Diagnosis of Inflammatory Bowel Disease-Associated Peripheral Arthritis: A Systematic Review.

BACKGROUND: Inflammatory bowel disease (IBD)-associated peripheral spondyloarthritis (pSpA) decreases quality of life and remains poorly understood. Given the prevalence of this condition and its negative impact, it is surprising that evidence-based disease definitions and diagnostic strategies are lacking. This systematic review summarizes available data to facilitate development and validation of diagnostics, patient-reported outcomes, and imaging indices specific to this condition. METHODS: A literature search was conducted. Consensus or classification criteria, case series, cross-sectional studies, cohort studies, and randomized controlled trials related to diagnosis were included. RESULTS: A total of 44 studies reporting data on approximately 1500 patients with pSpA were eligible for analysis. Data quality across studies was only graded as fair to good. Due to large heterogeneity, meta-analysis was not possible. The majority of studies incorporated patient-reported outcomes and a physical examination. A total of 13 studies proposed or validated screening tools, consensus, classification, or consensus criteria. A total of 28 studies assessed the role of laboratory tests, none of which were considered sufficiently accurate for use in diagnosis. A total of 17 studies assessed the role of imaging, with the available literature insufficient to fully endorse any imaging modality as a robust diagnostic tool. CONCLUSIONS: This review highlights existing inconsistency and lack of a clear diagnostic approach for IBD-associated pSpA. Given the absence of an evidence-based approach, a combination of existing criteria and physician assessment should be utilized. To address this issue comprehensively, our future efforts will be directed toward pursuit of a multidisciplinary approach aimed at standardizing evaluation and diagnosis of IBD-associated pSpA.

This systematic review highlights the lack of an evidence-based approach to the diagnosis of inflammatory bowel disease­associated peripheral spondyloarthritis and the need to standardize evaluation and diagnosis via multidisciplinary collaboration with development of patient-reported outcomes and imaging indices.

Myeloid Cells and Sphingosine-1-Phosphate Are Required for TCRαß Intraepithelial Lymphocyte Recruitment to the Colon Epithelium.

Intraepithelial lymphocytes (IELs) are T cells important for the maintenance of barrier integrity in the intestine. Colon IELs are significantly reduced in both MyD88-deficient mice and those lacking an intact microbiota, suggesting that MyD88-mediated detection of bacterial products is important for the recruitment and/or retention of these cells. Here, using conditionally deficient MyD88 mice, we show that myeloid cells are the key mediators of TCRαß+ IEL recruitment to the colon. Upon exposure to luminal bacteria, myeloid cells produce sphingosine-1-phosphate (S1P) in a MyD88-dependent fashion. TCRαß+ IEL recruitment may be blocked using the S1P receptor antagonist FTY720, confirming the importance of S1P in the recruitment of TCRαß+ IELs to the colon epithelium. Finally, using the TNFΔARE/+ model of Crohn's-like bowel inflammation, we show that disruption of colon IEL recruitment through myeloid-specific MyD88 deficiency results in reduced pathology. Our results illustrate one mechanism for recruitment of a subset of IELs to the colon.

Oral Cannabis consumption and intraperitoneal THC:CBD dosing results in changes in brain and plasma neurochemicals and endocannabinoids in mice.

