovium. 2021 Mar Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease affecting joints and causing progressive damage and disability. Macrophages are of critical importance in the initiation and perpetuation of synovitis in RA, they can function as antigen presenting cells leading to T-cell dependent B-cell activation, assume a variety of inflammatory cell states with the production of destructive cytokines, but also contribute to tissue homeostasis/repair. The recent development of high-throughput technologies, including bulk and single cells RNA-sequencing, has broadened our understanding of synovial cell diversity, and opened novel perspectives to the discovery of new potential therapeutic targets in RA. In this review, we will focus on the relationship between the synovial macrophage infiltration and clinical disease severity and response to treatment. We will then provide a state-of-the-art picture of the biological roles of synovial macrophages and distinct macrophage subsets described in RA. Finally, we will review the effects of approved conventional and biologic drugs on the synovial macrophage component and highlight the therapeutic potential of future strategies to re-program macrophage phenotypes in RA.
33771834 Current view on the pathogenic role of anti-citrullinated protein antibodies in rheumatoid 2021 Mar Epidemiological findings suggest a potential role for anti-citrullinated protein antibodies (ACPAs) in rheumatoid arthritis (RA) pathogenesis. ACPA-positive RA is associated with unique genetical and environmental risk factors, in contrast to seronegative RA. ACPA-positive healthy individuals are at risk of developing RA and can develop joint pain and bone loss already before disease onset. ACPA injection triggered bone loss and pain-like behaviour in mice and, in the presence of additional arthritis inducers, exacerbated joint inflammation. In cell culture experiments, ACPAs could bind to and modulate a variety of cellular targets, such as macrophages, osteoclasts, synovial fibroblasts, neutrophil granulocytes, mast cells, dendritic cells and platelets, further underlying a potential role for these autoantibodies in triggering pathogenic pathways and providing clues for their mechanisms of action. Patient-derived ACPA clones have been characterised by unique cellular effects and multiple ways to act on the target cells. ACPAs might directly induce stimulatory signals by ligating key citrullinated cell surface molecules or, alternatively, act as immune complexes on Fc receptors and potentially other molecules that recognise carbohydrate moieties. On the contrary to experimentally manufactured ACPA clones, patient-derived ACPAs are highly promiscuous and cross-reactive, suggesting a simultaneous binding to a range of functionally relevant and irrelevant targets. Moreover, several ACPA clones recognise carbamylated or acetylated targets as well. These features complicate the identification and description of ACPA-induced pathogenic mechanisms. In the current review, we summarise recent data on the functional properties of patient-derived ACPAs and present mechanistic models on how these antibodies might contribute to RA pathogenesis.
34864624 Systemic pharmacological verification of Baixianfeng decoction regulating TNF-PI3K-Akt-NF- 2022 Feb Traditional Chinese medicine has a long history of treating complex diseases, especially for the conditioning of systemic diseases. It has been reported that Baixianfeng (BXF) decoction used to treat rheumatoid arthritis (RA) may be due to its systemic regulatory effect, but the specific mechanism still remains to be elucidated. The research philosophy and methods of systemic pharmacology were used to explore the mechanism of BXF decoction in treating RA in this study. TCMSP database was used to search the ingredients of BXF decoction and screen the ADME parameters. The parameter index was set as OB ≥ 30%, DL ≥ 0.18, HL ≥ 4 h. The targets of the screened compounds were searched and predicted by TCMSP and Target-Prediction platforms. The disease targets of RA were obtained through the DisGeNET, OMIM, and PharmGkb databases. A series of network construction and analysis relied on Cytoscape 3.2.1 software, and the DAVID database was used for pathway enrichment. The adjuvant arthritis rat model was used for the verification of animal experiments to verify the predicted pathway results in terms of pathological phenotype, inflammatory factors, and pathway protein expression. The results showed that the related targets of 81 active ingredients in the drug crossed 56 targets of RA, and these common targets were enriched in 83 significant pathways, among which the TNF signaling pathway had research significance. Animal experiments have proved that BXF decoction was effective in treating adjuvant arthritis rats. The drug relieved the pathological phenotype of rats in dose-dependent. It reduced the serum content of TNF-α and IL-1β, and reduced the gene expression of TNF-α and IL-6 in spleen tissue. In the cartilage tissue protein of rats, it inhibited the degradation of collagen Ⅱ protein. Further, BXF decoction reduced the activation of p-PI3K, p-Akt, and p-P65 protein, and decreased the overexpression of apoptotic proteins such as cleaved-caspase8 and cleaved-caspase3 in cartilage tissue. Meanwhile, it inhibited the protein expression of MMP9, TNF-α, IL-6, and IL-1β. In conclusion, this study successfully practiced the combination of systemic pharmacology and experimental verification, and clarified that BXF decoction inhibited the progression of adjuvant arthritis rats through the TNF-PI3K-Akt-NF-κB signal axis. It provides new evidence for the study of the mechanism of BXF decoction in treating RA.
