RESUMO
OBJECTIVE: Although the reasons for secondary loss of response to infliximab (IFX) maintenance therapy in Crohn's disease vary, dose intensification is usually recommended. This study investigated the cost-effectiveness of interventions defined by an algorithm designed to identify specific reasons for therapeutic failure. DESIGN: Randomised, controlled, single-blind, multicentre study. 69 patients with secondary IFX failure were randomised to IFX dose intensification (5 mg/kg every 4 weeks) (n=36) or interventions based on serum IFX and IFX antibody levels using the proposed algorithm (n=33). Predefined co-primary end points at week 12 were proportion of patients responding (Crohn's Disease Activity Index (CDAI) decrease ≥ 70, or ≥ 50% reduction in active fistulas) and accumulated costs related to treatment of Crohn's disease, expressed as mean cost per patient, based on the Danish National Patient Registry for all hospitalisation and outpatient costs in the Danish healthcare sector. RESULTS: Costs for intention-to-treat patients were substantially lower (34%) for those treated in accordance with the algorithm than by IFX dose intensification: 6038 vs 9178, p<0.001. However, disease control, as judged by response rates, was similar: 58% and 53%, respectively, p=0.81; difference 5% (-19% to 28%). For per-protocol patients, treatment costs were even lower (56%) in the algorithm-treated group ( 4062 vs 9178, p<0.001) and with similar response rates (47% vs 53%, p=0.78; difference -5% (-33% to 22%)). CONCLUSIONS: Treatment of secondary IFX failure using an algorithm based on combined IFX and IFX antibody measurements significantly reduces average treatment costs per patient compared with routine IFX dose escalation and without any apparent negative effect on clinical efficacy. TRIAL REGISTRATION NO: NCT00851565.
Assuntos
Algoritmos , Anti-Inflamatórios não Esteroides/administração & dosagem , Anticorpos Monoclonais/administração & dosagem , Doença de Crohn/tratamento farmacológico , Medicina de Precisão/economia , Adulto , Idoso , Idoso de 80 Anos ou mais , Anti-Inflamatórios não Esteroides/sangue , Anti-Inflamatórios não Esteroides/imunologia , Anticorpos Monoclonais/sangue , Anticorpos Monoclonais/imunologia , Análise Custo-Benefício , Doença de Crohn/sangue , Doença de Crohn/economia , Dinamarca , Tolerância a Medicamentos , Feminino , Humanos , Infliximab , Análise de Intenção de Tratamento , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Método Simples-Cego , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Adulto JovemRESUMO
BACKGROUND: Whether infliximab therapy can be successfully discontinued after patients with Crohn's disease have attained sustained, clinical, biochemical, and endoscopic remission is unknown. METHODS: We conducted a multicenter, randomized, double-blind, placebo-controlled withdrawal study of infliximab in patients with Crohn's disease who were in clinical, biochemical, and endoscopic remission after standard infliximab maintenance therapy for at least 1 year. Patients were randomly assigned 1:1 to continue infliximab therapy or to receive matching placebo for 48 weeks. The primary end point was time to relapse. RESULTS: This study randomly assigned 115 patients to either the infliximab-continuation group or to the infliximab-discontinuation group. No relapses were observed among the 59 patients continuing infliximab, whereas 23 of 56 patients discontinuing infliximab experienced relapse. Time to relapse was significantly shorter among patients who discontinued infliximab than among those who continued infliximab (hazard ratio, 0.080; 95% confidence interval [CI], 0.035 to 0.186; P<0.001). At the end of the trial at week 48, relapse-free survival was 100% in the infliximab-continuation group and 51% in the infliximab-discontinuation group. The key secondary end point, time to loss of remission, was significantly shorter among patients discontinuing infliximab therapy than those continuing infliximab (hazard ratio, 0.025; 95% CI, 0.003 to 0.187; P<0.001). No unexpected adverse events were reported. CONCLUSIONS: Discontinuation of infliximab for patients with Crohn's disease receiving long-term infliximab therapy and in clinical, biochemical, and endoscopic remission leads to a considerable risk of relapse. (Funded by the Nordic Trial Alliance [NordForsk], the Medical Fund of the Danish Regions [Regionernes Medicin og Behandlingspulje], the Danish Colitis-Crohn Association, and the A.P. Moller Foundation; ClinicalTrials.gov number, NCT01817426; EudraCT number, 2012-002702-51.)
