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ID PMID Title PublicationDate abstract
32514494 The role of advanced MRI in the development of treat-to-target therapeutic strategies, pat 2020 In this commentary, we discuss the potential of advanced imaging, particularly Dynamic Contrast Enhanced (DCE) magnetic resonance imaging (MRI) for the objective assessment of the inflammatory process in rheumatoid arthritis (RA). We emphasise the potential of DCE-MRI in advancing the field and exploring new areas of research and development in RA. We hypothesize that different grades of bone marrow edema (BME) and synovitis in RA can be examined and monitored in a more sensitive manner with DCE-MRI. Future treatments for RA may benefit from the application of enhanced imaging of BMEs and synovitis. DCE-MRI may also facilitate enhanced stratification and phenotyping of patients enrolled in clinical trials.
33281053 Computed tomography in rheumatology - From DECT to high-resolution peripheral quantitative 2020 Dec In this chapter, we discuss current updates and applications of Dual Energy Computed Tomography (DECT), iodine-DECT mapping, and high-resolution peripheral quantitative CT (HR-pQCT) in rheumatology. DECT provides a noninvasive diagnosis of gout and can help to differentiate gout from CPPD. Accuracy of DECT varies in various stages of gout. DECT needs specialized hardware, software, and skilled post-processing and interpretation. Sensitivity reduces significantly with deeper tissues such as hip and shoulder. Iodine map enables to delineate inflammatory lesions such as capsulitis and tenosynovitis by improving iodine contrast. Iodine quantification with an iodine map is a promising objective method to evaluate therapeutic effect of inflammatory arthritis. HR-pQCT allows for highly sensitive and specific measures of bone erosions and osteophytes in inflammatory joint diseases, documenting change over time, e.g. in cohorts undergoing immunosuppressive treatments. However, assessing the images requires trained readers, and (semi)-automated scripts to detect bone damage are still undergoing validation and further development.
32410713 Targeting a cysteine protease from a pathobiont alleviates experimental arthritis. 2020 May 14 BACKGROUND: Several lines of evidence suggest that the pathobiont Porphyromonas gingivalis is involved in the development and/or progression of auto-inflammatory diseases. This bacterium produces cysteine proteases, such as gingipain RgpA, endowed with the potential to induce significant bone loss in model systems and in patients. OBJECTIVE: We sought to gain further insight into the role of this pathobiont in rheumatoid arthritis (RA) and to identify novel therapeutic targets for auto-inflammatory diseases. METHODS: We profiled the antibody response to RgPA-specific domains in patient sera. We also tested the potential protective effects of RgpA domains in an experimental arthritis model. RESULTS: Pre-immunization of rats with purified recombinant RgpA domains alleviated arthritis in the joints of the rodents and reduced bone erosion. Using a functional genomics approach at both the mRNA and protein levels, we report that the pre-immunizations reduced arthritis severity by impacting a matrix metalloprotease characteristic of articular injury, a chemokine known to be involved in recruiting inflammatory cells, and three inflammatory cytokines. Finally, we identified an amino acid motif in the RgpA catalytic domain of P. gingivalis that shares sequence homology with type II collagen. CONCLUSION: We conclude that pre-immunization against gingipain domains can reduce the severity of experimentally induced arthritis. We suggest that targeting gingipain domains by pre-immunization, or, possibly, by small-molecule inhibitors, could reduce the potential of P. gingivalis to translocate to remote tissues and instigate and/or exacerbate pathology in RA, but also in other chronic inflammatory diseases.
