It has been postulated that oxidative stress, nitric oxide (NO), and transforming growth factor beta(1) (TGF- beta(1)) have major roles in the pathophysiology of Crohn's disease (CD). The aim of this study was to determine the salivary levels of total antioxidant capacity (TAC), specific antioxidants (i.e., uric acid, albumin, transferrin, and thiol molecules), lipid peroxidation (LPO), NO, and TGF- beta(1) in CD patients and control subjects and to also investigate their correlation with activity of the disease. Twenty-eight patients with confirmed diagnosis of CD were enrolled and whole saliva samples were obtained. Smokers, diabetics, those who suffered from periodontitis, and those who were consuming antioxidant supplements were excluded from the study. The Crohn's Disease Activity Index (CDAI) was used to determine the severity of the disease. Twenty healthy subjects were also recruited. In CD patients significant reductions in salivary levels of TAC (0.248 +/- 0.145 vs. 0.342 +/- 0.110 mmol/L), albumin (1.79 +/- 0.42 vs. 2.3 +/- 0.2 microg/mL), and uric acid (3.1 +/- 1.4 vs. 4.1 +/- 2.0 mg/dL) were found. TGF-beta(1) was significantly increased in CD patients compared to healthy subjects (3.02 +/- 1.54 vs. 2.36 +/- 0.52 ng/mL). A fourfold increase in NO levels (198.8 +/- 39.9 vs. 50.2 +/- 21.3 micromol/L) along with a fivefold increase in LPO concentration (0.146 +/- 0.064 vs. 0.027 +/- 0.019 micromol/L) was documented in CD patients in comparison to the control group. CDAI significantly correlated with the TAC, LPO, and the interaction between TAC and LPO (r(2) = 0.625, r(2) = 0.8, F-test's P < 0.00005). Saliva of CD patients exhibits an abnormal feature with respect to oxidative stress, NO, and TGF-beta(1). TAC and LPO modify the effect of each other in determination of CD severity, which underlines the importance of oxidative stress in the pathogenesis of CD.
The use of infliximab (Remicade) has revolutionized the care of Crohn's disease (CD) patients who have proved refractory to standard treatment. The use of infliximab is very well tolerated in the majority of patients but in a small subset of patients may lead to the production of antibodies (termed "antibodies to infliximab"-ATI). The production of these antibodies has been associated with the development of both acute and delayed infusion reactions, although even in patients who develop ATIs, these reactions are relatively uncommon. Nonetheless, these reactions may occasionally be severe enough to lead to intolerance to infliximab. Another group of patients, after initially having excellent responses to infliximab, experience an attenuated response or loss of response over time. What is the cause of this loss of efficacy? ATIs may play a role in some patients but other potential reasons for this phenomenon have provoked much debate. The importance of other cytokines after TNF-alpha has been neutralized may be relevant as (this has been shown to be the case in rheumatoid arthritis (RA) is the idea of beneficial autoimmunity production to TNF-alpha. (Wildbaum G, Nahir MA, Karin N. Beneficial autoimmunity to proinflammatory mediators restrains the consequences of self-destructive immunity. Immunity 2003;19:679-88.) It has been shown that during the course of an autoimmune condition, the immune system mounts a beneficial autoantibody response to proinflammatory mediators. This response counteracts, to a certain degree, the autoimmune pathology. This natural counteraction has been illustrated in animal models of autoimmunity, and there has been evidence demonstrated that this occurs in human RA. Whether this occurs in Crohn's is unknown; infliximab is a chimeric monoclonal antibody containing an approximately 25% murine region. It had been hoped that the development of humanized or fully human monoclonal antibodies would provide therapeutic antibodies that did not induce an immune response. While this has unfortunately not proven to be the case-these products still have significant immunogenicity-these products do present an alternative therapy when infliximab cannot be used. In light of this, adalimumab (Humira) a human monoclonal antibody used for treating rheumatologic conditions has been investigated as an alternate treatment for patients with CD who after initially responding to infliximab experience intolerance or loss of efficacy. Is this a viable alternative?
BACKGROUND: The potential clinical implications of autoimmunity during treatment with infliximab are unclear.
AIM: To determine the frequency and correlation of autoantibody formation in patients with Crohn's disease treated with infliximab in a routine clinical setting.
