, Volume 16, Issue 2, pp 111-148
Date: 15 Aug 2012

Infliximab

Rent the article at a discount

Rent now

* Final gross prices may vary according to local VAT.

Get Access

Summary

Abstract

Infliximab is a chimeric monoclonal antibody that binds to tumour necrosis factor-α (TNFα) and neutralises its effects. TNFα plays an important role in the development of both Crohn’s disease and rheumatoid arthritis.

In a large, double-blind, randomised study involving patients with active, refractory Crohn’s disease, significantly more recipients of intravenous infliximab, compared with placebo, achieved a clinical response after 4 weeks’ follow-up. Moreover, infliximab administration was associated with a rapid improvement in endoscopic and histological findings in clinical trials involving patients with active, refractory Crohn’s disease. The results of the A Crohn’s Disease Clinical Trial Evaluating Infliximab in a New Long-Term Treatment Regimen (ACCENT) I study showed that maintenance infliximab therapy prolonged response and remission in patients with moderate to severe Crohn’s disease.

In patients with enterocutaneous fistulae associated with Crohn’s disease who were involved in a double-blind, randomised study, significantly more patients who received multiple infusions of infliximab, compared with placebo, experienced a ≥50% reduction from baseline in the number of draining fistulae at ≥2 consecutive study visits.

In patients with active rheumatoid arthritis refractory to treatment with methotrexate who were enrolled in a large, double-blind, randomised study [the Anti-TNF Trial in Rheumatoid Arthritis with Concomitant Therapy (ATTRACT) study], American College of Rheumatology (ACR) 20, 50 and 70% response rates were seen in significantly more patients who received multiple infusions of infliximab plus methotrexate, compared with methotrexate plus placebo, after 30 and 54 weeks’ treatment. Moreover, the ACR 20% response rate was maintained after 102 weeks’ treatment. In addition, significantly less radiographic progression was seen in infliximab plus methotrexate, compared with methotrexate plus placebo, recipients after 54 weeks’ treatment.

Infliximab therapy was also associated with improvements in health-related quality of life in patients with Crohn’s disease or rheumatoid arthritis.

Infliximab was generally well tolerated in clinical trials with the most common adverse events including upper respiratory tract infection, headache, nausea, coughing, sinusitis and diarrhoea. Infliximab therapy may be associated with an increased risk of reactivation of tuberculosis in patients with latent disease.

In conclusion, infliximab is an important treatment option in patients with active Crohn’s disease who have not responded to conventional therapy and in patients with Crohn’s disease who have fistulae. Moreover, infliximab plus methotrexate is effective in patients with active rheumatoid arthritis who have not responded adequately to traditional disease-modifying antirheumatic drugs, in terms of reducing symptoms and signs, improving physical function and delaying the progression of structural damage.

Pharmacodynamic Properties

Tumour necrosis factor-α (TNFα) plays an important role in the development of both Crohn’s disease and rheumatoid arthritis. Infliximab is a chimeric monoclonal antibody against TNFα. Administration of infliximab reduced the expression of proinflammatory cytokines and chemokines in biopsy samples from patients with Crohn’s disease [e.g. TNFα, interferon-γ, monocyte chemoattractant protein-1 (MCP-1), macrophage inhibitory protein-2 and regulated upon activation, normal T cell expressed and secreted] or rheumatoid arthritis [TNFα, interleukin (IL)-8 and MCP-1]. Levels of proinflammatory cytokines and chemokines in the sera of patients with Crohn’s disease (e.g. IL-6) or rheumatoid arthritis (e.g. IL-6 and IL-1β) were also reduced.

Infliximab therapy also reduced the expression of endothelial adhesion molecules in biopsy samples from patients with Crohn’s disease [intercellular adhesion molecule-1 (ICAM-1)] or rheumatoid arthritis (E-selectin and vascular cell adhesion molecule-1). Levels of endothelial adhesion molecule were also reduced in the sera of patients with Crohn’s disease (ICAM-1) or rheumatoid arthritis (E-selectin and ICAM-1). This reduction in endothelial adhesion molecule expression is potentially responsible, in part, for the reduced influx of leucocytes into the gut mucosa of patients with Crohn’s disease who received infliximab and the reduced movement of granulocytes into the joints of patients with rheumatoid arthritis who received infliximab.