33354232 Anti-carbamylated protein antibody isotype pattern differs between palindromic rheumatism 2020 BACKGROUND: A restricted response against citrullinated peptides/proteins, with less isotype usage, has been found in palindromic rheumatism (PR) in comparison with rheumatoid arthritis (RA). We hypothesized that this different antibody response may be observed for other post-translational modified proteins. We compared the prevalence and isotype usage of two specificities of anti-carbamylated peptide/protein antibodies (Anti-CarP) in patients with PR and RA. METHODS: Cross-sectional study including 54 patients with pure PR and 53 patients with RA, matched by sex, age, disease duration and ACPA. Anti-CarP specificities were determined by home-made enzyme-linked immunosorbent assay tests using a synthetic chimeric fibrin/filaggrin homocitrullinated peptide (CFFHP) and fetal calf serum (FCS) homocitrullinated protein as antigens. IgG, IgA and IgM isotypes were measured. RESULTS: Anti-CarP were positive (CFFHP or FCS) in 24% and 64% of patients with PR and RA, respectively (p < 0.005). All Anti-CarP isotype proportions were significantly lower in PR than in RA: Anti-CarP-IgG (24% versus 51%), Anti-CarP-IgA (7% versus 34%) and Anti-CarP-IgM (7% versus 36%). Mean titers of Anti-CarP isotypes were also lower in PR. In Anti-CarP positive patients, the isotype distribution differed between PR and RA: IgG Anti-CarP was used in all PR patients and in 79% of RA patients. By contrast, a significantly lower isotype usage of both IgA (31% versus 53%) and IgM (31% versus 56%) was observed in PR patients. No significant differences in clinical or demographic characteristics were observed according to Anti-CarP status in PR patients, except for a higher prevalence of ACPA and higher mean titers of ACPA and rheumatoid factor in Anti-CarP positive patients. CONCLUSION: Anti-CarP are found in patients with PR but in a lower proportion and with a different isotype usage from in RA, suggesting a distinct B cell response to homocitrullinated antigens in PR.
32216648 Amelioration of adjuvant-induced arthritis by exposure to low dose gamma radiation and res 2020 Jul Purpose: Low dose radiation has been reported as an effective treatment for rheumatoid arthritis via multiple dose exposures. The present study was designed to increase the therapeutic efficacy of low dose radiation with the minimum exposure level in arthritic rats by concurrent administration of resveratrol (RSV) as an adjunctive therapy with anti-inflammatory properties.Materials and methods: Rats were rendered arthritic by sub-plantar injection of Freund's complete adjuvant (FCA) and exposed to low dose radiation at a total exposure level of 0.5 Gy (2 × 0.25). During the exposure course, RSV (50 mg/kg) was orally administered once daily for two weeks. Diclofenac (3 mg/kg) was administered as a standard anti-inflammatory drug. Paw volume was measured every 4 days. After 28 days of induction, rats were sacrificed and serum was collected for estimation of tumor necrosis factor-alpha (TNF-α), interleukin-1beta (IL-1β), thiobarbituric acid reactive substances (TBARS), and total nitrate/nitrite (NO(x)). Furthermore, paws were dissected for histopathological examinations and immuno-histochemical estimation of nuclear factor-kappa B p65 (NF-κB p65) expression.Results: Administration of RSV during the low dose radiation exposure course produced a significant decrease in the paw swelling and a potentiated inhibition in the serum levels of TNF-α, IL-1β, TBARs, and NO(x). The dual treatment strategy alleviated the histopathological damage to a greater extent than that produced by each treatment. Moreover, a pronounced suppression of NF-κB p65 expression in the synovial tissue was observed in the combination group. The combination treatment showed a nearly similar potency to that observed in the diclofenac treated group.Conclusion: Administration of RSV augmented the modulatory activity of low dose radiation with minimum exposure level on the disease progression.
33088738 In Vivo Effects of Nonselective, Partially Selective, and Selective Non Steroidal Anti-Inf 2020 Jul BACKGROUND: The relationship between oxidative stress, decreased antioxidant status, and rheumatoid arthritis (RA) has been widely investigated. To date, few clinical studies have assessed the role of conventional nonsteroidal anti-inflammatory drugs (NSAIDs) in the modulation of oxidative stress in patients with RA. AIM: The aim of this study was to compare the effects of nonselective, partially selective, and selective cyclooxygenase (COX) inhibitors on markers of oxidative stress in patients with RA. MATERIALS AND METHODS: Thirty RA patients were enrolled in this open label, prospective study for 12 weeks and randomly assigned to either group receiving diclofenac 100 mg, meloxicam 15 mg, or celecoxib 200 mg daily (n = 10 in each group). Patients were evaluated for superoxide dismutase (SOD) and serum malondialdehyde (MDA) as oxidative markers at the baseline and at the end of 12 weeks. Various parameters for efficacy were also assessed. RESULTS: The baseline values of the SOD enzyme were significantly lower and MDA values were significantly elevated in patients randomized to the three treatment groups as compared to the control group (P < 0.05). MDA level was significantly decreased in patients across all the treatment groups (P < 0.05) after 12 weeks. There was an improvement in mean SOD enzyme levels at the end of 12 weeks; the difference for SOD was significant as compared to the baseline in the meloxicam group only (P < 0.05) but not in diclofenac- and celecoxib-treated patients. Significant improvement was observed in all the treatment groups as regards patient assessment of pain visual analog scale, tender and swollen joint count, and patient global assessment. CONCLUSIONS: Diclofenac, meloxicam, and celecoxib carry antioxidant effects to a variable extent. NSAID possesses additional mechanism independent of COX inhibition which modulates oxidative stress.