METHODS: Sixty-three patients with refractory/inflammatory (31) and/or fistulising Crohn's disease (32), received an infliximab infusion at a dose 5 mg/kg in weeks 0, 2 and 6, and were evaluated for the development of antinuclear, anti-double-stranded DNA, anti-Sm, anti-RNP, anti-SSA, anti-SSB and antihistone antibodies. The correlates with pharmacological treatments, the response to infliximab and adverse events were evaluated.
RESULTS: Antinuclear antibodies were found in five of the 63 patients (8%) at baseline and in 26 (42%) after 10 weeks (P < 0.001). Of the 26 antinuclear antibody-positive patients who were further subtyped, nine of 63 (17%) had anti-double-stranded DNA (P = 0.003), and 1.5% were extractable nuclear antigen (ENA) and antihistone-positive. Five patients were initially positive for anticardiolipin antibodies and two more patients became positive during infliximab treatment. New autoantibody formation was more frequent in the patients with inflammatory/refractory disease than in those with fistulising disease (17 vs. 7; P = 0.02). One patient developed drug-induced lupus without major organ damage.
CONCLUSIONS: Autoantibody formation occurs in 42% of patients (8% of these patients were positive before infliximab treatment) with Crohn's disease receiving induction treatment with infliximab, but the clinical significance of this remains to be determined.
PURPOSE OF REVIEW: Despite the advent of the anti-TNF agent, infliximab, an important unmet medical need characterizes the medical treatment of inflammatory bowel diseases. This review aims to summarize recent progress in the field.
RECENT FINDINGS: For Crohn's disease, the fully human IgG1 anti-TNF monoclonal antibody, adalimumab and the humanized anti-alpha4 integrin IgG4 antibody, natalizumab have yielded the most promising results in controlled trials, but agents inhibiting the crucial IL12/interferon-gamma feedback loop also suggest therapeutic potential. Maintenance treatment with azathioprine, although efficacious, is not tolerated by up to 25% of individuals, but 6-thioguanine, an active metabolite, is associated with liver toxicity and is no longer recommended. For severe ulcerative colitis, low intravenous cyclosporine doses have been demonstrated to be efficacious, and may serve to limit the toxicity with this agent. Biologic treatment is being developed to target severe ulcerative colitis. Efficacy of infliximab to stop fistula draining as a maintenance agent for fistulizing Crohn's disease has been demonstrated in a large controlled trial, but MRI imaging indicates that the improvement of inflammation in fistula tracks is delayed.
SUMMARY: In conclusion, medical therapy of inflammatory bowel diseases is a constantly moving field and recent evolutions will undoubtedly change clinical practice in the years to come.
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.
AIM: To evaluate CDP571, a humanized monoclonal antibody to tumour necrosis factor-alpha, for the treatment of corticosteroid-dependent Crohn's disease.
METHODS: Patients with corticosteroid-dependent Crohn's disease (use of prednisolone 15-40 mg/day or budesonide 9 mg/day for at least 8 weeks, a previous failed attempt to discontinue corticosteroids within 8 weeks, and Crohn's Disease Activity Index score 150 points or less) were enrolled in a 16-week, randomized, double-blind, placebo-controlled trial. The patients received intravenous CDP571 (20 mg/kg at week 0 and 10 mg/kg at week 8) or placebo. Corticosteroid therapy was decreased following a predefined schedule. The primary efficacy end-point was the percentage of patients with corticosteroid-sparing [i.e. no disease flare (Crohn's Disease Activity Index score > or =220 points) and no longer requiring corticosteroid therapy] at week 10. The major secondary efficacy end-point was corticosteroid-sparing at week 16.
RESULTS: Seventy-one patients received treatment. Corticosteroid-sparing was achieved by 19 of 39 (48.7%) CDP571 patients and 13 of 42 (40.6%) placebo patients (P = 0.452) at week 10, and by 18 of 39 (46.2%) CDP571 patients and seven of 32 (21.9%) placebo patients (P = 0.032) at week 16. CDP571 therapy was well-tolerated and the incidence of serious adverse events was similar to placebo.
CONCLUSIONS: The CDP571 was effective for corticosteroid-sparing at week 16 but not week 10, and was well-tolerated in patients with corticosteroid-dependent Crohn's disease.
