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PubMed2005

Infliximab therapy in established rheumatoid arthritis: an observational study.

PURPOSE: To investigate the efficacy, toxicity and drug discontinuation rate in an observational study of patients with established rheumatoid arthritis treated with infliximab. SUBJECTS AND METHODS: Between September 1999 and June 2003, we enrolled 84 patients with rheumatoid arthritis who were being treated with infliximab. All patients met the American College of Rheumatology criteria for rheumatoid arthritis and had been refractory to (or did not tolerate) at least two disease-modifying antirheumatic drugs. Patients entering the study had a negative purified protein derivative skin test, were fully informed about the treatment regimen, and were followed up at predefined times according to a standardized protocol. Data concerning infliximab dosage, tolerability, adverse events, concomitant therapy, dosage interval, and drug discontinuation were all recorded. In addition, the clinical and laboratory variables according to the American College of Rheumatology 20% and 50% response criteria and the disease activity score for the 28 joint indices were also recorded. RESULTS: There were 61 women and 23 men with a mean age of 59 +/- 8 years and mean disease duration of 11 +/- 6 years. Seventy-five percent (63/84) were seropositive for IgM rheumatoid factor. After the first year of treatment, 84.5% of patients continued to be treated with infliximab, whereas this percentage was 73% after the second year and 59% after the third year of treatment. The American College of Rheumatology 20% response criteria was met by 59/84 (70%) of patients, and 38/84 (45%) of the patients achieved the 50% response criteria in the first year of treatment. At the second year of therapy, the American College of Rheumatology 20% response criteria were reached by 35/84 (42%) of the patients and the 50% response criteria by 27/84 (32%). At the third year of treatment with infliximab, the American College of Rheumatology 20% and 50% response criteria were achieved by 13/84 (15.5%) and 10/84 (12%) of the patients, respectively. Twenty-eight of eighty-four (33%) patients discontinued infliximab therapy. The risk of drug discontinuation decreased with the concomitant use of methotrexate. The main reasons for drug discontinuation were adverse drug reactions (16/84, 19%), followed by lack of efficacy (9/84, 11%). The main reasons for drug discontinuation due to side effects were immediate hypersensitivity reactions (9/84, 11%) and infections (6/84, 7%). CONCLUSION: Infliximab was found to be an alternative treatment with a relatively acceptable toxicity profile, despite the fact that two patients developed pulmonary tuberculosis. After the third year of therapy, 59% of patients continued to be treated with infliximab. The concomitant use of methotrexate was associated with the continuation of infliximab therapy.

Antibodies, Monoclonal↗
PubMed2003

Infliximab but not etanercept induces apoptosis in lamina propria T-lymphocytes from patients with Crohn's disease.

BACKGROUND & AIMS: Steroid-refractory Crohn's disease responds to therapy with the chimeric anti-tumor necrosis factor (TNF)-alpha antibody infliximab. Etanercept, a recombinant TNF receptor/immunoglobulin G fusion protein, is highly effective in rheumatoid arthritis but not in Crohn's disease. Because both infliximab and etanercept are TNF-alpha-neutralizing drugs, we investigated the differences in TNF-alpha-neutralizing capacity and human lymphocyte binding and apoptosis-inducing capacity of both molecules. METHODS: We used a nuclear factor kappaB reporter assay and a cytotoxicity bioassay to study TNF-alpha neutralization by infliximab and etanercept. Lymphocyte binding and apoptosis-inducing capacity was investigated using fluorescence-activated cell sorter analysis, annexin V staining, and cleaved caspase-3 immunoblotting using mixed lymphocyte reaction-stimulated peripheral blood lymphocytes (PBL) from healthy volunteers and lamina propria T cells from patients with Crohn's disease. RESULTS: Both infliximab and etanercept neutralized TNF-alpha effectively. Infliximab bound to activated PBL and lamina propria T cells, whereas binding of etanercept was equal to a nonspecific control antibody. Infliximab but not etanercept induced peripheral and lamina propria lymphocyte apoptosis when compared with a control antibody. Infliximab activated caspase 3 in a time-dependent manner, whereas etanercept did not. CONCLUSIONS: Although both infliximab and etanercept showed powerful TNF-alpha neutralization, only infliximab was able to bind to PBL and lamina propria T cells and subsequently to induce apoptosis of activated lymphocytes. These data may provide a biological basis for the difference in efficacy of the 2 TNF-alpha-neutralizing drugs.

Antibodies, Monoclonal↗
PubMed2002

Anti-tumor necrosis factor-alpha therapy with infliximab as an alternative to corticosteroids in the treatment of human leukocyte antigen B27-associated acute anterior uveitis.

