Effectiveness of infliximab after adalimumab failure in Crohn's disease

AIM: To evaluate the effectiveness of infliximab as a second-line therapy in Crohn’s disease patients after adalimumab failure.METHODS: A historical cohort study in a community-based gastroenterology practice evaluated Crohn’s disease patients treated with infliximab (induction plus maintenance) after adalimumab failure. Patients were identified using a large Spanish database (ENEIDA).RESULTS: We included 15 Crohn’s disease patients who received infliximab after adalimumab failure. Five patients discontinued adalimumab due to loss of response, 3 due to adverse events and 7 due to partial response. After infliximab therapy was started, all patients who had interrupted adalimumab due to loss of efficacy regained response. All patients who discontinued adalimumab due to adverse events responded to infliximab and maintained this response; one of these patients had an uneventful course on infliximab, but 2 developed adverse events. None of the 7 patients who interrupted adalimumab due to partial response reached remission with infliximab.CONCLUSION: Switching from adalimumab to infliximab may be useful in patients who develop adverse effects or loss of response, however, the benefit of infliximab in primary nonresponders was not established.     

Clinical experience with infliximab and adalimumab in a single-center cohort of patients with Crohn's disease

Abstract

Background and aims: Patients with Crohn's disease (CD) may need anti-inflammatory drugs for decades. Anti-TNF-α agents have good efficacy and adverse events similar to placebo in randomized controlled trials (RCTs), but there are still questions about long-term safety and efficacy. In this respect, reports from clinical practice may be useful. We currently report on the clinical experience with infliximab and adalimumab in a single-center cohort of patients with CD. Material and Methods: Patients with CD treated with infliximab or adalimumab from 2000 to 2010 were reviewed. Patient and disease characteristics at start, reason for discontinuation, and adverse events were recorded retrospectively. Corticosteroid use, the need for hospitalization, and surgeries before and during anti-TNF-α therapy were recorded. Results: Eighty-three patients had received anti-TNF-α treatment against CD, median treatment duration was 11.4 months (0.2–99.5), and follow-up time 59 months (8–135). Eighteen of 43 patients using corticosteroids at treatment start discontinued corticosteroids during TNF-α therapy. Need for hospitalizations (6.13 vs. 3.28 days/year, p < 0.001) and surgeries (0.56 vs. 0.16 operations/year, p < 0.001) were lower during anti-TNF-α therapy than before treatment. Twenty-six percent discontinued therapy due to adverse events and 26% due to lack or loss of response. Two of four deaths observed during follow-up were believed to be related to anti-TNF-α treatment. Conclusions: Anti-TNF-α therapy was beneficial in many patients with CD, but the majority of patients discontinued treatment during follow-up. Reports from clinical experience with anti-TNF-α treatment may be valuable for clinicians treating patients with CD.     

Intravenous hydrocortisone premedication reduces antibodies to infliximab in Crohn's disease: a randomized controlled trial

BACKGROUND & AIMS: We assessed the relationship between antibodies to infliximab (ATI) and the loss of response postinfliximab, infusion reactions and, in a randomized trial, investigated whether intravenous hydrocortisone premedication can reduce ATI. METHODS: Initially, we prospectively evaluated clinical response, adverse events, and ATI levels in 53 consecutive patients with Crohn's disease who received 199 infliximab (5 mg/kg) infusions. Subsequently, 80 patients with Crohn's disease were randomized to intravenous hydrocortisone 200 mg or placebo immediately before their first and subsequent infliximab infusions. The primary endpoint was reduction in median ATI levels at week 16. Analysis was by intention to treat. RESULTS: Nineteen of our initial 53 patients (36%) developed ATI, including all 7 patients with serious infusion reactions (median ATI level, 19.6 microg/mL). Eleven of 15 patients (73%) who lost their initial response were ATI positive compared with none of 21 continuous responders, (8.9 vs. 0.7 microg/mL, P < 0.0001). Administering a second infusion within 8 weeks of the first (OR, 0.13; 95% CI, 0.03-0.5; P = 0.0007) or concurrent immunosuppressants (OR, 0.19; 95% CI, 0.04-1.03; P = 0.007) significantly reduced ATI formation. In the placebo-controlled trial, ATI levels were lower at week 16 among hydrocortisone-treated patients (1.6 vs. 3.4 microg/mL, P = 0.02), and 26% of hydrocortisone-treated patients developed ATI compared with 42% of placebo-treated patients, P = 0.06. CONCLUSIONS: Loss of initial response and infusion reactions post-infliximab is strongly related to ATI formation and level. Administering a second infusion within 8 weeks of the first and concurrent immunosuppressant therapy significantly reduce ATI formation. Intravenous hydrocortisone premedication significantly reduces ATI levels but does not eliminate ATI formation or infusion reactions.     

