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Abstract Background Intermittent fasting (IF) has shown benefits in various pathological conditions. Although its anti-inflammatory potential has been recognized, its effects on the mechanism underlying rheumatoid arthritis (RA) remain insufficiently characterized. This study aimed to investigate the effects of IF in a murine model of RA. Methods Collagen-induced arthritis (CIA) was developed in sixteen male DBA/1 mice, randomly assigned to two groups, with one undergoing IF every other day for four weeks. The effects of IF on joint inflammation and remodeling were evaluated clinically, histologically, and through tomography. Transcriptomic changes were characterized using expression microarrays, validated by RT-qPCR, and confirmed by immunohistochemistry. Additionally, modifications in gut microbiota were assessed through 16 S sequencing. Results Mice subjected to IF significantly reduced the incidence and severity of clinical arthritis. Histological and radiographic assessments confirmed a decrease in inflammation and joint damage. Transcriptomic analysis revealed that IF led to the upregulation of 364 genes and the downregulation of 543 genes, with notable reductions in inflammatory signaling pathways associated with RA-related genes, including Cd72, Cd79a, Ifna, Il33, and Bglap 2. Notably, IL33 emerged as a pivotal mediator in the inflammatory processes mitigated by fasting. Key regulators associated with IF effects, such as CEBPA, FOXO1, HIF1A, PPARG, and PPARA, were identified, indicating a complex interplay between metabolic and inflammatory pathways. Furthermore, differential expression of microRNAs and lncRNAs, including miR-15b, miR-103-2, miR-302a, miR-6985, and miR- 5624, was observed. Metagenomic analysis indicated that IF enhanced the abundance and diversity of the gut microbiome, explicitly promoting anti-inflammatory bacterial populations, notably within the genus Ruminococcaceae. Conclusion Our findings suggest that IF exerts significant anti-inflammatory and immunoregulatory effects in the context of CIA. Given its non-risky nature, further investigation into the potential benefits of IF in patients with RA is warranted. Clinical trial number Not applicable.

Chronic noncommunicable diseases (NCDs) are responsible for approximately 74% of deaths globally. Medicinal plants have traditionally been used to treat NCDs, including diabetes, cancer, and rheumatic diseases, and are a source of anti-inflammatory compounds. This study aimed to evaluate the anti-inflammatory effects of Rhus trilobata (Rt) extracts and fractions in lipopolysaccharide (LPS)-induced inflammation models in vitro and in vivo. The aqueous extract (RtAE) and five fractions (F2 to F6) were obtained via C18 solid-phase separation and tested in murine LPS-induced J774.1 macrophages. Key inflammatory markers, such as IL-1β, IL-6, TNF-α, and COX-2 gene expression were measured using RT-qPCR, and PGE2 production was assessed via HPLC-DAD. The in vivo effects were tested in an LPS-induced paw edema model in Wistar rats. Results showed that RtAE at 15 μg/mL significantly decreased IL-1β and IL-6 gene expression in vitro. Fraction F6 further reduced IL-1β, TNF-α, and IL-6 gene expression, COX-2 expression, and PGE2 production. In vivo, F6 significantly reduced LPS-induced paw edema, inflammatory infiltration, and IL-1β and COX-2 protein expression. Chemical characterization of F6 by UPLC/MS-QTOF revealed at least eight compounds with anti-inflammatory activity. These findings support the anti-inflammatory potential of RtAE and F6, reinforcing the medicinal use of Rt.

Conclusion: VAT confers a complex and blended pathogenic transcriptomic profile in obese patients, where abnormal processes are mainly controlled by activating intracellular signaling pathways that exhibit a high degree of redundancy. Identifying shared cross points between those pathways could allow specific targeting treatments to exert a widespread effect over multiple pathogenic processes.

