Long-Term Outcomes of Treatment With and De-Escalation From a Combination of Vedolizumab and Another Biologic or Tofacitinib for Inflammatory Bowel Disease

Introduction: There are scant data on long-term outcomes of treatment of inflammatory bowel disease (IBD) with a combination of advanced therapies, including after de-escalation. Method(s): We identified patients with IBD at a tertiary center who began therapy with vedolizumab (VDZ) in combination with another advanced therapy (biologic or JAK inhibitor) between 2016 and 2020 and examined their outcomes through 6/1/22. We defined biochemical remission as CRP, 5 mg/L and calprotectin < 150 mcg/g, and endoscopic remission as Mayo endoscopic subscore 0 or simple endoscopic score for Crohn's disease (CD) 0. Short-term outcomes of this cohort were previously reported. Result(s): Fourteen patients with a median of 322 (IQR 251-322) weeks of follow up were identified. 10 had ulcerative colitis, 3 CD, and 1 indeterminate colitis. VDZ was combined with tofacitinib in 9 patients, ustekinumab in 3 and adalimumab in 2. Median time on combination therapy was 94 weeks (IQR 17-133). Eight patients achieved objective remission (3 biochemical, 5 endoscopic), 1 changed combination with subsequent endoscopic remission, 2 had primary non-response, 1 had secondary non-response, 1 stopped within 1 month due to reported adverse effect (paresthesia), and 1 lacked follow-up data. Eight patients de-escalated to a single agent, 4 at physician direction and 4 due to insurance denial. Before de-escalation, 6 had objective remission (2 biochemical, 4 endoscopic). After de-escalation, 3 patients maintained objective remission (2 biochemical, 1 endoscopic), 3 had disease flare, of which 1 required colectomy, and 2 lacked data. All 3 patients with disease flare had de-escalated following an insurance denial. Two patients remained on combination therapy through follow up: 1 has endoscopic remission after changing one drug of their combination and 1 has ongoing moderate endoscopic disease despite combination therapy. There were 2 infections requiring hospitalization (rotavirus, C. difficile), and 8 non-serious infections (5 mild SARS-COV-2, 1 peristomal cellulitis, 1 pneumonia, 1 sinus) while on combination therapy. Conclusion(s): In long-term follow up of this small cohort, there were no new signals on effectiveness or safety of combining advanced agents. De-escalation to a single agent was tolerated in half of patients with follow-up data;all patients who flared following de-escalation had adjusted therapy due to insurance denial. More data is needed to inform de-escalation decisions.

The Association Between Stool Shedding of SARS-Cov-2 Microbiome Diversity and Intestinal Inflammation

Introduction: The transmission of the etiologic virus of COVID-19 (severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2]) is thought to occur mainly via respiratory droplets even though limited evidence has shown the virus can be found in feces and involve the gastrointestinal (GI) tract. The aim of this study was to assess if patients with COVID-19 present with fecal shedding of SARS-CoV-2, intestinal inflammation or changes in their microbiota. Method(s): This was a prospective cohort study that included outpatients that presented with symptoms of COVID-19 and were tested using a nasopharyngeal PCR test (NPT). Two cohorts were selected: one with a (1) NPT and a control group with a (-) NPT. Stool and a clinical data were collected at baseline and then, days 14, 28 and 42. SARS-CoV-2 viral loads were measured in stool using PCR and stool microbiome was analyzed using 16S rRNA gene sequencing (V3/V4 region). Fecal calprotectin levels were also measured on each sample and used as a surrogate marker of intestinal inflammation. Result(s): 101 patients were recruited (410 total samples). Of those, 55 had a (1) COVID-19 NPT. Most patients with a (1) COVID-19 NPT PCR had a detectable fecal viral load (71%). Among these patients, 23 (55%) had detectable viral stool loads only at baseline, 12 through day 14, 6 through day 28 and 1 through day 42. One patient had a (-) NPT but detectable SARS-CoV-2 in the baseline stool sample. Subjects with (1) NPT presented more commonly with myalgias (p=0.02), dysgeusia (p=0.019) and anosmia (p=0.03) when compared to those with (-) NPT but there were no differences in any other symptoms including GI manifestations.Within the group with a (1) NPT, those patient with detectable SARS-CoV-2 in the stool were younger but no differences were seen in demographic, symptoms, or fecal calprotectin levels (Table). There was no correlation between fecal SARS-CoV-2 loads and fecal calprotectin levels (rho: 0.007 [p=0.95]). Patients with a (1) NPT PCR had higher evenness when compared to those that tested (-) for a NPT PCR. However, no differences were seen in other alpha or beta diversity (Figures 1A and 1B, respectively). Conclusion(s): Even though intestinal viral shedding of SARS-CoV-2 in patients with COVID-19 is common, these patients do not present with evidence of inflammation of the GI tract, a significantly disrupted gut microbiome or a higher incidence of GI symptoms when compared to patients with respiratory symptoms and no COVID-19.