Assuntos
Doença de Crohn , Fármacos Gastrointestinais , Infliximab , Humanos , Infliximab/uso terapêutico , Infliximab/administração & dosagem , Infliximab/efeitos adversos , Doença de Crohn/tratamento farmacológico , Feminino , Masculino , Adulto , Método Duplo-Cego , Fármacos Gastrointestinais/uso terapêutico , Fármacos Gastrointestinais/administração & dosagem , Fármacos Gastrointestinais/efeitos adversos , Pessoa de Meia-Idade , Recidiva , Indução de Remissão , Adulto Jovem , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/efeitos adversos , Suspensão de Tratamento/estatística & dados numéricos , Resultado do TratamentoRESUMO
INTRODUCTION: Reasons for infliximab failure in Crohn's disease and ulcerative colitis are debated. Serum levels of infliximab and anti-infliximab antibodies have been associated with loss of response. We aimed at determining cut-off levels for infliximab and anti-infliximab antibody concentrations associated with clinical response to infliximab maintenance therapy. METHODS: Patients with inflammatory bowel disease (n = 106) were retrospectively classified as having maintained response or loss of response to infliximab maintenance therapy. Trough concentrations were measured by fluid-phase radioimmunoassays. RESULTS: Infliximab levels were significantly lower, and anti-infliximab antibody levels significantly higher, in Crohn's disease patients with loss of response (median infliximab 0 µg/ml, median anti-infliximab antibodies 35 U/ml) compared to patients with maintained response (median infliximab 2.8 µg/ml, median anti-infliximab antibodies 0 U/ml; p < 0.0001). Receiver operating characteristic (ROC) analysis identified optimal cut-off values: infliximab <0.5 µg/ml, which was associated with loss of response with sensitivity 86% [64-97] and specificity 85% [72-94]; and anti-infliximab antibodies ≥10 U/ml yielding a sensitivity of 81% [61-93] and specificity 90% [79-96]. Combined measurements of infliximab and anti-infliximab antibodies using these cut-off values had higher accuracy yielding a sensitivity of 81% [57-94] and specificity 94% [82-98]. Similar pattern was observed in a smaller cohort of patients with ulcerative colitis. CONCLUSIONS: Combined measurements of infliximab and anti-infliximab antibodies using cut-off levels provided high accuracy for discriminating between clinical response types to infliximab maintenance therapy. Cut-off levels are considered a prerequisite to further investigations of clinical usefulness of measurements of infliximab and anti-infliximab antibodies in patients failing infliximab therapy.
Assuntos
Anti-Inflamatórios/sangue , Anti-Inflamatórios/uso terapêutico , Anticorpos Monoclonais/sangue , Anticorpos Monoclonais/uso terapêutico , Anticorpos/sangue , Doença de Crohn/tratamento farmacológico , Adulto , Anti-Inflamatórios/imunologia , Anticorpos Monoclonais/imunologia , Colite Ulcerativa/sangue , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/imunologia , Doença de Crohn/sangue , Doença de Crohn/imunologia , Feminino , Humanos , Infliximab , Masculino , Pessoa de Meia-Idade , Curva ROC , Radioimunoensaio , Estudos Retrospectivos , Sensibilidade e Especificidade , Falha de TratamentoRESUMO
BACKGROUND: Certolizumab pegol is a pegylated humanized Fab' fragment with a high binding affinity for tumor necrosis factor alpha that does not induce apoptosis of T cells or monocytes. METHODS: In our randomized, double-blind, placebo-controlled trial, we evaluated the efficacy of certolizumab pegol maintenance therapy in adults with moderate-to-severe Crohn's disease. As induction therapy, 400 mg of certolizumab pegol was administered subcutaneously at weeks 0, 2, and 4. Patients with a clinical response (defined as reduction of at least 100 from the baseline score on the Crohn's Disease Activity Index [CDAI]) at week 6 were stratified according to their baseline C-reactive protein level and were randomly assigned to receive 400 mg of certolizumab pegol or placebo