Thalidomide in luminal and fistulizing Crohn's disease resistant to standard therapies

BACKGROUND: Thalidomide has been shown to be an effective treatment in Crohn's disease. AIM: To assess the efficacy and tolerability of thalidomide in refractory Crohn's disease patients. METHODS: Twenty-five patients were treated. Retrospective 'estimated' Crohn's Disease Activity Indices were assessed at baseline and at the end of follow-up. Clinical response was defined as symptomatic improvement and a reduction in the 'estimated' Crohn's Disease Activity Index of >100 points, > or =50% reduction in draining fistulas or clinical improvement in perianal ulcers. Clinical remission was defined as symptom resolution and an 'estimated' Crohn's Disease Activity Index <150, complete fistula closure or complete ulcer healing. RESULTS: Six of eight patients treated for luminal disease responded to thalidomide at a median follow-up of 12 months (three clinical responses, three clinical remissions). The median reduction in 'estimated' Crohn's Disease Activity Index was 212 points (P = 0.005). Nine of 11 patients with active fistulizing disease responded to thalidomide (six responses; three remissions). The four patients treated for both luminal and fistulizing disease had fistula response. Three of them had a response in luminal disease activity. One of two patients with ulcerating perianal disease responded. Twelve patients discontinued treatment because of adverse effects (three sedation; two abdominal pain; one leucopoenia; six neuropathy). CONCLUSION: Thalidomide is an effective short- to medium-term treatment in selected patients with refractory luminal and fistulizing Crohn's disease. Its long-term use is limited by toxicity.     

Basic fibroblast growth factor as a response parameter to infliximab in fistulizing Crohn's disease

BACKGROUND: Fibroblast growth factors play an important role in (patho)physiological processes such as wound healing and tissue repair. We previously showed that basic fibroblast growth factor is actively involved in inflammatory bowel disease processes. In the present retrospective study, we assessed whether serum basic fibroblast growth factor levels in Crohn's disease patients reflect the response to anti-tumour necrosis factor-alpha antibody infliximab treatment. AIM AND METHODS: Serum samples, biopsies and patient data from a subgroup of patients included in two placebo-controlled trials were used. Fistulizing Crohn's disease patients (n = 42) were administered placebo or infliximab intravenously three times and evaluated for response up to 18 weeks. Biopsies from a subgroup of patients were stained for basic fibroblast growth factor using indirect immunohistochemistry. In the active Crohn's disease trial, patients (n = 24) received either placebo or infliximab once, and disease activity and serum basic fibroblast growth factor were assessed at weeks 0 and 4. RESULTS: Basic fibroblast growth factor levels at inclusion were comparable in the fistulizing Crohn's disease patients regardless of whether the fistulas did or did not respond or completely heal (median range: 9.3-10.6 pg/mL). At the end of follow-up basic fibroblast growth factor levels were lower in patients who responded (9.2 pg/mL, P = 0.06) or who were completely healed (8.9 pg/mL, P = 0.009) when compared with patients did not respond/heal (14.5 pg/mL), the latter not significantly increased from baseline. Decreases in the perianal disease activity index and open fistula scores at the end of the follow-up were significantly correlated with the decrease in basic fibroblast growth factor (R = 0.41; P = 0.012 and R = 0.35; P =0.027, respectively). Immunohistological evaluation also showed a trend towards decreased basic fibroblast growth factor expression in intestinal biopsies of these patients. Patients with active disease, i.e. a Crohn's disease activity index > or = 220 combined from the two studies, were found to have significantly (P = 0.0046) lower baseline serum basic fibroblast growth factors levels than those with inactive disease (5.3 vs. 10.3 pg/mL, respectively). Treatment of the active disease patients did not affect the serum basic fibroblast growth factor level, although a general decrease in disease activity was observed with infliximab treatment. CONCLUSIONS: Healing of fistulizing/perianal Crohn's disease seems to be reflected by a decrease in high serum basic fibroblast growth factor. Basic fibroblast growth factor levels do not relate with response in active Crohn's disease patients.     

