Life-prolonging treatment restrictions and outcomes in patients with cancer and COVID-19: an update from the Dutch Oncology COVID-19 Consortium.

AIM OF THE STUDY: The coronavirus disease 2019 (COVID-19) pandemic significantly impacted cancer care. In this study, clinical patient characteristics related to COVID-19 outcomes and advanced care planning, in terms of non-oncological treatment restrictions (e.g. do-not-resuscitate codes), were studied in patients with cancer and COVID-19. METHODS: The Dutch Oncology COVID-19 Consortium registry was launched in March 2020 in 45 hospitals in the Netherlands, primarily to identify risk factors of a severe COVID-19 outcome in patients with cancer. Here, an updated analysis of the registry was performed, and treatment restrictions (e.g. do-not-intubate codes) were studied in relation to COVID-19 outcomes in patients with cancer. Oncological treatment restrictions were not taken into account. RESULTS: Between 27th March 2020 and 4th February 2021, 1360 patients with cancer and COVID-19 were registered. Follow-up data of 830 patients could be validated for this analysis. Overall, 230 of 830 (27.7%) patients died of COVID-19, and 60% of the remaining 600 patients with resolved COVID-19 were admitted to the hospital. Patients with haematological malignancies or lung cancer had a higher risk of a fatal outcome than other solid tumours. No correlation between anticancer therapies and the risk of a fatal COVID-19 outcome was found. In terms of end-of-life communication, 50% of all patients had restrictions regarding life-prolonging treatment (e.g. do-not-intubate codes). Most identified patients with treatment restrictions had risk factors associated with fatal COVID-19 outcome. CONCLUSION: There was no evidence of a negative impact of anticancer therapies on COVID-19 outcomes. Timely end-of-life communication as part of advanced care planning could save patients from prolonged suffering and decrease burden in intensive care units. Early discussion of treatment restrictions should therefore be part of routine oncological care, especially during the COVID-19 pandemic.

Prevalence and Phenotype of Concurrent Psoriasis and Inflammatory Bowel Disease.

BACKGROUND: Psoriasis, psoriatic arthritis (PsA), and inflammatory bowel disease (IBD) are related inflammatory immune-mediated diseases, with considerable overlap. However, it is as yet unclear whether co-occurrence of these diseases affects disease course and characteristics of the individual complaints. The objective of this study was to identify the prevalence of IBD and PsA in a psoriasis cohort and to examine whether patients with concurrent psoriasis and IBD carry a distinct phenotype. METHODS: Data of all patients with psoriasis visiting a general hospital in the Netherlands between 2009 and 2014 were retrospectively retrieved from electronic patient files. In addition, clinical characteristics of patients with concurrent psoriasis and IBD (n = 40) were compared with psoriasis-only (n = 1643) and IBD-only (n = 385) cohorts. RESULTS: Among 1669 hospital-based patients with psoriasis, prevalence of PsA was 12.2% (n = 203, 95% confidence interval, 10.5-13.7) and of IBD 1.6% (n = 26, 95% confidence interval, 1.0-2.2), including 12 Crohn's disease (CD) and 14 ulcerative colitis. Psoriasis-PsA patients were more likely to have IBD than psoriasis-only patients (3.0 versus 1.4%).Psoriasis-CD patients were younger at CD diagnosis (20.0 versus 32.0 yr, P = 0.001), and psoriasis diagnosis (28.0 versus 43.5 yr, P = 0.004) than psoriasis-only patients. Psoriasis-IBD patients had a mild psoriasis phenotype similar to psoriasis-only patients, but the CD-phenotype was significantly more severe than in CD-only patients. CONCLUSIONS: The prevalence of IBD in psoriasis was approximately 4 times higher than that in the general population, with the highest risk for psoriasis-PsA patients. Psoriasis-CD patients have a mild (early-onset) psoriasis but an earlier-onset and severe CD-phenotype.

