Vol.:(0123456789) Clinical Rheumatology https://doi.org/10.1007/s10067-025-07568-9 ORIGINAL ARTICLE Biosimilars and reference biological medicines in the treatment of rheumatoid arthritis: a multicenter cross‑sectional study in Catalonia, Spain Joan Mas Marin1 · Marina Molina‑Olano1 · Nuria Rudi Sola1,2  · Núria Miserachs‑Aranda1,3 · Paula Montoliu Alcón1,4 · Jan T. De Pourcq1,5  · Carles Quiñones Ribas1,6 · Laura Borràs Trias1,2  · Eva Fernández‑Cañabate1,3 · Juan González‑Valdivieso1,4 · Carlos Figueiredo‑Escribá1  · René Delgado‑Hernández1  · Antonio J. Braza1  · Cecilia F. Lastra1  · Eduardo L. Mariño1  · Pilar Modamio1 Received: 7 March 2025 / Revised: 23 June 2025 / Accepted: 3 July 2025 © The Author(s) 2025 Abstract Objective The objective of this study is to compare the effectiveness of reference biologic medicines used in the treatment of rheumatoid arthritis (RA) specifically adalimumab, etanercept, and infliximab, with corresponding biosimilar medicines, based on an exploratory analysis of clinical data obtained in patients treated with these medicines in five hospitals in the region of Catalonia, Spain. Methods There is a consultation of the database of the Registry of Patients and Treatments of the Catalan Health Service: extraction of data from adult patients diagnosed with moderate and severe active RA and with active prescription of at least one biological drug (reference or biosimilar) or JAK inhibitor. To compare the effectiveness of each reference biologic with its biosimilar, differences in mean DAS28-ESR values before and after treatment were assessed for adalimumab and its biosimilar, etanercept and its biosimilar, and infliximab and its biosimilar. Results The study consisted of 643 patients. The most dispensed medicines were anti-TNFs, with 303 patients on treatment. Thirty-six percent of all patients were using biosimilars. No statistically significant differences were observed in any of the three comparisons between the reference biologic medicine and its biosimilar. These findings suggest that biosimilars have comparable effectiveness to reference biologics in reducing DAS28-ESR; in addition, they can provide substantial savings to public health systems. Conclusions A significant number of patients diagnosed with moderate to severe active RA were treated with biological medicines and receiving the available biosimilar treatments. Future research should be conducted to confirm comparable effectiveness found to their reference biologic medicines in this exploratory analysis. Key Points • Biosimilar use: 36% of rheumatoid arthritis (RA) patients in Catalonia are treated with biosimilars, exceeding the 12% recommendation. This reflects growing acceptance of these alternatives. • Comparative effectiveness: Biosimilars of adalimumab, etanercept, and infliximab showed comparable therapeutic benefit to their reference biologics in reducing disease activity in active rheumatoid arthritis. • Real-world data: The study provides real-world data from five hospitals, making biosimilar medicines a viable choice for rheumatologists in routine rheumatoid arthritis management. Keywords Biological medicine · Biosimilar · Disease-modifying antirheumatic drug · Drug utilization study · JAK inhibitor · Rheumatoid arthritis Introduction Chronic inflammatory rheumatic diseases such as rheu- matoid arthritis (RA) represent a significant challenge for healthcare systems due to their disabling nature, Joan Mas Marin and Marina Molina-Olano first authors with equal contribution in this article. Extended author information available on the last page of the article Clinical Rheumatology progressive course, and substantial economic burden. Over recent decades, biologic therapies have transformed the clinical management of these conditions by providing more effective control of inflammation and substantially improving patients’ quality of life. However, the high cost of these innovative biological medicines has restricted access [1–4]. In this context, biosimilars have emerged as a highly relevant therapeutic alternative. A biosimilar is a biologic medicine that exhibits high similarity to a reference bio- logical product in terms of quality, biological activity, safety, efficacy, and immunogenicity, although minor dif- ferences may exist due to the inherent complexity of bio- technological manufacturing processes. The introduction of biosimilars into the market holds the potential to sig- nificantly reduce the cost of biological treatments, foster competition within the pharmaceutical sector, and enhance the sustainability of healthcare systems [5]. In rheumatology in particular, where many patients require long-term biologic therapy—often in combina- tion with other immunomodulatory agents—the avail- ability of biosimilars represents a critical opportunity to expand access without compromising