A national, multicenter, secondary data use study evaluating efficacy and retention of first-line biologic treatment with tocilizumab in patients with rheumatoid arthritis in real-life setting: results from TURKBIO registry

Tocilizumab (TCZ) is a recombinant humanized monoclonal antibody that targets the IL-6 receptor. TCZ found to be efficacious and has a good tolerated safety profile in rheumatoid arthritis (RA) patients. The aim of this study was to describe the disease activity and retention rate in Turkish RA patients who were prescribed TCZ as first-line biologic treatment in a real-world setting. Secondary data obtained from adult RA patients’ files was used in a multicenter and retrospective context. Clinical Disease Activity Index (CDAI), Disease Activity Score in 28 joints with ESR (DAS28-ESR), and retention rates of TCZ were evaluated at related time points. 130 patients (87.7% female) with a mean age of 53 years (SD; 15.0) were included in the study. Mean RA duration was 14 years and median duration of follow-up was 18.5 months. Number of patients with ongoing TCZ treatment at 6, 12, and 24 months were 121 (93%), 85 (65%), and 46 (35%), respectively. Remission rates at 6, 12, and 24 months per CDAI (< 2.8) and DAS28-ESR (< 2.6) scores were 61.5, 44.6, 30%, and 54.6, 40.8, 27.7%, respectively. Both CDAI and DAS28-ESR scores significantly improved at 6, 12 and 24 months (p < 0.001 for both). At 24 months, 23 patients (17.6%) discontinued TCZ, of whom majority (17/23) were due to unsatisfactory response. Retention rates of TCZ at 6, 12, and 24 months were 93, 84.3, and 72.2%, respectively. In this real-world study, TCZ as a first-line biologic therapy was found to be efficacious and showing high retention rates. These real-world study results are in line with previous randomized studies.

Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease characterized by erosive synovitis that results in pain and swelling of peripheral joints, joint deformity, functional disability, and decreased health-related quality of life (QoL). In addition, the disease may involve extra-articular manifestations including skin, heart, lung, eye, nervous, renal, and gastrointestinal systems 1 . It is the most common inflammatory arthritis, affecting about 0.5-1% of the population in the United States and northern Europe 2 . The goals of therapy for RA are to decrease joint inflammation and pain, preserve the ability of patients to function in activities of daily living and work, and prevent joint deformity and joint destruction. Optimal treatment regimen consists of a combined approach that includes both pharmacologic and non-pharmacologic therapies. Since complete recovery from RA is not possible, clinical remission is considered a good outcome 3 . Early treatment with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), such as methotrexate, has become the standard of care as several studies have suggested that it can slow down disease progression, and potentially induce clinical remission 4 . If the patient fails to respond adequately to methotrexate, the current standard approach is to add other synthetic or biological DMARD to the treatment regimen. Although the therapeutic efficacy and safety of tumour necrosis factor (TNF) inhibitors have been proven in a number of studies, it has been found that 30-40% of patients develop an inadequate response, either due to a lack of primary response or adverse events 5 . Moreover, most TNF inhibitors require concomitant methotrexate for maximum clinical efficacy, whereas tocilizumab (TCZ) has similar efficacy either it is combined with methotrexate or used as monotherapy 6 .
Tocilizumab (TCZ) is a recombinant humanized monoclonal antibody targeting the human IL-6 receptor. Intravenous TCZ (TCZ-IV) has been licensed in Europe in 2009, for the management of RA patients refractory to csDMARDs and TNF inhibitors, followed by the approval of subcutaneous TCZ (TCZ-SC) formulation in the year 2014 7 . TCZ-IV is approved in over 100 countries and has demonstrated efficacy with a well-established safety profile in patients with RA. Two phase III studies of TCZ, namely SATORI and SAMURAI studies, each have revealed the efficacy of TCZ monotherapy in RA patients who are refractory to treatment with DMARDs including methotrexate 8,9 . In a further randomized clinical trial, 69% of patients achieved an effective clinical response with a non-TNF biological vs. 52% of patients who took a second anti-TNF drug 10 .
The efficacy and safety of TCZ-SC has been evaluated in recent phase III clinical trials. SUMMACTA study evaluated the efficacy and safety of TCZ-SC in combination with DMARDs in patients with moderate-tosevere RA and inadequate response to one or more DMARD(s). The study demonstrated non-inferiority of TCZ-SC 162 mg weekly (qw) to TCZ-IV 8 mg/kg every 4 weeks (q4w) with regard to the American College of Rheumatology criteria (ACR20) response at week 24. TCZ-SC displayed a similar safety profile as TCZ-IV 11 .
This study was aimed to provide data regarding the retention rate, efficacy, and safety of TCZ use for RA in a real-world setting utilizing a patient registry.

