Effectiveness and safety of switching to adalimumab biosimilar ABP 501 in Crohn's disease: the extrapolation concept.

We sincerely thank Viscido et al. for their appropriate and sharable comments on our recent study on adalimumab biosimilar ABP 501 in Crohn's disease (CD). The use of a biosimilar in inflammatory disorders is one of the current main topics, given the great opportunity to save resources that can be invested in innovative drugs and the ethical problems that non-medical switching can generate.

Correction: PD-L1 in small bowel adenocarcinoma is associated with etiology and tumor-infiltrating lymphocytes, in addition to microsatellite instability.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

PD-L1 in small bowel adenocarcinoma is associated with etiology and tumor-infiltrating lymphocytes, in addition to microsatellite instability.

Small bowel adenocarcinomas (SBAs) are often associated with poor prognosis and have limited therapeutic options. Programmed cell death protein-1 (PD-1)/programmed cell death ligand 1 (PD-L1) pathway blockade is an effective treatment in many microsatellite instability-high (MSI-H) solid tumors. We aimed at investigating PD-L1 and PD-1 expression in non-hereditary, non-ampullary SBAs, associated with celiac disease (CeD), Crohn's disease (CrD), or sporadic, recruited through the Small Bowel Cancer Italian Consortium. We assessed PD-L1 and PD-1 by immunohistochemistry in a series of 121 surgically resected SBAs, including 34 CeD-SBAs, 49 CrD-SBAs, and 38 sporadic SBAs. PD-L1 and PD-1 expression was correlated with several clinico-pathological features, such as the etiology, microsatellite instability status, and tumor-infiltrating lymphocyte (TIL) density. The prevalence of PD-L1 positivity according to combined positive score (CPS) was 26% in the whole cohort of SBAs, with significantly (p = 0.001) higher percentage (35%) in both CeD-SBAs and CrD-SBAs in comparison with sporadic SBAs (5%). CPS ≥ 1 SBAs were significantly (p = 0.013) more frequent in MSI-H cases (41%) than in non-MSI-H ones (18%); however, 15 CPS ≥ 1 microsatellite stable SBAs were also identified. CPS ≥ 1 SBAs showed higher TIL and PD-1+ immune cell density, more frequently medullary histotype, as well as a better outcome in comparison with CPS < 1 cases. This study demonstrates an increased proportion of PD-L1+ cases in both CeD-SBAs and CrD-SBAs in comparison with sporadic SBAs. In addition, the identification of a subset of PD-L1+ microsatellite stable SBAs supports the need to ascertain additional biomarkers of response to immune checkpoint inhibitors along with MSI-H.

Vedolizumab for treatment of chronic refractory pouchitis: a systematic review with pool analysis.

BACKGROUND AND OBJECTIVES: about 1%-2% of patients with chronic refractory pouchitis, in the context of ulcerative colitis, end up with a permanent ileostomy. The aim of this systematic review was to collect all published studies involving patients treated with vedolizumab for chronic refractory or antibiotic-dependent pouchitis and then pool the data regarding the effectiveness of this therapeutic strategy. METHODS: a MEDLINE and Web of Science search of all studies published in English until March 17, 2019 was conducted using the terms "vedolizumab and pouchitis". RESULTS: seven studies with a total of 44 patients with chronic pouchitis were included. Twenty-three out of 44 patients (52.3%) had undergone previous treatment with anti-tumor necrosis factor (TNF) drugs. At week 12, 33 out of 44 patients (75%) reported clinical improvement. Endoscopic improvement, evaluated within 6 months of the start of vedolizumab therapy, was obtained in 28 out of the 38 patients in whom such data were available (73.7%). CONCLUSIONS: this first systematic review published in the literature on this issue suggests that vedolizumab has significant efficacy in chronic refractory or antibiotic-dependent pouchitis, also in patients who failed to respond to other treatments including those with anti-TNF agents.

Effectiveness and safety of adalimumab biosimilar ABP 501 in Crohn's disease: an observational study.

