Herma H. Fidder

Mucosal healing predicts long‐term outcome of maintenance therapy with infliximab in Crohn's disease

Background: Infliximab (IFX) treatment induces mucosal healing (MH) in patients with Crohns disease (CD) but the impact of MH on the long‐term outcome of IFX treatment in CD is still debated. Methods: We studied MH during long‐term treatment with IFX in 214 CD patients. A total of 183 patients (85.5%) responded to induction therapy and 31 patients (14.5%) were primary nonresponders. They underwent lower gastrointestinal (GI) endoscopy within a median of 0.7 months (interquartile range [IQR] 0.1–6.8) prior to first IFX and after a median of 6.7 months (IQR 1.4–24.6) after start of IFX and were further analyzed. The relationship between the outcome of IFX treatment long‐term and MH was studied. Results: MH was observed in 67.8% of the 183 initial responders (n = 124), with 83 patients having complete healing (45.4%) and 41 having partial healing (22.4%). Scheduled IFX treatment from the start resulted in MH more frequently (76.9% MH rate) than episodic treatment (61.0% MH rate; P = 0.0222, odds ratio [OR] 2.14, 95% confidence interval [CI] 1.11–4.12). Concomitant treatment with corticosteroids (CS) had a negative impact on MH (37.9% in patients with CS versus 63.2% in patients without CS; P = 0.021, OR 0.36, 95% CI 0.16–0.80). MH was associated with a significantly lower need for major abdominal surgery (MAS) during long‐term follow‐up (14.1% of patients with MH needed MAS versus 38.4% of patients without MH; P < 0.0001). Conclusions: MH induced by long‐term maintenance IFX treatment is associated with an improved long‐term outcome of the disease especially with a lower need for major abdominal surgeries. (Inflamm Bowel Dis 2009;)

Long-term outcome of treatment with infliximab in 614 patients with Crohn's disease: results from a single-centre cohort

Background and aims: This observational study assessed the long-term clinical benefit of infliximab (IFX) in 614 consecutive patients with Crohn’s disease (CD) from a single centre during a median follow-up of 55 months (interquartile range (IQR) 27–83). Methods: The primary analysis looked at the proportion of patients with initial response to IFX who had sustained clinical benefit at the end of follow-up. The long-term effects of IFX on the course of CD as reflected by the rate of surgery and hospitalisations and need for corticosteroids were also analysed. Results: 10.9% of patients were primary non-responders to IFX. Sustained benefit was observed in 347 of the 547 patients (63.4%) receiving long-term treatment. In 68.3% of these, treatment with IFX was ongoing and in 31.7% IFX was stopped, with the patient being in remission. Seventy patients (12.8%) had to stop IFX due to side effects and 118 (21.6%) due to loss of response. Although the yearly drop-out rates of IFX in patients with episodic (10.7%) and scheduled treatment (7.1%) were similar, the need for hospitalisations and surgery decreased less in the episodic than in the scheduled group. Steroid discontinuation also occurred in a higher proportion of patients in the scheduled group than in the episodic group. Conclusions: In this large real-life cohort of patients with CD, long-term treatment with IFX was very efficacious to maintain improvement during a median follow-up of almost 5 years and changed disease outcome by decreasing the rate of hospitalisations and surgery.

Healthcare costs of inflammatory bowel disease have shifted from hospitalisation and surgery towards anti-TNFα therapy: results from the COIN study.

