Ustekinumab safety and effectiveness in patients with ulcerative colitis: results from a large real-life study.

BACKGROUND: Ustekinumab (UST) is an interleukin-12/interleukin-23 receptor antagonist recently approved for treating ulcerative colitis (UC) but with limited real-world data. Therefore, we evaluated the effectiveness and safety of UST in patients with UC in a real-world setting. RESEARCH DESIGN AND METHODS: This is a multicenter, retrospective, observational cohort study. The primary endpoints were the clinical remission rate (partial Mayo score, PMS, ≤1) and the safety of UST. Other endpoints were corticosteroid-free remission (CSFR) rate, clinical response rate (PMS reduction of at least 2 points), and fecal calprotectin (FC) reduction at week 24. RESULTS: We included 256 consecutive patients with UC (M/F 139/117, median age 52). The clinical remission and clinical response rates at eight weeks were 18.7% (44/235) and 53.2% (125/235), respectively, and 27.6% (42/152) and 61.8% (94/152) at 24 weeks, respectively. At 24 weeks, CSFR was 20.3% (31/152), and FC significantly dropped at week 12 (p = 0.0004) and 24 (p = 0.038). At eight weeks, patients naïve or with one previous biologic treatment showed higher remission (p = 0.002) and clinical >response rates (p = 0.018) than patients previously treated with ≥ 2. Adverse events occurred in six patients (2.3%), whereas four patients (1.6%) underwent colectomy. CONCLUSION: This real-world study shows that UST effectively and safely treats patients with UC.

Real-world efficacy and safety of vedolizumab in managing ulcerative colitis versus Crohn's disease: results from an Italian multicenter study.

BACKGROUND: Vedolizumab (VDZ) can be used to treat refractory ulcerative colitis (UC) and Crohn's disease (CD). We assessed whether there are differences in treating UC vs CD with VDZ. RESEARCH DESIGN AND METHODS: Mayo score in UC and the Harvey-Bradshaw Index (HBI) in CD scored the clinical activity. Achievement and maintenance of clinical remission during the follow-up, and safety were the primary endpoints. RESULTS: 729 patients (475 with UC and 254 with CD), median follow-up of 18 (IQR 6-36) months, were enrolled. Clinical remission at the 6th month of treatment was achieved in 488 (66.9%) patients (74.4% in CD vs 62.9% in UC, p<0.002) while, during the follow-up, no difference was found (81.5% in the UC group and 81.5% pts in the CD group; p=0.537). The clinical remission at the 6th month of treatment (p=0.001) and being naïve to biologics (p<0.0001) were significantly associated with prolonged clinical remission. The clinical response was significantly higher in UC (90.1%) vs CD (84.3%) (p=0.023), and surgery occurred more frequently in CD (1.9% in UC vs 5.1% in CD, p=0.016). CONCLUSION: We found differences when using VDZ in UC vs CD in real life. These parameters can help the physician predict this drug's longterm efficacy.

Residual Lung Abnormalities in Survivors of Severe or Critical COVID-19 at One-Year Follow-Up Computed Tomography: A Narrative Review Comparing the European and East Asian Experiences.

The literature reports that there was a significant difference in the medical impact of the coronavirus disease (COVID-19) pandemic between European and East Asian countries; specifically, the mortality rate of COVID-19 in Europe was significantly higher than that in East Asia. Considering such a difference, our narrative review aimed to compare the prevalence and characteristics of residual lung abnormalities at one-year follow-up computed tomography (CT) after severe or critical COVID-19 in survivors of European and East Asian countries. A literature search was performed to identify articles focusing on the prevalence and characteristics of CT lung abnormalities in survivors of severe or critical COVID-19. Database analysis identified 16 research articles, 9 from Europe and 7 from East Asia (all from China). Our analysis found a higher prevalence of CT lung abnormalities in European than in Chinese studies (82% vs. 52%). While the most prevalent lung abnormalities in Chinese studies were ground-glass opacities (35%), the most prevalent lung abnormalities in European studies were linear (59%) and reticular opacities (55%), followed by bronchiectasis (46%). Although our findings required confirmation, the higher prevalence and severity of lung abnormalities in European than in Chinese survivors of COVID-19 may reflect a greater architectural distortion due to a more severe lung damage.

Update on ozanimod for ulcerative colitis.