33858362 Rosai-Dorfman-Destombes (RDD) disease presenting as palindromic rheumatism. 2021 Apr 15 BACKGROUND: Rosai-Dorfman-Destombes (RDD) disease, is a rare proliferative and inflammatory disorder of non-Langerhans cell histiocytes. CASE PRESENTATION: We report a 35-year-old woman, who originally presented with recurrent episodes of lower extremity joint/bone pain and chronic nasal stuffiness and congestion. Her worsening nasal congestion was due to an obstructing nasal cavity lesion which was subsequently biopsied. Pathology was consistent with RDD. (18)F-FDG PET images demonstrated intense uptake in the paranasal sinuses and a large pelvic lymph node. Focal osseous lesions with intense (18)F-FDG uptake were also observed in the lower extremity, corresponding to areas of peri-articular pain. Rheumatologic work-up was consistent with palindromic rheumatism. She was diagnosed with immune-related disseminated RDD, presenting as palindromic rheumatism. CONCLUSIONS: This is the first case of RDD presenting as palindromic rheumatism. RDD should be considered as a possible but rare diagnosis in young patients with sinus-related symptoms and lymphadenopathy. The disease can on rare occasions be disseminated and can also present as immune-related RDD, such as in this patient.
34043301 Impact of Diverse Ion Channels on Regulatory T Cell Functions. 2021 May 28 The population of regulatory T cells (Tregs) is critical for immunological self-tolerance and homeostasis. Proper ion regulation contributes to Treg lineage identity, regulation, and effector function. Identified ion channels include Ca(2+) release-activated Ca(2+), transient receptor potential, P2X, volume-regulated anion and K(+) channels Kv1.3 and KCa3.1. Ion channel modulation represents a promising therapeutic approach for the treatment of autoimmune diseases such as rheumatoid arthritis and multiple sclerosis. This review summarizes studies with gene-targeted mice and pharmacological modulators affecting Treg number and function. Furthermore, participation of ion channels is illustrated and the power of future research possibilities is discussed.
