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

doi:10.1016/S0016-5085(99)70332-X

Gastroenterology

Volume 117, Issue 4, October 1999, Pages 761-769

https://doi.org/10.1016/S0016-5085(99)70332-X Get rights and content

Abstract

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.

GASTROENTEROLOGY 1999;117:761-769

Section snippets

Materials and methods

This randomized, double-blind, placebo-controlled, parallel group clinical trial evaluated the efficacy, safety, pharmacokinetics, and immunogenicity of repeated treatments with 10 mg/kg infliximab compared with placebo in patients showing a clinical response to an initial infliximab treatment.

Patients were originally enrolled in a randomized, double-blind, placebo-controlled study that has been reported previously.⁹ In that study, patients were randomized to receive an intravenous infusion of

Results

Seventy-three patients who had demonstrated a clinical response to an initial infusion of infliximab or placebo were randomly assigned to repeated treatment with infliximab (n = 37) or placebo (n = 36) (Table 1). Four of these patients had received an initial infusion of placebo and showed a clinical response (the investigators, all other study personnel, and patients were kept blinded at the time patients were determined to be eligible for the retreatment extension); 1 patient was retreated

Discussion

Crohn's disease is a chronic inflammatory disorder of the intestine with a relapsing course. Therefore, the long-term management of this chronic disease is an important challenge to clinicians.

Standard medical therapy in Crohn's disease is associated with limited efficacy. Corticosteroids are the mainstay of current treatments, but as many as 20% of patients are resistant to treatment and 36% of the responders develop steroid dependency.¹³ Most patients who respond to corticosteroids will

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Cited by (1085)