Objective The introduction of anti tumour necrosis factor-α (anti-TNFα) therapy might impact healthcare expenditures, but there are limited data regarding the costs of inflammatory bowel diseases (IBD) following the introduction of these drugs. We aimed to assess the healthcare costs and productivity losses in a large cohort of IBD patients. Design Crohns disease (CD) and ulcerative colitis (UC) patients from seven university hospitals and seven general hospitals were invited to fill-out a web-based questionnaire. Cost items were derived from a 3 month follow-up questionnaire and categorised in outpatient clinic, diagnostics, medication, surgery and hospitalisation. Productivity losses included sick leave of paid and unpaid work. Costs were expressed as mean 3-month costs per patients with a 95% CI obtained using non-parametric bootstrapping. Results A total of 1315 CD patients and 937 UC patients were included. Healthcare costs were almost three times higher in CD as compared with UC, €1625 (95% CI €1476 to €1775) versus €595 (95% CI €505 to €685), respectively (p<0.01). Anti-TNFα use was the main costs driver, accounting for 64% and 31% of the total cost in CD and UC. Hospitalisation and surgery together accounted for 19% and <1% of the healthcare costs in CD and 23% and 1% in UC, respectively. Productivity losses accounted for 16% and 39% of the total costs in CD and UC. Conclusions We showed that healthcare costs are mainly driven by medication costs, most importantly by anti-TNFα therapy. Hospitalisation and surgery accounted only for a minor part of the healthcare costs.

Results from the 2nd Scientific Workshop of the ECCO (I): Impact of mucosal healing on the course of inflammatory bowel disease

Over the past years, mucosal healing has emerged as a major therapeutic goal in clinical trials in inflammatory bowel diseases. Accumulating evidence indicates that mucosal healing may change the natural course of the disease by decreasing the need for surgery and reducing hospitalization rates in both ulcerative colitis and Crohns disease. Mucosal healing may also prevent the development of long-term disease complications, such as bowel damage in Crohns disease and colorectal cancer in ulcerative colitis. Histologic healing may be the ultimate therapeutic goal in ulcerative colitis, whereas its impact on the course of Crohns disease is unknown. Complete mucosal healing may be required before considering drug withdrawal. Targeting early Crohns disease is more effective than approaches aimed at healing mucosa in longstanding disease. Several questions remain to be answered: should mucosal healing be systematically used in clinical practice? Should we optimize therapies to achieve mucosal healing? What is the degree of intestinal healing that is required to change the disease course? Large prospective studies addressing these issues are needed.

Outcome of pregnancy in women with inflammatory bowel disease treated with antitumor necrosis factor therapy

Background: Infliximab (IFX) and adalimumab (ADA) are attractive treatment options in patients with inflammatory bowel disease (IBD) also during pregnancy but there is still limited data on the benefit/risk profile of IFX and ADA during pregnancy. Methods: This observational study assessed pregnancy outcomes in 212 women with IBD under antitumor necrosis factor alpha (TNF) treatment at our IBD unit. Pregnancy outcomes in 42 pregnancies with direct exposure to anti‐TNF treatment (35 IFX, 7 ADA) were compared with that in 23 pregnancies prior to IBD diagnosis, 78 pregnancies before start of IFX, 53 pregnancies with indirect exposure to IFX, and 56 matched pregnancies in healthy women. Results: Thirty‐two of the 42 pregnancies ended in live births with a median gestational age of 38 weeks (interquartile range [IQR] 37–39). There were seven premature deliveries, six children had low birth weight, and there was one stillbirth. One boy weighed 1640 g delivered at week 33, died at age of 13 days because of necrotizing enterocolitis. A total of eight abortions (one patient wish) occurred in seven women. Trisomy 18 was diagnosed in one fetus of a mother with CD at age 37 under ADA treatment (40 mg weekly) and pregnancy was terminated. Pregnancy outcomes after direct exposure to anti‐TNF treatment were not different from those in pregnancies before anti‐TNF treatment or with indirect exposure to anti‐TNF treatment but outcomes were worse than in pregnancies before IBD diagnosis. Conclusions: Direct exposure to anti‐TNF treatment during pregnancy was not related to a higher incidence of adverse pregnancy outcomes than IBD overall. (Inflamm Bowel Dis 2011;)

Levels of C-reactive protein are associated with response to infliximab therapy in patients with Crohn's disease.

