, Volume 22, Issue 2, pp 107-132
Date: 22 Sep 2012

Infliximab

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Summary

Abstract

Infliximab (Remicade®), a biological disease-modifying antirheumatic drug (DMARD), binds to and inhibits the activity of tumour necrosis factor-α, which is thought to play an important role in the pathophysiology of rheumatoid arthritis. Intravenous infliximab plus methotrexate is recommended in patients with rheumatoid arthritis who have not achieved satisfactory disease control with adequate courses of other DMARDs.

Pharmacoeconomic analyses have been based on efficacy data from the pivotal placebo-controlled Anti-Tumour Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy (ATTRACT) trial in patients with active, refractory rheumatoid arthritis. Infliximab every 8 weeks plus methotrexate demonstrated rapid and sustainable improvements in clinical response, delayed radiographic progression, and/or improved functional status and health-related QOL compared with placebo plus methotrexate at weeks 30, 54 and 102.

In cost-utility analyses of infliximab plus methotrexate conducted from a healthcare payer and/or societal perspective in the US, Europe, Portugal, Sweden and the UK, infliximab 3 mg/kg every 8 weeks plus methotrexate was associated with acceptable (<$US50 000 per discounted QALY gained) cost-utility ratios relative to methotrexate alone in patients with active, refractory rheumatoid arthritis. When only direct costs were considered, the lifetime incremental cost per discounted QALY gained with infliximab plus methotrexate relative to methotrexate alone was $US30 500–38 700 (year of costing 1998 or not reported; treatment duration 54 or 102 weeks or lifelong) in the US and Europe analyses, and €39 500 (year of costing not reported; lifelong treatment) in the Portuguese analysis. The cost-utility ratios were more favourable when lost productivity costs or the additional benefit of infliximab on radiographic stabilisation were considered. In the Swedish and UK analyses with a 10-year time horizon, infliximab plus methotrexate for 1 or 2 years was associated with cost-utility ratios of €28 600–56 100 (year of costing not reported) when direct costs were considered, and €3440–48 200 when direct costs plus loss-of-productivity costs were considered.

In conclusion, cost-utility analyses, which were based on modelling of data from the pivotal clinical trial of infliximab plus methotrexate, indicate that infliximab plus methotrexate is associated with acceptable cost-effectiveness ratios (<$US50 000 per discounted QALY gained) relative to methotrexate monotherapy in patients with active rheumatoid arthritis who have not responded to previous methotrexate or other DMARD therapy. The cost effectiveness of infliximab versus other DMARDs is at present unclear, but will be clarified when appropriate data from directly comparative clinical and/or pharmacoeconomic studies become available. In patients in whom adequate courses of other DMARDs have failed to achieve satisfactory disease control, infliximab plus methotrexate may prevent or delay disability, which may produce reductions in nondrug costs that can help offset its acquisition cost.

Rheumatoid Arthritis

Rheumatoid arthritis is a chronic autoimmune disease characterised by symmetrical joint swelling and tenderness, stiffness in the morning that lasts for an hour or longer, subcutaneous rheumatoid nodules, and radiographic evidence of joint damage. An inflammatory cascade, which involves the secretion of inflammatory mediators including tumour necrosis factor-á and results in the destruction and resorption of articular cartilage and bone, appears to play a role in its pathogenesis. Rheumatoid arthritis has a worldwide prevalence of approximately 1%, is generally progressive and is associated with pain, loss of function, disability and an increased risk of premature mortality.

Rheumatoid arthritis is associated with substantial direct, indirect and intangible costs, which increase as the severity of the disease increases. Healthcare costs are approximately 2- to 3-fold higher in patients with rheumatoid arthritis than in age-matched individuals without rheumatoid arthritis. Drug costs are the largest contributors to direct healthcare costs; disability-related loss of productivity is the largest contributor to indirect costs. Rheumatoid arthritis can impair the individual’s health-related QOL (HR-QOL), psychological well being and physical function, which results in considerable intangible costs.

Recent guidelines recommend early aggressive treatment of rheumatoid arthritis, as early treatment may prevent or delay disease progression. The majority of patients with rheumatoid arthritis should be started on disease-modifying antirheumatic drug (DMARD) therapy within 3 months of diagnosis. Biological DMARDs, such as infliximab, are recommended in the treatment of patients in whom adequate courses of other DMARDs have failed to achieve satisfactory disease control or have resulted in adverse effects limiting their use.

