Increased Disease Activity Research Articles

OA11 Maintained improvement in patient reported outcomes in early axial spondyloarthritis following certolizumab pegol dose reduction

Abstract Background/Aims Certolizumab pegol (CZP), a PEGylated TNFi without an Fc region, has previously shown efficacy and safety in patients with axial spondyloarthritis (axSpA). EULAR guidelines recommend that tapering of a biologic can be considered for patients in sustained remission. The C-OPTIMISE trial (NCT02505542) identified early (<5 years) axSpA patients in sustained remission who may benefit from dose tapering or stopping treatment. Here we report whether a reduced CZP maintenance dose is associated with sustained improvements in patient reported outcomes (PROs) in patients with axSpA at Week (Wk) 96. Methods C-OPTIMISE was a two-part, multicentre, phase 3b study in adult patients. Part A: up to Wk48 (open-label), patients received CZP 200mg Q2W. At Wk48 (Part B), patients who achieved sustained remission at Wk32 or 36 (ASDAS <1.3), were randomised 1:1:1 to double-blind CZP 200 mg Q2W (full maintenance dose), CZP 200 mg Q4W (reduced maintenance dose), or placebo (PBO [drug withdrawal]) for additional 48Wks. We report disease activity and PROs (BASDAI, PtGADA, nocturnal apinal pain, morning stiffness, fatigue, and ASQoL) during Part B (Wks48-96). Flare is defined as ASDAS ≥2.1 at two consecutive visits, or ASDAS >3.5 at any visit. Results At Wk48 (Part A), 43.9% (323/736) of patients achieved sustained remission, of which 313 patients were randomised to Part B (Wks48-96). During Wks48-96, 87/104 (83.7%) patients receiving the full maintenance dose, 83/105 (79.0%) patients receiving the reduced maintenance dose, and 21/104 (20.2%) patients receiving PBO remained flare-free. Patients receiving full maintenance and those on reduced dose have similar disease activity measures (BASDAI; mean [SD], 0.8 [0.8] vs 0.8 [1.0]) at Wk96 (Table). Sustained improvements in PROs were similar for CZP full maintenance dose and CZP reduced maintenance dose, including ASQoL, fatigue and nocturnal spinal pain, while PBO showed increased disease activity (Table). Conclusion In axSpA patients who achieved sustained remission, CZP reduced dosage resulted in sustained improvements in disease activity and PROs similar to those receiving full maintenance dose. This suggests that dose reduction can be a viable strategy without compromising PROs. Disclosure A. Chan: Member of speakers’ bureau; AC has received speaker bureau from Novartis, UCB, Abbvie, Janssen, Amgen. Grants/research support; AC has received grant support for service and educational projects from Novartis and UCB Pharma. Other; AC has received honoraria/advisory boards from Novartis, Abbvie, UCB, Janssen, Amgen, Lilly. J. Wood: Other; JW is an employee of UCB Pharma. L. Burns: Other; LBu is an employee of UCB Pharma. R. Tham: Other; RT is employed by Veramed and a contractor for UCB Pharma. T. Kumke: Other; TK is an employee and shareholder of UCB Pharma. B. Hoepken: Other; BH is an employee and shareholder of UCB Pharma. M. Kim: Other; MK is an employee of UCB Pharma. L. Bauer: Other; LBa is an employee and shareholder of UCB Pharma. K. MacKay: Other; KM received consultancy & speaker meetings for UCB, AbbVie, Novartis, Lilly, AZ, Janssen and Roche. K. Gaffney: Shareholder/stock ownership; KG is a shareholder of Rheumatology Events. Grants/research support; KG has received grants/research support from NASS, Versus Arthritis, AbbVie, Pfizer, UCB Pharma, Norvartis, Eli Lilly, Cellgene, Celltrion, Janssen, Gilead and Biogen. Other; KG has received honoraria/ consultation fees from Novartis, AbbVie, UCB Pharma, Lilly and Pfizer, KG has received speaker’s bureau from Novartis, UCB Pharma, AbbVie and Lilly; meeting expenses from AbbVie, Lilly, Roche, Novartis, Pfizer and UCB Pharma.

