Baricitinib inhibits structural joint damage progression in patients with rheumatoid arthritis – a comprehensive review

Baricitinib is an oral selective inhibitor of Janus kinase (JAK)1 and JAK2 that has proved effective and well tolerated in the treatment of rheumatoid arthritis (RA) in an extensive programme of clinical studies of patients with moderate-to-severe disease. In a phase 2b dose-ranging study of baricitinib in combination with traditional disease-modifyingantirheumatic drugs (DMARDs) in RA patients, magnetic resonance imaging showed that baricitinib 2 mg or 4 mgonce daily provided dose-dependent suppression of synovitis, osteitis, erosion and cartilage loss at weeks 12 and 24versus placebo. These findings correlated with clinical outcomes and were confirmed in three phase 3 studies (RA-BEGIN, RA-BEAM and RA-BUILD) using X-rays to assess structural joint damage. In patients naïve to DMARDs (RA-BEGINstudy), baricitinib 4 mg once daily as monotherapy or combined with methotrexate produced smaller mean changesin structural joint damage than methotrexate monotherapy at week 24. Differences versus methotrexate werestatistically significant for combined therapy. In patients responding inadequately to methotrexate (RA-BEAM study),baricitinib 4 mg plus background methotrexate significantly inhibited structural joint damage at week 24 versus placebo, and the results were comparable to those observed with adalimumab plus background methotrexate. Inpatients responding inadequately to conventional synthetic DMARDs (csDMARDs; RA-BUILD study), baricitinib 4 mgagain significantly inhibited radiographic progression compared with placebo at week 24. Benefits were also observedwith baricitinib 2 mg once daily, but the effects of baricitinib 4 mg were more robust. The positive effects of baricitinib4 mg on radiographic progression continued over 1 and 2 years in the long-term extension study RA-BEYOND, withsimilar effects to adalimumab and significantly greater effects than placebo. Findings from the phase 3 studies ofpatients with RA were supported by preclinical studies, which showed that baricitinib has an osteoprotective effect, increasing mineralisation in bone-forming cells. In conclusion, baricitinib 4 mg once daily inhibits radiographic jointdamage progression in patients with moderate-to-severe RA who are naïve to DMARDs or respond inadequately to csDMARDs, including methotrexate, and the beneficial effects are similar to those observed with adalimumab

Climatic predictors of species distributions neglect biophysiologically meaningful variables

This is the final version. Available on open access from Wiley via the DOI in this record.Aim: Species distribution models (SDMs) have played a pivotal role in predicting how species might respond to climate change. To generate reliable and realistic predictions from these models requires the use of climate variables that adequately capture physiological responses of species to climate and therefore provide a proximal link between climate and their distributions. Here, we examine whether the climate variables used in plant SDMs are different from those known to influence directly plant physiology. Location: Global. Methods: We carry out an extensive, systematic review of the climate variables used to model the distributions of plant species and provide comparison to the climate variables identified as important in the plant physiology literature. We calculate the top ten SDM and physiology variables at 2.5 degree spatial resolution for the globe and use principal component analyses and multiple regression to assess similarity between the climatic variation described by both variable sets. Results: We find that the most commonly used SDM variables do not reflect the most important physiological variables and differ in two main ways: (i) SDM variables rely on seasonal or annual rainfall as simple proxies of water available to plants and neglect more direct measures such as soil water content; and (ii) SDM variables are typically averaged across seasons or years and overlook the importance of climatic events within the critical growth period of plants. We identify notable differences in their spatial gradients globally and show where distal variables may be less reliable proxies for the variables to which species are known to respond. Main conclusions: There is a growing need for the development of accessible, fine-resolution global climate surfaces of physiological variables. This would provide a means to improve the reliability of future range predictions from SDMs and support efforts to conserve biodiversity in a changing climate

Patient disease trajectories in rheumatoid arthritis patients treated with baricitinib 4-mg in 4 phase 3 clinical studies

Introduction: We sought to identify and compare treatment response groups based on individual patient responses (rather than group mean response) over time on the Clinical Disease Activity Index (CDAI) for rheumatoid arthritis (RA), in patients treated with baricitinib 4 mg in 4 Phase 3 studies. Methods: Trajectory subgroups were identified within each study using growth mixture modeling. Following grouping, baseline characteristics and disease measures were summarized and compared. Results: In each study, 3 response trajectories were identified. In the 3 studies of patients naïve to biological disease modifying anti rheumatic drugs (bDMARDs) patients had, on average, high disease activity, as measured by CDAI. In these studies, a group of rapid responders (65 71% of patients) had the lowest baseline CDAI scores and achieved mean CDAI ≤10 by week 16. Gradual responders (10 17%) had higher baseline CDAI, but generally achieved low disease activity (CDAI ≤10) by Week 24. A group of partial responders (18 22%) had higher baseline CDAI and did not achieve mean CDAI ≤10. In bDMARD experienced patients, the subgroups were rapid responders, who achieved mean CDAI ≤10 (42% of patients); partial responders, with mean CDAI decrease of ~15 points from baseline (42% of patients); and limited responders (15% of patients). Changes in modified total sharp score (mTSS; assessed only in biologic-naïve patients) were below the smallest detectable difference at 24/52 weeks for >90% of patients in each group, excepting partial responders in RA-BEGIN (≥75% no detectable change). Discussion and Conclusion: In patients receiving baricitinib 4-mg, lower baseline CDAI was generally associated with rapid response, while higher baseline CDAI scores were generally seen for patients who either reached treatment targets more gradually, or who had a partial or limited response. Maintenance of response was observed with continued baricitinib treatment in all response groups and generally included maintenance of mTSS.</p