Curt Tysk | Örebro University (original) (raw)

Papers by Curt Tysk

European Journal of Clinical Investigation, 1997

The production of nitric oxide (NO) is increased in active ulcerative colitis and in Crohn&#3... more The production of nitric oxide (NO) is increased in active ulcerative colitis and in Crohn's disease. We have studied NO production in collagenous colitis (CC) and lymphocytic colitis (LC), both of which are inflammatory bowel disorders of unknown aetiology. NO levels were measured directly in gas sampled from the colon during colonoscopy. Plasma levels of NO metabolites (nitrate/nitrite) were also measured. Luminal NO levels were more than 100 times higher in patients with CC compared with controls. In addition, plasma levels of nitrate/nitrite were increased in the patients as compared with controls. Measurements of NO directly in the colon or its oxidation products in plasma may be a helpful tool in further understanding the role of NO in the pathophysiology of CC and LC. Moreover, it is tempting to speculate that these measurements could be clinically useful in the diagnosis and therapy monitoring of these two inflammatory bowel diseases.

European Journal of Human Genetics, 1999

Crohn's disease (CD) is a complex genetic disorder for which a susceptibility gene, IBD1, has bee... more Crohn's disease (CD) is a complex genetic disorder for which a susceptibility gene, IBD1, has been mapped within the pericentromeric region of chromosome 16. In order to refine the location of IBD1, 77 multiplex CD families were genotyped for 26 microsatellite markers evenly spaced by approximately 1 cM. Nonparametric linkage analyses exhibited a maximum NPL score of 3.49 (P=2.37610 74 ) in a region centred by markers D16S3136, D16S3117 and D16S770. Simulation studies showed that the probability for IBD1 to be located in a 5 cM region around these markers was 70%. A 2.5 Mb YAC and BAC contig map spanning this genetic region on chromosome band 16q12 was built. TDT analyses demonstrated suggestive association between the 207 bp allele of D16S3136 (P50.05) and a new biallellic marker hb27g11f-end (P=0.01). These markers were located in the hb27g11 and hb87b10 BAC clones from the contig. Taken together, the present results provide a crucial preliminary step before an exhaustive linkage disequilibrium mapping of putatively transcribed regions to identify IBD1. European Journal of Human Genetics (2001) 9, 731 ± 742.

European Journal of Human Genetics, 2003

Crohn's disease (CD) is a complex genetic disorder for which aetiology is unknown. Recently, gene... more Crohn's disease (CD) is a complex genetic disorder for which aetiology is unknown. Recently, genetic factors for susceptibility have been described. Several genetic loci have been mapped and partially explain the familial aggregations of the disease. However, environmental factors may also contribute to these aggregations. We considered that if the role of non-genetic factors was negligible, CD patients would be randomly distributed in sibships with multiple affected siblings. On the other hand if there was a significant environmental contribution, the siblings would be affected non-randomly over exposure status. In order to test this hypothesis, we studied 102 sibships with two or more affected siblings. A statistical test, named Cluster of Affected Sibling Test or CAST, was developed, based on the exact calculation of the probability of observing a given number of clusters of affected siblings in multiplex families. The null hypothesis of a random distribution of affected siblings was rejected (P=0,005). The observed excess of affected sibling clusters indicates that birth order influences the disease status. Considering that an adjacent order of birth is a global estimate of environmental sharing, this observation strongly suggests that environmental factors contribute to the observed familial aggregations of the disease. This observation provides evidence that familial CD is a relevant tool for further studies of environmental factors and gene-environment interaction. More generally, the CAST statistics may be widely applicable to estimate the involvement of environmental factors in the aetiology of other binary traits which may be observed in multiple members of the same sibship.

Journal of Pediatric Gastroenterology & Nutrition, 1999

Sv Lakaresallskapets Handl Hygiea, 2005

Lakartidningen, 2009

... Fortsatta studier krävs dock för att fastställa den bästa rescue-behandlingen vid svårt skov ... more ... Fortsatta studier krävs dock för att fastställa den bästa rescue-behandlingen vid svårt skov av steroidrefraktär ulcerös kolit och den ... eller jävsförhållanden: Curt Tysk har fått föreläsararvode från Astra-Zeneca och Schering-Plough, Ragnar Befrits och Stefan Lindgren har fått ...

Gastroenterology, Jan 5, 1991

The American journal of gastroenterology, 2009

Inflammatory bowel disease (IBD), e.g., Crohn's disease (CD) and ulcerative colitis (UC), is ... more Inflammatory bowel disease (IBD), e.g., Crohn's disease (CD) and ulcerative colitis (UC), is a complex genetic disorder. Tumor necrosis factor (ligand) superfamily, member 15 (TNFSF15) has been previously identified as a susceptibility gene for CD in Japanese and UK cohorts. This replication study was designed in order to confirm and further validate the role of TNFSF15 in IBD. A total of 666 IBD families (corresponding to 2,982 relatives) with European ancestry were genotyped for the rs6478108 and rs7869487 polymorphisms, which define the main TNFSF15 haplotypes previously associated with CD. An association between the main haplotypes and CD, UC and IBD was tested using the Genehunter TDT and Unphased statistics. Caspase recruitment domain 15 (CARD15)/TNFSF15 interaction and genotype/phenotype correlations were also studied. The previously reported "high-risk" haplotype (A) was associated with IBD (P=0.001) (OR=1.25 (1.05-1.50)) and CD (P=0.02) (OR=1.31 (1.03-1.67)) w...

