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ID PMID Title PublicationDate abstract
31575842 First steps to understand productivity loss in Portuguese patients with rheumatoid arthrit 2019 Jul Rheumatoid Arthritis (RA), in consequence of joint inflammation and damage, is known to lead to productivity loss. Developments during the 21st century, such as biologic treatments, allowed remission/low disease activity to be achieved in more RA patients. Despite this, evidence is equivocal concerning work outcomes improvement. Our goal was to evaluate work status and productivity in a Portuguese population with RA from 3 Rheumatology Departments through the questionnaire Work Productivity and Activity Impairment General Health (WPAI).
31792368 Genetic and clinical prediction models for the efficacy and hepatotoxicity of methotrexate 2020 Jun The objective of the study is to develop genetic and clinical prediction models for the efficacy and hepatotoxicity of methotrexate (MTX) in patients with rheumatoid arthritis (RA). Among RA patients treated with MTX, 1966 polymorphisms of 246 enzymes/transporters relevant to pharmacokinetics and pharmacodynamics were measured by the Drug Metabolism Enzymes and Transporters (DMET) microarray and direct sequencing, and clinical variables at baseline were collected. For efficacy, response criteria of the European League Against Rheumatism were used to classify patients as responders or non-responders. Hepatotoxicity was defined as elevations of aspartate aminotransferase or alanine aminotransferase ≥1.5 times the reference range upper limit. Among 166 patients, a genetic prediction model for efficacy using seven polymorphisms showed the area under the receiver operating characteristic curve (AUC) was 0.822, with 74.3% sensitivity and 76.8% specificity. A combined genetic and clinical model indicated the AUC was 0.844, with 81.5% sensitivity and 76.9% specificity. By incorporating clinical variables into the genetic model, the overall category-free net reclassification improvement (NRI) was 0.663 (P < 0.0001) and the overall integrated discrimination improvement (IDI) was 0.083 (P = 0.0009). For hepatotoxicity, a genetic prediction model using seven polymorphisms showed the AUC was 0.783 with 70.0% sensitivity and 80.0% specificity, while the combined model indicated the AUC was 0.906 with 85.1% sensitivity and 87.8% specificity (overall category-free NRI: 1.002, P < 0.0001; overall IDI: 0.254, P < 0.0001). Our genetic and clinical models demonstrated moderate diagnostic accuracy for MTX efficacy and high accuracy for hepatotoxicity. These findings should, however, be validated and interpreted with a caution until external validation.
30001257 Experience With the Use of Rituximab for the Treatment of Rheumatoid Arthritis in a Tertia 2019 Sep BACKGROUND/OBJECTIVE: There is evidence supporting that there are no relevant clinical differences between dosing rituximab 1000 mg or 2000 mg per cycle in rheumatoid arthritis (RA) patients in clinical trials, and low-dose cycles seem to have a better safety profile. Our objective was to describe the pattern of use of rituximab in real-life practice conditions. METHODS: Rituximab for RA in clinical practice (RITAR) study is a retrospective cohort study from 2005 to 2015. Eligibility criteria were RA adults treated with rituximab for active articular disease. Response duration was the main outcome defined as months elapsed from the date of rituximab first infusion to the date of flare. A multivariable analysis was performed to determine the variables associated with response duration. RESULTS: A total of 114 patients and 409 cycles were described, 93.0% seropositive and 80.7% women. Rituximab was mainly used as second-line biological therapy. On demand retreatment was used in 94.6% of cases versus fixed 6 months retreatment in 5.4%. Median response duration to on demand rituximab cycles was 10 months (interquartile range, 7-13). Multivariable analysis showed that age older than 65 years, number of rituximab cycles, seropositivity, and first- or second-line therapy were associated with longer response duration. The dose administered at each cycle was not significantly associated with response duration. CONCLUSIONS: Our experience suggests that 1000 mg rituximab single infusion on demand is a reasonable schedule for long-term treatment of those patients with good response after the first cycles, especially in seropositive patients and when it is applied as a first- or second-line biological therapy.
30902159 Long term drug related remission may encourage drug withdrawal in patients with rheumatoid 2019 Apr Remission is the goal of therapy in patients with rheumatoid arthritis (RA). However, drug free remission has not been investigated adequately. Early and intensive treatment may increase the chances of successful drug free remission. Effect of long term remission while on medical therapy on the success of drug withdrawal has not been previously evaluated in RA. Long term immune suppression has been shown to have beneficial effects on relapse rates in other diseases with dysregulated immune tolerance. Therefore, drug withdrawal could be an acceptable option in RA patients in long term remission.
