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.
Adalimumab; Biologics; Crohn’s disease; Infliximab; Switch
Crohn's disease is a chronic inflammatory bowel disease of unknown etiology which may affect any part of the bowel. Fistulas are a common and often serious complication of Crohn's disease. The treatment for fistulizing Crohn's disease can be medical, surgical or a combination of the two. Recently, adalimumab, a fully human anti-tumor necrosis factor monoclonal antibody, has been suggested as a safe and effective treatment for the induction and maintenance of remission in adult patients with moderate to severe Crohn's disease, who are refractory to conventional therapy or intolerant to infliximab. However, large studies focusing on evaluating the efficacy of adalimumab in fistulizing Crohn's disease have not yet been published.
We report the cases of three patients, of European Caucasian ethnicity and Greek nationality, with active luminal and fistulizing Crohn's disease. All of the cases were treated successfully with adalimumab. Patient 1 (a 44-year-old man) and patient 2 (an 18-year-old woman) developed early post-surgical enterocutaneous fistulas, while patient 3 (a 20-year-old woman) had peri-anal fistulizing Crohn's disease. Adalimumab treatment (160 mg subcutaneously at week zero, 80 mg at week two, and 40 mg every other week) was used for three different indications: (1) after the failure of other conservative medical treatments for Crohn's disease (patient 1); (2) as a monotherapy in treating a naive patient (patient 2); (3) after an intolerance to infliximab (patient 3). A remission of the active luminal and fistulizing disease was achieved soon after the initiation of adalimumab and sustained thereafter with maintenance doses. No further surgical intervention was required and no adverse effects were observed in any of the cases.
Fistulizing Crohn's disease remains a challenge in clinical practice. Adalimumab seems to be an effective, well-tolerated and safe treatment option for the induction and maintenance of remission in patients with moderate to severe peri-anal fistulizing Crohn's disease. Furthermore, adalimumab seems to be a promising treatment option for patients with moderate to severe fistulizing Crohn's disease with enterocutaneous fistulas. However, this clinical observation needs to be investigated in further clinical trials.
Orbital myositis is a rare extra-intestinal manifestation of inflammatory bowel disease. Seventeen cases of Crohn’s disease associated orbital myositis and 3 cases of ulcerative colitis associated orbital myositis have been reported in the published literature since 1970. We report the use of adalimumab (Abbott, Canada, Inc.) for orbital myositis in a patient with Crohn’s disease who discontinued infliximab (Janssen, Canada, Inc.) and review of the published literature.
A 35 year-old male with a 7-year history of Crohn’s disease was treated with an ileocolonic resection and re-anastomosis followed by infliximab which maintained full endoscopic and clinical remission for four years. After stopping the infliximab for infusion-related reactions he presented with 3-day history of severe right eye pain, pain with ocular movement, proptosis, and conjunctival injection. He had no intestinal symptoms and endoscopic assessment revealed no active luminal disease. CT of the orbit revealed an enlarged right medial rectus muscle with tendonous involvement and a diagnosis of orbital myositis was made. Treatment with 80 mg per day prednisone with tapering dose and adalimumab, induction and maintenance, resulted in rapid resolution of the orbital myositis and ocular symptoms with no recurrences on follow-up at 10 months.
The current case demonstrates a rare extraintestinal manifestation of Crohn’s disease, orbital myositis, and its temporal relationship to the discontinuance of infliximab therapy and its successful treatment, without recurrence with tapering prednisone and adalimumab.
Crohn’s disease; Ulcerative colitis; Orbital myositis; Extraintestinal manifestations; Inflammatory bowel disease; Infliximab; Adalimumab
Corticosteroids and immunomodulators have been the mainstay therapies for Crohn’s disease. Corticosteroids are highly effective to control symptoms in the short-term, but they are not effective in maintaining remission, they heal the mucosa in a reduced proportion of cases, and long-time exposure is associated with an increased risk of infections and mortality. Immunomodulators, azathioprine and methotrexate, heal the mucosa in a higher proportion of patients that corticosteroids but their onset of action is slow and they benefit less than half of patients with Crohn’s disease. In the last decade, medical therapy for Crohn’s disease has experienced a remarkable change due to the introduction of biologic therapy, and particularly the use of anti-tumour necrosis factor-alpha agents. Infliximab, adalimumab, and certolizumab pegol have demonstrated efficacy for induction and maintenance of remission in active Crohn’s disease. These agents have raised the bar for what is a suitable symptomatic response in Crohn’s disease and modification of the natural history of the disease has become a major goal in the treatment of Crohn’s disease. There are several data in the literature that suggest that early use of biologic therapy and achievement of mucosal healing contribute to disease course modification. However, many questions on early biological therapy for Crohn’s disease remain still unanswered.