Benefit of Earlier Anti-TNF Treatment on IBD Disease Complications?

BACKGROUND: Anti-tumour necrosis factor [anti-TNF] treatment was demonstrated to have disease-modifying abilities in inflammatory bowel disease [IBD]. In this study, we aimed to determine the effect of anti-TNF treatment timing on IBD disease complications and mucosal healing [MH]. METHODS: The following IBD-related complications were tested in relation to timing of anti-TNF therapy start in newly diagnosed IBD patients [n = 413]: fistula formation, abscess formation, extra-intestinal manifestations [EIM], surgery, referral to academic centre, and MH. RESULTS: A total of 85 patients [21%] received anti-TNF (66 Crohn's disease [CD], 16 ulcerative colitis [UC], 3 inflammatory bowel disease unclassified [IBDU]) of whom 57% [48 patients] were treated < 16 months after diagnosis. Patients receiving anti-TNF early [< 16 months] did not differ from patients receiving anti-TNF late [> 16 months] regarding gender, age, smoking status, and familial IBD. More importantly, patients receiving anti-TNF early did not suffer less IBD-related complications during follow-up as compared with patients started on anti-TNF late, nor was more MH observed. Similar results were obtained when anti-TNF treated patient were stratified more stringently, ie < 12 months [40 patients] vs >2 4 months [24 patients]. Cox regression analysis showed no beneficial correlations between anti-TNF timing and IBD-related complications. Anti-TNF treated patients achieving MH were 11 times less likely to develop EIMs compared with patients who did not achieved MH while on anti-TNF. CONCLUSIONS: This study was unable to confirm a benefit of earlier anti-TNF treatment on IBD disease complications. This could be explained by more aggressive treatment earlier in disease, resulting in fewer IBD complications. However, it seems more likely that inappropriate selection of patients for therapy leads to suboptimal treatment and subsequently suboptimal outcome.

Disappointing durable remission rates in complex Crohn's disease fistula.

BACKGROUND: Despite potent drugs and surgical techniques, the treatment of perianal fistulizing Crohn's disease (CD) remains challenging. We assessed treatment strategies for perianal fistulizing CD and their effect on remission, response, and relapse. METHODS: Patients with perianal fistulizing CD visiting the Erasmus MC between January 1, 1980 and January 1, 2000 were identified. Demographics, fistula characteristics, and received treatments aimed at the outcome of these strategies were noted. RESULTS: In total, 232 patients were identified (98 male; 42.2%). Median follow-up was 10.0 years (range, 0.5-37.5 yr). Complex fistulas were present in 78.0%. Medical treatment (antibiotics, steroids, immunosuppressants, and anti-tumor necrosis factor) commenced in 79.7% of the patients and in 53.2%, surgery (colectomy, fistulectomy, stoma, and rectum amputation) was performed. Simple fistulas healed more often than complex fistulas (88.2% versus 64.6%; P < 0.001). Rectum involvement was not associated with a lower remission rate, and anti-tumor necrosis factor therapy did not increase complete fistula healing rates in simple and complex fistula. Initially, healed fistulas recurred in 26.7% in case of simple fistulas and in 41.9% in case of complex fistulas (P = 0.051). Only 37.0% of the complex fistulas were in remission at the end of follow-up compared with 66.7% of the simple fistulas (P < 0.001). CONCLUSIONS: Only the minority of CD complex perianal fistulas were in remission after conventional treatment strategies after a median follow-up of 10 years. Simple fistulas were more likely to heal than complex fistulas, and less of these healed fistulas relapsed. However, more than 3 quarters of the patients had complex perianal fistulas.

Suppression of p21Rac signaling and increased innate immunity mediate remission in Crohn's disease.

