Bismuth quadruple three-in-one single capsule three times a day increases effectiveness compared with the usual four times a day schedule: results from the European Registry on Helicobacter pylori Management (Hp-EuReg).

BACKGROUND: The recommended schedule for single capsule bismuth quadruple therapy (scBQT, Pylera) includes a proton pump inhibitor (PPI) two times a day and three scBQT capsules four times a day. Four times a day treatments are inconvenient and reduce adherence. In contrast, adherence improves with three times a day schedules. In clinical practice, many gastroenterologists use four capsule scBQT three times a day. However, the effectiveness and safety of this latter approach remain uncertain. AIM: To assess the effectiveness and safety of scBQT administered three times a day in the patients included in the European Registry on Helicobacter pylori Management (Hp-EuReg). METHODS: All Spanish adult patients registered in the Asociación Española de Gastroenterología Research Electronic Data Capture (REDCap) database from June 2013 to March 2021 receiving 10-day scBQT were analysed. Modified intention-to-treat effectiveness, adherence and the safety of scBQT given three times a day were calculated and compared with the four times a day schedule. A multivariate analysis was performed to determine independent factors predicting cure of the infection. RESULTS: Of the 3712 cases, 2516 (68%) were four times a day and 1196 (32%) three times a day. Mean age was 51 years, 63% were women and 15% had a peptic ulcer. The three times a day schedule showed significantly better overall cure rates than four times a day (1047/1112, 94%; 95% CI 92.7 to 95.6 vs 2207/2423, 91%; 95% CI 89.9 to 92.2, respectively, p=0.002). Adherence and safety data were similar for both regimens. In the multivariate analysis, three times a day dosage, first-line therapy, use of standard or high-dose PPIs and adherence over 90% were significantly associated with cure of the infection. CONCLUSIONS: ScBQT prescribed three times a day was more effective than the traditional four times a day schedule. No differences were observed in treatment adherence or safety.

Serological response to vaccines against SARS-CoV-2 in patients with inflammatory bowel disease. / Respuesta serológica a las vacunas frente a SARS-CoV-2 en pacientes con enfermedad inflamatoria intestinal.

OBJECTIVE: To study the serological response (SR) and tolerability of COVID-19 vaccine in patients with inflammatory bowel disease (IBD) and its relation with IBD treatment and type of vaccine. METHODS: Observational, cross-sectional study in patients with IBD vaccinated against COVID-19 without known previous infection. SR was analyzed by the determination of IgG antibodies against the S1 subunit. Safety was studied using a questionnaire to identify adverse effects (AE). RESULTS: 280 patients with IBD were included. Type of vaccines: Comirnaty® 68.8%; Spikevax® 10.8%, Vaxzevria® 18.3%, Ad26.COV2-S® 2.2%. 51.3% had AE, being 100% mild. 65% developed IgG antibodies after vaccination. The SR was higher for vaccines with mRNA technology (100% Spikevax®, 68.5% Comirnaty®) compared to those based on adenovirus vector (38.0% Vaxzevria®, 33.3% Ad26.COV2-S®) (P<.001). In the multivariate analysis, SR was related to age (<60 years; OR: 3.8, 95% CI 1.9-7.0; P<.001). The SR in patients with aminosalicylates was 65.4%, 61.4% with immunosuppressants, 65.8% with anti-TNF, and 68.7% with non-anti-TNF biologicals (P=.9). CONCLUSIONS: One third of patients with IBD did not develop antibodies with the initial vaccination against SARS-CoV-2. The SR to vaccines based on mRNA technology was higher, and it was related to age (higher in younger patients). Immunosuppressants and biologicals did not decrease SR. More than half of the patients presented AD, being mild in all cases.

Extraintestinal Manifestations in Patients with Inflammatory Bowel Disease: Study Based on the ENEIDA Registry.