Abstract Background and aims Spondyloarthritis (SpA) is a group of autoinflammatory disorders, of which the primary extra-articular manifestation is inflammatory bowel disease (IBD). The oral cavity being a part of gastrointestinal tract, is significantly compromised in IBD, and in many cases, it is the first site of clinical manifestations of IBD. This study aimed to identify changes in the oral mucosa associated with the onset of IBD and their association with endoscopic/histological findings. Materials and methods The study assessed 80 patients with SpA and 52 healthy controls. Oral, rheumatological, and gastroenterological assessments were performed. The ileocolonoscopy was performed via digital magnification chromoendoscopy. The statistical analysis consisted of Chi-square, Fisher's exact, and multiple correspondence discriminant analysis tests. Results From the disease cohort, 63.0% patients showed oral lesions (p = 0.050). These manifestations ranged from gingivitis (55.0%, p = 0.001), aphthous stomatitis (3.8%, p = 0.091), angular cheilitis (2.6%, p = 0.200), and perioral erythema with scaling (1.3%, p = 0.300). All patients who presented with alterations in colonic mucosa also had oral lesions associated with IBD (p = 0.039), specifically gingivitis/aphthous stomatitis (p = 0.029). Conclusion The patients with SpA without IBD present significant oral signs and symptoms. Gingivitis seems to be the most relevant because of its associations with early endoscopic and histological findings. Clinical relevance An integral approach to the diagnostic tests that includes evaluations of oral, rheumatological and gastroenterological tissues may favor timely attention and improve patients’ quality of life.

COVID-19 vaccination is recommended in patients with rheumatic diseases (RDs) to prevent hospitalized COVID-19 and worse outcomes. However, patients’ willingness to receive a SARS-CoV-2 vaccine and the associated factors vary across populations, vaccines, and time. The objective was to identify factors associated with COVID-19 vaccine acceptance (VA) in Mexican outpatients with RDs. This multicenter study was performed between March 1 and September 30, 2021, and four national centers contributed with patients. Participants filled out a questionnaire, which included 32 items related to patients’ perception of the patient-doctor relationship, the COVID-19 vaccine component, the pandemic severity, the RD-related disability, comorbid conditions control, immunosuppressive treatment impact on the immune system, and moral/civil position of COVID-19 vaccine. Sociodemographic, disease-related, and treatment-related variables and previous influenza record vaccination were also obtained. Multiple logistic regression analyses identified factors associated with VA, which was defined based on a questionnaire validated in our population. There were 1439 patients whose data were analyzed, and the most frequent diagnoses were Rheumatoid Arthritis in 577 patients (40.1%) and Systemic Lupus Erythematosus in 427 (29.7%). Patients were primarily middle-aged women (1235 [85.8%]), with (mean±SD) 12.1 (±4.4) years of formal education. Years of education, corticosteroid use, patient perceptions about the vaccine and the pandemic severity, patient civil/moral position regarding COVID-19 vaccine, and previous influenza vaccination were associated with VA. In Mexican patients with RDs, COVID-19 VA is associated with individual social-demographic and disease-related factors, patient´s perceptions, and previous record vaccination. This information is crucial for tailoring effective vaccine messaging in Mexican patients with RDs.

Abstract Background Determining potential predictors of clinical response would allow a more personalized rheumatoid arthritis (RA) treatment approach in heterogeneous populations such as Latin American (LA) patients. Methods Post hoc analysis to identify baseline characteristics predictive of clinical remission in response to treatment with etanercept (ETN) plus methotrexate (MTX) in LA patients with moderate to severe MTX-resistant RA. We report data from the group of patients who received ETN 50 mg/week plus MTX (ETN + MTX, n = 281) in a clinical trial consisting of an initial 24-week open-label phase, followed by a 104-week extension. Remission was defined as 28-joint Disease Activity Score with erythrocyte sedimentation rate (DAS28-ESR) score 28.5 kg/m2 (OR 3.24), disease duration > 3.7 years (OR 2.22), ESR ≤ 42 mm/h (OR 2.72), PGA ≤ 6 (OR 3.21), tender joint count ≤ 14 (OR 2.25), and total HAQ score ≤ 1.6 (OR 2.86). At Week 128, age ≤ 42 years (OR 2.21), SF-36 Mental Health Scale score > 39.6 (OR 2.16), White race (OR 4.07), > 18 swollen joints (OR 2.11), and VAS Pain ≤ 41 (OR 6.05) at baseline were the best subset of significant predictors of remission. Conclusions In LA patients with RA, younger age, higher BMI, longer disease duration, higher SF-36 Mental Health Scale score, higher swollen joint count, and overall lower disease activity predicted clinical response to ETN + MTX therapy. Trial registration: ClinicalTrials.gov Identifier: NCT00848354.