the quality of care. Nevertheless, to ensure the confidence of healthcare pro- fessionals and patients, rigorous comparative studies are essential to demonstrate the equivalence of a biosimilar to its reference product. These studies must encompass clinical, pharmacodynamic, pharmacokinetic, and immu- nogenicity parameters, in accordance with international regulatory standards [6, 7]. RA is a multifactorial, systemic autoimmune disease of unknown etiology. It is characterized by chronic inflamma- tion primarily affecting the synovial joints, leading to pan- nus formation, progressive bone erosion, and ultimately, joint destruction [1, 2]. RA tends to be more active during its early stages and, if left untreated or poorly managed, progresses to joint deformity and irreversible damage [3, 4]. The most prominent clinical symptom is pain, which significantly affects patients’ quality of life and may even- tually necessitate joint replacement or orthopedic surgery [5]. Beyond the joints, the persistent systemic inflamma- tion associated with RA may cause a wide range of extra- articular manifestations and comorbidities [1–4]. According to the EPISER 2016 study on the epidemi- ology of rheumatic diseases in Spain [8], the estimated prevalence of RA in the adult population is 0.82% (95% CI: 0.59–1.15). This figure is relatively high compared to other countries with similar demographic and healthcare characteristics. The prevalence is notably sex-specific, with a significantly higher rate observed in women (1.54%) compared to men (0.57%). The principal aim of RA treatment is to suppress inflammation, alleviate symptoms such as pain, swelling, and stiffness, and prevent long-term joint damage and deformity. Equally important is the preservation of func- tion and quality of life, reducing the risk of disability and increasing life expectancy. Treatment strategies also tar- get the prevention of complications such as cardiovascu- lar disease and osteoporosis, which are common in RA patients. A comprehensive, multidisciplinary approach is recommended, combining pharmacological interven- tions with lifestyle modifications, patient education, and physical therapy. Among pharmacologic treatments, early initiation of therapy with nonsteroidal anti-inflammatory drugs (NSAIDs), glucocorticoids, and disease-modifying antirheumatic drugs (DMARDs) is essential. Among DMARDs, methotrexate (MTX) remains the cornerstone therapy due to its well-established effectiveness and favorable risk–benefit profile [3, 9–11]. In cases where conventional DMARDs alone are insufficient, biologic agents are introduced—often in combination with MTX— to enhance clinical outcomes. This combination has shown increased effectiveness and durability of response, while also delaying structural joint damage, making it a pre- ferred therapeutic strategy [9–11]. At the time of the study, nine biologic agents were avail- able in Spain as first-line options for the treatment of moder- ate to severe RA [12]. These agents can be classified based on their mechanism of action: anti-TNF-α action, infliximab, adalimumab, and golimumab, which are monoclonal anti- bodies [13, 14]; certolizumab pegol, a PEGylated Fab′ frag- ment of a humanized antibody [15, 16]; etanercept, a fusion protein dimer [9, 17]; T-cell co-stimulation modulators: such as abatacept [18]; IL-6 receptor antagonists: includ- ing tocilizumab and sarilumab [19, 20]; and IL-1 inhibitors: such as anakinra, although its clinical use is limited due to lower comparative effectiveness [12, 21]. Rituximab, a B-cell depleting monoclonal antibody, is also approved for second-line use in patients who do not respond adequately or are intolerant to other biologics or DMARDs. Addition- ally, targeted synthetic DMARDs such as Janus kinase (JAK) inhibitors—including tofacitinib and baricitinib—offer an oral treatment alternative with proven effectiveness [22, 23]. The Spanish Society of Rheumatology (SER) has devel- oped a set of thirteen consensus-based clinical recom- mendations for the use of DMARDs and biologics in adult RA patients [24]. Risk management protocols specific to biologic therapies have also been published by SER [25]. Internationally, organizations such as the American College of Rheumatology (ACR) have issued updated guidelines, such as the 2021 ACR recommendations, to guide clinical decision-making and promote standardized care [5]. The overarching therapeutic goal in RA is disease remis- sion. This is assessed using validated composite indices, with the Disease Activity Score (DAS) endorsed by the European League Against Rheumatism (EULAR) as a Clinical Rheumatology standard tool. Specifically, the DAS28-ESR index incorpo- rates clinical evaluations of 28 joints, patient-reported health assessments, and erythrocyte sedimentation rate (ESR) val- ues to gauge disease