Transient increases in peripheral blood lymphocyte counts were commonly seen after administration of infliximab to patients with Crohn’s disease or rheumatoid arthritis. Changes in peripheral blood monocyte and neutrophil counts were also seen following infliximab administration; these were usually of transient duration.

Infliximab administration was also associated with reductions in serum levels of several other factors implicated in the pathogenesis of Crohn’s disease (phospholipase A2) or rheumatoid arthritis (matrix metalloproteinase-1 and -3, vascular endothelial growth factor), as well as reductions in nitric oxide synthase type 2 protein expression and nitric oxide synthase activity in patients with rheumatoid arthritis.

Pharmacokinetic Properties

Dose-dependent increases in maximum plasma concentration (192.1, 426.7 and 907.4 mg/L, respectively) and in the area under the concentration-time curve (49 909, 78 178 and 173 043 mg · h/L, respectively) were seen with administration of single intravenous infusions of infliximab 5, 10 or 20 mg/kg to patients with rheumatoid arthritis. Most of these patients still had detectable serum infliximab concentrations 10 weeks after treatment. In patients with rheumatoid arthritis, serum infliximab concentrations appeared to be sustained for longer with concomitant administration of methotrexate. Patients with Crohn’s disease who received multiple infliximab infusions had stable serum concentrations 8 weeks after each infusion; most patients had detectable serum infliximab concentrations 12 weeks after the last dose.

Administration of single intravenous infusions of infliximab 5, 10 or 20 mg/kg to patients with rheumatoid arthritis showed that the volume of distribution of infliximab is independent of dose (3.1 to 4.3L) [suggesting mainly intravascular distribution], as is the clearance (approximately 0.011 L/h) and the terminal elimination half-life (215 to 295 hours).

Clinical Efficacy

In Crohn’s Disease

In clinical trials, single infusions of intravenous infliximab 5 to 20 mg/kg were associated with a clinical response [defined as a reduction in the Crohn’s Disease Activity Index (CDAI) of ≥70 or >70 points] in 50 to 81% of patients with active, refractory Crohn’s disease after 4 weeks’ follow-up. In addition, after 4 weeks’ follow-up, remission (defined as a CDAI score of <150) had occurred in 20 to 75% of infliximab recipients. In a large, double-blind, randomised, 12-week trial, in which 108 patients with active, refractory Crohn’s disease received single infusions of intravenous infliximab 5, 10 or 20 mg/kg, significantly greater reductions from baseline in CDAI scores were seen in infliximab than placebo recipients 2 and 4 weeks’ after treatment, indicating rapid symptomatic improvement.

The results of the A Crohn’s Disease Clinical Trial Evaluating Infliximab in a New Long-Term Treatment Regimen (ACCENT) I study, involving 573 patients, showed that maintenance infliximab therapy prolonged response and remission in patients with moderate to severe Crohn’s disease. Significantly more recipients of infliximab 5 or 10 mg/kg, compared with placebo, demonstrated a clinical response (51.3 and 59.1 vs 27.3%), or were in clinical remission (38.9 and 45.5 vs 21.9%), after 30 weeks’ follow-up. Moreover, additional analyses of ACCENT I showed that infliximab therapy had a corticosteroid-sparing effect and that regular maintenance therapy was more effective than episodic on-demand treatment with regards to clinical response and remission rates.

Clinical trials involving patients with active, refractory Crohn’s disease indicate that rapid improvement in endoscopic findings was seen with single infusions of intravenous infliximab 3 to 20 mg/kg. Significant reductions from baseline in histology scores were also seen in recipients of infliximab 5 to 20 mg/kg, but not in placebo recipients, involved in a double-blind, randomised, 4-week trial (n = 30).