Methods
Study design. This study was designed as a national, multicenter, retrospective, and non-interventional study in which data collection was conducted between March 2020 and June 2020 with contributions of 15 different rheumatology centers in Turkey. Patients with a diagnosis of RA who were receiving TCZ as firstline biological treatment with follow-up data of at least 6 months were included in the study. Secondary data were obtained from the TURKBIO Registry, which is a web-based registry of patients with rheumatic diseases receiving biologic DMARDs.
Covariates. The primary objective was to assess the efficacy of TCZ as first-line biological treatment at 6, 12, and 24 months by mean change in Clinical Disease Activity Index (CDAI) and Disease Activity Score in 28 joints with ESR (DAS28-ESR) scores from baseline. Secondary objectives were to analyse the efficacy of TCZ by route of drug administration (TCZ-SC or TCZ-IV), to evaluate the retention rate and safety profile of TCZ over time, and to assess QoL by Health Assessment Questionnaire Disability Index (HAQ-DI) scores. Data were obtained from TURKBIO Registry for demographics, smoking status (current, previous or never), concomitant diseases, disease duration of RA, previous and concomitant csDMARD treatments, presence and number of swollen and tender joints, European Alliance of Associations for Rheumatology (EULAR) response rate (good or moderate), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) levels, CDAI score 12 , DAS28-ESR score 13 , HAQ-DI score 14  www.nature.com/scientificreports/ CDAI score was defined as remission (≤ 2.8), low disease activity (> 2.8 and ≤ 10), moderate disease activity (> 10 and ≤ 22) and high disease activity (> 22). Similarly, DAS28-ESR disease activity was defined as remission (< 2.6), low disease activity (≥ 2.6 and ≤ 3.2), moderate disease activity (> 3.2 and ≤ 5.1) and high disease activity (> 5.1).

Statistical analysis.
This was a secondary data use study of an existing registry, and therefore no study sample size was calculated. All data gathered during the course of the study were summarized using descriptive statistics; numeric variables were expressed as mean (standard deviation) or median (minimum and maximum or quartiles); categorical variables were expressed as number and percentage. Normality was assessed with visual (histogram and probability graphs) and analytical methods (Kolmogorov-Smirnov/Shapiro-Wilk tests
Of 118 patients who were using TCZ-IV, the decrease in CDAI and DAS28-ESR scores at 6, 12 and 24 months was statistically significant (p < 0.001 for all). In patients using TCZ-SC, only the decrease in CDAI and DAS28-ESR scores at 6 months was statistically significant in comparison to baseline scores (p = 0.003 for both). The change in disease activity scores per route of tocilizumab administration is given in Table 3. During the study, the number of patients who switched from TCZ-IV to TCZ-SC was four. None of the patients switched from TCZ-SC to TCZ-IV.

Discussion
In this study, the data from TURKBIO Registry were gathered with the aim to evaluate TCZ use as first-line biological treatment in patients with RA in a real-world setting. Our results indicated response rates similar to the ones found in TCZ phase III trials with high retention rates and a good safety profile 8,9 . Our patient population revealed a moderate to severe RA at baseline for almost all patients per DAS28-ESR scores and almost 90% of the patients had moderate to high disease activity per CDAI scores. Overall, there was a significant decrease in CDAI and DAS28-ESR scores at 6, 12 and 24 months compared to baseline. At six months after the initiation of TCZ treatment nearly 75% of the patients had EULAR good response. Regarding the real-life studies, the proportion of first line TCZ users who achieved DAS28-ESR remission was 51 and 52% at 6th and 24th months, respectively in the Italian biologics' registry Gruppo Italiano Studio Early Arthritis (GISEA) 15 . The rate of EULAR good responders in the 6th month was found 42% in the British Society for Rheumatology Biologics Registry for RA (BSRBR-RA) 16 . In terms of 6th month DAS28-ESR results, our study was found to be similar with other real-life studies. However, although the median DAS28-ESR scores decreased in time, the proportion of patients who achieved remission at one and two years was lower than the proportion of patients who achieved remission at 6 months, which is not consistent with many real-life data. The reason for this difference may be the decrease in the number of patients followed up at the 12th and 24th months in our study.
The decreases in HAQ-DI scores at 6, 12 and 24 months of TCZ treatment were also found to be significant in comparison to baseline scores. These findings are in line with the effectiveness and QoL results obtained from The majority of patients were given TCZ treatment via an intravenous route at baseline (90.8%), which strongly indicates that TCZ-IV is the more commonly preferred formulation in routine clinical practice in Turkey. The reason behind this may be that either TCZ-IV has demonstrated efficacy with a well-established safety profile in a range of clinical trials or TCZ-SC is approved for RA patients several years after TCZ-IV 18 . Despite the low number of patients administered with TCZ-SC, we found similar disease activity at 6 and 12 months in TCZ-IV and TCZ-SC subgroups. Only four patients switched from IV to SC formulation which also may indicate a preference for IV administration of TCZ.
In the current study, at two years almost 75% of the patients were still on TCZ treatment, which were considered as satisfactory for drug retention. The drug continuation at one year was estimated lower (64%) in the Swedish registry 19 , however, the rate (77%) was found similar in the BSRBR-RA registry 16 . In a recent study, www.nature.com/scientificreports/ in which data from 16 countries were collected to evaluate efficacy, safety and usage patterns of TCZ in real life settings, Kaplan-Meier estimates for the proportions of patients still receiving TCZ at 24 weeks were 81.3% for biologic-naive patients, which was also lower than our study 20 . However, given the low number of followed-up patients in our study, these results should be approached with caution. Despite recorded discontinuation of the concomitant medications, namely methotrexate and leflunomide, patients still continued with TCZ treatment. Even though methotrexate is indispensable in the treatment of RA, TCZ monotherapy seems to occupy a significant place in the management of RA patients who had an inadequate response or who develop intolerance to methotrexate and other DMARDs 21 . The safety profile of TCZ based on adverse events was also evaluated, and overall, no unexpected adverse events were seen. TCZ was considered to be a tolerable biological DMARD.
Our study has a few limitations. The number of patients using TCZ-SC was limited. Therefore, it is not possible to implicate definite results. Since a retrospective patient registry was used as a data source in the study, data from all patients were not available for several variables.