Anti tumor necrosis factor antibodies are used to treat both psoriasis and inflammatory bowel disease. Several paradoxical cases of psoriatic skin lesions induced by tumor necrosis factor antagonist therapy have been described in IBD patients in the recent years. Ustekinumab, a fully human anti-interleukin-12/-23 monoclonal antibody, is the first drug of a new class of biologic therapy approved for the treatment of moderate to severe plaque psoriasis. Data on the efficacy of ustekinumab in patients with moderate-to-severe Crohn's disease, especially in patients previously treated with infliximab, have been recently published. We report about the effectiveness of ustekinumab in the treatment of both severe scalp psoriasis lesions with alopecia and active Crohn's disease.
The prevalence of acute diverticulitis (AD) has progressively increased in recent decades, with correspondingly greater morbidity and mortality. The aim of the study is to develop a predictive score to identify patients with the highest risk of complicated AD. The clinical records of 1089 patients referred to the emergency department (ED) over a five-year period were reviewed. In multivariate analysis, male sex (p < 0.001), constipation (p = 0.002), hemoglobin < 11.9 g/dL (p < 0.001), C reactive protein > 80 mg/L (p < 0.001), severe obesity (p = 0.049), and no proton pump inhibitor treatment (p = 0.003) were independently associated with complicated AD. The predictive assessment of complicated (PACO)-diverticulitis (D) score, including these six variables, was applied to the retrospective cohort and then validated prospectively in a cohort including 282 patients. It categorized patients into three risk classes for complicated AD. The PACO-D score showed fair discrimination for complicated AD with an area under the receiver operating characteristic curve of 0.674 and 0.648, in the retrospective and prospective cohorts, respectively. The PACO-D score could be a practical clinical tool to identify patients at highest risk for complicated AD referred to the ED so that appropriate diagnostic and therapeutic resources could be appropriately allocated. Further external validation is needed to confirm these results.
VSL#3 is a high-potency probiotic mixture that has been used successfully in the treatment of pouchitis. The primary end point of the study was to assess the effects of supplementation with VSL#3 in patients affected by relapsing ulcerative colitis (UC) who are already under treatment with 5-aminosalicylic acid (ASA) and/or immunosuppressants at stable doses.A total of 144 consecutive patients were randomly treated for 8 weeks with VSL#3 at a dose of 3,600 billion CFU/day (71 patients) or with placebo (73 patients).In all, 65 patients in the VSL#3 group and 66 patients in the placebo group completed the study. The decrease in ulcerative colitis disease activity index (UCDAI) scores of 50% or more was higher in the VSL#3 group than in the placebo group (63.1 vs. 40.8; per protocol (PP) P=0.010, confidence interval (CI)₉₅(%) 0.51-0.74; intention to treat (ITT) P=0.031, CI₉₅(%) 0.47-0.69). Significant results with VSL#3 were recorded in an improvement of three points or more in the UCDAI score (60.5% vs. 41.4%; PP P=0.017, CI₉₅(%) 0.51-0.74; ITT P=0.046, CI₉₅(%) 0.47-0.69) and in rectal bleeding (PP P=0.014, CI₉₅(%) 0.46-0.70; ITT P=0.036, CI₉₅(%) 0.41-0.65), whereas stool frequency (PP P=0.202, CI₉₅(%) 0.39-0.63; ITT P=0.229, CI₉₅(%) 0.35-0.57), physician's rate of disease activity (PP P=0.088, CI₉₅(%) 0.34-0.58; ITT P=0.168, CI₉₅(%) 0.31-0.53), and endoscopic scores (PP P=0.086, CI₉₅(%) 0.74-0.92; ITT P=0.366, CI₉₅(%) 0.66-0.86) did not show statistical differences. Remission was higher in the VSL#3 group than in the placebo group (47.7% vs. 32.4%; PP P=0.069, CI₉₅(%) 0.36-0.60; ITT P=0.132, CI₉₅(%) 0.33-0.56). Eight patients on VSL#3 (11.2%) and nine patients on placebo (12.3%) reported mild side effects.VSL#3 supplementation is safe and able to reduce UCDAI scores in patients affected by relapsing mild-to-moderate UC who are under treatment with 5-ASA and/or immunosuppressants. Moreover, VSL#3 improves rectal bleeding and seems to reinduce remission in relapsing UC patients after 8 weeks of treatment, although these parameters do not reach statistical significance.
