Rheumatoid arthritis (RA) is an inflammatory-mediated immune disease (IMID), and its clinical manifestations represent a humanistic burden1,2 as well as a high economic burden on healthcare systems worldwide, due to the high resource consumption generated in the appropriate management of affected patients, both for the disease itself and the associated morbidity.3 The burden of the disease in Spain is much higher than in Europe and other parts of the world, and it also has a greater affectation for women.4 RA accounts for 5% of the total burden of rheumatic diseases in Spain (4.4% of the total burden of disease in Western Europe and 4% globally).4 The prevalence of RA and multimorbidity are increasing exponentially, as well as hospitalization rates (ranging between 31.6/100 000 inhabitants in 2002 and 56.3/100 000 inhabitants in 2017),5 lead in part by a reduction in mortality due to RA. This reduction was 43.8% in high-income countries, due to a better management of patients by disease control and treat-to-target treatments.2

RA is the most common chronic inflammatory rheumatic disease and its estimated prevalence in Spain has been reported to be 0.82% (95%CI 0.59–1.15) affecting predominantly women.6 In this study by Silva-Fernández et al, they also estimate that there are between 220 000 and 430 000 RA patients older than 20 years old in Spain. The majority of the patients were aged 40–59 years old, an age when patients have an active working life,1,6 which combined with its debilitating effect in those patients who suffer the disease, entails a high humanistic and economic burden.3

The treatment paradigm for these patients changed drastically 20 years ago with the development of biological disease modifying anti-rheumatic drugs (bDMARDs), which have supposed a great improvement for patient's lives by achieving a better control of the disease, a fewer consumption of steroids,7 and the attainment of a better overall quality of life.8 These bDMARDs have a significant impact over the disease effect and its progression.9 However, the costs associated with these therapies have been a constraint for their widespread use, an obstacle that has been addressed by the appearance of biosimilars, which maintain the benefit–risk profile at a lower cost.9,10

Currently, there are numerous bDMARDs, targeted synthetic, and biosimilar therapeutic alternatives for the management of RA, such as: abatacept, adalimumab, baricitinib, certolizumab, etanercept, golimumab, infliximab, rituximab, sarilumab, tocilizumab, tofacitinib, and upadacitinib,.11,12 Among them, tocilizumab (TCZ) has been approved for RA in the EU since 2009 for the treatment of methotrexate-naïve patients, as well as those patients with moderate to severe RA without response or intolerance to disease modifying anti-rheumatic drugs (DMARDs) or anti-tumor necrosis factor α drugs (anti-TNF-α).13 In the past years, it has been noted of paramount importance to follow closely the activity of the disease after diagnosis, to achieve “Treat to Target” guidance, which proposes that the therapeutic target in RA should be a state of remission, or alternatively a low disease activity.14 In Spain, the most commonly used index for evaluation of disease activity is the Disease Activity Score 28 (DAS28) which examines 28 joints and either ESR (erythrocyte sedimentation rate) or CRP (C reactive protein) and classifies the results into 4 categories.15–17

To make a well-informed decision for both the patient and the healthcare system according to efficacy–safety profile as well as costs associated with each treatment, it is mandatory to generate evidence that allows an appropriate decision-making process. The latest biosimilar approved and currently on the market in Spain aimed for the treatment of RA is MSB-11456, a tocilizumab biosimilar (bsTCZ), which prompted a refreshed search and updated evidence generation with its integration into the current market dynamics. Thus, the aim of this study is to develop a cost-effectiveness analysis of subcutaneous (SC) bsTCZ for the treatment of RA compared to the most common alternatives in Spain from the healthcare perspective.

To contrast bsTCZ administered subcutaneously to its comparators (SC abatacept, biosimilar SC adalimumab, oral -O- baricitinib, SC certolizumab, SC etanercept, O filgotinib, SC golimumab, biosimilar intravenous -IV- infliximab, IV rituximab, SC sarilumab, biologic SC tocilizumab -refTCZ-, O tofacitinib, and O upadacitinib), a cost-effectiveness model was constructed from the Spanish healthcare perspective. Studies including patients being treated with any of the comparators were included in the model.

Cost-effectiveness analysis

A Markov model 3-months cycle was built considering the Spanish clinical practice in the management of RA patients using 5 health states considering DAS28, the most used clinical parameter in Spain19: high disease activity, moderate disease activity, low disease activity, remission of the disease, and death as an absorbing health status (Fig. 1); and simulating a lifetime horizon to compare bsTCZ to all the available therapeutic alternatives. Patients initially present in a moderate-to-severe state, with the possibility of transitioning to any other states or to stay the same (High, Moderate, Low, Remision, or Death), according to the specific efficacy proportions of each treatment (Table 1). These efficacy estimates derive from literature retrieved and, in cases where data were insufficient, approximations have been made based on the closest comparable product within the same generation. Data for the first year were taken as the starting point and every 52 weeks the change of treatment was assessed depending on the treatment, the health state of the patient and whether the patient had changed the health state (improved/worsened) or stayed the same. Patients changing treatment after 52 weeks were in the high disease activity status and transitioned to a hypothetical pool of treatment alternatives with estimated efficacy based on corresponding clinical trials and market share of each treatment according to clinical experts For these estimations, the treatments in which the patient reached the high disease activity health status was disregarded in the pool. After the week 52, the transition probabilities were equal for all the treatments (Supplementary table 5).20 A discount of 3% was applied to both costs and effects.

