Purpose of Review
Osteoarthritis (OA) and rheumatoid arthritis (RA) are characterized by abnormal lipid metabolism manifested as altered fatty acid (FA) profiles of synovial fluid and tissues and in ...the way dietary FA supplements can influence the symptoms of especially RA. In addition to classic eicosanoids, the potential roles of polyunsaturated FA (PUFA)-derived specialized pro-resolving lipid mediators (SPM) have become the focus of intensive research. Here, we summarize the current state of knowledge of the roles of FA and oxylipins in the degradation or protection of synovial joints.
Recent Findings
There exists discordance between the large body of literature from cell culture and animal experiments on the adverse and beneficial effects of individual FA and the lack of effective treatments for joint destruction in OA and RA patients. Saturated 16:0 and 18:0 induce mostly deleterious effects, while long-chain n-3 PUFA, especially 20:5n-3, have positive influence on joint health. The situation can be more complex for n-6 PUFA, such as 18:2n-6, 20:4n-6, and its derivative prostaglandin E
2
, with a combination of potentially adverse and beneficial effects. SPM analogs have future potential as analgesics for arthritic pain.
Summary
Alterations in FA profiles and their potential implications in SPM production may affect joint lubrication, synovial inflammation, pannus formation, as well as cartilage and bone degradation and contribute to the pathogeneses of inflammatory joint diseases. Further research directions include high-quality randomized controlled trials on dietary FA supplements and investigations on the significance of lipid composition of microvesicle membrane and cargo in joint diseases.
Increasing evidence shows that adipokines play a vital role in the development of rheumatoid arthritis (RA). Fatty acid-binding protein 4 (FABP4), a novel adipokine that regulates inflammation and ...angiogenesis, has been extensively studied in a variety of organs and diseases. However, the effect of FABP4 on RA remains unclear. Here, we found that FABP4 expression was upregulated in synovial M1-polarized macrophages in RA. The increase in FABP4 promoted synovitis, angiogenesis, and cartilage degradation to exacerbate RA progression in vivo and in vitro, whereas BMS309403 (a FABP4 inhibitor) and anagliptin (dipeptidyl peptidase 4 inhibitor) inhibited FABP4 expression in serum and synovial M1-polarized macrophages in mice to alleviate RA progression. Further studies showed that constitutive activation of mammalian target of rapamycin complex 1 (mTORC1) by TSC1 deletion specifically in the myeloid lineage regulated FABP4 expression in macrophages to exacerbate RA progression in mice. In contrast, inhibition of mTORC1 by ras homolog enriched in brain (Rheb1) disruption specifically in the myeloid lineage reduced FABP4 expression in macrophages to attenuate RA development in mice. Our findings established an essential role of FABP4 that is secreted by M1-polarized macrophages in synovitis, angiogenesis, and cartilage degradation in RA. BMS309403 and anagliptin inhibited FABP4 expression in synovial M1-polarized macrophages to alleviate RA development. Hence, FABP4 may represent a potential target for RA therapy.
Purpose of Review
To review the burden of osteoporosis (OP) in rheumatoid arthritis (RA) and to describe the OP screening strategies applied in RA.
Recent Findings
RA is an inflammatory condition ...that predisposes patients to development of OP. OP in RA has a multifactorial pathogenesis with systemic inflammation and glucocorticoid use playing major roles. Newer studies have reported an intriguing association between RA autoantibodies and the development of OP. OP screening strategies in RA patients include clinical and vitamin D assessment, biochemical markers of bone remodeling, and bone imaging evaluations, particularly dual-energy X-ray absorptiometry (DXA).
Summary
Fragility fractures are an important comorbidity of RA. OP screening strategies are both feasible and effective in RA patients and recommended by most specialty organizations. Given the considerable exposure to factors related to OP development, such as pro-inflammatory cytokines and glucocorticoid treatment, special attention should be directed to biochemical and DXA results in RA patients.
Rituximab is a chimeric monoclonal anti-CD20 antibody that causes B-cell depletion in the peripheral B-cell pool and is used widely in several auto-immune diseases and B-cell malignancies. Patients ...with immuno- globulin deficiency are particularly at risk of contracting EV encephalitis and could have a lethal course.A 54-year-old lady with rheumatoid arthritis treated with four monthly Rituximab injections for the last three years was admitted with gradual onset of confusion, reduced mobility, and gastroenteritis. On admission, neurological examination showed disorientation with no focal neurological deficit. She had progressive neurological deterioration with delirium, agitation, and aphasia. MR Brain with contrast showed – hyper intense signals in pons possibility of infective rhombencephalitis.CSF examination showed – protein levels (0.52 g/dL), normal glucose, and positive Enterovirus RT-PCR. Immunoglobulin panel showed, severe hypogammaglobulinemia (Serum IgG- 3.12 g/dL (6-16) and Serum CD 19+ levels were – 0% (6-19% of lymphocyte) Subsequently, she developed decreased level of consciousness necessitating ITU admission, and received IV Immunoglobulins for five days. Her neuro- logical status improved along with improvement in serum IgG levels. Repeat CSF examination showed clearance of Enterovirus from CSF.Rituximab can cause profound, sometimes long-term, B-cell deficiency predisposing to severe EV Encepha- litis. Our case report reminds the need to have a high index of suspicion for CNS infections in such patients, and early detection and treatment with IVIg could dramatically improve patient outcomes.
