The Earlier You Find, the Better You Treat: Red Flags for Early Diagnosis of Inflammatory Bowel Disease.

Delayed diagnosis is a challenge in the management of inflammatory bowel disease (IBD). Several studies show a significant association between diagnostic delay and disease progression to complications and surgery, especially in Crohn's disease (CD). What risk factors are associated with diagnostic delay in IBD remains unclear. In order to reduce diagnostic delay, the Red Flags Index has been developed and validated. The combination of the Red Flags Index score and non-invasive biomarkers such as fecal calprotectin seems to be highly accurate in screening patients with underlying IBD to be referred for further diagnostic workup and eventual early effective treatment strategies. Our literature review aims to obtain a comprehensive overview of the impacts of diagnostic delay in IBD on the potential risk factors associated with IBD, how diagnostic tools may be effective in reducing diagnostic delay, and future perspectives in this field.

Early-onset versus late-onset Crohn's disease: An Italian cohort study.

BACKGROUND: Disease heterogeneity, according to the age at onset, has been reported in Crohn's disease (CD). OBJECTIVE: This study aimed to compare natural history in CD patients diagnosed ≤17 (early onset (EO)) versus ≥60 (late onset (LO)) years old. METHODS: EO CD and LO CD patients referred to two Italian inflammatory bowel disease (IBD) centres were included. Relevant data comprised sex, current smoking, disease location and behaviour, IBD family history, extra-intestinal manifestations and use of medical/surgical therapy during the follow-up period. RESULTS: Among 2321 CD patients, 160 met the inclusion criteria: 92 in the EO and 68 in the LO group (mean follow-up 11.7 ± 7.7 years). Family history of IBD was more frequent in EO compared to LO CD (26% vs. 4%; p < 0.0001). Ileocolonic, upper gastrointestinal and perianal involvement occurred more frequently in EO compared to LO CD (56% vs. 21%, p < 0.0001; 17% vs. 3%, p < 0.01; and 38% vs. 19%, p < 0.01, respectively). Progression to complicated disease occurred more frequently in EO CD (40% vs. 10% p < 0.005), with an increased use of corticosteroids and anti-tumour necrosis factor alpha agents within 10 years since diagnosis (81% vs. 58%, p = 0.004, and 36% vs. 16%, p = 0.01, respectively), while the cumulative probability of surgery did not differ between the two groups. CONCLUSIONS: Patients with EO CD are more likely to develop a more aggressive disease with perianal involvement and a greater use of drug treatment compared to those with LO CD, without carrying an increased need for surgery.

Separation of Low- Versus High-grade Crohn's Disease-associated Small Bowel Carcinomas is Improved by Invasive Front Prognostic Marker Analysis.

BACKGROUND AND AIMS: Crohn's disease-associated small bowel carcinoma is a rare event, usually reported to have a severe prognosis. However, in previous investigations we have found a minority of cases displaying a relatively favourable behaviour, thus outlining the need to improve the histopathological prediction of Crohn's disease-associated small bowel carcinoma prognosis. METHODS: As in recent studies on colorectal cancer, a substantial improvement in prognostic evaluations has been provided by the histological analysis of the tumour invasive front; we therefore systematically analysed the tumour budding and poorly differentiated clusters in the invasive front of 47 Crohn's disease-associated small bowel carcinomas collected through the Small Bowel Cancer Italian Consortium. RESULTS: Both tumour budding and poorly differentiated cluster analyses proved highly effective in prognostic evaluation of Crohn's disease-associated small bowel carcinomas. In addition, they retained prognostic value when combined with two other parameters, i.e. glandular histology and stage I/II, both known to predict a relatively favourable small bowel carcinoma behaviour. In particular, association of tumour budding and poorly differentiated clusters in a combined invasive front score allowed identification of a minor subset of cancers [12/47, 25%] characterised by combined invasive front low grade coupled with a glandular histology and a low stage [I or II] and showing no cancer-related death during a median follow-up of 73.5 months. CONCLUSIONS: The improved distinction of lower- from higher-grade Crohn's disease-associated small bowel carcinomas provided by invasive front analysis should be of potential help in choosing appropriate therapy for these rare and frequently ominous neoplasms.

