Inflammatory Flares Research Articles

P0769 Impact of Nurse-Led Day Case Management of Acute Inflammatory Bowel Disease Flares on Admissions to Hospital

Abstract Background To assess the impact on admissions to hospital when patients are treated on a nurse led day case unit for inflammatory bowel disease flares over a 1-year period. Methods During the COVID 19 pandemic, patients were reluctant to be admitted to hospital and where possible wanted care as day case patients. This has continued due to the pressures of the acute gastroenterology hospital ward and demand for bed spaces. The Gastroenterology and Medical Ambulatory Care Unit allowed for rapid assessment, diagnosis, and treatment with appropriate safety netting for this group of patients. 63 patients where identified. Those who needed admission were advised to do so based on presenting symptoms and response to treatment. Data Collection and Results 63 patients presented to the Unit with a pre-existing diagnosis of IBD, 88% (n=55) where Ulcerative Colitis and 12% (n=8) Crohns Disease and had failed to suppress the flare with oral steroid and topical therapies. Symptoms varied from loose stools, urgency, bleeding, pain, lethargic and dehydration, common signs of an IBD flare, (Sturm and White 2019). Patients were offered admission, however all wanted to be treated as a day case on the proviso that if needed admission would be arranged. The aim was to give the same initial flare treatment as would be received on the ward. Hydrocortisone 200mg IV am followed by 500mls of IV fluids and a further Hydrocortisone 200mg IV in the pm. Patients were also supported by the team on the Unit during their flare allowing perspective to be placed on their disease and management as a whole. Open dialogue was held with the Unit and IBD nursing teams further enhancing patient care. Bloods and faecal calprotectin were checked as a baseline for our interventions. Results Of the 63 only 9.5% (n=6) did not respond and needed admission. Conclusion: Outcome and Recommendations Overall patients were happy with and responded to treatment in the day case unit. This saved at least 171 bed days in hospital based on a minimum of 3 days per patient treated. Being able to access support as well as treatment worked well. Day case assessment treatment and care has a clear future for this group of patients providing patients are selected appropriately. References Sturm A and White L (2019) Inflammatory Bowel Disease Nursing Manual. Springer

P1155 Safety of Venous Thromboembolism Pharmacological Prophylaxis in Hospitalized Patients with Inflammatory Bowel Disease; A Single Center Retrospective Study (VISCOUS)

Abstract Background Hospitalization secondary to inflammatory bowel disease flare is a significant risk factor for venous thromboembolism (VTE). International guidelines recommend the use of pharmacological VTE prophylaxis; however, the risk of bleeding is unknown. We therefore aimed to evaluate the safety of pharmacological thromboprophylaxis in hospitalized patients with IBD. Methods This was a retrospective cohort study. A chart review of patients’ electronic health records with IBD hospitalized between August 2017 to December 2023 was reviewed. Our primary outcome is evaluating the safety of pharmacological VTE prophylaxis. This was investigated by examining increased bleeding risks during admission, which included worsening bloody stool frequency, drop in hemoglobin (>1g/dL from baseline) and development of hemorrhagic shock after starting VTE prophylaxis. Worsening bloody stool frequency was defined as increased bloody stool frequency >1 from baseline before starting VTE prophylaxis. Finally, any major bleeding was also considered. Results Between August 2017 and December 2023, 1045 patient encounters were reviewed. 524 patients met the study inclusion and exclusion criteria, of which 98 had missing information and 73 were duplicates and could not be included. Finally, 353 patients were included in our study. Mean age 34.7 years, 205 (58%) were female males and mean duration of hospitalization was 9 days. Majority of patients were hospitalized with acute severe ulcerative colitis (ASUC) 213 (60.3%), and 140 (39.7%) had Crohn’s disease (CD) flare. Of the total cohort, 264 (75%) patients received enoxaparin 40 mg for VTE prophylaxis, and the 89 (25%) patients received 5000 units of unfractionated heparin twice a day (figure 1). Eighteen (%5) patients had a history of VTE, and 4 female patients had VTE during admission. None of our cohort had any bleeding events including worsening bloody stool frequency, drop in hemoglobin, major bleeding and development of hemorrhagic shock after starting VTE prophylaxis up to the period patients were discharged. Conclusion we found no increased risk of gastrointestinal bleeding in patients admitted with IBD on pharmacological VTE prophylaxis. Therefore, it is important to reassure healthcare providers about the safety of pharmacological VTE prophylaxis in IBD and adopt strategies that guarantee prophylaxis is administered during hospitalization. Although that a balance should be established between the benefits and risks. References -Pleet JL, Vaughn BP, Morris JA, et al. The use of pharmacological prophylaxis against venous thromboembolism in hospitalised patients with severe active ulcerative colitis. Aliment Pharmacol Ther [Internet]. 2014;39(9):940–948. -Dawwas GK, Cuker A, Schaubel DE, et al. Effectiveness and safety of prophylactic anticoagulation among hospitalized patients with inflammatory bowel disease. Blood Adv [Internet]. 2024;8(5):1272–1280. -Kaddourah O, Numan L, Jeepalyam S, et al. Venous thromboembolism prophylaxis in inflammatory bowel disease flare-ups. Ann Gastroenterol. 2019;32(6):578–583.