Fig. 1.

Model structure. For each simulated patient, different health states are represented by ellipses and each transition between states is represented by an arrow between those states.

(0.16MB).

Table 1.

Estimated transition probabilities for a patient for the different treatments and health states.

Treatment	Moderate-high disease activity			Low disease activity			Remission of the disease
	12 weeks	24 weeks	52 weeks	12 weeks	24 weeks	52 weeks	12 weeks	24 weeks	52 weeks
Abatacept	78.54%	72.79%	45.45%	13.21%	15.91%	14.35%	8.25%	11.30%	40.20%
Adalimumab	67.88%	60.69%	52.00%	14.16%	13.30%	9.00%	17.96%	26.01%	39.00%
Baricitinib	56.08%	51.85%	44.00%	19.92%	16.72%	16.00%	24.00%	31.43%	40.00%
Certolizumab	55.45%	50.75%	35.94%	17.45%	15.85%	10.56%	27.10%	33.40%	53.50%
Etanercept	80.94%	76.22%	69.18%	14.02%	16.88%	12.12%	5.04%	6.90%	18.70%
Filgotinib	59.46%	48.06%	48.09%	18.24%	5.56%	5.71%	22.30%	46.38%	46.20%
Golimumab	79.93%	74.67%	74.14%	13.06%	15.73%	10.48%	7.01%	9.60%	15.38%
Infliximab	77.74%	71.67%	60.90%	13.06%	15.73%	10.30%	9.20%	12.60%	28.80%
Rituximab	79.88%	74.71%	75.88%	13.67%	16.47%	12.94%	6.44%	8.82%	11.18%
Sarilumab	53.07%	48.37%	33.57%	19.14%	17.39%	11.58%	27.78%	34.24%	54.85%
Reference tocilizumab	54.06%	48.82%	32.27%	16.78%	15.24%	10.15%	29.17%	35.94%	57.58%
TCZ biosimilar	54.06%	48.82%	32.27%	16.78%	15.24%	10.15%	29.17%	35.94%	57.58%
Tofacitinib	72.99%	69.09%	62.03%	11.41%	12.32%	8.21%	15.60%	18.58%	29.76%
Upadacitinib	53.09%	44.04%	32.90%	14.00%	13.06%	12.50%	32.91%	42.89%	54.60%

Population for the model was obtained from Leil et al. 202121 and was set as patients suffering RA with moderate to high disease activity (mean DAS28 5.7 (SE 0.52)), 80.6% women, mean age 52.7 (SE 1.0)) and mean disease duration 7.45 years (SE 2.72). The assessment of the quality of life for this baseline case varies depending on the progression of the disease using the values 0.839, 0.8, 0.679, and 0.492 for remission, low, moderate, and high disease activity states, respectively, as adapted from Chiou et al. (2004).22 These utilities were used to estimate the quality-adjusted life years (QALY) for the healthcare outcomes. According to a recent research, mortality was considered equal to the general population during the first 10 years of the disease23 and from then on, an increment on mortality was applied (standardized mortality rate 1.49 (95%CI 1.30–1.71).24 The Incremental Cost-Effectiveness Ratio scores cost per percentage of remission (€/remission) and cost per QALY (€/QALY) were calculated.

bDMARDs remain an essential pillar in the management of RA, however, due to their economic impact, their use has been limited in some cases29 and it was not until the introduction of biosimilars that they had a more widespread use. It is important to assess the efficiency of the updated therapeutic arsenal due to the increasing availability and use of biosimilars, to provide decision-makers and clinicians with all the tools to achieve an optimized patient management.

What is more important about the introduction of biosimilars is that efficacy of the treatment remains stable while costs are drastically reduced, entailing great benefits for the healthcare system, and improving its efficiency.30 In the findings of this study, it can be seen that bsTCZ is a good therapeutic alternative for patients suffering RA. Although the differences in the percentage of patients in the remission health status and in QALYs versus the other available treatments are minor, the lowest cost for bsTCZ among all the comparators makes bsTCZ dominate almost all the other alternatives according to their ICER. Even in cases where alternatives achieve higher QALYs, the small difference still positions bsTCZ as cost-effective. As bsTCZ has been recently approved in Europe,13 this is the first health-economic study with the aim to assess its cost-effectiveness in the treatment of patients with RA in Spain in comparison to all the available therapeutic alternatives from a healthcare system perspective.

