Rheumatol Ther (2022) 9:589–608 https://doi.org/10.1007/s40744-021-00423-8 ORIGINAL RESEARCH Real-World Treatment Patterns and Clinical Outcomes of Baricitinib in Rheumatoid Arthritis Patients in Spain: Results of a Multicenter, Observational Study in Routine Clinical Practice (The ORBIT-RA Study) Blanca Hernández-Cruz . José Rosas . César Dı́az-Torné . Joaquı́n Belzunegui . Rosario Garcı́a-Vicuña . José Inciarte-Mundo . Ana Pons . Ana M. Millán . Sicylle Jeria-Navarro . Jesús A. Valero . Noelia Garcı́a-Castañeda . Cristina Valero . Irene Llorente . Alberto Calvo . Silvia Dı́az-Cerezo . Mercedes Núñez Received: November 10, 2021 / Accepted: December 22, 2021 / Published online: January 18, 2022 Ó The Author(s) 2022, corrected publication 2022 ABSTRACT Methods: This retrospective longitudinal cohort study conducted in five rheumatology Introduction: Baricitinib is an oral Janus kinase units included adults with RA initiating barici- (JAK)1/JAK2 inhibitor approved to treat tinib (Sep-2017–May-19) with at least a rheumatoid arthritis (RA). This study aimed to 6-month-follow-up. Demographic/clinical investigate patients’ characteristics, prescription characteristics, prescription patterns, and patterns, effectiveness, and treatment persis- changes in disease activity and pain level were tence in patients receiving baricitinib in real- collected until treatment discontinuation/end world practice in Spain. of follow-up. Treatment persistence was esti- mated by Kaplan–Meier methods. Supplementary Information The online version Results: Data from 182 patients were included contains supplementary material available at https:// (mean (SD)): 83.5% women, 62.2 (12.3) years, doi.org/10.1007/s40744-021-00423-8. B. Hernández-Cruz (&) R. Garcı́a-Vicuña  N. Garcı́a-Castañeda  Rheumatology Department, University Hospital C. Valero  I. Llorente  A. Calvo Virgen Macarena, Calle Dr. Fedriani, 3, 41009 Rheumatology Department, University Hospital La Seville, Spain Princesa, IIS-IP, Calle de Diego de León, 62, 28006 e-mail: blancahcruz@gmail.com; Madrid, Spain blancae.hernandez.sspa@juntadeandalucia.es J. Inciarte-Mundo J. Rosas  A. Pons Arthritis Unit, Rheumatology Department, Hospital Rheumatology Department, Marina Baixa Hospital, Clinic of Barcelona, C. de Villarroel, 170, 08036 Av. Alcalde En Jaume Botella Mayor, 7, Villajoyosa, Barcelona, Spain 03570 Alicante, Spain S. Dı́az-Cerezo  M. Núñez C. Dı́az-Torné  A. M. Millán  S. Jeria-Navarro Medical Department, Lilly Spain, Av de la Industria Arthritis Unit, Rheumatology and Autoimmune 30, Alcobendas, 28108 Madrid, Spain Diseases Department, Santa Creu i Sant Pau Hospital, Carrer de Sant Quintı́, 89, 08041 Barcelona, Spain J. Belzunegui  J. A. Valero Rheumatology Department, Donostia University Hospital, Begiristain Doktorea Pasealekua, 20014 Guipúzcoa, Spain 590 Rheumatol Ther (2022) 9:589–608 body mass index 26.8 (5.1), disease duration 13.2 (10.8) years and Charlson Comorbidity Key Summary Points Index score 2.4 (2.0). All patients had received at least one conventional synthetic disease- Baricitinib is an oral Janus kinase (JAK)1/ modifying anti-rheumatic drugs (csDMARD) JAK2 inhibitor approved to treat before starting baricitinib and 78.0% at least moderate-to-severe rheumatoid arthritis one biologic disease-modifying anti-rheumatic (RA). Despite a robust clinical drugs (bDMARD). Furthermore, 90.1% started development, it is important to with baricitinib 4 mg/day; 43.4% in monother- complement these results with data in apy. One hundred and twelve (61.5%) of real-life conditions. patients continued baricitinib at data collection time; mean persistence was 14.1 (0.5) months. The ORBIT-RA retrospective study Overall treatment persistence was 79.7/64.8/ describes patient’s characteristics and 59.1% at 6/12/18 months. Seventy (38.5%) prescription patterns of baricitinib and to patients discontinued baricitinib during follow- estimate its effectiveness and persistence up due to loss of efficacy (68.6%) or adverse in a cohort of real-world Spanish RA events (18.6%). In those patients with available patients. scores at the different observed cut-off points, Baricitinib was mostly used in RA patients remission or low disease activity was reported in with failure to conventional synthetic 71.6 and 76.3% of patients at 6/12 months at disease modifying anti-rheumatic drugs any index: Disease Activity Score 28 joints using and biologics. In them, baricitinib proved erythrocyte sedimentation rate (DAS28-ESR) to be effective not only to achieve (73.1 and 73.5%), Simplified Disease Activity remission or low activity of the disease. Index (SDAI) (62.4 and 75.0%), and Clinical Also in the control of Patient Reported Disease Activity Index (CDAI) (66.7 and 78.1%). Outcomes, such as pain. Good or moderate European League Against Rheumatism (EULAR)-response was noted in In general, these results are consistent 80.0 and 78.2% of patients, respectively. with those obtained in baricitinib clinical Improvement from baseline in pain (Visual trials and previous observational studies, Analog Scale) was 2.5 cm and 3.0 cm at which reinforces baricitinib effectiveness 6/12 months, respectively. for the treatment of RA. Conclusions: This Spanish cohort of patients treated with baricitinib had a long-standing and refractory disease. Nevertheless, high persis- tence and improvements in disease activity and pain were found at 6 and 12 months after INTRODUCTION treatment initiation, independently of the composite disease activity measure used, rein- Rheumatoid arthritis (RA) is a chronic, multi- forcing the effectiveness of baricitinib in rou- systemic, autoimmune inflammatory disease tine clinical practice. characterized by joint inflammation with pain and swelling as its main clinical manifestations Keywords: Rheumatoid arthritis; Retrospective (1). The inflammation causes progressive joint observational study; Baricitinib; Treatment destruction and disability (1, 2). RA is associated patterns; Effectiveness; Persistence; Spain with extra-articular manifestations such as nodules, interstitial lung disease, and fatigue, as well as specific comorbidities such as depression and cardiovascular disease, which leads to an increase in mortality (1–4). RA incidence varies, depending on the country, from 0.1 to 0.5 RA Rheumatol Ther (2022) 9:589–608 591 cases per 1000 inhabitants/year, with a preva- inadequately to, or who are intolerant to one or lence of 0.2–1.1% in developed countries, and more csDMARDs, and can be prescribed as higher values in women (1–5). In Spain, the monotherapy or in combination with MTX prevalence is 0.88% in women and 0.76% in (15). men, peaking at middle age, especially over When marketing a new