Genetic polymorphisms predict response to anti-tumor necrosis factor treatment in Crohn's disease

AIM To investigate genetic factors that might help define which Crohn's disease(CD) patients are likely to benefit from anti-tumor necrosis factor(TNF) therapy. METHODS This was a prospective cohort study. Patients wererecruited from a university digestive disease practice database. We included CD patients who received antiTNF therapy,had available medical records(with information on treatment duration and efficacy) and who consented to participation. Patients with allergic reactions were excluded. Patients were grouped as ever-responders or non-responders. Genomic DNA was extracted from peripheral blood,and 7 single nucleotide polymorphisms(SNPs) were assessed. The main outcome measure(following exposure to the drug) was response to therapy. The patient genotypes were assessed as the predictors of outcome. Possible confounders and effect modifiers included age,gender,race,and socioeconomic status disease,as well as disease characteristics(such as Montreal criteria). RESULTS121 patients were included. Twenty-one were nonresponders,and 100 were ever-responders. Fas ligand SNP(rs763110) genotype frequencies,TNF gene-308 SNP(rs1800629) genotype frequencies,and their combination,were significantly different between groups on multivariable analysis controlling for Montreal disease behavior and perianal disease. The odds of a patient with a Fas ligand CC genotype being a non-responder were four-fold higher as compared to a TC or TT genotype(P = 0.009,OR = 4.30,95%CI: 1.45-12.80). The presence of the A(minor) TNF gene-308 allele correlated with three-fold higher odds of being a non-responder(P = 0.049,OR = 2.88,95%CI: 1.01-8.22). Patients with the combination of the Fas ligand CC genotype and the TNF-308 A allele had nearly five-fold higher odds of being a non-responder(P = 0.015,OR = 4.76,95%CI: 1.35-16.77). No difference was seen for the remaining SNPs.CONCLUSION The Fas-ligand SNP and TNF gene-308 SNP are associated with anti-TNF treatment response in CD and may help select patients likely to benefit from therapy.     

Crohn's disease: future anti-tumor necrosis factor therapies beyond infliximab

The dramatic benefit experienced by many Crohn's disease patients treated with the anti-tumor necrosis factor-alpha (TNF-alpha) antibody infliximab underscores the centrality of this cytokine in the pathogenesis of Crohn's disease and the potential use of the therapeutic strategy of blocking TNF-alpha in this disease. In the hopes of emulating and improving on the success of infliximab, numerous strategies are being devised and studied to inhibit the actions of TNF-alpha. This article focuses on those agents, other than infliximab, which target TNF-alpha to treat inflammatory bowel disease as their central mechanism of action.     

Demyelination during anti-tumor necrosis factor alpha therapy with infliximab for Crohn's disease

BACKGROUND: Inflammatory demyelinating disease of the central nervous system may be linked to anti-tumor necrosis factor alpha therapy. CASE HISTORY: A 19-year-old female with Crohn's ileocolitis developed right arm and leg numbness and right hand weakness 4 weeks after the initiation of infliximab. Neurologic examination confirmed upper and lower right extremity sensory and motor deficits. MRI examination of the head and thoracic cord showed multiple gadolinium-enhancing lesions with distribution and configuration most suggestive of multiple sclerosis or other demyelinating process. The infliximab therapy was immediately stopped and follow-up at 8 weeks revealed symptomatic improvement. CONCLUSION: This case report describes the onset of a demyelinating process after the institution of infliximab therapy in a patient with Crohn's disease.     

Functional modulation of Crohn's disease myofibroblasts by anti-tumor necrosis factor antibodies

BACKGROUND & AIMS: Infliximab induces immune cell apoptosis by outside-to-inside signaling through transmembrane tumor necrosis factor-alpha (mTNF). However, in inflamed gut, myofibroblasts also produce TNF-alpha, and the affects of anti-TNF antibodies on these structural cells are unknown. We investigated the action of infliximab on apoptosis, the production of matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinases (TIMP)-1, and migration of Crohn's disease (CD) myofibroblasts. METHODS: Colonic myofibroblasts were isolated from patients with active CD and controls. mTNF was evaluated by Western blotting and flow cytometry. Infliximab-treated myofibroblasts were analyzed for apoptosis by Annexin V staining and caspase-3. TIMP-1 and MMPs were measured by Western blotting, and fibroblast migration was assessed by using an in vitro wound-healing scratch assay. RESULTS: CD myofibroblasts showed higher mTNF expression than control myofibroblasts. Infliximab had no effect on CD myofibroblast apoptosis, caspase-3 activation, and production of MMP-3 and MMP-12. However, infliximab induced a significant dose-dependent increase in TIMP-1 production, which was inhibited by the p38 mitogen-activated protein kinase inhibitor SB 203580. The anti-TNF agents adalimumab, etanercept, and p55 TNF-receptor-human IgG fusion protein also increased TIMP-1 production. The migration of CD myofibroblasts was enhanced significantly by infliximab and recombinant human TIMP-1, and infliximab-induced migration was inhibited by anti-TIMP-1 neutralizing antibody. Infliximab also decreased CD myofibroblast collagen production. CONCLUSIONS: Our findings show a novel therapeutic pathway for anti-TNF therapies in enhancing TIMP-1 production and myofibroblast migration, which may reduce MMP activity and facilitate the wound healing.     