The efficacy of intravenous infliximab in patients with enterocutaneous abdominal or perianal fistulae was shown in a double-blind, randomised study in which 94 such patients received infliximab 5 or 10 mg/kg or placebo at weeks 0,2 and 6. Significantly more infliximab 5 and 10 mg/kg recipients (68 and 56%, respectively), compared with placebo recipients (26%), experienced a ≥50% reduction from baseline in the number of draining fistulae at ≥2 consecutive study visits (the primary endpoint). Moreover, a clinical response (defined as the absence of any draining fistulae at ≥2 consecutive study visits) was achieved in significantly more infliximab 5 and 10 mg/kg recipients than placebo recipients (55 and 38 vs 13%, respectively).

The results of clinical practice studies involving patients with active or fistulising Crohn’s disease tended to mirror those obtained in clinical studies. Infliximab has also shown efficacy in paediatric patients with Crohn’s disease. In a double-blind, randomised study involving 12 patients aged between 11 and 17 years who had refractory Crohn’s disease and who received a single infusion of intravenous infliximab 1, 5 or 10 mg/kg, five patients achieved remission.

In Rheumatoid Arthritis

The efficacy of combination therapy with intravenous infliximab plus methotrexate has been shown in two large (n = 428 and 101), double-blind, randomised studies involving patients with active rheumatoid arthritis who had not responded to prior methotrexate therapy. In the larger of these trials [the Anti-TNF Trial in Rheumatoid Arthritis with Concomitant Therapy (ATTRACT) study] patients received intravenous infliximab 3 or 10 mg/kg or placebo at weeks 0, 2 and 6 and every 4 or 8 weeks subsequently. All patients also received methotrexate (median dosage 15 mg/week). After 30 weeks’ treatment, American College of Rheumatology (ACR) 20% (50 to 58 vs 20%), 50% (26 to 31 vs 5%) and 70% (8 to 18 vs 0%) response rates were significantly higher in infliximab plus methotrexate, compared with methotrexate plus placebo, recipients. Similarly, ACR 20% (42 to 59 vs 17%), 50% (21 to 39 vs 8%) and 70% (10 to 25 vs 2%) response rates remained significantly higher in infliximab plus methotrexate, compared with methotrexate plus placebo, recipients after 54 weeks’ treatment. Moreover, ACR 20% response rates were maintained after 102 weeks’ treatment (39.5 to 48.3 vs 15.9%). Significantly greater improvements in individual disease parameters (swollen and tender joint counts and C-reactive protein level) were also seen in infliximab plus methotrexate, compared with methotrexate plus placebo, recipients. Importantly, after 54 weeks’ treatment, infliximab plus methotrexate was associated with significantly less radiographic progression than methotrexate plus placebo [as assessed by changes in modified Sharp total (−0.7 to +1.6 vs +7), erosion (−0.7 to +0.3 vs +4) and joint space narrowing (0 to +1.1 vs +2.9) scores]. In the smaller double-blind, randomised study, patients received intravenous infliximab 1,3 or 10 mg/kg, either alone or in combination with methotrexate, at weeks 0, 2, 6, 10 and 14. Compared with methotrexate plus placebo, the median duration of response was significantly longer in recipients of infliximab 1 mg/kg plus methotrexate, infliximab 3 mg/kg with or without methotrexate or infliximab 10 mg/kg with or without methotrexate (0 vs 16.5, 16.5, 17.2, >18.1 and 10.4 weeks).

In addition, results from a large noncomparative study (n = 235) showed that symptomatic improvement was seen within 48 hours of infliximab administration in patients with active rheumatoid arthritis who had not responded adequately to methotrexate therapy.

The results of two noncomparative studies (n = 31 and 61 evaluable patients) showed that leflunomide may be an alternative to methotrexate for use in combination with infliximab in rheumatoid arthritis. In one of the studies, tender and swollen joint counts were reduced by 45 and 55%, respectively, and the mean prednisone dosage was reduced from 7.5 to 5 mg/day.