Combining infliximab and methotrexate in fistulizing Crohn's disease resistant or intolerant to azathioprine

BACKGROUND: Crohn's disease is complicated by fistulas in 20-40% of patients at some time during the course of their illness. Azathioprine has been reported to heal fistulas in 30-40% of cases. Long-lasting effects by the anti-tumour necrosis factor-alpha antibody infliximab most often require repeated infusions. Methotrexate has been shown to be an effective drug in maintaining remission in Crohn's disease. AIM: To evaluate the combination of infliximab and methotrexate as therapy for fistulas in patients with Crohn's disease. METHODS: Twelve consecutive patients (mean age, 29.5 years) with fistulizing Crohn's disease resistant or intolerant to azathioprine were followed prospectively. Patients received three infusions of infliximab (5 mg/kg) and long-term methotrexate (20 mg/week). Therapy success was defined as sustained closure of fistulas > or = 6 months after fistula closure. RESULTS: In four of the 12 patients, complete closure of fistulas that persisted for > or = 6 months (median follow-up, 13.25 months) was observed. In three further patients, a partial response was noted. In five patients, persistent therapy success could not be achieved or therapy had to be stopped due to side-effects. CONCLUSIONS: A combination of infliximab with long-term methotrexate may be a promising concept in fistulizing Crohn's disease. Our data indicate the need for larger controlled trials.     

An open-label study of thalidomide for maintenance therapy in responders to infliximab in chronically active and fistulizing refractory Crohn's disease

BACKGROUND: Infliximab, a chimeric monoclonal antibody to tumour necrosis factor-alpha, is a new potent therapy for active Crohn's disease, but induces short-lived improvements. AIM: To evaluate the efficacy of thalidomide, a drug with anti-tumour necrosis factor-alpha activity, for the maintenance of infliximab-induced response in refractory Crohn's disease. METHODS: Fifteen patients with severe, refractory disease (10 females, five males; mean age, 40 years; eight with luminal disease, two with fistulizing disease and five with both luminal and fistulizing disease) were started on thalidomide (100 mg daily), 29 +/- 10 days after they had responded to infliximab (5 mg/kg infusions). RESULTS: The median follow-up period was 238 days (range, 10-458 days) from the initiation of thalidomide and 265 days (range, 10-537 days) from the last infliximab infusion. The median Crohn's disease activity indices were 322 (range, 170-525), 119 (range, 24-503) and 35 (range, -60-360) before infliximab, at the initiation of thalidomide and at the end of follow-up, respectively. Remission rates on thalidomide were 92%, 83% and 83% at 3, 6 and 12 months, respectively, after the last infliximab infusion (Kaplan-Meier). Four patients (two in remission) stopped thalidomide for suspected adverse effects. Side-effects (drowsiness, rash and peripheral neuropathy) were mild and mostly transient. CONCLUSIONS: Thalidomide appears to be an effective and relatively safe drug to maintain response to infliximab in chronically active and fistulizing refractory Crohn's disease.     

Health-economic analysis: cost-effectiveness of scheduled maintenance treatment with infliximab for Crohn's disease--modelling outcomes in active luminal and fistulizing disease in adults

Background  Infliximab has been shown to be efficacious in moderate-to-severe Crohn's disease (CD).
Aim  To evaluate the cost-effectiveness of scheduled maintenance treatment with infliximab in luminal and fistulizing CD patients.
Methods  Markov models were constructed to simulate the progression of adult CD patients with and without fistulae during treatment with infliximab (5 mg/kg). Transitions were estimated from published clinical trials of infliximab. Standard care, comprising immunomodulators and/or corticosteroids was used as a comparator. An average weight of 60 kg was used to estimate the dose of infliximab. The costs and outcomes were discounted at 3.5% over 5 years. The primary effectiveness measurement was quality-adjusted life years (QALYs) estimated using EQ-5D. One-way and probabilistic sensitivity analyses were performed by varying the infliximab efficacy estimates, costs and utilities.
Results  The incremental cost per QALY gained was £26 128 in luminal CD and £29 752 in fistulizing CD at 5 years. Results were robust and remained in the range of £23 752–£38 848 for luminal CD and £27 047–£44 206 for fistulizing CD. Patient body weight was the most important factor affecting cost-effectiveness.
Conclusion  Eight-week scheduled maintenance treatment with infliximab is a cost-effective treatment for adult patients suffering from active luminal or fistulizing CD.     