Late-onset Crohn's disease: a comparison of disease behaviour and therapy with younger adult patients: the Italian Group for the Study of Inflammatory Bowel Disease 'AGED' study.

BACKGROUND: Disease phenotype and outcome of late-onset Crohn's disease are still poorly defined. METHODS: In this Italian nationwide multicentre retrospective study, patients diagnosed ≥65 years (late-onset) were compared with young adult-onset with 16-39 years and adult-onset Crohn's disease 40-64 years. Data were collected for 3 years following diagnosis. RESULTS: A total of 631 patients (late-onset 153, adult-onset 161, young adult-onset 317) were included. Colonic disease was more frequent in late-onset (P < 0005), stenosing behaviour was more frequent than in adult-onset (P < 0003), but fistulising disease was uncommon. Surgery rates were not different between the three age groups. Systemic steroids were prescribed more frequently in young adult-onset in the first year, but low bioavailability steroids were used more frequently in late-onset in the first 2 years after diagnosis (P < 0.036, P < 0.041, respectively). The use of immunomodulators and anti-TNF's even in patients with more complicated disease, that is, B2 or B3 behaviour (Montreal classification), remained significantly inferior (P < 0.0001) in late-onset compared to young adult-onset. Age at diagnosis, Charlson comorbidity index, and steroid used in the first year were negatively associated with the use of immunomodulators and biologics. Comorbidities, related medications and hospitalizations were more frequent in late-onset. Polypharmacy was present in 56% of elderly Crohn's disease patients. CONCLUSION: Thirty-two percent of late-onset Crohn's disease presented with complicated disease behaviour. Despite a comparable use of steroids and surgery, immunomodulators and biologics were used in a small number of patients.

The PROSIT Cohort of Infliximab Biosimilar in IBD: A Prolonged Follow-up on the Effectiveness and Safety Across Italy.

BACKGROUND: We report a prospective, nationwide cohort evaluating the safety and effectiveness of CT-P13. METHODS: A structured database was used to record serious adverse events (SAEs), clinical remission/response, inflammatory biomarkers (CRP and calprotectin), and endoscopic findings. RESULTS: Eight hundred ten patients with inflammatory bowel disease (IBD) (452 Crohn's disease [CD]) were enrolled. Four hundred fifty-nine patients were naïve to anti-TNFα (group A), 196 had a previous exposure (group B), and the remaining 155 were switched to CT-P13 (group C). All patients were included in the safety evaluation with a mean follow-up of 345 ± 215 days and a total number of 6501 infusions. One hundred fifty-four SAEs were reported (19%), leading to cessation of the biosimilar in 103 subjects (12.7%). Infusion reactions were 71, leading to cessation of the biosimilar in 53 subjects (6.5%), being significantly more frequent in patients pre-exposed to anti-TNFα (P = 0.017). The efficacy of therapy was calculated in 754 IBD patients, with a mean follow-up of 329 ± 202 days. Forty-eight patients had a primary failure (6.4%), and 188 (25.6%) lost response during follow-up. Six hundred twenty-eight (364 CD) and 360 IBD patients (222 CD) completed the follow-up at 6 and 12 months, respectively. At 12 months, patients without loss of response were 71%, 64%. and 82% in groups A, B, and C, respectively (log rank P = 0.01). Clinical/endoscopic scores and inflammatory biomarkers dropped significantly in CD and UC patients (P = 0.01 and P < 0.0001) compared with baseline. CONCLUSIONS: In this large prospective cohort, no further signals of difference in safety and effectiveness of CT-P13 in IBD has been observed.

Therapeutic Drug Monitoring is More Cost-Effective than a Clinically Based Approach in the Management of Loss of Response to Infliximab in Inflammatory Bowel Disease: An Observational Multicentre Study.

