Adjunct professor and Senior consultant in Gastroenterology and hepatology, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden
Thiopurines such as azathioprine, mercaptopurine and tioguanine are antimetabolites that have bee... more Thiopurines such as azathioprine, mercaptopurine and tioguanine are antimetabolites that have been used for several decades in the treatment of multiple diseases including inflammatory bowel diseases. Still many questions remain unanswered. Thiopurine metabolism is complex due to the involvement of multiple enzymes, of which the activities are genetically determined and cell type dependent. In addition, several methods of therapeutic drug monitoring have been developed in an attempt to relate drug availability of thiopurines with efficacy and intolerance. Some drug interactions may optimize metabolism of thiopurines and consequently increase its efficacy and decrease drug intolerance. This review focuses on pharmacology and drug monitoring of thiopurines and provides an overview of clinically and scientifically challenging topics concerning thiopurine therapy in IBD treatment. Topics discussed herein also include the topics that were discussed at the first meeting of the Thiopurine ...
et al. Discontinuation of infliximab therapy in patients with Crohn's disease in sustained comple... more et al. Discontinuation of infliximab therapy in patients with Crohn's disease in sustained complete remission (the STOP IT study): protocol for a double-blind, randomised, placebocontrolled, multicentre trial.
Chronic inflammatory bowel diseases, ulcerative colitis and Crohn's disease, are steadily increas... more Chronic inflammatory bowel diseases, ulcerative colitis and Crohn's disease, are steadily increasing in prevalence, and one half to one per cent of the Swedish population are currently estimated to be affected. The aetiology remains unknown, but is probably multifactorial. Both dietary, microbiological and immunological causes have been discussed. Clinical studies, including several Swedish studies, have also shown genetic factors to be crucially involved. Findings in sophisticated molecular biological studies suggest certain specific genes to be involved, and a current EU project in which Sweden is participating has been launched to map the mode of inheritance in detail.
Objective: To find out if concentrations of platelet activating factor (PAF), which has been prop... more Objective: To find out if concentrations of platelet activating factor (PAF), which has been proposed as a mediator in the pathogenesis of ulcerative colitis and Crohn's disease, are increased in the rectal mucosa of patients with ulcerative colitis. Design: Open study. Setting: University hospital, Sweden. Subjects: 45 Patients with ulcerative colitis (19 with active disease and 26 in remission), and 6 control patients and 11 healthy volunteers who acted as controls. Interventions: Rectal biopsy. Main outcome measure: PAF content of rectal biopsy specimens. Results: There were no differences between the PAF content of rectal mucosa in patients with active disease (median 47 pmol/g wet weight), patients in remission (47 pmol/g), and controls (51 pmol/g). There was no correlation between PAF content and inflammation seen endoscopically or histologically. 13 Patients who had active disease were investigated on a second occasion 9 weeks later (range 7-17), when in remission having received steroids but steroid-free at that time. There was a slight but not significant trend towards lower concentrations of PAF (median 33 pmol/g) compared with their previous results, possibly as a result of treatment. PAF concentrations were significantly lower than those of a group of patients in clinically stable remission of longer duration (p < 0.05). Conclusions: We did not find high concentrations of PAF in the rectal mucosa of patients with active ulcerative colitis compared with patients in remission or controls. We therefore have no evidence that PAF has an important role as a mediator in the inflammation of ulcerative colitis.
In inflammatory bowel disease, the use of various diagnostic techniques to visualise the extent a... more In inflammatory bowel disease, the use of various diagnostic techniques to visualise the extent and severity of inflammation is of vital importance at the onset of disease, in the event of subsequent relapse, and when complications are suspected. Medical treatment and surgery can thus be optimised and limited operations performed, especially in Crohn's disease. The article consists in a summary of published reports from a single centre, representing 10 years' experience of three new techniques for assessing inflammatory bowel disease. Leucocyte scintigraphy is a non-invasive and well-tolerated method whereby the small and large bowels are assessed on the same occasion, and complications such as abscesses and possibly fistulas can be visualised. Intraoperative enteroscopy yields more accurate information than previous methods for deciding the extent of small bowel resections, and often permitting gut to be saved. Air enema radiography is a convenient and safe means of obtaining reliable information about the presence and depth of ulceration in ulcerative colitis. These methods facilitate the care of patients with inflammatory bowel disease, and should be made available at centres where such patients are treated.