BACKGROUND: While the use of orally consumed Cannabis, cannabidiol (CBD) and tetrahydrocannabinol (THC) containing products, i.e. "edibles", has expanded, the health consequences are still largely unknown. This study examines the effects of oral consumption of whole Cannabis and a complex Cannabis extract on neurochemicals, endocannabinoids (eCB), and physiological parameters (body temperature, heart rate) in mice. METHODS: In this pilot study, C57BL/6 J mice were treated with one of the following every other day for 2 weeks: a complex Cannabis extract by gavage, whole Cannabis mixed with nutritional gel through free feeding, or purified THC/CBD by intraperitoneal (i.p.) injection. Treatments were conducted at 4 doses ranging from 0-100 mg/kg/day of CBD with THC levels of ≤ 1.2 mg/kg/day for free feeding and gavage and 10 mg/kg/day for i.p. Body temperature and heart rate were monitored using surgically implanted telemetry devices. Levels of neurochemicals, eCB, THC, CBD, and 11-OH-THC were measured using mass spectrometry 48 h after the final treatment. Statistical comparisons were conducted using ANOVA and t-tests. RESULTS: Differences were found between neurochemicals in the brains and plasma of mice treated by i.p. (e.g. dopamine, p < 0.01), gavage (e.g., phenylalanine, p < 0.05) and in mice receiving whole Cannabis (e.g., 3,4-dihydroxyphenylacetic DOPAC p < 0.05). Tryptophan trended downward or was significantly decreased in the brain and/or plasma of all mice receiving Cannabis or purified CBD/THC, regardless of dose, compared to controls. Levels of the eCB, arachidonoyl glycerol (2-AG) were decreased in mice receiving lowest doses of a complex Cannabis extract by gavage, but were higher in mice receiving highest doses compared to controls (p < 0.05). Plasma and brain levels of THC and 11-OH-THC were higher in mice receiving 1:1 THC:CBD by i.p. compared to those receiving 1:5 or 1:10 THC:CBD. Nominal changes in body temperature and heart rate following acute and repeated exposures were seen to some degree in all treatments. CONCLUSIONS: Changes to neurochemicals and eCBs were apparent at all doses regardless of treatment type. Levels of neurochemicals seemed to vary based on the presence of a complex Cannabis extract, suggesting a non-linear response between THC and neurochemicals following repeated oral dosing.

Microbial Mechanisms of Rheumatoid Arthritis Pathogenesis.

PURPOSE OF REVIEW: Host-microbiome interactions have been implicated in the pathophysiology of rheumatoid arthritis (RA), but the data linking specific microbes to RA is largely associative. Here, we review recent studies that have interrogated specific mechanistic links between microbes and host in the setting of RA. RECENT FINDINGS: Several candidate bacterial species and antigens that may trigger the conversion of an anti-bacterial to an autoimmune response have been recently identified. Additional studies have identified microbial metabolic pathways that are altered in RA. Some of these microbial species and metabolic pathways have been validated in mouse models to induce RA-like immune responses, providing initial evidence of specific mechanisms by which the microbiota contributes to the development of RA. Several microbial species, antigens, and metabolites have been identified as potential contributors to RA pathophysiology. Further interrogation and validation of these pathways may identify novel biomarkers of or therapeutic avenues for RA.

IL-10mpting TH17 cell fate in the gut.

Interleukin-10 mediates regulatory functions of commensal-specific TH17 cells in murine small intestine.

Ambiguity in advertised compensation: Recruiting implications of nominal compliance with pay transparency legislation.

Pursuant to legislative mandates the proportion of job postings that include wage and salary information has rapidly increased. However, many organizations comply by advertising very broad salary ranges. Here, we examine how the width of a pay range influences prospective applicants' perceptions. Although in other contexts people often exhibit a preference for vaguely specified gains, we draw from decision and signaling theories to hypothesize negative reactions to highly ambiguous pay ranges and test them in three preregistered experiments. In Study 1, business students evaluate a job posting with the width of the salary range manipulated between subjects. Study 2 tests for moderating effects of ambiguity explanations using a within-subjects manipulation of pay range width counterbalanced across two job postings and a sample of college graduates with relevant work experience. In Study 3, a diverse sample of recent job seekers predict a salary offer for a hiring vignette in which both the extent of ambiguity in the advertised pay range and the chosen candidate's qualifications are manipulated; their qualitative impressions of the organization are also analyzed. Results provide converging evidence for modal aversion to high ambiguity resulting from negative effects on perceived organizational trustworthiness and skewed predictions of salary offers. Practical implications of this aspect of pay transparency are discussed, as well as broader theoretical implications for understanding outcome ambiguity effects in domains where decision makers vary in their beliefs about underlying reasons for vagueness in communicated information. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

MAIT cells drive chronic inflammation in a genetically diverse murine model of spontaneous colitis.