Baillière's Clinical Gastroenterology, 1998

Active Crohn's disease constitutes a major problem in gastroenterology. Symptoms vary with site, ... more Active Crohn's disease constitutes a major problem in gastroenterology. Symptoms vary with site, extent and local complications of the disease as well as with the absence or presence of extraintestinal manifestations. Due to the troublesome consequences of the disease new treatments have continuously been tried. However, the results have varied and no definite breakthrough has occurred in the medical treatment of active Crohn's disease during the last years. The new salicylates have shown some effect using higher doses, but have not fulfilled the expectations once connected with their development. The new steroids have compared well to, but not exceeded, the older corticosteroid preparations in terms of therapeutic efficacy but they have a better side-effect profile. The role of the purine analogs azathioprine/6-mercaptopurine has been further evaluated. The onset of their effect is slow, an intravenous loading dose might shorten this time span, and they are steroid sparing. The controlled data on methotrexate are limited and the long-term effects not well studied and there is concern about toxicity. Even the use of cyclosporine in active Crohn's disease is controversial and connected with serious adverse events. Studies on the new immune modulating therapies such as anti-TNF-cx antibodies, anti-CD4 antibodies, interleukin-10 and interferon have been encouraging but large scale studies are still awaited before the effect and the spectra of side-effects can be fully evaluated.

Journal of Crohn's and Colitis Supplements, 2008

Introduction: Fistulas belong to the most frequent complications in Crohn' s disease. In patients... more Introduction: Fistulas belong to the most frequent complications in Crohn' s disease. In patients suffering from fistulizing Crohn' s disease we often observed the presence of concomitant stenoses or significant luminal narrowing in the small or large bowel, suggesting a causal relation. By analyzing retrospective data of patients with fistulas from our IBD center cohort we searched for a concomitant presence of stenoses or luminal narrowing. Methods: We screened the medical records of all patients who presented with Crohn' s disease at our IBD-center since 1998. Patients having presented with fistulizing disease were selected for analysis, if the presence of fistulas was confirmed or diagnosed by physical examination, magnetic resonance (MR), or ileocolonoscopy. Furthermore, data on the status of the small and large bowel lumen were collected if ileocolonoscopy, MR enteroclysis technique, or surgery was performed within 6 months before or after the description of the fistulas. Significant luminal bowel narrowing was defined as stenosis, failure to pass the endoscope over the narrowed segment, or a reduction of the luminal diameter of more than 10mm over a length of more than 3 cm. Results: Among 771 patients since 1998 with Crohn' s disease at our IBDcenter at the University of Munich, 134 patients presented with fistulas. So far, 94 of the 134 patients with one or more fistulas could be analyzed retrospectively. Aside from perianal fistulas (n=41; 38.0%), entero-enteral (n=44; 40.7%), entero-cutaneous (n=12; 11.1%), entero-vesical (n=5; 4.6%) and entero-vaginal fistulas (n=6; 5.6%) were described. Signs of coexisting significant luminal bowel narrowing were described in 87 (92.6%) patients with fistulas. 35 of 41 patients with perianal fistulas had a significant luminal narrowing. Interestingly; of these 35 patients, 14 had a stenosis in the terminal ileum as the only sign of luminal narrowing (37.1%), and in none of these patients a fistula track could be followed back to the terminal ileum. Conclusion: The fact that in patients with Crohn' s disease and fistulas, in more then 90% significant luminal bowel narrowing was found suggests a causal relation. Since some stenoses were found without any spatial contact to the fistulas, an increased intraluminal pressure at the site of the narrowed segment together with an impaired barrier function may favour the formation of fistulas by fluid flux through the bowel wall. If prospective studies in patients presenting with newly found fistula confirm this correlation, future fistula therapies have to be directed more towards the stenoses and not primarily to the fistulas.

Journal of Crohn's and Colitis Supplements, 2009

8. Baron JA, Senn S, Voelker M, et al. Gastrointestinal adverse effects of short-term aspirin use... more 8. Baron JA, Senn S, Voelker M, et al. Gastrointestinal adverse effects of short-term aspirin use: a meta-analysis of published randomized controlled trials. Drugs R D 2013; 13: 9-16. 9. Pareek A, Chandukar N. Comparison of gastrointestinal safety and tolerability of aceclofenac with diclofenac: a multicenter, randomized, double-blind study in patients with knee osteoarthritis. Curr Med Res Opin 2013; 29: 849-59. 10. Matheson AJ, Jarvis B. Lansoprazole: an update of its place in the management of acid-related disorders.