Autoimmunity associated with anti-tumor necrosis factor alpha treatment in Crohn's disease: a prospective cohort study

BACKGROUND & AIMS: Infliximab therapy is an effective approach to treating Crohn's disease. Development of antinuclear antibodies has been described in patients treated, but the size of the problem and the relationship with autoimmunity have not been investigated. We investigated the occurrence of antinuclear antibodies in 125 consecutive Crohn's disease patients and studied the relationship with symptoms of autoimmunity. METHODS: Autoantibodies and clinical data were investigated before and 1, 2, and 3 months after infliximab infusion. If antinuclear antibodies were > or =1:80, further study of double-stranded DNA, single-stranded DNA, histones, and ENA was performed. RESULTS: Cumulative antinuclear antibody incidence at 24 months was 71 of 125 (56.8%). Almost half of these patients developed antinuclear antibodies after the first infusion, and >75% became antinuclear antibody positive after fewer than 3 infusions. So far, only 15 of 71 patients have become seronegative, after a median of 12 months. Of 43 antinuclear antibody-positive patients who were further subtyped, 14 of 43 (32.6%) had double-stranded DNA, 17 (39.5%) had single-stranded DNA, 9 (20.9%) had antihistone, and 0% were ENA positive. Two patients (both antihistone and double-stranded DNA positive) developed drug-induced lupus without major organ damage, and 1 developed autoimmune hemolytic anemia. Antinuclear antibodies were associated with the female sex (odds ratio, 3.166; 95% confidence interval, 1.167-8.585; P = 0.024) and with papulosquamous or butterfly rash (odds ratio, 10.016; 95% confidence interval, 1.708-58.725; P = 0.011). CONCLUSIONS: The cumulative incidence of antinuclear antibodies was 56.8% after 24 months in this cohort of infliximab-treated Crohn's disease patients. Antinuclear antibodies persisted up to 1 year after the last infusion, and only a few patients became seronegative. Two patients developed drug-induced lupus erythematosus. Antinuclear antibodies were associated with the female sex and skin manifestations.     

Demographic and clinical parameters influencing the short-term outcome of anti-tumor necrosis factor (infliximab) treatment in Crohn's disease

OBJECTIVE: Infliximab is an effective treatment for refractory or fistulizing Crohn's disease (CD). However, about 30% of patients do not respond to infliximab for unknown reasons. Identifying predictive factors of response is important for optimizing clinical management and for better understanding infliximab's mechanisms of action. The aim of this study was to assess whether demographic or clinical parameters influence short-term response to infliximab. METHODS: The first 240 CD patients of the Belgian Infliximab Expanded Access Program were studied for response to infliximab treatment and assessed at 4 (refractory luminal CD) or 10 wk (fistulizing CD) after the first infusion. Detailed demographic and clinical information on age, sex, type of disease (fistulizing or refractory), Crohn's Disease Activity Index score, C-reactive protein (CRP), smoking habits, disease duration, localization of disease, concomitant medication, and previous surgery were obtained from all patients. Logistic regression and decision tree analysis were performed. RESULTS: There were 73.5% responders and 26.5% nonresponders to treatment. Stepwise logistic regression identified age (OR = 0.971, 95% CI = 0.947-0.995, p = 0.018), isolated ileitis (OR = 0.359, 95% CI = 0.177-0.728, p = 0.004), and previous surgery (OR = 0.429, 95% CI = 0.233-0.787, p = 0.006) as inversely correlated with response, whereas isolated colitis (OR = 1.905, 95% CI = 1.010-3.597, p = 0.046) and concomitant immunosuppressive treatment (OR = 2.670, 95% CI = 1.430-5.016, p = 0.0022) were positively correlated with response to infliximab. Surprisingly, smoking habits were not retained as predictors for response. Decision tree analysis provided a working algorithm based on age and immunosuppressive treatment that warrants further exploration. CONCLUSIONS: In this large cohort of infliximab-treated CD patients, young age, Crohn's colitis, and concomitant immunosuppressive treatment were identified as independent variables favoring short-term response to infliximab.     

