Of 1073 patients enrolled from France (N = 220), Germany (N = 422), Italy (N = 191), Spain (N = 80), and the UK (N = 160), 510 initiated treatment with baricitinib (cohort A) and 563 initiated treatment with a bDMARD or any other tsDMARD (cohort B).

Baseline demographics and clinical characteristics, as well as RA treatment history, are described in Table 2. Compared with cohort B, patients in cohort A more frequently initiated therapy with baricitinib as a monotherapy. Within the baricitinib group, patients receiving 2 mg dosage were older (72.6 and 57.4 years for 2 mg and 4 mg, respectively), had a longer disease duration (12.3 and 9.8 years for 2 mg and 4 mg, respectively), and a higher proportion were receiving monotherapy (61.0% and 49.2% for 2 mg and 4 mg, respectively) compared with patients receiving 4 mg dosage. Compared with all other treatment groups, patients initiating TNFi had shorter mean disease duration (7.1 years), and a greater proportion were naïve to previous b/tsDMARDs (75.1%).

Post hoc analyses of patients < 65 and ≥ 65 years old demonstrated largely similar BMI, RA treatment patterns, and family history of RA (Table S4). Patients in the < 65 years population had a shorter mean disease duration for both cohorts (Table S4). As expected, the distribution of treatments was similar across age groups. A higher proportion of patients in the TNFi group for both age populations were naïve to b/tsDMARDs. Clinical characteristics and disease activity were similar for all cohorts.

At 24 months, 38.2% (n = 195, median time to discontinuation = not calculable, the median was unable to be calculated as it does not reach the probability of 0.5) of patients treated with baricitinib and 59.9% (n = 337) of patients treated with  a b/tsDMARD had discontinued RA treatment (Fig. 1). Among patients in cohort B, 59.1% (n = 199, median time to discontinuation = 15.6 months, 95% CI [12.2, 20.5]), 57.8% (n = 93, median time to discontinuation = 13.1, 95% CI [8.5, 24.0]), and 69.2% (n = 45, median time to discontinuation = 9.6, 95% CI [6.2, 17.0]) using a TNFi, non-TNFi, and any other tsDMARD, respectively, discontinued treatment at 24 months. Drug survival rates were consistent across overall, b/tsDMARD-naïve, and b/tsDMARD-experienced (Fig. 1), < 65, and ≥ 65-year-old patient subgroups (Fig. S4). Drug survival rates for cohort A were consistently higher than cohort B, regardless of baricitinib dosage or treatment pattern (Fig. S5).

Drug survival over 24 months for overall (a), b/tsDMARD-naïve (b), and b/tsDMARD-experienced patients (c). Instances where the median value is absent, indicates the median was unable to be calculated as it does not reach the probability of 0.5. Drug survival curves for patients < 65 and ≥ 65 years old can be found in Fig. S4. TNFi tumour necrosis factor inhibitor, tsDMARD targeted synthetic disease-modifying anti-rheumatic drugs

The comparative adjusted analysis for the primary objective, time to discontinuation, showed a lower discontinuation rate for baricitinib compared to TNFi and other mechanism of action (OMA) in the overall group (baricitinib vs. cohort B overall: rHR 0.6, 95% CI [0.5, 0.7]; vs. TNFi: rHR 0.5, 95% CI [0.4, 0.6]; vs. OMA: rHR 0.6, 95% CI [0.5, 0.7]), as well as naïve and experienced (Fig. 2).

Comparative adjusted analysis using FMA approach for time to discontinuation of baricitinib versus cohort B overall, TNFi, and OMA at 24 months for overall, b/tsDMARD-naïve, b/tsDMARD-experienced, < 65 years, and ≥ 65 years. Results are statistically significant if 1 is not covered by the 95% CI for the restricted hazard ratios. Results of the best performing model can be found in Fig. S6. bDMARD biologic disease-modifying anti-rheumatic drug, CI confidence interval, FMA frequentist model averaging, NRI non-responder imputation, OMA other mechanism of action, TNFi tumour necrosis factor inhibitor, tsDMARD targeted synthetic disease-modifying anti-rheumatic drug

Drug survival rates were consistently higher among the baricitinib cohort, compared with the b/tsDMARD cohort for both age cohorts (Fig. S4a, b). The comparative adjusted analysis for time to discontinuation also showed a lower discontinuation rate of baricitinib compared to TNFi and OMA for both age populations (Fig. 2).