activity and treatment response [11, 26, 27]. In the region of Catalonia, access to biologic therapies is regulated under the Pharmacotherapeutic Harmoniza- tion Program (PHF), which establishes specific criteria for their prescription in patients with moderate to severe active RA [28]. These criteria align with the guidelines set by the Spanish Society of Hospital Pharmacy (SEFH) [29] and are detailed in documents issued by relevant regional pharma- cotherapeutic committees, such as the CFT-MHDA and the CFT-SISCAT [12, 19, 22, 30]. The PHF seeks to ensure the rational use of medications by optimizing therapeutic effectiveness, safety, and efficiency [31]. The introduction of biosimilar medicines has played a significant role in reducing healthcare costs associated with RA treatment. For instance, in 2020, the average cost of anti- TNF-α therapies in Spain dropped by approximately 17% fol- lowing the introduction of biosimilars [32]. The SEFH has confirmed that biosimilars offer comparable quality, safety, and effectiveness to their originator biologics, but at a lower price point [6, 33]. This has facilitated broader access to advanced therapies and improved the sustainability of health- care systems managing chronic inflammatory conditions. The primary objective of this study was to compare the clinical effectiveness of reference biologic medicines—spe- cifically infliximab, etanercept, and adalimumab—and their corresponding biosimilars in the treatment of active RA. This evaluation was conducted through an exploratory analy- sis of real-world clinical data collected from patients with RA treated at five hospitals in Catalonia (Spain). Methods The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement (https:// www. strobe- state ment. org/ check lists/) was followed in this study. Study design and scope A descriptive cross-sectional multicenter study was carried out in five hospitals in the province of Barcelona (Spain). Population and sample Patients are diagnosed with active RA and with an active prescription for at least one biological medicine (reference or biosimilar) or JAK inhibitor, as of January 8th 2020 (the cut-off date chosen for the cross- sectional study). Inclusion criteria were: adult patients with moderate to severe active RA based on the use of DAS28 (moderate activity, severe activity) [27], with an inadequate response, such as ineffectiveness or intolerance, to conventional DMARDs (including MTX), according to the SER [23, 24], who were on active treatment at the date of data extraction and with a last recorded date of visit to the Rheumatology Service after October 8th 2019. The exclusion criteria were as follows: patients under 18 years of age, oncology patients, patients who did not attend the follow-up appointment at the Rheumatology Ser- vice at least 3 months before the cross-sectional cut-off date, and patients on biological therapy treatment in services other than rheumatology. Source of data collection and study variables The information was obtained from the Register of Patients and Treatments (RPT) of the Catalan Health Service (Cat- Salut), in the category of Medicines for Outpatient Hospital Medication (MHDA), which is available via the applications portal of the Generalitat de Catalunya Health Department. The studied variables were as follows: hospital (health center where patients were treated), demographic variables (age and sex), synthetic and/or biological medicines taken by the patient before the date of data extraction, current biologi- cal treatment (reference or biosimilar to analyze biosimilar medicines and reference biological medicines separately), and biosimilar prescribing physicians (in total and in each hospital to perform a comparative analysis to characterize the trend in the prescription of biosimilar medicines together with the role of the medical professional in promoting the use of these medicines). The targeted biological and syn- thetic medicines that these patients were receiving, i.e., the treatment of choice, were analyzed and classified according to the Anatomical, Therapeutic, Chemical Classification System (ATC). Another studied variable was the DAS28- ESR value before starting biological treatment and after biological treatment (value at the last medical visit prior to data extraction). The DAS28-ESR was interpreted as fol- lows: less than 2.6, disease remission; from 2.6 to < 3.2, low disease activity; and between 3.2 and 5.1, moderate disease activity; greater than 5.1, high disease activity [24, 26, 27]. PHF recommends that the patient be on the medication for 12 months before assessing response to determine whether there are differences between reference biological medi- cines, biosimilars, or JAK inhibitors [28]. Statistical analysis A descriptive analysis was performed, expressing dis- crete variables as proportions