The role of 5-aminosalicylic acid (5-ASA) in Crohn's disease is unclear. The outcome of the first course of 5-ASA monotherapy with emphasis on 5-ASA dependency was retrospectively assessed in consecutive cohort of 537 Crohn's disease patients diagnosed 1953-2007.
Following outcome definitions were used: Immediate outcome (30 days after 5-ASA start) defined as complete/partial response (total regression/improvement of symptoms) and no response (no regression of symptoms with a need of corticosteroids, immunomodulator or surgery). Long-term outcome defined as prolonged response (still in complete/partial response 1 year after induction of response); 5-ASA dependency (relapse on stable/reduced dose of 5-ASA requiring dose escalation to regain response or relapse =1 year after 5-ASA cessation regaining response after 5-ASA re-introduction).
One hundred sixty-five (31%) patients had monotherapy with 5-ASA. In 50% 5-ASA monotherapy was initiated =1 year after diagnosis (range 0-49 years). Complete/partial response was obtained in 75% and no response in 25% of patients. Thirty-six percent had prolonged response, 23% developed 5-ASA dependency and 38% were non-responders in long-term outcome. Female gender had higher probability to develop prolonged response or 5-ASA dependency (OR 2.89, 95%CI: 1.08-7.75, p=0.04). The median duration (range) of 5-ASA monotherapy was 34 months (1-304) in prolonged responders, 63 (6-336) in 5-ASA dependent and 2 (0-10) in non-responders.
A selected phenotype of Crohn's disease patients may profit from 5-ASA. Fifty-nine percent of patients obtained long-term benefit with 23% becoming 5-ASA dependent. Prospective studies are warranted to assess the role of 5-ASA in Crohn's disease.
BACKGROUND AND AIMS: Adverse events (AE) leading to discontinuation or dose-reduction of thiopurine therapy (TP) occur in 9-28% of patients with inflammatory bowel disease. 6-Thioguanine (6-TG) has been proposed as an alternative treatment in patients intolerant for azathioprine (AZA), but some concerns have been raised about drug safety. METHODS: We evaluated in a prospective manner the tolerance and efficacy of 6-TG in 23 Crohn's disease (CD) patients (13 men, median age 41 (19-65) years) with prior intolerance (n=18) or resistance (n=5) to AZA and/or 6-mercaptopurine (6-MP). In addition, eight patients had tried mycophenolate mofetil. Seventeen patients (74%) had undergone intestinal resection, often several times. RESULTS: Patients were treated with a median daily dose of 40 mg 6-TG (range 20-60) for 259 (15-2272) days. Seven of 13 patients (54%) with active disease went into remission after 8 (4-26) weeks. Sixteen patients (70%) experienced AE that lead to discontinuation (n=10) after 85 (15-451) days or dose reduction (n=6) after 78 (10-853) days. Ten of 18 patients (56%) with prior TP-intolerance discontinued 6-TG treatment due to AE compared to none of five patients with TP-resistance (p=0.046). Of 13 patients that tolerated 6-TG, eight discontinued the drug due to therapeutic failure (n=5) or safety concerns (n=3). Eight patients (35%) continued treatment beyond 12 months. There was no significant difference in maximum thioguanine nucleotide levels between patients with AE leading to discontinuation/dose reduction and patients without AE, 652 (99-2488) vs. 551 (392-1574) pmol/8 x 10(8) RBC; p=0.80. CONCLUSIONS: In this cohort of CD patients with severe disease failing traditional thiopurine treatment, a small fraction (22%) had long-term benefit of 6-TG-treatment. 6-TG therapy seems to offer a limited therapeutic gain for patients intolerant to both AZA and 6-MP and other treatment options should be considered.
Crohn's disease (CD) is common among women of fertile age, and it often requires maintenance medical treatment. Adherence to medical treatment among women with CD prior to, during, and after pregnancy has, however, never been examined. Although CD women have increased risk of adverse pregnancy outcomes, little is known about predictors for these outcomes in women with CD. In addition, the impact of breastfeeding on disease activity remains controversial.
The aims of this PhD thesis were to determine adherence to treatment and to investigate predictors for and prevalence rates of non-adherence to maintenance medical treatment among women with CD prior to, during, and after pregnancy; to assess pregnancy outcomes among women with CD, taking medical treatment, smoking status, and disease activity into account; to assess breastfeeding rates and the impact of breastfeeding on the risk of relapse.