In the overall population, discontinuation due to adverse events was similar across all treatment groups, with the greatest proportion of discontinuations in the any other tsDMARD group in cohort B (20.0%; Table 3). Discontinuation due to ineffectiveness was highest for patients discontinuing TNFi (22.6%) and lowest for those discontinuing baricitinib (14.3%). Additionally, a high proportion of patients in cohort B had discontinued treatment at 24 months for other reasons including patient or physician decision, non-compliance, cannot afford medication, unknown causes, COVID-19-related causes (medical and non-medical reasons), or other (TNFi, 29.1%; non-TNFi, 29.2%; tsDMARD, 30.8%) compared to baricitinib (16.1%). Discontinuation due to ineffectiveness was greater among experienced patients (baricitinib, 20.4%; TNFi, 26.2%; non-TNFi, 22.3%; tsDMARD, 29.3%) compared to naïve (baricitinib, 7.8%; TNFi, 21.3%; non-TNFi, 16.4%; tsDMARD, 0%), while discontinuation due to adverse events was similar between both groups (naïve baricitinib, 8.2%; TNFi, 8.3%; non-TNFi, 9.0%; tsDMARD, 16.7%; experienced baricitinib, 7.5%; TNFi, 4.8%; non-TNFi, 8.5%; tsDMARD, 22.0%; Table 3). The reasons for treatment discontinuation were largely consistent between the cohorts for both age groups (Table 3). Discontinuation due to ineffectiveness was lowest among patients treated with baricitinib for both age populations.

For unadjusted results at 24 months, 41.1% of patients overall treated with baricitinib and 36.4% (TNFi), 30.4% (non-TNFi), and 35.5% (tsDMARD) of patients in cohort B achieved LDA (Table 4). Remission was achieved by 15.2% of patients treated with baricitinib and by 16.2% (TNFi), 7.6% (non-TNFi), and 21.0% (tsDMARD) in cohort B.

Among those naïve to b/tsDMARD therapy, LDA was achieved by 46.6% of patients treated with baricitinib, and 39.0% (TNFi), 46.2% (non-TNFi), and 39.1% (tsDMARD) of patients in cohort B. Among naïve patients treated with baricitinib, 18.1% achieved remission, while 17.9% receiving TNFi, 12.3% receiving non-TNFi, and 26.1% receiving tsDMARDs in cohort B achieved remission. For those with previous b/tsDMARD experience, LDA was achieved by 36.2% of patients treated with baricitinib, and 28.4% (TNFi), 19.4% (non-TNFi), and 33.3% (tsDMARD) of patients in cohort B. Remission was achieved by 12.7% of patients treated with baricitinib, while 11.1% (TNFi), 4.3% (non-TNFi), and 17.9% (tsDMARD) of patients in cohort B achieved remission. Compared to patients experienced to b/tsDMARD therapy, naïve patients achieved an overall higher rate of LDA and remission (Table 4).

For the comparative analysis, LDA response was statistically significant between cohorts A and B across overall (OR 1.5; 95% CI [1.1, 1.9]) and within experienced (OR 1.9; 95% CI [1.2, 2.8]) patients using the imputed data. Additionally, using NRI (non-responder imputation), LDA was statistically significant for baricitinib vs. OMA (OR 1.9; 95% CI [1.2, 3.1]) and vs. TNFi (OR 1.7; 95% CI [1.0, 3.1]) for experienced patients (Fig. 3). There were no statistical differences in remission rates over the 24 months, for both observed and NRI.

Comparative adjusted analysis using FMA approach of remission and LDA for baricitinib versus cohort B overall, TNFi, and OMA at 24 months for overall (a), b/tsDMARD-naïve (b), and b/tsDMARD-experienced patients (c). NRI results are depicted by filled circles, and as-observed results are depicted by hollow circles. Results are statistically significant if 1 is not covered by the 95% CI for the odds ratios. Remission is defined as CDAI score ≤ 2.8, and LDA is defined as CDAI score > 2.8 and ≤ 10. Results of the best performing model can be found in Fig. S7. bDMARD biologic disease-modifying anti-rheumatic drug, CDAI Clinical Disease Activity Index, CI confidence interval, FMA frequentist model averaging, LDA low disease activity, NRI non-responder imputation, OMA other mechanism of action, TNFi tumour necrosis factor inhibitor, tsDMARD targeted synthetic disease-modifying anti-rheumatic drug

The proportion of patients achieving LDA and remission was consistent across cohorts for both age populations, with slightly greater proportions reported for patients in the ≥ 65 years group for cohort A and cohort B–TNFi for both measures (Table 4).

