Thrombotic Occlusion of All Left Coronary Branches in a Young Woman with Severe Ulcerative Colitis

Background. The thrombosis risk is increased in active ulcerative colitis. The limited number of reported complications have predominantly been cerebrovascular but other vessel territories may also be affected. Patient. During a severe attack of ulcerative colitis a 37-year-old woman suffered occlusion of all left coronary artery branches. Serial angiographies showed progressive recanalisation of the coronary arteries during anticoagulation, but no atherosclerotic stenosis. The cause of infarction was thus considered to be an extensive coronary thrombosis. However, a large battery of blood tests failed to identify any procoagulant abnormality. Conclusion. Evidence is now accumulating that the increased thrombosis risk also may involve the coronary arteries, even in young patients. To the best of our knowledge this is the third reported case of myocardial infarction despite angiographically normal coronary arteries in a patient with active ulcerative colitis. The extent of affected myocardium was in this case exceptionally large

Non-invasive evaluation of ventricular refractoriness and its dispersion during ventricular fibrillation in patients with implantable cardioverter defibrillator

BACKGROUND: Local ventricular refractoriness and its dispersion during ventricular fibrillation (VF) have not been well evaluated, due to methodological difficulties. METHODS: In this study, a non-invasive method was used in evaluation of local ventricular refractoriness and its dispersion during induced VF in 11 patients with VF and/or polymorphic ventricular tachycardia (VT) who have implanted an implantable cardioverter defibrillator (ICD). Bipolar electrograms were simultaneously recorded from the lower oesophagus behind the posterior left ventricle (LV) via an oesophageal electrode and from the right ventricular (RV) apex via telemetry from the implanted ICD. VF intervals were used as an estimate of the ventricular effective refractory period (VERP). In 6 patients, VERP was also measured during sinus rhythm at the RV apex and outflow tract (RVOT) using conventional extra stimulus technique. RESULTS: Electrograms recorded from the RV apex and the lower esophagus behind the posterior LV manifested distinct differences of the local ventricular activities. The estimated VERPs during induced VF in the RV apex were significantly shorter than that measured during sinus rhythm using extra stimulus technique. The maximal dispersion of the estimated VERPs during induced VF between the RV apex and posterior LV was that of 10 percentile VF interval (40 ± 27 ms), that is markedly greater than the previously reported dispersion of ventricular repolarization without malignant ventricular arrhythmias (30–36 ms). CONCLUSIONS: This study verified the feasibility of recording local ventricular activities via oesophageal electrode and via telemetry from an implanted ICD and the usefulness of VF intervals obtained using this non-invasive technique in evaluation of the dispersion of refractoriness in patients with ICD implantation

Withdrawal of infliximab or concomitant immunosuppressant therapy in patients with Crohn's disease on combination therapy (SPARE): a multicentre, open-label, randomised controlled trial.