A Rare Etiology for Ulcerative Colitis Flare

Introduction: Prior to colonoscopy, it is well understood that patients must undergo bowel cleansing. Based on the type of laxative, colonoscopy preparations fall into two categories - polymer-based formulas (PEG) and saline-based formulas (NaP). Both types of bowel preparations are deemed to be relatively safe and part of routine practice. However, we describe the rare case of an ulcerative colitis (UC) flare due to the bowel preparation formula. Case Description/Methods: A 29-year-old female with diagnosis of UC, presently in clinical and biochemical remission on oral mesalamine, contracted COVID-19 and had reactivation of UC symptoms. After being on budesonide tablets and rectal foam for two months, patient achieved clinical remission, and a surveillance colonoscopy was performed which revealed normal colon and terminal ileum except mild congestion in the cecum (Figure A). Pathology revealed unremarkable mucosa in the entire colon except for chronic active colitis in the cecum. Immediately following this colonoscopy, the patient started to experience another severe UC flare requiring hospitalization. The patient's laboratory work-up was normal except for an elevated fecal calprotectin (1710). Stool infectious work-up was negative and the patient denied any NSAID or antibiotic use. The patient underwent a repeat colonoscopy which revealed severe Mayo 3 pancolitis (Figure B) in comparison to a stable colonoscopy a few weeks prior. It was revealed that for her initial colonoscopy, she had used SUPREP bowel prep kit. On prior colonoscopies she had used MiraLAX bowel prep with no adverse effects. During hospitalization, the patient was started on biologic therapy with good effect. Discussion(s): There are no clear guidelines on appropriate bowel preparation formula for the inflammatory bowel disease (IBD) population. Sufficient literature exists to confirm that NaP can irritate the intestinal mucosal wall. Moreover, numerous animal experiments have employed dextran sodium sulfate for chemical induction of intestinal inflammation to mimic UC flares in humans [1]. Thus, it can be surmised that because SUPREP ingredients contain sodium sulfate, the potential for UC flare is higher. It is pertinent for practitioners to be aware of the possible rare adverse effects of saline-based formulas, especially when treating the IBD population.

Serum-calprotectin for identification of severe COVID-19 in hospitalized patients

Introduction: The disease severity of COVID-19 varies from mild upper respiratory tract infection to life-threatening lower respiratory tract infection. Biomarkers can support severity assessment. We aimed to compare scalprotectin with routine biomarkers to study if s-calprotectin could identify patients with risk for severe COVID-19. We also aimed to study if ongoing corticosteroid therapy would alter levels of s-calprotectin. Method(s): We collected serum samples within 8 days from admission from 162 adult patients hospitalized for COVID-19 from April to October 2020. The serum tubes were centrifuged within 2 h and serum was aspirated and frozen in aliquots at -80 degreeC. scalprotectin was measured according to the routine method at Karolinska University Laboratory. Study endpoint was severe COVID-19 any time during the hospital stay. Severe COVID-19 was defined as treatment with either low-flow oxygen >= 10 l/min, high-flow nasal oxygen, non-invasive ventilation, or invasive mechanical ventilation. For patients hospitalized before the results of the RECOVERY Dexamethasone study were presented, a propensity score matched sub-study was performed, comparing patients treated and not treated with corticosteroids prior to study sample. Result(s): Median s-calprotectin was, 2.7 ml/L (IQR, 1.6-4.2) for nonsevere COVID-19 cases (n = 59) and 5.0 ml/l (IQR, 3.5-9.1) for severe COVID-19 (n = 103) (p < 0.001). ROC-curve analysis compering s-calprotectin, C-reactive protein (CRP), neutrophils, 1/lymphocytes, and D-dimer, showed the highest AUC for s-calprotectin, 0.775 (Fig. 1). In the sub-study of with corticosteroid treated (n = 35) and non-treated patients (n = 26), the median s-calprotectin was 4.0 (IQR, 2.5-5.6) and 3.8 (IQR, 2.7-3.8), respectively (p = 1.0). Conclusion(s): The study showed a good performance of s-calprotectin for identification of severe COVID-19, in agreement with previous studies. It also indicated that s-calprotectin results are not affected by ongoing corticosteroid treatment.

Topic: AS04-MDS Biology and Pathogenesis/AS04a-Normal, MDS, and leukemic stem cells: CALPROTECTIN (S100A8/A9) EFFECTS ON HEALTHY CD34+ HEMATOPOIETIC STEM AND PROGENITOR CELLS ARE AMPLIFIED IN CHRONIC MYELOID MALIGNANCIES

Background And Aims: S100A8 and S100A9 alarmins and their heterodimer calprotectin are diversely involved in myeloid neoplasm pathophysiology as well as infectious and inflammatory diseases. In the context of COVID-19, circulating calprotectin was identified as a powerful biomarker of disease severity. Calprotectin impact on CD34+ hematopoietic stem and progenitor cells remains poorly understood. Method(s): Calprotectin effects on healthy donor and chronic myeloid neoplasm-derived CD34-positive hematopoietic stem and progenitor cells were tested in liquid culture for up to 7 days. The pro-inflammatory cytokine IL-6 was used as a control. Cytokine effects alone or in combination were explored by the use of bulk and single cell RNA sequencing, Assay for Transposase-Accessible Chromatin with high-throughput sequencing, cytokine secretion analyses and semi-solid cultures. Result(s): CD34+ cells exposed to IL-6 generate monocytic cells that overproduce calprotectin. Calprotectin inhibits erythroid differentiation of healthy CD34+ cells, possibly through CD36 receptor. Chronic myeloid neoplasm CD34+ cells over-react to calprotectin, with large transcriptomic rewiring of erythro-megakarocytic and granulo-monocytic populations. Calprotectin-induced inhibition of erythroid progenitor proliferation correlates with increased synthesis of ribosomal subunits and p53 pathway activation, while the cytokine impact on granulo-monocytic cells indicates an autocrine or paracrine amplification loop. Conclusion(s): Calprotectin secreted by monocytes generated by CD34+ cells upon IL-6 stimulation may be a pathophysiological component of inflammatory anemia, a role that is amplified in the context of myeloid neoplasms in which calprotectin effects extend to the granulo-monocytic lineage.Copyright © 2023 Elsevier Ltd. All rights reserved.