32222059 The value, impact and role of nurses in rheumatology outpatient care: Critical review of t 2020 Sep BACKGROUND: As rheumatology nurses make substantial contributions to intensive management programmes following 'treat to target' principles of people with rheumatoid arthritis (RA), there is a need to understand the impacts of their involvement. A structured literature review was undertaken of qualitative studies, clinical trials and observational studies to assess the impacts of rheumatology nurses on clinical outcomes and the experiences of patients with RA and to examine the skills and training of the nurses involved. METHOD: A structured literature review was conducted to examine the value, impact and professional role of nurses in RA management. RESULTS: The literature search identified 657 publications, and 20 of them were included comprising: seven qualitative studies (242 patients), nine trials (a total of 2,440 patients) and four observational studies (1,234 patients). In clinical trials, nurses achieved similar patient clinical outcomes to doctors, and nurses also enhanced patients' satisfaction of received care and self-efficacy. In the qualitative studies reviewed, the nurses increased patients' knowledge and promoted their self-management. The observational studies studied examined found that nursing care led to improved patients' global functioning. The nurses in the various studies had a wide range of titles, experiences and training. DISCUSSION: Our structured literature review provides strong evidence that rheumatology nurses are effective in delivering care for RA patients. However, their titles, experience and training were highly variable. CONCLUSION: There is a convincing case to maintain and extend the role of nurses in managing RA, but further work is needed on standardisation of their titles and training.
31936504 Emerging Concepts and Challenges in Rheumatoid Arthritis Gene Therapy. 2020 Jan 9 Rheumatoid arthritis (RA) is a systemic inflammatory joint disease affecting about 1% of the population worldwide. Current treatment approaches do not ensure a cure for every patient. Moreover, classical regimens are based on nontargeted systemic immune suppression and have significant side effects. Biological treatment has advanced considerably but efficacy and specificity issues remain. Gene therapy is one of the potential future directions for RA therapy, which is rapidly developing. Several gene therapy trials done so far have been of moderate success, but experimental and genetics studies have yielded novel targets. As a result, the arsenal of gene therapy tools keeps growing. Currently, both viral and nonviral delivery systems are used for RA therapy. Herein, we review recent approaches for RA gene therapy.
32744683 MiR-20a regulates fibroblast-like synoviocyte proliferation and apoptosis in rheumatoid ar 2020 Jul Since this article has been suspected of research misconduct and the corresponding authors did not respond to our request to prove originality of data and figures, "MiR-20a regulates fibroblast-like synoviocyte proliferation and apoptosis in rheumatoid arthritis, by X.-J. Wei, X.-W. Li, J.-L. Lu, Z.-X. Long, J.-Q. Liang, S.-B. Wei, C.-X. Lu, W.-Z. Lu, published in Eur Rev Med Pharmacol Sci 2017; 21 (17): 3886-3893-PMID: 28975975" has been withdrawn. The Publisher apologizes for any inconvenience this may cause. https://www.europeanreview.org/article/13351.
33403019 Immunosuppressive agents for rheumatoid arthritis: a systematic review of clinical trials 2020 AIMS: With the arrival of conventional synthetic (csDMARDs), biological (bDMARDS) and then targeted synthetic (tsDMARDs) disease-modifying anti-rheumatic drugs, the therapeutic arsenal against rheumatoid arthritis (RA) has recently expanded. However, there are still some unmet needs for patients who do not achieve remission and continue to worsen despite treatments. Of note, most randomized controlled trials show that, for methotrexate-inadequate responders, only 20% of patients are ACR70 responders. With our better understanding of RA pathogenesis, finding new treatments is a necessary challenge. The objective of our study was to analyse the whole pipeline of immunosuppressive and immunomodulating drugs evaluated in RA and describe their mechanisms of action and stage of clinical development. METHODS: We conducted a systematic review of all drugs in clinical development in RA, in 17 online registries of clinical trials. RESULTS: The search yielded 4652 trials, from which we identified 243 molecules. Those molecules belong to csDMARDs (n = 22), bDMARDs (n = 118), tsDMARDs (n = 103). Twenty-four molecules are already marketed in RA in at least one country: eight csDMARDs, 10 bDMARDs and six tsDMARDs. Molecules under current development are mainly bDMARDs (n = 34) and tsDMARDs (n = 33). Seven of those have reached phase III. A large number of molecules (150/243, 61.7%) have been withdrawn. CONCLUSION: Despite the availability of 24 marketed molecules, the development of new targeted molecules is ongoing with a total of 243 molecules in RA. With seven molecules currently reaching phase III, we can expect an increase in the armamentarium in the years to come.