BACKGROUND AND AIMS: Empirical dose intensification and therapeutic drug monitoring [TDM] of infliximab [IFX] trough levels [ITLs] and antibody to infliximab [ATI] assays are recognized approaches for managing loss of response [LoR] in patients with inflammatory bowel disease [IBD]. The aim of the study was to compare these two interventions in a clinical setting, in terms of effectiveness and cost savings. METHODS: Consecutive IBD patients experiencing LoR were clinically managed according to a TDM algorithm. A historical group of empirically treated patients, for whom sera for ITLs and ATI assays had been collected, served as the control group. Clinical outcomes 12 weeks after the therapeutic interventions were compared between the two groups. A cost-minimization analysis was performed to compare the economic impact of these two approaches. RESULTS: Ninety-six patients were enrolled prospectively and compared with 52 controls. The two cohorts were similar in characteristics and in the distribution of TDM results. In the prospective cohort, however, we observed less IFX dose escalations compared with in the controls [45% versus 71%, p = 0.003]. Also, more patients were switched to a different anti-TNFα in the prospective cohort than in the control cohort [25% versus 4%, p = 0.001]. The percentages of patients achieving a clinical response at 12 weeks were 52% and 54% for the prospective and control groups, respectively. By cost analysis, we estimated a savings of 15% if the TDM algorithm was applied. CONCLUSIONS: In our population, applying a TDM algorithm for LoR to IFX resulted in less dose escalations, without loss of efficacy, compared with empirical adjustment. In addition, the TDM approach was cost-effective.

The Time Course of Diagnostic Delay in Inflammatory Bowel Disease Over the Last Sixty Years: An Italian Multicentre Study.

BACKGROUND AND AIMS: Inflammatory bowel disease [IBD] patients are still under-diagnosed or diagnosed with serious delay. We examined whether diagnostic delay [DD] in IBD has changed over the last 60 years, and explored the risk factors of longer DD. METHODS: In total, 3392 IBD patients recorded in the registry of four IBD Italian centres were divided according to the year of diagnosis into a historical cohort [HC: 1955-84] and modern cohort [MC: 1985-2014]. DD, i.e. time lapse between onset of symptoms indicative of IBD and definitive diagnosis, was divided into four sub-periods [0-6, 7-12, 13-24, >24 months], which were correlated with age and disease location/behaviour at diagnosis. RESULTS: Median DD in IBD was 3.0 months, it was significantly [P < 0.0001] higher in Crohn's disease [CD] [7.1 months] than in ulcerative colitis [UC] [2.0 months], and did not differ either between the HC and the MC or over the last three decades. However, the proportion of patients with a DD>24 months was significantly [P < 0.0001] higher in the HC [26.0%] than in the MC [18.2%], and the same trend was evident over the last three decades [1985-94: 19.9%; 1995-2004: 16.4%; 2005-14: 13.9%; P = 0.04]. At logistic regression analysis, age at diagnosis >40 years (CD: odds ratio 1.73, 95% confidence interval [CI] 1.31-2.28, P < 0.0001; UC: 1.41, 95% CI 1.02-1.96, P = 0.04) and complicated disease at CD diagnosis [1.39, 95% CI 1.06-1.82, P = 0.02] were independently associated with a DD>24 months. CONCLUSIONS: DD duration has not changed over the last 60 years in Italy, but the number of IBD patients with a longer DD significantly decreased. Older age at diagnosis and a complicated disease at CD diagnosis are risk factors for longer DD.

The PROSIT-BIO Cohort: A Prospective Observational Study of Patients with Inflammatory Bowel Disease Treated with Infliximab Biosimilar.

BACKGROUND: Few data are available on the safety and efficacy of infliximab biosimilar CT-P13 in patients with ulcerative colitis and Crohn's disease. METHODS: A prospective, multicenter, cohort study using a structured database. RESULTS: Consecutive patients (313 Crohn's disease and 234 ulcerative colitis) were enrolled from 31 referral centers; 311 patients were naive to anti-tumor necrosis factor alpha, 139 had a previous exposure to biologics, and the remaining 97 were switched to CT-P13 after a mean of 18 ± 14 infusions of infliximab. The mean follow-up was 4.3 ± 2.8 months, and the total follow-up time was 195 patient-years. After 2061 infusions, 66 serious adverse events were reported (12.1%), 38 (6.9%) of them were infusion-related reactions. The biosimilar had to be stopped in 29 (5.3%) cases for severe infusion reactions (8 naive, 19 previous exposed, and 2 switch), and in further 16 patients (2.9%) for other serious adverse events. Infusion reactions were significantly more frequent in patients pre-exposed to infliximab than to other anti-tumor necrosis factor alpha (incidence rate ratio = 2.82, 95% CI: 1.05-7.9). The efficacy of the biosimilar was evaluated in 434 patients who received treatment for at least 8 weeks, using time-to-event methods for censored observations: 35 patients were primary failures (8.1%). After further 8, 16, and 24 weeks, the efficacy estimations were 95.7%, 86.4%, and 73.7% for naive, 97.2%, 85.2%, and 62.2% for pre-exposed, and 94.5%, 90.8%, and 78.9% for switch, respectively (log-rank P = 0.64). CONCLUSIONS: Although no direct comparison was performed, preliminary data on efficacy and safety of CT-P13 were in line with those of infliximab.