Which biomarker(s) to predict worsening of SARS-CoV2 infection? An ancillary study from the COVIDeF cohort

Introduction: COVID-19 has been responsible for millions of deaths and intensive care unit (ICU) admissions all over the world. Identifying the patients at risk of developing a severe form is crucial for an optimized orientation and allocation of resources. The main objective of our study was to identify among a selection of biomarkers, those predictive of short term worsening in COVID-19. Method(s): This is an ancillary study using clinical data and collected biobanking from the multicentric cohort study COVIDeF, which included prospectively from March 31th 2020 to March 30th 2021, patients admitted with a suspected Sars-CoV2 infection in the Assistance- Publique-Hopitaux de Paris network, France. Patients with confirmed COVID-19 were divided in 2 groups: a severe (ICU admission or invasive or non-invasive ventilation or ARDS or death) and a control group (no worsening). The routine blood tests and following biomarkers: troponin, C Reactive Protein (CRP), procalcitonin, Mild- Regional pro-Adrenomedulin (MR-proADM), pro-endothelin, SuPAR, NT-proBNP, calprotectin, PF4, D-dimers, were measured in plasma or serum and compared between both groups using a conditional logistic regression. Result(s): Among the 1040 first patients included in the COVIDEF cohort, we selected 512 patients having a blood sample drawn at admission before worsening, of which 60 secondarily worsened (severe group). The mean age was 59.5 (+/- 19.5) years and 50.2% were females. Among the biomarkers tested, three were independently associated with worsening: CRP (mg/l) OR 1.01 [IC 1.01-1.02], procalcitonin (ng/ml) OR 0.4428 [0.21-0.95] and MR-proADM (pg/ml) OR 3.012 [1.06-8.53]. Conclusion(s): Among a selection of biomarkers of interest, MRproADM appears to best identify at admission COVID-19 patients at risk of worsening. Future interventional studies should test the efficacy and security of this biomarker to rule-in and rule-out severe outcome and the usefulness for allocating resources.

Erythema nodosum -Expanding diagnostic workout in COVID-19 pandemic

Case report Erythema nodosum (EN) is considered a delayed type IV hypersensitivity reaction, triggered by exposure to an antigen, which diagnostic workout is usually challenging. Several conditions have been described as possible causes for EN, including infections, sarcoidosis, pregnancy, neoplasic and inflammatory diseases. Rarely, vaccines such as tetanus, diphtheria, BCG, hepatitis B, human papillomavirus, malaria, rabies, smallpox, typhoid, and cholera have been associated with subsequent EN. We present a 31-year- old leucodermic female with suppurative adenitis, who developed painful erythematous nodules on the pretibial area of the lower limbs. Ten days prior to presentation she had received the first dose of the COVID-19 mRNA-1273 vaccine. Fever, lymphadenopathy, fatigue, weight loss, arthritis, cough, diarrhoea, other organ-specifc symptoms and close contact with tuberculosis were excluded. She was under oral contraception for several years, that was not discontinued. Pregnancy was excluded. No positive signs were detected on physical examination besides the referred nodules. Laboratory tests revealed a normal complete blood count, erythrocyte sedimentation rate, C-reactive protein, antistreptolysin O titer, renal and hepatic tests. Interferon-gamma release assay was negative. Circulating rheumatoid factor was normal, anti-nuclear, anti-double stranded DNA and anti-neutrophil cytoplasmatic antibodies were negative. Angiotensin converting enzyme and protein electrophoresis were normal. Hepatitis B and C, HIV 1/2 and syphilis serologic profiles were negative. Urinalysis and fecal calprotectin were unremarkable. The patient was treated with naproxen and topic betamethasone dipropionate. Violaceous involution was reported, with complete resolution of the EN lesions over the following month. In the literature, there are rare reports of EN following SARS-COV2 infection and also after COVID-19 vaccination. To our knowledge this is the second report of EN after the COVID-19 mRNA-1273 vaccine. This case highlights the importance of clinical awareness for the possible association of COVID-19 vaccination and EN, adding to the already extensive list of causes included in the etiological investigation of these patients.

Novel heterozygous PLCG2 variant presenting with very early-onset perianal abscess

Case report Background: Mutations in the PLCG2 gene can cause PLCG2-associated antibody deficiency and immune dysregulation (PLAID) or auto-inflammation with PLCG2-associated antibody deficiency and immune dysregulation (APLAID). PLAID is characterized by urticarial eruptions triggered by evaporative cooling along with cutaneous granulomas. APLAID may present with early-onset skin inflammation and non-infectious granulomas, uveitis, and colitis. Method(s): Case report and literature review. We performed in silico analysis for variants of uncertain significance (VUS). Result(s): A 29-day-old boy presented to emergency department for failure to thrive. He was found to be SARS-CoV2 positive, had an E. coli UTI in the setting of bilateral perinephric masses which subsequently resolved. He also had a perianal soft tissue abscess measuring 4cm in diameter. Mom reported a similar infection when she was age 2. She also reported intermittent diffuse urticaria triggered following perspiration evaporation.Abscess wall histology showed diffuse neutrophil and lymphocytic infiltration, with cultures growing polymicrobial enteric flora. His serum immunoglobulins G, A, M, and E were within reference range. Naive and memory CD4, CD8, CD19 lymphocyte subsets (including NK cells) were also within age-appropriate reference range. He had a normal neutrophil oxidative burst measured using dihydrorhodamine (DHR) flow cytometry following PMA stimulation, which ruled out a diagnosis of chronic granulomatous disease. On evaporative cooling, the patient had a 2mm wheal with surrounding erythema which resolved rapidly with warming. A targeted primary immunodeficiency panel showed a heterozygous VUS in PLCG2, c.688C > G (p.Leu230Val). The variant was absent from major databases and had a calculated CADD score of 17.77. He had symptomatic resolution after completing 3 weeks of ceftriaxone and metronidazole antimicrobials. Given the concern for PLCG2-associated very early-onset inflammatory bowel disease (VEO-IBD), a fecal calprotectin was obtained at 3 months and found to be elevated (157 mcg/g [ < = 49 mcg/g]). However, he had no symptomatic or macroscopic evidence for VEO-IBD. Conclusion(s): Presence of very early onset abscesses has not been previously described in patients with heterozygous PLCG2 deficiency. This case adds to the expanding variable phenotype of PLCG-2-associated immune dysregulation.