Nitazoxanide protects against experimental ulcerative colitis through improving intestinal barrier and inhibiting inflammation

Ulcerative colitis is a chronic disease with colonic mucosa injury. Nitazoxanide is an antiprotozoal drug in clinic. Nitazoxanide and its metabolite tizoxanide have been demonstrated to activate AMPK and inhibit inflammation, therefore, the aim of the present study is to investigate the effect of nitazoxanide on dextran sulfate sodium (DSS)-induced colitis and the underlying mechanism. Oral administration of nitazoxanide ameliorated the symptoms of mice with DSS-induced colitis, as evidenced by improving the increased disease activity index (DAI), the decreased body weight, and the shortened colon length. Oral administration of nitazoxanide ameliorated DSS-induced intestinal barrier dysfunction and reduced IL-6 and IL-17 expression in colon tissues. Mechanistically, nitazoxanide and its metabolite tizoxanide treatment activated AMPK and inhibited JAK2/STAT3 signals. Nitazoxanide and tizoxanide treatment increased caudal type homeobox 2 (CDX2) expression, increased alkaline phosphatase (ALP) activity and promoted tight junctions in Caco-2 cells. Nitazoxanide and tizoxanide treatment restored the decreased zonula occludens-1(ZO-1) and occludin protein levels induced by LPS or IL-6 in Caco-2 cells. On the other hand, nitazoxanide and tizoxanide regulated macrophage bias toward M2 polarization, as evidenced by the increased arginase-1expression in bone marrow-derived macrophages (BMDM). Nitazoxanide and tizoxanide reduced the increased IL-6, iNOS and CCL2 pro-inflammatory gene expressions and inhibited JAK2/STAT3 activation in BMDM induced by LPS. In conclusion, nitazoxanide protects against DSS-induced ulcerative colitis in mice through improving intestinal barrier and inhibiting inflammation and the underlying mechanism involves AMPK activation and JAK2/STAT3 inhibition.

Ultrasonographic Evaluation of the Ankle Joint in Relation to Rheumatoid Factor Status and Disease Activity in Patients with Rheumatoid Arthritis

Abstract Background: Rheumatoid arthritis (RA) is a form of inflammatory disease whose clinical pattern is largely dependent on the presence of both anti-citrullinated protein antibodies and rheumatoid factor (RF). Although this is still debatable, seronegative RA seems to be a somewhat less serious condition. The present study aimed to evaluate ankle joint ultrasound in relation to RF status and disease activity in RA patients. Methods: A cross-sectional study involving RA patients from a single center was conducted. Laboratory test evaluations and clinical activity assessments were carried out. The ankle joint was examined using musculoskeletal ultrasound (US). Results: The study included 100 patients with established RA in total. Eighty-two patients tested positive for RF with a mean age of 42.3, whereas only 18 tested negative with a mean age of 39.6. Patients who tested positive for RF had a longer duration of illness (9.39 ± 5.39 vs. 4.56 ± 3.24). There were no differences in clinical activity scores between the seropositive and seronegative groups. The pathological US findings of any ankle joint showed no differences between the seropositive and seronegative groups. Patients with US findings of tibialis posterior tenosynovitis in the left ankle and synovitis and erosion in the right ankle, particularly in the tibiotalar and talonavicular joints, had significantly high Disease Activity Score 28-Erythrocyte sedimentation rate-scores. The increased disease activity was accompanied by significant erosions on both ankles. Conclusion: In terms of disease activity, there is no clinically significant difference between seropositive and seronegative RA patients. Sonographic ankle joint abnormalities do not appear to be associated with the patients’ RF status. High RA disease activity, on the other hand, is associated with synovitis and erosions, particularly in the talonavicular and tibiotalar joints, as well as tibialis posterior tenosynovitis.

Fecal microbiota is associated with extraintestinal manifestations in inflammatory bowel disease

Introduction A large proportion of patients with inflammatory bowel disease (IBD) experience IBD-related inflammatory conditions outside of the gastrointestinal tract, termed extraintestinal manifestations (EIMs) which further decreases quality of life and, in extreme cases, can be life threatening. The pathogenesis of EIMs remains unknown, and although gut microbiota alterations are a well-known characteristic of patients with IBD, its relationship with EIMs remains sparsely investigated. This study aimed to compare the gut microbiota of patients with IBD with and without EIMs. Methods A total of 131 Danish patients with IBD were included in the study, of whom 86 had a history of EIMs (IBD-EIM) and 45 did not (IBD-C). Stool samples underwent 16S rRNA sequencing. Amplicon sequence variants (ASVs) were mapped to the Silva database. Diversity indices and distance matrices were compared between IBD-EIM and IBD-C. Differentially abundant ASVs were identified using a custom multiple model statistical analysis approach, and modules of co-associated bacteria were identified using sparse correlations for compositional data (SparCC) and related to patient EIM status. Results Patients with IBD and EIMs exhibited increased disease activity, body mass index, increased fecal calprotectin levels and circulating monocytes and neutrophils. Microbiologically, IBD-EIM exhibited lower fecal microbial diversity than IBD-C (Mann–Whitney’s test, p = .01) and distinct fecal microbiota composition (permutational multivariate analysis of variance; weighted UniFrac, R 2 = 0.018, p = .01). A total of 26 ASVs exhibited differential relative abundances between IBD-EIM and IBD-C, including decreased Agathobacter and Blautia and increased Eggerthella lenta in the IBD-EIM group. SparCC analysis identified 27 bacterial co-association modules, three of which were negatively related to EIM (logistic regression, p < .05) and included important health-associated bacteria, such as Agathobacter and Faecalibacterium. Conclusions The fecal microbiota in IBD patients with EIMs is distinct from that in IBD patients without EIM and could be important for EIM pathogenesis.