every 4 weeks through week 24, with follow-up through week 26. RESULTS: Among patients with a response to induction therapy at week 6 (428 of 668 [64%]), the response was maintained through week 26 in 62% of patients with a baseline C-reactive protein level of at least 10 mg per liter (the primary end point) who were receiving certolizumab pegol (vs. 34% of those receiving placebo, P<0.001) and in 63% of patients in the intention-to-treat population who were receiving certolizumab pegol (vs. 36% receiving placebo, P<0.001). Among patients with a response to induction therapy at week 6, remission (defined by a CDAI score of < or =150) at week 26 was achieved in 48% of patients in the certolizumab group and 29% of those in the placebo group (P<0.001). The efficacy of certolizumab pegol was also shown in patients taking and those not taking glucocorticoids or immunosuppressants and in patients who had and those who had not previously taken infliximab. Infectious serious adverse events (including one case of pulmonary tuberculosis) occurred in 3% of patients receiving certolizumab pegol and in less than 1% of patients receiving placebo. Antinuclear antibodies developed in 8% of the patients in the certolizumab group; antibodies against certolizumab pegol developed in 9% of all patients who entered the induction phase. CONCLUSIONS: Patients with moderate-to-severe Crohn's disease who had a response to induction therapy with 400 mg of certolizumab pegol were more likely to have a maintained response and a remission at 26 weeks with continued certolizumab pegol treatment than with a switch to placebo. (ClinicalTrials.gov number, NCT00152425 [ClinicalTrials.gov].).
Assuntos
Doença de Crohn/tratamento farmacológico , Fragmentos Fab das Imunoglobulinas/uso terapêutico , Polietilenoglicóis/uso terapêutico , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Adolescente , Adulto , Idoso , Anti-Inflamatórios/uso terapêutico , Anticorpos , Anticorpos Antinucleares , Anticorpos Monoclonais Humanizados , Proteína C-Reativa/análise , Certolizumab Pegol , Doença de Crohn/classificação , Doença de Crohn/imunologia , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Seguimentos , Humanos , Fragmentos Fab das Imunoglobulinas/efeitos adversos , Fragmentos Fab das Imunoglobulinas/imunologia , Imunossupressores/uso terapêutico , Injeções Subcutâneas , Masculino , Pessoa de Meia-Idade , Polietilenoglicóis/efeitos adversos , Indução de Remissão , Resultado do TratamentoRESUMO
Antibody constructs targeting tumour necrosis factor-alpha (TNF) have become important in the management of several chronic immunoinflammatory diseases. Four recombinant anti-TNF drugs are currently approved for clinical use in patients with various chronic inflammatory diseases, three of which are effective in chronic inflammatory bowel disease. These proteins can dramatically lower disease activity and, in some patients, induce remission. Unfortunately, however, not all patients respond favourably to anti-TNF antibodies. For example, patients suffering from Crohn's disease do not benefit from etanercept, and some patients treated with the other anti-TNF constructs either do not respond at all (primary response failure), or they respond initially but have later relapses (secondary response failure) despite increased dosage and/or more frequent administration of the drugs. The reason(s) for these response failures are not clear but inter-individual and even intra-individual differences in bioavailability and pharmacokinetics may contribute. Furthermore, immunogenicity of the drugs, causing patients to develop anti-drug antibodies (ADAs), contributes to treatment failure. Monitoring patients for circulating levels of functional anti-TNF drugs and ADAs is therefore warranted so that treatment can be tailored to the individual patient (individual medicine or personal medicine) in order that effective and economical long-term therapy can be given with minimal risks to the patients.