33365319 The Link Between Autonomic Nervous System and Rheumatoid Arthritis: From Bench to Bedside. 2020 Neuronal stimulation is an emerging field of research focused on the management and treatment of various diseases through the reestablishment of physiological homeostasis. Electrical vagus nerve stimulation has recently been proposed as a revolutionary therapeutic option for rheumatoid arthritis (RA) in combination with or even as a replacement for conventional and biological drugs. In the past few years, disruption of the autonomic system has been linked to RA onset and activity. Novel research on the link between the autonomic nervous system and the immune system (immune-autonomics) has paved the way for the development of innovative RA management strategies. Clinical evidence supports this approach. Cardiovascular involvement, in terms of reduced baroreflex sensitivity and heart rate variability-derived indices, and mood disorders, common comorbidities in patients with RA, have been linked to autonomic nervous system dysfunction, which in turn is influenced by increased levels of circulating pro-inflammatory cytokines. This narrative review provides an overview of the autonomic nervous system and RA connection, discussing most of the common cardiac and mental health-related RA comorbidities and their potential relationships to systemic and joint inflammation.
33346009 Ibuprofen-loaded calcium phosphate granules: A new bone substitute for local relieving sym 2021 Mar 1 Musculoskeletal diseases often demand a drug treatment at the specific site of injury or defect site. In this context, the use of calcium phosphates is attractive as it allows both the bone substitution and the local delivery of a drug substance. In this work, we present a drug delivery device that combines calcium phosphate bioceramic granules and ibuprofen, a widely used anti-inflammatory drug. After verifying in vitro biocompatibility of the ibuprofen-loaded calcium phosphate granules on murine preosteoblastic cells (MC3T3), we evaluated in vitro efficiency of the drug substance released from the bioceramic using rheumatoid arthritis synoviocytes. Our data document that ibuprofen-loaded calcium phosphate granules reduced inflammatory response and increased apoptosis of synoviocytes. In vivo study showed that both unloaded, and ibuprofen-loaded calcium phosphate granules induced a progressive osteogenesis, but in the case of ibuprofen-loaded implants, bone ingrowth was more limited in first weeks. However, as far as concerns inflammation, while unloaded granules showed inflammation up to 4 weeks, ibuprofen loaded granules did not show any significant inflammation. Ibuprofen concentration determination in blood samples showed that a very small amount of the drug reached the general circulation which render this drug delivery system suitable for both bone substitution and reduction of inflammation at the implantation site. Thus, this new drug carrier could be used to locally relieve inflammatory bone diseases symptoms including rheumatoid arthritis but, beyond this study, this kind of granules could be considered for the delivery of therapeutic agents such as antibiotic, analgesic or anticancer drugs.
33000421 Incidence and Complication Rates for Total Hip Arthroplasty in Rheumatoid Arthritis: A Sys 2020 Dec INTRODUCTION: Over the past several decades, management of rheumatoid arthritis (RA) has evolved significantly, but few studies have examined the real-world impact of these changes on orthopaedic surgery in patients with RA. This systematic review assessed total hip arthroplasty (THA) incidence and postoperative complication rates across the past four decades. METHODS: This is a systematic literature review sourcing data on THA in patients with RA from the electronic databases MEDLINE, EMBASE, Scopus, and Cochrane between January 1, 1980 and December 31, 2019. RESULTS: The search retrieved 1715 articles of which 44 were included for quantitative synthesis. The rate for THA decreased by almost 40% from 11/1000 patient years (PY) in the 2000s to 7/1000 PY in the 2010s, while the overall complication rate decreased from 9.9% in the 1990s to 5.3% in the 2010s. Throughout the duration of the study, THA incidence and overall complication rate decreased. However, not all individual complication rates decreased. For example, revision and periprosthetic fracture decreased, infection and aseptic loosening remained constant, and dislocation increased. CONCLUSION: Medical management of patients with RA has reduced the need for THA, while postoperative medical and surgical management has improved some postoperative outcomes. Nevertheless, there remains room for further improvement to postoperative outcomes through RA-specific management.