Endoscopic response to tumor necrosis factor inhibitors predicts long term benefits in Crohn's disease

BACKGROUND Identifying predictors of therapeutic response is the cornerstone of personalized medicine.AIM To identify predictors of long-term mucosal healing(MH) in patients with Crohn's disease(CD) treated with tumor necrosis factor α(TNF-α) inhibitors.METHODS Prospective single center study. Consecutive patients with clinically active CD requiring treatment with a TNF-α inhibitor were included. A baseline segmental CD Endoscopic Index of Severity(CDEIS) ≥ 10 in at least one segment or the presence of ulcerations were required for inclusion. Clinical, biological and endoscopic data were obtained at baseline, weeks 14 and 46. Endoscopic response(ER) was defined as a decrease ≥ 50% from baseline CDEIS and MH as partial CDEIS ≤ 5 in all segments.RESULTS Of 62 patients were included. At baseline, median CD Activity Index and CDEIS were 201 and 6.7, respectively with a significant reduction after one year of treatment(53 and 3.0 respectively, P 0.001). At week 14, 56% of patients achieved ER and 34% MH. At week 46, the corresponding percentages were 52%and 44%. Baseline disease characteristics or biomarkers did not predict MH. A decrease from baseline CDEIS at week 14 of at least 80% was the best predictor of MH at week 46(59% sensitivity and 91% specificity; area under the curve =0.778).CONCLUSION Clinical and biomarker data are not useful predictors of response to TNF-αinhibitors in CD, whereas ER to induction therapy, defined as 80% reduction in global CDEIS, is a robust predictor of long-term MH. Achievement of this endoscopic endpoint may be considered as a therapeutic target for anti-TNF-αtherapy.     

Predictors of response to anti-tumor necrosis factor therapy in ulcerative colitis

Ulcerative colitis(UC) is an immune-mediated, chronic inflammatory disease of the large intestine. Its course is characterized by flares of acute inflammation and periods of low-grade chronic inflammatory activity or remission. Monoclonal antibodies against tumor necrosis factor(anti-TNF) are part of the therapeutic armamentarium and are used in cases of moderate to severe UC that is refractory to conventional treatment with corticosteroids and/or immunosuppressants. Therapeutic response to these agents is not uniform and a large percentage of patients either fail to improve(primary non-response) or lose response after a period of improvement(secondary non-response/loss of response). In addition, the use of anti-TNF agents has been related to uncommon but potentially serious adverse effects that preclude their administration or lead to their discontinuation. Finally, use of these medications is associated with a considerable cost for the health system. The identification of parameters thatmay predict response to anti-TNF drugs in UC would help to better select for patients with a high probability to respond and minimize risk and costs for those who will not respond. Analysis of the major clinical trials and the accumulated experience with the use of anti-TNF drugs in UC has resulted to the report of such prognostic factors. Included are clinical and epidemiological characteristics, laboratory markers, endoscopic indicators and molecular(immunological/genetic) signatures. Such predictive parameters of long-term outcomes may either be present at the commencement of treatment or determined during the early period of therapy. Validation of these prognostic markers in large cohorts of patients with variable characteristics will facilitate their introduction into clinical practice and the best selection of UC patients who will benefit from anti-TNF therapy.     

Anti-tumor necrosis factor treatment restores the gut barrier in Crohn's disease

OBJECTIVES: A primary defect of the tight junctions and, hence, increased intestinal epithelial permeability has been proposed as a basic pathogenic event in Crohn's disease. Challenge of the mucosal immune system by the commensal gut flora would then result in chronic inflammation. Alternatively, increased permeability could be the result of inflammation. Our aim was to study intestinal permeability in refractory Crohn's disease before and after treatment with monoclonal chimeric antibodies directed against tumor necrosis factor (TNF) to investigate whether the abnormal permeability persists after control of inflammation. MErHODS: Twenty-three patients with active Crohn's disease were evaluated before and 4 wk after a single infusion of 5 mg/kg infliximab. Intestinal permeability was studied by measurement of urinary excretion of 51Cr-EDTA after oral intake. RESULTS: The increased permeation of 51Cr-EDTA through the small intestine (1.63% interquartile range [IQR] 1.06-2.07) and the overall permeation (3.27% IQR 2.40-4.38) before therapy decreased significantly after infliximab infusion to values (1.04% IQR 0.74-1.54 and 2.42% IQR 2.03-2.80, respectively) in the range of those found in normal volunteers (1.12% IQR 0.85-1.58 and 2.28% IQR 1.88-2.86, respectively). CONCLUSION: Inhibiting the proinflammatory cytokine tumor necrosis factor dramatically reduces gut inflammation and largely restores the gut barrier in Crohn's disease. Our data confirm the central role of TNF in gut barrier modulation in inflammatory conditions in vivo.     

