The impact of COVID-19 pandemic on IBD surgery: a single center experience.

OBJECTIVE: The spread of COVID-19 pandemic forced the national healthcare system to reorganize almost all surgical services, in order to maintain an adequate therapeutic offer. At General Surgery department of Fondazione Policlinico Gemelli in Rome, surgical procedures were progressively reduced to provide beds and personnel for COVID-19. The aim of our study was to analyze the effect of one year of COVID-19 pandemic on Inflammatory Bowel Disease (IBD) surgery in a cohort of patients and evaluate post-operative short-term complications. PATIENTS AND METHODS: Our team retrospectively analyzed the records of IBD patients who were referred to an IBD-related resective surgery from January 2020 to December 2020. These patients were compared to a comparable group of IBD patients who were operated from January 2019 to December 2019. RESULTS: A total of 160 patients were included in the study. Median age was 44 (range 15-77). Patients were referred for Ulcerative colitis (23.1%) and Crohn's disease (76.9%). Eighty-three patients underwent surgery from January 2020 to December 2020, which constitutes a 4.6% increase in the number of patients compared to the same period in 2019. Median post-operative hospital stay increased (7 days in 2019 vs. 6 days in 2020). Laparoscopic was the most frequently performed procedure during both periods (49% in 2019 and 59% in 2020). Complication rates, reported as Clavien-Dindo score 3 or 4, slightly decreased in 2020 (6.5 in 2019 vs. 4.8 in 2020). PCR test for detection of COVID-19 infection was conducted in all the patients before the hospitalization. Two patients out of 70 were tested positive for COVID-19 and their surgeries were rescheduled. CONCLUSIONS: There was no significant reduction in IBD resective surgeries at our center in 2020, nor a deterioration of the outcomes. A reduction of other elective surgical procedures had to be carried out and adequate protective measures for both patients and healthcare workers were established.

Simplified Histologic Mucosal Healing Scheme (SHMHS) for inflammatory bowel disease: a nationwide multicenter study of performance and applicability.

BACKGROUND: Assessment of mucosal healing is important for the management of patients with inflammatory bowel disease (IBD), but endoscopy can miss microscopic disease areas that may relapse. Histological assessment is informative, but no single scoring system is widely adopted. We previously proposed an eight-item histological scheme for the easy, fast reporting of disease activity in the intestine. The aim of the present study was to evaluate the performance of our Simplified Histologic Mucosal Healing Scheme (SHMHS). METHODS: Between April and May 2021 pathologists and gastroenterologists in Italy were invited to contribute to this multicenter study by providing data on single endoscopic-histological examinations for their IBD patients undergoing treatment. Disease activity was expressed using SHMHS (maximum score, 8) and either Simple Endoscopic Score for Crohn's Disease (categorized into grades 0-3) or Mayo Endoscopic Subscore (range 0-3). RESULTS: Thirty hospitals provided data on 597 patients (291 Crohn's disease; 306 ulcerative colitis). The mean SHMHS score was 2.96 (SD = 2.42) and 66.8% of cases had active disease (score ≥ 2). The mean endoscopic score was 1.23 (SD = 1.05), with 67.8% having active disease (score ≥ 1). Histologic and endoscopic scores correlated (Spearman's ρ = 0.76), and scores for individual SHMHS items associated directly with endoscopic scores (chi-square p < 0.001, all comparisons). Between IBD types, scores for SHMHS items reflected differences in presentation, with cryptitis more common and erosions/ulcerations less common in Crohn's disease, and the distal colon more affected in ulcerative colitis. CONCLUSIONS: SHMHS captures the main histological features of IBD. Routine adoption may simplify pathologist workload while ensuring accurate reporting for clinical decision making.

Acute pancreatitis and parathyroid carcinoma: a case report and literature review.