Biologic therapy; Crohn’s disease; Corticosteroids; Immunomodulators
Anti-tumor necrosis factor alpha (TNF-α) medications are a class of biologics employed in the treatment of patients with inflammatory bowel disease (IBD). Adalimumab is the first fully human monoclonal immunoglobulin directed against TNF-α, which binds with high affinity and specificity to membrane and soluble TNF. Adalimumab administered subcutaneously has demonstrated efficacy in the treatment of rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, and severe chronic psoriasis. Studies have shown that adalimumab is effective for inducing and maintaining remission of moderate-to-severe active Crohn’s disease (CD) patients at an induction dose of 160/80 mg (week 0 and 2) and at a maintenance dose of 40 mg every other week. The efficacy of adalimumab as a second-line therapy has also been documented for patients with loss of response or intolerance to infliximab. Adalimumab is also superior to placebo for inducing and maintaining complete perianal fistula closure. It also seems effective for reducing extraintestinal manifestations. The safety profile is similar to that of other anti-TNF therapy in CD patients, with lower immunogenicity and rate of adverse injection reactions than infliximab. Adalimumab is not approved for the treatment of ulcerative colitis (UC). Recently, however, the results of the first randomized, controlled trial on adalimumab for UC showed that adalimumab at 160/80 mg induction dose was safe and effective for inducing remission and clinical response after 8 weeks in patients with moderately-to-severely active UC failing treatment with corticosteroids and/or immunosuppressants. More data are necessary to clarify the therapeutic role of adalimumab in UC. This review of the literature summarizes available data on the efficacy and safety profile adalimumab in patients with IBD.
anti-TNF-α; adalimumab; Crohn’s disease; ulcerative colitis
Mucosal healing is gaining more acceptance as a measure of disease activity in Crohn's disease and ulcerative colitis, and it is also gaining acceptance as an endpoint in clinical trials. Recent publications have correlated achievement of mucosal healing with good outcomes. Currently, there is no validated definition of what constitutes mucosal healing in inflammatory bowel disease. In clinical trials of ulcerative colitis, mucosal healing has been achieved with 5-aminosalicylates, corticosteroids, azathioprine, and infliximab. For Crohn's disease, mucosal healing has been achieved with corticosteroids, infliximab, and adalimumab, and mucosal healing has been maintained with infliximab. Achievement of long-term mucosal healing has been associated with a decreased risk of colectomy and colorectal cancer in ulcerative colitis patients, a decreased need for cortico-steroid treatment in Crohn's disease patients, and a trend toward a decreased need for hospitalization in Crohn's disease patients. Unfortunately, assessment of mucosal healing requires regular use of endoscopy, which is associated with increased costs, patient discomfort, and side effects. Biomarkers such as fecal calprotec-tin, fecal lactoferrin, serum C-reactive protein, and fecal S1 00A1 2 have been shown to correlate with disease activity in ulcerative colitis and Crohn's disease; in the future, these biomarkers might be used as surrogate markers for mucosal healing. Newer clinical trials are incorporating mucosal healing as an endpoint for evaluation of efficacy. However, before mucosal healing will be sufficient to guide therapy, clinicians need a standard definition of mucosal healing and a consistently used, prospectively validated scale with good interobserver agreement.
Mucosal healing; ulcerative colitis; Crohn's disease; anti—tumor necrosis factor agents; corticosteroids; colonoscopy
Anti-tumour necrosis factor-α (TNF) therapy has revolutionised the management of chronic inflammatory conditions. With ever increasing numbers of patients being treated with these agents, uncommon adverse reactions will inevitably occur more frequently. Cutaneous manifestations are associated with many of these chronic conditions and can complicate anti-TNF therapy in about 20% of cases. Vasculitic complications are rarely associated with anti-TNF therapy. Henoch-Schönlein purpura (HSP), a small vessel vasculitis, has been described following infliximab and etanercept therapy but never with adalimumab, a fully humanized TNF antibody. The risk of such immune-mediated reactions is theoretically less with adalimumab compared to infliximab but can still occur. Here we report the first case in the literature of HSP that can be attributed to the use of adalimumab in a 19-year-old male with recalcitrant Crohn’s disease.