Trends in SARS-CoV-2 cycle threshold (Ct) values from nucleic acid testing predict the trajectory of COVID-19 waves

Forecasting COVID-19 waves helps with public health planning and resource allocation. Cycle threshold (Ct) values obtained from positive SARS-CoV-2 nucleic acid amplification test (NAAT) results offer limited value for individual patient management, but real-time analysis of temporal trends of aggregated Ct values may provide helpful information to predict the trajectories of COVID-19 waves in the community. Ct value trends on 59,609 SARS-CoV-2 NAAT-positive results from 574,403 tests using a single testing assay system, between September 2021 and January 2023, were examined to monitor the trend of the proportion of positive NAAT with lower Ct values (≤28) in relation to changing COVID-19 case numbers over time. We applied regression with autoregressive integrated moving average errors modelling approach to study the relation between Ct values and case counts. We also developed an insight product to monitor the temporal trends with Ct values obtained from SARS-CoV-2 NAAT-positive results. In this study, the proportion of lower Ct values preceded by a range of 7-32 days the rising population COVID-19 testing rate reflecting onset of a COVID-19 wave. Monitoring population Ct values may assist in predicting increased disease activity.

Influential factors on disease activity in Crohn’s disease and their Roc curve evaluation: a cross-sectional study

ObjectiveThis study aims to investigate the factors influencing disease activity in patients with Crohn’s disease (CD) and provide insights and references for the management and prevention of CD.MethodsWe recruited CD patients who met the inclusion and exclusion criteria and were treated at the First Affiliated Hospital of Soochow University from November 2022 to June 2023. Generalized linear mixed models were used to analyze the factors affecting disease activity in CD patients. Receiver operating characteristic (ROC) curve analysis was employed to assess the predictive value of these factors for disease activity.ResultsA total of 268 CD participants aged 18 to 65 were included in the study, with over 68% of them in remission or experiencing mild disease activity, indicating relatively good disease control. The results of the generalized linear mixed models showed that older age, absence of diabetes, high levels of physical activity, and a low dietary inflammatory index (DII) were protective factors for lower disease activity in CD patients (p < 0.05). ROC curve analysis demonstrated that physical activity level, age, and DII all had ROC areas greater than 0.6 in predicting disease activity in CD patients (p < 0.05).ConclusionThe factors influencing the disease activity of CD patients are numerous and should be given attention. CD patients who are younger, have low levels of physical activity, high DII, and have diabetes are at a higher risk of increased disease activity. By reducing or avoiding the mentioned risk factors and leveraging protective factors, it is possible to mitigate the disease activity of CD to some extent.

Ferulic Acid Derivatives Ameliorate Intestine Barrier Destruction by Alleviating Inflammatory Responses in Dextran Sulfate Sodium-Induced Inflammatory Bowel Disease.

Inflammatory bowel disease (IBD), a chronic disorder affecting the colon and rectum, involves the overproduction of pro-inflammatory cytokines causing damage to tight junctions (TJ) in the intestinal epithelial cells and chronic inflammation. The current mainstay of treatment, sulfasalazine, often causes adverse effects, thereby necessitating the exploration of alternative herbal medicines with fewer side effects. Portulaca oleracea L. (P. oleracea), a traditional medicinal herb, contains feruloyl amide compounds. We synthesized new compounds by conjugating ferulic acid (FA) with (±)-octopamine. Our study focused on novel FA derivatives that demonstrate protective effects against the intestinal epithelial barrier and inflammatory responses. In lipopolysaccharide-induced cells, C1 and C1a inhibited the production of inflammatory mediators. In Caco-2 cells, these compounds maintained the TJ protein expression, thereby demonstrating their protective effects on the epithelial barrier. In a mouse model of dextran sulfate sodium-induced IBD, a treatment with these compounds ameliorated features including a body weight reduction, colon shortening, an increased disease activity index, and histopathological changes. Furthermore, C1a demonstrated greater efficacy than C1 at the same concentration. These findings suggest that the novel FA derivative (C1a) effectively alleviates clinical signs and inflammatory mediators in IBD, making these compounds potential candidates as natural medicines for the treatment of IBD.