BACKGROUND AND OBJECTIVE: there are no studies in the literature about the effectiveness of adalimumab biosimilar ABP 501 in Crohn's disease. The aim of this study was to evaluate its effectiveness and safety. METHODS: an observational study was performed in Crohn's disease patients treated with ABP 501, with the classic induction and maintenance regimen and in Crohn's disease patients who were switched from the adalimumab originator to ABP 501. RESULTS: eighty-seven patients were included in the study, of which 25 were naïve to the adalimumab originator and 62 were switched to ABP 501. In adalimumab-naïve patients, clinical response at three months was 60% (15/25) and clinical remission at three months was 56% (14/25). At six months, 95.2% (59/62) of the patients switched to ABP 501 were still in therapy, without a significant increase of clinical activity (Harvey-Bradshaw index from 3.4, 95% CI = 2.4-4.4, to 3.8, 95% CI = 2.7-4.9, p = 0.23) and inflammatory biomarkers (C-reactive protein from 4.2 mg/l, 95% CI = 2.5-5.9 mg/l, to 3.6 mg/l, 95% CI = 2.2-5 mg/l, p = 0.32). There were no unexpected adverse events during the study period. CONCLUSIONS: our results support ABP 501 as an effective and well-tolerated drug, with a good interchangeability with its originator for the treatment of Crohn's disease.

Incidence of Prostate Cancer in Inflammatory Bowel Disease: A Meta-Analysis.

Background and objectives: Inflammatory bowel disease (IBD) is associated with an increased risk of developing colorectal cancer as well as some extra-intestinal tumors, but there are still limited data about the risk of prostate cancer (PC). To analyze if there is an increased risk of PC in patients affected by IBD, we performed a systematic review with meta-analysis. Materials and Methods: A Pubmed search of all studies comparing standardized incidence ratio (SIR) or odds ratio (OR) or relative risks (RR) of PC between IBD and non IBD groups, published until March 2020 was conducted. The study protocol was registered on PROSPERO. Twelve studies, mostly population studies, were included. The quality score of these studies, evaluated by the Newcastle-Ottawa Scale, was 7. The heterogeneity was high among the studies in which ulcerative colitis (UC) was considered separate from Crohn's disease (CD) and in the studies that considered UC and CD together ("IBD-studies"), while it was low in the studies which considered CD separate from UC. Results: The relative risk of developing PC was 1.71 (95% confidence interval [CI] 1.16-2.51, p = 0.007) in IBD, 1.10 (95%CI 0.98-1.25, p = 0.116) in CD, and 1.22 (95%CI 0.98-1.51, p = 0.07) in UC. Conclusions: Patients with IBD appear to have a slightly increased risk of PC compared to the general population.

Adalimumab versus azathioprine to halt the progression of bowel damage in Crohn's disease: application of Lémann Index.

Background: The Lémann Index (LI) was recently developed to evaluate the cumulative bowel damage in patients with Crohn's disease (CD).Aims: To search for a difference between adalimumab and azathioprine to halt the progression of bowel damage in active CD, using the LI.Methods: A single-centre, retrospective study was conducted. Patients with CD were included if they had colonoscopy and magnetic resonance enterography performed within 4 months from the start of adalimumab or azathioprine and repeated after 12 months of therapy. Primary outcome was reached if the increase of LI after 12 months of treatment was <0.3, the drug was not stopped, and the use of systemic steroids was continued for no more than 3 months.Results: Ninety-one patients were enrolled, 31 (34.1%) of them treated with adalimumab and 60 (65.9%) with azathioprine. Sixty-seven percent of patients treated with adalimumab reached the primary outcome compared to 28.3% of patients treated with azathioprine (p = .0006). The LI in the group on adalimumab therapy decreased after 12 months (from 9.9 to 8.8), while in the group on azathioprine therapy it increased (from 7.7 to 8.8).Conclusion: Treatment with adalimumab halts the progression of bowel damage in CD while that with azathioprine does not.

Risk factors of suspected spondyloarthritis among inflammatory bowel disease patients.