Lifestyle modifications in preclinical Rheumatoid Arthritis (RA) could delay the ongoing pathogenic immune processes and potentially prevent its onset. Physical exercise (PE) benefits RA patients; however, its impact in reducing the risk of developing RA has scarcely been studied. The objective was to describe the effects of low-intensity PE applied at the disease’s preclinical phase on the joints of DBA/1 mice with collagen-induced arthritis (CIA). Twelve mice with CIA were randomly distributed into two groups: the CIA-Ex group, which undertook treadmill PE, and the CIA-NoEx, which was not exercised. The effects of PE were evaluated through clinical, histological, transcriptomics, and immunodetection analyses in the mice’s hind paws. The CIA-Ex group showed lower joint inflammation and damage and a decreased expression of RA-related genes (Tnf Il2, Il10, Il12a, IL23a, and Tgfb1) and signaling pathways (Cytokines, Chemokines, JAK-STAT, MAPK, NF-kappa B, TNF, and TGF-beta). TNF-α expression was decreased by PE in the inflamed joints. Low-intensity PE in pre-arthritic CIA reduced the severity through joint down-expression of proinflammatory genes and proteins. Knowledge on the underlying mechanisms of PE in preclinical arthritis and its impact on reducing the risk of developing RA is still needed.

The fibroblast-like synoviocytes (FLS) have a crucial role in the pathogenesis of Rheumatoid Arthritis (RA); however, its precise mechanisms remain partially unknown. The involvement of the fibroblast in activating adjuvant-induced arthritis (AA) has not been previously reported. The objective was to describe the participation of footpads’ fibroblasts in the critical initial process that drives the AA onset. Wistar rats were injected with Complete Freund’s Adjuvant (CFA) or saline solution in the hind paws’ footpads and euthanized at 24 or 48 h for genetic and histological analyses. Microarrays revealed the differentially expressed genes between the groups. The CFA dysregulated RA-linked biological processes at both times. Genes of MAPK, Jak-STAT, HIF, PI3K-Akt, TLR, TNF, and NF-κB signaling pathways were altered 24 h before the arrival of immune cells (CD4, CD8, and CD68). Key markers TNF-α, IL-1β, IL-6, NFκB, MEK-1, JAK3, Enolase, and VEGF were immunodetected in fibroblast in CFA-injected footpads at 24 h but not in the control group. Moreover, fibroblasts in the CFA inoculation site overexpressed cadherin-11, which is linked to the migration and invasion ability of RA-FLS. Our study shows that CFA induced a pathological phenotype in the fibroblast of the inoculation site at very early AA stages from 24 h, suggesting a prominent role in arthritis activation processes.

Adipokines are associated with the pathogenesis of rheumatoid arthritis (RA) and are potential biomarkers of disease activity, periodontitis, and obesity. The aim of this was to establish the association between adipokine profile, RA disease activity, body mass index, and periodontal infection. This study evaluated 51 patients with early-RA and 51 controls including serum rheumatological markers, adipokine levels, detection of Porphyromonas gingivalis and serum anti-Porphyromonas gingivalis antibodies, clinical and periodontal measurements. Statistical analyses were run with SPSS® V26, with a logistic regression model to confirm associations. The results show high levels of leptin were more frequent in patients (p = 0.001) who simultaneously showed a higher frequency of Porphyromonas gingivalis (p = 0.004). Patients with concomitant presence of Porphyromonas gingivalis, high clinical activity score, and overweight were correlated with high levels of leptin (OR, 7.20; 95% CI, 2.68–19.33; p = 0.0001) and adipsin (OR, 2.69; 95% CI, 1.00–7.28; p = 0.005). The conclusion is that high levels of leptin and adipsin are associated with greater clinical activity in early-RA patients with overweight and periodontal infection, whereby overweight and Porphyromonas gingivalis may enhance RA activity. This may represent a pathological mechanism between these conditions, where adipokines seem to have a key role.