Retrograde colonic distribution of a new 4 g 5-aminosalicylic acid enema (mesalazine) was investi... more Retrograde colonic distribution of a new 4 g 5-aminosalicylic acid enema (mesalazine) was investigated in seven patients with ulcerative colitis, five of whom were in remission. The enema was labeled with 99m-technetium and imaged by a gamma camera. A median of 86 percent (range 57-90) of the enema had spread beyond the rectum during the first two hours after administration. In four of the five examined patients with left-sided ulcerative colitis, the diseased mucosa was covered within the first 4 hours. In the fifth patient, with involvement of the descending colon, the enema did not spread beyond the very tortuous sigmoid colon 4 or even 8 hours after enema administration.
Two cases of young patients with the chronic form of Budd-Chiari syndrome are reported. The first... more Two cases of young patients with the chronic form of Budd-Chiari syndrome are reported. The first concerns a 22-year-old woman with a 6-month history of hepatomegaly, who had used oral contraceptives almost continuously during the five years preceding diagnosis. In a thorough diagnostic work-up, thromboses were detected in all but one of the hepatic veins, and a possible non-occluding thrombosis in the retrohepatic portion of the inferior vena cava. In the blood and bone marrow, findings were compatible with polycythaemia rubra vera, and a high anti-cardiolipin antibody titre was found. The second case concerns a 25-year-old male smoker with normal bone marrow, who had thromboses in at least two of the hepatic veins, though the inferior vena cava was not occluded. In both cases a mesocaval shunt was interposed with synthetic grafts, and postoperatively the patients are doing well--at sixteen and five months, respectively. Both are maintained on anticoagulants, and even without diuretics there has been no recurrence of ascites. The woman takes a small dose of hydroxy-urea to control her hypercoagulability. To our knowledge, hers is the first case to be reported of Budd-Chiari syndrome with hypercoagulability due to the concomitant presence of oral contraceptives, polycythaemia rubra vera and anti-phospholipid antibodies.
Scandinavian Journal of Gastroenterology, Aug 20, 2021
Objectives: Clinical trials demonstrated that golimumab is effective in anti-TNF naïve patients w... more Objectives: Clinical trials demonstrated that golimumab is effective in anti-TNF naïve patients with ulcerative colitis. We aimed to assess the clinical effectiveness of golimumab in a real-world setting. Materials and methods: This was a prospective cohort study, conducted at 16 Swedish hospitals. Data were collected using an electronic case report form. Patients with active ulcerative colitis, defined as Mayo endoscopic subscore !2 were eligible for inclusion. The primary outcomes were clinical effectiveness at 12 weeks and 52 weeks, i.e. response (defined as a decrease in Mayo score by !3 points or 30% from baseline) and remission (defined as a Mayo score of 2 with no individual subscores >1). Results: Fifty patients were included. At study entry, 70% were previously exposed to anti-TNF, 16% to vedolizumab, and 96% to immunomodulators. The 12 and 52-week drug continuation rates were 37/50 (74%) and 23/50 (46%), respectively. The 12-week response rate was 14/50 (28%), the remission rate, 8/50 (16%) and the corresponding figures at week 52 were 13/50 (26%) and 10/50 (20%). Among patients who continued golimumab, the median Mayo score decreased from 7 (6-9) at baseline to 1 (0-5) at 52 weeks (p < .01) and the faecal calprotectin decreased from 862 (335-1759) mg/g to 90 (34-169) mg/g (p < .01). Clinical response at week 12 was highly predictive of clinical remission at week 52 (adjusted OR: 73.1; 95% CI: 4.5-1188.9). Conclusions: The majority of golimumab treated patients represented a treatment refractory patientgroup. Despite this, our results confirm that golimumab is an effective therapy in ulcerative colitis.
