Rheumatoid arthritis (RA) is a chronic, inflammatory, systemic, autoimmune disease that mainly affects the synovial membrane leading to the destruction of joint structures1,2.

Typical symptomatology includes joint pain, swelling, and stiffness, together with functional limitation of the affected joints2. It also manifests in general symptoms such as fatigue, malaise, morning stiffness, and weakness and depression which, in association with possible extra-articular involvement, reduce quality of life and life expectancy1.

In Spain, the prevalence of RA in adults is 1.07% (95% Confidence Interval [95%CI]: 0.70–1.44), and it is higher in women and persons older than 60 years3,4.

In recent years, we have witnessed a genuine revolution in the treatment of RA. The therapeutic approach includes the use of drugs aimed at short-term symptom control (anti-inflammatory drugs and corticosteroids) and the simultaneous initiation of the use of disease-modifying antirheumatic drugs (DMARDs). DMARDs are slow-acting drugs that target molecules directly involved in the pathogenesis of the disease. They are classified into three groups: conventional synthetic DMARDs (cDMARDs), biological DMARDs (bDMARDs), and targeted synthetic DMARDs (tsDMARDs)5,6.

Some drugs are currently available that block cytokines and cell costimulation, act as cell surface antagonists, and target intracellular Janus Kinase (JAK) enzymes involved in the transmission of cellular signals essential for the production of inflammatory cytokines. These drugs are known as JAK inhibitors (JAKi), which are small synthetic molecules for oral administration2,5–7.

The development of these new drugs has led to the implementation of treatment strategies for patients with RA, such as early treatment, targeted treatment, and close monitoring, and the development of tools that allow better monitoring of the disease at each of its stages5.

Baricitinib (BAR) is a reversible selective JAK1 and JAK2 inhibitor and tofacitinib (TOF) is a selective JAK1 and JAK3 inhibitor. Both drugs are indicated as monotherapy or in combination with methotrexate for the treatment of moderate-severe active RA in adults with inadequate response or intolerance to one or more DMARDs2,6.

Both drugs have undergone extensive phase III clinical trials and have demonstrated rapid improvements in disease activity, function, and patient-reported outcomes2,6,8. Several studies and meta-analyses have assessed the effectiveness and safety in real-world clinical practice of BAR and TOF in the treatment of RA in patients who have failed previous treatments with other cDMARDs and bDMARDs9–16.

JAKi are still a relatively novel RA treatment option, thus there is a need to utilize the experience gained with these drugs in real-life clinical settings to further evaluate their safety and utility11.

The main objective of this study was to investigate the effectiveness and safety of BAR and TOF in patients diagnosed with RA receiving treatment with them in our hospital. A secondary objective was to identify any differences between them in real-world clinical practice.

A single-centre, observational, retrospective study was carried out. We included patients diagnosed with RA who met the funding criteria established by the Central Autonomous Commission for Pharmacy and Therapeutics (CACFT) and who started treatment with BAR and TOF between January 2018 and December 2019 with a minimum period of 6 months of treatment.

The criteria established by the CACFT for the use of BAR and TOF are as follows17:

• •

  In the case of primary failure to an anti-tumour necrosis factor (anti-TNF) drug.

• •

  In the case of loss of efficacy of previous treatment with cDMARDs or bDMARDs, based on efficiency criteria and the characteristics of each patient.

The electronic medical record (IANUS version 04.53.0102) and the software application for outpatient dispensing (Silicon version 10.5.0) were used as sources of demographic, analytical, pharmacotherapeutic, and clinical data.

The following variables were collected: age and sex as demographic variables, rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPAs) as poor prognostic factors, previous treatment with cDMARDs and bDMARDs, treatment duration, concomitant treatment with corticosteroids, concomitant treatment with cDMARDs, number of swollen joints (NSJ) and painful joints (NPJ), visual analogue scale for pain (VAS) score, disease activity score of 28 joints (DAS28), adverse reactions (AR), discontinuation of treatment, and reason for discontinuation.

The primary endpoint used to assess effectiveness was decreases in the DAS28 at 6 months and 12 months of treatment. Secondary endpoints were decreases in the NSJ and NPJ and in VAS scores at 6 and 12 months after initiation of treatment.

Safety was assessed by reviewing the clinical manifestations of ARs recorded in medical records. Qualitative variables are expressed as absolute frequency and percentage, and quantitative variables are expressed as median and range. The Shapiro-Wilk normality test was performed to determine whether the dependent variables followed a normal distribution. Differences between BAR and TOF were analysed using the student t-test. A P-value of < 0.05 was used as a cutoff for statistical significance. All statistical analyses were performed using the R-Commander software package (version Rx64 3.6.1). All data were anonymised by the elimination of personal information.

Rheumatoid arthritis is the most prevalent form of chronic polyarthritis and has a major social and health impact in Spain. It can lead to varying degrees of disability, loss of quality of life, and even increased mortality1.

In Spain, current treatment guidelines and the CACFT treatment protocol recommend the use of cDMARDs as initial treatment as soon as RA is diagnosed. If the therapeutic target is not reached using this initial strategy, other cDMARDs can be used in sequential or combined therapy or a bDMARD can be added depending on the patients’ characteristics and the presence of poor prognostic factors. If treatment with the first bDMARD is unsuccessful, it is recommended that patients are treated with another bDMARD or a targeted synthetic drug1,17,18.