OBJECTIVE: To evaluate the potentials of infliximab, a mouse-human chimeric immunoglobulin G1 monoclonal antibody that binds both the soluble form and the membrane-bound precursor of tumor necrosis factor-alpha (TNF-alpha), thus inhibiting a broad range of biologic activities of TNF-alpha, in the therapy of patients with acute HLA B27-associated anterior uveitis. DESIGN: Prospective noncomparative case series. PARTICIPANTS: Seven consecutive patients with acute onset of HLA B27-associated anterior uveitis, with at least three anterior chamber cells. INTERVENTION: Infliximab IV (Centocor, Malvern, PA) at a dosage of 10 mg/kg body weight was used as the only anti-inflammatory drug. MAIN OUTCOME MEASURES: Anterior chamber cells and flare were evaluated before infliximab treatment and at defined time points after treatment. C-reactive protein (CRP) levels were assessed in all patients before IV delivery of infliximab and were re-evaluated after 1 week. RESULTS: Patients were observed for a mean period of 17 +/- 0.8 months. Seven patients received a single infliximab infusion of 10 mg/kg body weight. One patient received a second infusion 3 weeks after the first because of a uveitis flare-up. The median duration (+/- standard deviation) of uveitis was 8 +/- 12 days. All patients responded to infliximab with immediate improvement of clinical symptoms and a rapid decrease in anterior chamber cells. Total resolution of the uveitis was achieved with infliximab as the sole anti-inflammatory drug in all but one patient, who also showed systemic inflammatory activity, as indicated by a threefold increase in the serum CRP level. A relapse was seen in four patients after a median period of 5 +/- 6.4 months. CONCLUSION: Infliximab proved to be a powerful therapeutic agent in acute HLA B27-associated uveitis and may therefore be a future alternative or supplement to steroid treatment. Larger controlled studies on the efficacy and dosage of infliximab in different forms of anterior uveitis will nonetheless be needed to evaluate the effectiveness of anti-TNF-alpha treatment in acute, as well as chronic, uveitis.

Acute Disease↗
PubMed2004

Perianal Crohn's disease and infliximab therapy.

INTRODUCTION: Perianal manifestations occur in almost half of patients with Crohn's disease and often respond poorly to conventional therapies. The introduction of anti-tumour necrosis factor alpha agents (e.g. infliximab) has altered the management of patients who fail first and second line medical and surgical therapies. METHODS: We performed a literature search of the PubMed database using the Medical Search Headings infliximab, perianal Crohn's disease, fistulae, cost and safety. We also performed a manual search using references from these articles, review articles and proceedings from major gastroenterology meetings. RESULTS: Use of infliximab, at a dose of 5mg/kg at intervals of 0, 2 and 6 weeks, results in significant improvement in disease in approximately 70% of patients with fistulae. Prior examination under anaesthesia with placement of non-cutting seton sutures in fistula tracks is a useful adjunct in many patients. Preliminary results show a benefit from maintenance infliximab therapy and from concomitant use of immunosuppressants such as azathioprine. No clinical or biochemical markers have been identified which predict non-response to infliximab, although its use is contraindicated in patients with strictures. Acute infusion reactions are the most common side-effect of infliximab therapy and they are usually mild. Despite initial fears, the incidence of opportunistic infection is low. There is inadequate information, at present, regarding a possible increase in incidence of lymphoma with infliximab therapy. Infliximab is expensive compared with established therapies and its use will increase the lifetime cost of treating Crohn's disease. CONCLUSION: While infliximab is a useful adjunct in selected patients, the cornerstones of management of perianal Crohn's are essentially unchanged.

Antibodies, Monoclonal↗
PubMed2004

The safety profile of infliximab in patients with Crohn's disease: the Mayo clinic experience in 500 patients.

BACKGROUND AND AIMS: The aim of this study was to evaluate the short- and long-term safety of infliximab in patients with Crohn's disease in clinical practice. METHODS: The medical records of 500 consecutive patients treated with infliximab at the Mayo Clinic were reviewed and abstracted for demographic features and adverse events. The likelihood of a causal relationship to infliximab for each adverse event was determined by calculating an intrinsic likelihood (imputability) score. RESULTS: The 500 patients received a median of 3 infusions and had a median follow-up of 17 months. Forty-three patients (8.6%) experienced a serious adverse event, of which 30 (6%) were related to infliximab. Acute infusion reactions occurred in 19 of 500 patients (3.8%). Serum sickness-like disease occurred in 19 of 500 patients and was attributed to infliximab in 14 (2.8%). Three patients developed drug-induced lupus. One patient developed a new demyelination disorder. Forty-eight patients had an infectious event, of which 41 (8.2%) were attributed to infliximab. Twenty patients had a serious infection: 2 had fatal sepsis, 8 had pneumonia (of which 2 cases were fatal), 6 had viral infections, 2 had abdominal abscesses requiring surgery, one had arm cellulitis, and one had histoplasmosis. Nine patients had a malignant disorder, 3 of which were possibly related to infliximab. A total of 10 deaths were observed. For 5 of these patients (1%), the events leading to death were possibly related to infliximab. CONCLUSIONS: Short- and long-term infliximab therapy is generally well tolerated. However, clinicians must be vigilant for the occurrence of infrequent but serious events, including serum sickness-like reaction, opportunistic infection and sepsis, and autoimmune disorders.