Review article: Medical therapy for fistulizing Crohn's disease

BACKGROUND: Fistulae will develop in approximately one-third of patients with Crohn's disease. With an expected spontaneous healing rate of only 10%, fistulizing Crohn's disease requires a comprehensive strategy with a medical and possible surgical approach. AIM: To summarize the current literature evaluating various medical options for treating patients with fistulizing Crohn's disease. METHODS: A literature review was conducted using PubMed (search terms: Crohn's disease and fistula) and manual search of references among the identified studies and relevant review papers to identify papers that present data on medical treatment of fistulizing Crohn's disease. RESULTS: The first line of medical therapy remains antibiotics (metronidazole and ciprofloxacin). Mercaptopurine and azathioprine are medications that are effective in treating fistulizing Crohn's disease. The current gold standard of medical treatment to induce and maintain remission for fistulizing Crohn's disease is infliximab. Used as induction therapy, infliximab produced a 62% clinical response, and a complete closure rate of 46%. A maintenance therapy trial demonstrated at 54 weeks, 46% of patients receiving infliximab continued to respond to treatment, compared with 23% in the placebo group (P = 0.001). CONCLUSION: Further research to find new therapies and to improve our existing medical treatment of fistulizing Crohn's disease is required.     

Adherence rates with infliximab therapy in Crohn's disease

BACKGROUND: Inflammatory bowel disease is associated with non-adherence to treatment with oral medications. AIM: To assess the intravenous infliximab adherence rate and identify risk factors for non-adherence to treatment. METHODS: Infliximab infusion dates for 1 June 2002-30 October 2003 were obtained. Additional information was obtained from two other administrative and patient-based databases. Non-adherence was defined as a 'No Show' designation for a scheduled appointment. Non-adherence rate, odds ratios for associations to 'No Show' appointments and analysis were performed to identify patient characteristics associated with non-adherent behaviour. RESULTS: One thousand hundred and eighty-five infliximab infusions were scheduled for 274 patients. Forty-eight (4%) of appointments were classified as 'No Show'. Six patients accounted for 13/48 (27%) of failed appointments; another 35 patients missed one appointment. 'No Show' appointments were more likely to be for female patients, those on concomitant immunomodulators and those >18 weeks from initial infusion. Patients who missed >1 appointment were more likely to be female and have Medicaid vs. those with only one missed appointment (P < 0.05). Indication, patient area code and race were not significantly associated with single or repeated No Show behaviour. CONCLUSIONS: Overall, the non-adherence rate for infliximab is low. Risk factors that may contribute to non-adherence to treatment include female gender and maintenance dosing.     

Contrast-enhanced ultrasonography with SonoVue after infliximab therapy in Crohn's disease

The introduction of biological treatments like monoclonal anti TNF-a antibodies (infliximab), is changing the clinical history of Crohn's disease (CD). The effects of these therapies are monitored emplying clinical indexes of active disease, laboratory parameters, endoscopy and histology, and also with imaging techniques. A new ultrasound contrast agent, SonoVue (Bracco SpA, Milano, Italy), is opening new perspectives in the study of microvasculature of several organs. Aim of this study is to evaluate by SonoVue enhanced ultrasonography (US) the occurrence of modifications in bowel wall microvasculature of CD patients and to correlate them with parameters of disease activity and to follow up the findings during infliximab therapy. After performing a basal color-doppler ultrasonography, the study of the affected bowel loop is performed after i.v. injection of SonoVue and the enhancement is evaluated on a qualitative basis. We report on the preliminary results obtained in twenty patients, eight of which have been treated with three infusions of infliximab (induction cycle) and evaluated at baseline and after the treatment. While at baseline we describe a positive correlation of SonoVue enhancement of the affected bowel loop with CRP, alpha1-glycoprotein and white blood cell number, after infliximab treatment in 6/8 cases a definite improvement was detected. Ultrasonographic evaluation of the changes of bowel wall enhancement after i.v. SonoVue during infliximab therapy might represent an useful, not invasive and relatively low cost imaging modality for the clinical monitoring of activity of small bowel Crohn's disease.     