32978666 Acupuncture and Chronic Musculoskeletal Pain. 2020 Sep 25 PURPOSE OF REVIEW: Chronic musculoskeletal pain (CMP) attributable to conditions such as osteoarthritis, rheumatoid arthritis, fibromyalgia, and chronic low back pain is the most common cause of disability globally, for which no effective remedy exists. Although acupuncture is one of the most popular sensory stimulation therapies and is widely used in numerous pain conditions, its efficacy remains controversial. This review summarizes and expands upon the current research on the therapeutic properties of acupuncture for patients with CMP to better inform clinical decision-making and develop patient-focused treatments. RECENT FINDINGS: We examined 16 review articles and 11 randomized controlled trials published in the last 5 years on the clinical efficacy of acupuncture in adults with CMP conditions. The available evidence suggests that acupuncture does have short-term pain relief benefits for patients with symptomatic knee osteoarthritis and chronic low back pain and is a safe and reasonable referral option. Acupuncture may also have a beneficial role for fibromyalgia. However, the available evidence does not support the use of acupuncture for treating hip osteoarthritis and rheumatoid arthritis. The majority of studies concluded the superiority of short-term analgesic effects over various controls and suggested that acupuncture may be efficacious for CMP. These reported benefits should be verified in more high-quality randomized controlled trials.
32922758 Promising targets and drugs in rheumatoid arthritis: a module-based and cumulatively scori 2020 Aug AIMS: Rheumatoid arthritis (RA) is a systematic autoimmune disorder, characterized by synovial inflammation, bone and cartilage destruction, and disease involvement in multiple organs. Although numerous drugs are employed in RA treatment, some respond little and suffer from severe side effects. This study aimed to screen the candidate therapeutic targets and promising drugs in a novel method. METHODS: We developed a module-based and cumulatively scoring approach that is a deeper-layer application of weighted gene co-expression network (WGCNA) and connectivity map (CMap) based on the high-throughput datasets. RESULTS: Four noteworthy RA-related modules were identified, revealing the immune- and infection-related biological processes and pathways involved in RA. HLA-DMA, HLA-DMB, HLA-DPA1, HLA-DPB1, HLA-DQB1, HLA-DRA, HLA-DRB1, BLNK, BTK, CD3D, CD4, IL2RG, INPP5D, LCK, PTPRC, RAC2, SYK, and VAV1 were recognized as the key hub genes with high connectivity in gene regulation networks and gene pathway networks. Moreover, the long noncoding RNAs (lncRNAs) in the RA-related modules, such as FAM30A and NEAT1, were identified as the indispensable interactors with the hub genes. Finally, candidate drugs were screened by developing a cumulatively scoring approach based on the selected modules. Niclosamide and the other compounds of T-type calcium channel blocker, IKK inhibitor, and PKC activator, HIF activator, and proteasome inhibitor, which harbour the similar gene signature with niclosamide, were promising drugs with high specificity and broad coverage for the RA-related modules. CONCLUSION: This study provides not only the promising targets and drugs for RA but also a novel methodological insight into the target and drug screening.Cite this article: Bone Joint Res 2020;9(8):501-514.