Microscopic colitis as pre-inflammatory bowel disease model: from early-stage to tissular endpoint fibrosis

Abstract Background and aims Inflammatory bowel disease (IBD) cause chronic relapsing-remitting inflammatory flares in the gastrointestinal tract, resulting in abdominal pain, diarrhea, and gut dysmotility in non-destructive collagenous and lymphocytic microscopic colitis. In addition, classic IBDs Crohn´s disease and ulcerative colitis cause bloody diarrhea and extraintestinal symptoms. Non-destructive IBDs seem to restrain an overt immune response that will damage the tissue and impair wound healing. Thus, I will work under the premise that non-destructive IBDs are undeveloped forms of classic IBDs. Methods First, I aim to deeply characterize and compare immune cells and their activation levels in all forms of IBD using “immunomics” (spectral/computational cytometry) and validate my previous finding of two subtypes of lymphocytic colitis. To identify the microbiota that adheres to intestinal epithelial cell (IEC) and therefore alter permeability, and induce collagen deposition, I will coculture IEC and fibroblasts in organ-on-a-chip platforms to mimic gut conditions, including microflow shear stress. I will stimulate chips with patient-derived microbiota-containing luminal content or homogenized biopsies and resections from collagenous colitis (characterized by pathogenic collagen position) and intestinal fibrosis (a major, irreversible IBD complication that increases mortality), respectively, and study using different sequencing techniques. Of note, collagenous colitis could resemble early stages of intestinal fibrosis. My third objective aims to test my previous observation that regulatory B-cells in collagenous colitis might be responsible of restricting overt inflammation. Anticipated impact I will adapt spectral cytometry panels to characterize the state of mucosal B- and plasma cells. The support of my host, the well-established IBD immunologist Assoc. Prof. David Bernardo at the Institute of Biomedicine and Molecular Genetics (Valladolid, Spain, h-index=33) and me as coordinator of the biobank for the European Microscopic Colitis Group, ensure the feasibility to complete my ambitious research agenda and make a great impact on IBD field to discover disease-specific biomarkers, pathomechanisms, and new druggable targets.

Physiological Data Collected from Wearable Devices Identify and Predict Inflammatory Bowel Disease Flares.

Wearable devices capture physiological signals non-invasively and passively. Many of these parameters have been linked to inflammatory bowel disease (IBD) activity. We evaluated the associative ability of several physiological metrics with IBD flares and how they change before the development of flare. Participants throughout the United States answered daily disease activity surveys and wore an Apple Watch, Fitbit or Oura Ring. These devices collected longitudinal heart rate (HR), resting heart rate (RHR), heart rate variability (HRV), steps, and oxygenation (SpO2). C-reactive protein, erythrocyte sedimentation rate and fecal calprotectin were collected as standard of care. Linear mixed-effect models were implemented to analyze HR, RHR, steps, and SpO2, while cosinor mixed-effect models were applied to HRV circadian features. Mixed effect logistic regression was used to determine the predictive ability of physiological metrics. 309 participants were enrolled across 36 states. Circadian patterns of HRV significantly differed between periods of inflammatory flare and remission, and symptomatic flare and remission. Marginal means for HR and RHR were higher during periods of inflammatory flare and symptomatic flare. There was lower daily steps during inflammatory flares. HRV, HR, and RHR differentiated whether participants with symptoms had inflammation. HRV, HR, RHR, steps, and SpO2 were significantly altered up to 7 weeks prior to inflammatory and symptomatic flares. Longitudinally collected physiological metrics from wearable devices can identify and change prior to IBD flares, suggesting their feasibility to monitor and predict IBD activity.

Pharmacology of Intestinal Inflammation and Repair.