The American Journal of Gastroenterology, 2007

OBJECTIVES: Corticosteroids are a cornerstone in the treatment of a severe attack of ulcerative c... more OBJECTIVES: Corticosteroids are a cornerstone in the treatment of a severe attack of ulcerative colitis (UC). The long-term prognosis in this patient group is not well described. We studied the long-term colectomy and relapse rates in patients given intensive intravenous corticosteroid treatment (IIVT) for acute UC.

Scandinavian Journal of Gastroenterology, 2007

Adult-type hypolactasia (AtH) can be diagnosed by genotyping in addition to functional tests or i... more Adult-type hypolactasia (AtH) can be diagnosed by genotyping in addition to functional tests or intestinal biopsy. The aims of this study were to estimate the prevalence of AtH by genotyping and to investigate whether AtH prevalence has changed in Sweden during the 20th century. Schoolchildren (n=690) born in 1983 and 1989, and elderly individuals (n=392) born between 1920 and 1932 were genotyped for AtH using Pyrosequencing technology. The overall prevalence of AtH among children was 14.1%. The majority of children (92%, n=635) were Caucasians with genotype prevalences: CC, 61 (10%); CT, 259 (41%); TT, 307 (49%). The frequency of the mutated allele q was 0.300 in this cohort. The prevalence of AtH estimated from the Hardy-Weinberg equilibrium (HWE) (q 2), was 9.0% (95% CI: 6.7-11.2%). Eight percent (n=55) of the children were non-Caucasian; genotype prevalences were CC, 36 (66%); CT, 15 (27%); TT, 4 (7%). The prevalence of AtH in these children estimated from HWE was 62.5% (95% CI: 49.7-75.3%). The elderly subjects were all Caucasians. Their genotype prevalences were: CC, 20 (5%); CT, 166 (42%); TT, 206 (53%); the frequency of the mutated allele q was 0.262 and their AtH prevalence estimated from HWE was 6.8% (95% CI: 4.3-9.2%). The overall prevalence of AtH in children (14%) was higher than previously thought. Among Caucasians, higher figures were seen in children than in the elderly (9% versus 6.8%). The prevalence thus seems to be increasing and this may be due to the immigration of both non-Caucasian and Caucasian groups with a higher prevalence of AtH.

Scandinavian Journal of Gastroenterology, 2006

Assessment of health-related quality of life (HRQOL) is important in both clinical practice and c... more Assessment of health-related quality of life (HRQOL) is important in both clinical practice and clinical trials, and several multi-item questionnaires are currently in use. We have devised and evaluated a simplified four-item questionnaire, the Short Health Scale (SHS), representing each of four health dimensions: (a) symptom burden, (b) social function, (c) disease-related worry and (d) general well-being. Three hundred patients with ulcerative colitis completed the SHS and three other HRQOL questionnaires (IBDQ, RFIPC and PGWB). Half of the patients repeated the questionnaires after 6 months - or earlier if disease activity changed. Test-retest reliability was derived from measurements of the SHS questions, 2 weeks apart, on 18 patients in remission. Patients in relapse scored higher on each of the four SHS questions than patients in remission (p < 0.001). Each of the four SHS scores were associated with results of their corresponding health dimension obtained with the other three questionnaires (rs=0.57-0.78, p < 0.001) (validity). The results of the SHS proved stable on repeated measurement with a 2-week interval in patients in remission (rs=0.71-0.91, p < 0.01) (test-retest reliability). Patients with a change in disease activity had a significant change in their SHS scores (p < 0.05) (responsiveness). The SHS is a valid, reliable and responsive measure of subjective health in patients with ulcerative colitis. It is simple to administer, quickly completed and the results do not need further calculations. The SHS can be used in clinical trials and in clinical practice to identify the patient's main problems affecting health.

Scandinavian Journal of Gastroenterology, 2007

Selective leukocyte apheresis is a new type of non-pharmacological treatment for patients with ac... more Selective leukocyte apheresis is a new type of non-pharmacological treatment for patients with active ulcerative colitis and Crohn's disease. Preliminary data have indicated that this type of therapy is safe and efficacious, and large sham-controlled studies are currently in progress. In Scandinavia, a substantial number of patients with chronic inflammatory bowel disease have already received leukocyte apheresis on a compassionate use basis and the aim of this study was to report the clinical outcome and adverse events in the first patients treated. Clinical details of the first consecutive 100 patients with inflammatory bowel disease treated with granulocyte, monocyte/macrophage (Adacolumn) apheresis in Scandinavia were prospectively registered. Median length of follow-up was 17 months, (range 5-30). The study population comprised 52 patients with ulcerative colitis, 44 patients with Crohn's disease and 4 patients with indeterminate colitis. In 97 patients the indication for Adacolumn treatment was steroid-refractory or steroid-dependent disease. Clinical remission was attained in 48% of the patients with ulcerative colitis, and an additional 27% had a clinical response to the apheresis treatment. The corresponding figures for patients with Crohn's disease were 41% and 23%, respectively. Complete steroid withdrawal was achieved in 27 out of the 50 patients taking corticosteroids at baseline. Adverse events were reported in 15 patients and headache was most frequently reported (n=7). Granulocyte, monocyte/macrophage apheresis treatment seems to be a valuable adjuvant therapy in selected patients with refractory inflammatory bowel disease. The risk for toxicity or severe adverse events appears to be low.