drug, it is important 60 years (51.3%), with an incidence of 11.3/ to know its prescription pattern and to estimate 100,000 cases in women and 5.2/100,000 cases its effectiveness in the real world. The existence in men (5, 6). of a large variability in the rheumatologists’ The 2019 EULAR (European League Against prescribing patterns (16) and the hurdles in the Rheumatism) treatment recommendations implementation of the T2T strategies (1–3, 9) focus on early intervention and treat-to-target create a need to understand drug efficacy in a (T2T) strategies using old and new disease- real-world setting. Moreover, from the clini- modifying anti-rheumatic drugs (DMARDs) (7). cians’ point of view, there are substantial dif- The treatment target should be remission or low ferences in patient characteristics between disease activity, considering factors such as RCTs, registries, and observational studies in RA comorbidities and safety issues (1–3, 7). Con- (16). Clinical trials are the methodological gold ventional synthetic DMARDs (csDMARDs), standard for the evaluation of the efficacy and mainly methotrexate (MTX), with or without safety of new drugs, but they are inherently low dose of glucocorticoids (GCC), have long characterized by the lack of external validity as been the cornerstone of treatment (1–3, 7). In compared to observational studies (16, 17). case of inadequate response to this first-line To date, limited evidence on baricitinib treatment, a switch to biologics (bDMARDs) or usage in the real world is available (18–21). Two targeted synthetic DMARDs (tsDMARDs) as observational, retrospective, and prospective second- or third-line treatments is recom- studies of 56 and 446 RA patients treated with mended for patients with poor prognostic fac- baricitinib were conducted in Italy (20, 21). An tors (1–3, 7, 8). This strategy has proven to be observational, retrospective study with 40 RA beneficial in various disease outcomes, but patients conducted in Spain, published by Rosas unmet needs and a great disease burden are still et al. (18), and a retrospective study in UK with recognized (9). The main barriers to the imple- 69 RA patients (19), concluded that baricitinib mentation of an effective T2T strategy are well showed effectiveness and safety in real-world known and settle in the health system (costs, conditions. access to healthcare, delayed referral, and diag- The present study was designed to investi- nosis with difficulty in accessing specialists), gate patients’ characteristics, patterns of pre- patients (adherence, fears about toxicity), and scription, effectiveness, and drug persistence in physician factors (knowledge and experience) a cohort of RA patients treated with baricitinib (1–3, 7, 9, 10). in a real-world setting in Spain. The Janus kinase inhibitors (JAKi) are a novel class of tsDMARD that modulate the effect of multiple cytokines proven to be pivotal in the METHODS pathogenesis of RA. Baricitinib is an oral small molecule that provides reversible inhibition of Study Design JAK1 and JAK2 with a half-life of 12.5 h (1–3, 7, 8, 11, 12). Baricitinib has shown efficacy This is an observational, retrospective, longitu- in clinical trials involving all clinically relevant dinal cohort study based on medical chart re- RA patient populations: MTX naı̈ve, MTX views, conducted in five tertiary Spanish public inadequate responders (MTX-IR), and hospitals distributed along different geographic bDMARD-IR (12–14). Since September 2017, areas. baricitinib has been reimbursed and marketed The study inclusion period was from in Spain for the treatment of moderate-to-severe September 1, 2017 (date of approval of barici- active RA in adult patients who have responded tinib in Spain) to May 31, 2019. The data 592 Rheumatol Ther (2022) 9:589–608 Fig. 1 Study design collection period started in December 2019, to prescription patterns among RA patients treated guarantee a minimum follow-up of 6 months with baricitinib in real clinical practice in Spain. for each patient (Fig. 1). The investigators The secondary objectives were aimed at esti- extracted data from each patient’s correspond- mating baricitinib treatment persistence, effec- ing electronic clinical record form until treat- tiveness using different validated index/scales, ment discontinuation or end of study follow-up and impact of the treatment on the concomi- (per patient data collection date). The study did tant medication for RA. not have an impact on any treatment decision during clinical practice due to the retrospective Study Variables nature of the data collection. The study was conducted in accordance with the ethical prin- The following variables were collected at each ciples of the Declaration of Helsinki and Good site: Clinical Practice guidelines and was approved by the Ethics Committees of Virgen Macarena Baseline Patient Demographics and Clinical and Virgen Rocio University Hospitals in Seville Characteristics (Spain). Informed consent was collected when Patients’ characteristics included age, gender, required by each ethics committee. body mass index (BMI), smoking status, disease duration, working status, and Charlson Patient Selection Criteria Comorbidity Index (CCI). CCI includes age, myocardial infarction, congestive heart failure Patients eligible for inclusion in this study had a (CHF), peripheral vascular disease, cerebrovas- RA diagnosis according to the 2010 ACR/EULAR cular disease, chronic obstructive pulmonary criteria, initiated baricitinib (according to the disease (COPD), connective tissue disease, pep- summary of product characteristics (SmPC)) tic ulcer disease, liver disease: mild/moderate or during the inclusion period, were severe, diabetes mellitus: uncomplicated/end- aged C 18 years, and had a complete medical organ damage, hemiplegia, moderate-to-severe record at the participating site or at least since chronic kidney disease (CKD), any solid tumor: the RA diagnosis. Patients were excluded if they without metastasis/metastatic solid tumor, leu- had previously participated in any baricitinib kemia, lymphoma, and acquired immunodefi- clinical trial. No other explicit exclusion criteria ciency syndrome (AIDS). Each condition were defined. receives 1, 2, 3, or 6 points, depending on its independent mortality risk. Total score for CCI, Study Objectives which is derived by the sum of all comorbid conditions, rates from 0 to 37, with higher val- The primary objective was to describe the ues indicating a more severe condition and a demographic and clinical characteristics and worse prognosis. Rheumatol Ther (2022) 9:589–608 593 Table 1 Baseline patient sociodemographic and clinical characteristics Variable Total Total population, n (%) 182 (100) Age (years)/mean (SD) 62.2 (12.3) BMI (kg/m2): n/mean (SD) 102/26.8 (5.1) Time since RA diagnosis (years): n/mean (SD) 177/14.6 (10.8) Time since RA diagnosis to start of baricitinib treatment (years): n/mean (SD) 177/13.2 (10.8) Charlson Comorbidity Index: n/mean (SD) 182/2.4 (2.0) TJC (0–28): n/mean (SD) 177/6.7 (5.8) SJC (0–28): n/mean (SD) 177/4.4 (3.7) CRP (mg/l): n/mean (SD) 176/8.6 (15.8) ESR (mm/h): n/mean (SD) 171/29.7 (24.0) Gender n (%) Male 30 (16.5) Female 152 (83.5) Work status n (%) Employed 42 (23.1) Unemployed 18 (9.9) Retired 59 (32.4) Sick leave 12 (6.6) Unknown 51 (28.0) BMI (categorized) n (%) 1-Underweight (BMI \ 18.35) 1 (1.0) 2-Normal weight (18.5 B BMI \ 25) 40 (39.2) 3-Pre-obesity (25 B BMI B 30) 34 (33.3) 4-Obesity class I (30.0 \ BMI \ 35) 20 (19.6) 5-Obesity class II (35 [ BMI B 40) 5 (4.9) 6-Obesity class III (BMI [ 40) 2 (2.0) Smoking status n (%) Current smoker 27 (14.8) Ex-smoker ([ 6 months without smoking) 31 (17.0) Non-smoker 87 (47.8) Unknown 37 (20.3) Positive RF (rheumatoid factor), n (%) 144 (79.1) Positive ACPA (anti-citrullinated protein antibodies), n (%) 146 (80.2) 594 Rheumatol Ther (2022) 9:589–608 Table 1 continued Variable Total Bone erosions, n (%) 118 (64.8) Extra-articular manifestations, n (%) 58 (31.9) Type of extra-articular manifestations (multi-response), n (%) Rheumatoid nodules 34 (18.7) Sjögren syndrome 17 (9.3) Interstitial pneumonitis 14 (7.7) Atlantoaxial subluxation (AAS) 6 (3.3) Pleuritis 6 (3.3) Pneumological complications 6 (3.3) Rheumatoid vasculitis 3 (1.6) Felty’s syndrome 2 (1.1) Other manifestations (pericarditis, amyloidosis, Raynaud’s syndrome) 5 (2.6) DAS28-ESR categorizations, n (%) 101 (100) Remission: DAS28 \ 2.6 6 (5.9) Low activity: 2.6 B DAS28 \ 3.2 9 (8.9) Moderate activity: 3.2 B DAS28 \ 5.1 64 (63.4) High activity: DAS28 C 5.1 22 (21.8) SDAI categorizations, n (%) 135 (100) Remission: 0.0 B SDAI B 3.3 0 (0) Low activity: 3.3 \ SDAI B 11.0 10 (7.4) Moderate activity: 11.0 \ SDAI B 26.0 73 (54.1) High activity: 26.0 \ SDAI B 86.0 52 (38.5) CDAI categorizations, n (%) 135 (100) Remission: 0.0 B CDAI B 3.3 1 (0.7) Low activity: 3.3 \ CDAI B 11.0 12 (8.9) Moderate activity: 11.0 \ CDAI B 26.0 76 (56.3) High activity: 26.0 \ CDAI B 86.0 46 (34.1) Patient’s pain assessment, n 155 Mean (SD) 6.61 (1.97) Median (P25; P75) 7.0 (5.0; 8.0) Laboratory values at baseline n/mean (SD) Hemoglobin (g/dl) 155/12.0 (4.0) Rheumatol Ther (2022) 9:589–608 595 Table 1 continued Variable Total Platelets (9 103/mm3) 153/290.4 (86.4) 3 3 Leukocytes (9 10 /mm ) 155/7.7 (2.9) Triglycerides (mg/dl) 111/118.6 (59.3) Total cholesterol (mg/dl) 133/201.6 (37.2) Creatinine (mg/dl) 152/0.72 (0.16) CK (U/l) 25/ 81.4 (65.8) GFR (ml/min) 146/90.2 (18.1) TJC tender joint count, SCJ swollen joint count, CRP C-reactive protein, ESR erythrocyte sedimentation rate, CK creatinine kinase, GFR glomerular filtration rate, DAS28-ESR Disease Activity Score Erythrocyte Sedimentation Rate, SDAI Simplified Disease Activity Index, CDAI Clinical Disease Activity Index The disease characteristics collected were drugs (NSAIDs) were also recorded after barici- time from RA diagnosis, previous and con- tinib initiation. comitant treatments, seropositivity status, presence of extra-articular manifestations, and Baricitinib Effectiveness and Pain Assessment presence of bone erosions. The Disease Activity Effectiveness assessments available at 6 and Score 28 joints using erythrocyte sedimentation 12 months using DAS28-ESR, SDAI, CDAI, and rate (DAS28-ESR), Simplified Disease Activity EULAR response, and pain level based on VAS Index (SDAI), Clinical Disease Activity Index were obtained. (CDAI), EULAR response criteria, and pain by Persistence was summarized by mean treat- visual analogic scale (VAS) ranging from 0 (no ment duration on baricitinib until discontinu- pain) to 10 (maximum pain) cm were collected. ation or end of follow-up, and by the percentage Laboratory tests included acute phase reactants of patients who maintained baricitinib at 6, 12, (C-reactive protein (CRP) in mg/l and erythro- and 18 months of follow-up. sedimentation rate (ESR) in mm/h), hemoglo- Changes from baseline in DAS28-ESR, SDAI, bin (g/l), platelets (mm3 or 109/l), leukocytes and CDAI, and pain scores were calculated as (109/l or cells/l), triglycerides (mg/dl or mmol/ the difference between baseline (baricitinib l), total cholesterol (mg/dl or mmol/l), HDL initiation) and follow-up scores (at 6 and (mg/dl or mmol/l), LDL (mg/dl or mmol/l), 12 months). EULAR response criteria, evaluated serum creatinine, creatine kinase (CK U/l), and by improvement in the DAS28-ESR from base- glomerular filtration rate (GFR, ml/min). line, were described (good response, moderate response, and non-response) at 6 and Baricitinib Prescription Patterns 12 months. Date of baricitinib treatment initiation, posol- ogy and changes in dosing, and date and rea- Statistical Analysis sons of definitive treatment discontinuation (if applicable) were collected. History of previous A descriptive statistical analysis of the patients’ csDMARDs or bDMARDs was recorded to assess demographic and clinical characteristics was previous treatment exposures. Concomitant performed. Summaries were estimated for treatment medications for RA (GCC, patients with valid observations. Continuous csDMARDs, and non-steroid anti-inflammatory variables were summarized using the mean, standard deviation (SD), median, and 25th and 596 Rheumatol Ther (2022) 9:589–608 Table 2 Number of RA treatments received prior to baricitinib treatment Variable N (%) Total population 182 (100) Number of previous csDMARDs 1 csDMARDs 20 (11.0) 2 csDMARDs 67 (36.8) 3 or more csDMARDs 95 (52.2) Total with previous csDMARDs 182 (100%) a Number of previous bDMARDs 0 bDMARDs 40 (22.0) 1 bDMARDs 44 (24.2) 2 bDMARDs 31 (17.0) 3 or more bDMARDs 67 (36.8) Total with previous bDMARDs 142 (78%) Number of previous bDMARDs (TNFi) Total with previous TNFi 120 (66%) 0 TNFi 62 (34.1) 1 TNFi 51 (28.0) 2 TNFi 43 (23.6) 3 or more TNFi 26 (14.3) Number of previous bDMARDs (no TNFi) 0 No TNFi 79 (43.4) 1 No TNFi 54 (29.7) 2 No TNFi 33 (18.1) 3 or more No TNFi 16 (8.8) Total with previous bDMARDs (no TNFi) 103 (56.6%) A patient could have received more than one treatment and different types of treatments. bDMARDs include adalimumab, etanercept, infliximab, golimumab, certolizumab pegol, tocilizumab, rituximab, and abatacept a 7 patients treated with bDMARDs received subsequent treatment with tofacitinib, a JAK inhibitor. Accordingly, the percentage of patients treated with bDMARDs is equivalent to the percentage of patients treated with bDMARDs and JAK inhibitors 75th percentiles (P25 and