Background & aims: Lymphocytes that produce IL-17 can confer protective immunity during infections by pathogens, yet their involvement in inflammatory diseases is a subject of debate. Although these cells may perpetuate inflammation, resulting in tissue damage, they are also capable of contributing directly or indirectly to tissue repair, thus necessitating more detailed investigation. Mucosal-Associated-Invariant-T (MAIT) cells are innate-like T cells, acquiring a type III phenotype in the thymus. Here, we dissected the role of MAIT cells in vivo using a spontaneous colitis model in a genetically diverse mouse strain. Methods: Multiparameter spectral flow cytometry and scRNAseq were used to characterize MAIT and immune cell dynamics and transcriptomic signatures respectively, in the collaborative-cross strain, CC011/Unc and CC011/Unc- Traj33 -/- . Results: In contrast to many conventional mouse laboratory strains, the CC011 strain harbors a high baseline population of MAIT cells. We observed an age-related increase in colonic MAIT cells, Th17 cells, regulatory T cells, and neutrophils, which paralleled the development of spontaneous colitis. This progression manifested histological traits reminiscent of human IBD. The transcriptomic analysis of colonic MAIT cells from CC011 revealed an activation profile consistent with an inflammatory milieu, marked by an enhanced type-III response. Notably, IL-17A was abundantly secreted by MAIT cells in the colons of afflicted mice. Conversely, in the MAIT cell-deficient CC011-Traj33-/- mice, there was a notable absence of significant colonic histopathology. Furthermore, myeloperoxidase staining indicated a substantial decrease in colonic neutrophils. Conclusions: Our findings suggest that MAIT cells play a pivotal role in modulating the severity of intestinal pathology, potentially orchestrating the inflammatory process by driving the accumulation of neutrophils within the colonic environment.

Microbiota-dependent indole production stimulates the development of collagen-induced arthritis in mice.

Altered tryptophan catabolism has been identified in inflammatory diseases like rheumatoid arthritis (RA) and spondyloarthritis (SpA), but the causal mechanisms linking tryptophan metabolites to disease are unknown. Using the collagen-induced arthritis (CIA) model, we identified alterations in tryptophan metabolism, and specifically indole, that correlated with disease. We demonstrated that both bacteria and dietary tryptophan were required for disease and that indole supplementation was sufficient to induce disease in their absence. When mice with CIA on a low-tryptophan diet were supplemented with indole, we observed significant increases in serum IL-6, TNF, and IL-1ß; splenic RORγt+CD4+ T cells and ex vivo collagen-stimulated IL-17 production; and a pattern of anti-collagen antibody isotype switching and glycosylation that corresponded with increased complement fixation. IL-23 neutralization reduced disease severity in indole-induced CIA. Finally, exposure of human colonic lymphocytes to indole increased the expression of genes involved in IL-17 signaling and plasma cell activation. Altogether, we propose a mechanism by which intestinal dysbiosis during inflammatory arthritis results in altered tryptophan catabolism, leading to indole stimulation of arthritis development. Blockade of indole generation may present a unique therapeutic pathway for RA and SpA.

Interplay of gut microbiota and host epithelial mitochondrial dysfunction is necessary for the development of spontaneous intestinal inflammation in mice.

BACKGROUND: Intestinal epithelial cell (IEC) mitochondrial dysfunction involvement in inflammatory bowel diseases (IBD), including Crohn's disease affecting the small intestine, is emerging in recent studies. As the interface between the self and the gut microbiota, IECs serve as hubs of bidirectional cross-talk between host and luminal microbiota. However, the role of mitochondrial-microbiota interaction in the ileum is largely unexplored. Prohibitin 1 (PHB1), a chaperone protein of the inner mitochondrial membrane required for optimal electron transport chain function, is decreased during IBD. We previously demonstrated that mice deficient in PHB1 specifically in IECs (Phb1i∆IEC) exhibited mitochondrial impairment, Paneth cell defects, gut microbiota dysbiosis, and spontaneous inflammation in the ileum (ileitis). Mice deficient in PHB1 in Paneth cells (epithelial secretory cells of the small intestine; Phb1∆PC) also exhibited mitochondrial impairment, Paneth cell defects, and spontaneous ileitis. Here, we determined whether this phenotype is driven by Phb1 deficiency-associated ileal microbiota alterations or direct effects of loss of PHB1 in host IECs. RESULTS: Depletion of gut microbiota by broad-spectrum antibiotic treatment in Phb1∆PC or Phb1i∆IEC mice revealed a necessary role of microbiota to cause ileitis. Using germ-free mice colonized with ileal microbiota from Phb1-deficient mice, we show that this microbiota could not independently induce ileitis without host mitochondrial dysfunction. The luminal microbiota phenotype of Phb1i∆IEC mice included a loss of the short-chain fatty acid butyrate. Supplementation of butyrate in Phb1-deficient mice ameliorated Paneth cell abnormalities and ileitis. Phb1-deficient ileal enteroid models suggest deleterious epithelial-intrinsic responses to ileal microbiota that were protected by butyrate. CONCLUSIONS: These results suggest a mutual and essential reinforcing interplay of gut microbiota and host IEC, including Paneth cell, mitochondrial health in influencing ileitis. Restoration of butyrate is a potential therapeutic option in Crohn's disease patients harboring epithelial cell mitochondrial dysfunction. Video Abstract.