Adalimumab maintenance therapy for Crohn's disease with intolerance or lost response to infliximab: an open-label study

BACKGROUND: Adalimumab is effective in inducing remission in patients with active Crohn's disease who had secondary failure to infliximab therapy. AIM: To evaluate the efficacy and safety of adalimumab maintenance therapy in Crohn's disease patients who previously responded to infliximab and then lost response or became intolerant. METHODS: Twenty-four patients with Crohn's disease were enrolled in a 52-week open-label trial. The patients received a loading dose of adalimumab 80-mg at week 0, and then 40 mg every other week starting at week 2. The primary efficacy measure was clinical remission defined as Crohn's Disease Activity Index score < 150 at week 52. RESULTS: Five patients lost response to adalimumab. None of the patients experienced intolerance to adalimumab. Clinical remission rates were higher at weeks 4 (16/24, 67%) and 52 (14/24, 58%) compared with baseline (8/24, 35%) (P=0.043 at week 52). This was accompanied by a decrease in mean C-reactive protein concentration from 31.8 mg/mL at baseline to 9.7 mg/mL at week 52, and 3/4 (75%) patients achieved steroid-free remission. No serious toxicities occurred in the study. CONCLUSIONS: Adalimumab is well tolerated and appears to be effective in maintaining clinical remission in patients with Crohn's disease and lost response or intolerance to infliximab.     

Maintenance infliximab does not result in increased abscess development in fistulizing Crohn's disease: results from the ACCENT II study

BACKGROUND: Rapid fistula healing may predispose Crohn's disease patients to abscess development. AIM: Data from ACCENT II were analysed to determine whether fistula-related abscess development is affected by infliximab exposure. METHODS: Following infliximab 5 mg/kg infusions at weeks 0, 2 and 6, patients were evaluated for fistula response for two consecutive visits at least 4 weeks apart. Patients (N = 282) were randomized at week 14 to either placebo or infliximab 5 mg/kg every 8 weeks through week 46. If response was lost at or after week 22, patients could crossover to a 5 mg/kg higher infliximab dose. Fistula-related abscesses were diagnosed by physical examination or by imaging procedures according to usual practice. RESULTS: Infliximab exposure was approximately twofold higher for the infliximab maintenance group. Twenty-one (15%) patients in the infliximab maintenance group had at least one newly developed fistula-related abscess compared with 27 (19%) in the placebo maintenance group (P = 0.526). The proportion of patients with a new fistula-related abscess was similar regardless of whether or not patients crossed over to a 5 mg/kg higher infliximab dose. The number of fistula-related abscesses diagnosed over time did not differ between groups. CONCLUSION: Abscess development in patients with fistulizing Crohn's disease is not dependent on cumulative infliximab exposure.     

Response to infliximab is related to disease duration in paediatric Crohn's disease

BACKGROUND: Infliximab is an effective therapy in adult patients with refractory and fistulizing Crohn's disease. Experience in children is still limited. AIM: : To evaluate the experience in 22 children and adolescents treated with infliximab with refractory and/or fistulizing Crohn's disease, and to compare duration of response in children between early Crohn's disease and late Crohn's disease. METHODS: The experience in 22 children and adolescents treated with a total of 73 infusions was evaluated retrospectively. Treatment indication was refractory Crohn's disease in 9/22 patients, fistulizing Crohn's disease in 7/22 patients and both these conditions in 6/22. All patients with refractory Crohn's disease had late Crohn's disease (> 1 year), whereas 6/13 patients with fistulas had early disease (< 1 year). RESULTS: Mean Paediatric Crohn's Disease Activity Index (PCDAI) decreased from 41.2 to 16.2 at 4 weeks (P < 0.01), and to 15.4 at 18 weeks (P < 0.01). Mean PCDAI at 18 weeks in children with early Crohn's disease and late Crohn's disease was 5.5 and 18.1, respectively (P < 0.05). Complete closure of fistulas was obtained in 5/6 children with early Crohn's disease and in 2/7 children with late Crohn's disease. Immediate adverse reactions were observed in two children. CONCLUSIONS: Infliximab is a highly effective treatment in children and adolescents with both severe refractory or fistulizing Crohn's disease. Children with early Crohn's disease have a higher chance of prolonged response to infliximab than children with late Crohn's disease.     