P75, respectively). Categorical variables were summarized using frequencies and percentages. Changes from baseline in clinical scores (DAS28-ESR, SDAI, CDAI, and EULAR response criteria) and patient’s pain assessment were reported using 95% confidence intervals (CI) of the baseline follow-up difference and compared using paired t test; however, no inferential statistics should be considered as the testing hypothesis. Fig. 2 Distribution of number of treatments received for Baricitinib treatment persistence was esti- RA prior to baricitinib treatment mated as the mean time to discontinuation Rheumatol Ther (2022) 9:589–608 597 Table 3 Baricitinib prescription patterns Variable Total Baricitinib dose, n (%) 164 (90.1) 4 mg/day 18 (9.9) 2 mg/day Baricitinib monotherapy, n (%) 79 (43.4) Baricitinib ? csDMARD, n (%) 103 (56.6) Baricitinib ? MTX 68 (37.4) Baricitinib ? azathioprine 4 (2.2) Baricitinib ? sulfasalazine 27 (14.8) Days on treatment Mean (SD) 385.1 (219.6) Median (P25; P75) 373.0 (197.0; 569.0) Time until change in posology (days) Mean (SD) 272.3 (199.8) Median (P25; P75) 230.0 (105.0; 366.0) Patients with a change in posology since treatment initiation, n (%) N valid 182 (100) No 164 (90.1) Yes 18 (9.9) Number of changes in posology, n (%)* 20 (100) Decreasing dose (to 2 mg/day) 14 (70.0) Increasing dose (to 4 mg/day) 6 (30.0) Description of changes from 4 to 2 mg/day dose, n (%) 14 (100) Time until change in posology (days) Mean (SD) 325.6 (194.7) Median (P25; P75) 327.0 (131.0; 388.0) Reason of dose adjustment, n (%) Adverse reaction 2 (14.3) Dose reduction due to remission/low disease activity 9 (64.3) Other reason 3 (21.4) Description of changes from 2 to 4 mg/day dose, n (%) 6 (100) Time until change in posology (days) Mean (SD) 92.3 (40.2) Median (P25; P75) 91.5 (56.0; 126.0) 598 Rheumatol Ther (2022) 9:589–608 Table 3 continued Variable Total Reason of dose adjustment, n (%) Lack of efficacy 0 (0) Other reason 6 (100) Discontinuation, n (%) N valid 182 (100) No (ongoing treatment) 112 (61.5) Yes, the treatment was interrupted 70 (38.5) Lack of efficacy 48 (68.6) Primary: no response 29 (60.4) Secondary: decreasing response after an initial satisfactory response 19 (39.6) Adverse reaction 13 (18.6) Patient’s decision 3 (4.3) Lost to follow-up 2 (2.9) Other reasons 4 (5.7) *There were a total of 20 changes in posology registered in 18 patients. One of these patients followed a 2–4-2 mg/day pattern and the other one a 4–2-4 mg/day one using the Kaplan–Meier method, and treatment csDMARDs (baricitinib monotherapy (without maintenance at 6, 12, and 18 months after csDMARDs)/baricitinib? csDMARD). baseline. Patients who had discontinued baric- itinib at data extraction date due to loss of fol- low-up, lack of efficacy, adverse events, or other RESULTS reasons, were considered for persistence analysis up to the date of discontinuation. For patients Demographic and Clinical Characteristics who had not discontinued baricitinib, data was censored at the end of the follow-up (adminis- One hundred and eighty-two patients were trative censoring). Deaths were not applied for included in the study, mostly women (83.5%) censoring since that information was not with a mean (SD) age of 62.2 (12.3) years, and a available. mean time since RA diagnosis of 14.6 (10.8) Additionally, analyses were conducted years. Mean BMI was 26.8 (5.1) kg/m2 and among different groups of patients to assess the 14.8% were current smokers. Most of the persistence rates at 6 and 12 months according patients were retired (32.4%) (Table 1). to: (1) the number of previous bDMARDs (0/ A significant proportion of patients pre- \ 3/ C 3), (2) seropositivity status (rheumatoid sented poor prognosis variables: RF? (79.1%), factor (RF) and anti-citrullinated protein anti- ACPA? (80.2%), bone erosions (64.8%), extra- bodies (ACPA): (ACPA? and RF?/ACPA? and articular manifestations (31.9%), and a mean RF-/ACPA- and RF?/ACPA- and RF-), (3) age CCI of 2.4 (2.0). Laboratory tests prior to (\ 65 years/ C 65 years), (4) gender, (5) CCI baricitinib treatment showed a mean CRP of 8.6 (B 2/ [ 2), and (6) concomitant use of (15.8) mg/l and an ESR of 29.7 (24.0) mm/h. Rheumatol Ther (2022) 9:589–608 599 Results of the remaining laboratory tests are characteristics of the patients who discontinued shown in Table 1. treatment due to lack of efficacy are provided in Most patients had received C 3 prior Table 1S. They were different in weight, RF, csDMARDs (52.2%). The overall number of ACPA positivity, and erosions. The median patients who had previously been treated with [P25; P75] time of baricitinib treatment during one, two, or three or more bDMARDs was 24.2, the study period was 373 days (197; 569) 17.0, and 36.8%, respectively (Table 2 and (Table 3). Fig. 2). Furthermore, 3.8% of patients had pre- A total of 150 patients (82.4%) received viously been treated with another JAKi (tofaci- concomitant treatments together with barici- tinib), 76.4% with GCC and 33.0% with tinib (in any time of baricitinib treatment): NSAIDs. DMARDs (56.6%), systemic corticosteroids The most common treatments received (54.9%) and NSAIDs (20.3%). From the total immediately prior to baricitinib were number of concomitant GCC treatments csDMARDs (69.8%), bDMARDs (61.5%), GCC (n = 112), 23.2% (n = 26) changed after barici- (54.9%), and NSAIDs (20.9%). MTX (63.0%) and tinib initiation to reduce or stop in 96.2% of the leflunomide (33.1%) were the most frequently cases. Median time until reduction or with- used csDMARD. Among patients receiving drawal of GCC was 116 and 111 days, respec- bDMARDs, 44.7% were treated with a TNF tively. With respect to NSAIDs administered inhibitor (TNFi) and 55.3% with a non-TNF during baricitinib treatment, 73.0% were occa- biologic (mainly abatacept, 56.4%). sionally taken. Patients included in the study had moderate (63.4, 56.3, and 54.1%) and high (21.8, 34.1, Baricitinib Effectiveness and 38.5%) disease activity at baseline accord- ing to DAS28-ESR, CDAI, and SDAI, respec- At baseline, the number of tender joint counts tively. Mean pain assessment at baseline was 6.6 (TJC) and swollen joint counts (SJC) was 6.7 (2.0) cm (Table 1). (5.8) and 4.4 (3.7), respectively (Table 1). Patients treated with baricitinib showed a Baricitinib Prescription Patterns reduction (mean (95%CI)) of 4.4 (- 5.5; - 3.3) and 5.2 (- 6.5; - 4.0 to 4) for TJC; and 2.8 Most patients included in the study started (- 3.6; - 2.0) and 4.0 (- 4.9; - 3.1) for SJC at 6 treatment with baricitinib at 4 mg/day (90.1%), and 12 months, respectively. Pain assessment and 43.4% received baricitinib as monotherapy (VAS 10 cm) was 6.6 (2.0) at baseline (Table 1) (Table 3). Eighteen patients (9.9%) changed