OBJECTIVE: Parathyroid carcinoma is a rare etiology of primary hyperparathyroidism (PHPT) and subsequent hypercalcemia. Among clinical manifestations of hypercalcemia, acute pancreatitis is very uncommon. Nevertheless, acute pancreatitis may be an initial clinical manifestation of parathyroid cancer. PATIENTS AND METHODS: We present a case report and literature review on hypercalcemia-induced acute pancreatitis secondary to parathyroid carcinoma. RESULTS: A 56 years-old man, who had previously received a diagnosis of pancreatic cancer with peritoneal and bone metastasis, complained of persistent postprandial epigastric pain, weight loss (12 kg) and hypercalcemia. He underwent endoscopic ultrasound, which did not identify any solid masses, but a pseudocyst of the pancreas body consistent with a local complication of acute pancreatitis. Plasma levels of parathyroid hormone were markedly increased, and neck ultrasound and scintigraphy confirmed the diagnosis of PHPT. Parathyroidectomy was performed and histological examination revealed parathyroid carcinoma. Searching on PubMed for the keywords "parathyroid carcinoma" AND "acute pancreatitis", from 1969 to March 2021 we found only 12 case reports of acute pancreatitis due to parathyroid cancer. The causal relationship between PHPT and acute pancreatitis has been widely discussed in literature but is still a controversial issue. CONCLUSIONS: Acute pancreatitis induced by primary hyperparathyroidism due to parathyroid carcinoma is an extremely rare condition. However, when hypercalcemia is found, serum PTH levels should always be determined in order to rule out PHPT and hypercalcemia-induced acute pancreatitis should be suspected in presence of hypercalcemia and abdominal symptoms.

Changes in admissions, and hospitalization outcomes of IBD patients in an Italian tertiary referral center over a 13-year period.

OBJECTIVE: The management of Inflammatory Bowel Disease (IBD) has changed significantly in recent years, mainly due to the introduction of biologic medications, however, other factors may also have a role. The aim of this study was to evaluate the evolution of IBD admissions, including trends, modality of admission and rates of surgical intervention, in a tertiary care center. PATIENTS AND METHODS: Hospitalization of patients with a diagnosis of Crohn's disease (CD) or ulcerative colitis (UC) were identified between 2000 and 2013, using ICD-9-CM codes for IBD, from our hospital database. The following parameters were evaluated for each admission: type of admission (ordinary vs. day care service), mode of admission (elective vs. emergency care, for ordinary admissions only), admission code, surgical procedures and complication rates. Comparison between pre- and post-biologic therapy introduction years was also performed. RESULTS: Between 2000 and 2013 a total of 8834 IBD-related admissions were recorded. Hospitalizations increased linearly reaching a peak in 2006, with a downward trend in the following years. The downward trend was especially marked for patients younger than 40 years. No significant differences in hospitalization trends between CD and UC were recorded. Disease flare represented the cause of hospitalization in approximately 50% of cases. Overall, 10.8% of patients underwent surgery with no difference between the two conditions. Complications occurred in 28.7% of admissions. CONCLUSIONS: Hospitalizations for IBD patients have decreased in recent years, especially in younger patients. However, a significant proportion of patients are still admitted to complete diagnostic workup, indicating the need to better implement outpatient services. A clear reduction in surgery occurrence over time could not be observed in our study.

Diagnostic interobserver variability in Crohn's disease- and ulcerative colitis-associated dysplasia: a multicenter digital survey from the IG-IBD Pathologists Group.