Scandinavian Journal of Gastroenterology, 2010

Disease-related worries constitute an important dimension of patient-reported perception of healt... more Disease-related worries constitute an important dimension of patient-reported perception of health status in inflammatory bowel disease (IBD). The Rating Form of IBD Patient Concerns (RFIPC) questionnaire is purported to measure IBD-related worries. This study evaluated the psychometric properties of a Swedish translation of RFIPC in an unselected population of Crohn's disease (CD) patients. The degree and nature of the worries were characterized and predictive factors for outcome of RFIPC and underlying dimensions were identified. The RFIPC was completed by 447 CD patients in conjunction with regular visits. A physician global assessment of disease activity and four other health-related quality of life (HRQL) questionnaires were used for construct validity. Reliability and responsiveness were evaluated with follow-up visits. Underlying dimension and predictive factors were identified with factor analysis and multiple linear regression analysis. Test-retest reliability was 0.90, correlation with corresponding HRQL measures 0.60-0.80 and responsiveness ratio 0.84. Median RFIPC sum score was lower than in previous studies. Top three concerns were ostomy, energy level and bowel control. Four dimensions were identified in descending order of concern: disease-related complications, daily-life achievements, intimacy, and stigmatization. Predictors of RFIPC score were disease activity, gender, and BMI (p < 0.001-0.008). The Swedish version of RFIPC exhibited an adequate psychometric performance in CD patients, but was less sensitive to change in disease activity. The patients were more concerned about complications and achievement than intimacy and stigmatization. The strongest predictors of more worry were active disease, female gender and higher BMI.

New England Journal of Medicine, 2001

A history of appendectomy is rare in patients with ulcerative colitis. This suggests a protective... more A history of appendectomy is rare in patients with ulcerative colitis. This suggests a protective effect of appendectomy or that appendicitis and ulcerative colitis are alternative inflammatory responses. We sought to characterize this inverse relation further. We studied a cohort of 212,963 patients who underwent appendectomy before the age of 50 years between 1964 and 1993 and a cohort of matched controls who were identified from the Swedish Inpatient Register and the nationwide census. The cohort was followed until 1995 for any subsequent diagnosis of ulcerative colitis. Patients who underwent appendectomy for appendicitis and mesenteric lymphadenitis had a low risk of ulcerative colitis (for patients with perforated appendicitis, the adjusted hazard ratio was 0.58 [95 percent confidence interval, 0.38 to 0.87]; for those with nonperforated appendicitis it was 0.76 [95 percent confidence interval, 0.65 to 0.90]; and for those with mesenteric lymphadenitis it was 0.57 [95 percent confidence interval, 0.36 to 0.89]). In contrast, patients who underwent appendectomy for nonspecific abdominal pain had the same risk of ulcerative colitis as the controls (adjusted hazard ratio, 1.06; 95 percent confidence interval, 0.74 to 1.52). For the patients who had appendicitis, an inverse relation with the risk of ulcerative colitis was found only for those who underwent surgery before the age of 20 years (P<0.001). Appendectomy for an inflammatory condition (appendicitis or lymphadenitis) but not for nonspecific abdominal pain is associated with a low risk of subsequent ulcerative colitis. This inverse relation is limited to patients who undergo surgery before the age of 20 years.

Nature Genetics, 2011

Genome-wide association studies (GWAS) have identified dozens of risk loci for many complex disor... more Genome-wide association studies (GWAS) have identified dozens of risk loci for many complex disorders, including Crohn's disease 1,2 . However, common disease-associated SNPs explain at most ~20% of the genetic variance for Crohn's disease. Several factors may account for this unexplained heritability 3-5 , including rare risk variants not adequately tagged thus far in GWAS 6-8 . That rare susceptibility variants indeed contribute to variation in multifactorial phenotypes has been demonstrated for colorectal cancer 9 , plasma high-density lipoprotein cholesterol levels 10 , blood pressure 11 , type 1 diabetes 12 , hypertriglyceridemia 13 and, in the case of Crohn's disease, for NOD2 (refs. 14,15). Here we describe the use of high-throughput resequencing of DNA pools to search for rare coding variants influencing susceptibility to Crohn's disease in 63 GWAS-identified positional candidate genes. We identify low frequency coding variants conferring protection against inflammatory bowel disease in IL23R, but we conclude that rare coding variants in positional candidates do not make a large contribution to inherited predisposition to Crohn's disease.