Aryl hydrocarbon receptor activity in intestinal epithelial cells in the formation of colonic tertiary lymphoid tissues.

After birth, the development of secondary lymphoid tissues (SLTs) in the colon is dependent on the expression of the aryl hydrocarbon receptor (AhR) in immune cells as a response to the availability of AhR ligands. However, little is known about how AhR activity from intestinal epithelial cells (IECs) may influence the development of tertiary lymphoid tissues (TLTs). As organized structures that develop at sites of inflammation or infection during adulthood, TLTs serve as localized centers of adaptive immune responses, and their presence has been associated with the resolution of inflammation and tumorigenesis in the colon. Here, we investigated the effect of the conditional loss of AhR activity in IECs in the formation and immune cell composition of TLTs in a model of acute inflammation. In females, loss of AhR activity in IECs reduced the formation of TLTs without significantly changing disease outcomes or immune cell composition within TLTs. In males lacking AhR expression in IECs, increased disease activity index, lower expression of functional-IEC genes, increased number of TLTs, increased T-cell density, and lower B- to T-cell ratio were observed. These findings may represent an unfavorable prognosis when exposed to dextran sodium sulfate (DSS)-induced epithelial damage compared with females. Sex and loss of IEC AhR also resulted in changes in microbial populations in the gut. Collectively, these data suggest that the formation of TLTs in the colon is influenced by sex and AhR expression in IECs.NEW & NOTEWORTHY This is the first research of its kind to demonstrate a clear connection between biological sex and the development of tertiary lymphoid tissues (TLT) in the colon. In addition, the research finds that in a preclinical model of inflammatory bowel disease, the expression of the aryl hydrocarbon receptor (AhR) influences the development of these structures in a sex-specific manner.

Spirituality is Associated with Immune Parameters and Disease Activity in Primary Sjögren’s Syndrome: A Cross-Sectional Study

Introduction The role of spirituality in health and disease is a complex and emerging area of research. Incorporating spirituality into the bio-psycho-social model of health and disease leading to the bio-psycho-social-spiritual model provides a more comprehensive framework. In this context, chronic disorders like primary Sjögren’s syndrome (pSS) are of interest due to their intricate interactions between biological, psychological, and spiritual factors.ObjectivesTo study possible relationships between spirituality, immune parameters, and disease activity in pSS patients.Methods Patient recruitment for the study took place at the Autoimmune Sjögren specialty clinic, University of Debrecen, resulting in 112 patients. Assessing spirituality of the patients happened through 4 direct questions and the Sprituality Transcendence Scale (24 items). Besides, clinical data of the patients were involved in the study including blood cell counts, rheumatoid factor, immunoglobulin G, Sjögren-specific autoantibodies and disease activity scores (semi-objective and patient reported,). The statistical analysis was conducted applying group comparisons between spiritual and non-spiritual groups, and linear and logistic regression analyses adjusted for sex, age, disease duration, settlement type, education, living in partnership and smoking. Out of the 112 patients 4 gave incomplete response, and therefore got excluded from the analysis, resulting in a total sample size of 108.ResultsSemi-objective disease activity score (ESSDAI) and perceived vaginal dryness was significantly lower in the non-spiritual group. Spirituality was proven as a significant predictor of anti-SSB autoantibody serum activity and ESSDAI, while engaging in prayer/meditation and its duration predicted significantly anti-SSA autoantibody serum activity, perceived skin and tracheal dryness. Concerning logistic regression analysis, we found that an increase of one unit in spirituality reduces the probability with 81.6% of having a detectable, semi-objective disease activity at all. Significant associations were found between the duration of prayer/meditation and both semi-objective and patient reported disease activity scores and autoantibody anti-SSB with an inverse ratio based on logistic regression model.ConclusionsSpirituality is associated with immune parameters and disease activity in pSS. Patients with spiritual attitude are less likely to have increased disease activity. Besides being spiritual, engagement in individual spiritual activities, such as prayer/meditation has beneficial disease modifying effect. These changes are supposedly due to psychoneuroimmunological pathways. In addition to the biologically measurable variables, the alleviation and aggravation of perceived symptoms (e.g. dryness) are important outcomes of spiritual engagement and practice.Disclosure of InterestNone Declared

Deciphering the shift from benign to active relapsing-remitting multiple sclerosis: Insights into T regulatory cell dysfunction and apoptosis regulation