32843922 Mesenchymal stem cells and mesenchymal stem cell-derived extracellular vesicles: Potential 2020 Jul 26 BACKGROUND: Mesenchymal stem cells (MSCs) have been widely investigated in rheumatic disease due to their immunomodulatory and regenerative properties. Recently, mounting studies have implicated the therapeutic potency of MSCs mostly due to the bioactive factors they produce. Extracellular vesicles (EVs) derived from MSCs have been identified as a promising cell-free therapy due to low immunogenicity. Rheumatic disease, primarily including rheumatoid arthritis and osteoarthritis, is a group of diseases in which immune dysregulation and chronic progressive inflammation lead to irreversible joint damage. Targeting MSCs and MSC-derived EVs may be a more effective and promising therapeutic strategy for rheumatic diseases. AIM: To evaluate the potential therapeutic effectiveness of MSCs and EVs generated from MSCs in rheumatic diseases. METHODS: PubMed was searched for the relevant literature using corresponding search terms alone or in combination. Papers published in English language from January 1999 to February 2020 were considered. Preliminary screening of papers concerning analysis of "immunomodulatory function" or "regenerative function" by scrutinizing the titles and abstracts of the literature, excluded the papers not related to the subject of the article. Some other related studies were obtained by manually retrieving the reference lists of papers that comply with the selection criteria, and these studies were screened to meet the final selection and exclusion criteria. RESULTS: Eighty-six papers were ultimately selected for analysis. After analysis of the literature, it was found that both MSCs and EVs generated from MSCs have great potential in multiple rheumatic diseases, such as rheumatoid arthritis and osteoarthritis, in repair and regeneration of tissues, inhibition of inflammatory response, and regulation of body immunity via promoting chondrogenesis, regulating innate and adaptive immune cells, and regulating the secretion of inflammatory factors. But EVs from MSCs exhibit much more advantages over MSCs, which may represent another promising cell-free restorative strategy. Targeting MSCs and MSC-derived EVs may be a more efficient treatment for patients with rheumatic diseases. CONCLUSION: The enormous potential of MSCs and EVs from MSCs in immunomodulation and tissue regeneration offers a new idea for the treatment of rheumatism. However, more in-depth exploration is needed before their clinical application.
32303994 Golimumab as the First-, Second-, or at Least Third-Line Biologic Agent in Patients with R 2020 Jun INTRODUCTION: While golimumab (GLM) has demonstrated efficacy in rheumatoid arthritis (RA), psoriatic arthritis (PsA), and ankylosing spondylitis (AS) in several randomized clinical trials with biologic-naïve patients, observational data from biologic-experienced patients are sparse. We aimed to assess the effectiveness of GLM used as the first-, second-, or at least third-line biologic agent in RA, PsA, and AS patients in a real-world setting. METHODS: Post hoc analysis of the noninterventional, prospective, 24-month GO-NICE study of RA, PsA, and AS patients who initiated GLM 50 mg subcutaneously once monthly in a real-world setting in Germany. RESULTS: In 1454 patients with RA, PsA, or AS, GLM was administered as the first-line (n = 305, 286, 292, respectively), second-line (n = 104, 136, 130, respectively), or at least third-line (n = 64, 79, 58, respectively) biologic agent. In RA patients (n = 473), the time since first diagnosis was 9.7, 10.1, and 14.3 years, respectively. The DAS28 score at BL was 5.0, 4.9, and 5.1 in patients using GLM as a first-, second-, and third-line biologic agent, respectively, and dropped significantly in all groups. After 3 months of treatment, 27.5%, 19.5%, and 14.5% of patients were in remission; the corresponding values after 24 months were 45.3%, 50.0%, and 33.3%, respectively. In PsA patients (n = 501), time since fist diagnosis was 12.4, 13.7, and 13.8 years, respectively. Based on PsARC, a response was achieved at 24 months in the first-, second-, and third-line use of GLM in 76.4%, 51.0%, and 50.0% of the patients. In AS patients (n = 480), the time since first diagnosis was 9.4, 9.8, and 12.4 years in patients using GLM as the first-, second-, and at least third-line biologic agent, respectively. After 24 months of treatment, the mean BASDAI scores decreased significantly (p < 0.001 vs. BL) to 2.1, 2.9, and 2.9 in the patients using GLM as the first-, second-, and at least third-line treatment, respectively. CONCLUSIONS: Golimumab is an effective treatment in patients with RA, PsA, and AS, irrespective of any pretreatment with biologic agents. STUDY REGISTRATION: ClinicalTrials.gov NCT01313858.