BACKGROUND: The combination of infliximab and immunosuppressant therapy is a standard management strategy for patients with Crohn's disease. Concerns regarding the implications of long-term combination therapy provided the rationale for a formal clinical trial of treatment de-escalation. Our aim was to compare the relapse rate and the time spent in remission over 2 years between patients continuing combination therapy and those stopping infliximab or immunosuppressant therapy. METHODS: This multicentre, open-label, randomised controlled trial was performed in 64 hospitals in seven countries in Europe and Australia. Adult patients with Crohn's disease in steroid-free clinical remission for more than 6 months, on combination therapy of infliximab and immunosuppressant therapy for at least 8 months were randomly assigned (1:1:1) to either continue combination therapy (combination group), discontinue infliximab (infliximab withdrawal group), or discontinue immunosuppressant therapy (immunosuppressant withdrawal group). Randomisation was stratified according to disease duration before start of first anti-TNF treatment (≤2 or >2 years), failure of immunosuppressant therapy before start of infliximab, and presence of ulcers at baseline endoscopy. The patient number and group of each stratum were assigned by a central online randomisation website. Treatment was optimised or resumed in case of relapse in all groups. Participants, those assessing outcomes, and those analysing the data were not masked to group assignment. The coprimary endpoints were the relapse rate (superiority analysis) and time in remission over 2 years (non-inferiority analysis, non-inferiority margin 35 days). Analyses were done on an intention-to-treat basis. This study is registered with ClinicalTrials.gov, NCT02177071, and with EU Clinical Trials Register, EUDRACT 2014-002311-41. The trial was completed in April, 2021. FINDINGS: Between Nov 2, 2015, and April 24, 2019, 254 patients were screened. Of these, 211 were randomised and 207 were included in the final analysis (n=67 in the combination group, n=71 in the infliximab withdrawal group, and n=69 in the immunosuppressant withdrawal group). 39 patients had a relapse (eight [12%] of 67 in the combination group, 25 [35%] of 71 in the infliximab withdrawal group, six [9%] of 69 in the immunosuppressant withdrawal group). 2-year relapse rates were 14% (95% CI 4-23) in the combination group, 36% (24-47) in the infliximab withdrawal group, and 10% (2-18) in the immunosuppressant withdrawal group (hazard ratio [HR] 3·45 [95% CI 1·56-7·69], p=0·003, for infliximab withdrawal vs combination, and 4·76 [1·92-11·11], p=0·0004, for infliximab withdrawal vs immunosuppressant withdrawal). Of 28 patients who had a relapse and were retreated or optimised according to protocol, remission was achieved in 25 patients (one of two in the combination group, 22 of 23 in the infliximab withdrawal group, and two of three in the immunosuppressant withdrawal group). The mean time spent in remission over 2 years was 698 days (95% CI 668-727) in the combination group, 684 days (651-717) in the infliximab withdrawal group, and 706 days (682-730) in the immunosuppressant withdrawal group. The difference in restricted mean survival time in remission was -14 days (95% CI -56 to 27) between the infliximab withdrawal group and the combination group and -22 days (-62 to 16) between the infliximab withdrawal group and the immunosuppressant withdrawal group. The 95% CIs contained the non-inferiority threshold (-35 days). We recorded 31 serious adverse events, in 20 patients, with no difference in frequency between groups. The most frequent serious adverse events were infections (four in the combination group, two in the infliximab withdrawal group, and one in the immunosuppressant withdrawal group) and Crohn's disease exacerbation (three in the combination group, four in the infliximab withdrawal group, and one in the immunosuppressant withdrawal group). No death nor malignancy was recorded. INTERPRETATION: In patients with Crohn's disease in sustained steroid-free remission under combination therapy with infliximab and immunosuppressant therapy, withdrawal of infliximab should only be considered after careful assessment of risks and benefits for each patient, whereas withdrawal of immunosuppressant therapy could generally represent a preferable strategy when considering treatment de-escalation. FUNDING: European Union's Horizon 2020

Alkaline Sphingomyelinase; A Potential Inhibitor in Colorectal Carcinogenesis

Sphingomyelin (SM) is present both in eucaryotic cells and the diet. Sphingomyelinase (SMase) hydrolyses SM and generates ceramide that has been implicated in the regulation of cell growth, differentiation and apoptosis. Previously a SMase with alkaline pH optimum was identified in the intestinal tract. The thesis studied the distribution pattern, the species difference and the clinical implications of this enzyme. Unlike neutral and acid SMase, which are present in most tissues, alkaline SMase is specifically located to the intestinal tract. The distribution pattern in human intestine was similar to other species such as rats, mice and hamsters, the highest values were demonstrated in the jejunum and lower in the colon. Man was the only species examined with an additional alkaline SMase in the bile. After giving SM orally to ileostomists, both SM and ceramide were accumulated in the stoma output indicating that the colonic mucosa is exposed to ceramide. When the activities of three SMases were determined in patients with human colorectal carcinoma (CRC), all SMases were reduced in cancer tissue compared to the surrounding mucosa, but the most predominant reduction being for alkaline SMase by (75%, p=0.004). Furthermore, the enzyme activity was markedly decreased by 90% (p<0.001) in adenoma tissue and in flat mucosa of patients with familial adenomatous polyposis compared to controls. These results suggested a potential link to APC mutations. However, when the activities of the enzyme were studied in the Min mouse (germline APC mutations) and human CRC tissue (Somatic APC mutations), no direct link was identified. Finally, we studied the effect of a purified rat intestinal alkaline SMase on growth in human HT-29 colon carcinoma cells and non-transformed rat intestinal IEC-6 cells. Alkaline SMase inhibited cell proliferation of HT-29 cells but not IEC-6 cells. In contrast, a bacterial neutral SMase had no effect. Alkaline SMase did not induce apoptosis. The antiproliferative effect was accompanied by SM hydrolysis and ceramide production. Alkaline SMase did not induce apoptosis whereas C2-ceramide and sulindac did. In conclusion, alkaline SMase is a gut specific enzyme with antiproliferative properties. The enzyme may be important in cell growth regulation and its reduction may facilitate the development of colorectal cancer

The cost-effectiveness of biological therapy cycles in the management of Crohn’s disease