Adolescent↗
PubMed2004

Infliximab maintenance therapy for fistulizing Crohn's disease.

BACKGROUND: Infliximab, a monoclonal antibody against tumor necrosis factor, is an effective maintenance therapy for patients with Crohn's disease without fistulas. It is not known whether infliximab is an effective maintenance therapy for patients with fistulas. METHODS: We performed a multicenter, double-blind, randomized, placebo-controlled trial to evaluate the efficacy of infliximab maintenance therapy in 306 adult patients with Crohn's disease and one or more draining abdominal or perianal fistulas of at least three months' duration. Patients received 5 mg of infliximab per kilogram of body weight intravenously on weeks 0, 2, and 6. A total of 195 patients who had a response at weeks 10 and 14 and 87 patients who had no response were then randomly assigned to receive placebo or 5 mg of infliximab per kilogram every eight weeks and to be followed to week 54. The primary analysis was the time to the loss of response among patients who had a response at week 14 and underwent randomization. RESULTS: The time to loss of response was significantly longer for patients who received infliximab maintenance therapy than for those who received placebo maintenance (more than 40 weeks vs. 14 weeks, P<0.001). At week 54, 19 percent of patients in the placebo maintenance group had a complete absence of draining fistulas, as compared with 36 percent of patients in the infliximab maintenance group (P=0.009). CONCLUSIONS: Patients with fistulizing Crohn's disease who have a response to induction therapy with infliximab have an increased likelihood of a sustained response over a 54-week period if infliximab treatment is continued every 8 weeks.

Adult↗
PubMed2006

Low-dose infliximab treatment for ankylosing spondylitis--clinically- and cost-effective.

OBJECTIVES: Infliximab has been shown to be effective in the treatment of ankylosing spondylitis (AS) when treated in a dose of 5 mg/kg at 6 weekly intervals. This dose of infliximab has not been determined by any structured randomized trials and has significant cost implications. We describe our experience of treating AS with low-dose infliximab (3mg/kg at 8 weekly intervals). The efficacy and cost implications are discussed. METHODS: Patients who had active AS [Bath AS Disease Activity Index (BASDAI) > or = 4] were treated with infliximab 3 mg/kg at 0, 2, 6 weeks and thereafter at 8 weekly intervals. Response to treatment was defined as 50% improvement in BASDAI. Other response criteria such as ASAS 20, 40 and five of the six criteria were also assessed. Direct drug costs for infliximab were determined. RESULTS: Twenty-two consecutive AS patients received infliximab. All 22 completed treatment for 3 months, 15 patients for 6 months and 14 for 12 months. Mean age was 45 years (range 21-62) and mean disease duration 14.5 years (range 2-43). Of the patients, 54% achieved a 50% BASDAI response at 3 months and the benefit was sustained at 12 months in 63%. Similar response rate was seen with the other assessment criteria. Direct drug costs were significantly lower when low-dose infliximab regimen was used. CONCLUSIONS: Low-dose infliximab (3 mg/kg at 8 weekly infusions) is effective in the treatment of AS. Higher doses are required in a small proportion of patients when treatment is only partially effective. Titrating the dose and frequency of infusions may be required in individual patients to achieve optimal response. Using low-dose infliximab has significant economic implications.

Adult↗
PubMed2006

The treatment of disc-herniation-induced sciatica with infliximab: one-year follow-up results of FIRST II, a randomized controlled trial.