31385361 Protein kinase C-α upregulates sodium channel Nav1.9 in nociceptive dorsal root ganglion 2020 Jan Previous studies have found that increased expression of Nav1.9 and protein kinase C (PKC) contributes to pain hypersensitivity in a couple of inflammatory pain models. Here we want to observe if PKC can regulate the expression of Nav1.9 in dorsal root ganglion (DRG) in rheumatoid arthritis (RA) pain model. A chronic knee joint inflammation model was produced by intra-articular injection of the complete Freund's adjuvant (CFA) in rats. Nociceptive behaviors including mechanical, cold, and heat hyperalgesia were examined. The expression of Nav1.9 and PKCα in DRG was detected by a quantitative polymerase chain reaction, Western blot, and immunofluorescence. The in vitro and in vivo effects of a PKC activator (phorbol 12-myristate 13-acetate [PMA]) and a PKC inhibitor (GF-109203X) on the expression of Nav1.9 were examined. Moreover, the effects of PKC modulators on nociceptive behaviors were studied. Increased mechanical, heat, and cold sensitivity was observed 3 to 14 days after CFA injection. Parallel increases in messenger RNA and protein expression of Nav1.9 and PKCα were found. Immunofluorescence experiments found that Nav1.9 was preferentially colocalized with IB4+DRG neurons in RA rats. In cultured DRG neurons, PMA increased Nav1.9 expression while GF-109203X prevented the effect of PMA. PMA increased Nav1.9 expression in naïve rats while GF-109203X decreased Nav1.9 expression in RA rats. In naïve rats, PMA caused mechanical and cold hyperalgesia. On the other hand, GF-109203X attenuated mechanical and cold hyperalgesia in RA-pain model. Nav1.9 might be upregulated by PKCα in DRG, which contributes to pain hypersensitivity in CFA-induced chronic knee joint inflammation model of RA pain.
33015082 Celastrol Efficacy by Oral Administration in the Adjuvant-Induced Arthritis Model. 2020 Background: We previously demonstrated that celastrol has significant anti-inflammatory and bone protective effects when administered via the intraperitoneal route. For further preclinical evaluation, an effective oral administration of celastrol is crucial. Here we aimed to study the therapeutic dose range for its oral administration. Methods: Celastrol (1-25 μg/g/day, N = 5/group) was administrated orally to female adjuvant-induced arthritis (AIA) rats after 8 days of disease induction for a period of 14 days. A group of healthy (N = 8) and arthritic (N = 15) gender- and age-matched Wistar rats was used as controls. During the treatment period, the inflammatory score, ankle perimeter, and body weight were measured. At the end of the treatment, the animals were sacrificed, blood was collected for clinical pathology, necropsy was performed with collection of internal organs for histopathological analysis, and paw samples were used for disease scoring. Results: Doses higher than 2.5 μg/g/day of celastrol reduced the inflammatory score and ankle swelling, preserved joint structure, halted bone destruction, and diminished the number of synovial CD68+ macrophages. Bone resorption and turnover were also reduced at 5 and 7.5 μg/g/day doses. However, the dose of 7.5 μg/g/day was associated with thymic and liver lesions, and higher doses showed severe toxicity. Conclusion: Oral administration of celastrol above 2.5 μg/g/day ameliorates arthritis. This data supports and gives relevant information for the development of a preclinical test of celastrol in the setting of a chronic model of arthritis since rheumatoid arthritis is a long-term disease.
33226566 A Review of the Prevalence and Unmet Needs in the Management of Rheumatoid Arthritis in Af 2021 Mar Estimates of the global prevalence of rheumatoid arthritis (RA) range from 0.24 to 1%, but vary considerably around the globe. A variation in RA prevalence is also expected across Africa and the Middle East, due to ethnic, climate, and socioeconomic differences. To assess the prevalence of RA in Africa and the Middle East, we searched Medline (via PubMed) and databases of major rheumatology conferences. Seventeen journal articles and 0 abstracts met the inclusion criteria. Estimated prevalence ranged from 0.06 to 3.4%. Most studies reported values near or below 0.25%. Consistent with data from other regions, RA was more prevalent among urban than rural populations, and among women than men. The women:men prevalence ratio ranged from 1.3:1 to 12.5:1, which suggests notable differences from the global average of 2:1. Relative increases in prevalence were observed in North Africa and the Middle East (13% since 1990) and Western Sub-Saharan Africa (14%), whereas rates in Eastern, Central, and Southern Sub-Saharan Africa show decreases (4-12%). Low disease awareness, delays to visit rheumatologists, and socioeconomic factors appear to hinder early diagnosis and aggressive treatment. Few countries have developed RA-specific treatment guidelines, and many physicians and patients face limited access to even basic treatments. An improved understanding of the epidemiology and management of RA, and the related socioeconomic consequences is necessary, so that targeted attempts can be made to encourage early diagnosis and treatment.