Kathleen M. Fox, PhD

Etanercept (Enbrel), adalimumab (Humira), and infliximab (Remicade) are the commonly prescribed tumor necrosis factor-alpha (TNF-alpha) antagonists for rheumatoid arthritis (RA) in routine clinical practice. These agents are indicated for reducing the signs and symptoms of RA, inhibiting the progression of structural damage, and improving physical function in patients with moderate to severe RA.

 These 3 products have additional indications other than RA, including ankylosing spondylitis, plaque psoriasis, polyarticular-course juvenile idiopathic arthritis, and psoriatic arthritis for etanercept; polyarticular-course juvenile idiopathic arthritis, ankylosing spondylitis, Crohn’s disease, psoriatic arthritis, and plaque psoriasis for adalimumab; and ankylosing spondylitis, psoriatic arthritis, plaque psoriasis, Crohn’s disease, and ulcerative colitis for infliximab.

The etanercept dose recommended by the US Food and Drug Administration (FDA) for RA is 50 mg per week administered as a single 50-mg subcutaneous (SC) injection or two 25-mg SC injections.

 The FDA-recommended dose of adalimumab for RA is 40 mg every 

week as 1 subcutaneous injection, with the option to increase the dosing frequency to 40 mg 

week in patients who are not concurrently taking methotrexate.

 The FDA-recommended dose of infliximab for RA is 3 mg/kg, administered as an intravenous infusion followed by additional infusions at 2 and 6 weeks after the first infusion and then every 8 weeks thereafter with the option to adjust the dose upward to 10 mg/kg as often as every 4 weeks.

Clinical trials have established the safety and efficacy of the anti-TNF-alpha agents in the treatment of RA.

 However, not all patients respond adequately to the recommended starting dose. It was reported that the most common reason for increasing the dose of infliximab was insufficient clinical response.

 St. Clair and colleagues noted breakthrough joint pain and swelling several weeks prior to the next infliximab infusion in up to 25% of patients.

A potential mechanism for reduced efficacy of a biologic is the development of antibodies to the drug.

 In clinical studies, approximately 6% of etanercept-treated subjects with RA, psoriatic arthritis, ankylosing spondylitis, or plaque psoriasis developed antibodies to etanercept.

 However, no neutralizing antibodies (ie, antibodies that neutralize the function of the drug) were detected and no correlation between antibody production and clinical response or safety was noted.

 In contrast, the incidence of anti-infliximab antibodies was approximately 10% in subjects receiving infliximab for up to 2 years.

 Patients who were antibody positive were more likely to have higher rates of clearance and reduced efficacy, and to experience an infusion reaction.

 According to the adalimumab product label, approximately 5% of adult RA patients developed low-titer antibodies to adalimumab at least once during treatment, which were neutralizing in vitro.

 In a 2007 study, Bartelds et al found the presence of anti-adalimumab antibodies in RA subjects receiving adalimumab monotherapy was correlated with reduced serum concentration and reduced clinical response.

Higher-than-recommended doses may result in higher costs for payers and potentially for patients through higher co-payments or coinsurance. Ollendorf et al examined dosing patterns and costs among RA patients newly treated with infliximab and found that annualized RA-related costs were higher by more than 50% among patients with upward dose adjustment.

 Hence, agents that achieve and maintain clinical response at the recommended starting dose should be less costly to payers and patients.

A review article by Ariza-Ariza et al revealed that a large proportion of infliximab patients underwent dose escalation, whereas the mean dose increase of the etanercept was not statistically significant.

 Dose escalation for adalimumab patients was not reported because no studies on adalimumab met the inclusion criteria.

 Without dosing information on infliximab, the objective of this study was to investigate the rate of dose increases for etanercept and adalimumab and direct costs for all 3 biologics.