Chronic inflammation is a common trait in the pathogenesis of several diseases of the gut, including inflammatory bowel disease and celiac disease. Control of the inflammatory response is crucial in these pathologies to avoid tissue destruction and loss of intestinal function. Over the last 50years, the identification of the mechanisms and mediators involved in the acute phase of the inflammatory response, which is characterized by massive leukocyte recruitment, has led to a number of therapeutic options. New drugs targeting inflammatory flares are still under development. However, interest on the other end of the spectrum-the resolution and repair phases-has emerged, as promoting tissue functional repair may maintain remission and counteract the chronicity of the disease. This review aims to discuss the current and future pharmacological approaches to the treatment of chronic intestinal inflammation and the restoration of functional tissues.

Late-Onset Inflammatory Bowel Disease and Flares In Adenoviral and Inactivated Coronavirus Vaccine Recipients.

Late-Onset Inflammatory Bowel Disease and Flares In Adenoviral and Inactivated Coronavirus Vaccine Recipients.

Subcortical plaques and inflammation reflect cortical and meningeal pathologies in progressive multiple sclerosis.

It remains elusive whether lesions and inflammation in the sub/juxtacortical white matter reflect cortical and/or meningeal pathologies. Elucidating this could have implications for MRI monitoring as sub/juxtacortical lesions are detectable by routine MRI, while cortical lesions and meningeal inflammation are not. By large-area microscopy, we quantified total and mixed active plaque loads along with densities and sizes of perivascular mononuclear infiltrates (infiltrates) in the sub/juxtacortical white matter ≤2 mm from the cortex, intra-cortically and in the meninges. Data were related to ante-mortem clinical parameters in a false discovery rate-corrected analysis. We compared 12 patients with primary progressive multiple sclerosis (PPMS) and 15 with secondary progressive MS to 22 controls. Fifteen patients and 11 controls contributed with hemispheric sections. Sections were stained with haematoxylin-eosin, for myelin and for microglia/macrophages. B cells and T cells were confirmed in a subset. Immunoglobulin G depositions in selected cortical plaques resembled depositions described before in "slowly expanding" plaques in the white matter. We quantified plaque activity by measuring microglia-dominated and macrophage-dominated areas. Sub/juxtacortical plaques (load and activity) reflected plaque activity in the cerebral cortex. Plaque activity and infiltrates were more pronounced in the sub/juxtacortical white matter than in the cerebral cortex while conversely, the total plaque load was highest in the cortex. Infiltrates correlated trans-cortically and sub/juxtacortical plaque activity reflected cortical and meningeal infiltrates. Sub/juxtacortical infiltrate sizes correlated with shorter survival after progression onset. Two patients with PPMS and putatively fatal brain stem lesions argue against incidental findings. Trans-cortical inflammatory flares and plaque activity may be pathogenic in progressive MS. We suggest emphasis on sub/juxtacortical MRI lesions as plausible surrogates for cortical and meningeal pathologies and, when present, as indicators for cognitive testing.

Post-Discharge Outcomes of Elderly Patients Hospitalized for Inflammatory Bowel Disease Flare Complicated by Clostridioides difficile Infection.

Elderly hospitalized patients with inflammatory bowel disease (IBD) flare and concurrent Clostridioides difficile infection (CDI) are considered at high risk of IBD-related complications. We aimed to evaluate the short, intermediate, and long-term post-discharge complications among these patients. A retrospective multicenter cohort study assessing outcomes of elderly individuals (≥60 years) hospitalized for an IBD flare who were tested for CDI (either positive or negative) and discharged. The primary outcome was the 3-months post-discharge IBD-related complication rates defined as: steroid dependency, re-admissions (emergency department or hospitalization), IBD-related surgery, or mortality. We assessed post-discharge IBD-related complications within 6-months and mortality at 12-months among secondary outcomes. Risk factors for complication were assessed by multivariable logistic regression. In a cohort of 654 patients hospitalized for IBD (age 68.9 [interquartile range {IQR}]:63.9-75.2) years, 60.9% ulcerative colitis), 23.4% were CDI-positive. Post-discharge complication rates at 3 and 6-months, and 12-months mortality, did not differ significantly between CDI-positive and CDI-negative patients (32% vs. 33.1%, p=0.8; 40.5% vs. 42.5%, p=0.66; and 4.6% vs. 8%, p=0.153, respectively). The Charlson comorbidity index was the only significant risk factor for complications within 3-months (aOR 1.1), whereas mesalamine (5-aminosalicylic acid [5-ASA]) use was protective (aOR 0.6). An ulcerative colitis diagnosis was the sole risk factor for complication at 6-months (aOR 1.5). CDI did not significantly impact outcomes or interact with IBD type. In elderly IBD patients hospitalized for IBD flare and subsequently discharged, a concurrent CDI infection was not associated with post-discharge IBD-related complications or mortality up to 1-year.