and continuous variables as mean ± standard deviation. Normality was assessed using Clinical Rheumatology the Shapiro–Wilk test for variables with fewer than 30 cases and the Kolmogorov–Smirnov test for the remaining vari- ables. Bivariate analysis included the Chi-square test for frequencies and Student’s t-test or ANOVA for means, with the Wilcoxon test as a non-parametric alternative. Fisher’s exact test was used to analyze DAS28-ESR status evolution. In cases where statistically significant differences were not verified due to small sample sizes, more robust methods such as bootstrapping were employed. Statistical significance was set at p < 0.05, and analyses were conducted using R soft- ware (v4.2.2). Ethical aspects According to Spanish regulation (Order SAS/3470/2009, of December 16, which publishes the guidelines on post- authorization studies of an observational type for medicines for human use and Chapter VI of Royal Decree 577/2013, of July 26, which regulates pharmacovigilance of medicinal products for human use), studies prior to January 2021 were not legally required to obtain permission from the Ethical Review Committee or register the study protocol. Instead, a protocol was developed and approved in March 2020 (code number 20204002) by the Research Committee of one of the hospitals of this multicenter study (Hospital General de Granollers, Granollers, Barcelona, Spain). The extraction of information was carried out anony- mously, and the relationship was not available to recover which real cases the information corresponds to. Informed consent was waived since an Ethical Review Committee approval of a protocol was not required at the time of the study. Results Demographic variables The study was conducted in 838 patients with active RA and being treated with at least one biologic (reference or biosimilar) medicine or JAK inhibitor, after demonstrat- ing a lack of response or intolerance to MTX or another previously prescribed conventional DMARD. One hun- dred ninety-five patients were excluded because they did not meet the inclusion criteria and/or did not attend the follow-up consultation in the Rheumatology Service at least 3 months before the cross-section. Finally, 643 adult patients over 18 years of age with active biological treatment were included. Of the total number of patients included in the study, 487 were women (75.8%) and 156 men (24.3%); in addition, 60.3% were under 65 years of age (minimum value 20), and the remaining 39.7% were over 65 years of age (maximum value 92) (Fig. 1). The mean age was 61.3 ± 13.1 years. Treatment analysis All drugs belonged to the ATC group of antineoplastic and immunomodulators and, within this, to immunosuppressive agents (L04). The most commonly used were tumor necrosis factor-alpha (TNF-α) inhibitors, followed by JAK inhibitors and interleukin inhibitors (Table 1). In this study, 144 patients were being treated with adali- mumab, etanercept, and infliximab (only these three bio- logical medicines had biosimilars marketed at the time of Fig. 1 Distribution in the form of a population pyramid, according to sex and age, of the patients included in the study Clinical Rheumatology the study). Only 81 patients were being treated with their respective biosimilars (36% of the total 225). When broken down by medicine, the percentage of biosimilars represented 15.5%, 47.4%, and 64.7% for adalimumab, etanercept, and infliximab, respectively (Fig. 2). Table 2 shows the list of the 643 patients used for the study, indicating the drug, sex, and age range distribution. Significantly more frequent use was observed in patients younger than 65  years (42.9%), compared to 26.1% in those over 65 years of age (p < 0.01). Higher use in women (37.4%) than in men (32.3%), although without statistical significance (p = 0.48) (Fig. 3). Thus, 25 of the 30 rheumatologists analyzed had pre- scribed one of the three alternative biosimilars registered in Spain (adalimumab, etanercept and infliximab); 17 of the 30 (56.7%) had prescribed a biosimilar medicine at least once, and the remaining 13 specialists (43.4%) had not prescribed any. Analysis of disease evolution In the case of patients who were treated with adalimumab (reference biological medicine) the mean value of the pre- treatment DAS28-ESR was 3.89. After treatment, the value dropped to 2.71 (post-treatment DAS28-ESR value). In the case of its biosimilar, the improvement of the disease even presented a better evolution, since the pre-treatment value DAS28-ESR was 4.46 and became 2.63. Statistically sig- nificant differences were found between the pre- and post- treatment DAS28-ESR values (Fig. 4(A1) and (A2)). The comparison of etanercept (reference biological medi- cine) with its biosimilar indicated something similar. The mean DAS28-ESR value of the patients before treatment was 4.13, and