BackgroundRelapsing-remitting multiple sclerosis (RRMS), a common demyelinating disease among young adults, follows a benign course in 10–15% of cases, where patients experience minimal neurological disability for a decade following disease onset. However, there is potential for these benign cases to transition into a clinically active, relapsing state. ObjectiveTo elucidate the biological mechanisms underlying the transition from benign to active RRMS using gene expression analysis. MethodsWe employed complementary-DNA microarrays to examine peripheral-blood gene expression patterns in patients with benign MS, defined as having a disease duration exceeding 10 years and an Expanded Disability Status Scale (EDSS) score of ≤3.0. We compared the gene expression pattern between patients who switched to active disease (Switching BMS) with those who maintained a benign state (Permanent-BMS) during an additional 5-year follow-up. ResultsWe identified two primary mechanisms linked to the transition from benign MS to clinically active disease. The first involves the suppression of regulatory T cell activity, and the second pertains to the dysfunction of nuclear receptor 4 A family-dependent apoptosis. These mechanisms collectively contribute to an augmented autoimmune response and increased disease activity. ConclusionsThe intricate gene regulatory networks that operate in switching-BMS are related to suppression of immune tolerance and aberrant apoptosis. These findings may lead to new therapeutic targets to prevent the escalation to active disease.

Impact of body composition on clinical outcomes in patients with active radiographic axial spondyloarthritis under biological therapy.

To assess the association of body composition, evaluated by bioimpedance analysis (BIA), with disease activity, physical function, and mobility in patients with axSpA undergoing bDMARD treatment for one year. Patients with AS (radiographic axSpA) were enrolled in an extension of the German Spondyloarthritis Inception Cohort (GESPIC). Patients were required to be candidates for bDMARD therapy at baseline presenting high disease activity despite previous treatment with nonsteroidal anti-inflammatory drugs. Outcomes (disease activity, function, and mobility) and body composition parameters were assessed at baseline and every 6 months thereafter. Body composition was assessed by BIA. The association between body composition parameters and outcomes over 1 year was analyzed using longitudinal generalized estimating equations. Seventy-four patients with radiographic axSpA were included in current analysis with a mean age of 36.5 years, disease duration of 6.2 years and ASDAS-CRP score of 3.4 at baseline. Fat mass value and fat mass index were positively associated with disease activity (ASDAS: ß = 0.01, 95% CI [-0.01, 0.03] and ß = 0.04, 95% CI [-0.01, 0.08], respectively) and functional disability (BASFI). Visceral adipose tissue (VAT) was associated with reduced spine mobility (BASMI: ß = 0.20, 95% CI [0.07, 0.33]). Additionally, increase in VAT and fat mass parameters was linked to worse disease activity and functional disability in women, while they were strongly associated with reduced spinal mobility in men. Higher levels of body fat and VAT were positively associated with increased disease activity, functional disability, and reduced spinal mobility in patients with radiographic axSpA treated with bDMARDs.

Ameliorative effect of an acidic polysaccharide from Phellinus linteus on ulcerative colitis in a DSS-induced mouse model

Phellinus linteus, a rare medicinal fungus, displays strong antitumor and anti-inflammatory activities because of its active metabolites, particularly polysaccharides. We investigated effects of P. linteus acidic polysaccharide (PLAP) on amelioration of dextran sodium sulfate (DSS)-induced ulcerative colitis (UC) in a mouse model, and associated mechanisms. PLAP treatment alleviated major UC symptoms (weight loss, reduced food intake, increased disease activity index), and ameliorated histopathological colon tissue damage, reduced levels of pro-inflammatory factors (TNF-α, IL-6, IL-1β), enhanced anti-inflammatory factor IL-10 level, reduced levels of oxidative stress-related enzymes iNOS and MPO, and enhanced expression of tight junction proteins (ZO-1, occludin, claudin-1). qPCR analysis revealed that PLAP downregulated phosphorylation levels of p65 and p38 and transcriptional level of TLR-4. High-throughput sequencing showed that PLAP restored gut microbiota diversity and species abundances in the UC model, and gas chromatographic analysis showed that it increased levels of beneficial short-chain fatty acids. Our findings indicate that PLAP has strong potential for development as an anti-UC agent based on its reduction of inflammation and oxidative stress levels, modulation of gut microbiota composition, and promotion of normal intestinal barrier function.

Low-Dose Aspirin Use Does Not Increase Disease Activity in Pregnant Patients with Inflammatory Bowel Disease.

