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Supplements Improving Clinical and Managed Care Outcomes in Rheumatoid arthritis: a Focus on Comparative Effecti

Implications for Managed Care and Specialty Pharmacy in Rheumatoid Arthritis

William J. Cardarelli, PharmD
Treatment of rheumatoid arthritis (RA) can be very costly. Cost-effectiveness studies provide insight into the value of treatment from a number of perspectives (eg, societal, healthcare). In most cases, the indirect costs of RA can offset the direct costs in 2 ways. Prevention of disease progression can limit future costs, such as those related to surgery and hospitalization. When disease progression is minimized, patients feel better and can have improved work productivity. Disease control of RA has improved over time, and this is attributed primarily to the introduction of more effective therapies. Despite the effectiveness of new therapies, there are a number of barriers to optimal treatment. Barriers include lack of education for patients and practitioners about RA, poor patient-provider communication, uncertainty regarding which treatments to choose, cost, and lack of adherence. Specialty pharmacy and disease therapy management programs can assist patients by providing structure, education, and mechanisms to improve treatment adherence and persistence to optimize therapy.

(Am J Manag Care. 2012;18:S315-S324)
The European League Against Rheumatism (EULAR) recently endorsed 3 overarching principles for the treatment of rheumatoid arthritis (RA).1 The principles state that rheumatologists are the specialists who should primarily care for patients with RA, that the treatment of patients with RA should aim at the best care (based on a shared decision between the patient and the rheumatologist), and that RA is expensive with regard to medical costs and productivity costs, both of which should be considered by the treating rheumatologist.1 The 2012 update of the 2008 American College of Rheumatology (ACR) recommendations for medication management of RA provides a written framework, based on evidence, for handling the medication management of patients with RA, as outlined in the second article by Gibofsky in this supplement.2,3 This article will provide an overview of direct and indirect costs associated with RA, with a focus on treatmentrelated costs, the role of specialty pharmacy and managed care, and mechanisms to provide disease management that optimizes economic outcomes.

Direct and Indirect Costs of RA

Significant patient, healthcare, and societal costs are associated with RA. According to recent estimates, the per patient annual direct medical cost of RA ranges from $2000 to $10,000. Estimates for indirect costs range from $1500 to $22,000.4,5 These costs depend on the cost estimates of the model, year of the estimate, degree of inflation over time, severity of disease, and treatment approach. To provide a degree of perspective, a study conducted between 1993 and 1994 in a US group-model health maintenance organization (HMO) compared resource utilization and cost of care in 365 patients with RA with 10,101 patients with osteoarthritis (OA).6 The average individual cost of arthritis care was $2162 for RA and $543 for OA, a nearly 4-fold greater cost for RA. In that study, the respective utilization of various resources was compared, including prescription medication cost (62% vs 32% for RA and OA, respectively), ambulatory care costs (21% vs 22%, respectively) and hospital visits (16% vs 46%, respectively). Despite the higher cost per patient for RA, the total population cost was $703,053 for RA and $4,728,425 for OA, suggesting that the HMO cost for RA was substantially less (approximately 7-fold) than that for OA due to the relative infrequency of RA.6 It is important to note that these data are relatively old, and more expensive therapies have been introduced for both diseases; therefore, if inflation were applied, the assumptions should be similar.

As suggested in the HMO study,6 medications account for a large portion of the direct medical expenses associated with RA. Ambulatory care costs include primary care and specialist visits, urgent ambulatory care visits, joint imaging, laboratory assessment, joint aspiration and injection, and nerve conduction studies. Hospital care involves admission for disease symptoms or adverse effects, admission for joint surgery (including joint replacement), emergency department visits, physical therapy, and radiologic costs.6 Other medical costs beyond treatment of joint disease in RA are associated with extraarticular RA.7 Joyce and colleagues sought to determine the attributable annual costs of cardiovascular disease and depression coexistent with RA using a healthcare claims database.7 Of 10,298 patients identified, 8916 (86.6%) had RA alone, 608 (5.9%) had RA with cardiovascular disease (CVD), 716 (7%) had RA with depression, and 58 (0.5%) had RA with depression and CVD. Adjusted mean total healthcare costs were highest in the RA plus CVD group ($14,145), followed by RA plus depression and CVD ($13,513), RA plus depression only ($12,225), and RA alone ($11,404). The mean RA-related healthcare costs were similar among groups ($6100-$6600), suggesting that the extraarticular manifestations of RA are an important component of the cost of healthcare.7

Cardiovascular complications associated with RA are an important contributor to mortality in RA.8 An ideal therapy would increase life expectancy and quality of life. In a recent analysis of mortality with non-biologic disease-modifying antirheumatic drugs (DMARDs) and tumor necrosis factor (TNF) inhibitors, rituximab, and other biologics, mortality per 1000 patient years adjusted for age, sex, treatment, and comorbid conditions was improved with TNF inhibitors relative to DMARDs (hazard ratio [HR], 0.65; P = .0004). Mortality associated with rituximab (HR, 0.81; P = .34) and other biologics (HR, 0.84; P = .42) was similar to that associated with DMARDs. Across the population, each 1-point increase in the disease activity score in 28 joints (DAS28) was associated with a 15% higher death rate (HR, 1.15; P = .002). Increased prednisone use was also associated with higher mortality (HR per 5 mg/day increment of prednisone dose, 1.2; P = .003).9 The reduction in cardiovascular events with TNF inhibitors relative to DMARDs was demonstrated in some,10,11 but not all, recent studies.12