30769772 MicroRNA-766-3p Contributes to Anti-Inflammatory Responses through the Indirect Inhibition 2019 Feb 14 MicroRNA (miRNA) is small RNA of 20 to 22 nucleotides in length and is stably present in plasma. Regulating the expression of miRNA taken into cells has been suggested as a general therapeutic approach. We identified the novel anti-inflammatory miRNA hsa-miR-766-3p and investigated its biological function in human rheumatoid arthritis (RA) fibroblast-like synoviocyte MH7A cells. To verify the function of the miRNA present in the plasma of RA patients, we performed a comprehensive analysis of the miRNA expression during abatacept treatment and identified eight miRNAs with significantly altered expression levels. Among these eight miRNAs, miR-766-3p was found to have a clear function. The expression of inflammatory genes in response to inflammatory stimuli was suppressed in MH7A transduced with miR-766-3p. We showed that miR-766-3p indirectly reduced the activation of NF-κB and clarified that this mechanism was partially involved in the reduction of the mineralocorticoid receptor expression. In addition, the inflammatory responses were suppressed in other types of cells. These results indicate the novel function of miR-766-3p, findings that may aid in the development of therapies to suppress inflammation, not only in RA but also in other diseases.
31465186 [Subclinical markers of atherosclerosis and cardiovascular risk factors in early arthritis 2019 Aug 29 BACKGROUND: Mortality from cardiovascular disease (CVD) is increased in rheumatoid arthritis, not explained by traditional cardiovascular risk factors (CVRF), suggesting a role of inflammation. This process would occur early. The common sonographic markers of subclinical atherosclerosis (SA), are increased carotid intima-media thickness (cIMT) or the presence of carotid atherosclerotic plaque and they are closely related to CVD. AIMS: To evaluate sonographic markers and cardiovascular risk factors in early Arthritis (EA). METHODS: A case control study of patients with EA, defined by 3 joints swollen with <1 year of evolution, served consecutively from January 2011 to may 2013, matched with healthy controls, by sex, age and cardiovascular risk factors (hypertension, diabetes mellitus, cardiovascular disease -IAM and ACV, dyslipidemia, family history of CVD) was conducted. We studied demographics data, cardiovascular risk factors, carotid ultrasound measuring increased cIMT or the presence of carotid atherosclerotic plaque in Common Carotid Artery (CCA) and Carotid Bulb (BC), laboratory test that included cholesterol, LDL, HDL, triglycerides in mg%, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR ), anti citrullinated peptide (ACCP), rheumatoid factor (RF), antinuclear antibodies (ANA). EA activity was measured by DAS 28, considering high disease activity (HDA) 5.1; moderate (MDA) from 5.1 to 3.2; and low (LDA) <3.2. Statistics: test Mann-Whitney and chi-square were used, p <0.05 was significant. RESULTS: 25 women, 5 men, average age 43 years (DS 14.7) and 30 controls were included. The average DAS 28 was 4, 8 ± 1. 8; 47% had HDA, 33%MDA and 20%BDA. Both groups had similar values cIMT CCA (0, 57 ± 0.10 mm vs. 0.58 ± 0.15 mm, respectively, P = 0.82) and cIMT BC (0.18mm ± 0.67 vs 0.62 ± 0.15 mm respectively, P = 0.47). There were no carotid plaques. The median total cholesterol was 181,5 vs 183,5 (p = 0.35); triglycerides 99 vs 92,5 (p = 0.68); HDL 54,5 vs 52,5 (p = 0.921 and LDL 105 vs 110 (p = 0.27) in EA and controls respectively. The cIMT CCA and CB were not related to RF, ACCP, CRP, DAS 28 and smoking (NS). There was no difference in other cardiovascular risk factors CONCLUSIONS: Ultrasound evidence of atherosclerosis subclinical markers was not found in this study, suggesting that this process may occur after a year of diagnosis.