Microbiota-dependent indole production is required for the development of collagen-induced arthritis.

Altered tryptophan catabolism has been identified in inflammatory diseases like rheumatoid arthritis (RA) and spondyloarthritis (SpA), but the causal mechanisms linking tryptophan metabolites to disease are unknown. Using the collagen-induced arthritis (CIA) model we identify alterations in tryptophan metabolism, and specifically indole, that correlate with disease. We demonstrate that both bacteria and dietary tryptophan are required for disease, and indole supplementation is sufficient to induce disease in their absence. When mice with CIA on a low-tryptophan diet were supplemented with indole, we observed significant increases in serum IL-6, TNF, and IL-1ß; splenic RORγt+CD4+ T cells and ex vivo collagen-stimulated IL-17 production; and a pattern of anti-collagen antibody isotype switching and glycosylation that corresponded with increased complement fixation. IL-23 neutralization reduced disease severity in indole-induced CIA. Finally, exposure of human colon lymphocytes to indole increased expression of genes involved in IL-17 signaling and plasma cell activation. Altogether, we propose a mechanism by which intestinal dysbiosis during inflammatory arthritis results in altered tryptophan catabolism, leading to indole stimulation of arthritis development. Blockade of indole generation may present a novel therapeutic pathway for RA and SpA.

A Review of Difficult-to-Treat Rheumatoid Arthritis: Definition, Clinical Presentation, and Management.

PURPOSE OF REVIEW: A subset of patients with rheumatoid arthritis (RA) who fail multiple biologic therapies are deemed to have "difficult-to-treat" (D2T) RA. In 2021, a European Alliance of Associations for Rheumatology (EULAR) task force proposed a clinical definition of D2T RA. Here we review RA phenotypes and clinical assessment of RA, propose a different definition of D2T RA, discuss possible D2T RA risk factors, and summarize existing literature on the management of D2T RA. RECENT FINDINGS: High disease activity at the time of diagnosis or prior to treatment with a biologic is associated with the development of D2T RA. Prolonged time from diagnosis to beginning treatment has been consistently associated with the development of D2T RA. Other clinical factors such as burden of disease, extraarticular disease, obesity, smoking, pain, fatigue, and psychological conditions have inconsistent associations with D2T RA according to current literature. D2T RA is a relatively new concept that represents an area of great need for research regarding the characterization of those with the disease as well as how best to treat the disease. With this gained knowledge, rheumatologists will be able to better identify patients at the time of diagnosis that are likely to develop D2T RA to help guide management.

3,3-dimethyl-1-butanol and its metabolite 3,3-dimethylbutyrate ameliorate collagen-induced arthritis independent of choline trimethylamine lyase activity.

Previous studies have identified significant alterations in intestinal carnitine metabolism in mice with collagen-induced arthritis (CIA), potentially linking bacterial dysbiosis with autoimmunity. Bacterial trimethylamine (TMA) lyases metabolize dietary carnitine to TMA, which is oxidized in the liver to trimethylamine-N-oxide (TMAO). TMAO is associated with inflammatory diseases, such as atherosclerosis, whose immunologic processes mirror that of rheumatoid arthritis (RA). Therefore, we investigated the possibility of ameliorating CIA by inhibiting TMA lyase activity using 3,3-dimethyl-1-butanol (DMB) or fluoromethylcholine (FMC). During CIA, mice were treated with 1% vol/vol DMB, 100mg/kg FMC, or vehicle. DMB-treated mice demonstrated significant (>50%) reduction in arthritis severity compared to FMC and vehicle-treated mice. However, in contrast to FMC, DMB treatment did not reduce cecal TMA nor circulating TMAO concentrations. Using gas chromatography, we confirmed the effect of DMB is independent of TMA lyase inhibition. Further, we identified a novel host-derived metabolite of DMB, 3,3-dimethyl-1-butyric acid (DMBut), which also significantly reduced disease and proinflammatory cytokines in CIA mice. Altogether, our study suggests that DMB the immunomodulatory activity of DMB and/or its metabolites are protective in CIA. Elucidating its target and mechanism of action may provide new directions for RA therapeutic development.