Assuntos
Anti-Inflamatórios/farmacologia , Anticorpos/farmacologia , Fármacos Gastrointestinais/farmacologia , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/imunologia , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Adalimumab , Anti-Inflamatórios/farmacocinética , Anticorpos/imunologia , Anticorpos Monoclonais/farmacocinética , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais Humanizados , Disponibilidade Biológica , Certolizumab Pegol , Etanercepte , Fármacos Gastrointestinais/farmacocinética , Humanos , Fragmentos Fab das Imunoglobulinas/farmacologia , Imunoglobulina G/farmacologia , Imunoterapia/métodos , Infliximab , Polietilenoglicóis/farmacocinética , Polietilenoglicóis/farmacologia , Radioimunoensaio , Receptores do Fator de Necrose Tumoral , Fator de Necrose Tumoral alfa/imunologiaRESUMO
BACKGROUND: It remains uncertain whether the increasing incidence of inflammatory bowel disease (IBD) during the last decades has been accompanied by an alteration in the presentation, course, and prognosis of the disease. To answer this question, 3 consecutive population-based IBD cohorts from Copenhagen, Denmark (1962-2005), were assessed and evaluated. METHODS: Phenotype, initial disease course, use of medications, cumulative surgery rate, standardized incidence ratio of colorectal cancer (CRC), and standardized mortality ratio (SMR) were compared in the 3 cohorts, which had a total of 641 patients with Crohn's disease (CD) and 1575 patients with ulcerative colitis (UC). RESULTS: From 1962 to 2005, the proportion of IBD patients suffering from CD increased (P < 0.001), time from onset of symptoms to diagnosis of CD decreased (P = 0.001), and median age at diagnosis of UC increased (P < 0.01). The prevalence of upper gastrointestinal involvement and pure colonic CD varied significantly between cohorts. UC patients diagnosed in the 1990s had a higher prevalence of proctitis, received more medications, and had a milder initial disease course than did previous patients. The surgery rate decreased significantly in CD but not in UC. The risk of CRC in IBD was close to expected over the entire period, whereas the mortality of patients with CD increased (overall SMR, 1.31; 95% CI, 1.07-1.60). CONCLUSIONS: Despite variations in the presentation and initial course of IBD during the last 5 decades, its long-term prognosis remained fairly stable. Treatment of IBD changed recently, and future studies should address the effect of these changes on long-term prognosis.
Assuntos
Colite Ulcerativa/epidemiologia , Doença de Crohn/epidemiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anti-Inflamatórios/uso terapêutico , Causas de Morte , Criança , Estudos de Coortes , Colite Ulcerativa/diagnóstico , Colite Ulcerativa/terapia , Neoplasias Colorretais/epidemiologia , Doença de Crohn/diagnóstico , Doença de Crohn/mortalidade , Doença de Crohn/terapia , Dinamarca/epidemiologia , Progressão da Doença , Feminino , Humanos , Fatores Imunológicos/uso terapêutico , Incidência , Masculino , Pessoa de Meia-Idade , Prevalência , Proctocolectomia Restauradora , Prognóstico , RiscoRESUMO
The risk of colorectal cancer (CRC) and dysplasia in patients with inflammatory bowel disease (IBD) has been highly debated as risk estimates from different studies vary greatly. The present national Danish guideline on colonoscopy surveillance for dysplasia and colorectal cancer in patients with IBD is based on a thorough review of existing literature with particular focus on recent studies from Denmark revealing a lower risk of CRC than previously assumed. The overall risk of CRC in the Danish IBD population does not appear to be different from that of the background population; however, in some subgroups of patients the risk is increased. These subgroups of patients, who should be offered colonoscopy surveillance, include patients with ulcerative colitis having extensive disease and a long disease duration (10-13 years); early age at onset (less than 19 years of age) of ulcerative colitis; and patients with ulcerative colitis as well as Crohn's disease with a concomitant diagnosis of primary sclerosing cholangitis. A colonoscopy surveillance program is recommended in these subgroups with intervals ranging from every 3-6 months to every 5 years, using chromoendoscopy with targeted biopsies of the lesion and adjacent mucosa, instead of conventional colonoscopy with random biopsies. Preferably, the colonoscopy should be performed during clinical remission. If a lesion is detected the endoscopical resectability together with the pathology of the lesion and the adjacent mucosa determine how the lesion should be treated.