Clinical Efficacy

In randomised, placebo-controlled, double-blind, multicentre trials, noncomparative trials and in clinical practice, multiple infusions of infliximab in combination with methotrexate resulted in rapid, sustainable clinical responses in patients with active, refractory rheumatoid arthritis who had not responded to previous DMARD therapy.

In the pivotal Anti-Tumour Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy (ATTRACT) trial, response to intravenous infliximab 3 or 10 mg/kg at weeks 0, 2 and 6 plus methotrexate (median dosage 15 mg/week) was rapid (within 2 weeks of starting treatment) and was maintained for up to 102 weeks with continued infliximab treatment every 4 or 8 weeks. American College of Rheumatology (ACR) 20, 50 and 70 response rates were significantly higher with infliximab plus methotrexate than with methotrexate plus placebo after 30 and 54 weeks’ treatment. At 102 weeks, a significantly greater proportion of infliximab plus methotrexate recipients than methotrexate plus placebo recipients had an ACR20 response (42.6% vs 15.9%). Radiographic progression was significantly less in the combined infliximab plus methotrexate group than in the methotrexate plus placebo group at weeks 54 and 102 (mean change in total radiographic score 0.6 vs 7 points and 0.7 points vs 12.6 points).

Functional disability and HR-QOL also improved with infliximab plus methotrexate. In the ATTRACT trial, median improvements from baseline in Health Assessment Questionnaire (HAQ) scores and physical component summary scores of the Medical Outcomes Study Short-form 36-item Health Survey were significantly greater in the combined infliximab plus methotrexate group than in the methotrexate plus placebo group at week 54 (23% vs 3% and 34% vs 9%).

Infliximab plus methotrexate may improve the ability for individuals with rheumatoid arthritis to participate in the work force.

In retrospective clinical practice studies in the US, patients with rheumatoid arthritis receiving infliximab tend to stay longer on therapy, have a lower rate of discontinuation and higher rates of compliance than those receiving methotrexate and/or etanercept.

In clinical trials involving patients with rheumatoid arthritis, adverse events associated with infliximab were generally mild in severity. Patients receiving infliximab plus methotrexate and those receiving methotrexate plus placebo had similar incidences of total (95% vs 94%) and serious adverse events (44% vs 35%) in the ATTRACT trial. Infusion-related reactions were more common with infliximab than placebo, and were generally mild to moderate in severity. Infections were the most common serious adverse events.

Pharmacoeconomic Analyses

The cost utility of infliximab plus methotrexate relative to methotrexate in Analyses patients with active refractory rheumatoid arthritis was predicted by incorporating efficacy data from the ATTRACT trial into HAQ-based Markov models. These analyses assumed that therapies with a cost per QALY gained of <$US50 000 or <€50 000 are cost effective. Using a Markov model and considering only direct healthcare costs, infliximab 3 mg/kg administered every 8 weeks plus methotrexate was cost effective relative to methotrexate in analyses with a lifetime horizon in the US and Europe (cost per discounted QALY gained $US30 500–38 700; year of costing 1998 or not reported; treatment duration 54 or 102 weeks or lifelong) and Portugal (€39 500; year of costing not reported; lifelong treatment). The discounted incremental cost per QALY gained is further improved when societal (loss of productivity) costs are considered in addition to direct costs, or when the additional benefit of infliximab on radiographic stabilisation is considered. In Swedish and UK analyses with a 10-year time horizon that used a different Markov model, treatment with infliximab 3 mg/kg every 8 weeks plus methotrexate administered over 1 or 2 years was associated with incremental discounted costs per QALY gained relative to methotrexate monotherapy of €28 600–56 100 (year of costing not reported) when direct costs were considered and €3440–48 200 when direct costs plus loss-of-productivity costs were considered. Infliximab plus methotrexate remained cost effective with the input of reasonable variations in key model parameters in sensitivity analyses. Using an alternative model (which eliminated the placebo effect in the methotrexate treatment group with or without a loss of effect in the year after discontinuation) in sensitivity analysis, infliximab plus methotrexate for 1 year was cost saving relative to methotrexate alone when direct plus indirect costs were considered in the Swedish study.

In 1-year cost analyses conducted from a societal or healthcare perspective in The Netherlands and the US, the per-patient total annual costs of infliximab were greater than those of etanercept. Although the annual per-patient drug costs of the agents were similar, other annual medical costs were higher with infliximab than with etanercept and were driven by assumptions made regarding costs associated with administering intravenous infliximab in an outpatient facility. The cost of administration can vary substantially across regions and settings. In a French analysis, the relative 1-year costs of infliximab and etanercept were influenced by the setting in which etanercept was dispensed.