European Journal of Clinical Investigation, 1997

The production of nitric oxide (NO) is increased in active ulcerative colitis and in Crohn&#3... more The production of nitric oxide (NO) is increased in active ulcerative colitis and in Crohn's disease. We have studied NO production in collagenous colitis (CC) and lymphocytic colitis (LC), both of which are inflammatory bowel disorders of unknown aetiology. NO levels were measured directly in gas sampled from the colon during colonoscopy. Plasma levels of NO metabolites (nitrate/nitrite) were also measured. Luminal NO levels were more than 100 times higher in patients with CC compared with controls. In addition, plasma levels of nitrate/nitrite were increased in the patients as compared with controls. Measurements of NO directly in the colon or its oxidation products in plasma may be a helpful tool in further understanding the role of NO in the pathophysiology of CC and LC. Moreover, it is tempting to speculate that these measurements could be clinically useful in the diagnosis and therapy monitoring of these two inflammatory bowel diseases.

European Journal of Human Genetics, 1999

Crohn's disease (CD) is a complex genetic disorder for which a susceptibility gene, IBD1, has bee... more Crohn's disease (CD) is a complex genetic disorder for which a susceptibility gene, IBD1, has been mapped within the pericentromeric region of chromosome 16. In order to refine the location of IBD1, 77 multiplex CD families were genotyped for 26 microsatellite markers evenly spaced by approximately 1 cM. Nonparametric linkage analyses exhibited a maximum NPL score of 3.49 (P=2.37610 74 ) in a region centred by markers D16S3136, D16S3117 and D16S770. Simulation studies showed that the probability for IBD1 to be located in a 5 cM region around these markers was 70%. A 2.5 Mb YAC and BAC contig map spanning this genetic region on chromosome band 16q12 was built. TDT analyses demonstrated suggestive association between the 207 bp allele of D16S3136 (P50.05) and a new biallellic marker hb27g11f-end (P=0.01). These markers were located in the hb27g11 and hb87b10 BAC clones from the contig. Taken together, the present results provide a crucial preliminary step before an exhaustive linkage disequilibrium mapping of putatively transcribed regions to identify IBD1. European Journal of Human Genetics (2001) 9, 731 ± 742.

European Journal of Human Genetics, 2003

Crohn's disease (CD) is a complex genetic disorder for which aetiology is unknown. Recently, gene... more Crohn's disease (CD) is a complex genetic disorder for which aetiology is unknown. Recently, genetic factors for susceptibility have been described. Several genetic loci have been mapped and partially explain the familial aggregations of the disease. However, environmental factors may also contribute to these aggregations. We considered that if the role of non-genetic factors was negligible, CD patients would be randomly distributed in sibships with multiple affected siblings. On the other hand if there was a significant environmental contribution, the siblings would be affected non-randomly over exposure status. In order to test this hypothesis, we studied 102 sibships with two or more affected siblings. A statistical test, named Cluster of Affected Sibling Test or CAST, was developed, based on the exact calculation of the probability of observing a given number of clusters of affected siblings in multiplex families. The null hypothesis of a random distribution of affected siblings was rejected (P=0,005). The observed excess of affected sibling clusters indicates that birth order influences the disease status. Considering that an adjacent order of birth is a global estimate of environmental sharing, this observation strongly suggests that environmental factors contribute to the observed familial aggregations of the disease. This observation provides evidence that familial CD is a relevant tool for further studies of environmental factors and gene-environment interaction. More generally, the CAST statistics may be widely applicable to estimate the involvement of environmental factors in the aetiology of other binary traits which may be observed in multiple members of the same sibship.

Journal of Pediatric Gastroenterology & Nutrition, 1999

Sv Lakaresallskapets Handl Hygiea, 2005

Lakartidningen, 2009

... Fortsatta studier krävs dock för att fastställa den bästa rescue-behandlingen vid svårt skov ... more ... Fortsatta studier krävs dock för att fastställa den bästa rescue-behandlingen vid svårt skov av steroidrefraktär ulcerös kolit och den ... eller jävsförhållanden: Curt Tysk har fått föreläsararvode från Astra-Zeneca och Schering-Plough, Ragnar Befrits och Stefan Lindgren har fått ...

Gastroenterology, Jan 5, 1991

The American journal of gastroenterology, 2009

Inflammatory bowel disease (IBD), e.g., Crohn's disease (CD) and ulcerative colitis (UC), is ... more Inflammatory bowel disease (IBD), e.g., Crohn's disease (CD) and ulcerative colitis (UC), is a complex genetic disorder. Tumor necrosis factor (ligand) superfamily, member 15 (TNFSF15) has been previously identified as a susceptibility gene for CD in Japanese and UK cohorts. This replication study was designed in order to confirm and further validate the role of TNFSF15 in IBD. A total of 666 IBD families (corresponding to 2,982 relatives) with European ancestry were genotyped for the rs6478108 and rs7869487 polymorphisms, which define the main TNFSF15 haplotypes previously associated with CD. An association between the main haplotypes and CD, UC and IBD was tested using the Genehunter TDT and Unphased statistics. Caspase recruitment domain 15 (CARD15)/TNFSF15 interaction and genotype/phenotype correlations were also studied. The previously reported "high-risk" haplotype (A) was associated with IBD (P=0.001) (OR=1.25 (1.05-1.50)) and CD (P=0.02) (OR=1.31 (1.03-1.67)) w...