Purpose of Review
Over the last few years, the scientific community has made significant progress in understanding the etiology of rheumatoid arthritis (RA). In this review, we summarize those key ...findings and trends.
Recent Findings
New data strongly implicates respiratory exposures, obesity, diet and microbiome, genetics, and their interactions in the etiology of RA. Furthermore, anti-posttranslationally modified protein antibodies (AMPAs) and abnormal glycosylation may be additional biomarkers for RA. Finally, functional genomics techniques implicate loss of certain macrophage populations and proliferation of synovial fibroblasts in RA.
Summary
These findings support the notion that RA originates at mucosal sites, augmented by genetic predisposition, and mediated by certain cell types including macrophages and fibroblasts. Weight loss, physical activity, and diet are additional modifiable factors beyond smoking cessation that can reduce risk of RA. Future epidemiologic and translational studies leveraging multi-omics approaches will help map the precise sequence of events in RA pathogenesis.
Ferroptosis is a type of programmed cell death driven by iron-dependent lipid peroxidation. The TNF-mediated biosynthesis of glutathione has been shown to protect synovial fibroblasts from ...ferroptosis in the hyperplastic synovium. Ferroptosis induction provides a novel therapeutic approach for rheumatoid arthritis (RA) by reducing the population of synovial fibroblasts. The beginning and maintenance of synovitis in RA are significantly influenced by macrophages, as they generate cytokines that promote inflammation and contribute to the destruction of cartilage and bone. However, the vulnerability of macrophages to ferroptosis in RA remains unclear. In this study, we found that M2 macrophages are more vulnerable to ferroptosis than M1 macrophages in the environment of the arthritis synovium with a high level of iron, leading to an imbalance in the M1/M2 ratio. During ferroptosis, HMGB1 released by M2 macrophages interacts with TLR4 on M1 macrophages, which in turn triggers the activation of STAT3 signaling in M1 macrophages and contributes to the inflammatory response. Neutralization of HMGB1 or blockade of TLR4 decreased the level of cytokines produced by M1 macrophages. The ferroptosis inhibitor liproxstatin-1 (Lip-1) started at the presymptomatic stage in collagen-induced arthritis (CIA) model mice, and GPX4 overexpression in M2 macrophages at the onset of collagen antibody-induced arthritis (CAIA) protected M2 macrophages from ferroptotic cell death and significantly prevented the development of joint inflammation and destruction. Thus, our study demonstrated that M2 macrophages are vulnerable to ferroptosis in the microenvironment of the hyperplastic synovium and revealed that the HMGB1/TLR4/STAT3 axis is critical for the ability of ferroptotic M2 macrophages to contribute to the exacerbation of synovial inflammation in RA. Our findings provide novel insight into the progression and treatment of RA.
M2 macrophages are more vulnerable to ferroptosis than M1 macrophages in the environment of the arthritis synovium. Ferroptotic M2 macrophages release DAMPs molecule HMGB1, which interacts with TLR4 on M1 macrophages. This interaction triggers the activation of STAT3 signaling in M1 macrophages and contributes to the exacerbation of synovial inflammation. Display omitted
BackgroundJAK inhibitor (JAKi) and TNF inhibitor (TNFi) are the important therapeutic agent for the treatment of rheumatoid arthritis (RA). However there is still few studies of improvement of ...ultrasonographic findings in RA treats comparison with JAKi and TNFi.ObjectivesTo evaluate the improvement of ultrasonographic findings in JAKi treated RA patients comparison with TNFi.MethodsParticipants comprised 40 and 43 Japanese RA patients who had recently received each JAKi (BAR26, PEF9, UPA5) and TNFi (CZP30, ADA5, ETN4, GLM4). All patients with a diagnosis of RA according to the 2010 ACR/EULAR criteria. Patients underwent clinical and laboratory assessments every 4 weeks from baseline to 24 weeks, and US assessments at baseline, 4, 12 and 24 weeks. Gray scale (GS) and power doppler (PD) signals were scored using a semi-quantitative scale from 0 to 3 at 26 (0-78) synovial sites (22 joints) in the following joints: bilateral first to fifth metacarpopharangeal (MCP) joints (dorsal recess); first interphalangeal (IP) and second to fifth proximal interphalangeal (PIP) (dorsal recess) joints; and the wrists (dorsal radial, median and ulnar). We evaluated the improvement of GS and PD score from baseline to week 24.ResultsIn the patients receiving JAKi (n=40) and TNFi (n=43), the mean age was 56.0 vs 54.0 years old (p=0.514), disease duration was 7.3 vs 5.9 years (p=0.343), the rate of MTX use was 70% vs 86% (p=0.076), the mean MTX dose was 10.0 vs 9.9 mg/w (p=0.888), the rate of ACPA positive