Background: Occurring in approximately 20-30% of patients, spondyloarthritis is the most common extraintestinal manifestation in inflammatory bowel disease (IBD).Aims: To look for risk factors of spondyloarthritis among inflammatory bowel disease patients.Methods: We modified the STRIPP questionnaire created for psoriatic patients and we created a rapid questionnaire for rheumatologic investigation in IBD patients (STRII). We submitted the questionnaire to all consecutive patients with a known spondyloarthritis in our centre and to patients with a negative rheumatological diagnosis to find the cut-off value. Finally, we prospectively submitted the STRII questionnaire to all consecutive IBD patients in our centre.Results: A cut-off ≥3 correlated with spondyloarthritis with an AUC = 0.91. The STRII questionnaire was submitted to 1147 IBD patients. Two hundred and forty-four out of 1147 (21.3%) collected a STRII score of ≥3. Female sex (p < .0001) and Crohn's disease (p = .023) were risk factors. Patients with a history of at least 1 immunosuppressant or biologic drug (p = .002 and p < .0001, respectively) had a higher rate of positivity to STRII questionnaire.Conclusion: Among IBD patients, females, Crohn's disease, those with a history of at least 1 immunosuppressive or biological therapy are at increased risk of spondyloarthritis.

Dual biological therapy with anti-TNF, vedolizumab or ustekinumab in inflammatory bowel disease: a systematic review with pool analysis.

Background: Inflammatory bowel diseases patients eligible for biological therapy represent a group with considerable disease burden and biologics only achieve 40% clinical remission rates in responders after 1 year of therapy. Aims: To collect all the published data about patients treated with dual biological therapy with an Anti-TNF, vedolizumab or ustekinumab, for a period of at least 3 months and to pool the data about the effectiveness and safety. Methods: A MEDLINE, and Web of Science search of all studies published in English until 1 January 2019 was conducted. Results: We included 7 studies with a total of 18 patients. Fifteen patients were treated with a combination of an anti-TNF and vedolizumab, 3 patients were treated with vedolizumab and ustekinumab. Fifty-six percent of patients were affected by Crohn's disease and 50% of patients were treated with an immunosuppressant drug or steroid too. A clinical improvement was obtained in 100% of patients, and an endoscopic improvement in 93% of patients. No serious adverse events were reported. Conclusions: The use of dual biological therapy is an attractive therapeutic option and may be an opportunity to better tailor and personalize the therapies for patients. Further studies, as randomized control trials, to provide comparative efficacy and safety endpoints of combination therapies, and to clarify potential advantages of combined biological therapies, are needed.

Apparent diffusion coefficient and enhancement patterns in MR imaging as markers of severe or moderate ileum inflammation in Crohn's disease.

BACKGROUND AND PURPOSE: magnetic resonance enterography has been increasingly used for the diagnosis and follow-up of Crohn's disease (CD). The purpose of the study was to compare the apparent diffusion coefficient (ADC) with wall enhancement for the differentiation of severe, moderate or no inflammation activity in the ileum. METHODS: a prospective, blinded study was conducted of 46 CD patients with a clinical Crohn's disease activity index (CDAI) ≥ 220 and a simple endoscopic score for Crohn's disease (ES-CD) ≥ 7, which yielded 58 inflamed segments with CD. Twenty controls were also included. All segments were characterized by four ADC readings. The two different enhancement patterns observed in inflamed segments, transmural or mucosal, were associated with severely (23) or moderately (35) active CD. RESULTS: the ADC value decreased from 2.79 ± 0.35 x 10-3 mm2/s for normal segments to 1.81 ± 0.39 x 10-3 mm2/s for the moderately inflamed segments and 1.15 ± 0.20 x 10-3 mm2/s for severely inflamed segments (p ≤ 0.0001). ROC curve analysis on the basis of the three ADC distributions showed a very good discrimination capability with an area under the curve of 0.95. Three groups were defined as follows: normal ileum ADC > 2.4 x 10-3 mm2/s, moderate stages of inflammation 1.5 x 10-3 mm2/s < ADC ≤ 2.4 x 10-3 mm2/s and severe stages of ADC ≤ 1.5 x 10-3 mm2/s. CONCLUSIONS: the ADC value reliably discriminates between normal and inflamed ileum and also distinguishes between severe and moderate inflammation.

Correlation between Thiopurine S-Methyltransferase Genotype and Adverse Events in Inflammatory Bowel Disease Patients.