Use of Upadacitinib in 11 Tofacitinib-Refractory Ulcerative Colitis Patients at a Single Tertiary Care Center

INTRODUCTION: Ulcerative colitis (UC) is a chronic inflammatory condition characterized by diarrhea, abdominal pain, rectal bleeding, and weight loss. Upadacitinib is an oral, selective, small molecule Janus Kinase (JAK) inhibitor that was recently approved in the United States for moderate to severe UC. Clinical trials evaluating the efficacy of upadacitinib excluded patients with a previous exposure to tofacitinib, a nonselective JAK inhibitor;therefore, the efficacy of upadacitinib in patients with previous exposure to tofacitinib remains largely unknown. METHOD(S): We present a small retrospective case series of all patients with a diagnosis of ulcerative colitis seen at our institution between with a prior exposure to tofacitinib who were initiated on upadacitinib between May and August of 2022. Demographic data was collected as well as outcome data on clinical improvement, steroid-free remission, biochemical improvement, colectomy status, and adverse events. RESULT(S): Eleven tofacitinib-refractory patients with ulcerative colitis were initiated on upadacitinib. Mean age was 38.1 years, five (45.5%) patients were female, nine (81.8%) patients were white, seven (63.6%) patients had pancolitis, and mean duration of UC was 7.4 years (Table 1). In this group, there were high rates of prior targeted therapy failures. These patients were followed for a mean of 121 days. The clinical course of each patient is presented in Table 2. Of the 11 patients included in our study, nine (81.8%) patients reported symptomatic improvement, six (54.5%) patients were able to successfully taper corticosteroids, and two (18.2%) patients underwent colectomy, one of which was elective and planned prior to initiating upadacitinib. The mean fecal calprotectin improvement was 1430mg/kg of patients with both baseline and follow-up testing. Three (27.3%) patients experienced an adverse event;two (18.2%) patients with mild COVID-19 not requiring hospitalization and one (9.1%) patient with Enteropathogenic E. Coli. DISCUSSION: This real-world single-center case series of 11 patients, suggests that upadacitinib may be an effective option for patients with a previous tofacitinib exposure. Larger prospective studies are needed to confirm these findings. [Formula presented] [Formula presented]Copyright © 2023

Switching from intravenous to subcutaneous infliximab: Clinical and patient experience outcomes

Background: Intravenous (IV) infliximab (IFX) monotherapy is associated with significant loss of response. Therapeutic drug monitoring shows an association with low serum trough drug levels and development of anti-IFX antibodies. Combination therapy with immunomodulators is not always possible, and IFX dose escalation leads to higher drug costs and time pressure on infusion units. Both approaches have raised heightened patient safety concerns due to the Covid-19 pandemic. Subcutaneous (SC) IFX pharmacokinetics lead to improved drug trough levels, which could lead to better clinical outcomes. Method(s): The NHS Greater Glasgow and Clyde biologics database was used to identify selected patients currently treated with IV IFX for IBD for suitability for SC switch. Patients were contacted to allow informed choice to opt in or out of switch. Baseline clinical data was collected, and patients were reviewed at week 8 and week 24 for assessment of clinical disease activity scores, IFX trough levels/anti-drug antibody levels, and faecal calprotectin. Patient experience outcomes were assessed using a quality of life questionnaire (CUCQ-8). Result(s): 31 patients consented to switch;F:M = 17:14. The majority of patients (16) had Crohn's disease, with 13 with UC and 2 IBDU. Mean duration of disease was 9.1 years and duration of prior IV therapy was 3.3 years. 28 patients were reviewed at week 8 and 24 at week 24. At week 24, 71% of patients were in clinical remission (Harvey-Bradshaw index score <5 or partial Mayo score <2), 96% had CRP <5 mg/Land 87% had FCP <250mug/g. 21% of patients had subtherapeutic IFX trough levels at baseline, all had increased by week 8 and there were no subtherapeutic levels measured by week 24. One patient had detectable antibodies at week 24, compared with 9 patients at baseline. Three patients required oral steroid therapy during the 24-week follow up period. There were no hospital admissions, significant infections or adverse reactions within the cohort. 15 patients submitted CUCQ-8 scores, of these 7 patients' scores had worsened at week 8 but by week 24 13/15 were stable or improved compared to baseline. Conclusion(s): Switching from IV to SC infliximab is welcomed by most patients. The efficacy, tolerability, increased drug level and safety which has previously been demonstrated is reproduced in our cohort. This study is the first to explore patient experience outcomes. The finding of initial worsening of the CUCQ-8 score, but overall improvement by week 24 opens further opportunity for engaging patient involvement in switch programmes.