An in vitro analysis of the interaction between infliximab and granulocyte–monocyte apheresis
2024, Gastroenterologia y Hepatologia
Primary non-response and secondary loss of response to anti-TNF agents are common in inflammatory bowel disease. Increasing drug concentrations are correlated to better clinical response and remission rates. Combination of granulocyte–monocyte apheresis (GMA) with anti-tumor necrosis factor (TNF) agents could be an option in these patients. The objective of our study was to perform an in vitro assay to determine if the GMA device can lead to infliximab (IFX) adsorption.
A blood sample was obtained from a healthy control. It was incubated with three concentrations of IFX (3, 6, and 9 μg/ml) at room temperature for 10 min. At that time, 1 ml was collected to determine the IFX concentration. Then, 10 ml of each drug concentration was incubated with 5 ml of cellulose acetate (CA) beads from the GMA device at 200 rpm for 1 h at 37 °C to simulate physiological human conditions. A second sample of each concentration was collected and IFX levels were determined.
No statistically significant differences were observed in the IFX levels in the blood samples before and after incubation with the CA beads (p = 0.41) and after repeated measurements (p = 0.31). Mean change was 3.8 μg/ml.
The in vitro combination of GMA and IFX did not change the circulating levels of IFX at the three concentrations tested, suggesting that there is no interaction between the drug and the apheresis device in vitro and that they might be safely combined with each other.
La falta de respuesta primaria y la pérdida de respuesta secundaria a los agentes antifactor de necrosis tumoral (TNF) son comunes en la enfermedad inflamatoria intestinal. El aumento de los niveles de fármaco se correlaciona con una mejor respuesta clínica y de las tasas de remisión. La combinación de la aféresis selectiva de granulocitos y monocitos (GMA) con agentes anti-TNF podría ser una opción en estos pacientes. El objetivo de nuestro estudio fue realizar un ensayo in vitro para determinar si el dispositivo de GMA puede interaccionar con infliximab (IFX).
Se obtuvo una muestra de sangre de un control sano. Se incubó con 3 concentraciones de IFX (3, 6 y 9 μg/ml) a temperatura ambiente durante 10 minutos. En ese momento, se recogió 1 ml para determinar la concentración de IFX. Luego, se incubaron 10 ml de cada concentración de fármaco con 5 ml de cuentas de acetato de celulosa del dispositivo GMA a 200 rpm durante una hora a 37 °C para simular las condiciones fisiológicas humanas. Se recogió una segunda muestra de cada concentración y se determinaron los niveles de IFX.
No se observaron diferencias estadísticamente significativas en los niveles de IFX en las muestras de sangre antes y después de la incubación con las cuentas de acetato de celulosa (p = 0,41) ni tras mediciones repetidas (p = 0,31). La media de cambio fue de 3,8 μg/ml.
La combinación in vitro de IFX y GMA no modificó los niveles circulantes del fármaco en las 3 concentraciones probadas, lo que indica que no existe interacción entre el fármaco y el dispositivo de aféresis in vitro y que podrían combinarse de forma segura.
Maintenance of clinical remission with biologics and small molecules in inflammatory bowel disease according to trial design: Meta-analysis
2024, Digestive and Liver Disease
Design of randomised controlled trials (RCTs) examining maintenance of clinical remission in inflammatory bowel disease (IBD) varies, with some trials re-randomising patients who have responded to active drug during induction to either active drug or placebo and others treating patients through with active drug or placebo from baseline. Whether this influences therapeutic gain of drug over placebo is unknown.
We searched the literature to January 2023 for maintenance of remission trials of biologics or small molecules versus placebo in IBD. We extracted maintenance of remission rates according to trial design; either trials re-randomising patients or trials treating patients through. We pooled data in a meta-analysis for all patients, and according to type of IBD. We calculated the number needed to treat (NNT), with a 95% confidence interval (CI), to assess therapeutic gain of active drug over placebo according to trial design.
We identified 37 maintenance of remission trials (12,075 patients). Rates of maintenance of clinical remission were higher (41.9% with active drug, versus 20.3% with placebo), and NNT lowest (5; 95% CI 4–6), in trials re-randomising patients compared with those treating through (maintenance of remission rate 30.9% with active drug versus 14.6% with placebo, NNT = 7; 95% CI 5–9). Results were similar when trials were analysed according to IBD type but were more marked in ulcerative colitis RCTs (maintenance of remission rates in re-randomised trials 39.4% with active drug versus 17.8% with placebo, NNT = 5; 95% CI 3–7; treat-through trials 27.3% with active drug versus 11.9% with placebo, NNT = 7; 95% CI 5–11.5).
Trials re-randomising patients had generally higher maintenance of remission rates, lower NNTs, and greater therapeutic gains over placebo.
Withdrawal of infliximab or concomitant immunosuppressant therapy in patients with Crohn's disease on combination therapy (SPARE): a multicentre, open-label, randomised controlled trial
2023, The Lancet Gastroenterology and Hepatology
The combination of infliximab and immunosuppressant therapy is a standard management strategy for patients with Crohn's disease. Concerns regarding the implications of long-term combination therapy provided the rationale for a formal clinical trial of treatment de-escalation. Our aim was to compare the relapse rate and the time spent in remission over 2 years between patients continuing combination therapy and those stopping infliximab or immunosuppressant therapy.