Evaluation of adalimumab therapy in multidisciplinary strategy for perianal Crohn's disease patients with infliximab failure

BackgroundInfliximab has improved the management of perianal Crohn's disease, but intolerance and loss of efficacy can occur. The use of a second antibody can be less effective.ObjectiveOur aim was to determine if the use of adalimumab, based on a multidisciplinary strategy, can enhance outcomes for patients with fistulizing disease and infliximab failure.Material and methodsSixteen patients with perianal disease and infliximab failure were treated with adalimumab. Complex fistulas were assessed using magnetic resonance imaging (MRI). Patients with severe conditions as determined by radiology were examined under anesthesia, and seton placement was performed when appropriate. Setons were removed when external discharge had ceased and there was no radiological evidence of fistula activity.ResultsNine patients (56%) underwent MRI. Setons were inserted in seven (43%). The baseline perianal disease activity index (PDAI) decreased after 4 weeks and remained at similar levels 24 and 48 weeks after treatment. The complete response rate was 50% after four weeks and 87.5% of these patients remained in remission after 48 weeks of treatment.ConclusionsFor patients with Crohn's perianal fistulas and infliximab failure, adalimumab as a multidisciplinary approach to management, using MRI to guide surgical drainage when necessary, results in a favourable response and low recurrence rate.     

Acute and delayed hypersensitivity reactions to infliximab and adalimumab in a patient with Crohn's disease

A 61 year old woman with active luminal Crohn's disease was successfully treated with infliximab induction therapy followed by 5 infusions every 8 weeks. However, symptoms returned in the weeks preceding the 7th and 8th infusions. The 9th infusion was therefore given only 4 weeks after the 8th infusion, but an acute severe anaphylactoid reaction occurred immediately after start of the infusion. Anti-infliximab IgG antibody concentration was high (100 U/ml) prior to the 8th infusion and up to 1 year after infliximab discontinuation (81 U/ml). Anti-infliximab IgE antibodies were not found, and the anti-infliximab antibodies did not cross react with adalimumab. One week after the anaphylactoid reaction to infliximab, adalimumab therapy was initiated. Twelve days after the first adalimumab administration (80 mg), a delayed hypersensitivity reaction occurred. This was likely caused by rapidly generated anti-adalimumab IgG antibodies (45 U/ml), as these antibodies appeared to be specific for adalimumab in that infliximab failed to compete with adalimumab/anti-adalimumab antibody binding ex vivo. In conclusion, immunogenicity to infliximab and adalimumab may be associated with both acute anaphylactoid reactions and delayed hypersensitivity reactions. Reactions may be precipitated by newly induced specific anti-drug antibodies rather than by cross-reactivity of previously generated antibodies.     

Profiles of circulating cytokines in patients with Crohn's disease under maintenance therapy with infliximab

Background and aimsThe effects of maintenance infliximab for Crohn's disease vary widely among patients. The aim of this study was to examine the cytokine profiles and to identify possible markers predictive of therapeutic effect of maintenance infliximab.MethodsCytokine profiles of 35 Crohn's disease patients under maintenance infliximab therapy were analyzed prospectively. Blood samples were obtained prior to, and 2 and 6 weeks after infliximab infusion. Circulating cytokine values of interleukin (IL)-23, IL-17A, IL-12, IL-6, interferon gamma (IFN-γ), and tumor necrosis factor alpha (TNF-α) were compared according to the disease activity and therapeutic efficacy. Patients were classified into either the active or quiescent phase according to their disease activity at baseline. Patients were also divided into a sustained response group and non-sustained response group according to therapeutic efficacy of infliximab determined 2 and 6 weeks after infliximab infusion.ResultsAt baseline, serum levels of IL-23 (p < 0.05), IL-17A (p < 0.01), IFN-γ (p < 0.05), and IL-6 (p < 0.01) were significantly higher in active Crohn's disease than in quiescent disease. These cytokine levels remained unchanged during the follow-up period. When serum cytokine levels were compared between groups classified by therapeutic efficacy of infliximab, patients in the non-sustained response group had a significantly higher level of serum IL-17A than those in the sustained response group (p < 0.05). There were also trends toward higher serum IL-23 and IL-12 in the former than in the latter.ConclusionHigher levels of IL-17A, IL-23, and IL-12 at baseline may be predictive markers for poor therapeutic response to maintenance infliximab therapy.     

