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Tripterine (Trip) is frequently applied to alleviate inflammation in various diseases such as rheumatoid arthritis. Macrophages have both anti-inflammatory and pro-inflammatory functions. However, whether Trip can inhibit cell inflammation in gouty arthritis (GA) remains undiscovered and whether the mechanism involved in macrophage polarization is also undetermined. This paper aims to study the effects of Trip on inflammation and macrophage polarization in GA. Monosodium urate (MSU) crystals were used to establish GA mouse models, and bone marrow-derived macrophages (BMDMs) were induced to construct GA cell models. Pretreatments of Trip and injection of Antagomir-449a/Agomir-449a were performed on mice for 6 days. The effects of Trip and miR-449 on toe swelling, joint damage of GA mouse were examined. The alternations on cell morphology, cell proliferation marker Ki67, inflammatory cytokines, NLRP3 inflammasome, and NF-κB signaling-related proteins were also determined both in vivo and in vitro. Dual-luciferase reporter gene assay and RIP assay were adopted to estimate the targeting relationship between miR-449a and NLRP3. GA mouse model had increased M1 macrophage, intensified inflammation response, along with suppressed miR-449a expression. Following administration of Trip attenuated cell inflammation, promoted macrophage polarize to M2 phenotype, elevated miR-449a expression, repressed the phosphorylation levels of NF-κB signaling-related proteins, and diminished IκBα expression in vivo and in vitro. However, inhibition of miR-449a hindered the favorable effect of Trip on GA and increased NLRP3 inflammasome expression. MiR-449a directly targeted NLRP3. Overexpression of NLRP3 partially eliminated the biological effects of miR-449a agonist. Trip regulates macrophage polarization through miR-449a/NLRP3 axis and the STAT3/NF-κB pathway to mitigate GA. The elucidation on the molecular mechanism of Trip in GA may provide theoretical guidance for clinical therapy of GA.

Background Anticitrullinated peptide antibodies (ACPA) and acute phase reactants may be increased before arthritis becomes clinically detectable, suggesting that the processes underlying rheumatoid arthritis (RA) start preclinically. Whether local inflammation occurs in the preclinical phase is unknown. Therefore, we studied the small joints of ACPA positive arthralgia patients for local subclinical inflammation. Methods Imaging was performed using 1.5 T extremity MRI. Painful hand or foot joints of 21 ACPA positive arthralgia patients without clinical arthritis were imaged. For comparison, hand and foot joints of 22 ACPA positive RA patients and 19 symptom free controls were studied. Within ACPA positive arthralgia patients, painful and symptom free joint regions were imaged. Scoring was performed according to the Outcome Measures in Rheumatology Clinical Trials (OMERACT) Rheumatoid Arthritis Magnetic Resonance Imaging Scoring (RAMRIS) method. Analyses were performed on joint region level and focused on inflammation (synovitis plus bone marrow oedema). Results The mean combined inflammation scores of the metacarpophalangeal/proximal interphalangeal joints of controls, painful joints of ACPA positive arthralgia patients and ACPA positive RA patients were 0.1, 0.7 and 3.7, respectively (p<0.001). Likewise, the mean combined inflammation scores of the wrist were 0.9, 2.3 and 10.3, respectively (p<0.001) and that of the metatarsophalangeal joints 0.5, 0.9 and 3.8, respectively (p=0.10). At the MCP joints, the combined inflammation score was significantly correlated with C reactive protein and erythrocyte sedimentation rate levels (rs=0.83 and rs=0.78, respectively) Conclusions The present data suggest that local subclinical inflammation occurs in ACPA positive arthralgia patients.

We report a case of gangrene and osteomyelitis of the toe in a young, previously healthy male with undiagnosed essential thrombocythemia (ET). The patient experienced persistent right fifth toe pain, discolouration and ulceration for 3–4 months, unresponsive to antibiotics. Despite multiple normal X-rays, 2 months later, MRI revealed osteomyelitis. On inpatient admission, testing revealed thrombocytosis and abnormal blood flow to right fourth and fifth toes without thrombus, consistent with vasospasm. This ultimately resulted in ischemia, gangrene and osteomyelitis of the toe, necessitating amputation. The patient was subsequently treated with hydroxyurea for ET. This unusual presentation underscores the importance of a broad differential in cases when conventional treatments fail to yield improvement.

