Are all JAK inhibitors for the treatment of rheumatoid arthritis equivalent? An adjusted indirect comparison of the efficacy of tofacitinib, baricitinib, upadacitinib, and filgotinib.

INTRODUCTION: Comparisons of Janus kinase inhibitors (JAKi) for treatment of rheumatoid arthritis in patients with inadequate response to biologic disease-modifying anti-rheumatic drugs are lacking. We assessed the relative efficacy and safety of four JAKi (tofacitinib, baricitinib, upadacitinib, and filgotinib) in this context. METHOD: We performed an adjusted indirect comparison (IC) of randomized clinical trials using Bucher's method with an IC and mixed calculator. Endpoints were Disease Activity Score C-reactive protein (DAS28-CRP) and American College of Rheumatology-20 (ACR20). Equivalence was assessed using the equivalent therapeutic alternatives (ETA) guidelines. RESULTS: We included four of 133 potentially relevant studies. IC showed no statistically significant differences between the four JAKi regarding DAS28-CRP < 3.2. Results were similar in terms of ACR20 except for tofacitinib showing lower efficacy than upadacitinib (RAR -18.4% [IC95% -33.4 to -3.5], p=0.0157). Statistically significant differences were related to the relevant difference for tofacitinib in both endpoints. Despite no statistical differences for baricitinib, we observed a probably clinically relevant difference regarding DAS28-CRP. Probably clinically relevant differences were found for tofacitinib vs. upadacitinib in both endpoints, and for baricitinib vs. upadacitinib in DAS28-CRP. Safety, drug-drug interactions, and convenience considerations did not modify the result of therapeutic equivalence assessment based on efficacy data. CONCLUSIONS: In conclusion, our results show that filgotinib and upadacitinib are ETA. Baricitinib and upadacitinib are also ETA due to a lack of clear differences and for showing superiority over placebo. The results for tofacitinib and upadacitinib show some inconsistency and more data are needed. Key Points • To date, neither a head-to-head comparison nor an indirect comparison between the Janus kinase inhibitors has been performed in patients with rheumatoid arthritis and an inadequate response to biologic disease-modifying anti-rheumatic drugs. • We performed an adjusted indirect comparison that included randomized clinical trials of tofacitinib, baricitinib, upadacitinib, and filgotinib to assess their equivalence in this scenario. • Our results show that baricitinib and filgotinib are equivalent therapeutic alternatives compared to upadacitinib. However, there is some inconsistency in the results of tofacitinib in front of upadacitinib.

Predictive performance of glomerular filtration rate equations based on cystatin C, creatinine and their combination in critically ill patients.

OBJECTIVE: 24-hour urine creatinine clearance (ClCr 24 hours) remains the gold standard for estimating glomerular filtration rate (GFR) in critically ill patients; however, simpler methods are commonly used in clinical practice. Serum creatinine (SCr) is the most frequently used biomarker to estimate GFR; and cystatin C, another biomarker, has been shown to reflect GFR changes earlier than SCr. We assess the performance of equations based on SCr, cystatin C and their combination (SCr-Cyst C) for estimating GFR in critically ill patients. METHODS: Observational unicentric study in a tertiary care hospital. Patients with cystatin C, SCr and ClCr 24 hours measurements in ±2 days admitted to an intensive care unit were included. ClCr 24 hours was considered the reference method. GFR was estimated using SCr-based equations: Chronic Kidney Disease Epidemiology Collaboration based on creatinine (CKD-EPI-Cr) and Cockcroft-Gault (CG); cystatin C-based equations: CKD-EPI-CystC and CAPA; and Cr-CystC-based equations: CKD-EPI-Cr-CystC. Performance of each equation was assessed by calculating bias and precision, and Bland-Altman plots were built. Further analysis was performed with stratified data into CrCl 24 hours <60, 60-130 and ≥130 mL/min/1.73 m2. RESULTS: We included 275 measurements, corresponding to 186 patients. In the overall population, the CKD-EPI-Cr equation showed the lowest bias (2.6) and best precision (33.1). In patients with CrCl 24 hours <60 mL/min/1.73 m2, cystatin-C-based equations showed the lowest bias (<3.0) and CKD-EPI-Cr-CystC was the most accurate (13.6). In the subgroup of 60≤ CrCl 24 hours <130mL/min/1.73 m2, CKD-EPI-Cr-CystC was the most precise (20.9). However, in patients with CrCl 24 hours ≥130mL/min/1.73 m2, cystatin C-based equations underestimated GFR, while CG overestimated it (22.7). CONCLUSIONS: Our study showed no evidence of superiority of any equation over the others for all evaluated parameters: bias, precision and Lin's concordance correlation coefficient. Cystatin C-based equations were less biased in individuals with impaired renal function (GFR <60 mL/min/1.73 m2). CKD-EPI-Cr-CystC performed properly in patients with GFR from 60-130 mL/min/1.73 m2 and none of them were accurate enough in patients ≥130 mL/min/1.73 m2.