New insights on hidradenitis suppurativa phenotypes and treatment response: An exploratory automated analysis of the SUNSHINE and SUNRISE trials.

Defining hidradenitis suppurativa (HS) subtypes was previously limited by small sample sizes and poor interrater reliability; no study has investigated subtype treatment responses. The objective of this analysis was to characterize HS clusters in adult patients with moderate to severe HS and evaluate secukinumab treatment responses between clusters. Clusters were identified via an unsupervised machine learning clustering analysis using baseline data from the randomized, placebo-controlled SUNSHINE (NCT03713619) and SUNRISE (NCT03713632) phase 3 trials. To assess treatment responses, patients received secukinumab every 2 (SECQ2W) or 4 weeks (SECQ4W) or placebo, for 16 weeks, after which, placebo patients randomly switched to SECQ2W/SECQ4W, and SECQ2W/SECQ4W patients maintained their original treatment, until week 52. Baseline outcomes included patient characteristics, disease characteristics and severity, HS-associated comorbidities and previous treatment exposures. Treatment response was assessed via the HS clinical response (HiSCR), abscess and inflammatory nodule (AN) count, flares and NRS30 (skin pain). Based on baseline data, three clusters were identified from 1084 patients (Cluster 1: 54.1%, Cluster 2: 17.8%, Cluster 3: 28.1%). Cluster 1 was predominantly female (65.4%) and was characterized by milder HS. Cluster 2 had more patients from the Asia Pacific, Middle East and Africa region (58.5%) and was characterized by moderate HS. Cluster 3 had the highest rates of previous exposure to biologics (45.9%) and prior HS-related surgeries (47.5%) and was characterized by severe HS. SECQ2W and SECQ4W demonstrated efficacy versus placebo in all clusters at week 16; SECQ2W and SECQ4W efficacy was maintained to week 52. SECQ2W treatment showed a trend for greater efficacy versus SECQ4W in Cluster 3 through week 52. Three HS clusters were identified. Secukinumab demonstrated benefit over placebo in all clusters. However, patients with more severe disease may take longer to respond and more frequent secukinumab dosing may be required for these patients. SUNSHINE (NCT03713619) and SUNRISE (NCT03713632).

COVID-19 vaccine updates for people under different conditions.

SARS-CoV-2 has caused global waves of infection since December 2019 and continues to persist today. The emergence of SARS-CoV-2 variants with strong immune evasion capabilities has compromised the effectiveness of existing vaccines against breakthrough infections. Therefore, it is important to determine the best utilization strategies for different demographic groups given the variety of vaccine options available. In this review, we will discuss the protective efficacy of vaccines during different stages of the epidemic and emphasize the importance of timely updates to target prevalent variants, which can significantly improve immune protection. While it is recognized that vaccine effectiveness may be lower in certain populations such as the elderly, individuals with chronic comorbidities (e.g., diabetes with poor blood glucose control, those on maintenance dialysis), or those who are immunocompromised compared to the general population, administering multiple doses can result in a strong protective immune response that outweighs potential risks. However, caution should be exercised when considering vaccines that might trigger an intense immune response in populations prone to inflammatory flare or other complications. In conclusion, individuals with special conditions require enhanced and more effective immunization strategies to prevent infection or reinfection, as well as to avoid the potential development of long COVID.

Short-Term Efficacy of Ophthalmic Cyclosporine: A 0.1% Cationic Emulsion in Dry Eye Patients Assessed Under Controlled Environment.