BACKGROUND: Patients with inflammatory bowel disease (IBD) may present extraintestinal manifestations (EIMs) that affect the joints, skin, eyes, and hepatobiliary area, among others. AIMS: Our aim was to analyse the prevalence and characteristics of EIMs in patients with IBD and to identify the possible risk factors associated with the development of EIMs in the largest series published to date. METHODS: Observational, cross-sectional study including patients from the Spanish ENEIDA registry promoted by GETECCU. We retrospectively identified all cases of EIMs in the ENEIDA registry until January 2018. RESULTS: The study included 31,077 patients, 5779 of whom had at least one EIM (global prevalence 19%; 95% CI 18.2-19.0). Among the different types of EIMs, rheumatic manifestations had a prevalence of 13% (95% CI 12.9-13.7; 63% of EIMs), with a prevalence of 5% (95% CI 4.7-5.2) for mucocutaneous manifestations, 2.1% (95% CI 1.9-2.2) for ocular manifestations, and 0.7% (95% CI 0.6-0.8) for hepatobiliary manifestations. The multivariable analysis showed that the type of IBD (Crohn's disease, p < 0.001), gender (female, p < 0.001), the need for an immunomodulator (p < 0.001) or biologic drugs (p < 0.001), a previous family history of IBD (p < 0.001), and an extensive location of IBD (p < 0.001) were risk factors for the presence of EIMs. CONCLUSIONS: One-fifth of patients with IBD may have associated EIMs, with rheumatic manifestations as the most frequent (> 60% of EIMs). Female patients with severe Crohn's disease represent the group with the highest risk of developing EIMs. These patients should therefore be specially monitored and referred to the corresponding specialist when suggestive symptoms appear.

Idiopathic acute pancreatitis in patients with inflammatory bowel disease: A multicenter cohort study.

BACKGROUND: Idiopathic acute pancreatitis (IAP) in patients with inflammatory bowel disease (IBD) is not well characterized. Our purpose was to better understand this condition and its natural history. METHODS: Retrospective cohort study conducted at nine Spanish IBD referral centers. Patients with IBD and a first episode of acute pancreatitis (AP) between 1998 and 2018 were included. Patients with a previous episode of AP or a diagnosis of chronic pancreatitis were excluded. IAP and non-IAP were compared by multivariate logistic regression and survival analysis. RESULTS: We identified 185 patients with IBD (68.7% Crohn's disease) and a first episode of AP. Thirty-eight of those 185 (20.6%) fulfilled criteria for IAP. There were no severe cases of IAP. On multivariate analysis, AP before IBD diagnosis (21.1% vs. 3.4%, p = 0.04) and ulcerative colitis (52.6% vs. 23.1%, p = 0.002) were significantly more common in IAP. Further work-up was performed in 16/38 (42%) IAP patients, and a cause was identified in 6/16 (37.5%). Median time from AP to the end of follow-up was 6.3 years (3.1-10). Five-year risk of AP recurrence was significantly higher in IAP group (28% vs. 5.1%, log-rank p = 0.001), with a median time to first recurrence of 4.4 months (2.9-12.2). CONCLUSIONS: IAP represents the second cause of AP in patients with IBD. It is more frequent in ulcerative colitis, and presents a high risk of recurrence. Additional imaging work-up after a first episode of IAP in IBD patients is highly advisable, as it identifies a cause in more than one-third of cases.

Limitations of the determination of faecal calprotectin in patients with ulcerative colitis and inflammatory polyps. / Limitaciones de la determinación de calprotectina fecal en pacientes con colitis ulcerosa y pólipos inflamatorios.

INTRODUCTION: Faecal calprotectin is a useful technique for detecting activity in patients with ulcerative colitis. However, there may be high levels due to factors other than the activity of ulcerative colitis. Our aim was to analyse possible false positive results of calprotectin for the activity of ulcerative colitis owing to the presence of inflammatory polyps. PATIENTS AND METHODS: Retrospective, observational, descriptive study. Data was collected from patients monitored for 2 years in whom a colonoscopy had been requested within 3 months after detecting high calprotectin values (>150µg/g) and before modifying the treatment. RESULTS: We reviewed 39 patients and in 5 of them, with previous diagnosis of extensive ulcerative colitis, inflammatory polyps were detected. Three patients were on treatment with mesalazine, one with azathioprine and other with infliximab. All of them were asymptomatic and the endoscopy did not show macroscopic activity (endoscopic Mayo score=0) or histological activity. The median values of calprotectin were 422µg/g (IQR: 298-2,408) and they remained elevated in a second measurement. In 4 of the patients the inflammatory polyps were multiple and small in size. The other patient had a polyp measuring 4cm. DISCUSSION: In clinical practice we can find high faecal calprotectin levels not due to the presence of ulcerative colitis activity, but due to other lesions such as inflammatory polyps. This fact must be taken into account before carrying out relevant changes such as step-up therapy to immunosuppressive drugs or biological drugs in patients with confirmed high calprotectin levels.