This multicentre, open-label, randomised controlled trial was performed in 64 hospitals in seven countries in Europe and Australia. Adult patients with Crohn's disease in steroid-free clinical remission for more than 6 months, on combination therapy of infliximab and immunosuppressant therapy for at least 8 months were randomly assigned (1:1:1) to either continue combination therapy (combination group), discontinue infliximab (infliximab withdrawal group), or discontinue immunosuppressant therapy (immunosuppressant withdrawal group). Randomisation was stratified according to disease duration before start of first anti-TNF treatment (≤2 or >2 years), failure of immunosuppressant therapy before start of infliximab, and presence of ulcers at baseline endoscopy. The patient number and group of each stratum were assigned by a central online randomisation website. Treatment was optimised or resumed in case of relapse in all groups. Participants, those assessing outcomes, and those analysing the data were not masked to group assignment. The coprimary endpoints were the relapse rate (superiority analysis) and time in remission over 2 years (non-inferiority analysis, non-inferiority margin 35 days). Analyses were done on an intention-to-treat basis. This study is registered with ClinicalTrials.gov, NCT02177071, and with EU Clinical Trials Register, EUDRACT 2014-002311-41. The trial was completed in April, 2021.
Between Nov 2, 2015, and April 24, 2019, 254 patients were screened. Of these, 211 were randomised and 207 were included in the final analysis (n=67 in the combination group, n=71 in the infliximab withdrawal group, and n=69 in the immunosuppressant withdrawal group). 39 patients had a relapse (eight [12%] of 67 in the combination group, 25 [35%] of 71 in the infliximab withdrawal group, six [9%] of 69 in the immunosuppressant withdrawal group). 2-year relapse rates were 14% (95% CI 4–23) in the combination group, 36% (24–47) in the infliximab withdrawal group, and 10% (2–18) in the immunosuppressant withdrawal group (hazard ratio [HR] 3·45 [95% CI 1·56–7·69], p=0·003, for infliximab withdrawal vs combination, and 4·76 [1·92–11·11], p=0·0004, for infliximab withdrawal vs immunosuppressant withdrawal). Of 28 patients who had a relapse and were retreated or optimised according to protocol, remission was achieved in 25 patients (one of two in the combination group, 22 of 23 in the infliximab withdrawal group, and two of three in the immunosuppressant withdrawal group). The mean time spent in remission over 2 years was 698 days (95% CI 668–727) in the combination group, 684 days (651–717) in the infliximab withdrawal group, and 706 days (682–730) in the immunosuppressant withdrawal group. The difference in restricted mean survival time in remission was –14 days (95% CI –56 to 27) between the infliximab withdrawal group and the combination group and –22 days (–62 to 16) between the infliximab withdrawal group and the immunosuppressant withdrawal group. The 95% CIs contained the non-inferiority threshold (–35 days). We recorded 31 serious adverse events, in 20 patients, with no difference in frequency between groups. The most frequent serious adverse events were infections (four in the combination group, two in the infliximab withdrawal group, and one in the immunosuppressant withdrawal group) and Crohn's disease exacerbation (three in the combination group, four in the infliximab withdrawal group, and one in the immunosuppressant withdrawal group). No death nor malignancy was recorded.
In patients with Crohn's disease in sustained steroid-free remission under combination therapy with infliximab and immunosuppressant therapy, withdrawal of infliximab should only be considered after careful assessment of risks and benefits for each patient, whereas withdrawal of immunosuppressant therapy could generally represent a preferable strategy when considering treatment de-escalation.
European Union's Horizon 2020.
Definition of a therapeutic range for predicting long-term infliximab response in patients with inflammatory bowel disease
2023, Medicina Clinica
Monitoring plasma levels of Infliximab plays an important role in optimising treatment in patients with inflammatory bowel disease (IBD). The aim of the following study has been to determine the predictive potential of monitoring infliximab plasma levels for sustained clinical response and evaluate its usefulness to improve treatment efficacy and symptom control, in patients with IBD.
This single-centre retrospective study (2017–2019) included patients diagnosed with IBD treated with infliximab. Serum levels and the occurrence of drug-associated immunogenicity were analysed at Week 8 post-induction and 6, 12 and 24 months. Clinical parameters and inflammatory markers were recorded such as subjective global assessment (SGA), C-reactive protein (CRP) and faecal calprotectin (FC). Factors associated with early discontinuation and dose intensification of infliximab were determined.
Multivariate analysis determined that IFX concentrations > 7 μg/mL at week 8, and at 6 months, are associated with inflammatory remission (p = 0.046, 0.045). IFX > 7 μg/mL at 12 months predicted remission at 18 months of treatment (p = 0.006). IFX values > 3 μg/mL at 12 months are associated with stable SGA at 18 months (p = 0.001). Such values at 18 months are associated with stable SGA at 24 months (p = 0.044).
The predictive potential of monitoring IFX plasma levels as a strategy to evaluate sustained long-term clinical response was confirmed. Our results highlight the importance of its introduction into routine clinical practice to enable early identification of non-responders, treatment optimisation, relapse prevention and improve long-term therapy maintenance.
La monitorización de infliximab (IFX) juega un papel importante en la optimización del tratamiento en pacientes con enfermedad inflamatoria intestinal (EII). El objetivo del estudio fue determinar el potencial predictivo de la monitorización de IFX para la respuesta clínica sostenida, y evaluar su utilidad en la eficacia del tratamiento y del control de los síntomas.