In the present study, all patients received treatment with cDMARDs. Of these patients, the majority (75% of the TOF group and 91.7% of the BAR group) received more than 1 previous bDMARD. The patients received a median of 2 treatment lines, the most frequent being etanercept. These results are similar to those obtained in a study by Mueller et al.11, in which 84.7% of patients had received at least 1 previous bDMARD with a median of 2.2 treatment lines.

Regarding demographic data, patients were slightly younger and had fewer poor prognostic factors in the TOF group than patients in the BAR group: however, there were more women in the TOF group than in the BAR group. These results differ from those published in previous studies, in which the majority of patients were female: however, the patients were older in the TOF groups than patients in the BAR groups11–16.

Although the baseline DAS28 and VAS scores were similar in the two groups, the BAR group had a higher NSJ and NPJ. These results are similar to those described in a study by Guidelli et al., in which they evaluated the efficacy and safety of BAR. The patients had a baseline DAS28 score of 4.67 ± 1.05, NPJ of 7.6 ± 5.7, and NSJ of 5.5 ± 4.5 (mean ± standard deviation [SD])14.

The doses administered were those described in the summary of product characteristics (SPC). Although the SPC specifies that 2 mg/d BAR may be appropriate in patients aged at least 75 years19, it should be noted that all BAR patients, including older patients, received 4 mg/d. This dose is the same as that administered in previous studies, although the patients had a mean age of less than 75 years13,14,16. Although some patients received a higher dose than that recommended for their age in the SPC, no related adverse drug reactions were observed.

Since JAKi were launched, several real-life studies have assessed the effectiveness and safety of BAR and TOF and have obtained similar results to those obtained in the two study groups.

Iwamoto et al. conducted a study to evaluate the effectiveness and safety of TOF. They observed a decrease in the DAS28 (mean ± SD) from 5.04 ± 1.33 to 3.83 ± 1.11 at 4 weeks, to 3.69 ± 1.19 at 12 weeks, and to 3.53 ± 1.17 at 24 weeks12.

Spinelli et al. conducted a study to assess the effectiveness and safety of BAR over 48 weeks in 59 patients diagnosed with RA. At weeks 4, 12, 24, and 48, the results (median [interquartile range]) showed a reduction in the DAS28 from an initial 4.68 (1.5) to 3.41 (1.6), to 2.79 (1.52), to 2.79 (1.66), and to 2.77 (1.55), respectively. At the same time points, the NPJ decreased from 8 (7) to 4 (5), to 2 (4), to 1 (5.5), and to 1 (4.5) and the NSJ decreased from 4 (4) to 1 (3), to 0 (2.25), to 0 (4), and to 0 (1), respectively. In addition, the VAS scores showed significant improvements in patient-reported outcomes13. These results are similar to the DAS28 and VAS scores observed in our study. The baseline NSJ was higher in our sample than that in their study, and so the reduction was greater; however, the results on the NPJ were similar in both studies.

In the present study, treatment was discontinued due to loss of effectiveness in 10% of the BAR patients and 25% of the TOF. These results are similar to those reported for both drugs in previous studies13,15. However, fewer patients discontinued treatment for this reason in the BAR group in the present study than in the study by Fitton et al.16, in which 14 out of 54 patients in the TOF group and 15 out of 69 patients in the BAR group discontinued treatment due to inefficacy.

Glucocorticoids are among the most commonly used anti-inflammatory and immunosuppressive drugs for RA. In other developed countries, patients with active RA use concomitant glucocorticoids and cDMARDs in percentages ranging from 38% to 55%1. Spinelli et al.13, reported that 78.0% of patients were taking concomitant corticosteroids at the start of treatment with BAR. By the end of the study period, this percentage had decreased to 34.8%. Guidelli et al.14 found that the percentage of patients taking concomitant corticosteroids decreased from 70% at the beginning of the study period to 32% at the end of the period. These results are similar to those described in our study. In addition, we found no significant differences in the need for corticosteroids during treatment with both drugs.

The aforementioned studies and the pivotal studies investigated the safety of BAR and TOF. The most frequently described ARs to TOF were infections followed by headache, nausea, hypertension, and diarrhoea, and the ARs to BAR were increased LDL concentrations, elevated liver enzymes, and nausea1,2,6,11–18,20. We observed similar ARs to the two drugs in our study population. Nevertheless, it is striking that we observed no signs of infection, despite this AR being one of the most common in this type of treatment. Moreover, only a small percentage of patients discontinued treatment due to severe ARs.

However, in 2019, the Spanish Agency for Medicines and Health Products published a recommendation on restrictions to the use of TOF due to the increased risk of dose-dependent venous thromboembolism in patients with at least one risk factor21. No such effect was observed in our study population.

Our study is limited by its having a retrospective observational design, being a single-centre study with a small number of patients, and having possible biases due to the absence of data in the medical records. However, it was conducted in the setting of real-world clinical practice, and thus the results can be extrapolated to other hospital settings.

Based on our results, BAR and TOF have been shown to be effective and safe for use in decreasing DAS28, NSJ, NPJ, and VAS scores. In addition, both drugs demonstrated similar effectiveness and safety in real-world clinical practice in the treatment of RA.

No funding.

No conflict of interest.