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.     

Efficacy and safety of retreatment with anti-tumor necrosis factor antibody (infliximab) to maintain remission in Crohn's disease.

BACKGROUND & AIMS: Infliximab, an anti-tumor necrosis factor monoclonal antibody, rapidly reduces signs and symptoms of active Crohn's disease. The aim of this study was to determine whether repeated infusions of infliximab would effectively and safely maintain the remitting benefit. METHODS: The efficacy, safety, pharmacokinetics, and immunogenicity of 4 repeated treatments with 10 mg/kg infliximab given every 8 weeks were compared with the effects of placebo in a randomized, double-blind, placebo-controlled, parallel group trial. Seventy-three patients with active Crohn's disease who had not adequately responded to conventional therapies and then had demonstrated a clinical response (>/=70-point decrease in the Crohn's Disease Activity Index) to an initial infusion of infliximab (or placebo) were studied. RESULTS: Retreatment with infliximab maintained the clinical benefit through the retreatment period and 8 weeks after the last infusion in nearly all patients retreated with infliximab. Median values for Crohn's Disease Activity Index, inflammatory bowel disease questionnaire (a quality of life measurement), and serum C-reactive protein concentration were maintained at remission levels with infliximab retreatment, but not with placebo retreatment. Retreatment with infliximab every 8 weeks maintained serum infliximab concentration and was well tolerated with a low incidence of immunogenicity. One case of lymphoma and 1 case of suspected lupus were reported; the complete long-term safety profile of infliximab requires additional clinical investigation. CONCLUSIONS: Long-term treatment with infliximab showed efficacy and tolerability in managing symptoms of patients with active Crohn's disease not responding to conventional treatments.     

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.     

Endoscopic and histological healing with infliximab anti-tumor necrosis factor antibodies in Crohn's disease: A European multicenter trial

BACKGROUND & AIMS: Tumor necrosis factor (TNF) is a pivotal cytokine in intestinal inflammation. Controlled trials using a chimeric anti-TNF antibody (infliximab) have shown its efficacy in refractory Crohn's disease. METHODS: Endoscopic and histological response to infliximab was investigated in a multicenter, randomized, double-blind, and placebo-controlled trial including 30 patients with active Crohn's disease undergoing ileocolonoscopy before and 4 weeks after intravenous administration of 5, 10, or 20 mg/kg of infliximab or placebo as a single infusion. Lesions were scored by means of the validated Crohn's Disease Endoscopic Index of Severity (CDEIS). Endoscopic biopsy specimens were taken during both procedures from 9 of 30 patients and scored by a single gastrointestinal pathologist. RESULTS: CDEIS scores decreased significantly in most infliximab-treated patients without an apparent dose response. No endoscopic improvement was observed in the placebo group. The changes in CDEIS correlated highly with those of the Crohn's Disease Activity Index. At a histological level, disappearance of the inflammatory infiltrate was observed in infliximab-treated patients but not in placebo-treated ones; however, architectural changes persisted in most patients. Strictures developed in several patients. CONCLUSIONS: Clinical improvement after infliximab therapy in active Crohn's disease is accompanied by significant healing of endoscopic lesions and disappearance of the mucosal inflammatory infiltrate.     

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.     

Demographic, clinical, and treatment parameters influencing the outcome of acute cystitis.

A meta-analysis of six double-blinded clinical trials was undertaken to identify risk factors associated with bacteriologic outcome in 3,108 women with acute cystitis. Eleven antibiotic regimens were used, including ciprofloxacin, ofloxacin, norfloxacin, trimethoprim-sulfamethoxazole, and nitrofurantoin. Entry criteria for all studies were identical. Among 2,409 patients who were defined to be valid for efficacy analysis, pathogens included Escherichia coli (78.6%), Staphylococcus saprophyticus (4.4%), Klebsiella pneumoniae (4.3%), Proteus mirabilis (3.7%), and "other" (9%). Causative bacteria were eradicated at the end of treatment in 93% of patients. The following parameters were associated with successful bacteriologic outcome: not using a diaphragm (P = .0041), treatment for > or = 3 days (P = .0043), pathogen not "other" (P = .0043), symptom duration of < 2 days (P = .0096), and African American race (P = .0147). K. pneumoniae (P = .0496) and "other" pathogens (P = .0018) were associated with increased probability of bacteriologic treatment failure. The presence of pyuria (> or = 10 WBCs per high-power field) did not correlate with outcome and was inversely correlated with the finding of > or = 10(5) bacterial colony-forming units per mL of urine (P < .001). This large database identifies new parameters associated with treatment outcomes of acute cystitis and calls into question current clinical trial guidelines.     