30819683 Immune checkpoint inhibitor-induced rheumatoid arthritis: insights into an increasingly co 2019 Feb 27 Nivolumab is an immune checkpoint inhibitor that is used in the treatment of a variety of cancers in the adjuvant or metastatic setting. Adverse effects include non-specific activation of T cells, leading to immune-related adverse events in downstream organs. We present a case of a 36-year-old man with unresectable oropharyngeal squamous cell carcinoma who developed nivolumab-induced rheumatoid arthritis. As immune checkpoint inhibitor use is becoming widespread in the medical oncology domain, the purpose of this case report is to increase awareness of an increasingly common cause of rheumatic disease and to alert clinicians to consider immunotherapy in their differential diagnosis of polyarthritis. This case also highlights the importance of working in an interdisciplinary manner to enhance cancer care for the patient as well as to increase awareness of the potential adverse effects of immunotherapy in patients with cancer.
31631790 Interleukin-6 and tumour necrosis factor-α cooperatively promote cell cycle regulators an 2019 Sep Objective: To elucidate the roles of interleukin-6 (IL-6) and tumour necrosis factor-α (TNF-α) in cell cycle regulation and proliferation of rheumatoid arthritis fibroblast-like synovial cells (RA-FLSs). Methods: Under stimulation with IL-6/soluble interleukin-6 receptor (sIL-6R) and TNF-α, we examined the expression of cell cycle regulators [p16(INK4a), p21(Cip1), p27(Kip1), cyclin-dependent kinase-4 (CDK4), CDK6, Cyclin D, Cyclin E, and retinoblastoma protein (pRB)] by quantitative polymerase chain reaction, Western blotting, and immunofluorescence staining. The expression of pRB, with or without 10% foetal bovine serum, was examined by Western blotting. DNA synthesis and cell viability were examined by the BrdU assay and WST-8 assay, respectively. After transfection with siRNA/p16(INK4a), siRNA/p21(Cip1), siRNA/p27(Kip1), siRNA/CDK4, or siRNA/CDK6, RA-FLSs were successively stimulated with or without IL-6/sIL-6R or TNF-α to determine cell viability. Results: IL-6/sIL-6R significantly decreased the expression of p16(INK4a), and increased p21(Cip1), Cyclin E1, CYCLIN D, and pRB. TNF-α decreased the expression of CDK4, and significantly increased p27(Kip1), CDK6, Cyclin E1/E2, CYCLIN D, CYCLIN E, pRB, and phosphorylated pRB (phospho-pRB). By immunofluorescence staining, CYCLIN D and phospho-pRB were simultaneously stained in the single cell. In serum-free culture, the expression of pRB was apparently decreased. DNA synthesis and cell viability were significantly increased by IL-6/sIL-6R and TNF-α. Silencing of CDK6 attenuated the cell viability induced by IL-6 and TNF-α. Conclusion: The results indicate that IL-6 and TNF-α interact with each other in regulating the cell cycle and accelerate the proliferation of RA-FLSs.
31563994 Synthesis and Biological Activities of Chemical Drugs for the Treatment of Rheumatoid Arth 2019 Sep 28 Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease that primarily affects the joints, with the main clinical manifestations being chronic, symmetrical, and peripheral multi-joint inflammatory lesions. Drugs, including nonsteroidal anti-inflammatory drugs (NSAIDs), glucocorticoids (GCs), disease-modifying anti-rheumatic drugs (DMARDs), and biologics play a very important role in the treatment of RA. Of these, the most commonly used are chemical drugs, such as NSAIDs, GCs, and DMARDs. In recent years, a number of new compounds have emerged for the treatment of RA, such as SYK inhibitors, JAK inhibitors, NSAID-CAI drugs, and Syk/PDGFR-α/c-Kit inhibitors. In this review, we summarize the most recently developed anti-RA chemical drugs and discuss the synthesis and biological activities of these various new compounds.
31802869 Therapeutic Potential Of Foeniculum vulgare Mill. Derived Selenium Nanoparticles In Arthri 2019 PURPOSE: Rheumatoid arthritis is an inflammatory autoimmune multifactorial disorder that primarily affects the joints. Currently available treatment options, although effective, still present some side effects. This study proposes an alternative treatment option for rheumatoid arthritis through elucidation of therapeutic potential of Foeniculum vulgare Mill.-derived selenium nanoparticles in arthritic Balb/c mice. METHODS: Synthesis and characterization of selenium nanoparticles were followed by their toxicity analysis on healthy mice. Subsequently, anti-arthritic efficacy of two doses (5 mg/kg and 10 mg/kg) of synthesized selenium nanoparticles was checked on arthritic mice using multiple parameters. RESULTS: Selenium nanoparticles in 10 mg/kg dose turned out to be more effective in treatment of rheumatoid arthritis as evident by significant reduction in paw volume and normal clinical chemistry parameters of treated arthritic mice. This dose also showed significant antioxidant activity in 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay. CONCLUSION: Foeniculum vulgare Mill.-derived selenium nanoparticles retain significant anti-arthritic and antioxidant potential and consequently can further be explored as an alternative treatment option for rheumatoid arthritis.