the and showed a reduction of 2.5 (- 3.0; - 2.0) starting dose during follow-up; of the total and 3.0 (- 3.6; - 2.5) cm at 6 and 12 months, number of changes (n = 20), 14 (70.0%) were respectively. These changes were statistically dose reductions to 2 mg/day due to remission significant (p value \ 0.0001). Figure 3 and (64.3%) and adverse events (14.3%). The mean Table 4 show the evolution progress and chan- time until change in posology was 272 (200) ges in the score of the different indexes during days, and 326 (195) days until decreasing the the follow-up period. dose from 4 to 2 mg daily. Six (30.0%) dose The activity indexes measured at baseline increases from 2 to 4 mg daily were observed. (DAS28-ESR, CDAI, and SDAI) were 4.4 (1.1), The mean time until increasing the dose from 2 23.6 (10.5), and 25.0 (10.4), respectively to 4 mg daily was 92 (40) days. Baricitinib (Table 1). In those patients with available scores treatment was discontinued during follow-up in at the different observed cut-off points, reduc- 70 patients (38.5%). The main reasons for dis- tions at 6 and 12 months were (mean (95% CI)) continuation were lack of efficacy (68.6%; 1.7 (- 2.0; - 1.4) and 1.7 (- 2.1; - 1.2) for (n = 48/182); 60.4% primary, 39.6% secondary) DAS28-ESR; 13.0 (- 15.3; - 10.6) and 13.7 and adverse reactions (18.6%; (n = 13/182). The (- 16.7; - 10.7) for CDAI; and 13.4 (- 15.8; main patient sociodemographic and clinical - 11.0) and 14.4 (- 17.4; - 11.3) for SDAI 600 Rheumatol Ther (2022) 9:589–608 Rheumatol Ther (2022) 9:589–608 601 b Fig.3 Evolution of the disease activity variables and (- 8.1; 0.1) (n = 113) and - 6.3 (- 11.9; - 0.7) indexes after baricitinib initiation at 6 and 12 months (n = 65) mm/h) was observed. Changes in lab- oratory values showed a reduction in hemo- globin (- 0.4 [- 1.0; 0.1] g/l) and leukocytes (- 0.4 [- 2.1; 0.9] 109/l); and a small increase in (Table 4, Fig. 3). The changes from baseline at 6 platelets 42 [- 10.0; 83.0] 109/l, total choles- and 12 months were statistically significant for terol 14 [- 3.0; 35.0] mg/dl, creatinine 0.1 [0.0; all indexes (p value \ 0.0001). The percentage 0.1], and CK 44 [- 33.0; 62.0] (median [P25; of patients who presented remission or low P75] values) when considering baseline values disease activity according to DAS28-ESR, CDAI, and last available record in the medical and SDAI was 73.1% (n = 57/78), 66.7% (n = 62/ chart after baricitinib initiation (Table 5). 93), and 62.4% (n = 58/93) at 6 months; and 73.5% (n = 36/49), 78.1% (n = 50/64), and Baricitinib Persistence 75.0% (n = 48/64) at 12 months, respectively. Based on previous data, remission or low disease At the time of data collection, 61.5% of patients activity was reported in 71.6% (n = 83/116) and were on treatment with baricitinib, and the 76.3% (n = 58/76) of patients at 6/12 months at mean time on treatment was 14.1 (0.5) months. any index. Baricitinib showed a persistence at 6, 12, and At 6 months, 80.0% (n = 75) of patients 18 months of 79.7, 64.8, and 59.1%, respec- showed moderate or good response according to tively. The persistence varied among the differ- EULAR criteria. A similar response was observed ent subpopulations studied, ranging from 90.0, from 6 to 12 months of follow-up in patients 81.9, and 72.6% in patients with no previous who continue in treatment (78.2%) (n = 46). bDMARDs to 80.8, 65.5, and 58.0% in patients A mean (95% CI) reduction at 6 and who failed \ 3 previous bDMARDs and to 71.9, 12 months compared to baseline in levels of 53.4, and 51.3% in patients who failed C 3 CRP (- 4.7 (- 7.7; - 1.8) (n = 115) and - 4.9 bDMARDs at 6, 12, and 18 months, respectively (- 9.0; - 0.9) (n = 85) mg/l) and ESR (- 4.0 (Fig. 4). Regarding seropositive status, Table 4 Changes in disease activity indexes during baricitinib treatment At 6 months after BARI At 12 months after BARI Variable N Score Score after Changes p value N Score Score after Changes p value prior to 6 months from prior to 12 months from starting with baseline starting on BARI baseline BARI BARI BARI DAS28- 75 4.3 (1.1) 2.6 (1.2) - 1.7 \ 0.0001 46 4.2 (1.0) 2.5 (1.2) - 1.7 \ 0.0001 ESR* (1.4) (1.5) SDAI* 91 24.3 10.9 (10.3) - 13.4 \ 0.0001 62 23.3 8.9 (8.7) - 14.4 \ 0.0001 (10.1) (11.6) (10.3) (12.0) CDAI* 91 23.0 10.1(9.9) - 13.0 \ 0.0001 62 21.9 8.2 (8.5) - 13.7 \ 0.0001 (10.0) (11.4) (10.4) (11.8) Pain VAS 93 6.6 (2.0) 4.1 (2.5) - 2.5 \ 0.0001 75 6.5 (2.2) 3.4 (2.2) - 3.0 \ 0.0001 (0–10 cm) (2.6) (2.4) *Mean (SD), BARI baricitinib; DAS28-ESR Disease Activity Score Erythrocyte Sedimentation Rate, SDAI Simplified Disease Activity Index, CDAI Clinical Disease Activity Index. Change calculation used the n available at each cut-off point 602 Rheumatol Ther (2022) 9:589–608 Table 5 Evolution of laboratory values after baricitinib initiation Variable Baseline With baricitinib Change from treatment* baseline Hemoglobin (g/dl) Mean (SD) 12.0 (4.0) 11.5 (3.9) – 0.6 (1.5) Median (P25; P75) 13.2 (11.7;14.0) 12.7 (11.4;13.6) – 0.4 (– 1.0;0.1) N valid 155 156 154 3 3 Platelets (9 10 /mm ) Mean (SD) 290.4 (86.4) 332.6 (95.6) 41.3 (72.2) Median (P25; P75) 275.0 (235.0; 323.5 (258.0; 382.0) 42.0 (– 10.0; 83.0) 336.0) N valid 153 154 153 3 Leukocytes (9 10 / Mean (SD) 7.7 (2.9) 7.2 (3.0) – 0.5 (3.2) mm3) Median (P25; P75) 7.7 (5.8; 9.3) 6.9 (5.4; 9.1) – 0.4 (– 2.1; 0.9) N valid 155 156 155 Triglycerides (mg/dl) Mean (SD) 118.6 (59.3) 117.6 (72,2) 5.1 (63.6) Median (P25; 106.0 (77.0; 129.3) 100.0 (70.0; 138.0) 0.0 (– 23.0; 22.0) P75)) N valid 111 112 95 Total cholesterol (mg/ Mean (SD) 201.6 (37.2) 216.6 (41.0) 16.7 (35.0) dl) Median (P25; P75) 199.0 (179.0; 217.0 (188.0; 242.0) 14.0 (– 3.0; 35.0) 223.0) N valid 133 133 121 Creatinine (mg/dl) Mean (SD) 0.7 (0.2) 0.8 (0.2) 0.1 (0.1) Median (P25; P75) 0.7 (0.6; 0.8) 0.8 (0.6; 0.9) 0.1 (0.0; 0.1) N valid 152 151 150 CK (U/l) Mean (SD) 81.4 (65.8) 125.8 (91.0) 26.7 (80.3) Median (P25; P75) 54.0 (40.0; 97.0) 97.5 (81.0; 143.0) 44.0 (– 33.0; 62.0) N valid 25 22 15 *Change from baseline to the last available value registered in the medical chart ACPA? RF? subpopulation showed the best However, higher values were found in patients persistence with values of 82.2, 71.0, and 64.5% who had less than 2 CCI in comparison with at 6, 12, and 18 months, respectively; in the those who had C 2, and in those who were on ACPA- RF- subgroup persistence values were baricitinib in combination with csDMARDs, as 70.4, 45.4, and 45.4% at 6, 12, and 18 months, opposed to those in monotherapy (Fig. 4). respectively. Additional information on the baseline patient There were no relevant differences in persis- sociodemographic and clinical characteristics of tence of treatment according to age or gender. these two