The effect of immunosuppressants on the prognosis of SARS-CoV-2 infection.

BACKGROUND: Immunosuppression may worsen severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. We conducted a nationwide cohort study of the effect of exposure to immunosuppressants on the prognosis of SARS-CoV-2 infection in Denmark. METHODS: We identified all SARS-CoV-2 test-positive patients from February 2020 to October 2020 and linked healthcare data from nationwide registers, including prescriptions for the exposure (immunosuppressant drugs). We estimated relative risks of hospital admission, intensive care unit (ICU) admission and death (each studied independently up to 30 days from testing) with a log-linear binomial regression adjusted for confounders using a propensity score-based matching weights model. RESULTS: A composite immunosuppressant exposure was associated with a significantly increased risk of death (adjusted relative risk 1.56 (95% CI 1.10-2.22)). The increased risk of death was mainly driven by exposure to systemic glucocorticoids (adjusted relative risk 2.38 (95% CI 1.72-3.30)), which were also associated with an increased risk of hospital admission (adjusted relative risk 1.34 (95% CI 1.10-1.62)), but not of ICU admission (adjusted relative risk 1.76 (95% CI 0.93-3.35)); these risks were greater for high cumulative doses of glucocorticoids than for moderate doses. Exposure to selective immunosuppressants, tumour necrosis factor inhibitors or interleukin inhibitors was not associated with an increased risk of hospitalisation, ICU admission or death, nor was exposure to calcineurin inhibitors, other immunosuppressants, hydroxychloroquine or chloroquine. CONCLUSIONS: Exposure to glucocorticoids was associated with increased risks of hospital admission and death. Further investigation is needed to determine the optimal management of coronavirus disease 2019 (COVID-19) in patients with pre-morbid glucocorticoid usage, specifically whether these patients require altered doses of glucocorticoids.

Increased risk of acute arterial events in young patients and severely active IBD: a nationwide French cohort study.

OBJECTIVE: Magnitude and independent drivers of the risk of acute arterial events in IBD are still unclear. We addressed this question in patients with IBD compared with the general population at a nationwide level. DESIGN: Using the French National Hospital Discharge Database from 2008 to 2013, all patients aged 15 years or older and diagnosed with IBD were identified and followed up until 31 December 2013. The rates of incident acute arterial events were calculated and the impact of time with active disease (period around hospitalisation for IBD flare or IBD-related surgery) on the risk was assessed by Cox regression adjusted for traditional cardiovascular risk factors. RESULTS: Among 210 162 individuals with IBD (Crohn's disease (CD), n=97 708; UC, n=112 454), 5554 incident acute arterial events were identified. Both patients with CD and UC had a statistically significant overall increased risk of acute arterial events (standardised incidence ratio (SIR) 1.35; 95% CI 1.30 to 1.41 and SIR 1.10; 95 CI 1.06 to 1.13, respectively). The highest risk was observed in patients under the age of 55 years, both in CD and UC. The 3-month periods before and after IBD-related hospitalisation were associated with an increased risk of acute arterial events in both CD and UC (HR 1.74; 95 CI 1.44 to 2.09 and 1.87; 95% CI 1.58 to 2.22, respectively). CONCLUSION: Patients with IBD are at increased risk of acute arterial events, with the highest risk in young patients. Disease activity may also have an independent impact on the risk.

Comparison of Infliximab and Adalimumab in Biologic-Naive Patients With Ulcerative Colitis: A Nationwide Danish Cohort Study.

BACKGROUND & AIMS: This study compares the effectiveness and safety of infliximab and adalimumab in biologic-naive patients with ulcerative colitis (UC), in a nationwide register-based propensity score-matched cohort study. METHODS: From 1719 adults with UC, between ages 15 and 75 years in Denmark treated with either infliximab or adalimumab as their first biologic agent, we compared rates of all-cause hospitalization, UC-related hospitalization, major abdominal surgery, and serious infections after a variable 2:1 propensity score matching, accounting for baseline clinical characteristics, disease severity, health care utilization, and use of UC-related medications. RESULTS: As compared with infliximab-treated patients, adalimumab-treated patients had higher rate of all-cause hospitalization (hazard ratio [HR], 1.84; 95% CI, 1.18-2.85) and a trend toward higher rate of UC-related hospitalization (HR, 1.71; 95% CI, 0.95-3.07), particularly in a stratum of patients on concomitant immunomodulator therapy. However, risk of abdominal surgery (HR, 1.35; 95% CI, 0.62-2.94) was not different between the 2 treatment groups. Risk of serious infection requiring hospitalization was significantly higher in adalimumab-treated patients (HR, 5.11; 95% CI, 1.20-21.80). CONCLUSIONS: In this nationwide propensity score matched-cohort study of biologic-naive adults with UC, use of adalimumab as first-line biologic over infliximab was associated with higher risk of hospitalization and serious infections, although risk of surgery was not different. In the absence of head-to-head trials, this evidence may assist patients, health care providers, purchasers, and policy makers to make informed decisions that may improve health care in UC.