31520227 Defining response to TNF-inhibitors in rheumatoid arthritis: the negative impact of anti-T 2019 Nov Current guidelines recommend treating rheumatoid arthritis (RA) patients to reach low disease activity or remission, however, most biologic-naive RA patients fail to reach treatment targets on their first biologic therapy. Approximately 90% of biologic-naive RA patients receive a tumor necrosis factor alpha inhibitor (anti-TNF) as their first biologic treatment, even though several alternative mechanism of action (MOA) therapies are approved as first-line options. After 3 months of therapy, patients may remain on anti-TNF therapy even if they fail to achieve the treatment target, mainly due to formulary structures. This means patients have to endure a second and even a third ineffective anti-TNF-called anti-TNF cycling-before changing MOA. This significantly delays patients from reaching their treatment targets. All anti-TNF drugs target the same molecular and inflammatory pathways; thus, it is not surprising that most patients who are primary non-responders to their initial anti-TNF therapy fail to achieve their treatment targets when cycled through alternative anti-TNFs. This suggests that primary non-responders should be switched to an alternative MOA therapy rather than enduring anti-TNF cycling. Avoiding anti-TNF cycling would prevent disease progression and improve quality of life for RA patients who are primary non-responders to anti-TNFs. The development of a personalized medicine approach to identify primary non-responders to anti-TNFs prior to treatment would allow significantly more patients to reach their treatment target by treating them with alternative MOA therapies as first-line therapies.
31228612 Altered cerebral pain processing of noxious stimuli from inflamed joints in rheumatoid art 2019 Oct OBJECTIVE: To our knowledge, this is the first study assessing brain activation in response to painful stimulation over disease-relevant (finger joint) vs. neutral area (thumb nail) in patients suffering from rheumatoid arthritis (RA) compared to healthy controls (HC). METHOD: Thirty-one RA patients and 23 HC underwent functional magnetic resonance imaging (fMRI) while stimulated with subjectively calibrated painful pressures corresponding to a pain sensation of 50 mm on a 100 mm VAS scale (P50) at disease-affected finger joint and thumbnail (left hand), and corresponding sites in HC. RESULTS: Compared to controls, RA patients had significantly increased pain sensitivity (lower P50) at the inflamed joints but not at the thumbnail. RA patients exhibited significantly less activation in regions related to pain- and somatosensory processing (S1, M1, anterior insula, S2, SMG and MCC) during painful joint stimulation, compared to HC. No group difference in cerebral pain processing was found for the non-affected thumbnail. Within RA patients, significantly less brain activation was found in response to painful stimulation over disease-affected joint compared to non-affected thumbnail in bilateral S1, bilateral S2, and anterior insula. Further, RA patients exhibited a right-sided dlPFC deactivation, psycho-physiologically interacting (PPI) with the left dlPFC in response to painful stimulation at disease-affected joints. CONCLUSION: The results indicate normal pain sensitivity and cerebral pain processing in RA for non-affected sites, while the increased sensitivity at inflamed joints indicate peripheral/spinal sensitization. Brain imaging data suggest that disease-relevant pain processing in RA is marked by aberrations and a failed initiation of cortical top-down regulation.