subgroups according to treatment Rheumatol Ther (2022) 9:589–608 603 Fig. 4 Persistence of baricitinib treatment by subgroups of interest (combination and monotherapy) is provided in DISCUSSION Table 2S. Patients in monotherapy seemed to be older, had longer disease, high levels of CRP, The ORBIT-RA study is an observational study and a lower percentage of smokers, although no conducted in Spain to describe the use of formal statistical tests for comparison were baricitinib in real-world conditions. This study made. showed that baricitinib provides remission or low disease activity and pain relief, even in 604 Rheumatol Ther (2022) 9:589–608 those who had previously failed several disease and these changes in dose have been csDMARDs and bDMARDs, thus reinforcing its described for the first time in our study. A total effectiveness in real clinical practice. of 13 dose reductions from 4 to 2 mg/day were Patients included in the ORBIT-RA study registered, nine of which were due to remission were predominantly older females with moder- or low disease activity. In contrast, six dose ate to highly active RA before starting barici- increases were recorded, none of them associ- tinib treatment. Clinical and sociodemographic ated with lack of effectiveness. In line with characteristics of these patients were reasonably these results, a longer follow-up time would be aligned with those of previous observational needed to understand if the sustained control of studies conducted in Spain, Italy, and the UK the disease translates into a stable decrement in (18–21) in terms of gender, age, years of disease, the dose of baricitinib. seropositivity status, comorbidities, and disease Adverse events were the reason for two dose activity scores (DAS28-ESR, SDAI and CDAI). reductions from 4 to 2 mg/day, similar to what Our study showed baseline moderate levels of has previously been described in Rosas (18) and disease activity scores (DAS28ESR 4.3 ± 1.1, Fitton (19) studies. From the total number of SDAI 10.9 ± 10.3 and CDAI 23 ± 10 like other patients included in the study, 13 discontinued observational studies (18–21) and lower than baricitinib due to safety (7%), which is a slightly those of the clinical trials with baricitinib. In lower value than the ones reported in Rosas the RA-BEAM study, the DAS28-ESR was (10%), Guidelli (13%), and Fitton (13%) studies 6.4 ± 1.0 and SDAI 40 ± 13 (14). This differ- (18–20). ences in activity are basically due to that the Concerning concomitant GCC treatments, patients in clinical practice have different clin- 23.2% were changed after baricitinib initiation; ical characteristics than those included in clin- 96.2% of which reduced or stopped as early as ical trials (16, 17), and because in clinical 116 days and 111 days (median), respectively. practice the treat to target strategy is applied, These data are consistent with results found in and that prevents patients from having high the Italian cohort (20), where the number of levels of the disease. Compared to the ORBIT-RA patients treated with GCC, as well as the dose, study, the sample from UK and Italian was halved per year, a result that may be prospective studies included younger patients, explained by the remission or low disease with less time since diagnosis and lower per- activity achieved after starting baricitinib or the centages of seropositivity (19, 20). pain relief effect. Regarding prescription patterns, we found The patients included in the study with that the use of baricitinib in the ORBIT-RA available activity measures (any index) showed study followed recommendations in the SmPC. an increase or maintenance in the percentages Most patients were bDMARD-IR (78%), which is of remission or low activity at 6 and 12 months. quite different compared to Rosas et al.’s reg- This result is in agreement with that reported by istry-based study in which 54% of patients were Fitton et al. (19) at 6 months for DAS28 in the naı̈ve to bDMARDs (18), supporting the great UK, but based on a longer follow-up period and variability observed in prescription patterns in analyzed using different disease activity routine clinical practice (16, 17, 19). Treatment indexes. Collectively, these data reveal that with baricitinib was started at 4 mg/day dose in baricitinib is an effective treatment for manag- 90.1% of patients since 2 mg daily is only indi- ing RA signs and symptoms in real clinical cated in patients older than 75 years, with a practice. previous history of chronic or recurrent infec- Of interest, the results regarding pain tions or renal impairment: explaining the use of assessment are consistent with those observed this starting dose in only 18 patients of this in other studies on the clinical benefit of cohort. baricitinib in pain control (19), already sup- Unlike other JAKi, baricitinib has the ported by the results of RA-BEAM (14), where a advantage of permitting dose reductions from 4 greater proportion of baricitinib-treated to 2 mg/day in case of sustained control of the patients vs. adalimumab achieved pain relief as Rheumatol Ther (2022) 9:589–608 605 early as week 2. The importance of this finding how the different assessed variables compares to is subscribed by the proportion of RA patients other treatments. Finally, since the analysis of who rate pain as one of their top three priorities baricitinib persistence by subgroup was based on prior evidence (68–88%) (22). The descriptive, any conclusion about the differ- QUEST-RA (23) and Studenic et al. (24) studies ences observed should be made with caution, showed pain to be the major determinant of and further research would be needed to con- patient global assessment scores, explaining firm it. 75.6% of score variability. In addition, the American College of Rheumatology Pain Man- agement Task Force also reinforces this evidence CONCLUSIONS stating that ‘‘pain is probably the most impor- tant patient-reported outcome in rheumatol- Patients with RA who received baricitinib ogy’’ (25). Results from the ORBIT-RA study treatment showed a long-standing and refrac- showed that not only can remission be achieved tory disease profile. Results from the ORBIT-RA with baricitinib, but also other patient-reported study reinforced evidence that baricitinib pro- outcomes. vides remission or low disease activity at Baricitinib persistence was especially 6 months and maintains the response at remarkable in our study, with higher values in 12 months in a high percentage of patients, patients not previously exposed to bDMARDs even in those who have failed previously to and lower ones in the bDMARDs-IR population, several csDMARDs and bDMARDs. The major consistent with data obtained by Guidelli and