STUDY DESIGN: A randomized controlled trial. OBJECTIVES: To evaluate the long-term efficacy of infliximab, a monoclonal antibody against tumor necrosis factor alpha (TNF-alpha), in patients with acute/subacute sciatica secondary to herniated disc. SUMMARY OF BACKGROUND DATA: The results of experimental studies and our open-label trial support the use of infliximab in sciatica. Here we report the 1-year results of a randomized controlled trial (FIRST II, Finnish Infliximab Related STudy) evaluating the efficacy and safety of a single infusion of infliximab for sciatic pain. METHODS: Inclusion criteria were unilateral sciatic pain with a disc herniation concordant with the symptoms and signs of radicular pain. Patients had to be candidates for discectomy. Criteria for discectomy included (in addition to a symptomatic disc herniation on MRI) neural entrapment (straight leg raising [SLR] < or =60 degrees ) with either a short-term (2-4 weeks) severe or long-term (4-12 weeks) moderate leg pain. Forty patients were allocated to a single intravenous infusion of either infliximab 5 mg/kg or placebo. Differences in the clinical examination parameters (straight leg raise [SLR], muscle strength, sensory defects, tendon reflexes), patient-reported symptoms (leg and back pain using a visual analog scale [VAS], Oswestry disability, quality-of-life [RAND-36]), sick leaves, number of discectomies, and adverse effects between the two treatment groups over the 1-year follow-up were compared using Mann-Whitney U test or Student's t test, repeated-measures analysis, or Cox proportional hazards model. Logistic regression was used to assess the predictors of good response. RESULTS: Sixty-seven percent of patients in the infliximab group reported no pain at 52 weeks compared with 63% in the control group (P = 0.72). Similar efficacy was observed between treatment groups for other outcomes. Eight patients in each group required surgery. Three nonserious adverse reactions were encountered in the infliximab group. The response (irrespective of the treatment) was significantly better with shorter symptom duration and less SLR restriction at baseline. Patients in the infliximab group appeared to especially benefit in cases of a L4-L5 (or L3-L4) herniation and if a Modic change was colocalized at the symptomatic level. CONCLUSIONS: Although the long-term results of this randomized trial do not support the use of infliximab compared with placebo for lumbar radicular pain in patients with disc herniation-induced sciatica, further study in a subgroup of patients with L4-L5 or L3-L4 herniations, especially in the presence of Modic changes, appears to be warranted.

Acute Disease↗
PubMed2006

Maintenance infliximab does not result in increased abscess development in fistulizing Crohn's disease: results from the ACCENT II study.

BACKGROUND: Rapid fistula healing may predispose Crohn's disease patients to abscess development. AIM: Data from ACCENT II were analysed to determine whether fistula-related abscess development is affected by infliximab exposure. METHODS: Following infliximab 5 mg/kg infusions at weeks 0, 2 and 6, patients were evaluated for fistula response for two consecutive visits at least 4 weeks apart. Patients (N = 282) were randomized at week 14 to either placebo or infliximab 5 mg/kg every 8 weeks through week 46. If response was lost at or after week 22, patients could crossover to a 5 mg/kg higher infliximab dose. Fistula-related abscesses were diagnosed by physical examination or by imaging procedures according to usual practice. RESULTS: Infliximab exposure was approximately twofold higher for the infliximab maintenance group. Twenty-one (15%) patients in the infliximab maintenance group had at least one newly developed fistula-related abscess compared with 27 (19%) in the placebo maintenance group (P = 0.526). The proportion of patients with a new fistula-related abscess was similar regardless of whether or not patients crossed over to a 5 mg/kg higher infliximab dose. The number of fistula-related abscesses diagnosed over time did not differ between groups. CONCLUSION: Abscess development in patients with fistulizing Crohn's disease is not dependent on cumulative infliximab exposure.

Abscess↗
PubMed2005

Infliximab treatment results in significant improvement in the quality of life of patients with severe psoriasis: a double-blind placebo-controlled trial.

BACKGROUND: Psoriasis is a chronic disease that significantly diminishes the health-related quality of life (HRQOL). Infliximab is a chimeric, tumour necrosis factor alpha monoclonal antibody that has been shown to improve the signs and symptoms of plaque psoriasis. OBJECTIVES: The objective of this study was to evaluate the effect of infliximab induction therapy on the HRQOL of patients with severe plaque psoriasis. METHODS: In this double-blind, placebo-controlled trial, 249 patients were randomly assigned to receive intravenous infusions of 3 or 5 mg kg(-1) of infliximab or placebo and were treated at weeks 0, 2 and 6. Patients completed the Dermatology Life Quality Index (DLQI) at baseline and week 10. RESULTS: Infliximab induction therapy resulted in a substantial improvement in HRQOL. At week 10, patients in the infliximab 3- and 5-mg kg(-1) groups showed a median percentage improvement in DLQI scores of 84.0% and 91.0%, respectively, compared with 0% in the placebo group (P < 0.001). The median decrease from baseline in DLQI score at week 10 was 8.0 and 10.0 for the 3 and 5 mg kg(-1) infliximab groups, respectively, compared with 0 in the placebo group (P < 0.001). Thirty-three per cent and 40% of patients in the 3 and 5 mg kg(-1) infliximab groups, respectively, had a DLQI score of 0 at week 10, compared with 2% in the placebo group (P < 0.001). There was a strong correlation between the percentage change from baseline at week 10 in Psoriasis Area and Severity Index (PASI) scores and the percentage change in DLQI scores during the same period (Spearman's correlation, 0.61, P < 0.001). When the infliximab and placebo treatment groups were combined, patients with at least 75% improvement in PASI scores between baseline and week 10 had a greater mean improvement in DLQI scores (81%) than those with 50-75% improvement in PASI during the same period (60%). CONCLUSIONS: Infliximab induction therapy resulted in significant improvement in HRQOL in patients with severe psoriasis.

