Advances in Rheumatology最新文献

Background: Endoplasmic reticulum stress (ERS) and the unfolded protein response (UPR) are adaptive mechanisms for conditions of high protein demand, marked by an accumulation of misfolded proteins in the endoplasmic reticulum (ER). Rheumatic autoimmune diseases (RAD) are known to be associated with chronic inflammation and an ERS state. However, the activation of UPR signaling pathways is not completely understood in Sjögren's disease (SD). This study evaluated the expression of ERS-related genes in glandular tissue of patients with primary SD (pSD), associated SD (aSD) with other autoimmune diseases, and non-Sjögren sicca syndrome (NSS).

Methods: In a cross-sectional study, minor salivary gland biopsies were obtained from 44 patients with suspected SD and 13 healthy controls (HC). Patients were classified as pSD, aSD, or NSS based on clinical, serological, and histological assessment. Histopathological analysis and mRNA expression analysis of genes associated with ERS and UPR (PERK, XBP1, ATF-6, ATF-4, CANX, CALR, CHOP, and BIP) were performed on the samples. Differences between groups (pSD, aSD, NSS, and HC) were assessed. The influence of chloroquine (CQ) on the ER was also investigated.

Results: Twenty-eight SD patients showed increased expression of PERK (p = 0.0117) and XBP1 (p = 0.0346), and reduced expression of ATF-6 (p = 0.0003) and CHOP (p = 0.0003), compared to the HC group. Increased expression of BIP (p < 0.0001), PERK (p = 0.0003), CALR (p < 0.0001), and CANX (p = 0.0111) was also observed in the SD group compared to the NSS group (n = 16). Patients receiving CQ (n = 16) showed a significant increase in ATF-6 (p = 0.0317) compared to patients not taking the medication (n = 29).

Conclusions: Altogether, the results suggest a greater activation of the ERS and UPR genes in patients with SD, especially in the pSD group. Antimalarial drugs, like CQ, used to treat RAD, may affect the ER function in exocrine glands.

Introduction: Transition clinics are conceived as programs dedicated to the active, multidimensional development of a process that addresses the medical, psychosocial, educational, and vocational needs of pediatric patients suffering from a chronic disease that will persist into adulthood. Their understanding is justified in physiological, psychological, and sociocultural terms on the basis of the differential morbidity and mortality associated with a chronic disease that begins in childhood and prevails into adulthood.

Materials and methods: Here, we reflect on the history, structure, and impact of transition clinics in pediatrics, with an emphasis on pediatric rheumatologic diseases. Additionally, we propose comprehensive reflection as an alternative for the patient, their family, and the medical team, outlining guidelines for development, implementation, and evaluation.

Results: The transition of care should commence in early adolescence, considering each patient's cognitive ability as a condition for the initiation of an educational process involving introspection into the disease. Interdisciplinarity is defined as a team that addresses the clinical, physical, emotional, and social dimensions of each patient and their interaction with the environment within the framework of individualized care and family support. Despite this, the lack of evidence supporting standardized guidelines for the implementation and overall effectiveness evaluation of these interventions was highlighted.

Conclusions: The transition process is considered successful when the patient is adherent and has a positive and informed perception of their health‒disease journey. We urge the generation of evidence documenting the comprehensiveness of processes inherent to transition clinics as the foundation of necessity.

Background: Osteoarthritis (OA) is a common degenerative joint disease. Circular RNA Phosphodiesterase 1 C (circ-PDE1C, hsa_circ_0134111) has participated in the IL-1β-induced chondrocyte damages. The objective of our study was to explore the molecular mechanism of circ-PDE1C.

Methods: Circ-PDE1C, microRNA-766-3p (miR-766-3p) or Small Glutamine Rich Tetratricopeptide Repeat Co-Chaperone Beta (SGTB) expression was determined using reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Cell counting kit-8 (CCK-8) assay and flow cytometry were used to analyze proliferation and apoptosis, respectively. Western blotting assay was performed for protein detection. The inflammatory cytokines were measured by Enzyme-linked immunosorbent assay (ELISA). Oxidative stress was assessed by commercial kits. Target analysis was conducted by dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assay.

Results: Circ-PDE1C was abnormally overexpressed in OA tissues and IL-1β-exposed chondrocytes. Downregulation of circ-PDE1C alleviated the IL-1β-induced cell apoptosis, inflammation, extracellular matrix degradation and oxidative stress. Circ-PDE1C could interact with miR-766-3p to serve as miRNA sponge. The function of si-circ-PDE1C was attributed to the inhibition of miR-766-3p. Additionally, miR-766-3p directly targeted the 3'UTR of SGTB. The miR-766-3p upregulation impeded the IL-1β-triggered cell damages through reducing the level of SGTB. Moreover, SGTB expression was regulated by circ-PDE1C via binding to miR-766-3p in IL-1β-induced chondrocytes.