The adverse effects of non-steroidal anti-inflammatory (NSAID) drugs on the gastrointestinal system are well recognized, but the effect of NSAID use on disease activity patients with inflammatory bowel disease (IBD) remains unresolved. Low-dose aspirin (LDA) is recommended for all pregnant patients with risk factors for developing preeclampsia, including autoimmune conditions. As recognition of risk factors for preeclampsia improves, the preventative use of LDA is likely to increase. To investigate if LDA use for prevention of preeclampsia increases the risk of disease activity in pregnant women with IBD. Single-center retrospective cohort study of pregnant patients with IBD who delivered from 2012 to 2020, comparing those with and without LDA use. Primary outcome was odds of clinical IBD activity in patients in remission at time of conception. Secondary outcomes were rate of elevated inflammatory biomarkers, defined as C-reactive protein > 5ug/mL or fecal calprotectin > 250ug/g, and rate of preeclampsia. Univariate analyses tested for associations. Patients taking LDA were older (p = 0.003) and more likely to have chronic hypertension (p = 0.002), to have undergone in vitro fertilization (p < 0.001), and to be on biologics (p = 0.03). Among patients in remission at conception, there was no difference in clinical disease activity or biomarker elevation during pregnancy based on LDA use (OR 1.27, 95% CI [0.55-2.94], p = 0.6). Rates of preeclampsia were similar between groups. LDA use for preeclampsia prevention did not increase the incidence of disease activity in pregnant patients with IBD.

Amygdalin Alleviates DSS-Induced Colitis by Restricting Cell Death and Inflammatory Response, Maintaining the Intestinal Barrier, and Modulating Intestinal Flora.

Inflammatory bowel disease (IBD) refers to a cluster of intractable gastrointestinal disorders with an undetermined etiology and a lack of effective therapeutic agents. Amygdalin (Amy) is a glycoside extracted from the seeds of apricot and other Rosaceae plants and it exhibits a wide range of pharmacological properties. Here, the effects and mechanisms of Amy on colitis were examined via 16S rRNA sequencing, ELISA, transmission electron microscopy, Western blot, and immunofluorescence. The results showed that Amy administration remarkably attenuated the signs of colitis (reduced body weight, increased disease activity index, and shortened colon length) and histopathological damage in dextran sodium sulfate (DSS)-challenged mice. Further studies revealed that Amy administration significantly diminished DSS-triggered gut barrier dysfunction by lowering pro-inflammatory mediator levels, inhibiting oxidative stress, and reducing intestinal epithelial apoptosis and ferroptosis. Notably, Amy administration remarkably lowered DSS-triggered TLR4 expression and the phosphorylation of proteins related to the NF-κB and MAPK pathways. Furthermore, Amy administration modulated the balance of intestinal flora, including a selective rise in the abundance of S24-7 and a decline in the abundance of Allobaculum, Oscillospira, Bacteroides, Sutterella, and Shigella. In conclusion, Amy can alleviate colitis, which provides data to support the utility of Amy in combating IBD.

Pharmacological Activation of TRPC6 Channel Prevents Colitis Progression.

We recently reported that transient receptor potential canonical (TRPC) 6 channel activity contributes to intracellular Zn2+ homeostasis in the heart. Zn2+ has also been implicated in the regulation of intestinal redox and microbial homeostasis. This study aims to investigate the role of TRPC6-mediated Zn2+ influx in the stress resistance of the intestine. The expression profile of TRPC1-C7 mRNAs in the actively inflamed mucosa from inflammatory bowel disease (IBD) patients was analyzed using the GEO database. Systemic TRPC3 knockout (KO) and TRPC6 KO mice were treated with dextran sulfate sodium (DSS) to induce colitis. The Zn2+ concentration and the mRNA expression levels of oxidative/inflammatory markers in colon tissues were quantitatively analyzed, and gut microbiota profiles were compared. TRPC6 mRNA expression level was increased in IBD patients and DSS-treated mouse colon tissues. DSS-treated TRPC6 KO mice, but not TRPC3 KO mice, showed severe weight loss and increased disease activity index compared with DSS-treated WT mice. The mRNA abundances of antioxidant proteins were basically increased in the TRPC6 KO colon, with changes in gut microbiota profiles. Treatment with TRPC6 activator prevented the DSS-induced colitis progression accompanied by increasing Zn2+ concentration. We suggest that TRPC6-mediated Zn2+ influx activity plays a key role in stress resistance against IBD, providing a new strategy for treating colitis.

Development of a novel clinimetric tool: PAtient Reported Disease Activity Index in Rheumatoid Arthritis (PARDAI-RA) by PANLAR, for the assessment of patients living with rheumatoid arthritis.