once treated, it became 2.69 (a decrease of 1.44 points). In the case of patients who were treated with the etanercept biosimilar, the DAS28-ESR value went from 4.73 to 2.95 (a decrease of 1.78). It should be noted that the drop in the DA28-ESR value was greater in the case of biosimilars than for the reference medicines, which indi- cates their adequate effectiveness. Statistically significant differences were found between the pre- and post-treatment DAS28-ESR values (Fig. 4(B1) and (B2)). Finally, we compared infliximab (reference biological medicine) with its biosimilar. The mean pre-treatment value DAS28-ESR was 4.15 and low to 2.27 post-treatment, once patients were treated with infliximab. In the case of its bio- similar, the mean value of DAS28-ESR went from 4.34 to 3.15, which represented a decrease of 1.88 points. In the case of the infliximab biosimilar, no statistical significance was reached (p = 0.056), although the p-value is very close to the conventional threshold of 0.05. This may be due to the low sample size, which limits the power of the test and increases the risk of type II error. In addition, the Wilcoxon test, being based on ranges and not absolute magnitudes, is less sensitive in small samples. To explore this possible limitation, a non-parametric bootstrap analysis was applied to the pre-post difference of this group. The 95% confidence interval for the mean of the differences was [0.19, 2.19], which does not include null (0). This result indicates that, although the Wilcoxon test did not reach conventional significance, there is statis- tical evidence of significant improvement after treatment with the biosimilar infliximab (Fig. 4(C1) and (C2)). However, the comparison of adalimumab and its bio- similar, etanercept and its biosimilar, and infliximab and its biosimilar, showed no statistically significant differ- ences in any of the three comparisons between the ref- erence biologic and its biosimilar (probability values of Table 1 Pharmacotherapeutic treatments prescribed to patients according to Anatomical Therapeutic Chemical (ATC) classification system Pharmacological group ATC Patients (n) TNF-α inhibitors L04AB 303 Adalimumab L04AB04 90 Certolizumab pegol L04AB05 47 Etanercept L04AB01 118 Golimumab L04AB06 31 Infliximab L04AB02 17 JAK inhibitors L04AF 132 Baricitinib L04AF02 74 Tofacitinib L04AF01 58 Interleukin inhibitors L04AC 119 Anakinra L04AC03 2 Sarilumab L04AC14 35 Tocilizumab L04AC07 82 Selective immunosuppressants L04AA 89 Abatacept L04AA24 89 Fig. 2 Use of biosimilar anti-TNF versus reference anti-TNF Clinical Rheumatology 0.279, 0.267, and 0.401, respectively). These findings sug- gest that biosimilars had an effectiveness similar to that of reference biologics. With respect to the qualitative aspects, changes in the clinical status of the disease were analyzed according to the different treatments, using an ordinal classification (0 = remission, 1 = low activity, 2 = moderate activity, and 3 = high activity). The results showed statistically significant differences in the evolution of disease status for most treatments, except for infliximab (p = 0.113). The problem detected here is that the sample size was small in relation to the rest of the cases (only 6 patients). With a larger number of patients, possibly statistically significant differences would have been found. In the case of inflixi- mab, bootstrapping was performed indicating that the pre- post-treatment differences were − 1.5. This result indicated a statistically significant improvement in disease status following treatment with infliximab, despite the small sample size (Fig. 5(A1) and (A2)). However, the comparison of adalimumab and its bio- similar, etanercept and its biosimilar, and infliximab and its biosimilar showed no statistically significant differences in any of the three comparisons between the reference biologic and its biosimilar in relation to change in disease status (probability values of 0.901, 0.164, and 0.443, respectively). These findings suggest Table 2 Number of patients receiving each medicine, distributed by sex and age range Medicine Patients (n) Man (n) Woman (n) Age (n) 20–34 years 35–49 years 50–64 years 65–79 years 80–95 years Adalimumab 76 20 56 2 9 32 27 6 Adalimumab biosimilar 14 2 12 1 4 6 3 0 Certolizumab pegol 47 10 37 4 20 9 10 4 Etanercept 62 17 45 0 10 21 26 5 Etanercept biosimilar 56 15 41 0 2 5 7 1 Golimumab 31 9 22 0 5 11 11 4 Infliximab 6 3 3 0 0 2 4 0 Infliximab biosimilar 11 2 9 0 2 6 3 0 Baricitinib 74 15 59 0 15 28 27 4 Tofacitinib 58 12 46 0 6 25 20 7 Anakinra 2 0 2 0 0 1 1 0 Sarilumab 35 7 28 2 13 9 10 1 Tocilizumab 82 17 65 0 9 33 37 3 Abatacept 89 25 64 0 12 29 38 10 Total 643 154 489 9 107 217 224 45 Fig. 3 Percentage of biosimilar medicines used by age and sex Clinical Rheumatology Fig. 4 Quantitative analysis (box plots: A-C) of