Switch from intravenous to subcutaneous maintenance infliximab in real world IBD cohort

Background: During the COVID-19 pandemic, there has been concern regarding patients attending hospitals for intravenous (IV) infusions due to increased COVID-19 exposure risk and demand on hospital resources. Data on switching patients from escalated dosing of IV infliximab (IFX) are limited. We describe a real-world experience of electively switching a cohort of patients on maintenance IV IFX for inflammatory bowel disease (IBD), at both standard and escalated dosing, to subcutaneous CT-P13 (Remsima). Method(s): Adult patients with IBD on IV IFX at Royal Adelaide Hospital were invited to switch to fortnightly dosing of subcutaneous IFX. We collected demographic data using medical records, and prospectively measured clinical assessment scores (CDAI/HBI for Crohn's disease (CD) and partial Mayo/SCCAI for Ulcerative Colitis (UC)), faecal calprotectin (FCal), CRP and trough IFX levels prior to switching to subcutaneous IFX, and at 6 months post switch. Clinical remission was defined as CDAI<=150/HBI<=4 (CD) or partial Mayo<=3 (no subscore>1)/ SCCAI<=2 (UC). Result(s): 29 patients were switched from IV IFX to subcutaneous CT-P13 between March 2021 and May 2022 (see Table 1 for baseline demographics). 23 had Crohn's disease (79%). 10/29 patients (31%) were on intensified IV dosing at baseline prior to switch. The majority of patients, 25/29 (86%) were in remission pre-switch. Of 19 patients with paired trough IFX levels, these increased significantly from baseline to 6 months post-switch (5.9mg/ml to 13.9mg/ml, respectively (p=0.0003), see Fig 1). The median FCal did not change pre-vs post switch (73mcg/g vs 80mcg/g, p=0.540), see Fig 2). Median CRP did not change pre-vs. post switch (1 mug/ml vs 2 mug/ml). Clinical assessment scores remained stable pre-vs. post-switch (CDAI 31 vs 31, (p=0.316) see Fig 3;HBI. 1 vs 2 (p=0.940);partial Mayo 0 vs 0, (p>0.999);and SCCAI 1 vs 2 (p=0.5000)). Regarding the subset of patients on escalated dosing at baseline, all patients were in clinical remission at 6 months post-switch. There was no significant change in IFX levels (8.4 vs 13.3, p=0.253). FCal did not significantly change (76mcg/g vs 79mcg/g (p=0.563), nor did median CDAI (37 vs 21 (p=0.5312) and median HBI (2 vs 2 (p=0.750)). Overall, only 1/29 (3%) patients were not in remission at 6 month follow-up. No patients in required steroids or surgery. Of the 9 patients with perianal disease, none had a flare. All patients with weight>100kg (n=4) remained in remission. Conclusion(s): Switching patients from IV to subcutaneous IFX delivered stable clinical outcomes in this real world cohort, with no change in disease biomarkers and clinical indices. IFX levels increased overall and all patients on escalated IV dosing were in clinical remission at 6 months post-switch.

Circulating calprotectin correlates with DLCO in patients four months after COVID-19

Background: After 4 months we have shown, that DLCO is lower in severe COVID-19 patients compared to nonsevere (Guler SA, et al. Eur Respir J. 2021 Apr 29;57(4):2003690). Contributing factors are unclear. Calprotectin is an inflammatory marker released by activated neutrophils and is increased in acute severe COVID-19. Aim(s): We hypothesized that circulating calprotectin correlates with persistent lung functional impairment after COVID-19. Method(s): Calprotectin serum levels were measured in 124 patients (50% male) 4 months after COVID-19 (NCT04581135). Calprotectin was correlated with clinical parameters (Spearman's correlation). Multivariate linear regression (MLR) was performed to evaluate the independent association of calprotectin in different models. Result(s): Post-ICU patients (72% male) compared to non-ICU were significantly older (age 59.4 +/- 13.6 vs 49.2 +/- 13.1 years) and more obese (BMI 28.7 +/- 4.5 vs 25.2 +/- 6.0 kg/m2) (p=0.001, each) compared to non-ICU. DLCO was lower in post-ICU patients (75.96 +/- 19.05 %-predicted) compared to non-ICU (p<0.01). Calprotectin was significantly higher in post-ICU patients (2.74 +/- 1.15 mug/ml) compared to non-ICU (1.81 +/- 0.94 mug/ml, p<0.001). In unadjusted analysis, calprotectin correlated with DLCO (r=-0.350, p<0.001) and FVC (r=-0.417, p<0.001). In MLR adjusted for age, sex and BMI, calprotectin correlates with DLCO (R2=0.276, p<0.001). Calprotectin significantly predicted DLCO (beta=-6.463, p=0.001). Conclusion(s): Serum calprotectin is higher in post-ICU patients compared with non-ICU 4 months after COVID-19. The relationship between calprotectin levels and DLCO suggests a potential role for calprotectin in persisting lung functional impairment.

Use of Upadacitinib in 11 Tofacitinib-Refractory Ulcerative Colitis Patients at a Single Tertiary Care Center

INTRODUCTION: Ulcerative colitis (UC) is a chronic inflammatory condition characterized by diarrhea, abdominal pain, rectal bleeding, and weight loss. Upadacitinib is an oral, selective, small molecule Janus Kinase (JAK) inhibitor that was recently approved in the United States for moderate to severe UC. Clinical trials evaluating the efficacy of upadacitinib excluded patients with a previous exposure to tofacitinib, a nonselective JAK inhibitor;therefore, the efficacy of upadacitinib in patients with previous exposure to tofacitinib remains largely unknown. METHOD(S): We present a small retrospective case series of all patients with a diagnosis of ulcerative colitis seen at our institution between with a prior exposure to tofacitinib who were initiated on upadacitinib between May and August of 2022. Demographic data was collected as well as outcome data on clinical improvement, steroid-free remission, biochemical improvement, colectomy status, and adverse events. RESULT(S): Eleven tofacitinib-refractory patients with ulcerative colitis were initiated on upadacitinib. Mean age was 38.1 years, five (45.5%) patients were female, nine (81.8%) patients were white, seven (63.6%) patients had pancolitis, and mean duration of UC was 7.4 years (Table 1). In this group, there were high rates of prior targeted therapy failures. These patients were followed for a mean of 121 days. The clinical course of each patient is presented in Table 2. Of the 11 patients included in our study, nine (81.8%) patients reported symptomatic improvement, six (54.5%) patients were able to successfully taper corticosteroids, and two (18.2%) patients underwent colectomy, one of which was elective and planned prior to initiating upadacitinib. The mean fecal calprotectin improvement was 1430mg/kg of patients with both baseline and follow-up testing. Three (27.3%) patients experienced an adverse event;two (18.2%) patients with mild COVID-19 not requiring hospitalization and one (9.1%) patient with Enteropathogenic E. Coli. DISCUSSION: This real-world single-center case series of 11 patients, suggests that upadacitinib may be an effective option for patients with a previous tofacitinib exposure. Larger prospective studies are needed to confirm these findings. (Table Presented).