We conducted a population-based prevalence study including 154 women with CD who had given birth within a six-year period. We combined questionnaire data, data from medical records, and medical register data.
Among 105 (80%) respondents, more than half reported taking medication with an overall high adherence rate of 69.8%. Counselling, previous pregnancy, and planned pregnancy seemed to decrease the likelihood of non-adherence, whereas smoking seemed to predict non-adherence prior to pregnancy, although our sample size prevented any firm conclusions. During pregnancy, the vast majority (95%) of CD women were in remission. The children's birth weight did not differ in relation to maternal medical treatment, but mean birth weight in children of smokers in medical treatment was 274 g lower than that of children of non-smokers in medical treatment. In our relatively small study CD women in medical treatment were not at increased risk of adverse pregnancy outcomes compared with untreated women with CD. In total, 87.6% of CD women were breastfeeding, and rates did not vary by medical treatment. Smoking and non-adherence seemed to predict relapse in CD during the postpartum period, whereas breastfeeding seemed protective against relapse.
Although we generally had low statistical precision this thesis suggests that counselling regarding medical treatment may be an important factor for medical adherence among CD women of fertile age. In addition CD women in medical treatment did not seem at increased risk of adverse pregnancy outcome, but smoking predicted lower birth weight. Breastfeeding did not seem to increase the risk of relapse in CD.
TNF inhibitors (TNFi) have been shown to reduce the need for surgery in Crohn's disease, but few studies have examined their effect beyond the first year of treatment.
To conduct a register-based observational cohort study in Sweden 2006-2014 to investigate the risk of bowel resection in bowel surgery naïve TNFi-treated Crohn's disease patients and whether patients on TNFi =12 months are less likely to undergo bowel resection than patients discontinuing treatment before 12 months.
We identified all individuals in Sweden with Crohn's disease through the Swedish National Patient Register 1987-2014 and evaluated the incidence of bowel resection after first ever dispensation of adalimumab or infliximab from 2006 and up to 7 years follow-up.
We identified 1856 Crohn's disease patients who had received TNFi. Among these patients, 90% treatment retention was observed at 6 months after start of TNFi and 65% remained on the drug after 12 months. The cumulative rates of surgery in Crohn's disease patients exposed to TNFi years 1-7 were 7%, 13%, 17%, 20%, 23%, 25% and 28%. Rates of bowel resection were similar between patients with TNFi survival
BACKGROUND: 5-Aminosalicylic acid (5-ASA) preparations are the firstline drugs in the treatment of inflammatory bowel disease. Data on the safety of these drugs in pregnancy are sparse. AIMS: To examine the risk of adverse birth outcome in women who were prescribed 5-ASA drugs during pregnancy. PATIENTS: Women were included in the study if they were prescribed 5-ASA drugs immediately before or during pregnancy. To examine the risk of malformations, we included 60 pregnancies exposed to 5-ASA drugs 30 days before pregnancy or in the first trimester. To examine stillbirths, preterm births, and low birth weight, we included 88 pregnancies exposed during the entire pregnancy. Outcomes were compared with those of 19 418 pregnancies in which no drugs were prescribed for mothers during the study period. METHODS: We conducted a Danish cohort study based on data from a population based prescription registry, the Danish Birth Registry, and the Hospital Discharge Registry in North Jutland County. RESULTS: Odds ratios for malformations, stillbirth, preterm birth, and low birth weight in women who received prescriptions for 5-ASA drugs were 1.9 (95% confidence interval 0.7-5.4), 6.4 (1.7-24.9), 1.9 (0.9-3.9), and 1.2 (0.4-3.3), respectively. The increased risk of stillbirth and preterm birth were found only in patients with ulcerative colitis. CONCLUSIONS: We found an increased risk of stillbirth and preterm birth in women who had been prescribed 5-ASA drugs during pregnancy but no substantial increased risk of malformations. It was difficult to distinguish the specific effects of disease activity and 5-ASA drugs.