Human anti-tumor necrosis factor monoclonal antibody (adalimumab) in Crohn's disease: the CLASSIC-I trial

BACKGROUND & AIMS: Tumor necrosis factor blockade has been shown to be an effective treatment strategy in Crohn's disease (CD). Adalimumab is a human immunoglobulin G1 (IgG(1)) monoclonal antibody targeting tumor necrosis factor (TNF). A randomized, double-blind, placebo-controlled, dose-ranging trial was performed to evaluate the efficacy of adalimumab induction therapy in patients with CD. METHODS: A total of 299 patients with moderate to severe CD naive to anti-TNF therapy were randomized to receive subcutaneous injections at weeks 0 and 2 with adalimumab 40 mg/20 mg, 80 mg/40 mg, or 160 mg/80 mg or placebo. The primary endpoint was demonstration of a significant difference in the rates of remission at week 4 (defined as a Crohn's Disease Activity Index score <150 points) among the 80 mg/40 mg, 160 mg/80 mg, and placebo groups. RESULTS: The rates of remission at week 4 in the adalimumab 40 mg/20 mg, 80 mg/40 mg, and 160 mg/80 mg groups were 18% (P = .36), 24% (P = .06), and 36% (P = .001), respectively, and 12% in the placebo group. Adverse events occurred at similar frequencies in all 4 treatment groups except injection site reactions, which were more common in adalimumab-treated patients. CONCLUSIONS: Adalimumab was superior to placebo for induction of remission in patients with moderate to severe Crohn's disease naive to anti-TNF therapy. The optimal induction dosing regimen for adalimumab in this study was 160 mg at week 0 followed by 80 mg at week 2. Adalimumab was well tolerated.     

Patients with Crohn's disease on anti-tumor necrosis factor therapy are at significant risk of inadequate response to the 23-valent pneumococcal polysaccharide vaccine

Background/aimsThe effect of immunosuppressants on the efficacy of a variety of vaccines is a controversial issue in patients with inflammatory bowel disease (IBD). In this study we determined whether specific immunosuppressants impair the serological response to the standard 23-valent pneumococcal polysaccharide vaccine (PPSV23) in a large cohort of patients with Crohn's disease (CD).MethodsThis was a multi-center, prospective observational study of adult patients with CD at 15 academic teaching hospitals in Korea. The study population received one intramuscular injection of PPSV23. Anti-pneumococcal IgG antibody titers were measured by immunoassay prior to and 4 weeks after vaccination. All vaccination-related adverse events and the effect of the vaccine on disease activity were also evaluated.ResultsThe overall serological response rate was 67.5% (133/197). The serological response rate was significantly lower in patients on anti-tumor necrosis factor (anti-TNF) therapy (50.0% on anti-TNF alone; 58.0% on anti-TNF combined with an immunomodulator, IM) than patients on 5-aminosalicylate (78.4%; all P-values vs. 5-aminosalicylate < 0.05); 45.6% (41/90) of patients on anti-TNF therapy were not protected against PPSV23. IM did not affect the immunologic response to the vaccine. Female gender and anti-TNF therapy were significant predictors of non-response to the vaccine (odds ratio [OR] 2.316, P = 0.015; OR 2.582, P = 0.048, respectively). Vaccination was generally safe and tolerated by all patients.ConclusionsPatients with CD on anti-TNF therapy are at significant risk of an inadequate response to PPSV23. The pneumococcal vaccination strategy should be optimized for patients with CD on anti-TNF therapy.     

Strategies targeting tumor necrosis factor in Crohn's disease

Tumor necrosis factor plays an important role in mediating the inflammation of Crohn's disease. Strategies aimed at reducing tumor necrosis factor in patients with Crohn's disease include the mouse/human chimeric monoclonal antibody infliximab, the humanized monoclonal antibody CDP571, the human recombinant tumor necrosis factor receptor fusion protein etanercept, and the small molecule thalidomide. Infliximab is effective for treating active Crohn's disease, maintaining remission, and closing fistulas. Side effects occurring in patients treated with infliximab include human anti-chimeric antibodies, infusion reactions, formation of autoantibodies, and rarely drug induced lupus. CDP571 is effective for treating active Crohn's disease, steroid sparing, and possibly for closing fistulas and maintaining remission. Side effects occurring in patients treated with CDP571 include anti-idiotype antibodies, infusion reactions, and formation of autoantibodies. Pilot studies have suggested that etanercept and thalidomide may also be beneficial. Anti-tumor necrosis factor therapies are effective for the treatment for Crohn's disease.