Baillière's Clinical Gastroenterology, 1998

Active Crohn's disease constitutes a major problem in gastroenterology. Symptoms vary with site, ... more Active Crohn's disease constitutes a major problem in gastroenterology. Symptoms vary with site, extent and local complications of the disease as well as with the absence or presence of extraintestinal manifestations. Due to the troublesome consequences of the disease new treatments have continuously been tried. However, the results have varied and no definite breakthrough has occurred in the medical treatment of active Crohn's disease during the last years. The new salicylates have shown some effect using higher doses, but have not fulfilled the expectations once connected with their development. The new steroids have compared well to, but not exceeded, the older corticosteroid preparations in terms of therapeutic efficacy but they have a better side-effect profile. The role of the purine analogs azathioprine/6-mercaptopurine has been further evaluated. The onset of their effect is slow, an intravenous loading dose might shorten this time span, and they are steroid sparing. The controlled data on methotrexate are limited and the long-term effects not well studied and there is concern about toxicity. Even the use of cyclosporine in active Crohn's disease is controversial and connected with serious adverse events. Studies on the new immune modulating therapies such as anti-TNF-cx antibodies, anti-CD4 antibodies, interleukin-10 and interferon have been encouraging but large scale studies are still awaited before the effect and the spectra of side-effects can be fully evaluated.

Journal of Crohn's and Colitis Supplements, 2008

Introduction: Fistulas belong to the most frequent complications in Crohn' s disease. In patients... more Introduction: Fistulas belong to the most frequent complications in Crohn' s disease. In patients suffering from fistulizing Crohn' s disease we often observed the presence of concomitant stenoses or significant luminal narrowing in the small or large bowel, suggesting a causal relation. By analyzing retrospective data of patients with fistulas from our IBD center cohort we searched for a concomitant presence of stenoses or luminal narrowing. Methods: We screened the medical records of all patients who presented with Crohn' s disease at our IBD-center since 1998. Patients having presented with fistulizing disease were selected for analysis, if the presence of fistulas was confirmed or diagnosed by physical examination, magnetic resonance (MR), or ileocolonoscopy. Furthermore, data on the status of the small and large bowel lumen were collected if ileocolonoscopy, MR enteroclysis technique, or surgery was performed within 6 months before or after the description of the fistulas. Significant luminal bowel narrowing was defined as stenosis, failure to pass the endoscope over the narrowed segment, or a reduction of the luminal diameter of more than 10mm over a length of more than 3 cm. Results: Among 771 patients since 1998 with Crohn' s disease at our IBDcenter at the University of Munich, 134 patients presented with fistulas. So far, 94 of the 134 patients with one or more fistulas could be analyzed retrospectively. Aside from perianal fistulas (n=41; 38.0%), entero-enteral (n=44; 40.7%), entero-cutaneous (n=12; 11.1%), entero-vesical (n=5; 4.6%) and entero-vaginal fistulas (n=6; 5.6%) were described. Signs of coexisting significant luminal bowel narrowing were described in 87 (92.6%) patients with fistulas. 35 of 41 patients with perianal fistulas had a significant luminal narrowing. Interestingly; of these 35 patients, 14 had a stenosis in the terminal ileum as the only sign of luminal narrowing (37.1%), and in none of these patients a fistula track could be followed back to the terminal ileum. Conclusion: The fact that in patients with Crohn' s disease and fistulas, in more then 90% significant luminal bowel narrowing was found suggests a causal relation. Since some stenoses were found without any spatial contact to the fistulas, an increased intraluminal pressure at the site of the narrowed segment together with an impaired barrier function may favour the formation of fistulas by fluid flux through the bowel wall. If prospective studies in patients presenting with newly found fistula confirm this correlation, future fistula therapies have to be directed more towards the stenoses and not primarily to the fistulas.

Journal of Crohn's and Colitis Supplements, 2009

8. Baron JA, Senn S, Voelker M, et al. Gastrointestinal adverse effects of short-term aspirin use... more 8. Baron JA, Senn S, Voelker M, et al. Gastrointestinal adverse effects of short-term aspirin use: a meta-analysis of published randomized controlled trials. Drugs R D 2013; 13: 9-16. 9. Pareek A, Chandukar N. Comparison of gastrointestinal safety and tolerability of aceclofenac with diclofenac: a multicenter, randomized, double-blind study in patients with knee osteoarthritis. Curr Med Res Opin 2013; 29: 849-59. 10. Matheson AJ, Jarvis B. Lansoprazole: an update of its place in the management of acid-related disorders.