In Other Indications

Infliximab therapy has shown efficacy in indications other than Crohn’s disease and rheumatoid arthritis (e.g. ulcerative colitis, juvenile chronic arthritis, psoriatic arthritis, ankylosing spondylitis and adult-onset Still’s disease). However, to date, most of these data are obtained from small comparative or noncomparative trials.

Health-Related Quality of Life and Cost Considerations

In Crohn’s Disease

After 4 weeks’ follow-up, significantly greater improvements from baseline in Inflammatory Bowel Disease Questionnaire scores were seen in infliximab 5, 10 and 20 mg/kg recipients, compared with placebo recipients, in a double-blind, randomised study that enrolled 108 patients with active refractory Crohn’s disease. Moreover, significantly more infliximab than placebo recipients reported other quality-of-life benefits (e.g. with regard to energy levels, participation in leisure and sports activities and school and work attendance).

Infliximab therapy was associated with reductions in healthcare resource utilisation according to the results of a retrospective review. In addition, the results of a modelling study indicate that infliximab therapy may be cost saving in patients with active, refractory Crohn’s disease in certain clinical scenarios (e.g. if patients were to achieve remission similar to that obtained with surgery).

In Rheumatoid Arthritis

After 54 weeks’ follow-up in the ATTRACT study, recipients of infliximab plus methotrexate, compared with methotrexate plus placebo, had significantly greater improvements from baseline in Health Assessment Questionnaire scores, the physical component summary score from the Medical Outcomes Study Short-form Health Survey, the arthritis specific health index and patient global assessment of disease activity.

A modelling study using data from the ATTRACT study found infliximab to be associated with acceptable cost-effectiveness ratios in patients with rheumatoid arthritis. The results of a Spanish modelling study showed that treating patients with rheumatoid arthritis with infliximab plus methotrexate was more costly than treatment with leflunomide; this was mainly attributable to the higher acquisition cost of infliximab. In addition, the results of a Dutch modelling study showed that the total cost of infliximab plus methotrexate therapy was greater than that of etanercept therapy in rheumatoid arthritis; the higher cost was because infliximab was administered intravenously in an outpatient setting in combination with methotrexate.

Tolerability

Infliximab was generally well tolerated in clinical trials involving patients with Crohn’s disease or rheumatoid arthritis. Pooled results of clinical trials revealed that the most commonly occurring adverse events in patients with Crohn’s disease (n = 199) or rheumatoid arthritis (n = 555) who received infliximab were upper respiratory tract infection (16 and 26%, respectively), headache (23 and 22%, respectively), nausea (17 and 17%, respectively), coughing (5 and 13%, respectively), sinusitis (5 and 13%, respectively) and diarrhoea (3 and 13%, respectively). Approximately 6% of infliximab recipients discontinued therapy because of adverse events.

In clinical studies involving patients with Crohn’s disease or rheumatoid arthritis, treated infections occurred in 32% of infliximab recipients and 22% of placebo recipients. With regard to serious infections, during 6 months follow-up of patients with Crohn’s disease who received infliximab (n = 770) or placebo (n = 192), pneumonia occurred in 1.2 and 0.5% of infliximab and placebo recipients, respectively, cellulitis occurred in 0.5 and 0%, respectively, sepsis occurred in 0.5 and 1%, respectively, and abscess occurred in 0.1 and 0.5%, respectively.

Postmarketing surveillance has revealed a possible association between infliximab therapy and tuberculosis. As of June 30 2001, 84 cases of tuberculosis had been reported in infliximab recipients worldwide. It was thought that most of these cases represented reactivation of latent disease.

Infusion-related reactions have been reported in 19% of infliximab recipients and in 8% of placebo recipients involved in clinical trials. Reactions tended to be mild in nature and of transient duration; anaphylaxis has been reported infrequently. In a clinical study, delayed hypersensitivity reactions were reported in 25% of patients with Crohn’s disease who received retreatment with infliximab 2 to 4 years after initial infusion, although 90% of patients who experienced a delayed reaction received a liquid formulation of infliximab that is no longer in use.