Treating moderate to severe ulcerative colitis (UC) has been enriched by the increasing number of drugs available for this disease. However, failure of conventional therapies, an incomplete response, or loss of response to biologics is experienced in many UC patients. Thus, there is still a growing need for new drugs in the therapeutic arsenal for UC. Ozanimod is a sphingosine-1-phosphate (S1P) receptor modulator which has been recently approved for UC therapy. In this review, we focus on the mechanism of action of ozanimod hydrochloride in preclinical studies of intestinal inflammation as well as its clinical effectiveness and safety in moderate to severe UC patients. In this population, ozanimod was shown to be significantly more effective than placebo to induce clinical remission. Additionally, in terms of clinical response, corticosteroid-free remission, endoscopic improvement and mucosal healing, ozanimod performed significantly better than placebo in this population. No significant safety concerns about ozanimod emerged from clinical trials in UC.

Dermatological Manifestations in Inflammatory Bowel Diseases.

Inflammatory bowel diseases (IBDs) may be associated with extra-intestinal manifestations. Among these, mucocutaneous manifestations are relatively frequent, often difficult to diagnose and treat, and may complicate the course of the underlying disease. In the present review, a summary of the most relevant literature on the dermatologic manifestations occurring in patients with inflammatory bowel diseases has been reviewed. The following dermatological manifestations associated with IBDs have been identified: (i) specific manifestations with the same histological features of the underlying IBD (occurring only in Crohn's disease); (ii) cutaneous disorders associated with IBDs (such as aphthous stomatitis, erythema nodosum, psoriasis, epidermolysis bullosa acquisita); (iii) reactive mucocutaneous manifestations of IBDs (such as pyoderma gangrenosum, Sweet's syndrome, bowel-associated dermatosis-arthritis syndrome, aseptic abscess ulcers, pyodermatitis-pyostomatitis vegetans, etc.); (iv) mucocutaneous conditions secondary to treatment (including injection site reactions, infusion reactions, paradoxical reactions, eczematous and psoriasis-like reactions, cutaneous infections, and cutaneous malignancies); (v) manifestations due to nutritional malabsorption (such as stomatitis, glossitis, angular cheilitis, pellagra, scurvy, purpura, acrodermatitis enteropathica, phrynoderma, seborrheic-type dermatitis, hair and nail abnormalities). An accurate dermatological examination is essential in all IBD patients, especially in candidates to biologic therapies, in whom drug-induced cutaneous reactions may assume marked clinical relevance.

Inhibitors of the Janus Kinases: A New Oral Treatment Option for Ulcerative Colitis.

BACKGROUND: The treatment of ulcerative colitis (UC) is based on conventional therapies (aminosalicylates, corticosteroids, and immunosuppressants) and when these are ineffective, biologic drugs. However, in a substantial portion of patients undergoing treatment with biologic agents there is primary or secondary loss of response. Thus, new therapeutic options are been actively explored; among these, there is interest in the Janus kinase (JAK) inhibitors, small molecules that can be administered orally. METHODS: We carried out an extensive literature search concerning the effects of JAK inhibitors for the treatment of patients with UC. RESULTS: Tofacitinib is the drug more extensively studied in this setting, and it was recently approved in Europe for the treatment of moderate to severe UC. The available data suggest that this drug can be effective in obtaining clinical and endoscopic remission in UC patients unresponsive to other treatments, even in those previously treated with biologic drugs. In addition, the drug was able to improve significantly the quality of life of these patients. There are still few data available for the treatment of UC with other JAK inhibitors. CONCLUSIONS: The JAK inhibitors, in particular tofacitinib, are a new class of orally administered drugs effective for the treatment of UC. However, more studies are needed to ascertain the safety of tofacitinib in the long term and whether other compounds of this class may be equally effective.

Localization of TNF alpha in ileocolonic biopsies of patients with inflammatory bowel disease.