Quality, safety and equity of care outcomes for inflammatory bowel disease patients at four tertiary referral centres in Australia using a cloud based management system Crohn's Colitis Care (CCCare): A real world observational study

Background: Inflammatory bowel disease (IBD) is a global problem and Australia has amongst the highest prevalence rates. This study looked to assess the quality, safety and equity of care across four specialised IBD centres in Australia over a 12-month period using the cloud-based IBD clinical management system called Crohn's Colitis Care (CCCare). This study aimed to define existing care at each centre and the range of performance across each centre to propose potential benchmarks for optimal quality IBD care. Method(s): The study was conducted across four tertiary IBD centres in Australia (Centres A, B, and C were public hospitals and D was a private centre). De-identified data within the backend CCCare research registry was audited between 1st of July 2021 to 31st August 2022. People with IBD who had a clinical assessment documented within the platform during this 12-month period were included. We assessed quality of IBD care using disease activity based on patient reported outcome measures (PROMs), biomarkers and endoscopy;surgery rates;health maintenance indicators including vaccination and skin cancer screening rates and;key performance indicators including steroid use, smoking rates and current opioid use. Safety of care was assessed using adverse events from therapy and hospital admission due to therapeutic complications. Equity of care examined education levels and ethnicity. Result(s): A total of 1889 patients were included. 63% had Crohn's disease and 37% had ulcerative colitis. 51% of the cohort was female. The median age was 39 years (IQR 30-53) and the median disease duration was 8.4 years (IQR 3.3-15.7) (Table 1). Current steroid use was between 6% to 15.4%. Faecal calprotectin (FCP) remission rates (250mug/mg) were between 65-84% and patient reported outcome (PRO-2) remission rates were between 76-88% with the highest rates observed at Centre D (Figure 1). 74 patients underwent a surgical procedure. COVID-19 vaccination rates were between 40.1% to 88.8% with the highest rates once again observed at Centre D. 3% of the cohort was documented as currently using opioid medications. 12.2% were recorded as currently smoking at Centre A compared to 2.6% at Centre D. 55 medication related adverse events were recorded and 94 patients had a hospital admission during the study period. Conclusion(s): This study showcases how CCCare can readily provide researchers with granular, real-world data to audit the quality of IBD care at 4 specialised centres in Australia over a 12-month period. While there were some differences (higher vaccination rates, lower smoking and steroid use rates at Centre D), quality and safety of care was still fairly uniform across the various sites and can serve as a standard of care for IBD patients in Australia.

Serological markers of tissue remodeling are elevated in patients with COVID-19 who develop interstitial lung disease

Background: Coronavirus disease-19 (COVID-19) is an infectious disease that can result in serious respiratory illness. It is associated with extensive systemic inflammation and changes to the lung extracellular matrix (ECM), which may result in diffuse alveolar damage and pulmonary fibrosis. In this study, the aim was to investigate whether ECM remodeling, wound healing, and neutrophil activity is altered in patients with COVID-19, with or without interstitial lung disease (ILD). Method(s): Serum was collected from 72 patients with COVID-19 infection 3 months after diagnosis, 10 of whom developed ILD, and from 16 healthy controls. A panel of neo-epitope specific ELISAs reflecting type III collagen crosslinking (PC3X), type III and VI collagen formation (PRO-C3 and PRO-C6), type I, III, and VI collagen degradation (C1M, C3M, and C6M), fibrin crosslinking (X-FIB), fibrin clot formation (PRO-FIB), elastin degradation (EL-NE and ELP-3), and calprotectin degradation (CPa9-HNE) were assessed in serum of patients. Result(s): Mean serum neo-epitopes PC3X (p<0.0001), PRO-C3 (p=0.0024), C3M (p=0.0085), PRO-FIB (p<0.0001), ELP-3 (p<0.0001), and CPa9-HNE (p<0.0001) were significantly elevated in patients with COVID-19 compared to healthy controls. Additionally, PC3X (p=0.023) and PRO-C3 (p=0.0317) were significantly elevated in COVID-19 patients who developed ILD when compared to those who did not. Conclusion(s): Non-invasive serological biomarkers reflecting tissue remodeling were significantly elevated in patients infected with COVID-19. Additionally, type III collagen crosslinking and formation may differentiate patients who develop ILD consequent to COVID-19 infection.

At Home Calprotectin a United Kingdom Patient Perspectives and Tertiary Center Experience