To evaluate the short-term efficacy of cyclosporine A (CsA)-0.1% cationic emulsion (CE) in patients with dry eye disease (DED) and mitigation of the inflammatory flares triggered by desiccating stress environments. A single-center non-randomized clinical trial was performed at a tertiary care setting. Twenty patients with DED treated with CsA 0.1% CE were exposed to a normal controlled environment (NCE) (23°C, 50% relative humidity) and an adverse controlled environment (ACE) (23°C, 10% relative humidity, 0.43m/s localized airflow) during baseline and the 1- and 3-month visits. Patients underwent the following evaluations: conjunctival hyperemia and staining, corneal fluorescein staining (CFS) using the Oxford and Cornea and Contact Lens Research Unit (CCLRU) scale, meibomian gland (MG) secretion quality, Dry Eye Questionnaire-5, Symptom Assessment in Dry Eye (SANDE II), and Change in Dry Eye Symptoms Questionnaire. Multivariate models were adjusted for statistical analysis. Nineteen women and one man (mean age, 58.9 ± 12.3years) completed the study. All symptom questionnaires, CFS, conjunctival hyperemia and staining, and MG secretion quality improved (p ≤ 0.003) with 1month of treatment; improvements were maintained after 3months (p ≤ 0.02), except for SANDE II (p ≥ 0.07). The CFS worsening (total CCLRU) after baseline ACE exposure (from 8.6 to 10.1) was higher, although not significant (p = 0.64), compared with 1month (from 5.4 to 5.8) and 3months (from 5.0 to 5.9) after treatment. Topical CsA-0.1% CE improved DED signs and symptoms after 1month of treatment under controlled environmental conditions. Future studies should confirm the benefit of CsA-0.1% CE in desiccating stress environments. ClinicalTrials.gov identifier, NCT04492878.

Pathogenic NLRP3 mutants form constitutively active inflammasomes resulting in immune-metabolic limitation of IL-1β production

Cryopyrin-associated periodic syndrome (CAPS) is an autoinflammatory condition resulting from monoallelic NLRP3 variants that facilitate IL-1β production. Although these are gain-of-function variants characterized by hypersensitivity to cell priming, patients with CAPS and animal models of the disease may present inflammatory flares without identifiable external triggers. Here we find that CAPS-associated NLRP3 variants are forming constitutively active inflammasome, which induce increased basal cleavage of gasdermin D, IL-18 release and pyroptosis, with a concurrent basal pro-inflammatory gene expression signature, including the induction of nuclear receptors 4 A. The constitutively active NLRP3-inflammasome of CAPS is responsive to the selective NLRP3 inhibitor MCC950 and its activation is regulated by deubiquitination. Despite their preactivated state, the CAPS inflammasomes are responsive to activation of the NF-κB pathway. NLRP3-inflammasomes with CAPS-associated variants affect the immunometabolism of the myeloid compartment, leading to disruptions in lipids and amino acid pathways and impaired glycolysis, limiting IL-1β production. In summary, NLRP3 variants causing CAPS form a constitutively active inflammasome inducing pyroptosis and IL-18 release without cell priming, which enables the host’s innate defence against pathogens while also limiting IL-1β–dependent inflammatory episodes through immunometabolism modulation.

P1105 Short-term exposure to environmental air pollution and inflammatory bowel disease flares: a time-stratified case cross-over study

Abstract Background Some epidemiological studies suggest that long-term exposure to environmental air pollutants, such as particulate matter (PM), could have a role in inflammatory bowel disease (IBD) incidence and pathogenesis. However, less is known about the potential effect of short-term air pollution exposure. The aim of this study is to investigate whether short-term exposure to environmental air pollution is associated with the occurrence of IBD flares. Methods Anonymized hospital discharge records (HDR) with ICD-9-CM codes 555 (Crohn’s disease) and 556 (ulcerative colitis) for years 2002-2009 from all hospitals of the Lombardy region were collected. All HDR of adult patients (18-75 years) resident in Milan were included, except for recurrent hospitalizations within 6 months. Each record was assigned daily PM ≤10 µm (PM10) concentrations at municipality level by averaging PM10 levels of the day of admission with the levels of the day before (lag01) and of each preceding day up to six days before (lag06). To evaluate the association between PM10 and IBD-related hospitalizations, a time-stratified case-crossover study design was applied. Conditional logistic regression models, calculating Odds Ratios (OR) and 95% Confidence Intervals (95%CI) per increments of 10 µg/m3 of PM10, were performed. Results Overall, 2,176 hospital admissions (males=1,137, Crohn’s disease=1,264, ulcerative colitis=912) were included. In the entire population no clear association between PM10 and IBD-related hospitalization was identified, notwithstanding a small risk increase for males (OR: 1.03; 95%CI: 0.99-1.08 at lag04). When further stratifying for ICD code, an increased risk of hospitalization for "left-sided ulcerative colitis" (ICD code: 556.5) was found in males only, for exposures in all days preceding hospitalization up to lag04 (1.28; 1.05-1.28; 59 cases, 207 controls) (Figure 1). In females, the association was weaker, although positive (1.14; 0.91-1.42; 49 cases, 164 controls). No relevant findings emerged when looking at other ICD codes. Conclusion We observed an increased risk of IBD-related hospitalization in male patients with left-sided ulcerative colitis per increasing levels of air pollution in the days preceding hospital admission. Although preliminary, our findings suggest the possible role of sex as an effect modifier of the influence that air pollution might exert on IBD flares. Further studies are needed to better comprehend the complex framework characterizing the interplay between environmental and individual factors contributing to IBD.