BACKGROUND: Although antitumor necrosis factor alfa (TNFα) agents are widely used to treat patients with inflammatory bowel diseases (IBD) - both Crohn's disease (CD) and ulcerative colitis (UC) - there is still some uncertainty in the cell type expressing TNFα in human ileo-colonic segments. AIMS: We investigated the immunohistochemical (IHC) expression of TNFα in the ileo-colonic segments of patients with both active CD and UC, to establish its anatomic and cellular localization in the inflamed sites. Our aim was to identify patients potentially resistant to anti TNFα agents. PATIENTS AND METHODS: Ileo-colonic slides of complete histological mapping of patients with CD and UC before any treatment was started were obtained, and serial sections assessed for TNFα expression, together with IHC markers for lymphocytes, macrophages, and plasma cells. RESULTS: TNFα was expressed in almost all inflamed segments of IBD patients, albeit with different strength, and was present, in addition to lymphocytes and, to a lesser extent, to macrophages, in plasma cells, where it had a strong positivity, as also demonstrated by colocalization of specific IHC staining. The expression of TNFα was mostly focal in CD patients and more diffuse in UC patients, likely due to the different patterns of inflammation (transmural and mucosal) of the two entities. CONCLUSIONS: In IBD, TNFα is strongly expressed also in plasma cells, and it is easily evidenced by conventional IHC techniques. It remains to be established whether this observation might be useful in future to establish in routine biopsy samples whether patients may be responsive to treatments toward this cytokine.

Colonic hypereosinophilia in ulcerative colitis may help to predict the failure of steroid therapy.

BACKGROUND: Although glucocorticosteroids (GS) and mesalazine are effective and widely employed to treat moderate-to-severe ulcerative colitis (UC), information regarding the factors responsible for response to such therapy is still scarce. One of these factors is thought to be an increased number of mucosal eosinophils. The aim of our study was to determine whether the presence of hypereosinophilia in colonic mucosa of UC patients might influence the short-term response to l treatment with GS and mesasalazine. METHODS: Clinical, endoscopic, and pathologic data from patients with a recent diagnosis of moderate UC, who had not undergone treatment, were obtained, and the short-term outcome after 1 month of conventional first-line treatment (mesalazine plus GS) was evaluated. RESULTS: There were 53 patients with a median age of 37 years (95% CI 30-47).Overall, at the end of treatment period 16 (30%) patients responded, whereas a response was not observed in the other 37 (70%) patients. Interestingly, all patients of this latter group had colonic mucosal hypereosinophilia. No significant differences were found between the two groups concerning sex and age at diagnosis, but hypereosinophilia was inversely correlated with the duration of the disease (p = 0.054), and significantly correlated to the localization of UC (p = 0.0023). In addition, The Mayo score was significantly higher in patients with hypereosinophilia (median 8; 95% CI 8-9;) when compared to patients without hypereosinophilia (median 7; 95% CI 7-7, p < 0.0001) including the Mayo endoscopic subscore (median 3; 95% CI 2-3 vs median 2; 95% CI 2-2, respectively; p = 0.007). CONCLUSIONS: The presence of colonic mucosal hypereosinophilia may be useful to predict the short-term outcome to conventional first-line therapy in treatment-naïve UC patients. It remains to be seen whether this might be important in modifying the first-line therapy in this subgroup of patients.

Novel oral-targeted therapies for mucosal healing in ulcerative colitis.

Ulcerative colitis (UC), a chronic, relapsing, remitting disease of the colon and rectum, is characterized by inflammatory ulceration of the mucosa. Current UC therapy relies on controlling acute episodes and preventing relapse. To predict modifications in the natural course of UC, mucosal healing (MH) has emerged as a major treatment goal. Endoscopic evaluation is considered the gold standard for assessing MH, which can be achieved by conventional drugs and biologics in many, but not all, patients. Consequently, interest is focusing on the development of new substances for UC therapy, and new oral agents are in the pipeline. This review will focus on the ability of newly developed oral drugs to induce and maintain MH in UC patients.

Usefulness of Different Pathological Scores to Assess Healing of the Mucosa in Inflammatory Bowel Diseases: A Real Life Study.

The concept of remission for patients with inflammatory bowel diseases has recently evolved, and should also include histological healing of the mucosa, difficult to evaluate since there is no agreement on pathological scores and those available are quite complex to use in the daily routine. We evaluated the possible usefulness of a simplified pathological score to assess histological healing of the mucosa in inflammatory bowel diseases patients compared with four commonly proposed pathological scores. Slides from 24 patients (12 Crohn's disease, 12 ulcerative colitis, age range 24-62 years), pre- and post-treatment with biological agents and displaying endoscopic remission were assessed by two pathologists. Pre- and post-treatment results and the time employed to calculate the various scores were obtained. All scores were useful to document highly significant post-treatment decreases of histological activity. However, the simplified score needed significant less time to be calculated for each slide, had high inter-rater agreement, and avoided subjectivity from the pathologists. The simplified score is easy to calculate and seems apt to document histological healing of the mucosa, in a manner similar to the more complex scores. It remains to be established whether this score could simplify the daily routinary practice in this context.