Colonoscopy surveillance for dysplasia and colorectal cancer in patients with inflammatory bowel disease.

The risk of colorectal cancer (CRC) and dysplasia in patients with inflammatory bowel disease (IBD) has been highly debated as risk estimates from different studies vary greatly. The present national Danish guideline on colonoscopy surveillance for dysplasia and colorectal cancer in patients with IBD is based on a thorough review of existing literature with particular focus on recent studies from Denmark revealing a lower risk of CRC than previously assumed. The overall risk of CRC in the Danish IBD population does not appear to be different from that of the background population; however, in some subgroups of patients the risk is increased. These subgroups of patients, who should be offered colonoscopy surveillance, include patients with ulcerative colitis having extensive disease and a long disease duration (10-13 years); early age at onset (less than 19 years of age) of ulcerative colitis; and patients with ulcerative colitis as well as Crohn's disease with a concomitant diagnosis of primary sclerosing cholangitis. A colonoscopy surveillance program is recommended in these subgroups with intervals ranging from every 3-6 months to every 5 years, using chromoendoscopy with targeted biopsies of the lesion and adjacent mucosa, instead of conventional colonoscopy with random biopsies. Preferably, the colonoscopy should be performed during clinical remission. If a lesion is detected the endoscopical resectability together with the pathology of the lesion and the adjacent mucosa determine how the lesion should be treated.

Risk of infections associated with biological treatment in inflammatory bowel disease.

Tumor necrosis factor-α (TNF-α) inhibitors are biological agents introduced in the late 1990s for the treatment of different immune-mediated diseases as inflammatory bowel disease, rheumatoid arthritis and psoriasis. The most commonly used TNF-α antagonists are infliximab, adalimumab, and certolizumab pegol, and though highly effective in lowering inflammation, the efficacy must be weighed against the potential for adverse events. The treatment-induced immunosuppression is suspected to increase the risk of infections, including the risk of reactivation of latent tuberculosis, as the TNF-α cytokine plays an important role in the immune function. In this topic highlight a short overview of the infection risk associated with TNF-α inhibiter therapy is outlined with a focus on the overall risk of serious infections, mycobacterial infection and latent viral infections.

Ehealth: low FODMAP diet vs Lactobacillus rhamnosus GG in irritable bowel syndrome.

AIM: To investigate the effects of a low fermentable, oligosaccharides, disaccharides, monosaccharides and polyols diet (LFD) and the probiotic Lactobacillus rhamnosus GG (LGG) in irritable bowel syndrome (IBS). METHODS: Randomised, unblinded controlled trial on the effect of 6-wk treatment with LFD, LGG or a normal Danish/Western diet (ND) in patients with IBS fulfilling Rome III diagnostic criteria, recruited between November 2009 and April 2013. Patients were required to complete on a weekly basis the IBS severity score system (IBS-SSS) and IBS quality of life (IBS-QOL) questionnaires in a specially developed IBS web self-monitoring application. We investigated whether LFD or LGG could reduce IBS-SSS and improve QOL in IBS patients. RESULTS: One hundred twenty-three patients (median age 37 years, range: 18-74 years), 90 (73%) females were randomised: 42 to LFD, 41 to LGG and 40 to ND. A significant reduction in mean ± SD of IBS-SSS from baseline to week 6 between LFD vs LGG vs ND was revealed: 133 ± 122 vs 68 ± 107, 133 ± 122 vs 34 ± 95, P < 0.01. Adjusted changes of IBS-SSS for baseline covariates showed statistically significant reduction of IBS-SSS in LFD group compared to ND (IBS-SSS score 75; 95%CI: 24-126, P < 0.01), but not in LGG compared to ND (IBS-SSS score 32; 95%CI: 18-80, P = 0.20). IBS-QOL was not altered significantly in any of the three groups: mean ± SD in LFD 8 ± 18 vs LGG 7 ± 17, LFD 8 ± 18 vs ND 0.1 ± 15, P = 0.13. CONCLUSION: Both LFD and LGG are efficatious in patients with IBS.

Risk of cardiovascular disease in inflammatory bowel disease.