Background and Objectives: In patients with inflammatory bowel diseases (IBD), the use of azathioprine results in adverse events at a rate of 5% to 20%. The aim of the study was to assess a possible correlation between genetic variability of the enzyme thiopurine S-methyltransferase (TPMT) and the development of toxicity to azathioprine. Materials and Methods: A retrospective, single center, blind, case-control study was conducted on 200 IBD patients, of whom 60 cases suspended azathioprine due to toxicity (leukopenia, pancreatitis, hepatitis, and nausea or vomiting), and 140 controls continued treatment with the drug without adverse events. Results: In the entire cohort, only 8 cases of heterozygous mutations of TPMT were observed, corresponding to 4% mutated haplotype rate, much lower than that reported in literature (close to 10%). No homozygous mutation was found. Regarding the TPMT allelic variants, we did not find any statistically significant difference between patients who tolerated azathioprine and those who suffered from adverse events. (OR = 0.77, 95% CI = 0.08-7.72; p = 0.82). Conclusions: According to our study, in IBD patients, the search for TPMT gene mutations before starting treatment with azathioprine is not helpful in predicting the occurrence of adverse events. Importantly, patients with allelic variants should not be denied the therapeutic option of azathioprine, as they may tolerate this drug.

The adherence to the therapy in inflammatory bowel disease: beyond the number of the tablets.

OBJECTIVES: The therapy of the inflammatory bowel diseases is quite complex. A partial compliance increases the relapse probability and the health expenditure. The aim of the study is to correctly study the adherence to the therapy in a single centre eliminating the bias of a different relationship of trust with different doctors. MATERIALS AND METHODS: We conducted a blind prospective study on the adherence evaluated for mesalazine. RESULTS: Three hundred and seventy-six patients were included in the final analysis. Of the patients, 57.4% never missed a single dose of mesalazine, 29.3% missed one or two doses, 7.4% missed three to four doses, 5.9% missed more than five doses. A greater adherence among males (p = .015) and, in ulcerative colitis, among the group with a disease duration of <2 years compared to the one with a disease duration between 2 and 5 years (p = .04) were found. In Crohn's diseases, among the patients who had never undergone to surgical interventions, the adherence was 49.6%, compared to 51.9% among patients who underwent to one surgical resection and 78.6% among patients underwent to multiple surgical resections (p = .001). CONCLUSIONS: The factors influencing the adherence to the therapy are only partly related to the prescribed therapy, but also to factors affecting the patient life: to increase the adherence rate it would be necessary not only interventions on the posology but also the psychological support to the patient at the time of the visit.

Adnexal localization of Crohn's disease and recurrent massive ovary cysts.

In a recent interesting case report, Saborit et al. reported three cases of ovarian involvement in Crohn's disease (CD). In the first two cases, there were pelvic abscesses due to fistulae of ileal loops affected by CD, with involvement of the right ovary, which also showed abscesses and typical granulomas. In the third case there was an ovarian abscess, extension of the process by contiguity. Granulomatous affectation of the ovaries is rare, with only 18 cases reported in the literature to date. Of this, in 17 cases the proposed mechanism of disease manifestation is direct fistulization between the small intestine and the ovary, which allows passage of vegetable material and results in the formation of reactive granulomas. In only one case a patient that did not demonstrate the histological features of either fistula-related disease (an intact ovarian capsule was found) or idiopathic granulomatous disease caused by the multiplicity of the granulomas and the presence of central necrosis has been reported. The authors therefore suggested that their findings were consistent with a diagnosis of metastatic CD of the ovary.

Prevalence and prognostic value of hepatic histological alterations in patients with Crohn's disease.

UNLABELLED: Variable degrees of liver histological changes in patients with Crohn's disease (CD) have been reported. OBJECTIVE: To evaluate the liver histological alterations and their prognostic significance in patients affected by CD without abnormalities of liver biochemical parameters and ultrasound features. MATERIAL AND METHODS: A prospective, single-blind study, including 35 consecutive patients with CD that underwent bowel resection with a contemporary performance of liver biopsy from 1992 to 2003. EXCLUSION CRITERIA: the presence of standard causes of liver disease, such as alcohol consumption exceeding 20 g/day, primary sclerosing cholangitis, viral infections, celiac disease, metabolic syndrome and alterations of the metabolism. Patients were followed up with regular evaluation of hepatic cytolysis, cholestasis, synthesis and ultrasound performance. After a mean interval of 14 years (from May to December 2013), liver fibrosis was assessed by Fibroscan®. RESULTS: Histological alterations were shown in 60% of patients, without serious liver injuries (no case of inflammation or significant fibrosis). Fibroscan® was performed in 33 subjects and no significant changes were observed (mean value of liver stiffness: 5.2 ± 1.2 kPa). The minimal microscopic damage did not evolve either in patients with a normal histology or in those with an altered histology at baseline (p = 0.9). Only patients who took azathioprine had a statistically significant increase of liver stiffness values (5.7 ± 1.5 kPa vs 4.7 ± 1.3 kPa, p = 0.017). CONCLUSIONS: Patients with CD do not need additional examinations compared to the general population, unless clinical or biochemical abnormalities are found.