pre- (first value in the medical record) and later- (last value available in the medical record) DAS28-ESR values of different patient groups (A1) patients treated with the reference medicine adalimumab, (A2) patients treated with the adalimumab biosimilar, (B1) patients treated with the reference medicine etanercept, (B2) patients treated with the etanercept biosim- ilar, (C1) patients treated with the reference medicine infliximab, and (C2) patients treated with the infliximab biosimilar Clinical Rheumatology that biosimilars had similar effectiveness to reference biologics. The analysis using the Fisher exact test allowed us to detect differences in the clinical course according to treat- ment. The absence of differences between reference medi- cines and biosimilars reinforces similar therapeutic benefit between them. The usefulness of the categorical approach to clinical status (remission, low, moderate or high activity) as a clinically relevant response variable was also confirmed. Discussion The results presented in Fig. 2 show a lower use of bio- similars than reference medicines (36% versus 64%, respectively), a percentage that nevertheless exceeds the recommendation established in the Catalonian PHF [22], which was 12%, according to sources consulted at the Pharmacy Services in the hospitals included in the study [34]. The low utilization of biosimilars may be due to a lack of trust on the part of the patient and the physician. Frantzen et al. [35] found precisely this situation: after providing information about biosimilar medicines to 629 patients, only 25% reported feeling safe to be treated with these medicines. A study by Kolbe et al. [36], conducted in the USA, found that there were gaps in knowledge and hesitation among physicians in the US healthcare system when it came to prescribing biosimilars. Of the three registered biosimilar medicines available in Spain at the time of the study, etanercept was the most prescribed medicine, accounting for 47% of biosimilar pre- scriptions. Adalimumab, with 12 biosimilar presentations, only had 16% of the biosimilar prescriptions. Infliximab, despite being the medicine that has been on the market for the longest time (1999), was the least dispensed medicine of these three. The lower percentage of adalimumab prescriptions may be related to a greater distrust of this medicine, although several studies have supported the efficacy of its biosimi- lars [37]. The possible differences between the different presentations of adalimumab could be due to limitations in the studies and biases of the centers in which they were performed and highlight the similarity in both efficacy and safety of biosimilars with respect to the biological medi- cine. Other studies, such as that of Bruni et al. [38], also demonstrated the safety of the biosimilar adalimumab in joint and autoimmune diseases. Among rheumatology specialists, 56.7% had prescribed a biosimilar medicine. This result is much higher than that found in the study by Delgado et al. [39], carried out in Europe during the 12 years to 2019, in which it was found Fig. 4 (continued) Clinical Rheumatology that in Spain only 25% of doctors had ever prescribed a biosimilar medicine. Currently, the European Medicines Agency (EMA) and the Heads of the Medicines Agencies have con- firmed that biosimilar medicines have proven to be comparable to their reference products in terms of effi- cacy, safety, and immunogenicity and are therefore inter- changeable [40]. Figures 4 and 5 show that patients who initiated treatment with the reference adalimumab, biosimilar adalimumab, reference etanercept, biosimilar etanercept, reference inf- liximab, and infliximab biosimilar in all cases improved the DAS28-ESR value. In some cases, this factor had been reduced, improving the patient’s life, and in other cases, the disease had disappeared. This could indicate that these three biosimilar medi- cines are comparable to their respective reference biologic medicines in their effectiveness. Unfortunately, there are few similar studies—with the analysis of the DAS28 or DAS28-ESR factor as evidence of the evolution of the rheumatic disease—with which to compare and evaluate the results of this study. A retrospective study of a patient cohort from two local health boards in Wales was con- ducted to analyze the clinical outcomes in terms of DAS28 of the etanercept biosimilar compared to the reference of etanercept in real-world practice [41]. In this study, although the authors assume a reduction in DAS28 as an improvement in treatment in both groups, they criticized the lack of more specific measures of disease activity. A single-center retrospective observational study conducted Fig. 5 Qualitative analysis (box plots: A-C) of previous (first value in the medical record) and later (last value available in the medical