Disease patterns in late-onset ulcerative colitis: Results from the IG-IBD "AGED study".

BACKGROUND: Late-onset UC represents an important issue for the near future, but its outcomes and relative therapeutic strategies are yet poorly studied. AIM: To better define the natural history of late-onset ulcerative colitis. METHODS: In a multicenter retrospective study, we investigated the disease presentation and course in the first 3 years in 1091 UC patients divided into 3 age-groups: diagnosis ≥65years, 40-64 years, and <40years. Disease patterns, medical and surgical therapies, and risk factors for disease outcomes were analyzed. RESULTS: Chronic active or relapsing disease accounts for 44% of patients with late-onset UC. Across all age-groups, these disease patterns require 3-6 times more steroids than remitting disease, but immunomodulators and, to a lesser extent, biologics are less frequently prescribed in the elderly. Advanced age, concomitant diseases and related therapies were found to be inversely associated with the use of immunomodulators or biologics, but not with surgery. CONCLUSIONS: The conclusion that late-onset UC follows a mild course may apply only to a subset of patients. an important percentage of elderly patients present with more aggressive disease. Since steroid use and surgery rates did not differ in this subgroup, lower use of immunosuppressive therapy and biologics may reflect concerns in prescribing these therapies in the elderly.

The role of interferon-gamma release assays in predicting the emergence of active tuberculosis in the setting of biological treatment: a case report and review of the literature.

Conversions and reversions of interferon-gamma (IFN-γ) release assays (IGRAs) were observed when these tests were repeated over time in the same individuals, including those treated with biological agents. In most studies, the variability of IFN-γ plasma levels was not paralleled by clinical change, but a few exceptions exist, in which IGRA conversion predicted the emergence of active tuberculosis (TB). We report the case of a Peruvian patient with rheumatoid arthritis (RA) and Crohn's disease scheduled for treatment with adalimumab. TB screening demonstrated latent TB infection (LTBI), and the patient was started on isoniazid (INH) for 9 months. Adalimumab was initiated after 1 month since INH. QuantiFERON-TB Gold In-Tube, one of the IGRAs currently available, was serially repeated to monitor the status of TB infection during treatment with the biological agent. The patient developed active TB preceded by progressively rising levels of released IFN-γ. We came to know that she had withdrawn INH after 2 months on her own initiative. Considering the low rate of INH completion, serial IGRAs may help in the clinical vigilance during prophylaxis as well as anti-TNF treatment, at least in patients presenting other risk factors aside from the state of immunosuppression.

Mucosal healing with thalidomide in refractory Crohn's disease patients intolerant of anti-TNF-α drugs: report of 3 cases and literature review.

Thalidomide is an oral immunomodulatory and anti-inflammatory drug with antitumor necrosis factor-α (TNF-α) activity. Several case reports and some clinical trials have demonstrated its efficacy in the treatment of refractory Crohn's disease (CD). We report the effect and tolerability of thalidomide in 3 patients with moderate-to-severe CD who were not responsive to anti-TNF-α therapies, and review the relevant literature. The first case is of a 28-year-old female affected by Crohn's colitis complicated by a severe fistulizing perianal disease; she was treated with infliximab, adalimumab, and certolizumab pegol, which were stopped because of intolerance. The second case is of a 39-year-old female with fistulizing ileocolitis complicated by severe arthralgias and perianal disease with loss of response to infliximab and intolerance of certolizumab pegol. The third case is of a 39-year-old male with gastric and ileocolonic CD refractory to immunosuppressors and intolerant of infliximab. All the 3 cases achieved complete clinical remission and endoscopic healing of mucosal lesions at a low dose of thalidomide (50 to 150 mg/d). In our CD patients who experienced loss of response or were unable to tolerate anti-TNF-α drugs, thalidomide was an effective and well-tolerated therapy for inducing and maintaining long-term remission.