33882986 Regulation of osteoclastogenesis by mast cell in rheumatoid arthritis. 2021 Apr 21 BACKGROUND: In the pathogenesis of rheumatoid arthritis (RA), the role of mast cells has not been revealed clearly. We aimed to define the inflammatory and tissue-destructive roles of mast cells in rheumatoid arthritis (RA). METHODS: Serum and synovial fluid (SF) concentration levels of tryptase, chymase, and histamine were quantified using ELISA. After activating mast cells using IL-33, the production of TNF-α, IL-1β, IL-6, IL-17, RANKL, and MMPs was determined using real-time PCR and ELISA. Osteoclastogenesis was assessed in CD14+ monocytes from peripheral blood and SF, which were cultured with IL-33-activated mast cells, by counting TRAP-positive multinucleated cells. RESULTS: The concentration levels of serum tryptase, chymase, and histamine and SF histamine were higher in patients with RA than in controls. FcεR1 and c-kit-positive mast cells were higher in RA synovium than in osteoarthritic (OA) synovium. Stimulation of mast cells by IL-33 increased the number of trypatse+chymase- and tryptase+chymase+ mast cells. IL-33 stimulation also increased the gene expression levels of TNF-α, IL-1β, IL-6, IL-17, RANKL, and MMP-9 in mast cells. Furthermore, IL-33 stimulated human CD14+ monocytes to differentiate into TRAP+ multinucleated osteoclasts. When CD14+ monocytes were co-cultured with mast cells, osteoclast differentiation was increased. Additionally, IL-33-activated mast cells stimulated osteoclast differentiation. The inhibition of intercellular contact between mast cells and monocytes using inserts reduced osteoclast differentiation. CONCLUSIONS: IL-33 increased inflammatory and tissue-destructive cytokines by activation of mast cells. Mast cells stimulated osteoclast differentiation in monocytes. Mast cells could stimulate osteoclastogenesis indirectly through production of tissue-destructive cytokines and directly through stimulation of osteoclast precursors.
33002286 Allele-Specific Quantification of HLA-DRB1 Transcripts Reveals Imbalanced Allelic Expressi 2021 Mar OBJECTIVE: HLA association fine-mapping studies have shown the effects of missense variants in HLA-DRB1 on rheumatoid arthritis (RA) susceptibility, prognosis, and autoantibody production. However, the phenotypic effects of expression changes in HLA-DRB1 remain poorly understood. Therefore, we investigated the allele-specific expression of HLA-DRB1 and its effect on an HLA-DRβ1 structure-associated trait in RA. METHODS: We quantified the allele-specific expression of each HLA-DRB1 3-field classic allele in 48 Korean RA patients with anti-citrullinated protein antibodies (ACPAs) and 319 healthy European subjects by using both RNA sequencing and HLA-DRB1 genotype data to calculate the relative expression strength of multiple HLA-DRB1 alleles (n = 14 in Koreans and n = 25 in Europeans) in each population. The known association between ACPA level and alanine at position 74 of HLA-DRβ1 in ACPA-positive RA was revisited to understand the phenotypic effect of allele-specific expression of HLA-DRB1 by modeling multivariate logistic regression with the genomic dosage or relative expression dosage of Ala-74 in 2 independent sets of 1,723 Korean RA patients with ACPA. RESULTS: The relative expression strength was highly allele-specific, causing imbalanced allelic expression in HLA-DRB1 heterozygotes. The association between HLA-DRβ1 Ala-74 and ACPA level in RA was better explained by relative expression dosage of Ala-74 than by the genomic dosage (change in Akaike's information criterion = -6.98). Moreover, the expression variance of Ala-74 in Ala-74 heterozygotes with no genomic variance of Ala-74 was significantly associated with ACPA level (P = 2.26 × 10(-3) ). CONCLUSION: Our findings illustrate the advantage of integrating quantitative and qualitative changes in HLA-DRB1 into a single model for understanding HLA-DRB1 associations.
34976302 Biological Anti-TNF-α Therapy and Markers of Oxidative and Carbonyl Stress in Patients wi 2021 Rheumatoid arthritis (RA) as a chronic inflammatory disease is associated with oxidative stress. Drugs targeting tumor necrosis factor-alpha (TNF-α) ameliorate inflammation and symptoms of RA in most patients. Whether markers of oxidative stress can be used for monitoring of treatment effects is unknown. The aim of our study was to analyze the effects of anti-TNF-α treatment on oxidative stress in plasma and saliva of patients with RA. Samples were collected from 26 patients with RA at baseline as well as 3 and 6 months after starting the anti-TNF-α treatment. Thiobarbituric acid-reacting substances (TBARS), advanced oxidation protein products (AOPP), advanced glycation end products (AGEs), and fructosamine were quantified using spectrophotometry and spectrofluorometry in plasma. TBARS were measured also in saliva. The disease activity score (DAS28) was used to assess the clinical status of patients. No significant dynamic changes were found except plasma TBARS that decreased continuously. At 6 months after starting the treatment, plasma TBARS were lower by 39% in comparison to baseline (p = 0.006). Salivary concentrations of TBARS did not reflect the dynamics in plasma. Although a trend was observed (r = 0.33), a significant correlation between plasma TBARS and DAS28 was not found. Our results indicate that anti-TNF-α treatment decreases plasma TBARS as a marker of lipid peroxidation. However, the lack of a significant correlation with DAS28 suggests that it cannot be used for monitoring of treatment. Other markers of oxidative stress and antioxidant capacity with lower biological variability should be tested in future studies.