Henoch-Schönlein purpura; Adalimumab; Anti-TNF therapy; Leukocytoclastic vasculitis; Crohn's disease
A 46-year-old female patient with terminal ileum Crohn’s disease and ankylosing spondylitis presented with recurrent angioedema and urticaria. Investigations ruled out hereditary angioedema, and environmental or food allergen triggers. She was diagnosed with chronic idiopathic urticaria with angioedema, and was treated with a trial of intravenous immunoglobulin immunotherapy, danazol, prednisone and hydroxyzine. Due to ongoing bowel and arthritic complaints, she was started on infliximab infusions and within 2 treatments, she had complete resolution of the angioedema and urticaria, as well as of the bowel and arthritic symptoms. Unfortunately she developed allergic reactions to the infliximab and was switched to another anti-tumor necrosis factor (TNF)-α agent, adalimumab. Since then, she has had no further angioedema or urticaria, and her Crohn’s disease has been quiescent. This is the first known case report of chronic idiopathic urticaria with angioedema coexistent with Crohn’s disease that was successfully treated with anti-TNF-α agents.
Angioedema; Anti-tumor necrosis factor-α; Biologics; Crohn’s disease; Cytokines; Inflammatory bowel disease; Infliximab; Urticaria
The anti-tumor necrosis factor (TNF)α medications demonstrate efficacy in the induction of remission and its maintenance in numerous chronic inflammatory conditions. With the increasing number of patients receiving anti-TNFα agents, however, less common adverse reactions will occur. Cutaneous eruptions complicating treatment with an anti-TNFα agent are not uncommon, occurring in around 20% of patients. Adalimumab, a fully humanized antibody against TNFα, may be expected to cause minimal immune-mediated skin reactions compared to the chimeric monoclonal antibody, infliximab. We, however, report a case of Stevens-Johnson syndrome that required hospitalization and cessation of adalimumab in a patient with Crohn’s disease (CD). In this case report, a 29-year-old male with colonic and perianal CD with associated erythema nodosum and large joint arthropathy developed severe mucositis, peripheral rash and desquamation, fevers and respiratory symptoms concomitant with a second dose of 40 mg adalimumab after a 2 mo break from adalimumab therapy. Skin biopsies of the abdominal wall confirmed erythema multiforme and the patient was on no other drugs and infective etiologies were excluded. The patient responded rapidly to IV hydrocortisone and was able to be commenced on infliximab without recurrence of the Stevens-Johnson syndrome. Desquamating skin reactions have now been described in three of the TNFα antagonists (infliximab, etanercept and adalimumab). These reactions can be serious and prescribers need to be aware of the potential mucocutaneous side effects of these agents, especially as Stevens-Johnson syndrome is associated with significant morbidity and mortality.
Stevens-Johnson syndrome; Crohn’s disease; Adalimumab; Serious adverse effect
Pulmonary abnormalities are not frequently encountered in patients with inflammatory bowel diseases. However, lung toxicity can be induced by conventional medications used to maintain remission, and similar evidence is also emerging for biologics. We present the case of a young woman affected by colonic Crohn’s disease who was treated with oral mesalamine and became steroid-dependent and refractory to azathioprine and adalimumab. She was referred to our clinic with a severe relapse and was treated with infliximab, an anti-tumor necrosis factor α (TNF-α) antibody, to induce remission. After an initial benefit, with decreases in bowel movements, rectal bleeding and C-reactive protein levels, she experienced shortness of breath after the 5th infusion. Noninfectious interstitial lung disease was diagnosed. Both mesalamine and infliximab were discontinued, and steroids were introduced with slow but progressive improvement of symptoms, radiology and functional tests. This represents a rare case of interstitial lung disease associated with infliximab therapy and the effect of drug withdrawal on these lung alterations. Given the increasing use of anti-TNF-α therapies and the increasing reports of pulmonary abnormalities in patients with inflammatory bowel diseases, this case underlines the importance of a careful evaluation of respiratory symptoms in patients undergoing infliximab therapy.
Interstitial lung disease; Crohn’s disease; Infliximab; Mesalamine; Drug-induced toxicity
Background: There is little information about the effect of infliximab on the clinical course of liver disease in Crohn’s disease patients with concomitant hepatitis B virus (HBV) infection. Theoretically, immunosuppression induced by infliximab will facilitate viral replication which could be followed by a flare or exacerbation of disease when therapy is discontinued. There are no specific recommendations on surveillance and treatment of HBV before infliximab infusion. Two cases of severe hepatic failure related to infliximab infusions have been described in patients with rheumatic diseases.
Patients and methods: Hepatitis markers (C and B) and liver function tests were prospectively determined to 80 Crohn’s disease patients requiring infliximab infusion in three hospitals in Spain.