A cohort study was conducted to assess dosing patterns and costs associated with TNF-alpha antagonists among RA patients with newly initiated TNF-alpha antagonist treatment. The Medstat MarketScan Commercial Claims and Encounters and Medicare Supplemental and Coordination of Benefits (COB) databases from January 1, 2002, through December 31, 2004, were utilized for this study. The Medstat databases capture person-specific clinical utilization, expenditures, and enrollment across inpatient, outpatient, prescription drug, and carve-out services from approximately 45 large employers, health plans, and government organizations. Specifically, the Commercial Claims and Encounters database provides data for active employees, early retirees, and their dependents who are insured by employer-sponsored plans. The Medicare Supplemental and COB database provides information about Medicareeligible retirees with employer-sponsored Medicare supplemental plans. Historically, more than 500 million claim records are available in the MarketScan databases.

July 1, 2002, through December 31, 2003, was established as the study intake period for identifying the initiation of anti-TNF-alpha therapy. The 6-month period preceding the start of anti-TNF-alpha therapy was used as a baseline to ensure that the patient was naïve to RA biologics. The 12-month period following initiation of anti-TNF-alpha therapy was used to assess dosing patterns and total cost of care.

Patients were eligible for the study if they (1) had at least 1 diagnosis of RA (

] codes 714.0, 714.1, 714.2 or 714.81); (2) had at least 2 claims for the same biologic; (3) had continuous enrollment for 6 months prior to the first biologic claim (baseline period); and (4) had 12 months continuous enrollment following the first biologic claim (follow-up period). Patients were excluded from the study if they met any of the following criteria: (1) had any claim for biologics of interest in the baseline period; (2) had a diagnosis of Crohn’s disease (

codes 555.0, 555.1, 555.2, 555.9, 565.1, 569.81), psoriasis or psoriatic arthritis (

codes 696.0, 696.1, 696.8), or ankylosing spondylitis (

code 720.0); or (3) had claims for 2 or more different biologics during the study period.

For adalimumab and etanercept, the weekly dose was calculated from the days supply field (converted into weeks) and dose (converted into milligrams) in the pharmacy claims. For infliximab, the unit of service was not available in the medical claims to verify the number ofvials (per Healthcare Common Procedure Coding SystemJ codes); hence, dosing pattern and dose increase couldnot be assessed for infliximab patients.

To quantify dose increases over time, an exposure-adjusted approach was used. Specifically, dose increase was estimated at each week based on the number of patients treated with a given biologic (denominator) and the number of patients with a dose increase greater than the weekly dose of the index prescription (numerator). To capture the overall trend of the dosing patterns, cumulative rates of dose increase were reported. Because 

the starting dose affects the rate of the dose increase,

analyses were conducted separately for patients with a

starting dose less than or equal to the recommended dose

In this study, costs were assessed from payer and patient perspectives by utilizing paid claims. For Medicare patients, both the Medicare-paid amount and the employer-paid supplemental insurance amounts were included. Net payment for each of the services (pharmacy, inpatient, and outpatient) was compared across the anti-TNF-alpha agents to reflect a health plan’s perspective. Similarly, patients’ out-of-pocket costs for each of the services were examined separately to determine the patient cost burden. Pharmacy costs were defined as total pharmacy costs for all drugs prescribed to the RA patients, including the biologics. Inpatient and outpatient costs included net payment for hospitalizations, emergency department visits, physician office visits, procedures, and laboratory tests. Patient’s out-of-pocket expense consists of coinsurance, co-payments, and deductibles. Costs were aggregated over 12 months of follow-up.

Descriptive statistics for eligible patients by treatment group were provided. The Wilcoxon rank-sum test was used for continuous measures, and the c2 test was used for discrete measures. Statistical comparisons were conducted using etanercept as the reference cohort. For mean values, nonparametric analysis of variance was used to detect statistically significant differences in costs between the anti-TNF-alpha agents. For median values, the Kruskal-Wallis test was used to detect statistically significant cost differences among the anti-TNF-a agents. All statistical analyses were performed using SAS version 9.1.3 (SAS Institute Inc, Cary, NC).

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