Impact of the COVID-19 Pandemic on Early Career Investigators in Rheumatology: Recommendations to Address Challenges to Early Research Careers.

OBJECTIVE: The COVID-19 pandemic has impacted the careers of trainees and early career investigators (ECIs). We sought to assess how the American College of Rheumatology (ACR) and the Rheumatology Research Foundation (RRF) can address the needs of those pursuing research careers. METHODS: The Committee on Research created a survey to assess the impact of COVID-19 and identify topics for the ACR and the RRF to address. In fall of 2020, we surveyed postdoctoral trainees and ECIs within 9 years of terminal training. Responses were analyzed using descriptive statistics and qualitative content analysis. RESULTS: Twenty-one percent of invitees responded to the survey (n = 365); of these, 60% were pursuing careers in academic research. Seventy-five percent of respondents in academic research career paths placed their primary projects on hold during the pandemic. The number of individuals pursuing a research career from 2020 to 2021 decreased by 5%. Respondents reported funding, caregiving, and lack of preliminary data as significant challenges. Suggested impactful interventions included increased funding, funding process reform, and expanding mentoring and networking resources. CONCLUSION: Major stressors identified during the pandemic included increased caregiving responsibilities and difficulty obtaining data and funding, for which respondents suggested increases and changes in funding programs as well as more mentoring and networking opportunities. Based on these, the Committee on Research proposes 3 priorities: 1) flexible funding mechanisms for ECIs and additional support for those impacted by caregiving; 2) virtual and in-person programs for career development and networking; and 3) curated content relevant to building a research career available on demand.

Mechanism-driven strategies for prevention of rheumatoid arthritis.

In seropositive rheumatoid arthritis (RA), the onset of clinically apparent inflammatory arthritis (IA) is typically preceded by a prolonged period of autoimmunity manifest by the presence of circulating autoantibodies that can include antibodies to citrullinated protein antigens (ACPA) and rheumatoid factor (RF). This period prior to clinical IA can be designated preclinical RA in those individuals who have progressed to a clinical diagnosis of RA, and an 'at-risk' status in those who have not developed IA but exhibit predictive biomarkers of future clinical RA. With the goal of developing RA prevention strategies, studies have characterized immune phenotypes of preclinical RA/at-risk states. From these studies, a model has emerged wherein mucosal inflammation and dysbiosis may lead first to local autoantibody production that should normally be transient, but instead is followed by systemic spread of the autoimmunity as manifest by serum autoantibody elevations, and ultimately drives the development of clinically identified joint inflammation. This model can be envisioned as the progression of disease development through serial 'checkpoints' that in principle should constrain or resolve autoimmunity; however, instead the checkpoints 'fail' and clinical RA develops. Herein we review the immune processes that are likely to be present at each step and the potential therapeutic strategies that could be envisioned to delay, diminish, halt or even reverse the progression to clinical RA. Notably, these prevention strategies could utilize existing therapies approved for clinical RA, therapies approved for other diseases that target relevant pathways in the preclinical/at-risk state, or approaches that target novel pathways.

Clonal IgA and IgG autoantibodies from individuals at risk for rheumatoid arthritis identify an arthritogenic strain of Subdoligranulum.