Glucose breath test and Crohn's disease: Diagnosis of small intestinal bacterial overgrowth and evaluation of therapeutic response.

OBJECTIVE: Small intestinal bacterial overgrowth (SIBO) is characterized by an abnormal proliferation of bacterial species in the small bowel. It has been shown that patients with Crohn's disease (CD) have a higher risk of SIBO development. The aim of the present study was to investigate SIBO prevalence in CD patients, possible clinical predictors of SIBO development and response to antibiotic therapy. MATERIAL AND METHODS: Sixty-eight patients (42 male, 26 female; mean age 49.3 ± 12.8 years) with CD reporting abdominal complaints were prospectively evaluated for SIBO with H2/CH4 glucose breath test (GBT). RESULTS: Of the 68 patients enrolled, 18 (26.5%) tested positive for SIBO. Patients with SIBO exhibited increased stool frequency and significant reduction of stool solidity (p = 0.014), were older than patients tested negative to GBT (54.3 ± 13.0 years vs. 47.5 ± 12.3 years, p = 0.049), reported a longer history of CD (21.2 ± 10.3 years vs. 15.7 ± 10.2 years, p = 0.031) and showed a significant higher frequency of prior surgery (p = 0.001), revealing an association of number of surgical procedures (OR = 2.8315, 95% CI = 1.1525-6.9569, p = 0.023) with SIBO. Breath test normalization occurred in 13/15 patients evaluated after antibiotic and probiotic therapy. Although vitamin B12 levels were lower in patients with SIBO (p = 0.045) and a significant improvement was found after treatment (p = 0.011), this could be due to the heterogeneity, regarding vitamin B12 treatment, in our cohort. CONCLUSION: SIBO is a frequent but underestimated condition in CD, which often mimics acute flare, effectively identified with GBT and could be treated with a combined antibiotic and probiotic therapy.

Development and validation of an endoscopic classification of diverticular disease of the colon: the DICA classification.

BACKGROUND: A validated endoscopic classification of diverticular disease (DD) of the colon is lacking at present. Our aim was to develop a simple endoscopic score of DD: the Diverticular Inflammation and Complication Assessment (DICA) score. METHODS: The DICA score for DD resulted in the sum of the scores for the extension of diverticulosis, the number of diverticula per region, the presence and type of inflammation, and the presence and type of complications: DICA 1 (≤ 3), DICA 2 (4-7) and DICA 3 (>7). A comparison with abdominal pain and inflammatory marker expression was also performed. A total of 50 videos of DD patients were reassessed in order to investigate the predictive role of DICA on the outcome of the disease. RESULTS: Overall agreement in using DICA was 0.847 (95% confidence interval, CI, 0.812-0.893): 0.878 (95% CI 0.832-0.895) for DICA 1, 0.765 (95% CI 0.735-0.786) for DICA 2 and 0.891 (95% CI 0.845-0.7923) for DICA 3. Intra-observer agreement (kappa) was 0.91 (95% CI 0.886-0.947). A significant correlation was found between the DICA score and C-reactive protein values (p = 0.0001), as well as between the median pain score and the DICA score (p = 0.0001). With respect to the 50 patients retrospectively reassessed, occurrence/recurrence of disease complications was recorded in 29 patients (58%): 10 (34.5%) were classified as DICA 1 and 19 (65.5%) as DICA 2 (p = 0.036). CONCLUSIONS: The DICA score is a simple, reproducible, validated and easy-to-use endoscopic scoring system for DD of the colon.