The American Journal of Gastroenterology, 2007

OBJECTIVES: Corticosteroids are a cornerstone in the treatment of a severe attack of ulcerative c... more OBJECTIVES: Corticosteroids are a cornerstone in the treatment of a severe attack of ulcerative colitis (UC). The long-term prognosis in this patient group is not well described. We studied the long-term colectomy and relapse rates in patients given intensive intravenous corticosteroid treatment (IIVT) for acute UC.

Scandinavian Journal of Gastroenterology, 2007

Adult-type hypolactasia (AtH) can be diagnosed by genotyping in addition to functional tests or i... more Adult-type hypolactasia (AtH) can be diagnosed by genotyping in addition to functional tests or intestinal biopsy. The aims of this study were to estimate the prevalence of AtH by genotyping and to investigate whether AtH prevalence has changed in Sweden during the 20th century. Schoolchildren (n=690) born in 1983 and 1989, and elderly individuals (n=392) born between 1920 and 1932 were genotyped for AtH using Pyrosequencing technology. The overall prevalence of AtH among children was 14.1%. The majority of children (92%, n=635) were Caucasians with genotype prevalences: CC, 61 (10%); CT, 259 (41%); TT, 307 (49%). The frequency of the mutated allele q was 0.300 in this cohort. The prevalence of AtH estimated from the Hardy-Weinberg equilibrium (HWE) (q 2), was 9.0% (95% CI: 6.7-11.2%). Eight percent (n=55) of the children were non-Caucasian; genotype prevalences were CC, 36 (66%); CT, 15 (27%); TT, 4 (7%). The prevalence of AtH in these children estimated from HWE was 62.5% (95% CI: 49.7-75.3%). The elderly subjects were all Caucasians. Their genotype prevalences were: CC, 20 (5%); CT, 166 (42%); TT, 206 (53%); the frequency of the mutated allele q was 0.262 and their AtH prevalence estimated from HWE was 6.8% (95% CI: 4.3-9.2%). The overall prevalence of AtH in children (14%) was higher than previously thought. Among Caucasians, higher figures were seen in children than in the elderly (9% versus 6.8%). The prevalence thus seems to be increasing and this may be due to the immigration of both non-Caucasian and Caucasian groups with a higher prevalence of AtH.

Scandinavian Journal of Gastroenterology, 2006

Assessment of health-related quality of life (HRQOL) is important in both clinical practice and c... more Assessment of health-related quality of life (HRQOL) is important in both clinical practice and clinical trials, and several multi-item questionnaires are currently in use. We have devised and evaluated a simplified four-item questionnaire, the Short Health Scale (SHS), representing each of four health dimensions: (a) symptom burden, (b) social function, (c) disease-related worry and (d) general well-being. Three hundred patients with ulcerative colitis completed the SHS and three other HRQOL questionnaires (IBDQ, RFIPC and PGWB). Half of the patients repeated the questionnaires after 6 months - or earlier if disease activity changed. Test-retest reliability was derived from measurements of the SHS questions, 2 weeks apart, on 18 patients in remission. Patients in relapse scored higher on each of the four SHS questions than patients in remission (p < 0.001). Each of the four SHS scores were associated with results of their corresponding health dimension obtained with the other three questionnaires (rs=0.57-0.78, p < 0.001) (validity). The results of the SHS proved stable on repeated measurement with a 2-week interval in patients in remission (rs=0.71-0.91, p < 0.01) (test-retest reliability). Patients with a change in disease activity had a significant change in their SHS scores (p < 0.05) (responsiveness). The SHS is a valid, reliable and responsive measure of subjective health in patients with ulcerative colitis. It is simple to administer, quickly completed and the results do not need further calculations. The SHS can be used in clinical trials and in clinical practice to identify the patient's main problems affecting health.

Scandinavian Journal of Gastroenterology, 2007

Selective leukocyte apheresis is a new type of non-pharmacological treatment for patients with ac... more Selective leukocyte apheresis is a new type of non-pharmacological treatment for patients with active ulcerative colitis and Crohn's disease. Preliminary data have indicated that this type of therapy is safe and efficacious, and large sham-controlled studies are currently in progress. In Scandinavia, a substantial number of patients with chronic inflammatory bowel disease have already received leukocyte apheresis on a compassionate use basis and the aim of this study was to report the clinical outcome and adverse events in the first patients treated. Clinical details of the first consecutive 100 patients with inflammatory bowel disease treated with granulocyte, monocyte/macrophage (Adacolumn) apheresis in Scandinavia were prospectively registered. Median length of follow-up was 17 months, (range 5-30). The study population comprised 52 patients with ulcerative colitis, 44 patients with Crohn's disease and 4 patients with indeterminate colitis. In 97 patients the indication for Adacolumn treatment was steroid-refractory or steroid-dependent disease. Clinical remission was attained in 48% of the patients with ulcerative colitis, and an additional 27% had a clinical response to the apheresis treatment. The corresponding figures for patients with Crohn's disease were 41% and 23%, respectively. Complete steroid withdrawal was achieved in 27 out of the 50 patients taking corticosteroids at baseline. Adverse events were reported in 15 patients and headache was most frequently reported (n=7). Granulocyte, monocyte/macrophage apheresis treatment seems to be a valuable adjuvant therapy in selected patients with refractory inflammatory bowel disease. The risk for toxicity or severe adverse events appears to be low.