Randomized clinical trial evaluating the effect of a visual educational leaflet on the preparation of colonoscopies in hospitalized patients.

BACKGROUND: the safety and diagnostic accuracy of colonoscopies depends on the quality of colon cleansing. Several factors have been reported that affect the quality of bowel cleansing, hospitalization being one of them. AIMS: the aim of the study was to investigate whether a visual educational leaflet improved the level of cleanliness achieved in hospitalized patients undergoing a colonoscopy and to identify predictors of a poor bowel preparation. METHODS: a prospective, single-center, endoscopist-blinded, randomized controlled trial was performed. The intervention group was given a visual educational leaflet and both groups received four liters of polyethylene glycol solution. Demographic data, personal history, reason for admission and indication for colonoscopy, work shift during which the procedure was performed and endoscopy findings were collected. The Boston Bowel Preparation Scale (BBPS) was used to assess the bowel preparation. RESULTS: one hundred and thirty-six patients were included in the study; 51.5% were male, with a mean age of 64.3 ± 17.6 years. The educational leaflet did not result in a difference in the total BBPS obtained between the standard group and the intervention group (7 [6-9] vs 6 [5.7-9]; p = 0.17). According to the multivariable analysis, the only factors associated with a poor bowel cleansing were heart disease (OR 3.37 [1.34-8.46]; p = 0.010) and colorectal cancer (OR 3.82 [1.26-11.61]; p = 0.018). CONCLUSION: the use of a visual educational leaflet for the preparation of colonoscopies did not provide a significant improvement in hospitalized patients in our health area. Heart disease was identified as the only predictor of poor preparation for colonoscopy.

Resources used in the treatment of perianal Crohn's disease and the results in a real-life cohort. / Recursos empleados en el tratamiento de la enfermedad de Crohn perianal y sus resultados en una serie de vida real.

OBJECTIVE: To study the multidisciplinary management of patients with Crohn's disease (CD) and perianal disease (perianal Crohn's disease, PCD), as well as to analyse a possible relationship between the recurrence of perianal symptoms, the type of fistula and the treatment used. PATIENTS AND METHODS: Descriptive, retrospective study of patients with PCD who were treated in the Inflammatory Bowel Disease Unit. Epidemiological, clinical, diagnostic and therapeutic variables were collected, as well as clinical outcome and response to treatment. RESULTS: Of the 300 patients who attended the outpatient clinic at a university hospital, 65 had PCD. Sixteen simple fistulas (24.6%) and 49 complex fistulas (75.4%) were diagnosed. The most commonly used diagnostic technique was the endoanal ultrasound (45%). Antibiotics were used in 77.4% of patients, and 70% needed anti-TNF therapy to manage the PCD. Surgery was performed on 75.4% of the patients overall. PCD recurred in 41.5% of cases, requiring a change of the biological drugs administered and/or surgery. Complex fistulas were more likely to require surgery (P=.012) and recurrence of PCD was also more common with complex fistulas (P=.036). CONCLUSION: Management of PCD must be multidisciplinary and combined. Most patients with complex PCD require treatment based on biological drugs. Despite therapy, remission of perianal symptoms is not achieved in a percentage of patients, supporting the need to develop new therapies for refractory cases.

Ratio of Circulating Estrogen Receptors Beta and Alpha (ERß/ERα) Indicates Endoscopic Activity in Patients with Crohn's Disease.

BACKGROUND: Data supporting a role of female hormones and/or their receptors in inflammatory bowel disease (IBD) are increasing, but most of them are derived from animal models. Estrogen receptors alpha (ERα) and beta (ERß) participate in immune and inflammatory response, among a variety of biological processes. Their effects are antagonistic, and the net action of estrogens may depend on their relative proportions. AIM: To determine the possible association between the balance of circulating ERß and ERα (ERß/ERα) and IBD risk and activity. METHODS: Serum samples from 145 patients with IBD (79 Crohn's disease [CD] and 66 ulcerative colitis [UC]) and 39 controls were retrospectively studied. Circulating ERα and ERß were measured by ELISA. Disease activities were assessed by clinical and endoscopic indices specific for CD and UC. RESULTS: Low values of ERß/ERα ratio were directly associated with clinical (p = 0.019) and endoscopic (p = 0.002) disease activity. Further analyses by type of IBD confirmed a strong association between low ERß/ERα ratio and CD clinical (p = 0.011) and endoscopic activity (p = 0.002). The receiver operating curve (ROC) analysis showed that an ERß/ERα ratio under 0.85 was a good marker of CD endoscopic activity (area under the curve [AUC]: 0.84; p = 0.002; sensitivity: 70%; specificity: 91%). ERß/ERα ratio was not useful to predict UC activity. CONCLUSIONS: An ERß/ERα ratio under 0.85 indicated CD endoscopic activity. The determination of serum ERß/ERα might be a useful noninvasive screening tool for CD endoscopic activity.