The mitochondrial biliverdin exporter ABCB10 in hepatocytes mitigates neutrophilic inflammation in alcoholic hepatitis

Acute liver failure caused by alcoholic hepatitis (AH) is only effectively treated with liver transplantation. Livers of patients with AH show a unique molecular signature characterized by defective hepatocellular redox metabolism, concurrent to hepatic infiltration of neutrophils that express myeloperoxidase (MPO) and form neutrophil extracellular traps (NETs). Exacerbated NET formation and MPO activity contribute to liver damage in mice with AH and predicts poor prognosis in AH patients. The identification of pathways that maladaptively exacerbate neutrophilic activity in liver could inform of novel therapeutic approaches to treat AH. Whether the redox defects of hepatocytes in AH directly exacerbate neutrophilic inflammation and NET formation is unclear. Here we identify that the protein content of the mitochondrial biliverdin exporter ABCB10, which increases hepatocyte-autonomous synthesis of the ROS-scavenger bilirubin, is decreased in livers from humans and mice with AH. Increasing ABCB10 expression selectively in hepatocytes of mice with AH is sufficient to decrease MPO gene expression and histone H3 citrullination, a specific marker of NET formation. These anti-inflammatory effects can be explained by ABCB10 function reducing ROS-mediated actions in liver. Accordingly, ABCB10 gain-of-function selectively increased the mitochondrial GSH/GSSG ratio and decreased hepatic 4-HNE protein adducts, without elevating mitochondrial fat expenditure capacity, nor mitigating steatosis and hepatocyte death. Thus, our study supports that ABCB10 function regulating ROS-mediated actions within surviving hepatocytes mitigates the maladaptive activation of infiltrated neutrophils in AH. Consequently, ABCB10 gain-of-function in human hepatocytes could potentially decrease acute liver failure by decreasing the inflammatory flare caused by excessive neutrophil activity.

Real-world outcomes of children treated with dupilumab for moderate-to-severe atopic dermatitis: a single-centre retrospective observational UK study.

Dupilumab is licensed for the treatment of moderate-to-severe atopic dermatitis (AD) in patients aged ≥ 6 months. The aim of this study was to examine real-world outcomes and safety of dupilumab in British children with moderate-to-severe AD attending a tertiary referral paediatric centre. Skin and quality of life scores, adverse events and discontinuation rates were assessed. Patients aged ≤ 18 years with moderate-to-severe AD were included if they had skin scores recorded at baseline and at least one follow-up visit. Efficacy and safety were assessed using descriptive statistics. In this retrospective observational survey, 72 children/teenagers, with a median age of 14 years (range 7-18) were included. Oral systemic immunosuppressants had failed to control AD in 88% of children recruited. All patients commenced on dupilumab had pretreatment eczema skin scores consistent with moderate-to-severe disease, with a median Eczema Area and Severity Index (EASI) score of 25 [interquartile range (IQR) 20-31]. EASI scores decreased by a median of 94% (IQR 82-100) and remained consistently low over 10-52 months of the study, with a median EASI score at final follow-up of 2 (IQR 0-6). Of the 72 children, 8 (11%) were able to discontinue dupilumab as they were in remission. Nineteen (26%) experienced adverse events, most commonly conjunctivitis (12 patients; 17%). Eight (11%) discontinued dupilumab (six with ongoing inflammatory skin flares, one with severe allergic conjunctivitis, one with intercurrent Wilson disease). Dupilumab was highly effective in treating most children with moderate-to-severe AD with good safety outcomes in the real world. However, 10% of children may need alternative therapy because of drug ineffectiveness or side-effects.

High iNOS and IL-1β immunoreactivity are features of colitis-associated colorectal cancer tumors, but fail to predict 5-year survival.