Serological markers for prediction of response to anti-tumor necrosis factor treatment in Crohn's disease

OBJECTIVES: The use of monoclonal anti-tumor necrosis factor (TNF) antibodies (infliximab, Remicade) is a new therapeutic approach for severe refractory luminal or fistulizing, Crohn's disease (CD). However, up to 30% of patients do not respond to this treatment. So far, no parameters predictive of response to anti-TNF have been identified. Our aim was to determine whether serological markers ASCA (anti-Saccharomyces cerevisiae antibodies) or pANCA (perinuclear antineutrophil cytoplasmic antibodies) could identify Crohn's patients likely to benefit from anti-TNF therapy. METHODS: Serum samples of 279 CD patients were analyzed for ASCA and pANCA before anti-TNF therapy. A blinded physician determined clinical response at week 4 (refractory luminal CD) or week 10 (fistulizing CD) after the first infusion of infliximab (5 mg/kg). RESULTS: Overall, there was no relationship between ASCA or pANCA and response to therapy. However, lower response rates were observed for patients with refractory intestinal disease carrying the pANCA+/ASCA- combination, although this lacked significance (p = 0.067). CONCLUSIONS: In this cohort of infliximab-treated patients, neither ASCA nor pANCA could predict response to treatment. However, the combination pANCA+/ASCA- might warrant further investigation for its value in predicting nonresponse in patients with refractory luminal disease.     

Pneumocystis carinii pneumonia during maintenance anti-tumor necrosis factor-alpha therapy with infliximab for Crohn's disease

BACKGROUND: Clinical trials using infliximab have not reported cases of Pneumocystis carinii pneumonia (PCP), and PCP infection during standard medical treatment of inflammatory bowel disease is uncommon. Postmarketing surveillance through June of 2001 has identified 10 cases of PCP occurring during treatment with infliximab; 3 patients died. CASE HISTORY: A 19-year-old man with Crohn's colitis developed thrush, leukopenia, fever, shortness of breath, and dry cough 21 months after initiating maintenance therapy with azathioprine and infliximab. Azathioprine had been at a stable dose of 75 mg per day (1 mg/kg) and the patient had received his 14th infusion of infliximab 4 weeks prior to presentation. Evaluation revealed the presence of Pneumocystis carinii on induced sputum. Azathioprine was discontinued, and the patient improved after initiating treatment with steroids and trimethoprim-sulfamethoxazole. Follow-up 2 weeks later confirmed clinical response to therapy. CONCLUSIONS: This case report describes the uncommon occurrence of Pneumocystis pneumonia in the setting of maintenance therapy for Crohn's disease using infliximab and azathioprine. Mechanisms by which azathioprine and infliximab may impair the natural defense mechanisms against Pneumocystis are discussed.     

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.     

Clinical outcome of Crohn's disease treated with infliximab

BACKGROUND/AIMS: Controlled studies in humans have shown the role of antibodies to tumor necrosis factor-alpha in the treatment of both fistulizing and inflammatory Crohn's disease. The aim of this study is to report the results of a multicenter clinical trial to evaluate efficacy of infliximab in Crohn's disease patients who are refractory to conservative drugs or fistulizing Crohn's disease. METHODOLOGY: This trial was carried out at 5 university and community hospitals, in Turkey. A total of 25 patients with Crohn's disease that were unresponsive to conventional medical therapy, participated; 17 of the 25 were in the fistulizing disease group and 8 were in the inflammatory disease group. Clinical response was classified according to fistula drainage, diarrhea as positive response or no response. RESULTS: Overall response rate was 92% (23/25), regardless of the disease group, after first infusion of infliximab. Sixteen out of 17 patients in the fistulizing disease group had a positive response. Fourteen of the 16 positive responders later relapsed. Median duration of response was 8 weeks (range, 2-35 wk). Active inflammatory disease patients had a positive response rate of 75% (6/8) and two of the patients were nonresponders. A further two patients relapsed at week 14. Two patients in both arms of the study were still in remission at the end of the study. Major adverse events were: pneumonia in one patient, skin infections in two patients, pulmonary thromboembolism and death in one patient. CONCLUSIONS: Infliximab treatment seems to be more effective in Crohn's disease patients especially in those with fistulizing disease than those with non-fistulizing, inflammatory disease. It is evident that maintenance of remission might be achieved with ongoing maintenance therapy. We suggest maintenance of infliximab therapy.     