Conclusion: Altogether, circ-PDE1C enhanced the IL-1β-induced dysfunction in chondrocytes via upregulating SGTB by targeting miR-766-3p.

Background: As a master immune system regulator, transforming growth factor β1 (TGF-β1) is closely linked to the complicated pathophysiology and development of systemic sclerosis (SSc), a multisystem fibrotic disease.

Objective: We aim to evaluate the transcriptional levels of TGF-β1 mRNA in PBMCs, assess the TGF-β1 serum levels of SSc patients, and compare them with those of healthy subjects.

Methods: PBMCs were isolated from whole blood of 50 SSc patients and in 30 healthy controls. After total RNA was extracted from isolated PBMCs, complementary DNA (cDNA) synthesis was performed. Afterward, the expression of TGF-β1 mRNA was assessed using quantitative real-time PCR using the SYBR Green, GAPDH, and TGF-β1 specific primers. The serum levels of TGF-β1 were determined using a commercially available ELISA kit.

Results: There was a significant upregulation of TGF-β1 relative expression (p < 0.0001), when SSc patients were compared to the control group. The diffuse subgroup was more common in patients with elevated TGF-β1 mRNA expression (p < 0.0001). However, an insignificant difference was observed between the disease subsets of SSc. Serum TGF- β1 levels were upregulated in SSc patients (78.35 ± 23.16) compared to healthy subjects (61.06 ± 15.90), and were considerably higher in SSc patients with ILD (p < 0.01) and positive anti-topo-Isomerase antibody (p < 0.0001).

Conclusion: In patients with SSc, elevated levels of TGF-β1 in serum and their correlation with clinical symptoms imply that this cytokine may serve as a marker for fibrotic and vascular involvement in SSc.

Objectives: Describe tofacitinib safety from an integrated analysis of randomized controlled trials (RCTs) in patients with ankylosing spondylitis (AS).

Method: Pooled data from Phase 2 (NCT01786668; 04/2013-03/2015)/Phase 3 (NCT03502616; 06/2018-08/2020) RCTs in AS patients were analyzed (3 overlapping cohorts): 16-week placebo-controlled (tofacitinib 5 mg twice daily [BID] [n = 185]; placebo [n = 187]); 48-week only-tofacitinib 5 mg BID (n = 316); 48-week all-tofacitinib (≥ 1 dose of tofacitinib 2, 5, or 10 mg BID; n = 420). Baseline 10-year atherosclerotic cardiovascular disease (ASCVD) risk was determined in patients without history of ASCVD (48-week cohorts). Adverse events (AEs)/AEs of special interest were evaluated/compared with findings from other tofacitinib programs (16 Phase 2/Phase 3 rheumatoid arthritis [RA]; 2 Phase 3 psoriatic arthritis [PsA] RCTs) and a real-world cohort of AS patients initiating biologic disease-modifying antirheumatic drugs (US MarketScan).

Results: Most patients (> 75%; 48-week cohorts) without history of ASCVD had low baseline 10-year ASCVD risk. One patient (tofacitinib 5 mg BID; in all 3 cohorts) had a serious infection (aseptic meningitis). Herpes zoster (non-serious) occurred in the 48-week only-tofacitinib 5 mg BID (n = 5 [1.6%]) and all-tofacitinib (n = 7 [1.7%]; one multi-dermatomal [tofacitinib 10 mg BID]) cohorts. No deaths, opportunistic infections, tuberculosis, malignancies, major adverse cardiovascular events, thromboembolic events, gastrointestinal perforations occurred.

Limitations: short RCT durations/low patient numbers within cohorts.

Conclusion: Tofacitinib 5 mg BID was well tolerated to 48 weeks in AS patients; safety profile was consistent with RA/PsA clinical programs and a cohort of AS patients from US routine clinical practice.

Clinical trial registration numbers: NCT01786668 (2013-02-06); NCT03502616 (2018-04-11).

Introduction: The prevalence of Fibromyalgia in patients with Systemic Lupus Erythematosus (SLE) is significantly higher compared to the general population. Despite this frequent association, Fibromyalgia remains underdiagnosed and consequently inadequately treated, negatively affecting the quality of life of these patients.

Objective: This study aims to evaluate the occurrence of Fibromyalgia and its impact on the quality of life of Brazilian patients with SLE treated at a University Hospital in the state of Paraiba.