It is widely known that an early establishment of treatment improves patient outcomes due to the reduction in the time in which the disease is active (such as joint damage). Moreover, there must be a treat-to-target strategy with the purpose of achieving disease remission or low disease activity as early as possible.15 The availability of treatments such as bsTCZ, which has a proven good efficacy profile and an affordable price, could make a difference in the management and treatment access for these patients.

Some assumptions had to be made for this model, for example, the basal distribution of patients among the different health states (low, moderate, and high disease activity) was calculated from the mean basal DAS28 distribution in Leil et al. (2021)21 assuming a normal distribution, and when there was no data regarding patients distribution between moderate-high, 15.3% were calculated to belong to the moderate disease activity health status. It was seen that in the older CTs, DAS28--ESR was mainly used in the past, but has progressively shifted into using DAS28-CRP in the newest trials as endpoint. According to Leil et al. (2021),21 the values between both markers are very similar and moreover, there was no possibility to estimate the health status, so data were assumed to be equivalent. Regarding the lifetime horizon, 2 assumptions were made: the effectiveness of the pivotal studies is assumed up to 52 weeks, from then on, the same transition probabilities have been applied for all treatments from a study for patients on anti-TNF-α therapy.20 From week 52 onwards, patients in the high disease activity health status switched to a treatment pool defined according to the market share in Spain. All the assumptions were made in a conservative manner, always in detriment of bsTCZ results so that obtained results and extracted conclusions from this analysis were not overestimating bsTCZ or underestimating its comparators. Even though a sensitivity analysis using different ranges of discount for the comparators was carried out, it should be considered that ex-factory prices are used in this analysis as final reimbursed prices are not publicly available and this might have an impact in the final results. We believe that it will prove to be useful for all relevant stakeholders involved in the treatment of RA to have an updated and refreshed pharmacoeconomic exercise available, due to the increasingly expanding availability of therapeutic options for this condition.

Even though there are no specific cost-effectiveness studies of bsTCZ for the treatment of RA in other countries, studies of other biosimilars in RA31,32 or bsTCZ in the treatment of other pathologies have shown that biosimilars are a cost-effective and cost-saving alternative33,34 and thus biosimilars should be positioned early in the treatment scheme to leverage its benefits. Introduction of biosimilars allows for cost savings and in the case of Spain, it has been reported that increased biosimilar adoption would allow additional patients to be treated by redirecting these savings,34 improving healthcare resource allocation and a better patient care.

In conclusion, this study demonstrates through a proposed model that bsTCZ is either dominant or at least cost-effective versus all the therapeutic alternatives for the treatment of RA from the Spanish healthcare system perspective.

This work was funded by Fresenius Kabi Spain S.A.U.

Organization 1: the European Alliance of Associations for Rheumatology

Venue: Messe Wien Congress Center, Vienna, Austria.

Date: June, 12th–15th, 2024

Organization 2: the Spanish Society of Rheumatology.

Venue: Palacio de Congresos Expomeloneras, Gran Canaria, Spain.

Date: May, 7th–10th, 2024

All authors accept the responsibilities defined by the International Committee of Medical Journal Editors (ICMJE). The study was performed using administrative and public data. No patient information was used.

The corresponding author, in the name of the rest of the signatories, declares that the data and information contained in the study are precise, transparent, and honest; that no relevant information has been omitted; and that all the discrepancies among authors have been adequately resolved and described”.

The co-authors accept the responsibilities defined by the International Committee of Medical Journal Editors (available at http://www.icmje.org/).

In the event of publication, the authors exclusively transfer to the Revista and, by extension, to SEFH their rights to reproducing, distributing, translating, and publicly communicating their work by any sound, audiovisual or electronic medium or format. To that effect, a letter transferring such rights shall be attached to the paper when submitting it through the online manuscript management system.

The study constitutes a cost-effectiveness comparison of biosimilar tocilizumab versus other therapeutic alternatives for the treatment of patients suffering moderate to severe rheumatoid arthritis in Spain.

The analysis provides an insight on the cost-effectiveness of different treatment alternatives thus, providing clinicians, hospital pharmacists, and decision makers with evidence to consider the most appropriate choice for the management of these patients from both a clinical and economic perspective.

Fernando Pérez-Ruiz: Writing – review & editing, Validation, Supervision, Conceptualization. Carlos Crespo-Diz: Writing – review & editing, Validation, Supervision, Conceptualization. Joan Antoni Schoenenberger-Arnaiz: Writing – review & editing, Validation, Supervision, Conceptualization. Mónica Cerezales: Writing – review & editing, Writing – original draft, Visualization, Project administration, Methodology, Investigation, Formal analysis, Conceptualization. Carlos Crespo: Writing – review & editing, Writing – original draft, Validation, Project administration, Methodology, Investigation, Formal analysis, Conceptualization. Marcelo Alejandro Guigini: Writing – review & editing, Validation, Supervision, Conceptualization. José Ignacio Peinado-Fabregat: Writing – review & editing, Validation, Supervision, Conceptualization. Mónica Climente-Martí: Writing – review & editing, Validation, Supervision, Conceptualization.