Background: Home faecal calprotectin tests (HFCT) have been available for some years with slow uptake to use in the UK. During the Sars-Cov-2 pandemic use increased as it allowed a measure of disease activity when lab testing in some areas ceased. In a United Kingdom tertiary referral IBD unit, CalproSmart was introduced in 2020. We analysed completion rates of HFCT and the barriers and enablers patients experienced in its use. Method(s): Data from the CalproSmart portal was analysed. Total patients registered was compared against the number that had completed a test. Age, sex and return rates per annum as well as local or out of area patients were included. All patients who enrolled to receive a HFCT were sent an anonymous online questionnaire using MS Forms. Descriptive statistics were used to analysis the results with a thematic analysis of free form text answers. Result(s): A total of N=304 patients were enrolled on the CalproSmart portal over a three-year period from October 2020 until July 2021. HFCT was completed by 118 (39%) of these patients. Completion was highest in 2020 78% of patients who enrolled on the system completed a HFCT. There was a slight trend towards females being more likely to complete at 23% versus 16% of males. There was no sign of age as a determinant to completion. Of the 118 patients who completed the HFCT 84 (71%) were out of local area patients and 34 (29%) local patients. There were 54 (17%) questionnaires returned. All but 4 (7%) respondents had attempted or completed the HFCT. When asked why they wanted to try a HFCT 39 (72%) patients indicated not having to go to hospital/GP as their primary reason with getting an instant result 29 (54%) and seeing your own result 27 (50%) coming in next. 13 (24%) cited more disease control as a reason to try the test. People found the test mostly easy to use but when comparing overall happiness with the HFCT kits 9 people reported they were somewhat unhappy or unhappy. People were either happy or unhappy with the HFC test usability is a theme that is generated as a barrier and a facilitator for some (see figure 1). When asked which they would prefer to do in future CalproSmart at home or bring your sample to either your GP or hospital n=45 (83%) preferred HFCT. Figure 1 Q 12 Overall how happy were you with CalproSmart home calprotectin kit? Free text answer comparison Conclusion(s): During the pandemic HFCT were popular and out of area patients were more likely to complete the kits. Despite the low return rates those that chose to complete HFCT were in most of cases happy to continue HFCT. With, attention to patient selection and enhanced training on the HFCT there is a case for the continued use in services that have altered significantly since the pandemic. (Figure Presented).

Effect of upadacitinib on inflammatory markers and clinical outcomes in patients with Crohn's disease in the phase 3, U-EXCEL, U-EXCEED, and U-ENDURE studies

Background: Improvement in clinical outcomes and normalisation of objective markers of inflammation, high-sensitivity C-reactive protein (hs-CRP) and faecal calprotectin (FCP), are considered treatment targets per STRIDE-II guidelines.1 We evaluated the effect of the oral selective Janus kinase inhibitor upadacitinib (UPA) on changes in hs-CRP, FCP, and clinical outcomes in patients with Crohn's disease (CD). Method(s): In 2 phase 3, randomized, double-blind, placebo-controlled induction studies (U-EXCEL, NCT03345849;U-EXCEED, NCT03345836), patients with moderate-to-severe CD received 12-week treatment with UPA 45 mg (UPA45) once daily (QD) or placebo (PBO). Patients with clinical response to UPA45 were rerandomised in U-ENDURE (NCT03345823) to receive 52-week maintenance treatment with UPA 30 mg QD (UPA30), UPA 15 mg QD (UPA15), or PBO. Endpoints included marker normalisation (hs-CRP <= 5 mg/L, FCP <= 250 mug/g) in patients with elevated baseline marker levels, normal marker and clinical remission by Crohn's Disease Activity Index (CDAI < 150) or very soft/liquid stool frequency (SF)/abdominal pain score (APS) (average daily SF <= 2.8 and average daily APS <= 1, neither greater than baseline), and >= 50% reduction from baseline in marker values with a decrease of at least 100 points in CDAI from baseline. Median changes from baseline in marker levels were also evaluated. Non-responder imputation with no special data handling for missing data due to COVID-19 was used. Result(s): Of 1021 enrolled patients, 645 (63.2%) had elevated hs-CRP (> 5 mg/L) and 750 (73.5%) had elevated FCP (> 250 mug/g) levels at baseline. Significantly greater proportions of patients with elevated baseline marker levels achieved normalisation with UPA compared with PBO at week 12 (Fig 1A/B) and week 52 (Fig 2A/B;nominal P < .001 for all). Decreases in marker levels from baseline with UPA were observed as early as week 2 and were significantly greater than with PBO through week 12 (Fig 1C) and week 52 (Fig 2C;nominal P < .001 for all). Patients achieved clinical endpoints and improvements in markers at significantly higher rates with UPA45 vs PBO at week 12 (Fig 1D-F) and with UPA15 and UPA30 vs PBO at week 52 (Fig 2D-F;P < .001 for all). The safety profile of UPA in CD was previously reported and no new safety concerns were identified. Conclusion(s): Improvements in clinical endpoints and normalisation of objective markers of inflammation were achieved as early as week 2 with UPA45 induction and sustained with UPA15 and UPA30 maintenance therapy in patients with CD. Median changes in hs-CRP and FCP with UPA support continued improvement of inflammation up to week 52 .

A 2-week course of Exclusive Enteral Nutrition followed by the Crohn Disease Exclusion Diet is effective for Induction and Maintenance of Remission in children with Crohn Disease;the DIETOMICS-CD trial