BACKGROUND & AIMS Infliximab is an antibody against tumor necrosis factor-α that is used to treat patients with moderate to severe Crohns disease (CD). C-reactive protein (CRP) is a marker used to identify and follow individuals with CD. We analyzed changes in levels of CRP in a large cohort of patients with CD undergoing treatment with infliximab. METHODS Serial levels of CRP were analyzed in 718 CD patients. Blood was collected before each infusion; a total of 8845 CRP levels were available for analysis. The correlations between CRP levels and need for dose adjustment, outcomes, and mucosal healing (based on endoscopic analysis of 253 patients) were evaluated. Therapy adjustment was considered successful if therapy continued without need for change. Subgroup analysis was performed by using data from 268 patients who received 8 weeks of maintenance therapy. RESULTS More patients with high baseline levels of CRP responded to infliximab than patients with normal levels (90.8% vs 82.6%; P = .014). Early normalization of CRP levels correlated with sustained long-term response (P < .001). CRP levels remained significantly higher among patients who lost their response to infliximab, compared with those with a sustained response (P = .001). At time of loss of response, CRP levels were significantly increased (median, 11.2 mg/L) and did not return to baseline levels (median, 18.2 mg/L; P = .039). CRP correlated with mucosal healing (P = .033). CONCLUSIONS CRP is a good marker of disease activity in patients treated with infliximab. Increased levels of CRP indicate mucosal inflammation and a likelihood of clinical relapse.

The joint-gut axis in inflammatory bowel diseases.

Inflammatory bowel diseases, Crohns disease and ulcerative colitis, are associated with a variety of extraintestinal manifestations. The most common extraintestinal manifestation, articular involvement, occurs in 16% to 33% of inflammatory bowel disease patients. These arthropathies may increase morbidity, resulting in a worse quality of life compared with inflammatory bowel disease patients without arthropathies. Thus, arthropathies in inflammatory bowel diseases represent a major medical problem in these patients. Arthritis associated with inflammatory bowel diseases is one of the diseases captured under the umbrella of spondyloarthritis. Spondyloarthritis is a group of inflammatory diseases with overlapping features and is linked to Human Leukocyte Antigen-B27. Arthropathy in inflammatory bowel diseases is clinically divided into peripheral and axial involvement. Peripheral arthritis often flares with relapses of bowel disease resulting in a different treatment approach than axial arthritis in which the course is independent of inflammatory bowel disease activity. Definitions, prevalence, pathophysiology and treatment of the arthropathies commonly seen in inflammatory bowel diseases such as peripheral arthritis, dactylitis, enthesitis, arthralgia, sacroiliitis, inflammatory back pain and ankylosing spondylitis are summarized.

Low fecal calprotectin predicts sustained clinical remission in inflammatory bowel disease patients : a plea for deep remission

BACKGROUND AND AIMS Mucosal healing has become the treatment goal in patients with ulcerative colitis (UC) and Crohns disease (CD). Whether low fecal calprotectin levels and histological healing combined with mucosal healing is associated with a further reduced risk of relapses is unknown. METHODS Patients with CD, UC or inflammatory bowel disease-unclassified (IBD-U) scheduled for surveillance colonoscopy collected a stool sample prior to bowel cleansing. Only patients with mucosal healing (MAYO endoscopic score of 0) were included. Fecal calprotectin was measured using a quantitative enzyme-linked immunosorbent assay (R-Biopharm, Germany). Biopsies were obtained from four colonic segments, and histological disease severity was assessed using the Geboes scoring system. Patients were followed until the last outpatient clinic visit or the development of a relapse, which was defined as IBD-related hospitalization, surgery or step-up in IBD medication. RESULTS Of the 164 patients undergoing surveillance colonoscopy, 92 patients were excluded due to active inflammation or missing biopsies. Of the remaining 72 patients (20 CD, 52 UC or IBD-U), six patients (8%) relapsed after a median follow-up of 11 months (range 5-15 months). Median fecal calprotectin levels at baseline were significantly higher for patients who relapsed compared with patients who maintained remission (284 mg/kg vs. 37 mg/kg. p < 0.01). Fecal calprotectin below 56 mg/kg was found to optimally predict absence of relapse during follow-up with 64% sensitivity, 100% specificity, 100% negative predictive value and 20% positive predictive value. The presence or absence of active inflammation determined by Geboes cut-off score of 3.1 was less strongly associated with the risk of relapse (64% sensitivity, 33% specificity, 9% negative predictive value and 92% positive predictive value. CONCLUSION Low calprotectin levels identify IBD patients who remain in stable remission during follow-up.