Abundant scientific evidence supporting an association between inflammatory bowel disease (IBD) and venous thromboembolic events, caused by an IBD related hypercoagulability, is acknowledged and thromboprophylactic treatment strategies are now implemented in the management of IBD patients. In contrary, the risk of arterial thromboembolic disease, as ischemic heart disease, cerebrovascular events, and mesenteric ischemia in patients with IBD remains uncertain and the magnitude of a potentially increased risk is continuously debated, with ambiguous risk estimates among studies. The evident role of inflammation in the pathogenesis of atherosclerosis forms the basis of a biological plausible link; the chronic systemic inflammation in IBD patients increases the risk of atherosclerosis and thereby the risk of thrombotic events. Further, studies have shown that the burden of traditional risk factors for atherosclerosis, such as obesity, diabetes mellitus, and dyslipidemia is lower in IBD populations, thus further strengthen the role of non-traditional risk factors, as chronic inflammation in the linking of the two disease entities. Likewise, mortality from cardiovascular disease in IBD remains questioned. The aim of the current review is to give an up-date on the existing evidence of the possible association between IBD and cardiovascular disease and to discuss traditional and non-traditional risk factors.

Ehealth monitoring in irritable bowel syndrome patients treated with low fermentable oligo-, di-, mono-saccharides and polyols diet.

In the present study we report on changes in irritable bowel syndrome-severity scoring system (IBS-SSS) and irritable bowel syndrome-quality of life (IBS-QoL) in 19 IBS patients, aged 18 to 74 years (F/M: 14/5), during 12 wk registering their symptoms on the web-application (www.ibs.constant-care.dk). During a control period of the first 6-wk patients were asked to register their IBS-SSS and IBS-QoL on the web-application weekly without receiving any intervention. Thereafter, low fermentable oligo-, di-, mono-saccharides and polyols (FODMAP) diet (LFD) was introduced for the next 6 wk while continuing the registration. Though a small sample size a significant improvement in disease activity (IBS-SSS) was observed during both the control period, median: 278 (range: 122-377), P = 0.02, and subsequently during the LFD period, median: 151 (range: 29-334), P < 0.01. The IBS-QoL solely changed significantly during the LFD period, median: 67 (37-120), P < 0.01. The significant reduction in disease activity during the control period shows a positive effect of the web-application on IBS symptoms when presented as a "traffic light". However adding the diet reduced IBS-SSS to < 150, inactive to mild symptoms. In the future results from larger scale trials are awaited.

Has the risk of colorectal cancer in inflammatory bowel disease decreased?

The association between inflammatory bowel disease (IBD) and colorectal cancer (CRC) has been acknowledged for almost a century and is assumedly promoted by a chronic inflammation-driven carcinogenic process in the intestine in combination with a genetic predisposition. The magnitude of the risk of CRC in IBD remains a continuing subject of debate. The early, high risk estimates for CRC in IBD were most likely overestimated due to selected patient populations originating from tertiary referral centers with a disproportional high percentage of patients with severe disease. Later population-based studies calculating risk estimates from a broad spectrum of IBD patients have found the risk to be significantly lower. At present, there is evidence that IBD patients with longstanding and extensive disease with uncontrolled inflammation are those at increased risk. Additional, other recognized risk factors include early age at onset, family history of CRC, and concomitant primary sclerosing cholangitis. A significant amount of effort is put into identifying potential preventive factors of CRC in IBD, including surveillance programs and chemopreventive agents but the individual effect of these remains uncertain. Interestingly, recent studies have reported a decline in risk of CRC over time. Surveillance programs and the new treatment strategies, particular biological treatment might be part of the reason for the observed decline in risk of CRC in IBD over time but future studies will have investigate this assumption.

Occurrence of demyelinating diseases after anti-TNFα treatment of inflammatory bowel disease: A Danish Crohn Colitis Database study.

INTRODUCTION: It remains uncertain whether patients with inflammatory bowel disease (IBD) are at increased risk of developing demyelinating diseases, primarily multiple sclerosis (MS) and whether the introduction of biologic drugs in the treatment of IBD has altered this risk. AIM AND METHODS: The aim was to conduct a systematic review of literature on occurrence of demyelinating diseases in IBD patients, to assess a national Danish anti-TNFα treated IBD cohort in order to search for and describe the IBD cases with coexisting demyelinating diseases, and finally to compare the occurrence of MS in the anti-TNFα cohort to the occurrence in the general Danish population. A systematic MEDLINE literature search was conducted, medical files were scrutinized for identification and description of cohort patients with demyelinating disease, and risk of MS was calculated as a standardized morbidity ratio (SMR) using general population data for comparison. RESULTS: Four studies on the risk of demyelinating diseases in IBD were identified. One study revealed an observed prevalence of MS at onset of IBD at 3.7 times the expected (95% CI, 0.8-10.8). In the Danish anti-TNFα IBD cohort, 4 out of 651 patients developed demyelinating disorders after anti-TNFα treatment. The SMR for developing MS among Danish IBD patients treated with anti-TNFα was 4.2 (95% CI, 0.1-23.0). CONCLUSION: The literature review revealed an up to four-fold increased risk of demyelinating diseases, in particular MS, in IBD patients in general. The risk of developing MS in the anti-TNFα treated Danish cohort did apparently not exceed this risk.