Clinical experience has shown that a single measure is not sufficient to assess disease activity in rheumatoid arthritis (RA). Various clinimetric tools are necessary to address the many clinical situations that can arise. In order to develop a comprehensive measurement tool, the Pan American League of Associations for Rheumatology searched for the most frequent measures of disease activity applied in RA by means of a semi-systematic review of the available literature. We found that the most frequently reported measures of disease activity were the 28-joint Disease Activity Score, C-reactive protein, and the erythrocyte sedimentation rate, followed by patient-reported measures of pain and stiffness and many other composite indices and patient-reported outcome measures. The most frequent physician-reported sign of disease was the swollen joint count, and the most frequently self-reported feature was the increase in disease activity or flares. In this article, we present a new clinimetric tool developed based on expert consensus and on data retrieved from our search. Disease activity can be better assessed by combining various data sources, such as clinical, laboratory, and self-reported outcomes. These variables were included in our novel clinimetric tool. Key Points • The goal of treatment of RA is to achieve the best possible control of inflammation, or even remission; therefore, disease management should include systematic and regular evaluation of inflammation and health status. • Clinimetric tools evaluate a series of variables (e.g., symptoms, functional capacity, disease severity, quality of life, disease progression) and can reveal substantial prognostic and therapeutic differences between patients. • Our clinimetric tool, which is based on a combination of data (e.g., clinical variables, laboratory results, PROMs), can play a relevant role in patient assessment and care.

Immunogenicity and safety of BNT162b2 vaccination in adolescents with systemic lupus erythematosus.

We evaluated the immunogenicity and safety of BNT162b2 vaccination in adolescents with systemic lupus erythematosus (adoSLE) receiving either high- or low-dose immunosuppressant (High-IS and Low-IS). Patients aged 12-18years diagnosed with SLE were enrolled. High-IS was defined as >7.5mg/day prednisolone or with other immunosuppressant, while Low-IS was defined as only ≤7.5mg/day of prednisolone and no immunosuppressant. Two doses of BNT162b2 vaccination were given 4weeks apart, followed by a booster (third) dose at 4-6months later. Anti-spike receptor binding domain (anti-RBD) IgG against Wuhan, neutralising antibody (NT) against Wuhan and Omicron variants, and cellular immune response by IFN-γ-ELISpot assay were evaluated following vaccination. Adverse events (AEs) and SLE flare were monitored. A total of 73 participants were enrolled, 40 and 33 in the High-IS and Low-IS group, respectively. At 4weeks following the 2nd dose, overall anti-RBD IgG seropositivity was 97.3%, with no difference between the groups (p = .498). AdoSLE on High-IS had lower anti-RBD IgG (p < .001), Wuhan NT (p < .001), and IFN-γ-ELISpot (p = .022) than those on Low-IS. A 3rd dose induced significantly higher antibody responses than after the 2nd dose (p < .001) in both groups and established seroconversion against Omicron variants, with persistent lower antibody levels in High-IS group. SELENA-SLEDAI scores within 12weeks after 2-dose vaccination was higher than before vaccination (3.1 vs 2.5; p < .036); however, the occurrence of disease flare by SELENA-SLEDAI flare index was not different after vaccination compared to before vaccination, consistent across groups. Non-severe AEs occurred similarly in both groups. AdoSLE on High-IS induced lower SARS-CoV-2 vaccine immune responses than Low-IS. Vaccination can increase disease activity and requires close monitoring for disease flare.

Hyperactivation and enhanced cytotoxicity of reduced CD8+ gamma delta T cells in the intestine of patients with Crohn’s disease correlates with disease activity

Background and aimsWe aimed to investigate the immune characteristics of intestinal CD8+ gamma delta T (CD8+ γδ T) cells in Crohn’s disease (CD) and their correlation with disease activity.MethodsThe study cohorts included 21 CD patients and 21 healthy individuals. CD8+ γδ T cells were isolated from human ileal mucosa for detection by flow cytometry. The activation or inhibition status of cells was detected by detecting the expression of activation marker HLA-DR and the immunosuppressive molecule PD-1 on cells. The cytotoxicity of cells was assessed by detecting the expression of cytotoxic molecules (Perforin, Granzyme B, and TRAIL) in cells. Ratios of investigated cells were calculated as prediction factors by receiver operating characteristic curve (ROC) analysis.ResultsThe study revealed a reduction in intestinal CD8+ γδT cells among active CD patients, with a more pronounced reduction observed in moderately active patients compared to mildly active patients. Moreover, active CD patients exhibited heightened activation levels in their intestinal CD8+ γδT cells, whereas the activation was comparatively weakened in moderately active patients compared with mildly active patients. Additionally, the cytotoxicity of intestinal CD8+ γδT cells was enhanced solely in mildly active patients, while it was impaired in moderately active patients compared with mildly active patients. Furthermore, HLA-DR+ CD8+ γδT cell ratio, CD8+ γδT ratio, and CD8+ γδT count were identified as indicators in the diagnosis of active CD. Meanwhile, the ratios of Granzyme B+ CD8+ γδT cell and Perforin+ CD8+ γδT cell were identified as indicators that distinguish mildly moderately active CD cases.ConclusionsIntestinal CD8+ γδT was reduced in active CD patients, but their activation and cytotoxicity were enhanced. However, with increased disease activity, intestinal CD8+ γδ T cells became dysfunctional. CD-specific perturbations observed in various phenotypic markers in CD8+ γδ T cells can be used as indicators to assist in diagnosing CD patients.