1Istituto di Medicina Interna e Geriatria, Università Cattolica del S. Cuore, Roma, Italy Correspondence: Alfredo Papa, MD, Istituto di Medicina Interna e Geriatria, Università Cattolica del S. Cuore, L.go A. Gemelli, 8, 00168 Roma, Italy. E-mail: [email protected]
Peripheral blood CD4+ CD25high Tregs from patients with active rheumatoid arthritis (RA) have shown reduced FoxP3 expression and suppressive function which can be reversed by treatment with an anti TNFα monoclonal antibody (infliximab) both in vitro and in vivo. Anti TNFα agents are also used for the treatment of IBD, where a defective Treg activity has been detected within CD4+ T cells in the periphery but not lamina propria T cells. We evaluated FoxP3+CD4+ Tregs by flow cytometry and cytokine levels by ELISA (IL-17 and IL-23) or by flow cytometry (Th1/Th2 11plex, Bender MedSystem) in peripheral blood from 13 patients with active Crohn's disease (CD) and 2 patients with ulcerative colitis (UC) before and after (45-60 days) a first course of anti TNFα therapy. Ten CD and two UC patients were treated with infliximab, while three CD patients received certolizumab pegol (a human pegilated anti TNFα Fab'). In a group of 9 patients that we defined as “biological responders”, median pre-treatment frequencies of CD25highFoxP3+ cells among total CD4+ T cells were equal to 2.55% (range 0.2-8.0), while after treatment their frequency increased to 8.7% (range 5.7-21.5; p=0.019, Mann-Whitney test for paired determinations). All of these patients were also clinical responders. Six other patients did not show an increase or even had a decrease of peripheral blood Tregs (median pre-treatment values equal to 3.7% - range 2.9-8 - and median post-treatment values equal to range 2.7% - range 1.8-4.8. Of them, three were not clinical responders. Of the assayed cytokines, only IL-8 has shown a relevant modification, increasing in sera after anti TNFα treatment (from 33.9, range 1-217 pg/ml to 213.4, range 37-1169 pg/ml; p= 0.04 by Mann-Whitney test for paired determinations). Our preliminary data suggest the possibility that Tregs pharmacological modulation by anti TNFα treatment could be an additional mechanism to explain the beneficial effect of these drugs in IBD, at least in a subset of patients.
Crohn's disease (CD) and ulcerative colitis (UC) are the two major forms of inflammatory bowel disease (IBD). Although their etiology is still unknown, the pathogenic mechanisms underlying intestinal inflammation have made impressive progress in our understanding. In particular, the abnormalities underlying IBD pathogenesis are not restricted to those mediated by classical immune cells such as T and B lymphocytes, macrophages and dendritic cells, but also nonimmune cells. Interestingly, endothelium has become one of the major areas of investigation in gut inflammation.