Scandinavian Journal of Gastroenterology, 2010

Disease-related worries constitute an important dimension of patient-reported perception of healt... more Disease-related worries constitute an important dimension of patient-reported perception of health status in inflammatory bowel disease (IBD). The Rating Form of IBD Patient Concerns (RFIPC) questionnaire is purported to measure IBD-related worries. This study evaluated the psychometric properties of a Swedish translation of RFIPC in an unselected population of Crohn's disease (CD) patients. The degree and nature of the worries were characterized and predictive factors for outcome of RFIPC and underlying dimensions were identified. The RFIPC was completed by 447 CD patients in conjunction with regular visits. A physician global assessment of disease activity and four other health-related quality of life (HRQL) questionnaires were used for construct validity. Reliability and responsiveness were evaluated with follow-up visits. Underlying dimension and predictive factors were identified with factor analysis and multiple linear regression analysis. Test-retest reliability was 0.90, correlation with corresponding HRQL measures 0.60-0.80 and responsiveness ratio 0.84. Median RFIPC sum score was lower than in previous studies. Top three concerns were ostomy, energy level and bowel control. Four dimensions were identified in descending order of concern: disease-related complications, daily-life achievements, intimacy, and stigmatization. Predictors of RFIPC score were disease activity, gender, and BMI (p < 0.001-0.008). The Swedish version of RFIPC exhibited an adequate psychometric performance in CD patients, but was less sensitive to change in disease activity. The patients were more concerned about complications and achievement than intimacy and stigmatization. The strongest predictors of more worry were active disease, female gender and higher BMI.

New England Journal of Medicine, 2001

A history of appendectomy is rare in patients with ulcerative colitis. This suggests a protective... more A history of appendectomy is rare in patients with ulcerative colitis. This suggests a protective effect of appendectomy or that appendicitis and ulcerative colitis are alternative inflammatory responses. We sought to characterize this inverse relation further. We studied a cohort of 212,963 patients who underwent appendectomy before the age of 50 years between 1964 and 1993 and a cohort of matched controls who were identified from the Swedish Inpatient Register and the nationwide census. The cohort was followed until 1995 for any subsequent diagnosis of ulcerative colitis. Patients who underwent appendectomy for appendicitis and mesenteric lymphadenitis had a low risk of ulcerative colitis (for patients with perforated appendicitis, the adjusted hazard ratio was 0.58 [95 percent confidence interval, 0.38 to 0.87]; for those with nonperforated appendicitis it was 0.76 [95 percent confidence interval, 0.65 to 0.90]; and for those with mesenteric lymphadenitis it was 0.57 [95 percent confidence interval, 0.36 to 0.89]). In contrast, patients who underwent appendectomy for nonspecific abdominal pain had the same risk of ulcerative colitis as the controls (adjusted hazard ratio, 1.06; 95 percent confidence interval, 0.74 to 1.52). For the patients who had appendicitis, an inverse relation with the risk of ulcerative colitis was found only for those who underwent surgery before the age of 20 years (P<0.001). Appendectomy for an inflammatory condition (appendicitis or lymphadenitis) but not for nonspecific abdominal pain is associated with a low risk of subsequent ulcerative colitis. This inverse relation is limited to patients who undergo surgery before the age of 20 years.

Nature Genetics, 2011

Genome-wide association studies (GWAS) have identified dozens of risk loci for many complex disor... more Genome-wide association studies (GWAS) have identified dozens of risk loci for many complex disorders, including Crohn's disease 1,2 . However, common disease-associated SNPs explain at most ~20% of the genetic variance for Crohn's disease. Several factors may account for this unexplained heritability 3-5 , including rare risk variants not adequately tagged thus far in GWAS 6-8 . That rare susceptibility variants indeed contribute to variation in multifactorial phenotypes has been demonstrated for colorectal cancer 9 , plasma high-density lipoprotein cholesterol levels 10 , blood pressure 11 , type 1 diabetes 12 , hypertriglyceridemia 13 and, in the case of Crohn's disease, for NOD2 (refs. 14,15). Here we describe the use of high-throughput resequencing of DNA pools to search for rare coding variants influencing susceptibility to Crohn's disease in 63 GWAS-identified positional candidate genes. We identify low frequency coding variants conferring protection against inflammatory bowel disease in IL23R, but we conclude that rare coding variants in positional candidates do not make a large contribution to inherited predisposition to Crohn's disease.