BACKGROUND: Crohn's disease (CD) and ulcerative colitis, two forms of inflammatory bowel disease (IBD), are chronic and relapsing conditions of the gastrointestinal tract both characterized by long lasting chronic inflammation and increased risk of dysplasia and colorectal cancer (CRC). The aim of our study was to evaluate the interobserver agreement about IBD-associated dysplasia among pathologists belonging to the Italian Group for Inflammatory Bowel Diseases (IG-IBD P). METHODS: The present multicenter survey was performed using telepathology, supported by an open source E-learning platform. Biopsy specimens from 30 colonoscopies and from 20 patients were included. The glass slides of any case, including clinical and endoscopic data, were digitalized and uploaded on the E-learning platform. All the digital slides were grouped in 54 diagnostic "blocks". Blinded histopathological evaluation on all the digital slides was performed by 20 gastrointestinal pathologists. Closed-ended questions about (1) the occurrence of IBD; (2) the classification of IBD (as UC or CD); (3) the presence of active versus quiescent disease; (4) the presence of dysplasia; (5) the possible association of dysplasia with the sites of disease (dysplasia-associated lesion or mass-DALM vs adenoma-like mass-ALM); (6) the grading of dysplasia according to the ECCO guidelines (negative, indefinite, low grade, high grade categories) and (7) the presence of associated serrated features, were proposed in each case. Inter-observer agreement was evaluated by mean agreement percentage and kappa statistic, when suitable. RESULTS: The diagnosis of IBD was confirmed in 19 of 20 patients, 17 of 19 being classified as UC, 2 as CD. The mean interobserver agreement percentages about (1) the evidence of IBD, (2) the presence of either UC or CD and (3) the activity grading resulted to be 80%, 69% and 86%, respectively. Dysplasia was detected in 8/20 patients, with moderate agreement between pathologists (mean 72%, k 0.48). Particularly, low grade dysplasia was found in 13 biopsies (combined k 0.38), whereas high grade dysplasia in 8 (combined k 0.47). When the endoscopic and histopathological data were combined, features consistent with DALM were found in 6 of 20 patients with low grade dysplasia and those consistent with ALM in 2 patients with low grade dysplasia in a single biopsy (mean agreement: 86%). An associated serrated pattern was discovered in 4 patients (7 biopsies). CONCLUSIONS: Our study showed moderate interobserver agreement about the histopathological detection and classification of IBD-associated dysplasia. Further efforts should be undertaken to integrate the histopathological data with both the ancillary tests and molecular investigations.

Severe eosinophilic asthma and aspirin-exacerbated respiratory disease associated to eosinophilic gastroenteritis treated with mepolizumab: a case report.

BACKGROUND: Mepolizumab (MEP) is the first anti Interleukin (IL)-5 add-on therapy approved for the treatment of severe refractory eosinophilic asthma. CASE PRESENTATION: We describe here the case of a 49 years-old woman with Aspirin-exacerbated respiratory disease (AERD), chronic rhinosinusitis, nasal polyposis and eosinophilic gastroenteritis successfully treated with MEP. Several laboratory and clinical items improved during therapy; moreover MEP showed to be useful as steroid sparing agent. CONCLUSIONS: This case supports that the use of mepolizumab can be effective also in other eosinophilic conditions different from asthma and this opens to new therapeutic perspectives.

Prevalence of cervical HPV and attitude towards cervical screening in IBD patients under immunomodulatory treatment: a multidisciplinary management experience.

OBJECTIVE: Therapeutic strategies for Inflammatory Bowel Diseases (IBD: Crohn's disease and Ulcerative Colitis) have improved but the risk for HPV infection in patients under immunomodulatory/biologic treatment is unclear. Objective of the study is to identify the attitude of patients and caregivers to cervical screening. To determine the prevalence of HPV and cervical lesions in IBD patients receiving immunomodulatory/biological treatment. PATIENTS AND METHODS: IBD patients treated with immunomodulators were enrolled from November 2016 to September 2017, thanks to a multidisciplinary cooperation. A survey was administered to enrolled patients as well as to a selected network of IBD expert physicians. Patients who consented underwent gynecological examination, smear, HPV DNA test, colposcopy, vaginal and cervical microbiological swabs. RESULTS: 294 patients from AMICI Onlus Association, 119 patients from the hospital clinic, 30 doctors from national IBD centers participated to the survey. 19 patients from the IBD clinic underwent cervical screening. More than 90% of doctors consider their patients at risk of cervical cancer. A low prevalence of high-risk genotypes and related HPV lesions and an increased prevalence of bacterial vaginosis emerged in the studied population. CONCLUSIONS: Biological drugs could lead to a positive immunomodulation towards HPV infection. In IBD patients an alteration of the vaginal and intestinal microbiota seems to be coexisting.

Paradoxical psoriasis in a large cohort of patients with inflammatory bowel disease receiving treatment with anti-TNF alpha: 5-year follow-up study.