Estudio retrospectivo unicéntrico (2017-2019) que incluyó pacientes con EII tratados con IFX. Se analizaron los niveles séricos y la inmunogenicidad asociada al fármaco en la semana 8 postinducción, y a los 6, 12 y 24 meses. Se registraron los parámetros clínicos y los marcadores inflamatorios correspondientes a la evaluación global subjetiva (SGA), proteína C reactiva (PCR) y calprotectina fecal (CF). Se determinaron los factores asociados a la interrupción precoz y a la intensificación de la dosis de IFX.
El análisis multivariante determinó que las concentraciones de IFX > 7 μg/ml en la semana 8, y a los 6 meses, se asocian a la remisión inflamatoria (p = 0,046-0,045). El IFX > 7 μg/ml a los 12 meses predijo la remisión a los 18 meses de tratamiento (p = 0,006). Los valores de IFX > 3 μg/ml a los 12 meses se asocian a una SGA estable a los 18 meses (p = 0,001). Dichos valores a los 18 meses se asocian a SGA estable a los 24 meses (p = 0,044).
Se confirma el potencial predictivo de la monitorización de los niveles plasmáticos de IFX como estrategia para evaluar la respuesta clínica sostenida a largo plazo. Nuestros resultados destacan la importancia de su introducción en la práctica clínica habitual para permitir la identificación temprana de los no respondedores, la optimización del tratamiento, la prevención de recaídas y mejorar el mantenimiento de la terapia a largo plazo.
Breaking Through the Therapeutic Ceiling: What Will It Take?
2022, Gastroenterology
Outcomes for patients starting a new treatment for inflammatory bowel disease are characterized by uncertainty of treatment response. Although it is natural to hope that new treatments will be characterized by better efficacy, remission is still far from a universal experience for patients living with inflammatory bowel disease. At times, an apparent “glass ceiling” appears to constrain progress toward a goal of maximal long-term health care–related quality of life for all. There are a number of areas that can and should be addressed if we are to make significant progress. These range from improved early diagnosis and initial management through better treatment stratification and response monitoring, to improvements in clinical trial design and selection of drugs in combination therapies. In this article, we discuss the steps required in all of these areas to make best use of new therapeutic options and shatter the glass ceiling.
Comparative efficacy and safety of biologic therapies for moderate-to-severe Crohn's disease: a systematic review and network meta-analysis
2021, The Lancet Gastroenterology and Hepatology
Data are needed to inform the positioning of biologic therapy in the treatment of moderate-to-severe Crohn's disease, both first line and after previous biologic exposure. We aimed to assess the comparative efficacy and safety of biologics in patients with Crohn's disease.
We did a systematic review and network meta-analysis of phase 2 and phase 3 randomised controlled trials done in adults (≥18 years) with moderate-to-severe Crohn's disease (Crohn's Disease Activity Index [CDAI] 220–450) treated with tumour necrosis factor (TNF) antagonists, anti-integrin, anti-interleukin (IL)-12 and IL-23p40, or anti-IL23p19 agents, either alone or in combination with immunosuppressants, as their first-line biologic or after previous biologic exposure, compared with placebo or an active comparator. The minimum duration of therapy was 14 days for trials reporting induction of remission in active disease and 22 weeks in trials reporting maintenance of remission. We searched Medline, EMBASE, the Cochrane CENTRAL Register of Controlled Trials, conference proceedings, trial registries, and unpublished data from inception to June 3, 2021, without any language restrictions. Summary estimates of the primary and secondary outcomes were extracted from the published reports; individual patient-level data were not sought. The primary endpoint was induction of clinical remission in patients with active disease (CDAI <150) and maintenance of remission in patients with response to induction therapy, with data extracted from published reports. A network meta-analysis with multivariate consistency model random-effects meta-regression was done, with rankings based on surface under the cumulative ranking curve (SUCRA) values.
The search strategy yielded 18 382 citations, of which 31 trials were eligible for inclusion. On the basis of 15 randomised controlled trials including 2931 biologic-naive patients, infliximab monotherapy (odds ratio [OR] 4·53 [95% CI 1·49–13·79]), infliximab combined with azathioprine (7·49 [2·04–27·49]), adalimumab (3·01 [1·25–7·27]), and ustekinumab (2·63 [1·10–6·28]) were associated with significantly higher odds of inducing remission compared to certolizumab pegol (all moderate confidence); infliximab and azathioprine combination therapy was also associated with significantly higher odds of inducing remission than vedolizumab (3·76 [1·01–14·03]; low confidence). On the basis of ten randomised controlled trials including 2479 patients with previous biologic exposure, adalimumab after loss of response to infliximab (OR 2·82 [95% CI 1·20–6·62]; low confidence), and risankizumab (2·10 [1·12–3·92]; moderate confidence), were associated with higher odds of inducing remission than vedolizumab. No differences between active interventions were observed in maintenance trials. Most trials were at low or uncertain risk of bias.
Although biologic treatment choices in patients with moderate-to-severe Crohn's disease must be individualised for each patient, this analysis suggests that either infliximab with azathioprine or adalimumab might be preferred as a first-line therapy, and adalimumab (after infliximab loss of response) or risankizumab might be preferred as a second-line therapy, for induction of clinical remission.
None.