Fourteen-day high-dose esomeprazole, amoxicillin and metronidazole as third-line treatment for Helicobacter pylori infection.

INTRODUCTION: The efficacy of currently recommended third-line therapies for Helicobacter pylori is suboptimal, even that of culture-guided treatments. Resistance to multiple antibiotics is the major factor related to treatment failure. The aim of this study was to evaluate the effectiveness and safety of a 14-day therapy using high-dose of amoxicillin, metronidazole and esomeprazole. MATERIAL AND METHODS: Multicenter open-label study as a register in routine clinical practice in patients with two previous failures of eradication therapy. A triple therapy with esomeprazole 40 mg b.d., amoxicillin 1 g t.d.s and metronidazole 500 mg t.d.s for 2 weeks was administered as a third-line therapy after a first treatment including clarithromycin and a second treatment including a quinolone. Helicobacter pylori status was determined by either histology or 13 C-UBT both before and after treatment. RESULTS: A total of 68 patients were included in this study. An interim analysis showed that only three out of eight patients who had received metronidazole in previous eradication regimens were cured (37%, 95% CI 8-75); as a result, after this interim analysis only metronidazole-naïve patients were included. The ITT eradication rate in metronidazole-naive patients was 64% (95% CI 51-76). Adverse events occurred in 58% of patients, all of them mild-to-moderate. Two patients (3%) did not complete >90% of the treatment because of side effects. No severe adverse events occurred. CONCLUSION: Cure rates of this 14-day schedule using high-dose esomeprazole, amoxicillin and metronidazole as a third-line eradication regimen were suboptimal, especially in patients who had received metronidazole in previous failed eradication regimens.

What is the real-life maintenance mesalazine dose in ulcerative colitis?

OBJECTIVE: To describe how mesalazine (MSZ) is used in our practice in ulcerative colitis (UC), at what dose, and the success rate (regarding adherence to therapy). METHODS: Observational, transversal study, including all patients with UC and with MSZ maintenance therapy seen from September 2014 to February 2015 at two IBD units in Spain. Treatment adherence was measured by the Morisky-Green scale. RESULTS: We included 203 patients (mean MSZ dose: 2.6 ± 1.0 g/d; median of treatment: 19.5 months [IQR: 8-48]). Doses < 2 g/d were used in 15.3% of cases, 2-2.9 g/d doses in 35.0%, 3-3.9 doses in 29.5%, and ≥ 4 g/d doses in the remaining 20.2%. A single daily dose was preferred in 51.2% of cases, two doses in 33.0% and three doses in 15.8%. A different MSZ brand had been previously used in 36.6% of patients. In 134 cases (66%), the maintenance dose had been increased during a flare-up, and in 49 (36.6% of cases) this higher dose had been kept for maintenance (dose ≥ 4 g/d in 36 patients). During the MSZ therapy, 14 patients (6.9%) suffered mild side effects (21.4% altered liver function tests). Therapy adherence was good in 81.8% of cases. CONCLUSIONS: Half of our UC patients take high MSZ doses (≥ 3 g/d) as maintenance therapy, with acceptable safety and good adherence. Half of all patients take a single daily dose, and one third needed a different commercial brand during therapy. Opting for a higher MSZ maintenance dose is a possible strategy for a satisfactory maintenance therapy.

Mercaptopurine and inflammatory bowel disease: the other thiopurine.