BACKGROUND: Psoriasis is an emerging paradoxical side effect in patients with inflammatory bowel disease (IBD) when treated with anti-TNF alpha. Patients with severe skin lesions unresponsive to topical therapy need to withdraw from treatment. AIM: To estimate the incidence of paradoxical psoriasis in a large cohort of IBD patients treated with anti-TNF alpha and to analyse its clinical correlates. METHODS: A retrospective cohort study on all IBD patients who started anti-TNF alpha at our IBD Centre from January 2008 to December 2013 was performed. Proportional hazards regression models were used to estimate the association between each predictor and time to the development of psoriasis. Time-dependent predictors were updated at each available time point. RESULTS: Four hundred and two patients were included. Participants contributed a total of 839 person-years of follow-up, during which 42 incident cases of psoriasis were recorded, with an incidence rate of five per 100 person-years. Cox-regression survival analysis revealed smoking as independent predictor of psoriasis (HR: 2.37, 95% CI: 1.36-4.48; P = 0.008). Conversely, concomitant immunosuppressive therapy was inversely related to psoriasis (HR: 0.33, 95% CI: 0.12-0.92; P = 0.03). CONCLUSIONS: Paradoxical psoriasis is a relevant side effect of anti-TNF alpha therapy, with an incidence rate of five per 100 person-years. Smoking is confirmed as the main risk factor for developing lesions. The combination therapy with anti-TNF alpha plus immunosuppressants is associated with a reduced risk of paradoxical psoriasis.

Review article: The pharmacokinetics and pharmacodynamics of drugs used in inflammatory bowel disease treatment.

BACKGROUND: The following review is a compilation of the recent advances and knowledge on the behaviour of the most frequently used compounds to treat inflammatory bowel disease in an organism. RESULTS: It considers clinical aspects of each entity and the pharmacokinetic/pharmacodynamic relationship supported by the use of plasma monitoring, tissue concentrations, and certain aspects derived from pharmacogenetics.

The role of tumour necrosis factor in the pathogenesis of immune-mediated diseases.

Immune-mediated inflammatory diseases (IMIDs), such as rheumatoid arthritis, psoriatic arthritis, psoriasis, axial spondyloarthropathies, Crohn's disease, ulcerative colitis and juvenile idiopathic arthritis, comprise a group of chronic disorders characterized by an immune-mediated pathogenesis. Although at clinical presentation these diseases appear unrelated, they have been recognized to share similar pathogenic mechanisms. Data from epidemiological and genetic studies further support the concept that IMIDs are interrelated, as they can co-occur in the same patient and share a similar genetic susceptibility. The specific aetiologies of IMIDs remain unknown, but all are known to involve dysregulation of the immune system, including an over-expression of the pro-inflammatory cytokine tumour necrosis factor (TNF). The pivotal role played by TNF in the pathogenesis and pathophysiology of IMIDs has been documented by extensive preclinical and clinical investigations, and confirmed by the efficacy of anti-TNF biotechnological drugs, such as etanercept, infliximab and adalimumab, in the therapeutic management of these disorders. In this narrative review, we discuss the available data on the TNF-dependent pathogenesis of IMIDs and associations among the different disorders. Although much remains to be discovered about the pathogenesis and aetiology of IMIDs, their common inflammatory pathological features may explain why they can be successfully targeted by anti-TNF drugs. Among these, adalimumab, a fully human monoclonal antibody, has been approved for treatment of nine distinct IMID indications and it is likely to become a valuable therapeutic tool for this complex cluster of chronic inflammatory disorders.

anti-TNF agents as therapeutic choice in immune-mediated inflammatory diseases: focus on adalimumab.

The complex pathogenesis of immune-mediated inflammatory diseases (IMIDs) has been extensively investigated and dysregulation of cytokines, such as tumour necrosis factor (TNF) has been shown to play a dominant role in the pathogenesis of various IMIDs, such as rheumatoid arthritis, ankylosing spondylitis, Crohn's disease, ulcerative colitis, psoriasis and psoriatic arthritis. The subsequent development of biological agents capable of blocking TNF has led to important advances in the pharmacotherapy of such diseases and confirmed the concept of a common pathophysiology among IMIDs with TNF having a predominant role. Five TNF inhibitors have currently been approved for treatment of one or more IMIDs; these include infliximab, etanercept, adalimumab, golimumab and certolizumab pegol. Given the similarities in the pathogenic background of IMIDs, one could expect that anti-TNF agents be similarly effective and with comparable tolerability profiles; however, this may not be the case. Structural and pharmacological differences among the anti-TNF drugs are likely to result in differences in efficacy and tolerability among the agents in the different IMIDs, together with differences in potency, therapeutic dose ranges, dosing regimens, administration routes, and propensity for immunogenicity. Among the five TNF inhibitors approved for treatment of IMIDs, adalimumab has the widest range of indications. Data from controlled clinical trials of adalimumab, showing its excellent efficacy and tolerability in a wide range of indications, are supported by real-world long-term data from observational studies, which confirm the value of adalimumab as a suitable choice in the management of IMIDs.