ANTECEDENTES Y OBJETIVOS: Investigar la eficacia y seguridad de certolizumab pegol (un fragmento Fab de polietileno-glicosilada "del factor de necrosis anti-tumoral, CDP870) en la enfermedad de Crohn. MÉTODOS: En un estudio controlado con placebo, de fase II, 292 pacientes con enfermedad moderada a grave enfermedad de Crohn recibieron por vía subcutánea pegol 100, 200, o 400 mg o placebo en las semanas 0, 4 y 8. El punto final primario fue el porcentaje de pacientes con una respuesta clínica en la semana 12 (Actividad a la enfermedad de Crohn índice de disminución mayor o igual a 100 puntos o remisión [de Crohn Disease Activity Index <o = 150 puntos]) en la intención de -el tratamiento de la población. RESULTADOS: Todas las dosis de certolizumab produce un beneficio clínico significativo sobre el placebo en la semana 2 (placebo, 15,1%; pegol 100 mg, 29,7% [p = 0,033], 200 mg, 30,6% [p = 0,026], 400 mg, 33,3% [p = 0,010]). En todos los puntos de tiempo, las tasas de respuesta clínica fueron más altos para pegol 400 mg, el más grande en la semana 10 (pegol 400 mg, 52,8%; placebo, 30,1%, p = 0,006), pero no significativa en la semana 12 (pegol 400 mg, 44,4 %; placebo, 35,6%, p = 0,278). Los pacientes con niveles basales de proteína C reactiva de 10 mg / L o más (n = 119) mostraron una separación más clara entre el tratamiento activo y placebo (12 semanas la respuesta clínica: pegol 400 mg, 53,1%; placebo, 17,9%, p = 0.005 , el análisis post hoc), debido a una tasa de respuesta a placebo más baja que los pacientes con niveles de proteína C reactiva de menos de 10 mg / L. Los eventos adversos fueron similares entre los grupos. CONCLUSIONES: pegol 400 mg puede ser eficaz y bien tolerado en pacientes con enfermedad de Crohn activa. Las altas tasas de respuesta al placebo en el subgrupo grande de pacientes con bajos niveles de proteína C reactiva puede haber oscurecido la separación estadística entre certolizumab y placebo. En curso de fase III de ensayos son necesarios para establecer la eficacia clínica de certolizumab.
OBJECTIVE: The purpose of this study was to describe the clinical experience with the anti-tumor necrosis factor chimeric monoclonal antibody, infliximab, in pediatric patients with Crohn disease in The Netherlands.
DESIGN: Descriptive.
METHODS: Clinical response and adverse effects of infliximab were recorded for pediatric patients with Crohn disease treated from October 1992 to January 2003.
RESULTS: Thirty patients (aged 7-18 years) with refractory Crohn disease (with or without severe fistulas) were treated with infliximab. Patients were treated with up to 30 infusions. Mean follow-up was 25.3 months. A total of 212 infusions were administered. Thirteen patients had refractory Crohn disease without fistulas. Six patients showed good long-term response to infliximab treatment (defined as clinical index < or =10 points). Sixteen patients had refractory Crohn disease with draining fistulas. Nine showed good long-term response (closure or nonproductiveness of fistulas). One patient with metastatic Crohn disease in the skin had a good long-term response. Six patients developed an allergic reaction during infusion. In one patient, the allergic reaction occurred after an infliximab-free interval of 9 years. One patient died of sepsis.
CONCLUSIONS: Infliximab was an effective therapy in 53% of patients with refractory pediatric Crohn disease, with or without fistulas. Approximately half of the patients become unresponsive to infliximab therapy. Randomized controlled studies are mandatory to assess long-term efficacy and safety to define the optimal therapeutic strategy of infliximab therapy in children with Crohn disease.
The past decade has brought forth a series of novel biologic agents targeting tumor necrosis factor (TNF) for the treatment of Crohn's disease. The introduction of infliximab has paved the way for additional anti-TNF strategies that have the potential to build on that drug's efficacy and safety profile. However, the anti-TNF strategies might not have identical efficacy and safety profiles and might differ in dosing compared with therapy for rheumatoid arthritis. Most recently, adalimumab has been approved by the US Food and Drug Administration for the treatment of rheumatoid arthritis and is undergoing evaluation in Crohn's disease, with promising initial results. This review discusses the results of controlled clinical trials of anti-TNF agents for Crohn's disease.