improvements in disease activity suggest the Fitton (19, 20). Persistence with baricitinib was good effectiveness and pain relief of baricitinib found to be associated with seropositivity, a treatment in real clinical practice for patients connection that has already been described for with moderate to highly active RA in Spain. abatacept and rituximab (26, 27), but not for tofacitinib (28), so further research is needed to confirm this relationship. Better persistence was ACKNOWLEDGEMENTS also related to lower CCI scores and the use of baricitinib in combination, as it has been The authors would like to thank the patients, described for several bDMARDs (29–34). No investigators, and institutions for their partici- impact on persistence was detected for variables pation in this study. such as age and gender. However, additional investigations will be necessary to determine Funding. Sponsorship for this study and whether all of these factors can be considered Rapid Service Fee were funded by Eli Lilly and influential in treatment persistence or not. Company, Indianapolis, IN, USA. Compared to previous observational studies available in the literature, some aspects of the Medical Writing, Editorial, and Other design of the ORBIT-RA study can be high- Assistance. Assistance in the preparation of lighted, such as the large sample size, the long this article was provided by IQVIA and funded observational period (18 months, with a mini- by Eli Lilly and Company, Indianapolis, IN, mum follow-up per patient of 6 months), and USA. The authors would like to acknowledge the use of multiple disease activity scores to Jennifer Redondo (trainee at Lilly during the assess effectiveness. The main study limitations development of the article) for her contribu- are related to its retrospective design and the tions (data quality check-review and medical availability of data in patients’ medical records writing assistance). to meet the study objectives, mainly for disease activity scores. Additionally, as routine clinical Authorship. All named authors meet the practice differs geographically, the generaliz- International Committee of Medical Journal ability of the results is also a limitation, as well Editors (ICMJE) criteria for authorship for their as the lack of a comparator group to determine contribution this article, take responsibility for 606 Rheumatol Ther (2022) 9:589–608 the integrity of the work as a whole, and have any non-commercial use, sharing, adaptation, given their approval for this version to be distribution and reproduction in any medium published. or format, as long as you give appropriate credit to the original author(s) and the source, provide Authorship Contributions. All authors con- a link to the Creative Commons licence, and tributed to the study conception, design, and indicate if changes were made. The images or data analysis. All authors have reviewed previ- other third party material in this article are ous versions of the manuscript and have read included in the article’s Creative Commons and approved the final one. licence, unless indicated otherwise in a credit line to the material. If material is not included Prior Presentation. These data were previ- in the article’s Creative Commons licence and ously accepted as an abstract for the congress of your intended use is not permitted by statutory the Spanish Society of Rheumatology 2020 regulation or exceeds the permitted use, you (SER2020) and presented as a poster in the will need to obtain permission directly from the congress of the Argentine Society of Rheuma- copyright holder. To view a copy of this licence, tology 2020 (SAR 2020). visit http://creativecommons.org/licenses/by- nc/4.0/. Disclosures. Mercedes Núnez and Silvia Dı́az are employees of Eli Lilly and Company (Spain) and hold Eli Lilly and Company shares. José Inciarte-Mundo was an employee of Eli Lilly REFERENCES and Company (Spain) at the time the study was conducted. Blanca Hernández-Cruz, José Rosas, 1. Scott IC, Machin A, Mallen CD, Hider SL. The extra- César Dı́az-Torné, Joaquı́n Belzunegui, Rosario articular impacts of rheumatoid arthritis: moving Garcı́a-Vicuña, Ana Pons, Ana M Millán, Sicylle towards holistic care [Internet]. BMC Rheumatol. Jeria-Navarro, Jesús A Valero, Noelia Garcı́a- 2018;2:1–15. Castañeda, Cristina Valero, Irene Llorente and 2. Carmona L, González-Álvaro I, Balsa A, Belmonte Alberto Calvo have received an economic MA, Tena X, Sanmartı́ R. Rheumatoid arthritis in compensation for their participation in the Spain: occurrence of extra-articular manifestations study through data collection, analysis, and and estimates of disease severity. Ann Rheum Dis [Internet]. 2003;62(9):897–900. interpretation tasks. 3. Alamanos Y, Voulgari PV, Drosos AA. Incidence and Compliance with Ethics Guidelines. The prevalence of rheumatoid arthritis, based on the study was conducted in accordance with the 1987 American College of rheumatology criteria: a systematic review. Semin Arthritis Rheum [Inter- ethical principles of the Declaration of Helsinki net]. 2006;36(3):182–8. and Good Clinical Practice guidelines and was approved by the Ethics Committees of Virgen 4. Se G. The epidemiology of rheumatoid arthritis. de la Macarena and Virgen del Rocio University Rheum Dis Clin North Am [Internet]. 2001;27(2): 269–81. Hospitals in Seville (Spain). Informed consent was collected when required by each ethics 5. Seoane-Mato D, Sánchez-Piedra C, Silva-Fernández committee. L, Sivera F, Blanco FJ, Pérez Ruiz F, et al. Prevalence of rheumatic diseases in adult population in Spain Data Availability. The datasets generated (EPISER 2016 study): aims and methodology. Reu- matol Clin. 2019;15(2):90–6. during and/or analyzed during the current study are available from the corresponding 6. Carbonell J, Cobo T, Balsa A, Descalzo MÁ, Car- author on reasonable request. mona L. The incidence of rheumatoid arthritis in Spain: results from a nationwide primary care reg- Open Access. This article is licensed under a istry. Rheumatol [Internet]. 2008;47(7):1088–92. Creative Commons Attribution-NonCommer- 7. Smolen JS, Landewé RBM, Bijlsma JWJ, Burmester cial 4.0 International License, which permits GR, Dougados M, Kerschbaumer A, et al. EULAR recommendations for the management of Rheumatol Ther (2022) 9:589–608 607 rheumatoid arthritis with synthetic and biological 18. Rosas J, Senabre-Gallego JM, Santos-Soler G, Bernal disease-modifying antirheumatic drugs: 2019 JA, Pons Bas A, Aire-Mb Grupo. Efficacy and safety update. Ann Rheum Dis [Internet]. 2020;79(6): of baricitinib in patients with rheumatoid arthritis S685–99. and inadequate response to conventional synthetic DMARDs and/or biological DMARDs: data from a 8. Taylor PC. Clinical efficacy of launched JAK inhi- local registry. Reumatol Clin (Engl Ed). 