Objective: Health is a complex and multi-dimensional entity and is neither easily determined nor ... more Objective: Health is a complex and multi-dimensional entity and is neither easily determined nor easily conveyed to others. Publications have often combined various variables of disease activity and health-related quality of life (HRQoL), used the variables interchangeably or utilized summation indices to compare health assessment. The aim of this study is to investigate the relationship between measurements of disease activity and HRQoL. Study: design Cross-sectional evaluation of disease activity and HRQoL. Study population: Two hundred and eleven consecutive patients with ulcerative colitis. Setting: The catchment area of Linköping University Hospital. Measurements: HRQoL was measured using two questionnaires, the Sickness Impact Profile (SIP) and the Rating Form of IBD Patient Concerns (RFIPC). Patients were also asked if they were 'feeling fit and well', as a measurement of general health perception. Disease activity was measured by means of symptom cards, laboratory tests and sigmoidoscopy. Results: The correlations (Spearman's r (r5)) between variables of disease activity and HRQoL were low. 'Feeling fit and well' was best correlated to worries and concerns (the RFIPC, rs 0.32, P < 0.05), while there was a decreasing association with subjective functional status (the SIP, rs 0.31, P < 0.05), symptoms (stools per day, rs 0.15, not significant) and biological variables (endoscopy score, rs 0.04, not significant). Conclusion: The correlations between traditional measurements of disease activity and various measures of HRQoL are low. We therefore propose a system whereby the process is conceptualized using a 'network strategy', ordering the measurements of disease activity and HRQoL into five dimensions: biological variables, symptoms, functional status, worries and concerns, and health perceptions. We feel that this method of interpretation more accurately reflects the overall health of a group of patients with IBD than more traditional summation indices.
Bakgrund: Randomiserade kontrollerade provningar har visat effekt av golimumab vid ulceros kolit ... more Bakgrund: Randomiserade kontrollerade provningar har visat effekt av golimumab vid ulceros kolit men studiedeltagare och forhallanden i kliniska provningar motsvarar inte alltid svensk klinisk vard ...
Background and Aims: Innate lymphoid cells [ILC] have been suggested to play a role in inflammato... more Background and Aims: Innate lymphoid cells [ILC] have been suggested to play a role in inflammatory bowel disease [IBD]. Here, we investigated the ILC compartment in intestinal biopsies and blood from distinct patient groups with Crohn's disease [CD] and ulcerative colitis [UC], either newly diagnosed or with disease established for at least 1 year. This approach allowed us to simultaneously investigate temporal, disease-specific, and tissue-specific changes in ILC composition in IBD. Methods: ILC subset frequencies, phenotype, and transcription factor profile in blood and intestinal biopsies were investigated by multi-parameter flow cytometry analysis. Endoscopic disease severity was judged using the ulcerative colitis endoscopic index of severity and the simple endoscopic score for Crohn´s disease. Results: The frequency of NKp44 + ILC3 was decreased in inflamed tissue, both in patients with CD and those with UC, already at the time of diagnosis, and correlated with disease severity. Simultaneously, the frequency of ILC1 was increased in patients with CD, whereas the frequency of ILC2 was increased in patients with UC. However, in patients with established UC or CD, both ILC1 and ILC2 were increased. In contrast to the ILC composition in inflamed tissue, ILC in noninflamed tissue or blood were unchanged compared with non-IBD controls. Finally, in patients undergoing treatment with an anti-α 4 β 7 antibody the frequencies of ILC in peripheral blood remained unchanged. Conclusions: We report both shared and distinct changes in ILC composition depending on diagnosis and disease duration. The alterations in ILC composition in IBD occur selectively at inflamed sites in the gut.
Nucleosides, Nucleotides & Nucleic Acids, Jun 10, 2010
Thiopurine drugs are widely used as immunomodulatory and corticosteroid-sparing agents in inflamm... more Thiopurine drugs are widely used as immunomodulatory and corticosteroid-sparing agents in inflammatory bowel disease. Despite being old drugs, a renewed research and clinical interest in their application has emerged during the last decade. The application of pharmacogenetic insights and metabolic monitoring, together with treatment strategies in combination with anti-TNFα-antibodies and possibilities to modulate their metabolism, has paved the way to a "modern" use of the thiopurines. These aspects are briefly overviewed herein.