Health-related quality of life is measurable through a number of general (Short Form-36) and disease-specific instruments (RA quality of life [QoL]), or combined with mortality into a health utility, like the quality-adjusted lifeyear (QALY).5 While mortality or cardiovascular events may not be tangible or measurable for most individual patients, productivity and quality of life are important components of indirect costs. Health benefits of RA treatment are expressed in terms of pain, fatigue, and loss of function.5 Physical function may be monitored through the disability index of the Health Assessment Questionnaire (HAQ), and fatigue may be measured using indices such as the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F). Fatigue occurs in about 90% of patients with RA. In a phase 3, placebo-controlled trial of golimumab, in patients who were inadequately responsive to methotrexate, HAQ (r = –0.62, P <.01) and DAS28 score (r = –0.42, P <.01) were significantly correlated with FACIT-F score.13 Fatigue was an independent predictor of physical function and disease activity, and higher baseline FACIT-F scores (less fatigue) were more likely associated with achieved remission at week 24 (P = .024). Golimumab was associated with improved FACIT-F scores relative to placebo at week 12 (57.5% vs 42.8%, P <.001) and at week 24 (65.8% vs 40.3%, P <.001).13 These findings were confirmed with other TNF inhibitors.14,15 A recent systematic review and meta-analysis confirmed a small, but significant, effect of any biologic agent in patients with an inadequate response to DMARDs or TNF inhibitors [effect size (ES), 0.45; 95% confidence interval [CI], 0.31- 0.58]. An ES of less than 0.5 was considered small, 0.5 to 0.8 was moderate, and greater than 0.8 was considered large. When TNF inhibitors plus DMARDs were compared with placebo plus DMARDs, the ES was smaller (ES, 0.36; 95% CI, 0.21-0.51). When biotherapies (anti-TNF, rituximab, or abatacept) plus DMARDs were compared with DMARDs plus placebo for an inadequate response to DMARDs, the ES was similar (ES, 0.38; 95% CI, 0.3-0.46). When abatacept, golimumab, or rituximab were given with DMARDs and compared with placebo plus DMARDs for an inadequate response to TNF inhibitors, the ES was moderate (ES, 0.57; 95% CI, 0.27-0.86).15 Thus, fatigue was minimized by improved disease activity attained with aggressive treatment.

Improvement in disease activity and fatigue can lead to functional improvement, which could improve work productivity. Work disability associated with RA has been estimated to be 3 times as expensive as the direct medical costs of managing the disease.5 Factors associated with work disability include the ability to retain employment, absenteeism, early retirement, and reduced work performance. Significant irreversible work disability usually occurs within 5 years of disease onset; however, by 1 year, about 20% of patients are no longer engaged in full-time work, and this number increases to about 50% by 15 years. The average disability costs are estimated at $10,000 per year. These estimates are variable and depend on the type of output of the company and the salary of the individual. Step activity is a measure of functional capacity in RA. A recent study of etanercept demonstrated that step activity could be improved along with improvements in HAQ and DAS28 disease activity, but this was only observed early in the disease (<5 years in duration), before irreversible joint damage occurred.16 A number of studies have demonstrated improvement in work productivity with TNF inhibitor therapy compared with DMARD therapy in early RA.17-19 In 1 of those studies, etanercept plus methotrexate improved work attendance by an estimated 22 to 37 days per patient, compared with methotrexate alone. The associated cost of productivity gained, converted to US dollars, was approximately $2500 to $4000 per person. When presenteeism (reduced work performance on the job) was included, the estimate increased to $4700.17 Thus, from a societal perspective, effective treatment of RA could improve work productivity. From an employer perspective, a study evaluated direct and indirect costs of RA in patients compared with matched controls.20 The estimated annual cost for a disabled patient with RA was $17,822, 3 times that of the average matched disabled control ($6131). Disability was more common among employees with RA (44%) than other matched controls (22%). Work loss costs for patients with RA, including disability and absenteeism, were 1.6 times that of matched controls.20 Caution should be used when interpreting these data. A limitation of modeling cost-effectiveness in RA is that extrapolation of long-term benefits is often made with little or no long-term data. If there were a way to determine which patients would have severe progressive disease or which medication would yield the best response in an individual patient, then the cost-effectiveness numbers would improve substantially. As research continues, we may find that early biologic intervention may induce durable drug-free remission, which would also improve the cost-effectiveness of these biologics.

Treatment-Related Costs

Costs of treatment include the cost of medication, tests for monitoring the effects (disease response) or adverse effects of the drug, and administration costs (if applicable).5 A number of studies have demonstrated that, over time, disease activity has improved in populations with RA. The improvement in disease activity and increased attainment of remission has been attributed to the introduction of newer therapies, an improved approach to treatment, and earlier initiation of treatment.21-23 Rather than provide an exhaustive review of all pharmacoeconomic studies for every available agent, this section will present select studies that focus on representative approaches to treatment, as suggested in the 2012 ACR treatment recommendations.2 The second article by Gibofsky in this supplement can be used to assess differences among available treatments.3

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