The development of human antichimeric antibodies (HACA) has been reported in 13.4% of patients with Crohn’s disease receiving infliximab in clinical trials. Patients who develop HACA appear to be more likely to experience infusion-related reactions. In patients with rheumatoid arthritis, concomitant administration of methotrexate appears to potentiate immunological tolerance to infliximab. HACA developed in 53, 21 and 7% of patients receiving infliximab 1, 3 or 10 mg/kg, respectively, without methotrexate, and in 15, 7 and 0% of patients receiving infliximab 1, 3 or 10 mg/kg, respectively, plus methotrexate. The development of antinuclear antibodies and antibodies against double-stranded DNA has also been reported in patients with Crohn’s disease or rheumatoid arthritis who received infliximab in clinical trials.

Long-term follow-up (3 years) of patients with Crohn’s disease or rheumatoid arthritis involved in clinical trials revealed the development of malignancy in 14 out of 770 infliximab recipients and in 1 out of 192 placebo recipients.

Preliminary reports indicate higher incidences of death and hospitalisation for worsening heart failure in infliximab recipients (especially those receiving the 10 mg/kg dose) than placebo recipients in a trial involving 150 patients with New York Heart Association class III to IV congestive heart failure who received three infusions of infliximab 5 or 10 mg/kg or placebo over 6 weeks. Seven out of 101 infliximab recipients died, compared with none of the 49 placebo recipients.

Infliximab and etanercept have both been associated with neurological adverse events (rare cases of optic neuritis, seizures and central nervous system demyelinating disorders, including multiple sclerosis).

Dosage and Administration

In Crohn’s disease, infliximab is indicated for use in patients with active disease (moderate to severe disease in the US and severe disease in the European Union) who have not responded to conventional treatment and in patients with fistulising disease (in the European Union patients with fistulae must be refractory to conventional therapy). The recommended dosage in active Crohn’s disease is a single intravenous infusion of 5 mg/kg; it is recommended that patients with fistulising Crohn’s disease receive intravenous infusions of infliximab 5 mg/kg at weeks 0, 2 and 6.

With regard to rheumatoid arthritis, in the US, infliximab is approved for use in combination with methotrexate to reduce symptoms and signs, inhibit the progression of structural damage and improve physical function in patients with active moderate-to-severe disease who have not had an adequate response to methotrexate. In the European Union, infliximab is approved for use in combination with methotrexate to reduce symptoms and signs in patients with active disease who have had an inadequate response to treatment with disease-modifying antirheumatic drugs (including methotrexate). Intravenous infusions of infliximab 3 mg/kg should be administered at weeks 0, 2 and 6 and every 8 weeks thereafter.

The US manufacturers of infliximab recommend that patients should undergo tuberculin skin testing prior to starting treatment with infliximab to help exclude the presence of latent infection. Patients found to have latent tuberculosis should commence antitubercular treatment before they start infliximab therapy. In the European Union the use of infliximab is contraindicated in patients with tuberculosis and all patients must be evaluated for active and latent tuberculosis prior to starting the drug.

Infliximab should not be given to patients with clinically important, active infections or initiated in patients with congestive heart failure. In Europe infliximab is contraindicated in patients with moderate or severe heart failure. Infliximab should be administered with caution to patients with chronic infection or a history of recurrent infection and to patients with central nervous system demyelinating disorders that are pre-existing or of recent onset. Infliximab should be discontinued in patients with congestive heart failure who experience a worsening of their condition, patients who develop serious infections, patients who develop severe infusion-related reactions and patients who develop symptoms suggestive of a lupus-like syndrome. Patients should be monitored for the presence of infection both during and after infliximab therapy and the cardiovascular status of patients with congestive heart failure who continue to receive infliximab therapy should be monitored.