Adult↗
PubMed2005

Infliximab improves signs and symptoms of psoriatic arthritis: results of the IMPACT 2 trial.

OBJECTIVES: To evaluate further in a phase III, double blind trial the efficacy of infliximab in patients with active psoriatic arthritis (PsA), as observed in the smaller IMPACT trial. METHODS: 200 patients with active PsA unresponsive to previous treatment were randomised to infusions of infliximab 5 mg/kg or placebo at weeks 0, 2, 6, 14, and 22. Patients with inadequate response entered early escape at week 16. The primary measure of clinical response was ACR20. Other measures included Psoriatic Arthritis Response Criteria (PsARC), Psoriasis Area and Severity Index (PASI), and dactylitis and enthesopathy assessments. RESULTS: At week 14, 58% of patients receiving infliximab and 11% of those receiving placebo achieved an ACR20 response and 77% of infliximab patients and 27% of placebo patients achieved PsARC (both p<0.001). Among the 85% of patients with at least 3% body surface area psoriasis involvement at baseline, 53/83 (64%) patients receiving infliximab had at least 75% improvement in PASI compared with 2/87 (2%) patients receiving placebo at week 14 (p<0.001). These therapeutic effects were maintained through the last evaluation (week 24). Fewer infliximab patients than placebo patients had dactylitis at week 14 (18% v 30%; p = 0.025) and week 24 (12% v 34%; p<0.001). Fewer infliximab patients (22%) than placebo patients (34%) had active enthesopathy at week 14 (p = 0.016); corresponding figures at week 24 were 20% and 37% (p = 0.002). Infliximab was generally well tolerated, with a similar incidence of adverse events in each group. CONCLUSIONS: Infliximab 5 mg/kg through 24 weeks significantly improved active PsA, including dactylitis and enthesopathy, and associated psoriasis.

Adult↗
PubMed2006

Infliximab maintains a high degree of clinical response in patients with active psoriatic arthritis through 1 year of treatment: results from the IMPACT 2 trial.

OBJECTIVE: To evaluate the efficacy and safety of infliximab through 1 year in patients with psoriatic arthritis (PsA) enrolled in the IMPACT 2 trial. METHODS: In this double blind, placebo controlled, phase III study, 200 patients with active PsA were randomised to receive infusions of infliximab 5 mg/kg or placebo at weeks 0, 2, 6, and every 8 weeks thereafter through 1 year. Patients with persistent disease activity could enter early escape at week 16, and all remaining placebo patients crossed over to infliximab at week 24. Patients randomised to infliximab who had no response or who lost response could escalate their dose to 10 mg/kg starting at week 38. Clinical efficacy was assessed based on the proportion of patients achieving ACR 20 and PASI 75 responses. Major clinical response (that is, maintenance of ACR 70 response for 24 continuous weeks) was assessed for the first time in PsA. RESULTS: Through 1 year of treatment, 58.9% and 61.4% of patients in the randomised infliximab and placebo/infliximab groups, respectively, achieved ACR 20; corresponding figures for PASI 75 were 50.0% and 60.3%. At week 54, major clinical response was achieved by 12.1% of patients in the infliximab group. The safety profile of infliximab through week 54 was consistent with that seen through week 24. Two malignancies occurred: basal cell skin cancer (placebo) and stage I Hodgkin's lymphoma (infliximab). CONCLUSION: Infliximab maintains a high degree of clinical efficacy and continues to be well tolerated in patients with PsA through 1 year of treatment.

Adult↗
PubMed2004

Infliximab in inflammatory bowel disease: clinical outcome in a population based cohort from Stockholm County.

