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Background and Objectives: Long-term treatment of patients with rheumatoid arthritis with tumor necrosis factor-α inhibitors leads to initial changes in disease activity that can predict a late treatment response. This observational and retrospective study aimed to determine when it is possible to foresee the response to therapy in the case of long-standing rheumatoid arthritis comparing also the efficacy of the original biologics with their biosimilars., Methods: A total of 1598 patients were recruited and treated with the original biologics, adalimumab and etanercept, or with biosimilars. Patients were monitored over a period of 48 months and disease activity scores (28-Joint Disease Activity Score, Simplified Disease Activity Index, and Clinical Disease Activity Index) were measured every 6 months., Results: No differences in disease activity levels were observed in etanercept versus biosimilars (GP2015/SB4) and adalimumab versus biosimilar (GP2017) patient groups. All scores significantly decreased in all treatments during the first 18 months of therapy, and after 24 months reached a minimum that lasted up to 48 months., Conclusions: We conclude that biosimilars of adalimumab and etanercept have equivalent effectiveness over a long period of time compared to their originator drugs, and also that the levels of disease activity after 6 months of tumor necrosis factor-α inhibitors (originator drugs and biosimilars) might predict the response to therapy at 4 years in patients with long-standing rheumatoid arthritis., (© 2024. The Author(s).)

Background: The International Medullary Thyroid Carcinoma Grading System (IMTCGS) divides medullary thyroid carcinoma (MTC) into two categories, high- and low-grade tumors, which has a profound impact on patient outcomes. The aim of this study was to explore the association between IMTCGS grading, clinical data, and molecular status in sporadic MTC. Methods: A retrospective cohort study was performed on consecutive sporadic MTCs from patients undergoing initial surgery between January 2000 and January 2022 at the Padua Endocrine Surgery Unit. Clinical, pathological, and follow-up data were collected, tumors were graded, and somatic mutations of RET and RAS genes were analyzed. Patient outcomes were based on Ct levels and MTC-related deaths. Survival analyses were carried out employing the Kaplan-Meier method and the log-rank test. A Cox proportional hazard regression model was employed for multivariable survival analysis with the following covariates: somatic RET mutation, MTC stage at diagnosis, sex, age at diagnosis, and IMTCGS grade. Results: We included 141 consecutive sporadic MTCs. The median follow-up was 80.0 months (interquartile ranges: 41.5-122.5 months). Seventeen patients (12.1%) died from disease-related causes. 107/141 (76.9%) were classified as low-grade tumors, 32/141 (23.1%) as high-grade. Patients carrying a RET mutation had more aggressive features and shorter disease-specific survival (DSS) ( p  = 0.001) and were more frequently classified high-grade than low-grade MTC ( p  < 0.001). At multivariable survival analysis, only IMTCGS grading was independently associated with DSS (hazard ratio 8.8 [confidence interval: 2.7-28.3], p  = 0.005). RET mutations, in particular RET -M918T, were more frequent in high-grade than in low-grade MTC (68.8% vs. 29.4% mutated in RET , 46.9% vs. 12.7% mutated in RET -M918T; p  < 0.001). None of the high-grade tumors was mutated in the RAS gene, but the mutation was present in 11.8% of low-grade tumors. Conclusions: IMTCGS grading was associated with DSS independently of other clinical, pathological, and molecular factors. Moreover, MTC grading was associated with RET and RAS patterns, which explains, at least in part, the molecular basis of the aggressive behavior of high-grade MTC.