Eosinophilia - associated basal plasmacytosis: an early and sensitive histologic feature of inflammatory bowel disease.

Basal plasmacytosis is an early-onset and highly predictive feature of inflammatory bowel disease (IBD), but may have several restrictions in routine histology. Considering evidences about cooperation between eosinophils and plasma cells in IBD pathogenesis, we investigated immunostain of these two cells as a marker of disease. 343 samplings from 83 patients (52 IBD, 31 non-IBD colitis) were evaluated. The sections were stained with monoclonal antibodies against plasma cells (CD138 and MUM1), and eosinophils (CD193). Eosinophilia-associated basal plasmacytosis (EBP) was related with the histologic diagnosis of IBD (90.3% IBD and 35.4% non-IBD colitides, p < 0.005, sensitivity 90.4%). A strong relation was detected between the occurrence of EBP and (i) the achieving of a complete endoscopic mapping; (ii) the presence of other characteristic lesions of IBD in single segmental sampling, although EBP was evident in more than 40% of samples without other IBD-related lesions. EBP is a sensitive histologic feature of IBD, especially at the first endoscopic sampling, even in the absence of the other characteristic histologic lesions, and may help in formulating a more precise diagnosis in this setting.

Enteric glial cells are susceptible to Clostridium difficile toxin B.

Clostridium difficile causes nosocomial/antibiotic-associated diarrhoea and pseudomembranous colitis. The major virulence factors are toxin A and toxin B (TcdB), which inactivate GTPases by monoglucosylation, leading to cytopathic (cytoskeleton alteration, cell rounding) and cytotoxic effects (cell-cycle arrest, apoptosis). C. difficile toxins breaching the intestinal epithelial barrier can act on underlying cells, enterocytes, colonocytes, and enteric neurons, as described in vitro and in vivo, but until now no data have been available on enteric glial cell (EGC) susceptibility. EGCs are crucial for regulating the enteric nervous system, gut homeostasis, the immune and inflammatory responses, and digestive and extradigestive diseases. Therefore, we evaluated the effects of C. difficile TcdB in EGCs. Rat-transformed EGCs were treated with TcdB at 0.1-10 ng/ml for 1.5-48 h, and several parameters were analysed. TcdB induces the following in EGCs: (1) early cell rounding with Rac1 glucosylation; (2) early G2/M cell-cycle arrest by cyclin B1/Cdc2 complex inactivation caused by p27 upregulation, the downregulation of cyclin B1 and Cdc2 phosphorylated at Thr161 and Tyr15; and (3) apoptosis by a caspase-dependent but mitochondria-independent pathway. Most importantly, the stimulation of EGCs with TNF-α plus IFN-γ before, concomitantly or after TcdB treatment strongly increased TcdB-induced apoptosis. Furthermore, EGCs that survived the cytotoxic effect of TcdB did not recover completely and showed not only persistent Rac1 glucosylation, cell-cycle arrest and low apoptosis but also increased production of glial cell-derived neurotrophic factor, suggesting self-rescuing mechanisms. In conclusion, the high susceptibility of EGCs to TcdB in vitro, the increased sensitivity to inflammatory cytokines related to apoptosis and the persistence of altered functions in surviving cells suggest an important in vivo role of EGCs in the pathogenesis of C. difficile infection.

The importance of histologic parameters of lacteal involvement in cases of canine lymphoplasmacytic enteritis.

BACKGROUND: The most frequent form of inflammatory bowel disease (IBD) in dogs is represented histologically, by lymphoplasmacytic enteritis (LPE), a histological category, often associated with other morphologic alterations including lymphangiectasia (LE). However, literature data on this latter topic are quite scarce and have mostly been obtained in single reports or in small series. AIM: We evaluated some morphologic parameters of intestinal villi and lacteals in a large cohort of dogs, and correlated them with serum albumin and cholesterol values. PATIENTS AND METHODS: We investigated 136 dogs (94 with LPE, and 42 with gastrointestinal problems different from IBD) and analyzed their clinical, laboratory (albumin and cholesterol values), endoscopic, and histologic variables. RESULTS: The LPE group showed significantly impaired clinical, laboratory, endoscopic, and histologic variables compared to controls. Affected dogs showed significant correlations between canine inflammatory bowel disease activity index (CIBDAI) scores and endoscopic and histologic variables. Moreover, the grade of hematologic changes were strongly related to the intestinal histologic variables, in particular those concerning villous and lacteals morphology. CONCLUSION: Dogs with LPE had intestinal histologic abnormalities (height, width, height/width ratio, calculated for both villi and lacteals), whose degree correlated with the severity of hypoalbuminemia and hypocholesterolemia. Evaluation of endoscopic and histologic variables in association to the clinical findings may reveal useful insights for the pathogenesis of LPE and, hopefully, might lead to more targeted therapeutic approaches.