At 24 months, greatest mean CFB in CDAI was reported by those receiving baricitinib in the overall, naïve, and both age groups (Table 4). Using comparative analyses, our data showed that patients treated with baricitinib demonstrated a significantly greater improvement in CDAI CFB compared to TNFi across overall, naïve, and experienced groups for observed and imputed data, with the exception of the experienced group, which was only significant for observed data, and compared to cohort B overall in the overall and naïve groups (Fig. 4). Similarly, significantly greater improvements in CDAI CFB compared to cohort B overall, TNFi, and OMA were noted in ≥ 65 age group and vs. TNFi in the < 65 age group for both observed and imputed data (Fig. S10).

Comparative adjusted analysis using FMA approach of CDAI, Pain VAS, and HAQ-DI for baricitinib versus cohort B overall, TNFi, and OMA at 24 months for overall (a), b/tsDMARD-naïve (b), and b/tsDMARD-experienced patients (c). *Significant differences observed in HAQ-DI. Overall group: barictinib vs. cohort B overall (LSMean difference − 0.075; 95% CI [− 0.123, − 0.012]), barictinib vs. OMA (LSMean difference − 0.094; 95% CI [− 0.152, − 0.015]); Naïve group: baricitinib vs. TNFi (LSMean difference − 0.089; 95% CI [− 0.182, 0.001]); Experienced group: baricitinib vs. OMA (LSMean difference − 0.081; 95% CI [− 0.16, − 0.001]). mBOCF results are depicted by filled circles, and as-observed results are depicted by hollow triangles. Results are statistically significant if 0 is not covered by the 95% CI. Results of the best performing model can be found in Fig. S9. bDMARD biologic disease-modifying anti-rheumatic drug, CDAI Clinical Disease Activity Index, CFB change from baseline, CI confidence interval, FMA frequentist model averaging, HAQ-DI Health Assessment Questionnaire-Disability Index, LSMean least squares mean, mBOCF modified Baseline Observation Carried Forward, OMA other mechanism of action, SD standard deviation, TNFi tumour necrosis factor inhibitor, tsDMARD targeted synthetic disease-modifying anti-rheumatic drug, VAS visual analogue scale (mm)

At 24 months, CFB in pain VAS was reported across overall, b/tsDMARD-naïve, and b/tsDMARD-experienced (Table 4). For the comparative analysis, average pain VAS was statistically reduced in patients treated with baricitinib vs. cohort B for the overall (LSMean difference − 3.2; 95% CI [− 6.1, − 0.03]) and experienced (imputed data) (LSMean difference − 3.9; 95% CI [− 7.1, − 0.7]) groups, and when compared with TNFi in the experienced group (LSMean difference − 6.2; 95% CI [− 10.1, − 0.9]) (Fig. 4). In the age subgroups, mean CFB in pain VAS was reported by patients across both groups, with the greatest mean CFB observed with baricitinib (< 65 [− 21.7 (standard deviation [SD] 30.6)] and ≥ 65 [− 29.6 (SD 30.1)]) (Table 4). Patients ≥ 65 treated with baricitinib demonstrated a significantly greater improvement in mean pain VAS CFB, for the imputed data, compared to cohort B overall (LSMean difference − 5.3; 95% CI [− 9.7, − 1.8]) and OMA (LSMean difference − 6.0; 95% CI [− 12.3, − 0.8]) (Fig. S10). These results for patients ≥ 65 were consistent for the observed data.

Differences in HAQ-DI were low between cohorts and across overall, naïve, experienced, and age subgroups; however, significant differences favouring baricitinib were observed for baricitinib vs. cohort B overall (LSMean difference − 0.075, 95% CI [− 0.123, − 0.012]), baricitinib vs. OMA (LSMean difference − 0.094, 95% CI [− 0.152, − 0.015]), naïve-baricitinib vs. TNFi (LSMean difference − 0.089, 95% CI [− 0.182, − 0.001]), and experienced-baricitinib vs. OMA (LSMean difference − 0.081, 95% CI [− 0.16, − 0.001]) (Fig. 4). Patients ≥ 65 treated with baricitinib demonstrated a significantly greater improvement in HAQ-DI CFB compared to cohort B overall, TNFi, and OMA (Fig. S10).