Results: Three Crohn’s disease patients with chronic HBV infection were identified. Two of the three patients with chronic HBV infection suffered severe reactivation of chronic hepatitis B after withdrawal of infliximab therapy and one died. A third patient, who was treated with lamivudine at the time of infliximab therapy, had no clinical or biochemical worsening of liver disease during or after therapy. From the remaining 80 patients, six received the hepatitis B vaccine. Three patients had antibodies to both hepatitis B surface antigen (anti-HBs) and hepatitis B core protein (anti-HBc) with normal aminotransferase levels, and one patient had positive anti-hepatitis C virus (HCV) antibodies, negative HCV RNA, and normal aminotransferase levels. Except for the patients with chronic HBV infection, no significant changes in hepatic function were detected.
Conclusions: Patients with Crohn’s disease who are candidates for infliximab therapy should be tested for hepatitis B serological markers before treatment and considered for prophylaxis of reactivation using antiviral therapy if positive.
Crohn’s disease; infliximab; chronic hepatitis B
The advent of anti-tumor necrosis factor (TNF) therapies revolutionized the treatment of inflammatory bowel disease. Adalimumab is a subcutaneous anti-TNF agent indicated for use in patients with moderate-to-severe Crohn’s disease and those with moderate-to-severe ulcerative colitis. In both diseases, it can be used for both induction of remission and for maintenance of remission. This review focuses on its use in Crohn’s disease as described in the EXTEND (Extend the Safety and Efficacy of Adalimumab through Endoscopic Healing) trial. Several clinical trials using traditional instruments to measure clinical response have had endoscopic substudies looking for endoscopic healing. The EXTEND trial is the first to use mucosal healing on endoscopy as a primary endpoint for patients with moderate-to-severe Crohn’s disease and baseline ulcerative disease treated with continuous adalimumab. In this well designed trial, the primary endpoint was narrowly missed, but the secondary endpoints further the notion that mucosal healing should be a more mainstream measure of drug efficacy. How this will translate from clinical trials to the clinic is not yet clear, but identifying noninvasive markers for mucosal healing, and understanding the implications of mucosal healing for safety, resource utilization, and quality of life are all worthy targets for further study. The aim of this review is to understand the role of mucosal healing, safety profile, and efficacy in patients treated with anti-TNF therapy, with particular attention to adalimumab and the EXTEND trial.
Crohn’s disease; tumor necrosis factor; adalimumab; clinical trials; inflammatory bowel disease
Crohn's disease is characterized by chronic inflammation involving any portion of the gastrointestinal tract. Treating Crohn's disease is a major challenge for clinicians, as no curative therapy currently exists. Pediatric Crohn's disease is characterized by frequent relapses, a wide extent of disease, a high prevalence of extraintestinal manifestations, and a severe clinical course. The classic therapeutic approach is known as the 'step-up' strategy, and follows a progressive course of treatment intensification as disease severity increases. Although this approach is usually effective for symptom control, many patients become either resistant to or dependent on corticosteroids. The efficacy of infliximab suggests that, rather than a progressive course of treatment, early intense induction may reduce complications associated with conventional treatment and improve quality of life. Intensive early therapy with infliximab is known as the 'top-down' strategy. Such therapy offers the potential for altering the natural history of Crohn's disease, and is changing treatment paradigms. However, the relatively new concept of an early aggressive or 'top-down' treatment approach is not yet widely accepted, especially in pediatric patients. The results of our current study demonstrate that early and intensive treatment of pediatric Crohn's disease patients with infliximab, at initial diagnosis, was more effective for maintaining remission and reducing flares.
Crohn's disease; Child; Treatment
Ankylosing spondylitis (AS) is a member of the family of spondyloarthropathies, which are inflammatory arthritides largely involving the axial skeleton and commonly accompanied by peripheral arthritis. Genetic factors, particularly the presence of HLA-B27, are major contributors to the susceptibility for AS. Despite some therapeutic advances, the treatment options for patients with AS and related disorders have been limited. Several lines of evidence have led to the hypothesis that patients with AS might benefit from treatment with tumor necrosis factor (TNF). Specifically, TNF concentrations are known to be significantly elevated in the synovium of patients with rheumatoid arthritis (RA), in the inflamed gut of patients with inflammatory bowel disease, and in the inflamed sacroiliac joints of patients with AS. The anti-TNF agents have been shown to be of benefit in, and currently have indications for, RA (etanercept, infliximab, adalimumab), Crohn's disease (infliximab), and psoriatic arthritis (etanercept). Because the spondyloarthropathies share pathogenetic mechanisms with the above-specified disease states, studies have been conducted to evaluate the effectiveness of anti-TNF agents in several disorders, including AS. Data from clinical trials so far with infliximab and etanercept show that patients with AS and related disorders achieve significant improvement in clinical signs and symptoms based on validated outcomes measures. Computed tomography and magnetic resonance imaging (MRI) can facilitate the early diagnosis of AS. Studies with infliximab using MRI together with updated scoring methods demonstrated significant decreases in associated spinal inflammation. TNF antagonist therapy is well tolerated in patients with AS, with a side effect profile consistent with the prior experience of patients with RA.
efficacy; etanercept; infliximab; spondyloarthropathies; tumor necrosis factor
Adalimumab induced clinical remission after four weeks in patients with active Crohn's disease in the CLASSIC I trial.