BACKGROUND: Several placebo controlled studies have demonstrated the efficacy of infliximab in inflammatory bowel disease (IBD) but the potential toxicity of this new biological compound has been less studied. AIM: To assess the use of infliximab in IBD in a population based cohort, with special emphasis on the occurrence of severe adverse events and mortality. PATIENTS: All patients with IBD treated with infliximab between 1999 and 2001 in Stockholm County were evaluated. METHODS: Prospective registration of clinical data was carried out. Retrospective analyses were made of possible adverse events occurring in relation to infliximab treatment. Adverse events requiring pharmacological treatment or hospitalisation were defined as severe. Clinical response was assessed as remission, response, or failure. RESULTS: A cohort comprising 217 patients was assembled: 191 patients had Crohn's disease (CD), and infliximab was used off label for ulcerative colitis (UC) in 22 patients. Four patients were treated for indeterminate colitis (IC). Mean age was 37.6 (0.9) years (range 8-79). The mean number of infliximab infusions was 2.6 (0.1) (range 1-11). Forty two severe adverse events were registered in 41 patients (CD, n = 35). Eleven of the severe adverse events occurred postoperatively (CD, n = 6). Three patients with CD developed lymphoma (of which two were fatal), opportunistic infections occurred in two patients (one with UC, fatal), and two patients with severe attacks of IBD died due to sepsis (one with CD, one postoperatively with UC). One additional patient with UC died from pulmonary embolism after colectomy. Mean age in the group with fatal outcome was 62.7 years (range 25-79). The overall response rate was 75% and did not differ between the patient groups. CONCLUSIONS: Infliximab was efficacious as an anti-inflammatory treatment when assessed in a population based cohort of patients with IBD. However, there appear to be a significant risk of deleterious and fatal adverse events, particularly in elderly patients with severe attacks of IBD. Off label use of infliximab in UC and IC should be avoided until efficacy is proven in randomised controlled trials. The underlying risk of developing malignancies among patients with severe or chronically active CD in need of infliximab treatment is not known but the finding of a 1.5% annual incidence of lymphoma emphasises the need for vigilant surveillance with respect to this malignant complication.

Adult↗
PubMed2001

A cost-cost study comparing etanercept with infliximab in rheumatoid arthritis.

OBJECTIVE: The objective of this study was to compare the total costs associated with the administration of two different tumour necrosis factor (TNF) strategies used in the treatment of rheumatoid arthritis (RA): etanercept, a soluble TNF receptor that can be administered at home by subcutaneous injection, versus infliximab, an antibody that requires an intravenous infusion in a hospital outpatient setting. DESIGN AND SETTING: The main analytical framework of the study was a cost-cost analysis comparing the total annual costs associated with the administration of etanercept and infliximab in adult RA patients. The perspective of the study was that of the Dutch society. An economic model was constructed to determine the costs of both treatments. The cost evaluation included direct medical costs, direct nonmedical costs and indirect costs. The base-case analysis compared monotherapy with etanercept versus a combination therapy with infliximab and methotrexate. Data for the economic model came from published literature, expert opinion and official price and tariff lists. All costs were in 1999 values. PATIENTS AND PARTICIPANTS: The analysis was performed for the adult RA population eligible for treatment with etanercept or infliximab in The Netherlands. MAIN OUTCOME MEASURES AND RESULTS: The analysis showed that the total annual drug costs per patient do not differ substantially between infliximab and etanercept, with costs of Netherland guilders (NLG)31,526 (12,610 US dollars) and NLG31,334 (12,534 US dollars), respectively. However, the other medical costs (i.e. excluding the costs of the two drugs themselves) are substantially higher for infliximab due to the additional costs associated with administration in an outpatient clinic and the use of methotrexate [NLG 12,621 (5048 US dollars) versus NLG269 (107 US dollars) for etanercept]. The impact of direct nonmedical costs (transportation) and indirect costs were negligible. Overall treatment with infliximab is more expensive than treatment with etanercept with total costs of NLG45 115 (18,046 US dollars) and NLG3I,621 (12,648 US dollars), respectively (42.7% increase). CONCLUSIONS: Based on the assumptions used in the model, we may conclude that the use of etanercept compares favourably with infliximab from a budgetary and health economic perspective: the total costs are substantially lower when the efficacy of etanercept is assumed to be at least equivalent to the efficacy of infliximab.

Adult↗
PubMed2006

A systematic review of the effectiveness of adalimumab, etanercept and infliximab for the treatment of rheumatoid arthritis in adults and an economic evaluation of their cost-effectiveness.