33826610 Use of corticoids and non-steroidal anti-inflammatories in the treatment of rheumatoid art 2021 Evidence on the use of non-steroidal anti-inflammatory drugs (NSAIDs) and corticoids for rheumatoid arthritis (RA) is inconclusive and is not up to date. This systematic review assessed the effectiveness and safety of these anti-inflammatories (AI) in the treatment of RA. COCHRANE (CENTRAL), MEDLINE, EMBASE, CINAHL, Web of Science and Virtual Health Library were searched to identify randomized controlled trials (RCT) with adults which used AI (dose represented in mg/day) compared with placebo or active controls and was carried out up to December of 2019. Reviewers, in pairs and independently, selected studies, performed the data extraction and assessed the risk of bias. The quality of the evidence was assessed by GRADE. Network meta-analyses were performed using the Stata v.14.2. Twenty-six articles were selected (NSAIDs = 21 and corticoids = 5). Naproxen 1,000 improved physical function, reduced pain and the number of painful joints compared to placebo. Etoricoxib 90 reduced the number of painful joints compared to placebo. Naproxen 750 reduced the number of swollen joints, except for etoricoxib 90. Naproxen 1,000, etoricoxib 90 and diclofenac 150 were better than placebo regarding patient assessment. Assessment physician showed that NSAIDs were better than placebo. Meta-analyses were not performed for prednisolone and prednisone. Naproxen 1,000 was the most effective drug and celecoxib 200 showed fewer adverse events. However, the low quality of the evidence observed for the outcomes with NSAIDs, the absence of meta-analyses to assess the outcomes with corticoids, as well as the risk of bias observed, indicate that future RCT can confirm such findings.
34756309 Human papilloma virus screening: evaluation of testing and surveillance in rheumatoid arth 2021 Nov BACKGROUND AND OBJECTIVES: Immunosuppression is a known risk factor for cervical cancer. Women with rheumatic conditions are immunosuppressed due to the disease and the treatments. One of the main risk factors for this neoplasm is the lack of adherence to early detection programmes for human papillomavirus. The objectives of this study were to evaluate the adherence to the screening programme of patients in the Rheumatology Clinic, as well as to evaluate the prevalence of cervical lesions and their association with the different disease characteristics and the treatments received. METHODS: A descriptive retrospective study. The electronic medical history of patients actively being followed up in a tertiary hospital with rheumatoid arthritis (RA), psoriatic arthritis (PSA) and systemic lupus erythematosus (SLE) were reviewed. RESULTS: Finally, 307 patients were included. No data were found for screening programme attendance in up to 42.4% of the patients (39.6% in RA, 43.8% in PSA and 46% in SLE). Among the patients who attended the screening programme at least once (57.6%), the prevalence of cervical dysplasia was 5.1%. No cases of neoplasia were found. In the simple logistic regression analysis, there was no association between attending the screening programme and any variable. The study also showed no association between the variables collected and the presence of infection and dysplasia. CONCLUSION: These results are influenced by the absence of screening data in a significant percentage of patients and by the low prevalence of dysplasia found in this series of patients with rheumatic diseases.