BACKGROUND: Data about use and effectiveness of mercaptopurine in inflammatory bowel disease are relatively limited. AIMS: To assess the possible therapeutic indications, efficacy and safety of mercaptopurine as an alternative to azathioprine in inflammatory bowel disease. METHODS: Retrospective observational study in patients treated with mercaptopurine in a total cohort of 1,574 patients with inflammatory bowel disease. RESULTS: One hundred and fifty-two patients received mercaptopurine, 15.7% of these patients as an initial thiopurine, 5.3% after azathioprine failure, and 79% after azathioprine intolerance. In 52.6% of patients (n = 80), adverse effects of mercaptopurine occurred, resulting in withdrawal in 49 of them. Mercaptopurine was effective in 39% of cases (95% CI 31-48%). In the remaining patients, failure was due mainly to withdrawal due to side effects (55.1%) and therapeutic step-up (33.7%). The average total time of mercaptopurine exposure was 36 months (IQR: 2-60). Myelotoxicity with mercaptopurine was more common in patients with intermediate TPMT activity than in those with normal activity (p = 0.046). CONCLUSIONS: In our setting, mercaptopurine is primarily used as a rescue therapy in patients with azathioprine adverse effects. This could explain its modest efficacy and the high rate of adverse effects. However, this drug is still an alternative in this group of patients, before a therapeutic step-up to biologics is considered.

Gallstone-related disease in the elderly: is there room for improvement?

BACKGROUND AND AIM: Elderly patients are frequently affected by gallstone-related disease. Current guidelines support cholecystectomy after a first acute biliary complication. In the aging, these recommendations are irregularly followed. METHODS: We analyzed data from patients 65 or older admitted between June 30, 2004 and June 30, 2013 with a diagnosis of acute pancreatitis, cholangitis, or cholecystitis. Diagnosis and severity assessment were defined according to current guidelines. Harms, mortality, and cholecystectomy rates were evaluated. Baseline factors independently predicting cholecystectomy were identified. RESULTS: A total of 491 patients were included. The median age was 78.8 years, and 51.7 % were women. Acute cholecystitis was present in 51.7 %, acute pancreatitis in 36.5 %, and acute cholangitis in 11.8 %. Cholecystectomy was performed in 47.1 %. Age, myocardial infarct, dementia, diabetes, nonmetastatic tumor, and severe liver disease were risk factors for not undergoing surgery. Complications related to hospital stay appeared in 33 % of patients. Surgery, cholecystostomy, and ERCP presented harms in 21-25 %. Overall mortality rate was 5.4 %: 10.4 % in acute cholangitis, 6.8 % in acute cholecystitis, and 2.2 % in acute pancreatitis. Mild cases presented a 1.3 % mortality, while 28.6 % of severe cases died. After discharge, 24.7 % of patients presented a new biliary complication, 9.7 % of them severe. Relapse was more frequent in patients managed without invasive procedures, 42.3 % than in cholecystectomy patients, 9.9 % (p < 0.001) and than in ERCP patients, 19.4 % (p = 0.01). CONCLUSIONS: Cholecystectomy should be recommended to elderly patients after a first acute biliary complication. If not previously performed, ERCP should be offered as an alternative when surgery is contraindicated or refused.

Response to letter: folate deficiency in Crohn's disease.

Folate deficiency in patients with Crohn's disease may be due to a combination of factors: poor diet, malabsorption, increased requirements due to inflammation of the mucosa, and the taking of certain drugs as sulfasalazine and methotrexate. A significant proportion of patients with Crohn's disease suffer from folate deficiency, suggesting that regular screening should be performed.

Serum and Urine Metabolomic Profiling of Newly Diagnosed Treatment-Naïve Inflammatory Bowel Disease Patients.

BACKGROUND AND AIMS: Inflammatory bowel disease (IBD) is a prevalent chronic noncurable disease associated with profound metabolic changes. The discovery of novel molecular indicators for unraveling IBD etiopathogenesis and the diagnosis and prognosis of IBD is therefore pivotal. We sought to determine the distinctive metabolic signatures from the different IBD subgroups before treatment initiation. METHODS: Serum and urine samples from newly diagnosed treatment-naïve IBD patients and age and sex-matched healthy control (HC) individuals were investigated using proton nuclear magnetic resonance spectroscopy. Metabolic differences were identified based on univariate and multivariate statistical analyses. RESULTS: A total of 137 Crohn's disease patients, 202 ulcerative colitis patients, and 338 HC individuals were included. In the IBD cohort, several distinguishable metabolites were detected within each subgroup comparison. Most of the differences revealed alterations in energy and amino acid metabolism in IBD patients, with an increased demand of the body for energy mainly through the ketone bodies. As compared with HC individuals, differences in metabolites were more marked and numerous in Crohn's disease than in ulcerative colitis patients, and in serum than in urine. In addition, clustering analysis revealed 3 distinct patient profiles with notable differences among them based on the analysis of their clinical, anthropometric, and metabolomic variables. However, relevant phenotypical differences were not found among these 3 clusters. CONCLUSIONS: This study highlights the molecular alterations present within the different subgroups of newly diagnosed treatment-naïve IBD patients. The metabolomic profile of these patients may provide further understanding of pathogenic mechanisms of IBD subgroups. Serum metabotype seemed to be especially sensitive to the onset of IBD.