In inflammatory bowel disease (IBD), large areas of apparently healthy mucosa lie adjacent to ulcerated intestine. Knowledge of the mechanisms that maintain remission in an otherwise inflamed intestine could provide important clues to the pathogenesis of this disease and provide rationale for clinical treatment strategies. We used kinome profiling to generate comprehensive descriptions of signal transduction pathways in inflamed and noninflamed colonic mucosa in a cohort of IBD patients, and compared the results to non-IBD controls. We observed that p21Rac1 guanosine triphosphatase (GTPase) signaling was strongly suppressed in noninflamed colonic mucosa in IBD. This suppression was due to both reduced guanine nucleotide exchange factor activity and increased intrinsic GTPase activity. Pharmacological p21Rac1 inhibition correlated with clinical improvement in IBD, and mechanistically unrelated pharmacological p21Rac1 inhibitors increased innate immune functions such as phagocytosis, bacterial killing, and interleukin-8 production in healthy controls and patients. Thus, suppression of p21Rac activity assists innate immunity in bactericidal activity and may induce remission in IBD.

Peripheral neutrophil functions and cell signalling in Crohn`s disease.

The role of the innate immunity in the pathogenesis of Crohn's disease (CD), an inflammatory bowel disease, is a subject of increasing interest. Neutrophils (PMN) are key members of the innate immune system which migrate to sites of bacterial infection and initiate the defence against microbes by producing reactive oxygen species (ROS), before undergoing apoptosis. It is believed that impaired innate immune responses contribute to CD, but it is as yet unclear whether intrinsic defects in PMN signal transduction and corresponding function are present in patients with quiescent disease. We isolated peripheral blood PMN from CD patients in remission and healthy controls (HC), and characterised migration, bacterial uptake and killing, ROS production and cell death signalling. Whereas IL8-induced migration and signalling were normal in CD, trans-epithelial migration was significantly impaired. Uptake and killing of E. coli were normal. However, an increased ROS production was observed in CD PMN after stimulation with the bacterial peptide analogue fMLP, which was mirrored by an increased fMLP-triggered ERK and AKT signal activation. Interestingly, cleavage of caspase-3 and caspase-8 during GMCSF-induced rescue from cell-death was decreased in CD neutrophils, but a reduced survival signal emanating from STAT3 and AKT pathways was concomitantly observed, resulting in a similar percentage of end stage apoptotic PMN in CD patients and HC. In toto, these data show a disturbed signal transduction activation and functionality in peripheral blood PMN from patients with quiescent CD, which point toward an intrinsic defect in innate immunity in these patients.

Phenotype of inflammatory bowel disease at diagnosis in the Netherlands: a population-based inception cohort study (the Delta Cohort).

BACKGROUND: To describe the clinical characteristics of inflammatory bowel disease (IBD) at diagnosis in The Netherlands at the population level in the era of biologics. METHODS: All patients with newly diagnosed IBD (diagnosis made between January 1, 2006 and January 1, 2007) followed in 9 general hospitals in the southwest of the Netherlands were included in this population-based inception cohort study. RESULTS: A total of 413 patients were enrolled, of which 201 Crohn's disease (CD) (48.7%), 188 ulcerative colitis (UC) (45.5%), and 24 IBD unclassified (5.8%), with a median age of 38 years (range, 14-95). Seventy-eight patients with CD (38.8%) had ileocolonic disease and 73 patients (36.3%) had pure colonic disease. In 8 patients (4.0%), the upper gastrointestinal tract was involved. Nineteen patients with CD (9.5%) had perianal disease. Thirty-nine patients with CD (19.4%) had stricturing phenotype. Of the patients with UC and IBDU, 39 (18.4%) suffered from pancolitis and 61 (29%) from proctitis. Severe endoscopic lesions at diagnosis were seen in 119 patients (28.8%, 68 CD, 49 UC, and 2 IBDU), whereas 98 patients (23.7%) had severe histological disease activity. Thirteen patients (3.1%, 10 CD and 3 UC) had extraintestinal manifestations at diagnosis. Twenty-three patients (5.6%, 20 CD and 3 UC) had fistula at diagnosis. CONCLUSIONS: In this cohort, 31% of the patients with CD had complicated disease at diagnosis, 39% had ileocolonic disease, 9.5% had perianal disease, and in 4% the upper gastrointestinal tract was involved. Most patients with UC suffered from left-sided colitis (51%). Severe endoscopic lesions were reported in 34% of the patients with CD and 26% of the patients with UC. Three percent of the patients with IBD had extraintestinal manifestations.