Towards a patient-centred definition for atopic dermatitis flare: a qualitative study of adults with atopic dermatitis.

The term 'flare' is used across multiple diseases, including atopic dermatitis (AD), to describe increased disease activity. While several definitions of an AD flare have been proposed, no single definition of AD flare is widely accepted and it is unclear what the term 'AD flare' means from the patient perspective. To understand AD flares from the adult patient perspective and to explore how adults with AD define an AD flare. Participants were adults with AD recruited from the National Eczema Association Ambassadors programme, a volunteer patient-engagement programme. They participated in online focus groups to discuss how they describe AD flares from their perspective, how they define its start and stop, and how they relate to existing definitions of flare. Using a grounded theory approach, transcripts were analysed and coded using an iterative process to identify concepts to support a patient-centred conceptual framework of 'flare'. Six 90-min focus groups of 3-8 participants each were conducted with 29 US adults (≥ 18 years of age) with AD who had at least one self-reported AD flare in the past year. When participants were presented with examples of previously published definitions of AD flare, participants found them problematic and unrelatable. Specifically, they felt that flare is hard to quantify or put on a numerical scale, definitions cannot solely be about skin symptoms and clinical verbiage does not resonate with patients' lived experiences. Concepts identified by patients as important to a definition of flare were changes from patient's baseline/patient's normal, mental/emotional/social consequences, physical changes in skin, attention needed/all-consuming focus, itch-scratch-burn cycle and control/loss of control/quality of life. Figuring out the trigger that initiated a flare was an underlying concept of the experience of flare but was not considered a contributor to the definition. The results highlight the complexity and diversity of AD flare experiences from the adult patient perspective. Previously published definitions of AD flares did not resonate with patients, suggesting a need for a patient-centred flare definition to support care conversations and AD management.

Patients' Preferences for Systemic Lupus Erythematosus Treatments-A Discrete Choice Experiment.

Symptoms of systemic lupus erythematosus (SLE) vary between patients, but those of increased disease activity typically include musculoskeletal and mucocutaneous manifestations such as joint pain, swelling, and rashes. Several treatment options are available to patients with SLE with variable efficacy. Many treatments, especially corticosteroids, cause unwanted side effects, although little is currently known about patients' preferences for treatments of SLE. We aimed to identify which attributes of SLE treatment are valued by patients and to quantify their relative importance. Adult participants with moderate-to-severe SLE were asked to make a series of choices between two hypothetical treatments in an online discrete choice experiment (DCE). A latent class model (LCL) was estimated to analyze choice data. Relative attribute importance (RAI) was calculated to determine the importance of each attribute to participants. A total of 342 participants from the USA completed the survey. A three-class LCL model was found to have the best fit. Class 1 (non-attenders) had non-significant preferences across all attributes. To achieve a better fit, a constrained LCL (cLCL) model was run with the two remaining classes. The most important attributes for participants in class 2 (benefit-seekers) were joint pain (RAI = 32.0%), non-joint pain (RAI = 21.8%), fatigue (RAI = 20.1%), and skin rashes and itching (RAI = 19.1%). The most important attributes for participants in class 3 (risk-avoiders) were risk of non-severe side effects from corticosteroids (RAI = 28.4%), risk of severe side effects from corticosteroids (RAI = 21.4%), and the risk of infections (RAI = 19.2%). Risk-avoiders were more likely to have been diagnosed with SLE for a longer period (>1 year) and were more likely to have experience with oral corticosteroids. SLE patients fall into two groups with distinct preferences: benefit-seekers, who prioritize reducing the impact of disease symptoms, and risk-avoiders, who prioritize avoiding treatment risks. The implication of this finding will depend on the reasons for these differences, which warrant further research. Our study suggests that these differences arise due to the impact of disease and treatment experience on preferences. If so, well-informed patients may not be willing to tolerate the risks associated with oral corticosteroids in exchange for their benefits.