Colonic motility in ulcerative colitis.

BACKGROUND: Inflammatory conditions affecting the gut may cause motility disturbances, and ulcerative colitis - one of the main disorders among the inflammatory bowel diseases - may display abnormal colonic motility. AIM: To review the abnormalities of the large bowel in ulcerative colitis, by considering the motility, laboratory (in vitro) and pathological studies dealing with this topic. METHODS: A comprehensive online search of Medline and the Science Citation Index was carried out. RESULTS: Patients with ulcerative colitis frequently display colonic motor abnormalities, including lack of contractility, an increase of propulsive contractile waves, an excessive production of nitric oxide, vasoactive intestinal polypeptide nerves, interleukin 1 beta, neurotensin, tachykinins levels and the weaker action of substance P, likely related to a neuromuscular dysfunction due to the inflammatory process. CONCLUSIONS: A better understanding of the pathophysiological grounds of altered colonic motility in ulcerative colitis may lead to a more in-depth knowledge of the accompanying symptoms and to better and more targeted therapeutic approaches.

Endoscopic biopsy samples of naïve "colitides" patients: role of basal plasmacytosis.

BACKGROUND: Although it is usually not difficult to diagnose inflammatory bowel disease (IBD) on surgical resection specimens, difficulties sometimes arise in differentiating these entities from other forms of colitis on endoscopic biopsy specimens. Basal plasmacytosis is considered as an early feature of IBD colitis, but it is rare in non-IBD colitides. AIMS: We assessed the value of basal plasmacytosis as an individual variable in untreated patients with colitis. PATIENTS AND METHODS: Archival slides of patients with untreated colitis (66 IBD and 49 non-IBD) and 20 controls with complete (from the terminal ileum to the rectum) endoscopic biopsy sampling were evaluated blindly for the presence of basal plasmacytosis and a possible association with the presence of eosinophils in the same anatomical location. RESULTS: Overall, basal plasmacytosis was present in at least one anatomical segment in 58% of cases, and it was always present in patients with IBD, whereas it was sparsely found (9%) in patients with other colitides and in controls. Basal plasmacytosis in three or more segments had more than 80% probability for a patient to be classified as IBD, with the segmental distribution being different between ulcerative colitis and Crohn's disease. Additionally, basal plasmacytosis was always accompanied by eosinophils intermingled with plasma cells in the same anatomical position. CONCLUSION: As an individual feature, basal plasmacytosis (accompanied by eosinophils) is a strong feature suggesting IBD, particularly when present in three or more colonic segments. This fact may be useful in the evaluation of endoscopic biopsies from patients with "colitis".

Gastrointestinal motility disorders in inflammatory bowel diseases.

The relationship between motility and inflammatory gastrointestinal disorders is at the same time complex and intriguing since these conditions might share some genetic, environmental, immunological and microbial predisposing factors. In addition, significant symptom overlapping may occur, muddling the waters within the clinical context. Although on one hand this represents a challenge for the clinician for a potential under- or over-treatment and diagnostic delay, on the other hand it possibly represents an opportunity for the researcher to better disclose the intimate relationship between chronic (often low-grade) inflammation, motor disorders and deranged sensory function. The best example is probably represented by Crohn's disease and ulcerative colitis. In fact, a number of gastrointestinal motor disorders have been described in association with these diseases, disorders which span from the esophagus to the anorectum, and which will be extensively covered in this review. It is conceivable that at least part of this derangement is strictly related to inflammatory cytokine trafficking and neuromuscular changes; however, given the high prevalence of functional gastrointestinal disorders in the general population, this overlap might also be serendipitous. However, it is worth noting that literature data on this topic are relatively scarce, sometimes quite outdated, and mostly focused on the interplay between irritable bowel syndrome and inflammatory bowel disease. Nevertheless, both researchers and clinicians must be aware that symptoms related to gastrointestinal motility disorders may be highly prevalent in both active and inactive inflammatory bowel disease, correlate with greater psychological comorbidity and poorer quality of life, and may negatively influence the therapeutic approaches.