Assuntos
Colo/patologia , Colonoscopia/métodos , Neoplasias Colorretais/diagnóstico , Doenças Inflamatórias Intestinais/complicações , Vigilância da População/métodos , Idade de Início , Biópsia/métodos , Colite Ulcerativa/complicações , Doença de Crohn/complicações , Dinamarca , Feminino , Humanos , Hiperplasia/diagnóstico , Mucosa Intestinal/patologia , Masculino , Fatores de TempoRESUMO
BACKGROUND: Patients with Crohn's disease (CD) have a higher risk of infectious diseases including pneumococcal infections, and the risk increases with immunotherapy. The primary endpoint of this study was to investigate the specific antibody response to two pneumococcal vaccines in CD patients with and without immunosuppressive treatment four weeks post vaccination. METHODS: In a randomized trial of the 23-valent pneumococcal polysaccharide vaccine (PPV23) and the 13-valent pneumococcal conjugated vaccine (PCV13), a group of CD patients treated with immunosuppressive drugs (IS) alone or in combination with TNF-α antagonists were compared to a group of CD patients not treated with any of these drugs (untreated). Specific pneumococcal antibody concentrations were measured against 12 serotypes common to the two vaccines before and 4 week after vaccination. RESULTS: PCV13 induced a significantly higher antibody response for one serotype (23F) in IS treated patients and for two serotypes (9V and 23F) in untreated patients compared to CD patients vaccinated with PPV23. Untreated PPV23 recipients had higher responses for serotypes 9V and 18C compared to IS+TNF-α treated PPV23 recipients. Comparison between treatment groups showed that immunosuppressive treatment impaired the antibody response to both vaccines and that TNF-a treatment further conveyed additional impairment of the response. CONCLUSION: PCV13 induces higher antibody response for some serotypes compared to PPV23. In addition, CD patients treated with immunosuppressive drugs alone or in combination with TNF-α antagonists had an impaired antibody response to both PPV23 and PCV13 compared to patients not receiving any of these treatments. The study has been registered in the European Clinical Trials Database (EudraCT, record no 2012-002867-86) and ClinicalTrials.gov (record no. NCT01947010).
Assuntos
Formação de Anticorpos/efeitos dos fármacos , Formação de Anticorpos/imunologia , Doença de Crohn/imunologia , Imunossupressores/farmacologia , Vacinas Pneumocócicas/imunologia , Polissacarídeos Bacterianos/imunologia , Vacinas Conjugadas , Adulto , Anticorpos Antibacterianos/sangue , Anticorpos Antibacterianos/imunologia , Doença de Crohn/tratamento farmacológico , Feminino , Humanos , Imunossupressores/uso terapêutico , Masculino , Pessoa de Meia-Idade , Infecções Pneumocócicas/prevenção & controle , Vacinas Pneumocócicas/administração & dosagem , Vacinas Pneumocócicas/efeitos adversos , Streptococcus pneumoniae/imunologia , Fator de Necrose Tumoral alfa/uso terapêutico , VacinaçãoRESUMO
INTRODUCTION: Infliximab (IFX), a monoclonal chimeric antibody against tumour necrosis factor (TNF) α, is effective for induction and maintenance of remission in moderate to severe Crohn's disease. Discontinuation of IFX maintenance therapy in patients in remission should be considered in order to reduce the potential long-term side effects and lower costs. METHODS AND ANALYSIS: This is a prospective, double-blind, randomised, placebo-controlled, multicentre study of patients with luminal Crohn's disease who have been treated with IFX for at least 1â year and are in sustained complete clinical, biochemical and endoscopic remission (ie, Crohn's Disease Activity Index (CDAI) score <150, complete mucosal healing and biochemical markers of inflammation within the normal range). These patients are randomised to receive placebo infusions or continue IFX maintenance therapy. The primary end point is the proportion of patients in maintained remission after 48â weeks (def. CDAI <150). ETHICS AND DISSEMINATION: It is estimated that the knowledge gained about how to optimally handle patients with Crohn's disease in complete long-term sustained remission on IFX is proportionate to the risks and inconveniences related to participation in this study. Prolonged exposure to IFX may cause severe side effects and increased risk of malignancies. Conversely, IFX discontinuation should not unnecessarily create a high risk of relapse. Thus, empirical evidence is needed concerning the safety of discontinuing IFX once a patient exhibits sustained remission. Study results will be published in an English language scientific medical journal. The study is approved by the Danish Medicines Agency (EudraCT-number: 2012-002702-51) and the Regional Ethics Committee of Region Hovedstaden Denmark (Approval-number: H-4-2012-099). The project is reported to the Danish Data Protection Agency (ID-number: 2007-58-0015/HEH.750.89-27), registered at Clinicaltrials.gov, and monitored by independent GCP units for the University of Copenhagen, Odense and Aarhus. The current approved protocol is V.3.2, dated 1 June 2014. TRIAL REGISTRATION NUMBER: http://clinicaltrials.gov/show/NCT01817426.
Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Doença de Crohn/tratamento farmacológico , Quimioterapia de Manutenção , Adolescente , Adulto , Anti-Inflamatórios não Esteroides/efeitos adversos , Anticorpos Monoclonais/efeitos adversos , Doença de Crohn/metabolismo , Método Duplo-Cego , Feminino , Humanos , Infliximab , Quimioterapia de Manutenção/efeitos adversos , Quimioterapia de Manutenção/estatística & dados numéricos , Masculino , Estudos Prospectivos , Recidiva , Indução de Remissão , Projetos de Pesquisa , Fator de Necrose Tumoral alfa/metabolismoRESUMO
BACKGROUND: A notable proportion of patients with inflammatory bowel disease (IBD) are switched from infliximab (IFX) to adalimumab (ADL). We investigated if immunogenicity of IFX influenced immunogenicity and clinical outcomes of later ADL therapy. METHODS: Single-center cohort study including all patients with IBD assessed for antibodies (Abs) against IFX or ADL. RESULTS: Anti-IFX Abs were evaluated in 187 patients treated with IFX as first line anti-TNF agent. Approximately, half (49%) were positive. Detected anti-IFX Abs had functional capacity as judged by a median IFX concentration below limit of detection (interquartile range, 0.0-0.0 µg/mL) versus 3.8 µg/mL (IQR, 1.3-7.9) in anti-IFX Ab-negative patients, P < 0.0001; but did not cross-react with ADL. Anti-ADL Abs were assessed in 57 ADL-treated patients. Twelve (21%) tested positive. Patients with previous anti-IFX Ab development were significantly more prone to develop anti-ADL Abs (33%) than those without (0%): odds ratio estimated 11, P = 0.04. The anti-ADL Abs were also functional because ADL was undetectable in all anti-ADL Ab-positive patients versus median 8.3 µg/mL (IQR 5.0-11.0) in anti-ADL-negative patients, P < 0.0001. The presence of anti-ADL Abs increased the risk of secondary ADL treatment failure with OR 28 (3-248), P < 0.001. ADL trough levels, irrespectively of anti-ADL Ab status, associated with efficacy of ADL maintenance therapy: AUC(ROC) 0.77 (0.62-0.93), P < 0.01. CONCLUSIONS: Switchers with anti-IFX Abs are prone to develop de novo anti-ADL Abs, which may result in therapeutic failure. Assessment of ADL immunogenicity in anti-IFX Ab-positive switchers is required to ensure optimal interventions at inadequate treatment responses and to avoid inappropriate ADL intensification regimens.
Assuntos
Anti-Inflamatórios/uso terapêutico , Anticorpos Anti-Idiotípicos/sangue , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Fármacos Gastrointestinais/uso terapêutico , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/imunologia , Adalimumab , Adolescente , Adulto , Reações Cruzadas , Feminino , Seguimentos , Fármacos Gastrointestinais/sangue , Fármacos Gastrointestinais/farmacocinética , Humanos , Doenças Inflamatórias Intestinais/sangue , Infliximab , Masculino , Estudos Retrospectivos , Falha de Tratamento , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Adulto JovemRESUMO
A 61 year old woman with active luminal Crohn's disease was successfully treated with infliximab induction therapy followed by 5 infusions every 8 weeks. However, symptoms returned in the weeks preceding the 7th and 8th infusions. The 9th infusion was therefore given only 4 weeks after the 8th infusion, but an acute severe anaphylactoid reaction occurred immediately after start of the infusion. Anti-infliximab IgG antibody concentration was high (100 U/ml) prior to the 8th infusion and up to 1 year after infliximab discontinuation (81 U/ml). Anti-infliximab IgE antibodies were not found, and the anti-infliximab antibodies did not cross react with adalimumab. One week after the anaphylactoid reaction to infliximab, adalimumab therapy was initiated. Twelve days after the first adalimumab administration (80 mg), a delayed hypersensitivity reaction occurred. This was likely caused by rapidly generated anti-adalimumab IgG antibodies (45 U/ml), as these antibodies appeared to be specific for adalimumab in that infliximab failed to compete with adalimumab/anti-adalimumab antibody binding ex vivo. In conclusion, immunogenicity to infliximab and adalimumab may be associated with both acute anaphylactoid reactions and delayed hypersensitivity reactions. Reactions may be precipitated by newly induced specific anti-drug antibodies rather than by cross-reactivity of previously generated antibodies.