Background: Exclusive enteral Nutrition (EEN) is considered a first line therapy for children with active Crohn disease (CD). CD Exclusion Diet (CDED)+Partial Enteral Nutrition (PEN) is effective for induction of remission in mild-moderate CD at weeks 6 and 12, with better tolerance than EEN. We assessed whether a 2-week course of EEN, followed by CDED+PEN is superior to 8 weeks of EEN in sustaining clinical remission at week 14, outcomes of CDED up to 24 weeks, and the utility of CDED in mild-severe CD. Method(s): This international, multicenter, randomized-controlled trial compared 2 weeks of EEN (Modulen, Nestle Health Science) followed by 3 phases of the CDED+PEN to 8 weeks of EEN, followed by PEN with free diet, both up to week 24. Children aged 8-18 with CD<3 years, mild-severe disease [paediatric CD activity index (PCDAI) 15-47.5], and active inflammation [elevated C-reactive protein (CRP) or faecal calprotectin (FCP)] were included. Stable immunomodulator (IM) treatment was allowed. Naive patients were allowed to start an IM from week 4. Result(s): Of the 63 eligible patients enrolled, 55 were randomized and included in the final intention to treat analysis (target recruitment failed due to COVID);Group 1 (CDED+PEN;29) and group 2 (EEN;26), mean age 12.7+/-2.4. Steroids-free sustained remission at week 14 was obtained in 20/29(69%) in group 1 and 16/26(61.5%) in group 2, p=0.56. Remission at week 8 was obtained in 22/29(76%) in group 1 and 14/26(54%) in group 2, p=0.08. 16/29(55%) in group 1 and 9/26(34%) in group 2 maintained clinical remission at week 24;p=0.12. Median PCDAI declined from 32.5[20-36.2] to 2.5[0-5.6] and 1.2[0-5.6] in group 1 (p<0.001 for all), and from 22.5[20-29.3] to 0[0-4.3] and 0[0-2.5] in group 2 (p<0.005 for all) at baseline, week 8 and 14 respectively. Median CRP improved in group 1 from 32 mg/L[6-69] to 5[2-16] and 3[2-10.1] (p<0.001 for both) and in group 2 from 10.35 mg/L[5-33] to 3.7[2.2-7.2], p=0.012 and 3.2[2.8-5], p=0.006 at baseline, week 8 and 14 respectively. Median FCP declined in group 1 from 1946 mug/g [862-3304] to 802[196-1312] at week 8 and 241[82-1175] at week 14 (p<0.01 for both), and in group 2 from 1615[605-2692] at baseline to 436[252-1389] at week 8, which then increased to 731[349-1305] at week 14 (p<0.01 for both). At week 14, 12/22(54%) received IM from group 1 and 15/16(93%) from group 2;p= 0.009. Conclusion(s): Two weeks of EEN followed by CDED&lPEN and EEN were successful in induction of clinical and biochemical remission in mild-severe paediatric CD, and most CDED+PEN patients-maintained remission to 24 weeks. Sustained clinical remission at week 14 was similar despite higher IM use in the EEN Group, suggesting that CDED might prevents diet-induced inflammation regardless of IM use.

Disease clearance: A potential target for management of patients with Ulcerative Colitis

Background: Disease clearance defined by the absence of symptoms and intestinal inflammation at endoscopic and histological examination, is proposed as a target in the evaluation of the ulcerative colitis (UC) course. The purpose of this study was to evaluate disease remission on the UC evolution according to disease clearance concept. Method(s): Between January 2020 - March 2022, 79 patients with UC were evaluated clinically, laboratory testing, endoscopically and histologically. Patients positive for COVID and CDI were not included in the study. Disease remission, in accordance with the concept of disease clearance it is defined as clinical (partial Mayo score <=2), endoscopic (endoscopic Mayo score <=1) and histological (Nancy Index) remission. Disease clearance was measured at inclusion in the study and during follow-up after 12 months. Results were compared in patients who did or did not achieve disease clearance. Result(s): The patients were divided into 2 groups according to disease clearence: Group 1: 35 out of 79 patients with UC evaluated, were considered with disease clearance at the initial moment of the evaluation. Group 1 did not present complications and did not require surgical interventions during the follow-up period, compared to group 2: Nondisease clearence patients, 44 out of 79 patients (0.0% vs. 31.8%, p=0.03, OR=23.1). During follow-up, 38.6% patients (N=17 pts, Incidence Rate=0.3864) from group 2 obtained clinical remission, of which 15.9% patients obtained endoscopic remission, 6.81% patients obtained histological remission (p=0.025) and 27.2% patients were under biological therapy. A total of 27 patients from both groups required hospitalization, significantly shorter for patients with initial values of fecal calprotectin below 200 mug/mg, and without endoscopic and/or histological activity (8.57% vs. 54.54%, p=0.002, OR=0.57, RR=0.224). 51.8% patients presented severe forms of disease with surgical and non-surgical complications (35.7% vs. 64.2%, p=0.91, OR=1.07). Surgical complications include toxic megacolon (N=2 pts, 14.2%), colonic perforation (N=1 pts, 7.1%), gastrointestinal hemorrhage (N=1 pts, 7.1%) and stricture with bowel obstruction (N=1 pts, 7.1%). Non-surgical complications include gastrointestinal hemorrhage (N=6 pts, 42.8%), venous thrombosis (N=1 pts, 7.1%) and colorectal cancer (N=2 pts, 14.2%). No deaths were reported. Conclusion(s): According to the concept of disease clearance, our data indicate that UC patients in clinical, endoscopic and histological remission present a significantly lower risk of hospitalization, complications and surgical intervention.

Ulcerative Colitis: Rapid Evidence Review

Ulcerative colitis is a relapsing and remitting inflammatory bowel disease of the large intestine. Risk factors include recent Salmonella or Campylobacter infection and a family history of ulcerative colitis. Diagnosis is suspected based on symptoms of urgency, tenesmus, and hematochezia and is confirmed with endoscopic findings of continuous inflammation from the rectum to more proximal colon, depending on the extent of disease. Fecal calprotectin may be used to assess disease activity and relapse. Medications available to treat the inflammation include 5-aminosalicylic acid, corticosteroids, tumor necrosis factor-alpha antibodies, anti-integrin antibodies, anti-interleukin-12 and -23 antibodies, and Janus kinase inhibitors. Choice of medication and method of delivery depend on the location and severity of mucosal inflammation. Other treatments such as fecal microbiota transplantation are considered experimental, and complementary therapies such as probiotics and curcumin have mixed data. Surgical treatment may be needed for fulminant or refractory disease. Increased risk of colorectal cancer and use of immunosuppressive therapies affect the preventive care needs for these patients. (Am Fam Physician. 2022;105(4):406-411. Copyright © 2022 American Academy of Family Physicians.)Copyright © 2022 American Academy of Family Physicians. All rights reserved.