Thiopurines such as azathioprine, mercaptopurine and tioguanine are antimetabolites that have bee... more Thiopurines such as azathioprine, mercaptopurine and tioguanine are antimetabolites that have been used for several decades in the treatment of multiple diseases including inflammatory bowel diseases. Still many questions remain unanswered. Thiopurine metabolism is complex due to the involvement of multiple enzymes, of which the activities are genetically determined and cell type dependent. In addition, several methods of therapeutic drug monitoring have been developed in an attempt to relate drug availability of thiopurines with efficacy and intolerance. Some drug interactions may optimize metabolism of thiopurines and consequently increase its efficacy and decrease drug intolerance. This review focuses on pharmacology and drug monitoring of thiopurines and provides an overview of clinically and scientifically challenging topics concerning thiopurine therapy in IBD treatment. Topics discussed herein also include the topics that were discussed at the first meeting of the Thiopurine ...
et al. Discontinuation of infliximab therapy in patients with Crohn's disease in sustained comple... more et al. Discontinuation of infliximab therapy in patients with Crohn's disease in sustained complete remission (the STOP IT study): protocol for a double-blind, randomised, placebocontrolled, multicentre trial.
Chronic inflammatory bowel diseases, ulcerative colitis and Crohn's disease, are steadily increas... more Chronic inflammatory bowel diseases, ulcerative colitis and Crohn's disease, are steadily increasing in prevalence, and one half to one per cent of the Swedish population are currently estimated to be affected. The aetiology remains unknown, but is probably multifactorial. Both dietary, microbiological and immunological causes have been discussed. Clinical studies, including several Swedish studies, have also shown genetic factors to be crucially involved. Findings in sophisticated molecular biological studies suggest certain specific genes to be involved, and a current EU project in which Sweden is participating has been launched to map the mode of inheritance in detail.
Objective: To find out if concentrations of platelet activating factor (PAF), which has been prop... more Objective: To find out if concentrations of platelet activating factor (PAF), which has been proposed as a mediator in the pathogenesis of ulcerative colitis and Crohn's disease, are increased in the rectal mucosa of patients with ulcerative colitis. Design: Open study. Setting: University hospital, Sweden. Subjects: 45 Patients with ulcerative colitis (19 with active disease and 26 in remission), and 6 control patients and 11 healthy volunteers who acted as controls. Interventions: Rectal biopsy. Main outcome measure: PAF content of rectal biopsy specimens. Results: There were no differences between the PAF content of rectal mucosa in patients with active disease (median 47 pmol/g wet weight), patients in remission (47 pmol/g), and controls (51 pmol/g). There was no correlation between PAF content and inflammation seen endoscopically or histologically. 13 Patients who had active disease were investigated on a second occasion 9 weeks later (range 7-17), when in remission having received steroids but steroid-free at that time. There was a slight but not significant trend towards lower concentrations of PAF (median 33 pmol/g) compared with their previous results, possibly as a result of treatment. PAF concentrations were significantly lower than those of a group of patients in clinically stable remission of longer duration (p < 0.05). Conclusions: We did not find high concentrations of PAF in the rectal mucosa of patients with active ulcerative colitis compared with patients in remission or controls. We therefore have no evidence that PAF has an important role as a mediator in the inflammation of ulcerative colitis.
In inflammatory bowel disease, the use of various diagnostic techniques to visualise the extent a... more In inflammatory bowel disease, the use of various diagnostic techniques to visualise the extent and severity of inflammation is of vital importance at the onset of disease, in the event of subsequent relapse, and when complications are suspected. Medical treatment and surgery can thus be optimised and limited operations performed, especially in Crohn's disease. The article consists in a summary of published reports from a single centre, representing 10 years' experience of three new techniques for assessing inflammatory bowel disease. Leucocyte scintigraphy is a non-invasive and well-tolerated method whereby the small and large bowels are assessed on the same occasion, and complications such as abscesses and possibly fistulas can be visualised. Intraoperative enteroscopy yields more accurate information than previous methods for deciding the extent of small bowel resections, and often permitting gut to be saved. Air enema radiography is a convenient and safe means of obtaining reliable information about the presence and depth of ulceration in ulcerative colitis. These methods facilitate the care of patients with inflammatory bowel disease, and should be made available at centres where such patients are treated.