Appropriateness of therapy for fistulizing Crohn's disease: findings from a national inflammatory bowel disease cohort

Aliment Pharmacol Ther 2010; 32: 1007–1016

Summary

Background About 30–50% of patients with Crohn’s disease (CD) develop fistulae, implying significant disease burden and complicated clinical management. Aim To assess appropriate use of therapy for fistulizing CD patients enrolled in the Swiss Inflammatory Bowel Disease Cohort using criteria developed by the European Panel on the Appropriateness of Crohn’s disease Therapy. Methods Specific questionnaires were used to gather information on disease and its management. We assessed appropriateness of therapy at enrolment for adult CD patients with one or several fistulae. Results Two hundred and eighty‐eight CD patients had fistulizing disease, of which 80% had complex fistulae and 32% currently had active draining fistulae. Mean age (s.d.) at diagnosis was 27 years (11), 51% males. Of the patients, 78% were judged as having globally an appropriate therapy, which was more often given for complex fistulae (87%) than for simple fistulae (67%). Antibiotics, azathioprine/MP, methotrexate and conservative surgery were almost always appropriate. Anti‐tumor necrosis factor α was considered globally appropriate (91%), although most often with an uncertain indication. The 5ASA compounds, steroids and aggressive surgery were most often inappropriate (84%, 58% and 86% respectively). Conclusions Formal appropriateness criteria for CD therapy were applied to a national cohort of IBD patients. For more than three‐quarters of the patients with fistulizing CD, therapy was globally appropriate.     

An analysis of factors influencing short-term and sustained response to infliximab treatment for Crohn's disease

BACKGROUND: 59-81% of patients given infliximab for Crohn's disease will respond. Although now in widespread use, little consensus exists regarding the optimal place in patient care. Recently developed guidelines have identified need for markers that predict response. AIMS: We aimed to identify markers of response to infliximab given for Crohn's disease. METHODS: Markers of response (defined at 4 weeks) were prospectively assessed in 74 infliximab-treated patients with Crohn's disease. Patients were followed-up to 1 year. RESULTS: Fifty-four of 74 (73%) patients responded. Univariate analysis identified that smokers were less likely to respond than non-smokers [P = 0.005, odds ratio (OR) 0.22]. Patients established on immunosuppression (P = 0.034, OR 7.31) and with isolated colonic disease (P = 0.042, OR 3.83) were more likely to respond. Multiple logistic regression confirmed smoking (P = 0.035, OR 0.24) and colonic disease (P = 0.035, OR 4.87) as independent markers of response. One-year relapse rates differed significantly between smokers and non-smokers (100% vs. 39.6%, P = 0.0026, relative risk 3.2) and between patients established on immunomodulators or not (58.0% vs. 92.8%, P = 0.0054, relative risk 2.6). CONCLUSIONS: Smoking has a strong adverse effect on the response rates and maintenance of response to infliximab. Patients on immunomodulators have a more favourable short- and long-term response. These results have important implications for clinical practice.     