To evaluate long term efficacy and safety of adalimumab maintenance therapy in Crohn's disease in a follow‐on randomised controlled trial (CLASSIC II).
In the preceding CLASSIC I trial, 299 patients with moderate to severe Crohn's disease naive to tumour necrosis factor antagonists received induction therapy with adalimumab 40 mg/20 mg, 80 mg/40 mg, or 160 mg/80 mg, or placebo, at weeks 0 and 2. In all, 276 patients from CLASSIC I enrolled in CLASSIC II and received open‐label adalimumab 40 mg at weeks 0 (week 4 of CLASSIC I) and 2; 55 patients in remission at both weeks 0 and 4 were re‐randomised to adalimumab 40 mg every other week, 40 mg weekly, or placebo for 56 weeks. Patients not in remission at both weeks 0 and 4 were enrolled in an open‐label arm and received adalimumab 40 mg every other week. With non‐response or flare, these patients could have their dosages increased to 40 mg weekly. Patients in the randomised arm with continued non‐response or disease flare could switch to open‐label adalimumab 40 mg every other week and again to 40 mg weekly. The primary end point was maintenance of remission (CDAI <150) in randomised patients through week 56.
Of 55 patients randomised at week 4, 79% who received adalimumab 40 mg every other week and 83% who received 40 mg weekly were in remission at week 56, v 44% for placebo (p<0.05). In all, 204 patients entered the open‐label arm. Of these, 93 (46%) were in clinical remission at week 56. Adalimumab was generally well‐tolerated in all patients.
Adalimumab induced and maintained clinical remission for up to 56 weeks in patients with moderate to severe Crohn's disease naive to anti‐TNF treatment.
gastroenterology; Crohn's disease; adalimumab; tumour necrosis factor antagonists; randomised controlled trial
Adalimumab (ADA) is applied to induce remission in patients with Crohn's disease (CD) naïve to chimeric anti-tumor necrosis factor-α (anti-TNF-α), infliximab or patients with loss of response to scheduled maintenance infliximab. Adsorptive granulocyte and monocyte apheresis (GMA) depletes elevated/activated myeloid lineage leucocytes as sources of inflammatory cytokines and has been used to treat patients with CD. This study was to investigate the efficacy of intensive GMA in combination with ADA as remission induction therapy in cases of CD refractory to medications including anti-TNF-α therapies. Between December 2010 and February 2012, 5 consecutive cases with refractory CD were treated with intensive GMA (2 sessions per week) plus ADA to induce remission. CD activity index (CDAI), C-reactive protein (CRP), and endoscopic findings based on the simple endoscopic score for CD (SES-CD) at baseline and 10 weeks post 5 ADA injections were applied to determine treatment efficacy outcomes. At week 10 post ADA treatment, clinical remission together with normal CRP levels were achieved in all 5 cases, while SES-CD scores reflected marked improvement in 3 cases and partial improvement in 2 cases who had extensive deep longitudinal CD lesions. The CDAI and CRP values at baseline were 324 ± 118 and 4.9 ± 3.3 mg/dl, respectively. The corresponding values after treatment were 100 ± 28 (p = 0.024) and 0.2 ± 0.2 mg/dl (p = 0.038). In these 5 cases with medication-refractory CD, combination therapy with intensive GMA followed by 5 ADA shots appeared to be an effective and safe intervention for inducing clinical remission.
Refractory Crohn's disease; Adalimumab; Intensive adsorptive granulocyte and monocyte apheresis; Clinical remission; Simple endoscopic score for Crohn's disease
Infliximab is a monoclonal antibody against tumor necrosis factor (TNF) which has become an established therapy for Crohn’s disease over the last 10 years. Given the similarities between Crohn’s disease and ulcerative colitis (UC), it is no surprise that gastroenterologists have used infliximab in patients with UC who have failed other therapies. Although the initial controlled trials with infliximab in steroid-refractory disease were unimpressive, subsequent controlled trials have demonstrated the efficacy of infliximab in both moderate to severe disease, and as rescue-therapy to avoid colectomy. The long-term remission rates, colectomy-sparing effects, and the impact of concomitant immunomodulator therapy, remain to be determined in these patients. Whether infliximab is a superior strategy to cyclosporine in patients with steroid-refractory disease is controversial. This review examines the data on the efficacy and safety of infliximab as an induction and maintenance agent for UC.
ulcerative colitis; infliximab; biologics
To assess the effect of adalimumab on work productivity and indirect costs in patients with Crohn’s disease (CD) using a meta-analysis of clinical trials.