Increased suppressor of cytokine signaling-3 expression predicts mucosal relapse in ulcerative colitis.

BACKGROUND: Most biomarkers predicting mucosal relapse of ulcerative colitis (UC) patients in clinical remission represent low levels of mucosal inflammation. Since SOCS3 expression may increase the vulnerability of intestinal epithelial cells (IECs) to various insults, we investigated whether its expression predicts mucosal relapse in UC patients in clinical remission without any signs of mucosal inflammation. METHODS: UC patients (n = 32) in clinical, endoscopic, and histological remission were followed up for 9 years. IEC expression of SOCS3, p-STAT3, and p-STAT1 were assessed with biopsies from the baseline colonoscopy, last colonoscopy before relapse, and colonoscopy at relapse. Clinical data, endoscopy, and histology reports were collected from patient charts. RESULTS: Twenty-six (81%) patients had histological relapse, 19 (59%) developed an endoscopic relapse, and 17 (53%) had a clinical relapse during follow-up. SOCS3 expression at first colonoscopy during remission correlated with shorter time to histological, endoscopic, and clinical relapse. SOCS3 expression was increased at the last colonoscopy before relapse, approaching relapse levels, whereas p-STAT3 expression was low during the entire remission. A positive correlation between IEC SOCS3 and its inducer p-STAT1 was shown. CONCLUSIONS: SOCS3 IEC expression during remission may be useful in predicting mucosal relapse in patients without any signs of mucosal inflammation. These data strengthen our hypothesis that SOCS3 contributes to enhanced vulnerability of IEC during remission. Thus, SOCS3 levels during remission may function as a therapeutic target for clinical monitoring and early induction of mucosal healing.

Majority of patients with inflammatory bowel disease in clinical remission have mucosal inflammation.

BACKGROUND: Management of inflammatory bowel disease (IBD) is increasingly focused on mucosal remission. We assessed the prevalence of mucosal inflammation during clinical remission, the clinical consequences, and the impact on disease course. METHODS: IBD patients from two referral centers who underwent a surveillance colonoscopy while clinically in remission between January 2001 and December 2003 were included. Follow-up ended May 1, 2009. Clinical data were collected from patient charts. Statistical analysis was performed using independent t-tests and nonparametric tests. RESULTS: In total, 152 IBD patients were included (98 [65%] ulcerative colitis, 46 [30%] Crohn's disease; 85 [56%] males). Median follow-up was 6.8 years (interquartile range [IQR] 6-8). Forty-seven (31%) patients had no signs of inflammation during endoscopy (group A). Of the remaining 105 (68%) patients, 51 (49%) had both endoscopic and histological inflammation (group B), 51 (49%) histological inflammation only (group C), two (2%) endoscopic lesions only (group D). Two years later, 29% of all patients had endoscopic inflammation and another 27% had only microscopic inflammation. In 39% the inflammation had resolved spontaneously. Inflammation was more often found in group B+C (n = 62/102; 61%) than in group A (n = 17/47; 36%; P = 0.21). Inflammation was not associated with more frequent clinical relapses nor with stricture formation, nor with the need for surgery. CONCLUSIONS: A large proportion of IBD patients have mucosal inflammation without clinical symptoms. Although one-third recover spontaneously, mucosal inflammation in patients who are clinically in remission is associated with more severe mucosal disease activity, but not with more complications or symptomatic flares during follow-up.