30593421 Nodular rheumatoid arthritis (RA): A distinct disease subtype, initiated by cadmium inhala 2019 Jan Nodular rheumatoid arthritis (RA) patients have raised rheumatoid factor (RF) and anti-citrullinated protein antibody (ACPA) levels, and are more likely to smoke than RA patients without nodules. Subcutaneous and pulmonary rheumatoid nodules (granulomas) frequently co-exist. Pulmonary rheumatoid nodules develop prior to RA development and have the immunological machinery to generate RF and ACPAs. Pulmonary granulomas have been observed in animal models exposed to cadmium (Cd) inhalation. Cigarette smoke increases pulmonary Cd exposure. It has been suggested that dust and cigarette smoke co-exposure increases localised pulmonary Cd adsorption. We hypothesise that subcutaneous nodular RA represents a distinct disease subtype induced by pulmonary rheumatoid nodule formation and the generation of high levels of RA associated autoantibodies initiated by Cd inhalation via cigarette smoke. Cohorts of RA patients attending rheumatology clinics in Cornwall, UK (total n = 504) were studied to determine the prevalence of nodular RA, with matched analysis (age, gender and social class) to compare urinary Cd, RF and ACPA levels stratifying for nodular disease and smoking. In cohort 1 45/303 (14.9%) of the RA patients under regular follow up had nodular disease. Of the RA smokers, 30/155 (19%) were nodular and of the RA non-smokers 15/148 (10%) were nodular. Smoking was significantly associated with nodular RA, odds ratio (OR) = 2.48 95% confidence interval (CI) 1.26-4.88, p = 0.008. Raised urinary Cd levels were significantly associated with nodular RA in non-dust exposed individuals, OR 2.26 (95% CI 1.08-4.73), p = 0.03 compared to dust exposed individuals, OR 0.78 (95% CI 0.35-1.76), p = 0.557, despite fewer pack years (py) at diagnosis (16 vs 20 py). Nodular RA smokers had significantly raised RF levels compared to RA smokers without nodular disease (median RF 171.5 (interquartile range (IQR) 48-394) vs median RF 31.7 (IQR 10.3-170.3), p < 0.00001). RF positivity was significantly more prevalent in nodular RA smokers compared to RA smokers without nodular disease (84/89 (94%) vs. 141/199 (71%), OR = 6.9 (95% CI 2.66-17.91), p < 0.00001). ACPA levels were also significantly raised in nodular smokers compared to non-nodular smokers (median ACPA 250 (IQR 145-426) vs 116 (1-257.5), p < 0.00001), as were ACPA positivity rates (83/89 (93%) vs 123/191 (64%), OR = 7.65 (95% CI 3.17-18.4), p < 0.0001). These pilot results support the hypothesis that nodular RA represents a distinct disease subtype initiated by cadmium inhalation, which we suggest induces pulmonary rheumatoid nodule formation and generation of RA-associated autoantibodies.
31557754 Coping and Life Satisfaction: Mediating Role of Ego-Resiliency in Patients with Rheumatoid 2020 OBJECTIVE: Ego-resiliency is attributed the status of a "meta resource" that is responsible for a flexible selection of coping strategies depending on the requirements of a specific difficult situation. A considerably burdensome critical life event is the development of a chronic illness such as rheumatoid arthritis (RA). Apart from coping with the symptoms, a fundamental task confronting patients is maintaining their quality of life. This raises the question of whether ego-resiliency serves as a mediator between coping strategies and quality of life. MATERIALS AND METHODS: 210 RA patients were invited to participate in this study. They were requested to complete a questionnaire that included the Satisfaction with Life scale, the stress coping inventory Mini-COPE, and the Ego-Resiliency scale. The collected data were analyzed by a simple mediation procedure and estimation of simple correlation coefficients. RESULTS: The analysis demonstrated that ego-resiliency (r = 0.46; p < 0.001) and emotion-focused coping (r = 0.39; p < 0.001) determined life satisfaction. Additionally, ego-resiliency mediated the relation between emotion-oriented coping strategies and life satisfaction. Partial mediation was observed (a = 0.45**; b = 0.36**; c = 0.39**; c' =0.22**; R2 = 0.24; F = 35.65; p < 0.001). CONCLUSION: Our observations partly support the assumption about a controlling role of ego-resiliency in the process of selecting coping strategies according to demands of situations.