2020. bitors in rheumatoid arthritis. Rheumatol (UK) https://doi.org/10.1016/j.reuma.2020.04.011. [Internet]. 2019;58(Suppl 1):17–26. (English, Spanish). 9. Taylor PC, Moore A, Vasilescu R, Alvir J, Tarallo M. 19. Fitton J, Melville AR, Emery P, Nam JL, Buch MH. A structured literature review of the burden of ill- Real-world single centre use of JAK inhibitors across ness and unmet needs in patients with rheumatoid the rheumatoid arthritis pathway. Rheumatol arthritis: a current perspective. Rheumatol Int. [Internet]. 2021;60(9):4048–54. 2016;36(5):685–95. 20. Guidelli GM, Viapiana O, Luciano N, De Santis M, 10. Silvagni E, Sakellariou G, Bortoluzzi A, Giollo A, Boffini N, Quartuccio L, et al. Efficacy and safety of Ughi N, Vultaggio L, et al. One year in review 2021: baricitinib in 446 patients with rheumatoid arthri- novelties in the treatment of rheumatoid arthritis tis: a real-life multicentre study. Clin Exp [Internet]. Clin Exp Rheumatol. 2021;39:705–20. Rheumatol [Internet]. 2021;39(4):868–73. 11. Fleischmann R, Schiff M, van der Heijde D, Ramos- 21. Perrone V, Losi S, Rogai V, Antonelli S, Fakhouri W, Remus C, Spindler A, Stanislav M, et al. Baricitinib, Giovannitti M, et al. Real-world analysis of thera- methotrexate, or combination in patients with peutic patterns in patients affected by rheumatoid rheumatoid arthritis and no or limited prior dis- arthritis in Italy: a focus on baricitinib. Rheumatol ease-modifying antirheumatic drug treatment. Ther [Internet]. 2020;7(3):657–65. Arthritis Rheumatol. 2017;69(3):506–17. 22. Ten Klooster PM, Veehof MM, Taal E, Van Riel 12. Dougados M, Van Der Heijde D, Chen YC, Green- PLCM, Van De Laar MAFJ. Changes in priorities for wald M, Drescher E, Liu J, et al. Baricitinib in improvement in patients with rheumatoid arthritis patients with inadequate response or intolerance to during 1 year of anti-tumour necrosis factor treat- conventional synthetic DMARDs: results from the ment. Ann Rheum Dis [Internet]. 2007;66(11): RA-BUILD study. Ann Rheum Dis. 2017;76(1): 1485–90. 88–95. 23. Khan NA, Spencer HJ, Abda E, Aggarwal A, Alten R, 13. Genovese MC, Kremer J, Zamani O, Ludivico C, Ancuta C, et al. Determinants of discordance in Krogulec M, Xie L, et al. Baricitinib in patients with patients’ and physicians’ rating of rheumatoid refractory rheumatoid arthritis [Internet]. J Miner- arthritis disease activity. Arthritis Care Res [Inter- alstoffwechsel N Engl J Med. 2016;23:60–1. net]. 2012;64(2):206–14. 14. Taylor PC, Keystone EC, van der Heijde D, Wein- 24. Studenic P, Radner H, Smolen JS, Aletaha D. Dis- blatt ME, del Carmen ML, Reyes Gonzaga J, et al. crepancies between patients and physicians in their Baricitinib versus Placebo or adalimumab in perceptions of rheumatoid arthritis disease activity. rheumatoid arthritis. N Engl J Med [Internet]. Arthritis Rheum [Internet]. 2012;64(9):2814–23. 2017;376(7):652–62. 25. American College of Rheumatology Pain Manage- 15. (EMEA). ETEAftEoMP. OlumiantÒ. Summary of ment Task Force. Report of the American College of Product Characteristics. 2021. https://www.ema. Rheumatology Pain Management Task Force. europa.eu/en/documents/product-information/ Arthritis Care Res (Hoboken). 2010;62(5):590–9. olumiant-epar-product-information_en.pdf. https://doi.org/10.1002/acr.20005. 16. Dhaon P, Das SK, Srivastava R, Dhakad U. Perfor- 26. Alten R, Mariette X, Lorenz HM, Nüßlein H, mances of Clinical Disease Activity Index (CDAI) Galeazzi M, Navarro F, et al. Predictors of abatacept and Simplified Disease Activity Index (SDAI) appear retention over 2 years in patients with rheumatoid to be better than the gold standard Disease Assess- arthritis: results from the real-world ACTION study. ment Score (DAS-28-CRP) to assess rheumatoid Clin Rheumatol [Internet]. 2019;38(5):1413–24. arthritis patients. Int J Rheum Dis [Internet]. 2018;21(11):1933–9. 27. Courvoisier DS, Chatzidionysiou K, Mongin D, Lauper K, Mariette X, Morel J, et al. The impact of 17. Takanashi S, Kaneko Y, Takeuchi T. CDAI and seropositivity on the effectiveness of biologic anti- DAS28 in the management of rheumatoid arthritis rheumatic agents: Results from a collaboration of in clinical practice [Internet]. Ann Rheum Dis. 16 registries. Rheumatol (UK) [Internet]. 2020;79:671–4. 2021;60(2):820–8. 608 Rheumatol Ther (2022) 9:589–608 28. Harrold L, Shan Y, Rebello S, Guo L, Connolly S, 31. Heiberg MS, Koldingsnes W, Mikkelsen K, Røde- Zhuo J, Kelly S, Lehman T. Association between vand E, Kaufmann C, Mowinckel P, et al. The baseline anti-citrullinated protein antibody status comparative one-year performance of anti-turmor and response to abatacept or non-TNF inhibitor necrosis factor a drugs in patients with rheumatoid therapy in patients with RA: results from a US arthritis, psoriatic arthritis, and ankylosing National Observational Study [abstract]. Arthritis spondylitis: results from a longitudinal, observa- Rheumatol. 2019;71(suppl 10):8. https:// tional, multicenter study. Arthritis Care Res [Inter- acrabstracts.org/abstract/association-between- net]. 2008;59(2):234–40. baseline-anti-citrullinated-protein-antibody-status- and-response-to-abatacept-or-non-tnf-inhibitor- 32. Favalli EG, Pregnolato F, Biggioggero M, Becciolini therapy-in-patients-with-ra-results-from-a-us- A, Penatti AE, Marchesoni A, et al. Twelve-year national-observational-study/. Accessed 19 Dec retention rate of first-line tumor necrosis factor 2021. inhibitors in rheumatoid arthritis: real-life data from a local registry. Arthritis Care Res [Internet]. 29. Gabay C, Riek M, Scherer A, Finckh A. Effectiveness 2016;68(4):432–9. of biologic DMARDs in monotherapy versus in combination with synthetic DMARDs in rheuma- 33. Zink A, Listing J, Kary S, Ramlau P, Stoyanova- toid arthritis: Data from the Swiss Clinical Quality Scholz M, Babinsky K, et al. Treatment continua- Management Registry. Rheumatol (UK) [Internet]. tion in patients receiving biological agents or con- 2015;54(9):1664–72. ventional DMARD therapy. Ann Rheum Dis [Internet]. 2005;64(9):1274–9. 30. Soliman MM, Ashcroft DM, Watson KD, Lunt M, Symmons DPM, Hyrich KL. Impact of concomitant 34. Kristensen LE, Saxne T, Nilsson JÅ, Geborek P. use of DMARDs on the persistence with anti-TNF Impact of concomitant DMARD therapy on adher- therapies in patients with rheumatoid arthritis: ence to treatment with etanercept and infliximab in results from the British Society for Rheumatology rheumatoid arthritis. Results from a six-year obser- Biologics Register. Ann Rheum Dis [Internet]. vational study in southern Sweden. Arthritis Res 2011;70(4):583–9. Ther [Internet]. 2006;8:6.