The clinical epidemiological studies included in this thesis fall into three parts. The first part includes studies on birth outcome in women with ulcerative colitis. The second part includes pharmacoepidemiological studies on birth outcome after anti-inflammatory drug therapy in pregnancy, including patients with ulcerative colitis and Crohn's disease. The third part (and the latest publications) includes birth outcome in women with Crohn's disease; and the methods of cohort establishment in these studies are developed and improved due to the knowledge gathered from conducting the earlier studies. The birth outcomes in women with ulcerative colitis are examined in a nationwide, Danish, cohort of women based on data from the Danish National Hospital Discharge Registry and the Danish Medical Birth Registry, and within a Hungarian case-control data set. Our data suggest: 1) Significantly increased risk of preterm birth when women give birth 0-6 months after establishment of the diagnosis. It is considered whether the increased risk may be influenced by disease activity around the time of establishing the diagnosis. 2) No increased risk of giving birth to children with low birth weight, intrauterine growth retardation or congenital abnormalities (evaluated overall). 3) Significantly increased risk of some selected congenital abnormalities (limb deficiencies, obstructive urinary and multiple congenital abnormalities). No other studies have examined the risk of selected congenital abnormalities in children born by women with ulcerative colitis. The pharmacoepidemiological studies on birth outcomes after use of anti-inflammatory drug therapy in pregnancy, including women with ulcerative colitis and Crohn's disease, are based on data from the Hungarian case-control data set, a countywide Danish prescription Database, the Danish National Hospital Discharge Registry, the Danish Medical Birth Registry, and review of selected medical records. After exposure to sulfasalazine during pregnancy our data suggest. No significantly increased overall relative risk of congenital abnormalities and no significantly increased risks of selected congenital abnormalities. After exposure to 5-aminosalicylic acid during pregnancy our data suggest. No significantly increased relative risk of low birth weight, intrauterine growth retardation or congenital abnormalities (evaluated overall). A significantly increased relative risk of preterm birth and stillbirth in ulcerative colitis women, compared to women with no prescription of reimbursed medicine in pregnancy - and also after comparing with women with chronic inflammatory bowel disease not taking 5-aminosalicylic acid during pregnancy. It is not clear whether these associations are causal or influenced by confounding by disease activity in particular. After maternal exposure to azathioprine/6-mercaptopurine during pregnancy our data suggest. An increased relative risk of preterm birth, congenital abnormalities, and perinatal mortality - also after using controls with similar underlying diseases. It is difficult to rule out an influence of uncontrolled confounding. These were the first published data from a controlled observational study on exposed women with chronic inflammatory bowel disease. After preconceptional paternal use of azathioprine/6-mercaptopurine our data suggest An increased risk of congenital abnormalities, although not significantly increased. The birth outcomes in women with Crohn's disease are examined in nationwide sub-cohorts classified according to type of anti-inflammatory drug exposure during pregnancy, and based on data from the Danish National Hospital Discharge Registry, the nationwide Danish Prescription Database and the Danish Medical Birth Registry. Furthermore, birth outcomes are examined in Crohn's disease women with disease activity during pregnancy, based on data from review of hospital records, the Danish National Hospital Discharge Registry and the Danish Medical Birth Registry. Our data suggest: 1) The risk of adverse birth outcomes in women with Crohn's disease varies according to the type of anti-inflammatory drug therapy in pregnancy. 2) Reassuring results according to low birth weight, intrauterine growth retardation, preterm birth and congenital abnormalities after use of sulfasalazine/5-aminosalicylic acid or steroids. 3) Worrisome findings of a significantly increased risk of preterm birth and an increased risk of congenital abnormalities (not significantly increased) after prescription of azathioprine/6-mercaptopurine during pregnancy. Some residual confounding by disease activity may have been left in the analyses of preterm birth. In Crohn's disease women with disease activity during pregnancy our data suggest: 1) A significantly increased relative risk of preterm birth in women with the highest degree of disease activity during pregnancy. 2) Disease activity does not seem to increase the risk of low birth weight, intrauterine growth retardation or congenital abnormalities. This study is the first epidemiological study of the risk of adverse birth outcomes in Crohn's disease women with disease activity during pregnancy, compared to women with no activity during pregnancy, and in which confounders have been taken into consideration. Exceeding the studies included in my previous PhD thesis, this thesis provides new evidence on the following subjects: i) the risk of selected congenital abnormalities in children of women with ulcerative colitis, ii) pharmacoepidemiological studies on the risk of adverse birth outcome after maternal azathioprine/6-mercaptopurine exposure in pregnancy, and the risk of congenital abnormalities in children fathered by men treated with azathioprine/6-mercaptopurine before conception, iii) the risk of adverse birth outcome in women with Crohn's disease according to type of anti-inflammatory drug treatment in pregnancy (sulfasalazine/5-aminosalicylic acid, steroids or azathioprine/6-mercaptopurine), and iv) the impact of disease activity in women with Crohn's disease on adverse birth outcome. We learned from the studies in this thesis that the traditional way of reporting birth outcome in women with chronic inflammatory bowel disease, i.e. without having valid information on the type of underlying disease, concurrent therapeutic drug treatment and disease activity, is of limited value. The studies show that the risk of specific adverse birth outcome in women with ulcerative colitis and Crohn's disease depends on several factors including the time of birth in relation the début of disease, the type of underlying disease (ulcerative colitis or Crohn's disease), the type of anti-inflammatory drug treatment during pregnancy, and the degree of disease activity during pregnancy. At the same time one also has to realize that the existing evidence is still limited, especially in the field of reproductive safety after therapeutic drug treatment during pregnancy and possible effects of preconceptional therapeutic drug exposure.