31217169 Non-response to rituximab therapy in rheumatoid arthritis is associated with incomplete di 2019 Oct OBJECTIVE: To gain more insight into the dynamics of lymphocyte depletion and develop new predictors of clinical response to rituximab in rheumatoid arthritis (RA). METHODS: RNA-based next-generation sequencing was used to analyse the B cell receptor (BCR) repertoire in peripheral blood and synovial tissue samples collected from 24 seropositive patients with RA treated with rituximab. Clonal expansion, mutation load and clonal overlap were assessed in samples collected before, at week 4 and at week 16 or 24 after treatment and correlated to the patients' clinical response. RESULTS: After 4 weeks of rituximab-induced B cell depletion, the peripheral blood BCR repertoire of treated patients consisted of fewer, more dominant and more mutated BCR clones. No significant changes in the synovial tissue BCR repertoire were detected until week 16 post-treatment, when a reduced clonal overlap with baseline and an increased mutation load were observed. In patients who were non-responders at month 3 (n=5) using the European League Against Rheumatism response criteria, peripheral blood samples taken at week 4 after rituximab treatment showed more dominant clones compared with moderate responders (n=9) (median (IQR): 36 (27-52) vs 18 (16-26); p<0.01) and more clonal overlap with the baseline (median (IQR): 5% (2%-20%) vs 0% (0%-0%); p≤0.01). CONCLUSION: Significant changes in BCR clonality are observed in peripheral blood of patients 4 weeks after rituximab treatment, while changes in synovial tissue were observed at later time points. Incomplete depletion of the dominant baseline peripheral blood BCR repertoire in the first month of treatment might predict clinical non-response at 3 months.
30911943 PRL -1149T allele (rs1341239) is associated with decreased risk of rheumatoid arthritis in 2019 Aug INTRODUCTION: Prolactin (PRL) is a sex hormone with immunomodulatory properties, and it is associated with the clinical activity of rheumatoid arthritis (RA). The -1149G>T polymorphism at the prolactin (PRL) gene has been associated with autoimmune diseases, but its functional effect is unclear. OBJECTIVE: To analyze the association of the PRL -1149G>T polymorphism with disease susceptibility, mRNA, and protein expression of PRL in RA patients from Southern Mexico. METHODS: We included 300 RA patients and 300 control subjects (CS). Genotypes were identified by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique, the PRL mRNA expression was determined by real-time PCR, and PRL serum levels were measured by enzyme-linked immunosorbent assay. RESULTS: Applying genetic models of inheritance (dominant, recessive, and additive), we found an association between the T allele and decreased RA susceptibility (OR = 0.55, 95% CI 0.35-0.87, p = 0.009; OR = 0.09, 95% CI 0.012-0.76, p = 0.011; OR = 0.49, 95% CI 0.32-0.76, p = 0.001, respectively). RA patients had higher mRNA expression and soluble levels of PRL than CS (p < 0.05). The PRL serum levels were similar in RA and CS according to genotypes. However, in CS, carriers of GT and TT genotypes showed lower PRL mRNA expression than GG genotype carriers (7.1-fold and 20-fold respectively, p = 0.006). CONCLUSIONS: This study demonstrated that the PRL -1149T allele is a genetic marker of decrease risk to RA in population from Southern Mexico, and it is associated with low PRL mRNA. KEY POINTS: • PRL -1149T allele is a marker of decreased RA susceptibility in population from southern Mexico. • PRL -1149TT genotype is associated with low PRL mRNA expression. • RA patients have higher mRNA expression and soluble levels of PRL than healthy subjects. • PRL serum levels are higher in those RA patients with < 2 years of disease evolution.
30916602 Interleukin-1 receptor-associated kinase 4 (IRAK4) inhibitors: an updated patent review (2 2019 Apr INTRODUCTION: Interleukin-1 receptor-associated kinase 4 (IRAK4) is the most upstream kinase in Toll/Interleukin-1 receptor (TIR) signaling. Human and rodent genetics support the role of IRAK4 in immune function and the involvement of IRAK4-dependent signaling in certain cancers is hypothesized. The accumulating evidence has motivated the discovery of IRAK4 inhibitors that could be used therapeutically. AREAS COVERED: This review summarizes patents published in 2016-2018 claiming IRAK4 inhibitors. Representative analogues from each patent are presented with a focus on compounds that have been profiled in cellular and in vivo assays. EXPERT OPINION: The last three years have seen an increased number of IRAK4 inhibitors with which to assess the therapeutic potential of the target. At least 5 companies are believed to have advanced to the clinic. Pfizer is in phase II for rheumatoid arthritis (RA). The outcomes of these studies should inform on the therapeutic potential in autoimmune disease and cancer.