Association between polymorphism in IgG Fc receptor IIIa coding gene and biological response to infliximab in Crohn's disease

AIM: To test the hypothesis of an association between polymorphism in FCGR3A (the gene coding for FcgammaRIIIa, which is expressed on macrophages and natural killer cells, is involved in antibody-dependent cell-mediated cytotoxicity and has recently been associated with a positive response to rituximab, a recombinant immunoglobulin G1 antibody used in non-Hodgkin's lymphomas) and response to infliximab in Crohn's disease. METHODS: FCGR3A-158 polymorphism was determined using an allele-specific polymerase chain reaction assay in 200 Crohn's disease patients who had received infliximab for either refractory luminal (n = 142) or fistulizing (n = 58) Crohn's disease. Clinical and biological responses (according to C-reactive protein levels) were assessed in 200 and 145 patients, respectively. RESULTS: There were 82.9% clinical responders in V/V patients vs. 72.7% in V/F and F/F patients (N.S.). Globally, the decrease in C-reactive protein was significantly higher in V/V patients than in F carriers (P = 0.0078). A biological response was observed in 100% of V/V patients, compared with 69.8% of F carriers (P = 0.0002; relative risk, 1.43; 95% confidence interval, 1.27-1.61). In the sub-group of patients with elevated C-reactive protein before treatment, the multivariate analysis selected the use of immunosuppressive drugs and FCGR3A genotype as independent factors influencing the clinical response to infliximab (P = 0.003). CONCLUSION: Crohn's disease patients with FCGR3A-158 V/V genotype have a better biological and, possibly, clinical response to infliximab.     

Increased plasma ghrelin following infliximab in Crohn's disease

Background  Ghrelin, a potent orexigenic peptide produced by the stomach, may be affected by circulating inflammatory mediators.
Aim  To assess the effect of an anti-TNFα antibody on ghrelin in patients with Crohn's disease (CD).
Methods  Fifteen patients with Crohn's receiving infliximab were studied before and 1 week after infusion. Following an overnight fast, blood was sampled before a meal and then every 20 min for 2 h. Total ghrelin and CRP were measured using ELISA. Acylated ghrelin and TNFα, IFNγ, IL-1β and IL-6 were measured with bioplex. Harvey Bradshaw Activity Index was assessed.
Results  Median (95% CI) 2-h integrated plasma total ghrelin increased from 162 (99–311) before infliximab to 200 (128–387) pg/mL h, ( P  = 0.02) after. Following infliximab, 20 min postmeal, median acylated ghrelin decreased from 50.3 (24–64) to 38.6 (26–82) pg/mL, ( P  = 0.04) thus reverting to a traditional meal related ghrelin curve. Median (range) disease activity decreased from 5 (2–28) before to 3 (0–22), ( P  = 0.0001) and Median (95% CI) TNFα decreased from 2.8 (1.89–4.48) to 1.31 (0.73–2.06) pg/mL ( P  = 0.002).
Conclusions  Infliximab increases circulating total ghrelin by 25% in CD and restores the postprandial response of acylated ghrelin to food intake. Acylated and de-sacyl ghrelin remain unchanged, suggesting that an alternate isoform could be affected by infliximab.     

Adalimumab for Crohn's disease with intolerance or lost response to infliximab: a 3-year single-centre experience

Background  Adalimumab is effective in inducing clinical remission in patients with Crohn's disease who lost response or became intolerant to infliximab.
Aim  To evaluate long-term efficacy and safety of adalimumab as a second line therapy in luminal and fistulizing Crohn's disease.
Methods  We report our single-centre experience in 53 patients. We evaluated maintenance of clinical response defined as the absence of adverse events leading to drug withdrawal, no major abdominal surgery and no loss of clinical response in initial responders. Major abdominal surgery, steroid sparing, complete fistula closure and safety were also assessed.
Results  The probability of maintaining clinical response was 77.2%, 67.8% and 50.8% at 26, 52 and 130 weeks respectively. The probability of remaining major abdominal surgery-free was 82.3% at 26, 52 and 130 weeks. Complete fistula closure occurred in six of 10 patients, and eight of 10 patients were able to taper steroid therapy. Adverse events occurred in 31 patients (58.5%) leading to adalimumab withdrawal in nine patients (17%).
Conclusion  Adalimumab therapy may be effective in the long term in both luminal and fistulizing Crohn's disease in infliximab-failure patients, half of patients maintaining clinical response and potentially avoiding major abdominal surgery in 80% of cases.