Assuntos
Anti-Inflamatórios/efeitos adversos , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais/efeitos adversos , Doença de Crohn/tratamento farmacológico , Hipersensibilidade a Drogas/etiologia , Adalimumab , Anafilaxia/etiologia , Hipersensibilidade a Drogas/diagnóstico , Feminino , Humanos , Hipersensibilidade Tardia/etiologia , Infliximab , Pessoa de Meia-IdadeRESUMO
Treatment of inflammatory bowel disease (IBD) with antibodies against tumour necrosis factor-alpha (TNF) is effective. Not all patients respond, however, and the effect wears off in a considerable fraction of initial responders over time. Individual differences in bioavailability, pharmacokinetics and immunogenicity are now recognized as essential problems in the use of biologicals, and blood measurements of functional anti-TNF antibodies and antibodies against anti-TNF drugs with robust and clinically relevant methods may optimize treatment of IBD through individualized therapeutic regimens.
Assuntos
Anti-Inflamatórios/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Doenças Inflamatórias Intestinais/tratamento farmacológico , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Anti-Inflamatórios/sangue , Anti-Inflamatórios/imunologia , Anti-Inflamatórios/farmacocinética , Anticorpos/sangue , Anticorpos Monoclonais/sangue , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/farmacocinética , Disponibilidade Biológica , Doença de Crohn/sangue , Doença de Crohn/tratamento farmacológico , Doença de Crohn/imunologia , Monitoramento de Medicamentos , Humanos , Doenças Inflamatórias Intestinais/sangue , Doenças Inflamatórias Intestinais/imunologia , Infliximab , Medicina de Precisão , Fatores de Tempo , Resultado do Tratamento , Fator de Necrose Tumoral alfa/imunologiaRESUMO
Crohn's disease (CD) and ulcerative colitis (UC) are chronic inflammatory bowel diseases that have a remitting, relapsing nature. During relapse, they are treated with drugs and surgery. The present study was based on individual data from patients diagnosed with CD or UC at Herlev University Hospital, Copenhagen, Denmark, during 1991 to 1993. The data were aggregated over calendar years; for each year, the number of relapses and the number of surgical operations were recorded. Our aim was to estimate Markov models for disease activity in CD and UC, in terms of relapse and remission, with a cycle length of 1 month. The purpose of these models was to enable evaluation of interventions that would shorten relapses or postpone future relapses. An exact maximum likelihood estimator was developed that disaggregates the yearly observations into monthly transition probabilities between remission and relapse. These probabilities were allowed to be dependent on the time since start of relapse and on the time since start of remission, respectively. The estimator, initially slow, was successfully optimized to shorten the execution time. The estimated disease activity model for CD fits well to observed data and has good face validity. The disease activity model is less suitable for UC due to its transient nature through the presence of curative surgery.
Assuntos
Colite Ulcerativa/prevenção & controle , Doença de Crohn/prevenção & controle , Cadeias de Markov , Colite Ulcerativa/epidemiologia , Colite Ulcerativa/cirurgia , Doença de Crohn/epidemiologia , Doença de Crohn/cirurgia , Dinamarca/epidemiologia , Humanos , Funções Verossimilhança , Prevenção Secundária , Índice de Gravidade de DoençaRESUMO
The transmural inflammation characteristic of Crohn's disease predisposes patients to the formation of fistulas. Up to 50% of patients with Crohn's disease are affected by fistulas, which is a major problem given the considerable morbidity associated with this complication. Appropriate treatment of fistulas requires knowledge of specific pharmacological and surgical therapies. Treatment options depend on the severity of symptoms, fistula location, the number and complexity of fistula tracts, and the presence of rectal complications. Internal fistulas, such as ileoileal or ileocecal fistulas, are mostly asymptomatic and do not require intervention. By contrast, perianal fistulas can be painful and abscesses may develop that require surgical drainage with or without seton placement, transient ileostomy, or in severe cases, proctectomy. This Review describes the epidemiology and pathology of fistulizing Crohn's disease. Particular focus is given to external and perianal fistulas, for which treatment options are well established. Available therapeutic options, including novel therapies, are discussed. Wherever possible, practical and evidence-based treatment regimens for Crohn's disease-associated fistulas are provided.