Spondyloarthritis (SpA) is a group that includes a wide spectrum of clinically similar diseases manifested by oligoarticular arthritis and axial or peripheral ankylosis. Although axial SpA is predominant in Caucasians and adult-onset patients, juvenile-onset and Latin American patients are characterized by severe peripheral arthritis and particularly foot involvement. The peripheral involvement of SpA can vary from tarsal arthritis to the most severe form named ankylosing tarsitis (AT). Although the cause and etiopathogenesis of axSpA are often studied, the specific characteristics of pSpA are unknown. Several animal models of SpA develop initial tarsitis and foot ankylosis as the main signs, emphasizing the role of foot inflammation in the overall SpA spectrum. In this review, we attempt to highlight the clinical characteristics of foot involvement in SpA and update the knowledge regarding its pathogenesis, focusing on animal models and the role of mechanical forces in inflammation.

IntroductionComplementary and alternative medicine (CAM) is frequently used by patients with rheumatic diseases (RD) to improve their symptoms; however, its diversity and availability have increased notably while scientific support for its effectiveness and adverse effects is still scarce.ObjectiveTo describe the prevalence and diversity of CAM in patients with RD in Chihuahua, Mexico.MethodsA cross-sectional study was conducted in 500 patients with RD who were interviewed about the use of CAM to treat their disease. The interview included sociodemographic aspects, characteristics of the disease, as well as a description of CAM use, including type, frequency of use, perception of the benefit, communication with the rheumatologist, among others.ResultsThe prevalence of CAM use was reported by 59.2% of patients, which informed a total of 155 different therapies. The herbal CAM group was the most used (31.4%) and included more than 50 different therapies. The use of menthol-based and arnica ointments was highly prevalent (35%). Most patients (62.3%) reported very little or no improvement in their symptoms. Only a fourth of the patients informed the rheumatologist of the use of CAM. The use of CAM was influenced by female sex, university degree, diagnosis delay, lack adherence to the rheumatologist's treatment, family history of RD, and orthopedic devices.ConclusionThe use of CAM in our population is highly prevalent and similar to reports in different populations suggesting a widespread use in many different societies. We found high use of herbal remedies; however, there were many different types suggesting a lack of significant effect. Patients continue using CAM despite a perception of no-effectiveness. Recurrent use of CAM is explained by factors other than its efficacy.

This article presents a study on the care provided by 11 men from different ethnic, health, and socioeconomic backgrounds to two indigenous Rarámuri males with ankylosing spondylitis. This chronic muscular and bone disease is known to evolve progressively, causing disability and immense suffering to the affected individual. Through anthropological research involving ethnographic description and interviews conducted in an urban setting of the City of Chihuahua in the state of Chihuahua, caring practices performed by men that contest prior assumptions about how men relate to each other in relation to their health and masculinity were encountered. To interpret findings, a “caring of the self” framework, along with elements of the discussion of personhood and masculinities, was used; this led to an analysis made through the elaboration of meaningful coding of patterns of caring practices. The patterns identified in the ethnographic data were organized into four groups, all of which represented caring practices performed by these men. The first three groups involve access to food, money, and infrastructure goods, which have a material nature that holds a positive relation to the well-being of the two Rarámuri males in regard to the implications of their disease. The last group is unique in that it pertains to circumstantial factors that required improvisations in the forms of favors exchanged by these males that also positively related to their well-being