OBJECTIVES: This report reviews the clinical effectiveness and cost-effectiveness of adalimumab, etanercept and infliximab, agents that inhibit tumour necrosis factor-alpha (TNF-alpha), when used in the treatment of rheumatoid arthritis (RA) in adults. DATA SOURCES: Electronic databases were searched up to February 2005. REVIEW METHODS: Systematic reviews of the literature on effectiveness and cost-effectiveness were undertaken and industry submissions to the National Institute for Health and Clinical Excellence (NICE) were reviewed. Meta-analyses of effectiveness data were also undertaken for each agent. The Birmingham Rheumatoid Arthritis Model (BRAM), a simulation model, was further developed and used to produce an incremental cost-effectiveness analysis. RESULTS: Twenty-nine randomised controlled trials (RCTs), most of high quality, were included. The only head-to-head comparisons were against methotrexate. For patients with short disease duration (<or=3 years) who were naïve to methotrexate, adalimumab was marginally less and etanercept was marginally more effective than methotrexate in reducing symptoms of RA. Etanercept was better tolerated than methotrexate. Both adalimumab and etanercept were more effective than methotrexate in slowing radiographic joint damage. Etanercept was also marginally more effective and better tolerated than methotrexate in patients with longer disease durations who had not failed methotrexate treatment. Infliximab is only licensed for use with methotrexate. All three agents, either alone (where so licensed) or in combination with ongoing disease-modifying antirheumatic drugs (DMARDs), were effective in reducing the symptoms and signs of RA in patients with established disease. At the licensed dose, the numbers needed to treat (NNTs) (95% CI) required to produce an American College for Rheumatology (ACR) response compared with placebo were: ACR20: adalimumab 3.6 (3.1 to 4.2), etanercept 2.1 (1.9 to 2.4), infliximab 3.2 (2.7 to 4.0); ACR50: adalimumab 4.2 (3.7 to 5.0), etanercept 3.1 (2.7 to 3.6), infliximab 5.0 (3.8 to 6.7); and ACR70: adalimumab 7.7 (5.9 to 11.1), etanercept 7.7 (6.3 to 10.0), infliximab 11.1 (7.7 to 20.0). In patients who were naïve to methotrexate, or who had not previously failed methotrexate treatment, a TNF inhibitor combined with methotrexate was significantly more effective than methotrexate alone. Infliximab combined with methotrexate had an increased risk of serious infections. All ten published economic evaluations met standard criteria for quality, but the incremental cost-effectiveness ratios (ICERs) ranged from being within established thresholds to being very high because of varying assumptions and parameters. All three sponsors who submitted economic models made assumptions favourable to their product. BRAM incorporates improvements in quality of life and mortality, but assumes no effect of TNF inhibitors on joint replacement. For use in accordance with current NICE guidance as the third DMARD in a sequence of DMARDs, the base-case ICER was around pound30,000 per quality-adjusted life-year (QALY) in early RA and pound50,000 per QALY in late RA. Sensitivity analyses showed that the results were sensitive to the estimates of Health Assessment Questionnaire (HAQ) progression while on TNF inhibitors and the effectiveness of DMARDs, but not to changes in mortality ratios per unit HAQ. TNF inhibitors are most cost-effective when used last. The ICER for etanercept used last is pound24,000 per QALY, substantially lower than for adalimumab ( pound30,000 per QALY) or infliximab ( pound38,000 per QALY). First line use as monotherapy generates ICERs around pound50,000 per QALY for adalimumab and etanercept. Using the combination of methotrexate and a TNF inhibitor as first line treatment generates much higher ICERs, as it precludes subsequent use of methotrexate, which is cheap. The ICERs for sequential use are of the same order as using the TNF inhibitor alone. CONCLUSIONS: Adalimumab, etanercept and infliximab are effective treatments compared with placebo for RA patients who are not well controlled by conventional DMARDs, improving control of symptoms, improving physical function, and slowing radiographic changes in joints. The combination of a TNF inhibitor with methotrexate was more effective than methotrexate alone in early RA, although the clinical relevance of this additional benefit is yet to be established, particularly in view of the well-established effectiveness of MTX alone. An increased risk of serious infection cannot be ruled out for the combination of methotrexate with adalimumab or infliximab. The results of the economic evaluation based on BRAM are consistent with the observations from the review of clinical effectiveness, including the ranking of treatments. TNF inhibitors are most cost-effective when used as last active therapy. In this analysis, other things being equal, etanercept may be the TNF inhibitor of choice, although this may also depend on patient preference as to route of administration. The next most cost-effective use of TNF inhibitors is third line, as recommended in the 2002 NICE guidance. Direct comparative RCTs of TNF inhibitors against each other and against other DMARDs, and sequential use in patients who have failed a previous TNF inhibitor, are needed. Longer term studies of the quality of life in patients with RA and the impact of DMARDs on this are needed, as are longer studies that directly assess effects on joint replacement, other morbidity and mortality.

Adalimumab↗
PubMed2006

TNF-alpha blockade down-regulates the CD40/CD40L pathway in the mucosal microcirculation: a novel anti-inflammatory mechanism of infliximab in Crohn's disease.

