Economic evaluation of infliximab, synthetic triple therapy and methotrexate in the treatment of newly diagnosed juvenile idiopathic arthritis

In this study, we demonstrated that during the first year of treatment of polyarticular JIA, IFX + MTX had the highest total costs. For IFX + MTX, costs of intravenous administration were a significant cost component. For TRIPLE or MTX, costs of intra articular injections, mainly costs of general anesthesia, were the largest cost component. Almost half of the patients originally in the MTX group did not reach the target and were switched mostly to biologic therapy. In the analyses, costs were calculated as an intention-to-treat fashion. Therefore, in MTX, costs of biologics in patients failing the original strategy were a significant cost component.

When calculating cost-effectiveness for IFX + MTX compared with MTX, incremental cost per additional month spent in inactive disease was less than 1000 €. Results were similar when applying cost per QALYs. ICER of IFX + MTX compared with MTX was within the QALY threshold limit £20,000–30,000 of NICE evaluations [20], indicating acceptable additional cost of a more effective treatment. However, interpretation of these results has to be made with extraordinary caution. The results are applicable only for patients with polyarticular JIA during the first year from disease onset, and in an aggressive treat-to-target setting.

Interestingly, when IFX + MTX was compared with TRIPLE using incremental costs per additional month spent in inactive disease or per QALY, estimates were quite favorable for TRIPLE. Furthermore, when analyzing all three strategies, at any acceptable willingness-to-pay level, TRIPLE seemed most optimal treatment. In adult patients with rheumatoid arthritis, triple conventional DMARD therapy has been shown to be effective and cost-effective [5, 6, 21]. However, European League against Rheumatism (EULAR) and ACR recommendations do not include triple therapy for treatment of early RA or JIA [3, 22].

In children, concerns for side-effects and difficulties with medication adherence of DMARDs in a real-life setting have limited considerably their use as a combination. In the ACUTE-JIA study, only 20% of the patients discontinued TRIPLE during the first year due to inefficacy or adverse effects and were started with biologics. A favorable efficacy and safety profile of conventional DMARDs was also shown in a recent Dutch study, where regardless of initial treatment, sequential DMARD monotherapy, MTX in combination with prednisolone or MTX with etanercept, children with early JIA reached inactive disease equally well [23]. It can be stated that considering cost-effectiveness, efficacy, and satisfactory tolerability, studies of new treatment strategies with synthetic DMARDs are warranted for patients with polyarticular JIA. Especially in circumstances with constrained resources, combination of csDMARDs might be a feasible alternative to bDMARDs.

Costs of JIA treatment vary from 952 Can$ (MTX alone) [11] to 45,227 € (majority of patients on biologics) [24]. These depend on country, healthcare system, and medication used in different studies, which makes comparisons of results challenging. Total costs measured in this study were comparable to those in earlier studies reporting all costs and using biologics for refractory patients [24]. In this study, infusion costs seemed to be a major cost component using IFX. In general, this is a considerable disadvantage for biologics administered intravenously [11].

In the present study, patients received original IFX product. Nowadays, more choices for cost-conscious clinicians are available. In adult rheumatoid arthritis (RA), biosimilars and the original IFX product have shown comparable efficacy [25]. In our analyses, we used prices of biosimilars to enable comparisons of costs between IFX + MTX and other treatments. Furthermore, we analyzed ICER at different IFX prices.

The strength of this study is that information on efficacy, and all costs were carefully collected from the patient records and case report forms and included as they occurred. Intensification of treatment occurred in similar approach than in current treatment guidelines. To our knowledge, this is among the first studies considering cost of time spent in CID. Time spent in CID seems to predict long-term outcome in JIA [26], and thus, cost per time spent in CID could be considered a valid instrument when assessing cost-effectiveness of therapies of JIA.

Infliximab, although not licensed, is widely used off-label in JIA. Considering the similarities in efficacy and adverse events profiles of anti-TNF inhibitors [7], the results of this study can be considered relevant in comparing anti-TNF agents as a group to therapy with DMARDs only. One limitation of this study is the time frame of 1 year. However, previous studies have pointed out the significance of attaining early disease control [27, 28], and therefore, the costs of the treatment during the first year are essential for the future course of the disease. For indirect costs, travel costs and parental work loss were included. Due to the short time frame of the study, costs for patient productivity loss or early retirement could not be calculated. To tackle the limited sample size of this study, cost-effectiveness acceptability frontier assessment based on 1000 non-parametric bootstrap iterations was performed. The rather small sample size did not seem to be an important factor in causing uncertainty.

Health utility impacts were not directly measured in the present study. Therefore, we converted CHAQ to utility values applying several algorithms created for converting adult HAQ values to utility values. Using the NICE quadratic algorithm in this work included assumptions of equality between adult HAQ and CHAQ, or EQ-5D and children’s health-related quality of life. We found the use of adult algorithm justifiable, because the utility values in active adult rheumatoid arthritis have shown similarities to utility values in active JIA [12]. In sensitivity analyses, additional equations were used. Furthermore, the primary endpoint, costs per time spent in CID, demonstrated similar results than the ICER estimates.

During one-year time horizon in patients with polyarticular JIA, both IFX + MTX and combination therapy of DMARDs can be considered cost-effective, when compared with MTX alone. A combination of DMARDs showed cost advantages, when compared with IFX + MTX. To confirm the short-term findings of this study, long-term real-world effectiveness and cost-effectiveness studies with larger number of patients are warranted. Combination of DMARDs should also be evaluated when contrasting biologics with other therapies for JIA. In future, economic evaluations on novel, non-TNF biologic therapies of JIA are also needed.

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