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^☆: Address requests for reprints to: Paul J. Rutgeerts, M.D., Ph.D, Department of Gastroenterology, University Hospital Gasthuisberg, Herestraat 49, Leuven, Belgium.

^☆☆: The Crohn's Disease Infliximab Study Group consists of the following centers and investigators (the number of patients enrolled at each center is given in parenthesis). Massachusetts General Hospital, Boston, MA (3 patients): D. Podolsky, B. E. Sands, M. T. Marcucci; Cedars-Sinai Medical Center, Los Angeles, CA (15 patients): S. R. Targan, E. A. Vasiliauskas, B. Voigt, J. Gaiennie; University of Chicago Hospital and Clinics, Chicago, IL (5 patients): S. B. Hanauer; University of Alabama School of Medicine, Birmingham, AL (1 patient): C. O. Elson, R. P. McCabe, Jr; Mount Sinai Medical Center, New York, NY (6 patients): L. Mayer, D. H. Present, C. Stamaty; Washington University School of Medicine, St. Louis, MO (2 patients): W. F. Stenson, J. J. O'Brien; Virginia Mason Medical Center, Seattle, WA (3 patients): R. Kozarek, M. Gelfand; Hospital of the University of Pennsylvania, Philadelphia, PA (3 patients): D. Bachwich, G. Lichtenstein, L. Hurd; McMaster University Medical Center, Hamilton, Ontario, Canada (2 patients): E. J. Irvine, S. Collins; Lahey Clinic, Burlington, MA (2 patients): A. S. Warner, L. J. Costa; University of North Carolina, Chapel Hill, NC (4 patients): K. L. Isaacs; University of Maryland Medical System, Baltimore, MD (3 patients): S. James, B. Greenwald, M. L. Mullen; University of Kentucky, Lexington, KY (5 patients): G. W. Varilek, B. Vivian; Academisch Ziekenhuis Leiden, Leiden, The Netherlands (4 patients): R. A. van Hogezand, M. J. Wagtmans; Institute for Clinical Immunology and Rheumatology, Erlangen, Germany (1 patient): J. Schonekas, J. R. Kalden, J. M. L. Bauer; University of Amsterdam, Amsterdam, The Netherlands (8 patients): S. J. H. van Deventer, C. M. J. Kothe, O. J. B. de Smit; Leeds General Infirmary, Leeds, England (1 patient): D. M. Chalmers, S. Chitturi, D. Toki; and Academisch Ziekenhuis Gasthuisberg, Leuven, Belgium (9 patients): P. J. Rutgeerts, G. R. A. M. D'Haens, A. F. M. Verstraeten.

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Rapid CommunicationsEfficacy and safety of retreatment with anti–tumor necrosis factor antibody (infliximab) to maintain remission in Crohn's disease☆,☆☆

Abstract

Section snippets

Materials and methods

Results

Discussion

Gastroenterology

Gastroenterology

Gastroenterology

Gastroenterology

Gastroenterology

Management of Crohn's disease in adults

Am J Gastroenterol

Tumour necrosis factor and Crohn's disease

Gut

Cytokines (immunoinflammatory hormones) and their natural regulation in inflammatory bowel disease (Crohn's disease and ulcerative colitis): a review

Dig Dis

Mucosal inflammatory cytokine production by intestinal biopsies in patients with ulcerative colitis and Crohn's disease

J Clin Immunol

Rapid Communications
Efficacy and safety of retreatment with anti–tumor necrosis factor antibody (infliximab) to maintain remission in Crohn's disease☆,☆☆