The mucosal origins hypothesis of rheumatoid arthritis (RA) proposes a central role for mucosal immune responses in the initiation or perpetuation of the systemic autoimmunity that occurs with disease. However, the connection between the mucosa and systemic autoimmunity in RA remains unclear. Using dual immunoglobulin A (IgA) and IgG family plasmablast-derived monoclonal autoantibodies obtained from peripheral blood of individuals at risk for RA, we identified cross-reactivity between RA-relevant autoantigens and bacterial taxa in the closely related families Lachnospiraceae and Ruminococcaceae. After generating bacterial isolates within the Lachnospiraceae/Ruminococcaceae genus Subdoligranulum from the feces of an individual, we confirmed monoclonal antibody binding and CD4+ T cell activation in individuals with RA compared to control individuals. In addition, when Subdoligranulum isolate 7 but not isolate 1 colonized germ-free mice, it stimulated TH17 cell expansion, serum RA-relevant IgG autoantibodies, and joint swelling reminiscent of early RA, with histopathology characterized by antibody deposition and complement activation. Systemic immune responses were likely due to mucosal invasion along with the generation of colon-isolated lymphoid follicles driving increased fecal and serum IgA by isolate 7, because B and CD4+ T cell depletion not only halted intestinal immune responses but also eliminated detectable clinical disease. In aggregate, these findings demonstrate a mechanism of RA pathogenesis through which a specific intestinal strain of bacteria can drive systemic autoantibody generation and joint-centered antibody deposition and immune activation.

Cytokine competent gut-joint migratory T Cells contribute to inflammation in the joint.

Although studies have identified the presence of gut-associated cells in the enthesis of joints affected by spondylarthritis (SpA), a direct link through cellular transit between the gut and joint has yet to be formally demonstrated. Using KikGR transgenic mice to label in situ and track cellular trafficking from the distal colon to the joint under inflammatory conditions of both the gut and joint, we demonstrate bona-fide gut-joint trafficking of T cells from the colon epithelium, also called intraepithelial lymphocytes (IELs), to distal sites including joint enthesis, the pathogenic site of SpA. Similar to patients with SpA, colon IELs from the TNFΔARE/+ mouse model of inflammatory bowel disease and SpA display heightened TNF production upon stimulation. Using ex vivo stimulation of photo-labeled gut-joint trafficked T cells from the popliteal lymph nodes of KikGR and KikGR TNFΔARE/+ we saw that the CD4+ photo-labeled population was highly enriched for IL-17 competence in healthy as well as arthritic mice, however in the TNFΔARE/+ mice these cells were additionally enriched for TNF. Using transfer of magnetically isolated IELs from TNF+/+ and TNFΔARE/+ donors into Rag1 -/- hosts, we confirmed that IELs can exacerbate inflammatory processes in the joint. Finally, we blocked IEL recruitment to the colon epithelium using broad spectrum antibiotics in TNFΔARE/+ mice. Antibiotic-treated mice had reduced gut-joint IEL migration, contained fewer Il-17A and TNF competent CD4+ T cells, and lessened joint pathology compared to untreated littermate controls. Together these results demonstrate that pro-inflammatory colon-derived IELs can exacerbate inflammatory responses in the joint through systemic trafficking, and that interference with this process through gut-targeted approaches has therapeutic potential in SpA.

Gender-based effect of absence of gut microbiota on the protective efficacy of Bifidobacterium longum-fermented rice bran diet against inflammation-associated colon tumorigenesis.

Dietary rice bran (RB) has shown capacity to influence metabolism by modulation of gut microbiota in individuals at risk for colorectal cancer (CRC), which warranted attention for delineating mechanisms for bidirectional influences and cross-feeding between the host and RB-modified gut microbiota to reduce CRC. Accordingly, in the present study, fermented rice bran (FRB, fermented with a RB responsive microbe Bifidobacterium longum), and non-fermented RB were fed as 10% w/w (diet) to gut microbiota-intactspf or germ-free micegf to investigate comparative efficacy against inflammation-associated azoxymethane/dextran sodium sulfate (AOM/DSS)-induced CRC. Results indicated both microbiota-dependent and independent mechanisms for RB meditated protective efficacy against CRC that was associated with reduced neoplastic lesion size and local-mucosal/systemic inflammation, and restoration of colonic epithelial integrity. Enrichment of beneficial commensals (such as, Clostridiales, Blautia, Roseburia), phenolic metabolites (benzoate and catechol metabolism), and dietary components (ferulic acid-4 sulfate, trigonelline, and salicylate) were correlated with anti-CRC efficacy. Germ-free studies revealed gender-specific physiological variables could differentially impact CRC growth and progression. In the germ-free females, the RB dietary treatment showed a ∼72% reduction in the incidence of colonic epithelial erosion when compared to the ∼40% reduction in FRB-fed micegf . Ex vivo fermentation of RB did not parallel the localized-protective benefits of gut microbial metabolism by RB in damaged colonic tissues. Findings from this study suggest potential needs for safety considerations of fermented fiber rich foods as dietary strategies against severe inflammation-associated colon tumorigenesis (particularly with severe damage to the colonic epithelium).