Association of trough serum infliximab to clinical outcome after scheduled maintenance treatment for Crohn's disease.

BACKGROUND & AIMS: The effect of infliximab infused at scheduled intervals on antibody formation, preinfusion trough serum concentrations of infliximab, and their clinical significance was evaluated in patients with Crohn's disease. METHODS: Antibodies to infliximab and trough serum infliximab were measured in 105 patients with Crohn's disease treated with 5 mg/kg infliximab for induction followed by maintenance episodic re-treatment (n = 23) or scheduled therapy at 6- to 8-week intervals (n = 82). RESULTS: After a median of 14 infusions (range, 2-45), 21% of patients had detectable antibodies, 25% were antibody negative, and 54% were antibody inconclusive. Antibody formation was higher after episodic compared with scheduled treatment (39% vs 16%; P = .036) and was associated with a higher rate of infusion reactions (50% vs 21%; P = .018). Ninety patients continued maintenance scheduled therapy beyond 12 months including 12 converted episodic patients, with a median follow-up of 23 months (range, 16-68 months). The rate of clinical remission was higher for patients with a detectable trough serum infliximab compared with patients in whom serum infliximab was undetectable, including those without antibodies (82% vs 6%; P < .001). A detectable trough serum infliximab was also associated with a lower C-reactive protein (2.0 vs 11.8 mug/L; P < .001) and a higher rate of endoscopic improvement (88% vs 33%; P < .001). Concurrent immunomodulators did not alter outcomes. CONCLUSIONS: For Crohn's disease patients treated with scheduled maintenance infusions of infliximab, the trough serum concentration of infliximab predicts clinical outcome. Factors in addition to antibody formation, likely pharmacokinetic, modulate serum infliximab and thus the response to infliximab therapy.     

Successful treatment of active ankylosing spondylitis with the anti-tumor necrosis factor alpha monoclonal antibody infliximab

OBJECTIVE: Tumor necrosis factor alpha (TNFalpha) has been detected in sacroiliac joint biopsy specimens from patients with spondylarthropathy. The present open pilot study was undertaken to test the efficacy of the anti-TNFalpha monoclonal antibody infliximab in the treatment of active ankylosing spondylitis (AS). METHODS: Eleven patients with AS of short duration (median 5 years, range 0.5-13 years) that had been active for at least 3 months (range 3-72 months) were treated with 3 infusions of infliximab (at weeks 0, 2, and 6), in a dosage of 5 mg/kg. Ten of the 11 patients had elevated C-reactive protein (CRP) levels (>6 mg/liter) before treatment; these elevations were known to have had persisted > 1 year in at least 3 patients. The Bath AS Disease Activity Index (BASDAI), the Bath AS Functional Index (BASFI), pain as measured on a visual analog scale, and the Bath AS Metrology Index (BASMI) were assessed. Quality of life was assessed using the Short Form 36 instrument. Laboratory markers of disease activity, including interleukin-6 (IL-6) levels, were determined. Dynamic magnetic resonance imaging (MRI) of the spine was performed in 5 patients. RESULTS: One patient withdrew from the study due to the occurrence of urticarial xanthoma 8 days after the first infusion. At study enrollment, 3 of 5 patients had evidence of spinal inflammation (spondylitis and spondylodiscitis) as detected by MRI; followup MRI 2-6 weeks after the third infusion revealed improvement in 2. Improvement of > or = 50% in activity, function, and pain scores was documented in 9 of 10 patients; the median improvement in the BASDAI after 4 weeks was 70% (range 41-94%). This clear-cut benefit lasted for 6 weeks after the third infusion in 8 of 10 patients. The median CRP level decreased from 15.5 mg/liter (range <6-90.8) to normal, and the median IL-6 level from 12.4 mg/liter (range 0-28.4) to normal (<5). There was improvement in all 9 SF-36 concepts; the improvement was significant for 6 concepts. CONCLUSION: These data suggest that anti-TNFalpha therapy is very effective for several weeks in AS. Whether this therapy, in addition to its antiinflammatory effect, prevents ankylosis remains to be determined.     

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.