Should we monitor vitamin B12 and folate levels in Crohn's disease patients?

OBJECTIVE: Crohn's disease commonly involves the small intestine, which is the site of vitamin B12 and folate absorption. Our aim was to define the prevalence of vitamin B12 and folate deficiency in patients with Crohn's disease and to identify predictive factors associated with such abnormalities. METHODS: Two years prospective study of 180 consecutive Crohn's disease patients. Vitamin B12 and folate deficiency was defined as serum levels below 200 pg/ml and 3 ng/ml, respectively. We analysed prevalence of these deficiencies and possible predictive factors including small intestine resection, disease location, activity and duration of disease. Controls were ulcerative colitis patients (n = 70). RESULTS: The prevalence of B12 deficiency in Crohn's disease was 15.6% (95%CI 9.7-20%) compared with 2.8% (95%CI 0.8-9.8%) in ulcerative colitis (p = 0.007). With regard to folate deficiency, the prevalence in patients with Crohn's disease was 22.2% (95%CI 16-28%) compared with 4.3% (95%CI 1.4-12%) in ulcerative colitis (p = 0.001); 7.8% of Crohn's disease patients had macrocytic anemia. Ileal resection was found to be a risk factor for B12 deficiency (OR 2.7; 1.2-6.7; p = 0.02), and disease activity a risk factor for folate deficiency (OR 2.4; 1.2-5.1; p = 0.01). CONCLUSION: A significant proportion of patients with Crohn's disease suffer from vitamin B12 and/or folate deficiency, suggesting that regular screening should be performed, with closer monitoring in patients with ileal resection or active disease.

Association of golimumab trough concentrations during maintenance with clinical, biological, endoscopic and histologic remission in patients with ulcerative colitis.

BACKGROUND: Optimal golimumab concentration thresholds for important outcomes during maintenance are lacking. AIMS: To investigate the association of golimumab trough concentrations during maintenance with key outcomes, including endoscopic and histologic remission, and long-term event-free persistence with golimumab, in patients with UC. METHODS: This multi-centre, cross-sectional study included patients with UC on golimumab maintenance recruited either in remission or during a flare. Colonoscopy was scheduled, and study-specific rectocolonic biopsies were taken for blind central histologic reading. Samples for golimumab trough concentrations were collected close to colonoscopy. RESULTS: Fifty-two patients were included. Median golimumab trough concentrations (µg/ml) were significantly higher in patients who had clinical remission (2.01 vs. 0.72, p = 0.047), combined clinical-biochemical remission (PMS ≤2 + faecal calprotectin <250 µg/g) (2.21 vs. 1.47, p = 0.041), endoscopic healing (Mayo endoscopic subscore 0) (2.52 vs. 1.47, p = 0.003), histologic remission (Geboes index ≤2.0) (2.33 vs. 1.50, p = 0.02) and disease clearance (clinical remission endoscopic healing + histologic remission) (2.52 vs. 1.70, p = 0.009), compared with those not meeting these criteria. Golimumab concentrations were significantly higher in patients who avoided golimumab dose escalation/discontinuation during follow-up (2.24 vs. 0.98, p = 0.012). Receiver-operating characteristic analyses identified golimumab thresholds [area under the curve] of 0.85 [0.76], 1.90 [0.76], 2.29 [0.75], 1.79 [0.68], 2.29 [0.72] and 1.56 [0.71] µg/ml as associated with clinical remission, combined remission, endoscopic healing, histologic remission, disease clearance and long-term event-free persistence with golimumab, respectively. CONCLUSIONS: Golimumab trough concentrations during maintenance are associated with favourable treatment outcomes including endoscopic healing, histologic remission and long-term persistence on golimumab. We identified the optimal golimumab thresholds most closely associated with key outcomes.