ANTECEDENTES: CDP870 es un fragmento Fab 'PEGilado de un anticuerpo monoclonal humanizado que neutraliza factor de necrosis tumoral-alfa.
Objetivo: Evaluar la seguridad y eficacia de una dosis intravenosa única de CDP870 o placebo durante un período de 12 semanas en pacientes con enfermedad de moderada a severa de Crohn.
MÉTODOS: Noventa y dos pacientes adultos con enfermedad de Crohn (enfermedad de Crohn Índice de Actividad: 220-450 puntos) fueron aleatorizados para recibir CDP870 [1,25 (n = 2), 5 (n = 26), 10 (n = 17) o 20 mg / kg (n = 23)] o placebo (n = 24). Las puntuaciones de enfermedad índice de actividad de Crohn se determinaron a las semanas 0, 2, 4, 8 y 12. El punto final primario fue el porcentaje de pacientes que consiguieron la respuesta clínica [es decir, una disminución de la puntuación de Enfermedades Índice de Actividad de Crohn> o = 100 puntos o remisión (puntuación de la enfermedad de Crohn Índice de Actividad: <o = 150 puntos)] en la semana 4 en el intento de tratar población.
RESULTADOS: El porcentaje de pacientes que alcanzaron el punto final primario fue similar en todos los grupos de tratamiento (56,0%, 60,0%, 58,8% y 47,8% para placebo, CDP870 5, 10 y 20 mg / kg, respectivamente). La tasa de remisión en la semana 2 fue 47,1% con CDP870 10 mg / kg frente a 16,0% para el placebo (P = 0,041). Todos los tratamientos fueron bien tolerados: eventos adversos, reportados por 43 pacientes tratados con CDP870 y 15 pacientes tratados con placebo, fueron principalmente leves a moderados en intensidad. No hubo reacciones a la infusión.
Conclusiones: Una sola dosis intravenosa de CDP870 fue bien tolerado por los pacientes con enfermedad de Crohn. Si bien no se observó ninguna diferencia estadísticamente significativa en las tasas de respuesta clínica entre CDP870 y placebo, el beneficio clínico en términos de remisión se demostró.
It has been postulated that oxidative stress, nitric oxide (NO), and transforming growth factor beta(1) (TGF- beta(1)) have major roles in the pathophysiology of Crohn's disease (CD). The aim of this study was to determine the salivary levels of total antioxidant capacity (TAC), specific antioxidants (i.e., uric acid, albumin, transferrin, and thiol molecules), lipid peroxidation (LPO), NO, and TGF- beta(1) in CD patients and control subjects and to also investigate their correlation with activity of the disease. Twenty-eight patients with confirmed diagnosis of CD were enrolled and whole saliva samples were obtained. Smokers, diabetics, those who suffered from periodontitis, and those who were consuming antioxidant supplements were excluded from the study. The Crohn's Disease Activity Index (CDAI) was used to determine the severity of the disease. Twenty healthy subjects were also recruited. In CD patients significant reductions in salivary levels of TAC (0.248 +/- 0.145 vs. 0.342 +/- 0.110 mmol/L), albumin (1.79 +/- 0.42 vs. 2.3 +/- 0.2 microg/mL), and uric acid (3.1 +/- 1.4 vs. 4.1 +/- 2.0 mg/dL) were found. TGF-beta(1) was significantly increased in CD patients compared to healthy subjects (3.02 +/- 1.54 vs. 2.36 +/- 0.52 ng/mL). A fourfold increase in NO levels (198.8 +/- 39.9 vs. 50.2 +/- 21.3 micromol/L) along with a fivefold increase in LPO concentration (0.146 +/- 0.064 vs. 0.027 +/- 0.019 micromol/L) was documented in CD patients in comparison to the control group. CDAI significantly correlated with the TAC, LPO, and the interaction between TAC and LPO (r(2) = 0.625, r(2) = 0.8, F-test's P < 0.00005). Saliva of CD patients exhibits an abnormal feature with respect to oxidative stress, NO, and TGF-beta(1). TAC and LPO modify the effect of each other in determination of CD severity, which underlines the importance of oxidative stress in the pathogenesis of CD.