Inflammatory bowel disease (IBD; mainly ulcerative colitis and Crohn's disease) is associated with the development of colorectal cancer (CRC) referred to as colitis-associated colorectal cancer (CAC). In inflammatory flares of IBD, the production of luminal nitric oxide (NO) increases due to the increased inducible nitric oxide synthase (iNOS) activity in inflamed tissue. It is believed that iNOS parallels pro-inflammatory interleukin-1β (IL-1β). How these biomarkers relate to CAC pathogenesis or survival is unknown. The primary aim of this study was to investigate iNOS and IL-1β immunoreactivity in CAC tumors in comparison with CRC and normal colonic mucosa, and the secondary aim was to determine if immunoreactivity correlates with 5-year survival of CAC. Immunohistochemistry was performed on tissue sections as follows: CAC (n = 59); sporadic CRC (sCRC) (n = 12); colonic mucosa >2 cm outside sCRC margin (normal mucosa) (n = 22); paracancerous IBD (pIBD) (n = 12). The expression of iNOS and IL-1β was quantified separately for epithelium and stroma. Data were evaluated using the Mann-Whitney U-test and the log-rank test for 5-year Kaplan-Meier survival curves. Results were compared with online mRNA databases. Immunoreactivity occurred predominantly in epithelial cells and to lesser extent in stroma. Compared with normal mucosa, immunoreactivity for iNOS (P < 0.01) and IL-1β (P < 0.005) was higher in CAC epithelium. In CAC stroma, iNOS immunoreactivity was lower than normal mucosa (P < 0.001), whereas IL-1β was higher (P < 0.05). Immunoreactivity differences of iNOS or IL-1β among CAC patients failed to correlate with 5-year survival. These findings were supported by online mRNA databases. Consistent with high NO production in IBD, there is more iNOS in CAC epithelium, albeit not in stroma. This immunoreactivity difference exists for IL-1β in both epithelium and stroma. The intervention of arginine or iNOS activity for CAC chemotherapy is not straightforward.

Complications after orthopaedic surgeries in patients with rheumatoid arthritis treated with Janus kinase inhibitors: A retrospective observational study.

The current study compared the outcome after orthopaedic surgeries in patients with rheumatoid arthritis receiving Janus kinase inhibitors (JAKis) versus biologic disease-modifying anti-rheumatic drugs (bDMARDs). This was a retrospective observational study of Japanese patients with rheumatoid arthritis. Sixty-two patients with rheumatoid arthritis using JAKi preoperatively underwent orthopaedic surgeries. Using propensity score matching, these 62 patients were matched with 62 patients using bDMARDs preoperatively. The number of adverse events was counted. We also examined whether the drug-withholding period in the JAKi-treated group was associated with the occurrence of major postoperative adverse events, namely inflammatory flares and delayed wound healing. JAKi-treated patients had a higher incidence of postoperative flares than bDMARD-treated patients (29% versus 12.1%, P = .01). The incidences of postoperative complications other than flares were not significantly different between the two groups. Among the JAKi-treated group, a longer perioperative drug-withholding period (≥11 days) was associated with a higher incidence of postoperative flares (P = .04). The incidences of delayed wound healing and surgical site infection were not associated with the duration of the JAKi-withholding period. JAKi-treated patients had a higher incidence of postoperative flares than bDMARD-treated patients. A total of ≥11 days of drug withdrawal was associated with postoperative flares.

Effect of a 2-week interruption in methotrexate treatment on COVID-19 vaccine response in people with immune-mediated inflammatory diseases (VROOM study): a randomised, open label, superiority trial