Objectives: to examine the cost-effectiveness of continued treatment for patients with moderate-severe Crohn’s disease in clinical remission, with a combination of anti-TNFα (infliximab) and immunosuppressant therapy compared to two different withdrawal strategies (1) withdrawal of the anti-TNFα therapy, and (2) withdrawal of the immunosuppressant therapy, respectively. Material and methods: A decision-tree model (Markov type) was constructed mimicking three treatment arms: (1) continued combination therapy with infliximab and antimetabolites, (2) withdrawal of infliximab, or (3) withdrawal of the immunosuppressant. Relapses in each arm are managed with treatment intensification. State dependent relapse risks, remission probabilities and quality of life weights were collected from previous published studies. Results: Combination therapy was less costly and more efficient than the withdrawal of the immunosuppressant, and more costly and more efficient than withdrawal of infliximab. The incremental cost-effectiveness ratio for the combination therapy compared with withdrawal of infliximab was estimated at SEK 755 449 per additional QALY. This is well above the informal willingness-to-pay threshold in Sweden (500 000 SEK/QALY). The estimated cost-effectiveness of the combination therapy was found highly sensitive to the unit cost of infliximab; at a 36% lower unit cost of infliximab, the combination treatment would become cost-effective. The qualitative content of these results were quite robust to changes in the clinical effectiveness and the quality-of-life figures adopted in the calculations. The qualitative content of these results were quite robust to changes in the clinical effectiveness and quality-of-life values. Conclusions: Combination therapy using a combination of anti-TNFα (infliximab) and immunosuppressant is cost effective in the treatment of Crohn’s disease compared to treatment cycles in which the immunosuppressant is withdrawn. Combination treatment is not cost effective compared to treatment cycles in which infliximab is withdrawn, at current pharmaceutical prices.I

The Cost-effectiveness of Biological Therapy Cycles in the Management of Crohn's Disease

OBJECTIVES: To examine the cost-effectiveness of continued treatment for patients with moderate-severe Crohn's disease in clinical remission, with a combination of anti-tumour necrosis factor alpha [anti-TNFα] [infliximab] and immunomodulator therapy compared with two different withdrawal strategies: [1] withdrawal of the anti-TNFα therapy; and [2] withdrawal of the immunomodulator therapy, respectively. METHODS: A decision-tree model was constructed mimicking three treatment arms: [1] continued combination therapy with infliximab and immunomodulator; [2] withdrawal of infliximab; or [3] withdrawal of the immunomodulator. Relapses in each arm are managed with treatment intensification and re-institution of the de-escalated drug according to a prespecified algorithm. State-dependent relapse risks, remission probabilities, and quality of life weights were collected from previous published studies. RESULTS: Combination therapy was less costly and more efficient than the withdrawal of the immunomodulator, and more costly and more efficient than withdrawal of infliximab. Whether or not combination therapy is cost-effective, compared with the alternatives, depends primarily on current pharmaceutical prices and the willingness-to-pay per additional quality-adjusted life-year [QALY]. CONCLUSIONS: Combination therapy using a combination of anti-TNFα [infliximab] and an immunomodulator is cost-effective in the treatment of Crohn's disease compared with treatment cycles in which the immunomodulator is withdrawn. Combination treatment is cost-effective compared with treatment cycles in which infliximab is withdrawn, at prices of infliximab below€192/100 mg, given a willingness-to-pay threshold at€49 020 [Sweden] per additional QALY

The Expression of Glutathione Transferase μ in Patients with Inflammatory Bowel Disease

BACKGROUND: Glutathione transferases (GST) are a group of multifunctional enzymes important in the detoxification of many electrophiles and, in addition, fatty acid hydroperoxides, thus limiting tissue damage from oxidative free radical attack. Of the four classes of GST (alpha, mu, pi, and theta), a class mu isoenzyme, GST mu, is dominantly inherited and is expressed in approximately half of the population. GST mu expression was examined in patients with inflammatory bowel disease and correlated to clinical course, extension, and age of onset of the diseases. METHODS: GST mu can be measured as GST activity against trans-stilbene oxide. This GST activity was measured in whole blood in 179 patients with ulcerative colitis, 109 patients with Crohn's disease, and 449 age-matched controls. RESULTS: Frequencies of GST mu expression were as follows: controls (n = 449, 51.2%), mild ulcerative colitis (n = 76, 47.3%), moderate ulcerative colitis (n = 43, 46.5%), and severe ulcerative colitis (characterized by colectomy) (n = 60, 36.7%). This trend was, however, not significant (p = 0.094). Patients with onset of the colitis before the age of 30 years (n = 91) had a lower frequency of GST mu expression (35.2%) than patients with a later onset (n = 88, 52.3%) (p < 0.05). This difference was more pronounced among the colectomized patients (19.4% versus 55.2%) (p < 0.01). In Crohn's disease, patients with colitis had a lower frequency of GST mu expression (n = 29, 31.0%) than controls; however, this was not statistically significant (p = 0.055). No difference was found with regard to age of onset. CONCLUSION: We conclude that in patients with ulcerative colitis, lack of GST mu is related to early age of onset and a more severe clinical course leading to colectomy