Retrograde colonic distribution of a new 4 g 5-aminosalicylic acid enema (mesalazine) was investi... more Retrograde colonic distribution of a new 4 g 5-aminosalicylic acid enema (mesalazine) was investigated in seven patients with ulcerative colitis, five of whom were in remission. The enema was labeled with 99m-technetium and imaged by a gamma camera. A median of 86 percent (range 57-90) of the enema had spread beyond the rectum during the first two hours after administration. In four of the five examined patients with left-sided ulcerative colitis, the diseased mucosa was covered within the first 4 hours. In the fifth patient, with involvement of the descending colon, the enema did not spread beyond the very tortuous sigmoid colon 4 or even 8 hours after enema administration.
Two cases of young patients with the chronic form of Budd-Chiari syndrome are reported. The first... more Two cases of young patients with the chronic form of Budd-Chiari syndrome are reported. The first concerns a 22-year-old woman with a 6-month history of hepatomegaly, who had used oral contraceptives almost continuously during the five years preceding diagnosis. In a thorough diagnostic work-up, thromboses were detected in all but one of the hepatic veins, and a possible non-occluding thrombosis in the retrohepatic portion of the inferior vena cava. In the blood and bone marrow, findings were compatible with polycythaemia rubra vera, and a high anti-cardiolipin antibody titre was found. The second case concerns a 25-year-old male smoker with normal bone marrow, who had thromboses in at least two of the hepatic veins, though the inferior vena cava was not occluded. In both cases a mesocaval shunt was interposed with synthetic grafts, and postoperatively the patients are doing well--at sixteen and five months, respectively. Both are maintained on anticoagulants, and even without diuretics there has been no recurrence of ascites. The woman takes a small dose of hydroxy-urea to control her hypercoagulability. To our knowledge, hers is the first case to be reported of Budd-Chiari syndrome with hypercoagulability due to the concomitant presence of oral contraceptives, polycythaemia rubra vera and anti-phospholipid antibodies.
Scandinavian Journal of Gastroenterology, Aug 20, 2021
Objectives: Clinical trials demonstrated that golimumab is effective in anti-TNF naïve patients w... more Objectives: Clinical trials demonstrated that golimumab is effective in anti-TNF naïve patients with ulcerative colitis. We aimed to assess the clinical effectiveness of golimumab in a real-world setting. Materials and methods: This was a prospective cohort study, conducted at 16 Swedish hospitals. Data were collected using an electronic case report form. Patients with active ulcerative colitis, defined as Mayo endoscopic subscore !2 were eligible for inclusion. The primary outcomes were clinical effectiveness at 12 weeks and 52 weeks, i.e. response (defined as a decrease in Mayo score by !3 points or 30% from baseline) and remission (defined as a Mayo score of 2 with no individual subscores >1). Results: Fifty patients were included. At study entry, 70% were previously exposed to anti-TNF, 16% to vedolizumab, and 96% to immunomodulators. The 12 and 52-week drug continuation rates were 37/50 (74%) and 23/50 (46%), respectively. The 12-week response rate was 14/50 (28%), the remission rate, 8/50 (16%) and the corresponding figures at week 52 were 13/50 (26%) and 10/50 (20%). Among patients who continued golimumab, the median Mayo score decreased from 7 (6-9) at baseline to 1 (0-5) at 52 weeks (p < .01) and the faecal calprotectin decreased from 862 (335-1759) mg/g to 90 (34-169) mg/g (p < .01). Clinical response at week 12 was highly predictive of clinical remission at week 52 (adjusted OR: 73.1; 95% CI: 4.5-1188.9). Conclusions: The majority of golimumab treated patients represented a treatment refractory patientgroup. Despite this, our results confirm that golimumab is an effective therapy in ulcerative colitis.