record) DAS28-ESR values of different patient groups (A1) patients treated with the reference medicine adalimumab, (A2) patients treated with the adalimumab biosimilar, (B1) patients treated with the refer- ence medicine etanercept, (B2) patients treated with the etanercept biosimilar, (C1) patients treated with the reference medicine inflixi- mab, and (C2) patients treated with the infliximab biosimilar Clinical Rheumatology in the UK by Madenidou et al. [42] also used DAS28 as a measure of treatment loss of effect, but in this case DAS28 was taken as a subjective measure. This study does not include the ACR response criteria. The ACR score is the most commonly used outcome in clini- cal trials and allows for a common standard among research- ers. In a systematic review, Konzett et al. [43] evaluated which ACR response definition (ACR20, 50, or 70) should be used primarily for efficacy claims in future RA medicine approval trials. But at the same time, their results support the selection of stricter thresholds if subsequent time points are to be evaluated, given their comparable but higher clinical validity. In Catalonia in real practice: the rheumatologist uses the DAS28 to measure the activity of the disease and the response to medicines. In fact, the CFT-MHDA of CFT- SISCAT uses DAS score to evaluate the levels of efficiency, effectiveness, and therapeutic utility of these medicines in their payment criteria [31]. This study wanted to explore if biosimilars were effective and safe medicines as reference products, being a viable choice for rheumatologists, with the aim of promoting their use in hospitals across Catalonia. This strategy was primarily moti- vated by economic considerations and the potential to gener- ate substantial savings for the public healthcare system [44]. Multiple studies have shown that the use of biosimilars results in significant cost savings within public health systems. In a study similar to ours, the adoption of biosimilars for adali- mumab, infliximab, and etanercept in 44.6% of 178 treated patients led to a total saving of €213,530 [45]. Extrapolating this approach to the entire autonomous community of Catalonia—where the prevalence of RA and other immune-mediated diseases requiring biological therapy is estimated at 0.5–0.7% of the adult population (approximately 30,000 to 40,000 patients)—the potential annual savings could exceed €100 million, assuming simi- lar biosimilar uptake rates. In an ideal scenario where all eligible patients were treated with biosimilars, the total eco- nomic benefit could range between €131 and €183 million per year, based on an average saving of €3,500 per patient. These projections underscore the considerable economic and strategic value of expanding biosimilar adoption as a means to enhance the sustainability and efficiency of the public healthcare system, without compromising treatment effectiveness or patient safety. This highlights the significant potential of biosimilars to contribute to a more efficient and resilient healthcare model. As a general assessment, the results we present correspond to a descriptive, cross-sectional, multicenter study. Cross- sectional designs, in particular, have limitations: they provide only a snapshot in time, limiting the assessment of changes or trends; they cannot establish causal relationships; and they are susceptible to various biases (e.g., selection or information bias). However, this study reflects what happens in routine clinical practice, being useful for identifying associations and generating hypotheses. Besides, the multicenter setting also enhances the generalizability. Conclusions This study conducted in five hospitals in Catalonia pro- vides an updated perspective on the use of biological ther- apies in patients with moderate to severe RA. The findings revealed that a significant number of patients are being treated with biological medicines, including biosimilars. Despite some initial mistrust toward the latter, clinical experience seems to indicate that patients obtain benefits of biosimilar medicines. Fig. 5 (continued) Clinical Rheumatology The analysis of real-world data suggests a similar effectiveness between reference biological medicines and their biosimilar counterparts, with evidence of clinical improvement and symptom reduction. These preliminary results support the potential of biosimilars as effective and cost-efficient therapeutic alternatives. Further research is warranted to confirm these findings. Such studies will allow for the evaluation of the thera- peutic performance and economic impact of biosimilars under routine clinical conditions and in broader, more rep- resentative patient populations. Abbreviations ACR :  American College of Rheumatology; ANOVA: Analysis of variance test; ATC : Anatomical Therapeutic Chemical Classification; CatSalut: Catalan