Crohn's disease (CD) is a chronic inflammatory disease of the gastrointestinal tract. Symptoms include but are not limited to abdominal pain, nausea, emesis, and diarrhea. Anti-TNF-a drugs are increasingly being used in patients with CD who have inadequate response to conventional therapy. However, these medications are quite expensive. The objective of this study is to evaluate the cost-utility of two anti-TNF-a drugs (infliximab, adalimumab) for refractory CD.
A Markov model was used to estimate the costs and QALYs of three treatments (usual care, infliximab, adalimumab) over a 5 year time horizon. After initial treatment, patients achieve remission, achieve treatment response or remain in the drug refractory health state. Patients who achieve remission or treatment response are at risk of relapse each 3 month model cycle. Patients in the drug refractory health state either remain in the health state or have surgery in each cycle. Different costs and utility values were assigned to the various model health states. Model input parameters including initial response rates, relapse rates, utility values were derived from published literature.
Usual care had both the lowest expected costs ($17,017) and QALYs (2.555), while infliximab had both the highest expected costs ($54,084) and QALYs (2.721). The incremental cost per QALY moving from usual care to adalimumab and from adalimumab to infliximab was estimated to be to be $193,305 and $451,165, respectively.
Based on common willingness to pay thresholds, ant-TNF-a drugs would not be perceived as a cost effective treatment for refractory CD.
Experimental evidence suggests the endogenous cannabinoid system may protect against colonic inflammation, leading to the possibility that activation of this system may have a therapeutic role in inflammatory bowel disease (IBD). Medicinal use of cannabis for chronic pain and other symptoms has been reported in a number of medical conditions. We aimed to evaluate cannabis use in patients with IBD.
One hundred patients with ulcerative colitis (UC) and 191 patients with Crohn's disease (CD) attending a tertiary-care outpatient clinic completed a questionnaire regarding current and previous cannabis use, socioeconomic factors, disease history and medication use, including complimentary alternative medicines. Quality of life was assessed using the short-inflammatory bowel disease questionnaire.
A comparable proportion of UC and CD patients reported lifetime [48/95 (51%) UC vs. 91/189 (48%) CD] or current [11/95 (12%) UC vs. 30/189 (16%) CD] cannabis use. Of lifetime users, 14/43 (33%) UC and 40/80 (50%) CD patients have used it to relieve IBD-related symptoms, including abdominal pain, diarrhoea and reduced appetite. Patients were more likely to use cannabis for symptom relief if they had a history of abdominal surgery [29/48 (60%) vs. 24/74 (32%); P=0.002], chronic analgesic use [29/41 (71%) vs. 25/81 (31%); P
Certolizumab pegol (Cimzia(®)) is currently the only PEGylated anti-TNFa biologic approved for the treatment of rheumatoid arthritis and Crohn disease. The product, developed by UCB, is a humanized antigen-binding fragment (Fab') of a monoclonal antibody that has been conjugated to polyethylene glycol. Certolizumab pegol was approved as a treatment for rheumatoid arthritis in the EU, US and Canada in 2009, and as a treatment for Crohn disease in Switzerland in 2007 and the US in 2008. Certolizumab pegol is entering into an increasingly competitive marketplace, especially in rheumatoid arthritis, but clinical data demonstrate benefits across a range of clinical, radiographic and patient reported outcomes.