Predictors of response to infliximab in patients with Crohn's disease

BACKGROUND & AIMS: Identifying predictors of response to infliximab in Crohn's disease may lead to better selection of patients for this therapy. METHODS: One hundred patients with either inflammatory or fistulous Crohn's disease and at least 3 months of follow-up after infliximab infusion were evaluated. Clinical response and duration of response were the primary outcome measures. RESULTS: For inflammatory disease, 73% of nonsmokers, compared with 22% of smokers, responded to infliximab (P < 0.001). Among patients taking concurrent immunosuppressives, 74% responded to infliximab compared with 39% not taking any immunosuppressives (P = 0.007). Prolonged response (duration >2 months) was achieved in 59% of nonsmokers compared with 6% of smokers (P < 0.001) and in 65% of patients on immunosuppressives compared with 18% not on immunosuppressives (P < 0.001). For fistulous disease, overall response rates were not different between nonsmokers and smokers, but nonsmokers had a longer duration of response (P = 0.046). Concurrent use of immunosuppressive medications had no effect on rate or duration of response. Multivariable logistic regression analysis confirmed the harmful effect of smoking and the beneficial effect of immunosuppressive use on response in patients with inflammatory disease. The same analysis for fistulous disease did not show an association between smoking or concurrent immunosuppressive use and response to infliximab. CONCLUSIONS: In patients with inflammatory disease, nonsmoking and concurrent immunosuppressive use are associated with higher rates of response and longer duration of response to infliximab. In patients with fistulous Crohn's disease, nonsmoking is associated with longer duration of response to infliximab.     

Retreatment and maintenance therapy with infliximab in fistulizing Crohn's disease.

OBJECTIVES: Infliximab has clearly demonstrated its efficacy in the short-term treatment of fistulizing Crohn's disease. We present here the results of retreatment and long-term maintenance therapy. PATIENTS AND METHODS: Eighty one consecutive patients with active fistulizing Crohn's disease, in whom previous treatments had failed, were treated with infliximab. All patients received as the initial treatment of 5 mg/kg i.v. infusions (weeks 0, 2, and 6). Those patients who failed to respond after the initial cycle (group 1, n = 25), or those who relapsed after having responded (group 2, n = 13), received retreatment with three similar doses (weeks 0,2, and 6). Those who responded to retreatment were included in a long-term maintenance programme (n = 44), with repeated doses (5 mg/kg i.v. infusions) every eight weeks for 1-2 years. RESULTS: In the initial treatment 56% of the patients responded partially; this response being complete in 44%. In the retreatment, 28% of group 1 (non-responders) presented a complete response, compared to 77% in group 2 (relapsers) (p < 0.0001). In the maintenance treatment, the global response was 88% (39/44). The mean number of doses per patient was 4.4 +/- 2 (range 1-9) with a duration of 36 +/- 12 weeks (range 8-72). Adverse effects were not significantly increased in either treatment. CONCLUSIONS: Both retreatment and long-term maintenance therapy with infliximab, are highly effective and well tolerated in fistulizing Crohn's disease patients.     

Effectiveness and safety of infliximab and adalimumab for ambulatory Crohn's disease patients in primary gastroenterology centres

BackgroundInfliximab (IFX) and adalimumab (ADA) are the key treatments for Crohn's Disease (CD), unresponsive to standard treatments. Our aim was to compare the efficacy and safety of IFX and ADA in treating CD in clinical practice.MethodsOne hundred and twenty-six patients (61 M, 65 F, mean age 36.2 years, range 19–67 years), affected by CD, were treated with infliximab (IFX, 59 patients) or adalimumab (ADA, 66 patients). Clinical efficacy, mucosal healing (MH), histological healing (HH), and safety were assessed. MH was defined complicated if healing of ulcers occurred with deformation of bowel profile and/or complete colonoscopy was impossible because of scars.ResultsPatients were followed-up for 36 months. No difference was found between IFX and ADA in maintaining long-term clinical remission, MH and HH. Complicated MH was present in 17 (28.8%) patients in IFX group and in 7 (10.6%) patients in ADA group (p = 0.012). In 9 (15.2%) patients in IFX group and 2 (3.0%) patients in ADA group colonoscopy was incomplete without cecal intubation or terminal ileum exploration (p = 0.024).Side effects were similar in both groups.ConclusionsBoth IFX and ADA seem to be effective and safe in long-term outpatient treatment of CD in clinical practice.     