Randomized controlled trials in steroid dependent and in severe colitis.

Intravenous steroids are considered the mainstay of treatment in patients with severe ulcerative colitis. Several randomized controlled trials have been designed to evaluate drugs that, as an adjunct to intravenous steroids, could obtain a clinical response and avoid colectomy in patients who do not respond to corticosteroids. For steroid refractory patients, cyclosporine and infliximab seem to be an effective alternative to colectomy in the short term, but more data are needed to evaluate if they can prevent colectomy also in the long term. Although there is no evidence from the published trials that antibiotics as adjunctive therapy may have an additional benefit, therapeutic protocols for severe ulcerative colitis generally include antibiotics for patients with signs of toxicity, or with worsening of symptoms despite the medical treatment. No additional benefit over steroids has been shown from bowel rest. Moreover, as bowel rest deprives the colonic enterocytes of the short-chain fatty acids vital to their metabolism and repair, it may even be harmful. Conflicting results have been published on heparin as primary treatment of severe ulcerative colitis; at the present time there is no evidence supporting its use. Although "steroid-free" clinical remission is, at this time, the most important end point of clinical studies in inflammatory bowel disease, only few data are available in steroid dependent colitis patients. Azathioprine seems to be effective in inducing steroid-free remission.

Distribution, proliferation, and function of Paneth cells in uncomplicated and complicated adult celiac disease.

Paneth cells, granulated epithelial cells located at the base of small bowel crypts, have a crucial role in innate immunity. Because controversies remain concerning Paneth cell numbers and function in celiac disease (CD), we quantified Paneth cells and human alpha-defensin (HD)-5 and HD-6 in 28 patients with uncomplicated CD, 8 patients with complicated CD (3 with ulcerative jejunoileitis, 2 with refractory sprue, and 3 with enteropathy-associated T-cell lymphoma), and 14 control subjects. Paneth cell numbers and proliferation did not differ in uncomplicated untreated and treated CD and control cases. However, the number of Paneth cells was significantly reduced in complicated CD. Mucosal HD-5 and HD-6 were comparable in uncomplicated untreated and treated CD and control cases. Ex vivo gliadin challenge of treated CD biopsy specimens had no effect on mucosal HD-5 and HD-6 transcripts. Paneth cell numbers and alpha-defensins are unchanged in the mucosa in uncomplicated CD. Further studies are needed to clarify the implications of reduction of numbers of Paneth cells in complicated CD.

Splenic function and IgM-memory B cells in Crohn's disease patients treated with infliximab.

BACKGROUND: Under experimental chronic inflammation, tumor necrosis factor (TNF)-alpha plays a role in damaging spleen marginal zone. This latter has a crucial function in mounting B cell-dependent immune responses against infections by encapsulated bacteria. In Crohn's disease (CD), a chronic inflammatory disorder where TNF-alpha is centrally involved, impaired splenic function may increase the susceptibility to bacterial infections. On this basis, we aimed to investigate the influence of anti-TNF therapy on splenic function in CD patients. METHODS: Peripheral blood samples were obtained from 15 CD patients before and after treatment with infliximab administered at weeks 0, 2, and 6 at a dose of 5 mg/kg. Counting of erythrocytes with membrane abnormalities (pitted red cells) was used as an indicator of splenic function. Multicolor flow cytometry was performed to analyze circulating B cells. RESULTS: A substantial clinical improvement in 10 of the 15 CD patients was associated with a significant reduction of pitted red cells (from median 6.0% to 3.6%; P < 0.01) after 10 weeks of treatment. In responder patients the improvement of splenic function was accompanied by a parallel increase of circulating IgM-memory B cells (from median 6.9% to 13.3%; P < 0.005). Splenic function was not ameliorated in nonresponder patients. CONCLUSIONS: Splenic function improved in CD patients who responded to infliximab and was accompanied by a concomitant restoration of the IgM-memory B cell pool responsible for the protection against encapsulated bacteria. Restoration of splenic function after infliximab treatment is intriguing and requires further investigation.