Objective: Health is a complex and multi-dimensional entity and is neither easily determined nor ... more Objective: Health is a complex and multi-dimensional entity and is neither easily determined nor easily conveyed to others. Publications have often combined various variables of disease activity and health-related quality of life (HRQoL), used the variables interchangeably or utilized summation indices to compare health assessment. The aim of this study is to investigate the relationship between measurements of disease activity and HRQoL. Study: design Cross-sectional evaluation of disease activity and HRQoL. Study population: Two hundred and eleven consecutive patients with ulcerative colitis. Setting: The catchment area of Linköping University Hospital. Measurements: HRQoL was measured using two questionnaires, the Sickness Impact Profile (SIP) and the Rating Form of IBD Patient Concerns (RFIPC). Patients were also asked if they were 'feeling fit and well', as a measurement of general health perception. Disease activity was measured by means of symptom cards, laboratory tests and sigmoidoscopy. Results: The correlations (Spearman's r (r5)) between variables of disease activity and HRQoL were low. 'Feeling fit and well' was best correlated to worries and concerns (the RFIPC, rs 0.32, P < 0.05), while there was a decreasing association with subjective functional status (the SIP, rs 0.31, P < 0.05), symptoms (stools per day, rs 0.15, not significant) and biological variables (endoscopy score, rs 0.04, not significant). Conclusion: The correlations between traditional measurements of disease activity and various measures of HRQoL are low. We therefore propose a system whereby the process is conceptualized using a 'network strategy', ordering the measurements of disease activity and HRQoL into five dimensions: biological variables, symptoms, functional status, worries and concerns, and health perceptions. We feel that this method of interpretation more accurately reflects the overall health of a group of patients with IBD than more traditional summation indices.
Bakgrund: Randomiserade kontrollerade provningar har visat effekt av golimumab vid ulceros kolit ... more Bakgrund: Randomiserade kontrollerade provningar har visat effekt av golimumab vid ulceros kolit men studiedeltagare och forhallanden i kliniska provningar motsvarar inte alltid svensk klinisk vard ...
Background and Aims: Innate lymphoid cells [ILC] have been suggested to play a role in inflammato... more Background and Aims: Innate lymphoid cells [ILC] have been suggested to play a role in inflammatory bowel disease [IBD]. Here, we investigated the ILC compartment in intestinal biopsies and blood from distinct patient groups with Crohn's disease [CD] and ulcerative colitis [UC], either newly diagnosed or with disease established for at least 1 year. This approach allowed us to simultaneously investigate temporal, disease-specific, and tissue-specific changes in ILC composition in IBD. Methods: ILC subset frequencies, phenotype, and transcription factor profile in blood and intestinal biopsies were investigated by multi-parameter flow cytometry analysis. Endoscopic disease severity was judged using the ulcerative colitis endoscopic index of severity and the simple endoscopic score for Crohn´s disease. Results: The frequency of NKp44 + ILC3 was decreased in inflamed tissue, both in patients with CD and those with UC, already at the time of diagnosis, and correlated with disease severity. Simultaneously, the frequency of ILC1 was increased in patients with CD, whereas the frequency of ILC2 was increased in patients with UC. However, in patients with established UC or CD, both ILC1 and ILC2 were increased. In contrast to the ILC composition in inflamed tissue, ILC in noninflamed tissue or blood were unchanged compared with non-IBD controls. Finally, in patients undergoing treatment with an anti-α 4 β 7 antibody the frequencies of ILC in peripheral blood remained unchanged. Conclusions: We report both shared and distinct changes in ILC composition depending on diagnosis and disease duration. The alterations in ILC composition in IBD occur selectively at inflamed sites in the gut.
Nucleosides, Nucleotides & Nucleic Acids, Jun 10, 2010
Thiopurine drugs are widely used as immunomodulatory and corticosteroid-sparing agents in inflamm... more Thiopurine drugs are widely used as immunomodulatory and corticosteroid-sparing agents in inflammatory bowel disease. Despite being old drugs, a renewed research and clinical interest in their application has emerged during the last decade. The application of pharmacogenetic insights and metabolic monitoring, together with treatment strategies in combination with anti-TNFα-antibodies and possibilities to modulate their metabolism, has paved the way to a "modern" use of the thiopurines. These aspects are briefly overviewed herein.
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