The ashwin gene, originally identified in Xenopus laevis, was found to be expressed first in the neural plate and later in the embryonic brain, eyes, and spinal cord. Functional studies of ashwin suggest that it participates in cell survival and anteroposterior patterning. Furthermore, ashwin is expressed zygotically in this species, which suggests that it participates in embryonic development. Nevertheless, the expression of this gene has not been studied in mammals. Thus, the aim of this study was to analyze the ashwin expression pattern in bovine fetal and adult tissues, as well as in three independent samples of immature and mature oocytes, and in two- to four-, and eight-cell embryos, morula, and blastocysts. Spatiotemporal expression was analyzed using real-time polymerase chain reaction (PCR); ashwin mRNA was detected in all tissues analyzed, immature and mature oocytes, and two- to eight-cell embryos. It was down-regulated in morula and blastocysts, suggesting that this expression profile is similar to that of maternal genes. Immunohistochemical localization of the ashwin protein in fetal and adult ovaries and testes reveals that this protein is consistently present during all stages of follicular development and during bovine spermatogenesis. These observations lead us to propose ashwin as an important gene involved in mammalian reproduction.

Systemic lupus erythematosus (SLE) is a perplexing and potentially severe disease, the pathogenesis of which is yet to be understood. SLE is considered to be a multifactorial disease, in which genetic factors, immune dysregulation, and environmental factors, such as ultraviolet radiation, are involved. Recently, the description of novel genes conferring susceptibility to develop SLE even in their own (monogenic lupus) has raised the interest in DNA dynamics since many of these genes are linked to DNA repair. Damage to DNA induces an inflammatory response and eventually triggers an immune response, including those targeting self-antigens. We review the evidence that indicates that patients with SLE present higher levels of DNA damage than normal subjects do and that several proteins involved in the preservation of the genomic stability show polymorphisms, some of which increase the risk for SLE development. Also, the experience from animal models reinforces the connection between DNA damage and defective repair in the development of SLE-like disease including characteristic features such as anti-DNA antibodies and nephritis. Defining the role of DNA damage response in SLE pathogenesis might be strategic in the quest for novel therapies.

Physical exercise (PE) is recommended for Rheumatoid Arthritis (RA), but the molecular and biological mechanisms that impact the inflammatory process and joint destruction in RA remain unknown. The objective of this study was to evaluate the effect of PE on the histological and transcriptional changes in the joints of adjuvant-induced arthritis (AIA) rat model. AIA rats were subjected to PE on a treadmill for eight weeks. The joints were subjected to histological and microarray analysis. The differentially expressed genes (DEGs) by PE in the arthritic rats were obtained from the microarray. The bioinformatic analysis allowed the association of these genes in biological processes and signaling pathways. PE induced the differential expression of 719 genes. The DEGs were significantly associated with pathogenic mechanisms in RA, including HIF-1, VEGF, PI3-Akt, and Jak-STAT signaling pathways, as well as response to oxidative stress and inflammatory response. At a histological level, PE exacerbated joint inflammatory infiltrate and tissue destruction. The PE exacerbated the stressed joint environment aggravating the inflammatory process, the hypoxia, and the oxidative stress, conditions described as detrimental in the RA joints. Research on the effect of PE on the pathogenesis process of RA is still necessary for animal models and human.

The danger model was proposed by Polly Matzinger as complement to the traditional self-non-self- (SNS-) model to explain the immunoreactivity. The danger model proposes a central role of the tissular cells’ discomfort as an element to prime the immune response processes in opposition to the traditional SNS-model where foreignness is a prerequisite. However recent insights in the proteomics of diverse tissular cells have revealed that under stressful conditions they have a significant potential to initiate, coordinate, and perpetuate autoimmune processes, in many cases, ruling over the adaptive immune response cells; this ruling potential can also be confirmed by observations in several genetically manipulated animal models. Here, we review the pathogenesis of rheumatic diseases such as systemic lupus erythematous, rheumatoid arthritis, spondyloarthritis including ankylosing spondylitis, psoriasis, and Crohn’s disease and provide realistic approaches based on the logic of the danger model. We assume that tissular dysfunction is a prerequisite for chronic autoimmunity and propose two genetically conferred hypothetical roles for the tissular cells causing the disease: (A) the Impaired cell and (B) the paranoid cell. Both roles are not mutually exclusive. Some examples in human disease and in animal models are provided based on current evidence.