Evaluation in a Cytokine Storm Model In Vivo of the Safety and Efficacy of Intravenous Administration of PRS CK STORM (Standardized Conditioned Medium Obtained by Coculture of Monocytes and Mesenchymal Stromal Cells).

Our research group has been developing a series of biological drugs produced by coculture techniques with M2-polarized macrophages with different primary tissue cells and/or mesenchymal stromal cells (MSC), generally from fat, to produce anti-inflammatory and anti-fibrotic effects, avoiding the overexpression of pro-inflammatory cytokines by the innate immune system at a given time. One of these products is the drug PRS CK STORM, a medium conditioned by allogenic M2-polarized macrophages, from coculture, with those macrophages M2 with MSC from fat, whose composition, in vitro safety, and efficacy we studied. In the present work, we publish the results obtained in terms of safety (pharmacodynamics and pharmacokinetics) and efficacy of the intravenous application of this biological drug in a murine model of cytokine storm associated with severe infectious processes, including those associated with COVID-19. The results demonstrate the safety and high efficacy of PRS CK STORM as an intravenous drug to prevent and treat the cytokine storm associated with infectious processes, including COVID-19.

Cytokine Profile and Anti-Inflammatory Activity of a Standardized Conditioned Medium Obtained by Coculture of Monocytes and Mesenchymal Stromal Cells (PRS CK STORM).

Intercellular communication between monocytes/macrophages and cells involved in tissue regeneration, such as mesenchymal stromal cells (MSCs) and primary tissue cells, is essential for tissue regeneration and recovery of homeostasis. Typically, in the final phase of the inflammation-resolving process, this intercellular communication drives an anti-inflammatory immunomodulatory response. To obtain a safe and effective treatment to counteract the cytokine storm associated with a disproportionate immune response to severe infections, including that associated with COVID-19, by means of naturally balanced immunomodulation, our group has standardized the production under GMP-like conditions of a secretome by coculture of macrophages and MSCs. To characterize this proteome, we determined the expression of molecules related to cellular immune response and tissue regeneration, as well as its possible toxicity and anti-inflammatory potency. The results show a specific molecular pattern of interaction between the two cell types studied, with an anti-inflammatory and regenerative profile. In addition, the secretome is not toxic by itself on human PBMC or on THP-1 monocytes and prevents lipopolysaccharide (LPS)-induced growth effects on those cell types. Finally, PRS CK STORM prevents LPS-induced TNF-A and IL-1Β secretion from PBMC and from THP-1 cells at the same level as hydrocortisone, demonstrating its anti-inflammatory potency.

Re-induction With Intravenous Ustekinumab in Patients With Crohn's Disease and a Loss of Response to This Therapy.

BACKGROUND: A significant percentage of patients treated with ustekinumab may lose response. Our aim was to evaluate the short-term efficacy and safety of intravenous re-induction with ustekinumab in patients with Crohn's disease who have lost the response to the treatment. METHODS: This is a retrospective, observational, multicenter study. Treatment efficacy was measured at week 8 and 16; clinical remission was defined when the Harvey-Bradshaw Index was ≤4 points, and clinical response was defined as a decrease of ≥3 points in the index compared with the baseline. Adverse events and treatment decisions after re-induction were also collected. RESULTS: Fifty-three patients from 13 centers were included. Forty-nine percent had previously failed to respond to 2 biological treatments, and 24.5% had failed to respond to 3. The average exposure time to ustekinumab before re-induction was 17.7 ± 12.8 months. In 56.6% of patients, the administration interval had been shortened to every 4 to 6 weeks before re-induction. At week 8 and 16 after re-induction, 49.0% (n = 26) and 43.3% (n = 23), respectively, were in remission, whereas 64.1% (n = 34) and 52.8% (n = 28) had a clinical response. Patients who achieved remission at week 16 had lower C-reactive protein levels than those who did not respond (2.8 ± 1.6 vs 12.5 ± 9.5 mg/dL; P = 0.001). No serious adverse events related to re-induction were observed. CONCLUSION: Intravenous re-induction with ustekinumab is an effective and safe strategy that recovers the response in approximately half of the patients with refractory Crohn's disease who experience a loss of response. Re-induction can be attempted before switching out of the therapy class.