Fecal calprotectin is an effective diagnostic tool that differentiates inflammatory from functional intestinal disorders.

BACKGROUND: The clinical pictures of functional gastrointestinal disorders and inflammatory diseases can be quite similar leading to inappropriate and expensive investigations. Objective. To investigate fecal calprotectin (FC) diagnostic performance in different gastrointestinal conditions. MATERIAL AND METHODS: Stool specimens of 66 outpatients referred for colonoscopy were collected for further FC determination. Diagnostic accuracy was assessed by the area under the curve (AUC). Sensitivity (Se), specificity (Sp), positive (PPV), and negative predictive values (NPV) were calculated according to the presence of inflammation and the main final diagnosis. RESULTS: Histological inflammation was found in 45 (68%) patients: 24 had a diagnosis of inflammatory bowel disease (IBD) while 21 reported miscellaneous conditions (5 microscopic colitis, 2 eosinophilic colitis, and 14 nonspecific chronic colitis). The diagnosis in the 21 (32%) patients without inflammation was irritable bowel syndrome (IBS). Median FC values were 268 µg/g (95% CI, 151-343) and 49 µg/g (95% CI, 23-101) in patients with and without inflammation, respectively (p = 0.0001). AUC value of FC was 0.811 (Se = 68.9%, Sp = 71.4%, PPV = 83.8%, and NPV = 56.3% with a cutoff value of 100 µg/g) for discriminating between patients with and without inflammation and 0.931 (Se = 87.5%, Sp = 90.5%, PPV = 91.3%, and NPV = 86.4% with a cutoff value of 150 µg/g) for discriminating between patients with IBS and IBD. Using the cutoff value recommended by the manufacturer (50 µg/g), we found Se =100%, Sp =52.4%, PPV =70.6%, and NPV =100% for the diagnosis of IBD. CONCLUSIONS: FC appears to be a reliable noninvasive biomarker of intestinal inflammation useful to improve the appropriateness of colonoscopy requests.

A multicentre case control study on complicated coeliac disease: two different patterns of natural history, two different prognoses.

BACKGROUND: Coeliac disease is a common enteropathy characterized by an increased mortality mainly due to its complications. The natural history of complicated coeliac disease is characterised by two different types of course: patients with a new diagnosis of coeliac disease that do not improve despite a strict gluten-free diet (type A cases) and previously diagnosed coeliac patients that initially improved on a gluten-free diet but then relapsed despite a strict diet (type B cases). Our aim was to study the prognosis and survival of A and B cases. METHODS: Clinical and laboratory data from coeliac patients who later developed complications (A and B cases) and sex- and age-matched coeliac patients who normally responded to a gluten-free diet (controls) were collected among 11 Italian centres. RESULTS: 87 cases and 136 controls were enrolled. Complications tended to occur rapidly after the diagnosis of coeliac disease and cumulative survival dropped in the first months after diagnosis of complicated coeliac disease. Thirty-seven cases died (30/59 in group A, 7/28 in group B). Type B cases presented an increased survival rate compared to A cases. CONCLUSIONS: Complicated coeliac disease is an extremely serious condition with a high mortality and a short survival. Survival depends on the type of natural history.

Bone mineral density at diagnosis of celiac disease and after 1 year of gluten-free diet.

Atypical or silent celiac disease may go undiagnosed for many years and can frequently lead to loss of bone mineral density, with evolution to osteopenia or osteoporosis. The prevalence of the latter conditions, in case of new diagnosis of celiac disease, has been evaluated in many studies but, due to the variability of epidemiologic data and patient features, the results are contradictory. The aim of this study was to evaluate bone mineral density by dual-energy X-ray absorptiometry in 175 consecutive celiac patients at time of diagnosis (169 per-protocol, 23 males, 146 females; average age 38.9 years). Dual-energy X-ray absorptiometry was repeated after 1 year of gluten-free diet in those with T-score value <-1 at diagnosis. Stratification of patients according to sex and age showed a higher prevalence of low bone mineral density in men older than 30 years and in women of all ages. A 1-year gluten-free diet led to a significant improvement in lumbar spine and femoral neck mean T-score value. We propose that dual-energy X-ray absorptiometry should be performed at diagnosis of celiac disease in all women and in male aged >30 years, taking into account each risk factor in single patients.