The emergence of severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), which caused the coronavirus disease-2019 (COVID-19) pandemic, has raised concern among health care teams, especially those caring for patients with immune-mediated inflammatory diseases, such as inflammatory bowel disease (IBD) [1]. Since we know that acute viral gastroenteritis can trigger the onset of IBD [2], a literature search was conducted in PubMed, using the words [inflammatory bowel diseases], [SARS-CoV-2], [de novo], [onset], [COVID-19], [trigger], [Crohn's disease] and [Ulcerative colitis], selecting articles on the de novo occurrence of IBD after COVID-19. Six cases of new-onset IBD, occurring after COVID-19 infection, were identified. There were four UC [3–6] cases and two CD [7,8] cases (Table 1). IBD following COVID-19 mainly occurred in women (four out of six). Half of the patients experienced gastrointestinal symptoms, particularly diarrhea, throughout the course of the COVID-19 infection. Three patients were hospitalized for COVID-19 symptoms, while none required mechanical ventilation or ICU admission. All patients presented with persistent or new-onset abdominal symptoms, along with positive inflammatory markers, including fecal calprotectin, despite having a negative nasopharyngeal swab for SARS-CoV-2. The time from the onset of digestive symptoms to the diagnosis of IBD ranged from less than one month to 4 months. The most frequently reported symptom was diarrhea, which started during or shortly after the diagnosis of COVID-19. The UC patients had bloody diarrhea, while the CD patients had watery or voluminous diarrhea. Half of the patients were treated with mesalamine as well as systemic or intestinal-releasing steroids for IBD. Table 1. - Characteristics of patients with inflammatory bowel disease (IBD) onset after SARS-CoV-2 infection Author(Ref.) Sex Age(years) COVID-19symptoms Therapy for COVID-19 Time from SARS-CoV-2 negativity to IBD diagnosis (months) Type of IBD Type of IBD treatment Calabrese et al. [5] F 19 Fever, nausea, vomiting, bloody diarrhea, loss of taste and smell, anemia HCQ 1 UC Oral BEC and MES Taxonera et al. [6] F NA Fever, sore throat, myalgia, bloodless watery diarrhea HCQ, LOP-RIT, AZI 4 UC Oral and topic MES Imperatore et al. [7] M 55 Pneumonia CS, AZI, HEP 4 UC NA Aydin et al. [8] M 50 Fever, dyspnea and pneumonia HCQ and AZI 1 UC Oral and topic MES Senthamizhselvan et al. [9] F 33 Sore throat, fever, myalgia ACE <1 CD CS and sulfasalazine Tursi et al. [10] F 47 Weakness, myalgia and diarrhea ACE 3 CD Oral BUD ACE, acetaminophen; AZI, azithromycin; BEC, beclomethasone dipropionate; BUD, budesonide; CD, Crohn's disease; CS, systemic corticosteroids; HCQ, hydroxychloroquine; HEP, heparin; LOP–RIT, lopinavir–ritonavir; MES, mesalamine; UC, ulcerative colitis. The role of the SARS-CoV-2 as a trigger for IBD in the reported patients is plausible because all patients reported no gastrointestinal symptoms before the COVID-19 infection. The pathogenesis of IBD is multifactorial. It consists of a dysregulated immune response to components of the gut microbiota in genetically predisposed individuals. This self-sustaining inflammatory process is likely associated with environmental factors, including infections, directly involving the intestinal tract. Several studies have reported the connection between enteric infection-related dysbiosis and the subsequent development of IBD [2]. On the basis of this, we hypothesized that SARS-CoV-2 was a potential trigger. The intestinal epithelial cells are a major cellular target for SARS-CoV-2, which penetrates cells after binding to its functional receptor, angiotensin-converting enzyme 2 (ACE2). This results in the increased production of TNF-α [9]. The enhanced T-helper (Th)-17 lymphocyte response in COVID-19 induces one of the hallmarks of the immune dysregulation seen in IBD patients. Various autoimmune diseases, involving multiple organs, have reportedly occurred among patients infected with COVID-19. Molecular mimicry due to the immune cross-reaction between viral epitopes and host antigens may be implicated in some of these autoimmune diseases. The onset of IBD was notably caused by the loss of self-tolerance against commensal microbial antigens due to transient immunosuppression and abnormal immune reconstitution in genetically predisposed subjects infected with COVID-19 [10]. Following SARS-CoV-2 infection, the dysregulated interferon production and cytokine activation disrupt immune tolerance, triggering an abnormal immune response in the gut. In conclusion, the current data highlighted the role of the SARS-CoV-2 virus as a possible trigger for the onset of IBD. However, further data from prospective studies that include large cohorts of patients with COVID-19 are needed to confirm this hypothesis and understand the extent of the event. Acknowledgements AT, LRL, AG, and AP designed the study, recruited the patients and collected and analysed the data. AT wrote the first draft of the article. Conflicts of interest There are no conflicts of interest.