Adalimumab in the treatment of immune-mediated diseases.

Tumour necrosis factor (TNF) plays an important role in the pathogenesis of immune-mediated inflammatory diseases (IMIDs). TNF inhibition results in down-regulation of abnormal and progressive inflammatory processes, resulting in rapid and sustained clinical remission, improved quality of life and prevention of target organ damage. Adalimumab is the first fully human monoclonal antibody directed against TNF. In this article, we review the role and cost effectiveness of adalimumab in the treatment of IMIDs in adults and children. The efficacy and tolerability of adalimumab has been demonstrated in patients with a wide range of inflammatory conditions, leading to regulatory approval in rheumatoid arthritis (RA), psoriatic arthritis (PsA), plaque psoriasis, inflammatory bowel diseases (Crohn's disease, ulcerative colitis, paediatric Crohn's disease, and intestinal Behçet's disease), ankylosing spondylitis (AS), axial spondyloarthritis (SpA) and juvenile idiopathic arthritis. The major tolerability issues with adalimumab are class effects, such as injection site reactions and increased risk of infection and lymphoma. As with all anti-TNF agents, adalimumab is immunogenic, although less than infliximab, and some patients receiving long-term adalimumab will develop anti-drug antibodies, causing a loss of response. Comparisons of its clinical utility and cost effectiveness have shown it to be a valid treatment choice in a wide range of patients. Recent data from Italian economic studies show the cost effectiveness of adalimumab to be below the threshold value for health care interventions for most indications. In addition, analysis of indirect costs shows that adalimumab significantly reduces social costs associated with RA, PsA, AS, Crohn's disease and psoriasis. The fact that adalimumab has the widest range of approved indications, many often presenting together in the same patient due to the common pathogenesis, may further improve the utility of adalimumab. Current clinical evidence shows adalimumab to be a valuable resource in the management of IMIDs. Further research, designed to identify patients who may benefit most from this drug, will better highlight the role and cost-effectiveness of this versatile TNF inhibitor.

Development of psoriasis scalp with alopecia during treatment of Crohn's disease with infliximab and rapid response to both diseases to ustekinumab.

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.

A case of pyoderma gangrenosum with ulcerative colitis treated with combined approach: infliximab and surgery.

Pyoderma gangrenosum (PG) is an ulcerating noninfectious disease of the skin seen in 1-2% of patients with inflammatory bowel disease (IBD). The pathogenesis of PG has yet to be determined, but may be related to abnormal T cell responses and the production of TNF-α, a pathway also involved in IBD pathogenesis. Infliximab, a chimeric monoclonal antibody to TNF-α, is used to treat moderate to severe IBD and several case reports and studies suggest the efficacy of infliximab in the treatment of PG. The surgical approach to PG is reserved to a few selected cases. We report here the case of a patient with ulcerative colitis (UC) and PG localized on the left breast, treated with a simultaneous combined medical and surgical approach.

Immune response to influenza A/H1N1 vaccine in inflammatory bowel disease patients treated with anti TNF-α agents: effects of combined therapy with immunosuppressants.