31508202 Emerging therapies in rheumatoid arthritis: focus on monoclonal antibodies. 2019 Advances in the treatment of rheumatoid arthritis (RA) are attributed to several aspects such as new classification criteria enabling early diagnosis and intensive treatment with the application of treat-to-target principles as well as better understanding of the pathogenesis of RA contributing to the development of targeted therapies. However, reaching remission is still not achieved in most patients with RA, which is one of the driving forces behind the continuous development of novel therapies and the optimization of therapeutic strategies. This review will outline several new therapeutic antibodies modulating anti-inflammatory cytokines interleukin (IL)-2 and IL-10 and pro-inflammatory mediators granulocyte-macrophage colony-stimulating factor, fractalkine, and IL-6 that are in various stages of clinical development as well as the progress in manufacturing biotechnologies contributing to the next generation of antibodies and their potential to expand the therapeutic armamentarium for RA. In addition, the fate of unsuccessful therapies including agents targeting IL-15, the IL-20 family, IL-21, chemokine CXCL10, B-cell activating factor (BAFF), and regulatory T (Treg) cells or a novel concept targeting synovial fibroblasts via cadherin-11 will be discussed.
30955314 [Value of musculoskeletal ultrasound in assessing the disease activity in rheumatoid arthr 2019 Apr 2 Objective: To investigate the value of musculoskeletal ultrasound (MSUS) in assessing the disease activity of rheumatoid arthritis (RA). Methods: As a retrospective study, clinical data, laboratory test results and MSUS results of 22 joints (2 wrist joints, 10 metacarpophalangeal joints, 2 thumb interphalangeal joints, 8 proximal interphalangeal joints) were collected from 403 hospitalized RA patients (including Han and Uygur patients) in the People's Hospital of the Xinjiang Uygur Autonomous Region from January 2016 to December 2016. Result: (1) There was a positive correlation between swollen joints count, tender joints count, erythrocyte sedimentation rate, C-reaction protein and sum scores of articular cavity effusion, Grey Scale (GS), Power Doppler (PD), tenosynovitis in RA patients; (2)there was a positive correlation between DAS28-ESR, DAS28-CRP, SDAI, CDAI and sum scores of effusion, GS, PD, tenosynovitis in RA patients. The ulnar extensor tendon of the wrist of RA patients was more susceptible to extensor tendon than other extensor tendons; (3)there was significant statistical difference between Uygur and Han RA patients in bone erosion (P<0.05), however the statistical difference between Uygur and Han RA patients in effusion, GS or PD score was not significant (P>0.05). Few Uygur RA patients achieved clinical remission and subclinical synovitis was not detected, while such subclinical synovitis was detected in Han RA patients who achieved clinical remission. Conclusion: The MUSU can assess the disease activity of RA patients, and provide a more direct and objective evidence for the rapid evaluation of disease.
29901407 Vaccination with a Novel Antigen-Specific Tolerizing DNA Vaccine Encoding CCOL2A1 Protects 2019 Jan Antigen-specific tolerizing DNA vaccines are one of the most promising strategies for rheumatoid arthritis (RA) treatment. They act by inducing potent immune tolerance instead of generalized immunosuppression. Recently, we developed a novel antigen-specific tolerizing DNA vaccine pcDNA-CCOL2A1 coding for chicken type II collagen (CCII) and confirmed its potent therapeutic efficacy in an established rat model of collagen-induced arthritis (CIA). Here we report the prophylactic vaccination efficacy of a single 300 μg/kg dose of pcDNA-CCOL2A1 against CIA incidence, severity, and onset. CCOL2A1 transcripts were detected in the blood of CIA rats 14-42 days after intramuscular injection by 300 μg/kg pcDNA-CCOL2A1. The expression of CCOL2A1 transcripts increased quickly on day 21, peaked at day 28, and then gradually decreased thereafter. Importantly, a single prophylactic vaccination of pcDNA-CCOL2A1 14 days before CIA establishment significantly reduced CIA incidence and severity, deferred its onset, and was as efficacious as the current gold standard drug, methotrexate. The marked effects on CIA incidence and severity closely corresponded to the expression of CCOL2A1. Furthermore, prophylactic vaccination with pcDNA-CCOL2A1 markedly decreased serum content of anti-type II collagen (CII) immunoglobulin G (IgG) antibodies, induced Th1-to-Th2 and Tc1-to-Tc2 shifts, and decreased the percentages of CD4(+)CD29(+) and Th17 T cells. Prophylactic vaccination with pcDNA-CCOL2A1 also downregulated various Th1 cytokines, while upregulating both the Th2-type cytokine interleukin-10 and the Th3-type cytokine transforming growth factor β. Our results indicate that the pcDNA-CCOL2A1 DNA vaccine acts as a highly efficient inducer of specific immunotolerance that could be a promising option for RA treatment in the near future.