Health Service; CFT- MHDA: Pharmacotherapeutics Committee for Outpatient Hospital Medication; CFT-SISCAT : Pharmacotherapeutics Commission - Inte- grated Public Healthcare System of Catalonia; DAS: Disease Activ- ity Score; DAS28-ESR: Disease Activity Score 28-Erythrocyte Sedi- mentation Rate; DMARDs: Disease-modifying antirheumatic drugs; EMA: European Medicines Agency; ESR: Erythrocyte sedimentation rate; EULAR: European League Against Rheumatism; IL-1: Interleu- kin-1; IL-6: Interleukin-6; JAK: Janus kinase family protein signaling pathway; MHDA: Outpatient Hospital Medication; MTX: Methotrexate; NSAIDs: Non-steroidal anti-inflammatory drugs; PHF: Pharmacothera- peutic Harmonization Program; RA: Rheumatoid arthritis; RPT: Reg- ister of Patients and Treatments; SEFH: Spanish Society of Hospital Pharmacy; SER: Spanish Society of Rheumatology; TNF-α: Tumor necrosis factor-alpha Acknowledgements We would like to thank the staff of the pharmacy services of the hospitals that participated in the study. Author contribution JMM and MM-O collected data, carried out the initial analyses, drafted the initial manuscript, and had an equal contribution; NRS, NM-A, PMA, JTDP, CQR, LBT, EF-C, and JG-V collected data and carried out the initial analyses in the hospitals included in the study; CF-E and RD-H designed the data collection instruments, carried out the statistical analysis of the data, and drafted the initial manuscript; ELM coordinated and supervised methodology and investigation and critically reviewed the manuscript for important intellectual content. AJB, CFL, and PM conceptualized and designed the study, supervised methodology and investigation, and reviewed the manuscript. All authors contributed to the article and approved the submitted version. Funding Open Access funding provided thanks to the CRUE-CSIC agreement with Springer Nature. Data availability The datasets used and/or analyzed during the cur- rent study are available from the corresponding authors on reasonable request. Compliance with ethical standards Ethics approval and consent to participate The study was approved by the research committee of the Hospital General de Granollers (Granollers, Barcelona, Spain) (code number 20204002) in March 2020. Consent for publication All authors agreed to the publication of this manuscript. Disclosures None. Open Access This article is licensed under a Creative Commons Attri- bution 4.0 International License, which permits use, sharing, adapta- tion, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. 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Gómez-Gómez D, Colón López De Dicastillo A, Ochagavía Sufrategui M, Valero Domínguez M (2015). Estimation of the real cost of anti-TNF therapies in rheumatic diseases (Spanish). Rev. O.F.I.L. 25(2):91–100. https:// www. ilaph ar. org/ estim acion- del- coste- real- de- las- terap ias- anti- tnf- en- enfer medad es- reuma ticas/ Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Clinical Rheumatology Authors and Affiliations Joan Mas Marin1 · Marina Molina‑Olano1 · Nuria Rudi Sola1,2  · Núria Miserachs‑Aranda1,3 · Paula Montoliu Alcón1,4 · Jan T. De Pourcq1,5  · Carles Quiñones Ribas1,6 · Laura Borràs Trias1,2  · Eva Fernández‑Cañabate1,3 · Juan González‑Valdivieso1,4 · Carlos Figueiredo‑Escribá1  · René Delgado‑Hernández1  · Antonio J. Braza1  · Cecilia F. Lastra1  · Eduardo L. Mariño1  · Pilar Modamio1 * Antonio J. Braza braza@ub.edu * Pilar Modamio pmodamio@ub.edu Joan Mas Marin joanmas96@gmail.com Marina Molina-Olano m_molina_olano@hotmail.com Nuria Rudi Sola nrudi@fphag.org Núria Miserachs-Aranda nmiserac@fhes.cat Paula Montoliu Alcón paula.montoliu@quironsalud.es Jan T. De Pourcq JDePourcq@santpau.cat Carles Quiñones Ribas carles.quinones@gencat.cat Laura Borràs Trias lborras@fphag.org Eva Fernández-Cañabate efernanc@fhes.cat Juan González-Valdivieso juan.gonzalezv@quironsalud.es Carlos Figueiredo-Escribá cdefigueiredoescriba@ub.edu René Delgado-Hernández renedelgado@ub.edu Cecilia F. Lastra ceciliafernandez@ub.edu Eduardo L. Mariño emarino@ub.edu 1 Clinical Pharmacy and Pharmaceutical Care Unit, Department of Pharmacy and Pharmaceutical Technology, and Physical Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, Av. Joan XXIII, 27-31, 08028 Barcelona, Spain 2 Pharmacy Service, Hospital General de Granollers, Av. Francesc Ribas s/n, 08402 Granollers, Barcelona, Spain 3 Pharmacy Service, Fundació Hospital de l’Esperit Sant, Av. Mossèn Pons i Rabadà s/n, 08923 Santa Coloma de Gramenet, Barcelona, Spain 4 Pharmacy Service, Hospital Universitari Sagrat Cor, C/ Viladomat, 288, 08029 Barcelona, Spain 5 Pharmacy Service, Hospital de la Santa Creu i Sant Pau, C/ Sant Antoni Mª Claret 167, 08025 Barcelona, Spain 6 Pharmacy Service, Hospital Universitari Germans Trias i Pujol, Carretera de Canyet s/n, 08916 Badalona, Barcelona, Spain