Study-level results were pooled from all clinical trials of adalimumab for moderate to severe CD in which work productivity outcomes were evaluated. Work Productivity and Activity Impairment Questionnaire outcomes (absenteeism, presenteeism and total work productivity impairment [TWPI]) were extracted from adalimumab trials. Meta-analyses were used to estimate pooled averages and 95% CIs of one-year accumulated reductions in work productivity impairment with adalimumab. Pooled averages were multiplied by the 2008 United States national average annual salary ($44,101) to estimate per-patient indirect cost savings during the year following adalimumab initiation.
The four included trials (ACCESS, CARE, CHOICE and EXTEND) represented a total of 1202 employed adalimumab-treated patients at baseline. Each study followed patients for a minimum of 20 weeks. Pooled estimates (95% CIs) of one-year accumulated work productivity improvements were as follows: −9% (−10% to −7%) for absenteeism; −22% (−26% to −18%) for presenteeism; and −25% (−30% to −20%) for TWPI. Reductions in absenteeism and TWPI translated into per-patient indirect cost savings (95% CI) of $3,856 ($3,183 to $4,529) and $10,964 ($8,833 to $13,096), respectively.
Adalimumab provided clinically meaningful improvements in work productivity among patients with moderate to severe CD, which may translate into substantial indirect cost savings from an employer’s perspective.
Adalimumab; Crohn’s disease; Indirect costs; Work productivity
With the availability of infliximab, nowadays recurrent Crohn's disease, defined as disease refractory to immunomodulatory agents that has been treated with steroids, is generally treated with infliximab. Infliximab is an effective but expensive treatment and once started it is unclear when therapy can be discontinued. Surgical resection has been the golden standard in recurrent Crohn's disease. Laparoscopic ileocolic resection proved to be safe and is characterized by a quick symptom reduction.
The objective of this study is to compare infliximab treatment with laparoscopic ileocolic resection in patients with recurrent Crohn's disease of the distal ileum with respect to quality of life and costs.
The study is designed as a multicenter randomized clinical trial including patients with Crohn's disease located in the terminal ileum that require infliximab treatment following recent consensus statements on inflammatory bowel disease treatment: moderate to severe disease activity in patients that fail to respond to steroid therapy or immunomodulatory therapy. Patients will be randomized to receive either infliximab or undergo a laparoscopic ileocolic resection. Primary outcomes are quality of life and costs. Secondary outcomes are hospital stay, early and late morbidity, sick leave and surgical recurrence. In order to detect an effect size of 0.5 on the Inflammatory Bowel Disease Questionnaire at a 5% two sided significance level with a power of 80%, a sample size of 65 patients per treatment group can be calculated. An economic evaluation will be performed by assessing the marginal direct medical, non-medical and time costs and the costs per Quality Adjusted Life Year (QALY) will be calculated. For both treatment strategies a cost-utility ratio will be calculated. Patients will be included from December 2007.
The LIR!C-trial is a randomized multicenter trial that will provide evidence whether infliximab treatment or surgery is the best treatment for recurrent distal ileitis in Crohn's disease.
Nederlands Trial Register NTR1150
Background and aims: Treatment with infliximab induces remission in about 70% of patients with steroid refractory Crohn's disease. Because Crohn's disease is considered to be mediated by uncontrolled activation of mucosal T lymphocytes, we hypothesised that infliximab could induce apoptosis of T lymphocytes.
Methods: Induction of apoptosis in vivo was studied in 10 patients with therapy refractory Crohn's disease. In vitro, resting or stimulated Jurkat T cells were incubated with infliximab.
Results: Infusion of infliximab (5 mg/kg) in steroid refractory patients with Crohn's disease induced a clinical response in 9/10 patients but did not influence expression of activation markers, homing receptors, memory cells, Fas expression, or Bax/Bcl-2 expression on peripheral blood T lymphocytes. In contrast, a significant increase in CD3 and TUNEL positive cells within colonic biopsies was detected 24 hours after infusion of infliximab, suggesting that infliximab stimulates apoptosis of activated T lymphocytes but not of resting T cells. To test this hypothesis, the effects of infliximab on Jurkat T cells were investigated. We observed that infliximab induced apoptosis and an increase in the Bax/Bcl-2 ratio of CD3/CD28 stimulated Jurkat T cells but not of unstimulated Jurkat cells.