Novel Biomarker of Collagen Degradation Can Identify Patients Affected With Both Axial Spondyloarthritis and Crohn Disease.

OBJECTIVE: Chronic inflammatory arthritis is a hallmark of axial spondyloarthritis (axSpA), where coexistence of Crohn disease (CD) is prominent. We investigated the association between biomarkers of collagen degradation in healthy controls (HCs) and in patients with axSpA, CD, and CD and axSpA overlap (CD-axSpA), with the aim to investigate the ability of the biomarkers to identify patients with CD-axSpA. METHODS: Patients with axSpA who fulfilled Assessment of Spondyloarthritis international Society criteria (n = 13), had biopsy-proven CD (n = 14), had CD-axSpA (n = 10), and HCs (n = 11) undergoing standard-of-care colonoscopies were included in the study. The collagen biomarkers measuring type III, IV, VI and X collagen (C3M, C4M, C6M, and C10C, respectively) were measured in plasma samples from all subject groups. Statistical analysis was performed using an ANCOVA adjusted for age, an area under the receiver-operating characteristic (AUROC) curve analysis, and Spearman correlation. RESULTS: C4M was significantly higher in patients with CD-axSpA overlap compared to axSpA, CD, and HCs (all P < 0.001). In an AUROC analysis, C4M showed a complete separation between the patients with CD-axSpA overlap compared to HC, axSpA and CD with an area under the curve (AUC) = 1.00 (P < 0.001). No differences were found between the patient groups for C3M, C6M, and C10C. No correlations were found between the collagen biomarkers and C-reactive protein, Bath Ankylosing Spondylitis Disease Activity Index, Simple Clinical Colitis Activity Index, or Harvey-Bradshaw Index scores. CONCLUSION: Degradation of type IV collagen quantified by C4M showed a complete separation of patients with CD-axSpA overlap, compared to axSpA, CD, and HCs, and indicates excessive collagen degradation and epithelial turnover. This biomarker could potentially be used to identify patients affected by both manifestations and to guide treatment decisions.

A United States expert consensus to standardise definitions, follow-up, and treatment targets for extra-intestinal manifestations in inflammatory bowel disease.

BACKGROUND AND AIMS: Extra-intestinal manifestations (EIMs) are a common complication of inflammatory bowel diseases (IBD), affecting up to half of the patients. Despite their high prevalence, information on standardised definitions, diagnostic strategies, and treatment targets is limited. METHODS: As a starting point for a national EIM study network, an interdisciplinary expert panel of 12 gastroenterologists, 4 rheumatologists, 3 ophthalmologists, 6 dermatologists, and 4 patient representatives was assembled. Modified Delphi consensus methodology was used. Fifty-four candidate items were derived from the literature review and expert opinion focusing on five major EIMs (erythema nodosum, pyoderma gangrenosum, uveitis, peripheral arthritis, and axial arthritis) were rated in three voting rounds. RESULTS: For use in a clinical practice setting and as part of the creation of a prospective registry of patients with EIMs, the panel developed definitions for erythema nodosum, pyoderma gangrenosum, uveitis, peripheral arthritis, and axial arthritis; identified the appropriate and optimal subspecialists to diagnose and manage each; provided methods to monitor disease course; offered guidance regarding monitoring intervals; and defined resolution and recurrence. CONCLUSIONS: Consensus criteria for appropriate and optimal means of diagnosing and monitoring five EIMs have been developed as a starting point to inform clinical practice and future trial design. Key findings include straightforward diagnostic criteria, guidance regarding who can appropriately and optimally diagnose each, and monitoring options that include patient and physician-reported outcomes. These findings will be used in a national multicenter study network to optimise the management of EIMs.