Adalimumab and Infliximab Are Equally Effective for Crohn's Disease in Patients Not Previously Treated With Anti–Tumor Necrosis Factor-α Agents

BACKGROUND & AIMS Infliximab (IFX) and adalimumab (ADA) are thought to have equal efficacy for the treatment of Crohns disease (CD), although no direct comparison has been performed. We compared the effectiveness and safety of IFX and ADA in carefully matched cohorts. METHODS We performed a retrospective cohort study of 200 patients with CD (100 treated with IFX and 100 treated with ADA, starting in 2006 or later) who had not received anti-tumor necrosis factor α agents previously; the patients were identified from databases of 6 hospitals in The Netherlands. The groups were matched carefully for indication, duration of disease, age, and Montreal classification. The primary end point was the steroid-free clinical response, defined by a combination of multiple clinical parameters, after 1 year. RESULTS Of the total patient population, 63.5% and 45% had a clinical response after 1 and 2 years, respectively. There were no significant differences between treatment groups: at 1 and 2 years, 62% and 41% of those receiving ADA vs 65% and 49% of those receiving IFX had responses, respectively. Kaplan-Meier curves showed identical decreases in response rates over time. Combining IFX or ADA with immunomodulator therapy was associated with a higher clinical response than monotherapy, although this was only significant among patients who received IFX (P = .03). There were no differences in numbers of side effects or opportunistic infections. CONCLUSIONS The effectiveness of ADA or IFX treatment in anti-tumor necrosis factor α-naive patients with CD is comparable after 1 and 2 years of follow-up evaluation. The efficacies of IFX and ADA each seem to increase when given with immunomodulator therapy, although only significantly for IFX.

LONG-TERM OUTCOME OF TREATMENT WITH INFLIXIMAB IN 440 CROHN'S DISEASE PATIENTS: RESULTS FROM A SINGLE CENTER COHORT

Background & Aims: This observational study assessed long term clinical benefit of infliximab (IFX) in 614 consecutive Crohn9s disease (CD) patients from a single centre during a median follow-up (FU) of 55 months (IQR 27-83). Methods: The primary analysis looked at the proportion of patients with initial response to IFX who had sustained clinical benefit at the end of FU. Long-term effects of IFX on the course of CD as reflected by the rate of surgeries and hospitalizations and need for corticosteroids were also analyzed. Results: 10.9% of patients were primary non-responders to IFX. Sustained benefit was observed in 347 of the 547 patients (63.4%) receiving long-term therapy. In 68.3% of these therapy with IFX was ongoing and in 31.7% IFX was stopped with the patient being in remission. Seventy patients (12.8%) had to stop IFX for side effects and 118 (21.6%) for loss of response. Although the yearly drop-out rates of IFX in patients with episodic (10.7%) and scheduled treatment (7.1%) were similar, the need for hospitalizations and surgeries decreased less in the episodic than in the scheduled group. Steroid discontinuation also occurred in a higher proportion of patients in the scheduled group than in the episodic group. Conclusions: In this large real-life cohort of CD patients long-term therapy with IFX was very efficacious to maintain improvement during a median FU of almost 5 years and changed disease outcome by decreasing the rate of hospitalizations and surgeries.