Assuntos
Doença de Crohn/diagnóstico , Doença de Crohn/terapia , Fístula Intestinal/terapia , Doença de Crohn/complicações , Humanos , Fístula Intestinal/etiologia , Fístula Retal/etiologia , Fístula Retal/terapia , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
OBJECTIVE: Selective leukocyte apheresis is a new type of non-pharmacological treatment for patients with active ulcerative colitis and Crohn's disease. Preliminary data have indicated that this type of therapy is safe and efficacious, and large sham-controlled studies are currently in progress. In Scandinavia, a substantial number of patients with chronic inflammatory bowel disease have already received leukocyte apheresis on a compassionate use basis and the aim of this study was to report the clinical outcome and adverse events in the first patients treated. MATERIAL AND METHODS: Clinical details of the first consecutive 100 patients with inflammatory bowel disease treated with granulocyte, monocyte/macrophage (Adacolumn) apheresis in Scandinavia were prospectively registered. Median length of follow-up was 17 months, (range 5-30). RESULTS: The study population comprised 52 patients with ulcerative colitis, 44 patients with Crohn's disease and 4 patients with indeterminate colitis. In 97 patients the indication for Adacolumn treatment was steroid-refractory or steroid-dependent disease. Clinical remission was attained in 48% of the patients with ulcerative colitis, and an additional 27% had a clinical response to the apheresis treatment. The corresponding figures for patients with Crohn's disease were 41% and 23%, respectively. Complete steroid withdrawal was achieved in 27 out of the 50 patients taking corticosteroids at baseline. Adverse events were reported in 15 patients and headache was most frequently reported (n=7). CONCLUSIONS: Granulocyte, monocyte/macrophage apheresis treatment seems to be a valuable adjuvant therapy in selected patients with refractory inflammatory bowel disease. The risk for toxicity or severe adverse events appears to be low.
Assuntos
Doenças Inflamatórias Intestinais/terapia , Leucaférese/métodos , Adolescente , Adulto , Idoso , Feminino , Seguimentos , Granulócitos , Humanos , Incidência , Doenças Inflamatórias Intestinais/epidemiologia , Macrófagos , Masculino , Pessoa de Meia-Idade , Monócitos , Estudos Prospectivos , Países Escandinavos e Nórdicos/epidemiologia , Resultado do TratamentoRESUMO
BACKGROUND & AIMS: To investigate the efficacy and safety of certolizumab pegol (a polyethylene-glycolated Fab' fragment of anti-tumor necrosis factor, CDP870) in Crohn's disease. METHODS: In a placebo-controlled, phase II study, 292 patients with moderate to severe Crohn's disease received subcutaneous certolizumab 100, 200, or 400 mg or placebo at weeks 0, 4, and 8. The primary end point was the percentage of patients with a clinical response at week 12 (a Crohn's Disease Activity Index decrease of > or = 100 points or remission [Crohn's Disease Activity Index < or = 150 points]) in the intent-to-treat population. RESULTS: All certolizumab doses produced significant clinical benefit over placebo at week 2 (placebo, 15.1%; certolizumab 100 mg, 29.7% [P = .033]; 200 mg, 30.6% [P = .026]; 400 mg, 33.3% [P = .010]). At all time points, the clinical response rates were highest for certolizumab 400 mg, greatest at week 10 (certolizumab 400 mg, 52.8%; placebo, 30.1%; P = .006) but not significant at week 12 (certolizumab 400 mg, 44.4%; placebo, 35.6%; P = .278). Patients with baseline C-reactive protein levels of 10 mg/L or greater (n = 119) showed clearer separation between active treatment and placebo (week 12 clinical response: certolizumab 400 mg, 53.1%; placebo, 17.9%; P = .005; post hoc analysis) owing to a lower placebo response rate than patients with C-reactive protein levels of less than 10 mg/L. Adverse events were similar among groups. CONCLUSIONS: Certolizumab 400 mg may be effective and is well tolerated in patients with active Crohn's disease. High placebo response rates in the large patient subgroup with low C-reactive protein levels may have obscured statistical separation between certolizumab and placebo. Ongoing phase III trials are necessary to establish the clinical efficacy of certolizumab.