Materials and methods: This descriptive, observational, and cross-sectional study included patients with SLE diagnosed according to the 2012 criteria of the Systemic Lupus Erythematosus International Collaborating Clinics (SLICC). The occurrence of Fibromyalgia was assessed using the American College of Rheumatology (ACR) criteria of 1990 and 2010/2011, revised in 2016. Quality of life was evaluated using the Short-Form 36 (SF-36) questionnaire for all patients, while the Fibromyalgia Impact Questionnaire (FIQ) was applied to those diagnosed with Fibromyalgia.

Results: The sample comprised 107 SLE patients, with an average age of 54.1 years (SD:12.1), of whom 95.4% (102) were women. The prevalence of Fibromyalgia among SLE patients was 19.1% (21), all of whom were women with a mean age of 45.6 years (SD 9.6). The SF-36 scores of SLE patients with Fibromyalgia were consistently lower across all eight domains compared to those without Fibromyalgia, indicating a significant negative impact of this comorbidity.

Conclusion: These findings are consistent with existing literature, highlighting the significant negative impact of Fibromyalgia on the quality of life of patients with SLE.

Conclusion: These findings are consistent with existing literature, highlighting the significant negative impact of Fibromyalgia on the quality of life of patients with SLE.

We investigated role of haematopoietic cell kinase (Hck) in osteoarthritis (OA) and to explore the underlying mechanisms driving its effects. An OA animal model was established and after OA induction, rats received intra-articular injections of lentivirus twice a week for four weeks. Rats were divided into four groups: control (healthy rats without OA), OA model (rats with induced OA), OA + Len-si-NC (OA rats treated with a non-targeting control lentivirus), and OA + Len-si-Hck (OA rats treated with lentivirus targeting Hck). Blood samples were collected, and serum cytokine levels were measured using ELISA. Afterward, the rats were sacrificed for histological analysis and TUNEL assay. In vitro, IL-1β-treated human chondrocytes were transfected with Hck, and the effects on cell viability, apoptosis, ECM degradation, and JAK-STAT3 signaling were assessed. Colivelin, a JAK-STAT3 agonist, was used to confirm the pathway's involvement. Results indicated increased Hck expression in the cartilage tissues of OA rats and in IL-1β-stimulated chondrocytes. Silencing Hck in vivo reduced IL-6 and TNF-α levels, apoptosis, and preserved cartilage structure. In vitro, Hck knockdown in IL-1β-treated chondrocytes resulted in enhanced cell viability, reduced apoptosis, and decreased ECM degradation. Notably, the expression of MMP3 and MMP13 was significantly lowered, while collagen II and aggrecan levels were restored. Additionally, Hck knockdown inhibited JAK-STAT3 activation, which was evident from reduced levels of phosphorylated JAK1 and STAT3. The addition of colivelin reversed these effects, confirming that Hck mediates its effects through the JAK-STAT3 pathway. Overall, our findings indicate that Hck is critical in OA progression by promoting inflammation, apoptosis, and ECM degradation through the JAK-STAT3 signaling pathway activation.

Background: Despite previous studies indicating a close relationship between immune system and ankylosing spondylitis (AS), the causal relationship between them remains unclear.

Methods: Genome-wide association data were utilized to explore the causal link between 731 immune cells and AS using a bidirectional two-sample MR approach. The data included immune cell data from Orrù et al.'s study and AS data from the FinnGen consortium. Cochran's Q test and leave-one-out checked instrument variable (IV) heterogeneity. IVW was the primary method for causal analysis, with MR-Egger and MR-PRESSO addressing horizontal pleiotropy. FDR correction was applied to both analysis directions to rectify multiple testing errors.

Results: In our study, 22 immune phenotypes out of 731 were casually linked to AS. After excluding 5 less robust features, 17 immune factors remained, with 4 being protective and the rest posing risks. Through FDR correction, we found a significant causal relationship between HLA DR on CD14- CD16+ monocyte and AS (OR (95%CI) = 0.70(0.60 ~ 0.83), P = 2.06*10^-5). In the reverse analysis with AS as exposure, potential effects on 34 immune features were discovered. After correction, we confirmed significant causal relationships between AS and two immune features, namely CD20- B cell %lymphocyte (OR (95%CI) = 1.16(1.08-1.25), P = 1.91*10^-5) and CD20- B cell %B cell (OR (95%CI) = 1.17(1.09-1.26), P = 1.50*10^-5).

Conclusions: Our study identified various features associated with AS in different types of immune cells. These findings provide important clues and a theoretical basis for further understanding the pathogenesis of AS, guiding clinical treatment, and drug design.