33040628 Challenges for biosimilars: focus on rheumatoid arthritis. 2021 Feb Healthcare systems worldwide are struggling to find ways to fund the cost of innovative treatments such as gene therapies, regenerative medicine, and monoclonal antibodies (mAbs). As the world's best known mAbs are close to facing patent expirations, the biosimilars market is poised to grow with the hope of bringing prices down for cancer treatment and autoimmune disorders, however, this has yet to be realized. The development costs of biosimilars are significantly higher than their generic equivalents due to therapeutic equivalence trials and higher manufacturing costs. It is imperative that academics and relevant companies understand the costs and stages associated with biologics processing. This article brings these costs to the forefront with a focus on biosimilars being developed for Rheumatoid Arthritis (RA). mAbs have remarkably changed the treatment landscape, establishing their superior efficacy over traditional small chemicals. Five blockbuster TNFα mAbs, considered as first line biologics against RA, are either at the end of their patent life or have already expired and manufacturers are seeking to capture a significant portion of that market. Although in principle, market-share should be available, withstanding that the challenges regarding the compliance and regulations are being resolved, particularly with regards to variation in the glycosylation patterns and challenges associated with manufacturing. Glycan variants can significantly affect the quality attributes requiring characterization throughout production. Successful penetration of biologics can drive down prices and this will be a welcome change for patients and the healthcare providers. Herein we review the biologic TNFα inhibitors, which are on the market, in development, and the challenges being faced by biosimilar manufacturers.
34623640 Semi-Mechanistic PK/PD Modeling and Simulation of Irreversible BTK Inhibition to Support D 2022 Feb Tirabrutinib is an irreversible, small-molecule Bruton's tyrosine kinase (BTK) inhibitor, which was approved in Japan (VELEXBRU) to treat B-cell malignancies and is in clinical development for inflammatory diseases. As an application of model-informed drug development, a semimechanistic pharmacokinetic/pharmacodynamic (PK/PD) model for irreversible BTK inhibition of tirabrutinib was developed to support dose selection in clinical development, based on clinical PK and BTK occupancy data from two phase I studies with a wide range of PK exposures in healthy volunteers and in subjects with rheumatoid arthritis. The developed model adequately described and predicted the PK and PD data. Overall, the model-based simulation supported a total daily dose of at least 40 mg, either q.d. or b.i.d., with adequate BTK occupancy (> 90%) for further development in inflammatory diseases. Following the PK/PD modeling and simulation, the relationship between model-predicted BTK occupancy and preliminary clinical efficacy data was also explored and a positive trend was identified between the increasing time above adequate BTK occupancy and better efficacy in treatment for RA by linear regression.
33238047 Citrullinated inter-alpha-trypsin inhibitor heavy chain 4 in arthritic joints and its pote 2021 Mar The citrullinated inter-alpha-trypsin inhibitor heavy chain 4 (cit-ITIH4) was identified as its blood level was associated with the arthritis score in peptide glucose-6-phosphate-isomerase-induced arthritis (pGIA) mice and the disease activity in patients with rheumatoid arthritis (RA). This study aimed to clarify its citrullination pathway and function as related to neutrophils. In pGIA-afflicted joints, ITIH4 and cit-ITIH4 levels were examined by immunohistochemistry (IHC), immunoprecipitation (IP) and Western blotting (WB), while peptidylarginine deiminase (PAD) expression was measured by reverse transcription-quantitative polymerase chain reaction (RT-qPCR), IHC and immunofluorescent methods. The pGIA mice received anti-lymphocyte antigen 6 complex locus G6D (Ly6G) antibodies to deplete neutrophils and the expression of cit-ITIH4 was investigated by WB. The amounts of ITIH4 and cit-ITIH4 in synovial fluid (SF) from RA and osteoarthritis (OA) patients were examined by I.P. and W.B. Recombinant ITIH4 and cit-ITIH4 were incubated with sera from healthy volunteers before its chemotactic ability and C5a level were evaluated using Boyden's chamber assay and enzyme-linked immunosorbent assay (ELISA). During peak arthritic phase, ITIH4 and cit-ITIH4 were increased in joints while PAD4 was over-expressed, especially in the infiltrating neutrophils of pGIA mice. Levels of cit-ITIH4 in plasma and joints significantly decreased upon neutrophil depletion. ITIH4 was specifically citrullinated in SF from RA patients compared with OA patients. Native ITIH4 inhibited neutrophilic migration and decreased C5a levels, while cit-ITIH4 increased its migration and C5a levels significantly. Cit-ITIH4 is generated mainly in inflamed joints by neutrophils via PAD4. Citrullination of ITIH4 may change its function to up-regulate neutrophilic migration by activating the complement cascade, exacerbating arthritis.