Non-operative management of trapeziometacarpal osteoarthritis (TMOA) demonstrates only short-term symptomatic alleviation, and no approved disease modifying drugs exist to treat this condition. A key issue in these patients is that radiographic disease severity can be discordant with patient reported pain, illustrating the need to identify molecular mediators of disease. This study characterizes the biochemical profile of TMOA patients to elucidate molecular mechanisms driving TMOA progression. Plasma from patients with symptomatic TMOA undergoing surgical (n=39) or non-surgical management (n=44) with 1-year post-surgical follow-up were compared using a targeted panel of 27 cytokines. Radiographic (Eaton-Littler), anthropometric, longitudinal pain (VAS, TASD, quick DASH) and functional (key pinch, grip strength) data were used to evaluate relationships between structure, pain, and systemic cytokine expression. Principal Component Analysis was used to identify clusters of patients. Patients undergoing surgery had greater BMI as well as higher baseline quick DASH, TASD scores. Systemically, these patients could only be distinguished by differing levels of Interleukin-7 (IL-7), with an adjusted odds ratio of 0.22 for surgery for those with increased levels of this cytokine. Interestingly, PCA analysis of all patients (regardless of surgical status) identified a subset of patients with an \"inflammatory\" phenotype, as defined by a unique molecular signature consisting of thirteen cytokines. Overall, this study demonstrated that circulating cytokines are capable of distinguishing TMOA disease severity, and identified IL-7 as a target capable of differentiating disease severity with higher levels associated with a decreased likelihood of TMOA needing surgical intervention. It also identified a cluster of patients who segregate based on a molecular signature of select cytokines.

Background. Given that clinical evaluation may underestimate the joint damage and that early treatment can slow down psoriatic arthritis (PsA) progression, screening psoriasis patients with imaging tools that can depict early PsA changes would entail clear benefits. Objective. To compare the ability of X-ray and ultrasound (US) examination in detecting morphological abnormalities consistent with early PsA in patients with psoriasis, using rheumatological evaluation as the gold standard for diagnosis. Methods. Patients with chronic plaque psoriasis and no previous PsA diagnosis attending our outpatient dermatology clinic and reporting finger/toe joint and/or tendon pain underwent X-ray and US evaluation; they were subsequently referred to a rheumatologist for clinical examination and review of imaging findings. Results. Abnormal US and/or X-ray findings involving at least one finger and/or toe (joints and/or tendons) were seen in 36/52 patients: 11 had one or more X-ray abnormalities, including erosion, joint space narrowing, new bone formation, periarticular soft tissue swelling, and periarticular osteoporosis; 36 had suspicious changes on US. Conclusion. US proved valuable in detecting joint and/or tendon abnormalities in the fingers and toes of patients with suspicious changes. The dermatologist should consider US to obtain an accurate assessment of suspicious findings.

Background:HLA-DRB1 shared epitope (HLA-SE), PTPN22 and CTLA4 alleles are associated with cyclic citrullinated peptide (CCP) and rheumatoid arthritis (RA).Objective:We examined associations between HLA-SE, PTPN22, CTLA4 genotypes and RA phenotypes in a large cohort to (a) replicate prior associations with CCP status, and (b) determine associations with radiographic erosions and age of diagnosis.Methods:A total of 689 RA patients from the Brigham RA Sequential Study (BRASS) were genotyped for HLA-SE, PTPN22 (rs2476601) and CTLA4 (rs3087243). Association between genotypes and CCP, rheumatoid factor (RF) erosive phenotypes and age at diagnosis were assessed with multivariable models adjusting for age, sex and disease duration. Novel causal pathway analysis was used to test the hypothesis that genetic risk factors and CCP are in the causal pathway for predicting erosions.Results:In multivariable analysis, presence of any HLA-SE was strongly associated with CCP+ (odds ratio (OR) 3.05, 95% CI 2.18–4.25), and RF+ (OR 2.53, 95% CI 1.83–3.5) phenotypes; presence of any PTPN22 T allele was associated with CCP+ (OR 1.81, 95% CI 1.24–2.66) and RF+ phenotypes (OR 1.84, 95% CI 1.27–2.66). CTLA4 was not associated with CCP or RF phenotypes. While HLA-SE was associated with erosive RA phenotype (OR 1.52, 95% CI 1.01–2.17), this was no longer significant after conditioning on CCP. PTPN22 and CTLA4 were not associated with erosive phenotype. Presence of any HLA-SE was associated with an average 3.6 years earlier diagnosis compared with absence of HLA-SE (41.3 vs 44.9 years, p = 0.002) and PTPN22 was associated with a 4.2 years earlier age of diagnosis (39.5 vs 43.6 years, p = 0.002). CTLA4 genotypes were not associated with age at diagnosis of RA.Conclusions:In this large clinical cohort, we replicated the association between HLA-SE and PTPN22, but not CTLA4 with CCP+ and RF+ phenotypes. We also found evidence for associations between HLA-SE, and PTPN22 and earlier age at diagnosis. Since HLA-SE is associated with erosive phenotype in unconditional analysis, but is not significant after conditioning on CCP, this suggests that CCP is in the causal pathway for predicting erosive phenotype.