BACKGROUND AND AIMS: Our first objective was to evaluate the immune response to the adjuvanted 2009 A/H1N1 pandemic (pH1N1) vaccine in inflammatory bowel disease (IBD) patients treated with anti-TNF-α alone or combined with immunosuppressants (IS). Second and third aims were the safety of pH1N1 vaccine and the effects on IBD clinical activity. METHODS: 36 patients with Crohn's disease (CD) and 26 with ulcerative colitis (UC) and thirty-one healthy control (HC) subjects were enrolled. 47 patients were on anti TNF-α maintenance monotherapy and 15 on anti TNF-α combined with IS. Sera were collected at baseline (T0) and 4 weeks after the vaccination (T1) for antibody determination by hemagglutination inhibition (HAI). Disease activity was monitored at T0 and T1. RESULTS: Seroprotective titers (≥1:40) in patients were comparable to HC. Seroconvertion rate (≥4 fold increase in HAI titer) was lower than HC in IBD patients (p=0.009), either on anti TNF-α monotherapy (p=0.034) or combined with IS (p=0.011). Geometric mean titer (GMT) of antibodies at T1 was significantly lower in patients on combined therapy versus those on monotherapy (p=0.0017) and versus HC (p=0.011). The factor increase of GMT at T1 versus T0 was significantly lower in IBD patients versus HC (p=0.042), and in those on combined immunosuppression, both versus monotherapy (p=0.0048) and HC (p=0.0015). None of the patients experienced a disease flare. CONCLUSION: Our study has shown a suboptimal response to pH1N1 vaccine in IBD patients on therapy with anti TNF-α and IS compared to those on anti-TNF-α monotherapy and HC.

Anti-TNF alpha therapy in the management of extraintestinal manifestation of inflammatory bowel disease.

Inflammatory bowel disease, Crohn's disease and ulcerative colitis, are immune-mediated disorders of unknown etiology that primarily affect the gastrointestinal tract. In addition, other organ systems can be involved such as joint/bones, skin, eyes, hepatobiliary tract, lungs and kidney. Overall, they represent extraintestinal manifestations of inflammatory bowel disease and may present before, in conjunction or after the onset of bowel disease. Extraintestinal manifestations are observed in 20-40% of patients and frequently have a negative impact on quality of patients' life. Some extraintestinal manifestations such as arthritis, erytema nodosum, pyoderma gangrenosum, iritis, uveitis have a pathogenic tumor necrosis factor alpha-dependent mechanism common with Crohn's disease and ulcerative colitis. Early recognition and treatment of extraintestinal manifestations can minimize potential severe complications. In this review we provide an overview on the prevalence and clinical aspects of the more commonly reported extraintestinal manifestations of Crohn's disease and ulcerative colitis and the role of tumor necrosis factor alpha inhibitors in their treatment.

New biological agents for the treatment of the "high risk" IBD patients.

BACKGROUND: Several new biological drugs have been introduced in the last decade or are under investigation for the treatment of IBD. They include anti TNFalpha agents, anti adhesion molecules, anti IL-12/23, anti IL-6R and others. Their role in IBD therapy will be discussed in regard of the association of chronic inflammation and cancer in the gut. The risk of colorectal cancer is increased in ulcerative colitis (UC) and, to some extent, in Crohn's disease (CD). This association is well known from many years. However, the mechanisms linking chronic inflammation and carcinogenesis are beginning to be elucidated only recently. RESULTS AND CONCLUSIONS: Experimental data indicate that several cytokines could play a role in promoting tumour development. In this perspective, the anti cytokine agents could be not only powerful tools in treating inflammation but also efficacious in preventing the onset of inflammation associated colorectal cancer.

Infliximab in Crohn's disease: early and long-term treatment.

The natural history of Crohn's disease is characterized by a remitting and relapsing course that progresses to complications and surgery in the majority of patients. Current treatment guidelines advocate a stepwise approach according to disease location and severity at presentation, with goals mainly aimed at inducing and maintaining clinical remission. Major advances in the understanding of the pathogenesis of Crohn's disease offered significant opportunities for the development of new therapies over the past years. Infliximab and other biologic agents have shown impressive results in Crohn's disease patients refractory to standard therapy, suggesting a potential disease course-modifying action. These led to the proposal to reverse the traditional therapeutic algorithms using these agents early in the course of the disease. Preliminary data suggest that early intervention may be a more effective treatment strategy in some Crohn's disease patients. As yet, early and indiscriminate use of biologics remains to be supported by convincing evidence. Data on long-term treatment of Crohn's disease with infliximab or other biologics are even more scarce. Future studies aimed to identify predictors of complicated disease and long-term randomized studies aimed to compare "step-up" and "top-down" strategies in high-risk groups should help to answer if early introduction of biological therapy alters the natural history of Crohn's disease.