Conclusions: Our data indicate that infliximab treatment causes a rapid and specific increase in apoptosis of T lymphocytes in the gut mucosa. These findings may explain the rapid and sustained therapeutic effects of infliximab in Crohn's disease.
apoptosis; T lymphocytes; Crohn's disease; infliximab; tumour necrosis factor
AIM: To assess adalimumab’s efficacy with concomitant azathioprine (AZA) for induction and maintenance of clinical remission in Japanese Crohn’s disease (CD) patients.
METHODS: This retrospective, observational, single-center study enrolled 28 consecutive CD patients treated with adalimumab (ADA). Mean age and mean disease duration were 38.1 ± 11.8 years and 11.8 ± 10.1 years, respectively. The baseline mean Crohn’s disease activity index (CDAI) and C-reactive protein were 177.8 ± 82.0 and 0.70 ± 0.83 mg/dL, respectively. Twelve of these patients also received a concomitant stable dose of AZA. ADA was subcutaneously administered: 160 mg at week 0, 80 mg at week 2, followed by 40 mg every other week. Clinical response and remission rates were assessed via CDAI and C-reactive protein for 24 wk.
RESULTS: The mean CDAI at weeks 2, 4, 8, and 24 was 124.4, 120.2, 123.6, and 135.1, respectively. The CDAI was significantly decreased at weeks 2 and 4 with ADA and was significantly suppressed at 24 wk with ADA/AZA. Overall clinical remission rates at weeks 4 and 24 were 66.7% and 63.2%, respectively. Although no statistically significant difference in C-reactive protein was demonstrated, ADA with AZA resulted in a greater statistically significant improvement in CDAI at 24 wk, compared to ADA alone.
CONCLUSION: Scheduled ADA with concomitant AZA may be more effective for clinical remission achievement at 24 wk in Japanese Crohn’s disease patients.
Crohn’s disease; Adalimumab; Immunomodulator; Azathioprine; Inflammatory bowel disease
Crohn’s disease (CD) is a chronic relapsing and remitting autoinflammatory disorder of the gastrointestinal tract that has many intestinal and extraintestinal complications. The purpose of treatment is long-term remission, reduction of complications, and improvement of patients’ quality of life. In many cases, this can be quite challenging and it is necessary to have a well thought out management strategy. We present the case of a 38-year-old woman with fistulizing CD that manifested as diffuse abdominal pain and bloody diarrhea accompanied by arthralgia. In addition, there were ulcerative lesions surrounded by cutaneous inflammation and erythema on her extremities, indicative of pyoderma gangrenosum. The patient was treated with high doses of parenteral methylprednisolone without any improvement and was started on adalimumab. A positive response to adalimumab therapy was observed: after 2 mo of therapy, the ulcerative skin lesion healed completely and the enterogastric fistula was closed after 5 mo adalimumab treatment. Adalimumab might be a suitable initial as well as maintenance therapy in patients with complicated CD.
Adalimumab; Crohn’s disease; Pyoderma gangrenosum
OBJECTIVE: To examine clinical characteristics, laboratory features, and outcomes of patients with lupus-like syndrome attributable to anti—tumor necrosis factor α (TNF-α) therapy.
PATIENTS AND METHODS: We performed a retrospective review of patients with lupus-like syndrome attributable to anti—TNF-α therapy at Mayo Clinic's site in Rochester, MN, between July 1, 2000, and June 30, 2008.
RESULTS: Of 14 patients (mean age at disease onset, 46.2 years), 12 (86%) were female. Ten patients (71%) had Crohn disease, and 4 (29%) had rheumatoid arthritis. Thirteen patients (93%) originally were treated with infliximab, and 1 (7%) was treated with adalimumab. A lupus-ike syndrome occurred after a mean treatment duration of 16.2 months. Features of lupus included presence of antinuclear antibodies (14 patients [100%]), arthritis (13 patients [93%]), anti—double-stranded-DNA antibodies (10 patients [71%]), cutaneous findings (malar rash, discoid rash, or photosensitivity, 4 patients [29%]), serositis (4 patients [29%]), hematologic abnormalities (4 patients [29%]), oral ulcers (4 patients [29%]), and lupus anticoagulant (1 patient [7%]). No patient had renal or neurologic abnormalities. All patients improved after stopping anti—TNF-α therapy (mean time to improvement, 2.9 months). Four (80%) of 5 patients tolerated an alternative TNF-α inhibitor (adalimumab, 3 patients; etanercept, 1 patient) without recurrence of lupus-like syndrome.
CONCLUSION: Compared with previous studies, cutaneous findings were less frequent and arthritis was more frequent in our cohort of patients. Some patients were able to tolerate an alternative TNF-α inhibitor without recurrence of lupus-like syndrome.