The CD40/CD40 ligand (CD40L) pathway is involved in Crohn's disease (CD) pathogenesis. In the patients' circulation, soluble CD40L (sCD40L) levels are elevated and surface CD40L is increased in platelets and T cells, whereas in the intestine CD40 is overexpressed in the microvasculature and CD40L in platelets and T cells. The therapeutic effects of infliximab in CD are attributed to its systemic anti-TNF-alpha action, but because TNF-alpha modulates both CD40 and CD40L, we investigated whether infliximab affects the CD40/CD40L pathway in the intestine. Eighteen CD patients were evaluated before and after infliximab therapy. Plasma sCD40L was measured by ELISA and platelet and peripheral blood T cell (PBT) CD40L expression by flow cytometry. Microvascular CD40 and VCAM-1 expression were assessed in mucosal biopsies by immunohistochemistry and by flow cytometry in human intestinal microvascular endothelial cells (HIMEC). Cell cultures were performed in the presence and absence of infliximab. Infliximab treatment significantly reduced plasma sCD40L levels and eliminated CD40 and VCAM-1 from mucosal microvessels. In vitro infliximab prevented TNF-alpha-induced CD40 and VCAM-1 expression by HIMEC, and reduced PBT, but not platelet, surface CD40L expression and sCD40L release. In addition, infliximab decreased T cell-induced VCAM-1 expression in HIMEC by down-regulating CD40L in T cells and promoting T cells apoptosis. These findings point to a novel mechanism of action of infliximab, i.e., the disruption of CD40/CD40L-dependent cognate interactions between intestinal microvessels and T cells. Thus, in addition to neutralizing TNF-alpha and inducing T cell death, the therapeutic effects of infliximab in CD appear to be also mediated by inhibition of vascular inflammation in the gut.

Adult↗
PubMedDate not supplied

Renal function in rheumatoid arthritis patients treated with methotrexate and infliximab.

OBJECTIVE: This study was aimed at monitoring the early and late effects of infliximab on renal proximal function in RA patients treated with methotrexate. N-acetyl-3-D-glucosaminidase (NAG) activity in urine served as an indicator of proximal tubular damage METHODS: NAG activity was estimated in 21 patients during the course of treatment with infliximab and methotrexate. In every patient NAG-enzymuria was estimated directly before and 60 min after infliximab infusions and 62 weeks after starting the therapy. RESULTS: The total of mean NAG activities observed before each infusion of infliximab was significantly lower (p < 0.02) than NAG-enzymuria before the start of infliximab treatment (7.4 UI/g vs 11.8 UI/g). The proportion of patients in whom NAG activity rose by more than 50% during treatment ranged from 5.3% to 25%. Administration of infliximab did not significantly change the mean serum creatinine levels or creatinine clearance. No significant differences were observed in the mean values of NAG values before and 60 min after infliximab infusion. Patients who demonstrated elevated NAG activities during the course of the whole treatment demonstrated significantly more pronounced NAG enzymuria before treatment and one hour after the first infusion (p < 0.0005), as well as higher RA activity (p < 0.05). There was no observed influence of NSAIDs or prednisone on the frequency of elevated NAG activities. Raised creatinine concentrations (> 1.3 mg/dL) were noted before and during the course of infliximab treatment in 3 patients. In 16 patients abdominal fat aspiration biopsy was performed and in 3 the presence of amyloid deposits was demonstrated. In these patients NAG activity exceeded twice the upper normal limit. CONCLUSION: The introduction of infliximab during methotrexate therapy demonstrated no early or delayed nephrotoxicity of the drug in patients with rheumatoid arthritis.

Acetylglucosaminidase↗
PubMed2004

Infliximab treatment for steroid-refractory acute graft-versus-host disease.

BACKGROUND AND OBJECTIVES: Tumor necrosis factor a is one of the principal cytokines involved in the pathogenesis of acute graft-versus-host-disease (GVHD). Infliximab is an antibody to this cytokine. DESIGN AND METHODS: We performed a retrospective analysis to evaluate the activity of infliximab in 32 patients with severe steroid-refractory acute GVHD. The patients received a median of 3 weekly courses of infliximab. The main organs involved in the patients were skin (n=2) liver (n=1), bowel (n=19), liver and bowel at the same stage (n=10). RESULTS: Nineteen out 32 patients (59%) responded to infliximab with 6 (19%) complete and 13 (40%) partial responses. Age younger than 35 years, intestinal involvement and a longer time between hematopoietic stem cell transplantation and infliximab administration were factors predicting a favorable response. Infective episodes developed in 23/32 (72%) patients. All the 13 unresponsive patients died of GVHD shortly after infliximab. Thirteen of 19 responsive patients were alive at a median follow-up of 449 days (range 155-842) after infliximab, with no signs of chronic GVHD (n=5), limited (n=5) or extensive involvement (n=3). Six patients who responded subsequently died, one of chronic lung GVHD, the others of vascular complications or infections (2 fungal diseases). INTERPRETATION AND CONCLUSIONS: We conclude that infliximab is active in the treatment of severe steroid-refractory acute GVHD, particularly when the intestine is involved. Infections commonly followed its administration. The clinical activity of infliximab and the possibility that it increases the risk of infections are worth investigating in prospective trials.

Acute Disease↗