Safety and efficacy of adalimumab (D2E7) in Crohn's disease patients with an attenuated response to infliximab

OBJECTIVES: Although infliximab is highly effective in the treatment of Crohn's disease (CD), attenuated response to infliximab may develop over time in a subgroup of patients. The aim of our study was to examine the safety and efficacy of adalimumab (D2E7), a fully humanized anti-TNF-alpha Ab, in CD patients who had experienced an attenuated response to infliximab. METHODS: Fifteen patients with active CD who experienced an attenuated response to infliximab were treated with adalimumab over a 6-month period. Patients, received a loading dose of 80 mg subcutaneously followed by 40 mg every 2 wk. The clinical response to adalimumab was classified as complete response, partial response, or nonresponse. RESULTS: Two patients received the loading dose of adalimumab but did not have adequate follow-up evaluations. Of the remaining 13 patients, 7 (54%) had a complete response, 4 (31%) had a partial response, and 2 (15%) were nonresponders. In six patients, the maintenance dose was increased in order to maintain clinical response. Eight of 11 (73%) patients on concurrent corticosteroids were able to discontinue or significantly decrease the dose of the steroids. Adalimumab was well tolerated without signs or symptoms of allergic reaction except in two patients who developed an injection site reaction. CONCLUSIONS: Our preliminary data suggest that adalimumab may be a safe and effective therapy for patients with CD who have experienced an attenuated response to infliximab.     

Combining infliximab with methotrexate for the induction and maintenance of remission in refractory Crohn's disease: a controlled pilot study

OBJECTIVES: Immunosuppression of chronic active Crohn's disease resistant or intolerant to purine antimetabolites still remains a clinical challenge. To obtain long-lasting effects with the anti-TNF-alpha antibody infliximab repeated infusions are often required. Methotrexate has been shown to be a moderately effective drug in maintaining remission in Crohn's disease. The aim of the present pilot study was to evaluate the combination of infliximab and methotrexate as therapy for refractory Crohn's disease. METHODS: Nineteen patients with chronic active Crohn's disease resistant or intolerant to azathioprine were enrolled. Patients received either two infusions of infliximab (5 mg/kg) alone (n=8) or in combination with long-term methotrexate at a dosage of 20 mg/week (n=11) over 48 weeks. RESULTS: Two out of eight patients receiving infliximab monotherapy and four out of 11 patients treated with infliximab and concomitant methotrexate had discontinued study treatment by week 48, solely because of lack of efficacy. Clinical remission at week 48 was observed in five out of seven patients treated with infliximab and methotrexate, but only in two out of six patients receiving infliximab monotherapy. In addition, patients treated with concomitant methotrexate achieved remission earlier (median time 2 versus 18 weeks) and needed fewer steroids (median prednisolone dose 0 versus 11.8 mg). Despite an increased mean number of adverse events per patient in the methotrexate group, the proportions of patients experiencing any adverse events and serious adverse events were similar across treatment groups. CONCLUSIONS: The combination of infliximab with long-term methotrexate may be a promising concept in refractory Crohn's disease. Our data prompt larger trials.     

Exploring the use of adalimumab for patients with moderate Crohn's disease: Subanalyses from induction and maintenance trials

BackgroundAnti-TNF agents are often reserved for patients with severe Crohn's disease (CD).AimsWe explored the predictive value of baseline disease activity and C-reactive protein (CRP) for disease course, adalimumab efficacy for remission (induction and maintenance) in patients with moderate and severe CD, and adalimumab efficacy in moderate CD by CRP category.MethodsPost hoc analyses of remission data were performed for all randomized patients from induction (CLASSIC I) and maintenance (CHARM, EXTEND) adalimumab trials in patients with moderate (CDAI ≤ 300) or severe (CDAI > 300) CD, and in high (≥ 10 mg/L) or low (< 10 mg/L) CRP moderate CD subgroups. Placebo-treated CHARM patients were evaluated for disease activity over time and time to CD-related hospitalization, by baseline disease severity and CRP.ResultsModerate CD patients had the highest clinical remission rate and largest treatment effect size compared with placebo at week 4 after 160/80 mg induction (46.3% adalimumab, 17.4% placebo; versus 22.9%, 3.6% for severe patients). Moderate-CD/high-CRP patients had the most pronounced efficacy (57.1% adalimumab, 6.7% placebo; versus 40.7%, 20.0% for lower CRP group). Adalimumab maintenance treatment (40 mg every-other-week) achieved superior remission versus placebo at one year in moderate (32.9% versus 13.7%) and severe (27.2% versus 7.5%) cohorts. Among moderate patients, efficacy was similar by CRP category. Moderate-CD/high-CRP placebo-treated patients experienced disease activity and hospitalization rates at week 56 of CHARM approaching those of severe CD patients.ConclusionsThis analysis suggests that moderate CD patients can be treated effectively with adalimumab, and supports using CRP to identify moderate CD patients at greatest risk of disease progression.