Methotrexate is the first-line treatment for immune-mediated inflammatory diseases and reduces vaccine-induced immunity. We evaluated if a 2-week interruption of methotrexate treatment immediately after COVID-19 booster vaccination improved antibody response against the S1 receptor binding domain (S1-RBD) of the SARS-CoV-2 spike protein and live SARS-CoV-2 neutralisation compared with uninterrupted treatment in patients with immune-mediated inflammatory diseases. We did a multicentre, open-label, parallel-group, randomised, superiority trial in secondary-care rheumatology and dermatology clinics in 26 hospitals in the UK. Adults (aged ≥18 years) with immune-mediated inflammatory diseases taking methotrexate (≤25 mg per week) for at least 3 months, who had received two primary vaccine doses from the UK COVID-19 vaccination programme were eligible. Participants were randomly assigned (1:1) using a centralised validated computer program, to temporarily suspend methotrexate treatment for 2 weeks immediately after COVID-19 booster vaccination or continue treatment as usual. The primary outcome was S1-RBD antibody titres 4 weeks after COVID-19 booster vaccination and was assessed masked to group assignment. All randomly assigned patients were included in primary and safety analyses. This trial is registered with ISRCTN, ISRCTN11442263; following a pre-planned interim analysis, recruitment was stopped early. Between Sept 30, 2021, and March 7, 2022, we screened 685 individuals, of whom 383 were randomly assigned: to either suspend methotrexate (n=191; mean age 58·8 years [SD 12·5], 118 [62%] women and 73 [38%] men) or to continue methotrexate (n=192; mean age 59·3 years [11·9], 117 [61%] women and 75 [39%] men). At 4 weeks, the geometric mean S1-RBD antibody titre was 25 413 U/mL (95% CI 22 227-29 056) in the suspend methotrexate group and 12 326 U/mL (10 538-14 418) in the continue methotrexate group with a geometric mean ratio (GMR) of 2·08 (95% CI 1·59-2·70; p<0·0001). No intervention-related serious adverse events occurred. 2-week interruption of methotrexate treatment in people with immune-mediated inflammatory diseases enhanced antibody responses after COVID-19 booster vaccination that were sustained at 12 weeks and 26 weeks. There was a temporary increase in inflammatory disease flares, mostly self-managed. The choice to suspend methotrexate should be individualised based on disease status and vulnerability to severe outcomes from COVID-19. National Institute for Health and Care Research.

Immunomodulatory Nanoparticles for Modulating Arthritis Flares.

Disease-modifying drugs have improved the treatment for autoimmune joint disorders, such as rheumatoid arthritis, but inflammatory flares are a common experience. This work reports the development and application of flare-modulating poly(lactic-co-glycolic acid)-poly(ethylene glycol)-maleimide (PLGA-PEG-MAL)-based nanoparticles conjugated with joint-relevant peptide antigens, aggrecan70-84 and type 2 bovine collagen256-270. Peptide-conjugated PLGA-PEG-MAL nanoparticles encapsulated calcitriol, which acted as an immunoregulatory agent, and were termed calcitriol-loaded nanoparticles (CLNP). CLNP had a ∼200 nm hydrodynamic diameter with a low polydispersity index. In vitro, CLNP induced phenotypic changes in bone marrow derived dendritic cells (DC), reducing the expression of costimulatory and major histocompatibility complex class II molecules, and proinflammatory cytokines. Bulk RNA sequencing of DC showed that CLNP enhanced expression of Ctla4, a gene associated with downregulation of immune responses. In vivo, CLNP accumulated in the proximal lymph nodes after intramuscular injection. Administration of CLNP was not associated with changes in peripheral blood cell numbers or cytokine levels. In the collagen-induced arthritis and SKG mouse models of autoimmune joint disorders, CLNP reduced clinical scores, prevented bone erosion, and preserved cartilage proteoglycan, as assessed by high-resolution microcomputed tomography and histomorphometry analysis. The disease protective effects were associated with increased CTLA-4 expression in joint-localized DC and CD4+ T cells but without generalized suppression of T cell-dependent immune response. The results support the potential of CLNP as modulators of disease flares in autoimmune arthropathies.

A Review of Therapeutic Escalation for Pediatric Patients Admitted for Inflammatory Bowel Disease Flares.

The objective was to complete a single hospital quality assessment to characterize the use, safety, and outcomes of the 5 specialty medications (infliximab, adalimumab, tofacitinib, ustekinumab, and vedolizumab) used for the treatment of pediatric inflammatory bowel disease following admission due to a disease flare. This was a single-center, retrospective, quality assessment of the current clinical practice. The electronic medical record was queried to identify patients ages 0 to 18 years admitted to our institution during a 2-year period from September 1, 2019, to September 30, 2021, who received infliximab, adalimumab, tofacitinib, ustekinumab, and/or vedolizumab for the treatment of Crohn's disease or ulcerative colitis followed by manual data collection and cohort analysis. The total population comprised 20 patients during 23 encounters. The biologic-naive group included 12 patients during 12 encounters, 2 of which are also included in the biologic-experienced group, which captured a total of 10 patients during 11 encounters. In the biologic-naive group, infliximab monotherapy comprised the largest percentage of therapy plans across encounters (91.6%), with a statistically significant greater number of readmissions within 6 months of discharge (p = 0.00031). The biologic-experienced cohort had a statistically significant longer duration of intravenous corticosteroid administration (p = 0.016) and a large variety of therapy plans. The diversity of practice observed within our institution supports the need for guidelines to define standard of therapy or guide selection of second-line therapies based on patient-specific factors.