was 90% vs 79% (p=0.171), the rate of b/ts DMARDs naïve patients was 65% vs 91% (p=0.005), DAS28-ESR was 5.03 vs 4.69 (p=0.102), CDAI was 24.5 vs 19.2 (p=0.038), GS score was 22.1 vs 18.3 (p=0.535) and PD score was 15.1 vs 11.1 (p=0.625). The degree of improvement respective changes in GS and PD score from baseline to 4, 12 and 24 weeks were as follows: GS: -5.7 vs -4.7 (p=0.762) and PD: -6.6 vs -3.1 (p=0.489) after 4 weeks, GS: -9.3 vs -6.7 (p=0.975) and PD: -8.7 vs -4.6 (p=0.340) after 12 weeks, GS: -11.5 vs -9.7 (p=0.732) and PD: -9.5 vs -7.1 (p=0.802) after 24 weeks between JAKi and TNFi (Figure 1, 2). Next, The improvement rate of respective changes in GS and PD score after 4, 12 and 24 weeks were as follows: GS: -16.2% vs -20.7% (p=0.463) and PD: -29.7% vs -20.8% (p=0.414) after 4 weeks, GS: -30.2% vs -27.9% (p=0.884) and PD: -34.0% vs -33.0% (p=0.830) after 12 weeks, GS: -42.4% vs -39.4% (p=0.712) and PD: -41.6% vs -54.0% (p=0.865) after 24 weeks between JAKi and TNFi. Next, we evaluated the improvement of ultrasonographic findings between b/ts DMARDs naïve and switch, with and without MTX in the JAKi-treated patients. The degree of improvement respective changes in GS and PD score from baseline to 24 weeks were as follows: GS: -13.8 vs -7.1 (p=0.313) and PD: -10.8 vs -6.9 (p=0.334) between b/ts DMARDs naïve and switch patients, GS: -11.7 vs -11.0 (p=0.988) and PD: -9.2 vs -10.0 (p=0.658) between with and without MTX patients.ConclusionThe present study provides evidence supporting the improvement in ultrasonographic findings in RA was similar for both JAKi and TNFi. Also In the JAKi-treated patients, similar improvement in ultrasonographic findings was observed regardless of whether the patients were naive or switch, with and without MTX.REFERENCES:NIL.Acknowledgements:NIL.Disclosure of InterestsYasuhide Kanayama Speakers bureau: YK has received speakers’ fees from AbbVie, Astellas, Asahi Kasei, Daiichi-Sankyo, Eisai, Eli Lilly, Ono and UCB Japan., Atsushi Nagata: None declared, Miyuki Shimotake: None declared, Fumiko Miyachi: None declared, Keisuke Fujita: None declared, Mai Koyama: None declared, Shiho Uno: None declared, Kyosuke Hattori: None declared.
We developed a semiconstrained total wrist prosthesis that was used in a series of patients with rheumatoid arthritis. We previously reported favorable clinical outcomes for up to 5 years after ...surgery; however, the longer-term outcomes remain unclear. The objective of this study was to evaluate the clinical outcomes of this wrist prosthesis for the treatment of severe wrist rheumatoid arthritis during a minimum 10 years of follow-up.
From 2010 through 2012, total wrist arthroplasty using the semiconstrained total wrist arthroplasty device was performed in 20 wrists in 20 patients with rheumatoid arthritis (five men and 15 women). The mean patient age was 64 years (range, 50–84 years). Preoperative radiographs showed Larsen grade IV changes in 16 wrists and grade V changes in four wrists. Patients were evaluated clinically and radiologically before surgery, 5 years after surgery, and 10 years or more after surgery. Evaluated parameters were the visual analog scale for pain, range of motion, Figgie score, and Disabilities of the Arm, Shoulder, and Hand score.
The minimum 10-year follow-up clinical results (mean, 11.3 years) were available for all 14 surviving patients (three men and 11 women). Significant improvements in the mean visual analog scale for pain, Figgie score, and Disabilities of the Arm, Shoulder, and Hand score, compared with those before surgery, were maintained from 5 years after surgery to the final follow-up. The mean wrist flexion angle tended to slightly decrease at 5 years after surgery compared with that before surgery but remained similar from 5 years after surgery to the final follow-up. The increase in the mean wrist extension angle, compared with that before surgery, was maintained from 5 years after surgery to the final follow-up. Radiographic evaluation had already revealed implant loosening in five of the 19 wrists at 5 years after surgery, but there were no new cases of component loosening identified at the final follow-up.
Total wrist arthroplasty using the semiconstrained arthroplasty system achieves favorable clinical outcomes with no serious complications requiring revision for 10 years after surgery.
Therapeutic IV.
This is a protocol for a Cochrane Review (intervention). The objectives are as follows:
The primary objective is to assess the benefits and harms of short‐term glucocorticoid therapy (six months or ...less) compared to placebo, for adults with rheumatoid arthritis who experience a disease flare while receiving standard disease‐modifying anti‐rheumatic drug (DMARD) therapy.
The secondary objective is to maintain the currency of the evidence, using a living systematic review approach.
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