33635235 Osteoprotegerin and osteocalcin are associated with atherosclerosis in patients with rheum 2021 Nov OBJECTIVES: Patients with rheumatoid arthritis (RA) have an accelerated progression of atherosclerosis. The aim of this study was to examine the associations between subclinical atherosclerosis, assessed by intima-media thickness (IMT), and regulators of bone formation, markers of bone turnover and bone mineral density (BMD) in patients with RA. METHODS: Patients with new-onset RA (n=79), aged ≤60 years at diagnosis, were consecutively included in a study of development of atherosclerosis. Ultrasound measurement of IMT of the common carotid artery was undertaken at inclusion (T0) and after 11 years (T11) (n=54). Bone turnover biomarkers were examined in samples collected at T0 and T11. BMD was assessed at T11. RESULTS: In patients with RA, osteocalcin (OCN) and osteoprotegerin (OPG) measured at T11 were significantly associated with IMT at T11, adjusted for systolic blood pressure (SBP) and age. BMD at T11 and the bone turnover markers procollagen type 1 N-terminal propeptide (P1NP) and carboxy-terminal crosslinked C-terminal telopeptide (CTX) were not associated with IMT. OPG, OCN and sclerostin at T0 were significantly associated with IMT at T11, and OPG and OCN at T0 were associated with change in IMT from T0 to T11. The associations between IMT and bone biomarkers were stronger in patients with joint erosions at onset of RA, than in patients with non-erosive disease. CONCLUSIONS: Atherosclerosis in patients with RA is associated with OPG and OCN, but not with BMD or markers reflecting ongoing bone turnover, indicating that atherosclerosis is not associated with bone turnover per se.
33185167 Evaluating the Efficacy of Intra-articular Injections of Platelet Rich Plasma (PRP) in Rhe 2021 BACKGROUND: Among rheumatoid arthritis patients (RA), general disease activity is well regulated by disease-modifying anti-rheumatic medications (DMARDS), but sometimes local inflammation still persists among a few joints. Adjuvant modern molecular interventions as Platelet Rich Plasma (PRP) with a suggested down regulating effect on inflammatory mediators has a proven effect in the management of RA. We aim to evaluate the therapeutic effect of intra-articular PRP versus steroid in RA patients and their impact on inflammatory cytokines IL1B, TNF α, local joint inflammation, disease activity and quality of life (QL). METHODS: Open-labeled parallel randomized control clinical trial was carried out on 60 RA patients randomly divided into 2 groups, Group 1: included 30 patients received 3 intra-articular injections of PRP at a monthly interval, Group 2: included 30 patients received single intra-articular injection of steroid. They were subjected to clinical, laboratory, serum IL1B and TNF α assessment at baseline and at 3, and 6 months post injection. RESULTS: Patients of both groups showed improvements in their scores of evaluating tools at 3months post injection and this improvement was persistent in the PRP group up to 6 months post injection while it was continued only for 3 months in the steroid group. CONCLUSION: PRP is a safe, effective and useful therapy in treating RA patients who had an insufficient response and persistent pain and inflammation in just one or two joints through its down regulating effect on inflammatory cytokines IL1B, TNF α with subsequent improvement of local joint inflammation, disease activity and QL.