The authors compared clinical characteristics, laboratory features, and outcomes of patients with lupus-like syndrome attributable to anti—tumor necrosis factor α therapy and noted that, compared with previous studies, cutaneous findings were less frequent and arthritis was more frequent in their patients. Some patients were able to tolerate an alternative anti—tumor necrosis factor α inhibitor without recurrent lupus-like syndrome.
Infliximab is usually administered by two monthly intravenous (iv) infusions, therefore requiring visits to hospital. Adalimumab is administered by self subcutaneous (sc) injections every other week. Both of these anti-TNF drugs appear to be equally efficacious in the treatment of Crohn's Disease and therefore the decision regarding which drug to choose will depend to some extent on patient choice, which may be based on the mode of administration.
The aims of this study were to compare preferences in Inflammatory Bowel Disease (IBD) patients for two currently available anti-TNF agents and the reasons for their choices.
An anonymous questionnaire was distributed to IBD patients who had attended the Gastroenterology service (Ulster Hospital, Dundonald, Belfast, N. Ireland. UK) between January 2007 and December 2007. The patients were asked in a hypothetical situation if the following administering methods of anti-TNF drugs (intravenous or subcutaneous) were available, which drug route of administration would they choose.
One hundred and twenty-five patients fulfilled the inclusion criteria and were issued questionnaires, of these 78 questionnaires were returned (62 percent response). The mean age of respondent was 44 years. Of the total number of respondents, 33 patients (42 percent) preferred infliximab and 19 patients (24 percent) preferred adalimumab (p = 0.07). Twenty-six patients (33 percent) did not indicate a preference for either biological therapy and were not included in the final analysis. The commonest reason cited for those who chose infliximab (iv) was: "I do not like the idea of self-injecting," (67 percent). For those patients who preferred adalimumab (sc) the commonest reason cited was: "I prefer the convenience of injecting at home," (79 percent). Of those patients who had previously been treated with an anti-TNF therapy (n = 10, all infliximab) six patients stated that they would prefer infliximab if given the choice in the future (p = 0.75).
There was a trend towards patient preference for infliximab (iv) treatment as opposed to adalimumab (sc) in patients with IBD. This difference may be due to the frequency of administration, mode of administration or differing 'times in the market-place', as infliximab had been approved for a longer period of time in Crohn's disease. Further studies are required in IBD patients to investigate whether patient choice will affect compliance, patient satisfaction and efficacy of treatment with anti-TNF therapies.
Reactivation of latent Mycobacterium tuberculosis (Mtb) infection is a major complication of anti-tumour necrosis factor (TNF)-α treatment, but its mechanism is not fully understood. We evaluated the effect of the TNF antagonists infliximab (Ifx), adalimumab (Ada) and etanercept (Eta) on anti-mycobacterial immune responses in two conditions: with ex vivo studies from patients treated with TNF antagonists and with the in vitro addition of TNF antagonists to cells stimulated with mycobacterial antigens. In both cases, we analysed the response of CD4+ T lymphocytes to purified protein derivative (PPD) and to culture filtrate protein (CFP)-10, an antigen restricted to Mtb. The tests performed were lymphoproliferation and immediate production of interferon (IFN)-γ. In the 68 patients with inflammatory diseases (rheumatoid arthritis, spondylarthropathy or Crohn's disease), including 31 patients with a previous or latent tuberculosis (TB), 14 weeks of anti-TNF-α treatment had no effect on the proliferation of CD4+ T lymphocytes. In contrast, the number of IFN-γ-releasing CD4+ T lymphocytes decreased for PPD (p < 0.005) and CFP-10 (p < 0.01) in patients with previous TB and for PPD (p < 0.05) in other patients (all vaccinated with Bacille Calmette-Guérin). Treatments with Ifx and with Eta affected IFN-γ release to a similar extent. In vitro addition of TNF antagonists to CD4+ T lymphocytes stimulated with mycobacterial antigens inhibited their proliferation and their expression of membrane-bound TNF (mTNF). These effects occurred late in cultures, suggesting a direct effect of TNF antagonists on activated mTNF+ CD4+ T lymphocytes, and Ifx and Ada were more efficient than Eta. Therefore, TNF antagonists have a dual action on anti-mycobacterial CD4+ T lymphocytes. Administered in vivo, they decrease the frequency of the subpopulation of memory CD4+ T lymphocytes rapidly releasing IFN-γ upon challenge with mycobacterial antigens. Added in vitro, they inhibit the activation of CD4+ T lymphocytes by mycobacterial antigens. Such a dual effect may explain the increased incidence of TB in patients treated with TNF antagonists as well as possible differences between TNF antagonists for the incidence and the clinical presentation of TB reactivation.