Hospitalization transfers from a skilled-nursing facility were studied. A hierarchically arranged questionnaire on acute medical deterioration and treatment aggressiveness was used to study the ...degree of discordance between the transfers actually made and the preferences of nursing home head nurses. According to the nurses, 37 per cent of the patients involved should not have been hospitalized even under the most compelling circumstances; however, 76 per cent of this subgroup had in fact been hospitalized under physician's orders. The nurses would have refrained from instituting any new treatment in 14 per cent of the cases, all of which involved chronic neurological impairments; 36 per cent of this subgroup had nevertheless been hospitalized in the 12 months prior to the study.
To develop treat-to-target (T2T) recommendations in giant cell arteritis (GCA) and polymyalgia rheumatica (PMR).
A systematic literature review was conducted to retrieve data on treatment targets and ...outcomes in GCA/PMR as well as to identify the evidence for the effectiveness of a T2T-based management approach in these diseases. Based on evidence and expert opinion, the task force (29 participants from 10 countries consisting of physicians, a healthcare professional and a patient) developed recommendations, with consensus obtained through voting. The final level of agreement was provided anonymously.
Five overarching principles and six-specific recommendations were formulated. Management of GCA and PMR should be based on shared decisions between patient and physician recognising the need for urgent treatment of GCA to avoid ischaemic complications, and it should aim at maximising health-related quality of life in both diseases. The treatment targets are achievement and maintenance of remission, as well as prevention of tissue ischaemia and vascular damage. Comorbidities need to be considered when assessing disease activity and selecting treatment.
These are the first T2T recommendations for GCA and PMR. Treatment targets, as well as strategies to assess, achieve and maintain these targets have been defined. The research agenda highlights the gaps in evidence and the need for future research.
To update the evidence on the efficacy and safety of pharmacological agents in psoriatic arthritis (PsA).
Systematic literature review of randomised controlled trials comparing pharmacological ...interventions in PsA: non-steroidal anti-inflammatory drugs, glucocorticoid, synthetic disease modifying antirheumatic drugs (sDMARDs) either conventional or targeted, biologicals (bDMARDs), placebo or any combination. Main outcomes were American College of Rheumatology (ACR)20-50, Psoriasis Area Severity Index 75, radiographic progression, and withdrawals due to adverse events (AEs). Multiple studies of the same intervention were meta-analysed using random effects.
In total, 25 papers and 12 abstracts were included. The efficacy of tumour necrosis factor inhibitors (including the recently added golimumab and certolizumab pegol) was confirmed and 16 articles/abstracts focused on 3 drugs with new modes of action: ustekinumab (UST), secukinumab (SEC) and apremilast (APR). All were placebo-compared trials and met their primary end point, ACR20. In 2 studies with UST ACR20 was met by 50% and 44% of patients with UST 90 mg, 42% and 44% with UST 45 mg vs 23% and 20% with placebo, respectively. In two studies with SEC ACR20 ranged 54% (SEC 300 mg), 50-51% (SEC 150 mg), 29-51% (SEC 75 mg) and 15-17% (placebo). In four studies with APR, ACR20 ranged 32-43% (APR 30 mg), 29-38% (APR 20 mg) and 17-20% (placebo). For all three drugs, no more withdrawals due to AEs than placebo were seen and, in general, safety appeared satisfactory. A strategy trial, TIght COntrol of Psoriatic Arthritis (TICOPA), showed better ACR responses with treatment adaptations upon tight control compared with standard care.
UST, SEC and APR are new drugs with efficacy demonstrated for the treatment of PsA. No major safety signals arise, but long-term studies are needed. This review informed about the European League Against Rheumatism recommendations for management of PsA.
Recent therapeutic advances in juvenile idiopathic arthritis (JIA) have made remission an achievable goal for most patients. Reaching this target leads to improved outcomes. The objective was to ...develop recommendations for treating JIA to target. A Steering Committee formulated a set of recommendations based on evidence derived from a systematic literature review. These were subsequently discussed, amended and voted on by an international Task Force of 30 paediatric rheumatologists in a consensus-based, Delphi-like procedure. Although the literature review did not reveal trials that compared a treat-to-target approach with another or no strategy, it provided indirect evidence regarding an optimised approach to therapy that facilitated development of recommendations. The group agreed on six overarching principles and eight recommendations. The main treatment target, which should be based on a shared decision with parents/patients, was defined as remission, with the alternative target of low disease activity. The frequency and timeline of follow-up evaluations to ensure achievement and maintenance of the target depend on JIA category and level of disease activity. Additional recommendations emphasise the importance of ensuring adequate growth and development and avoiding long-term systemic glucocorticoid administration to maintain the target. All items were agreed on by more than 80% of the members of the Task Force. A research agenda was formulated. The Task Force developed recommendations for treating JIA to target, being aware that the evidence is not strong and needs to be expanded by future research. These recommendations can inform various stakeholders about strategies to reach optimal outcomes for JIA.
This study investigated the effects of dose step-down in patients with rheumatoid arthritis (RA) who achieved sustained disease control with baricitinib 4 mg once a day.
Patients who completed a ...baricitinib phase 3 study could enter a long-term extension (LTE). In the LTE, patients who received baricitinib 4 mg for ≥15 months and maintained CDAI low disease activity (LDA) or remission (REM) were blindly randomised to continue 4 mg or taper to 2 mg. Patients could rescue (to 4 mg) if needed. Efficacy and safety were assessed through 48 weeks.
Patients in both groups maintained LDA (80% 4 mg; 67% 2 mg) or REM (40% 4 mg; 33% 2 mg) over 48 weeks. However, dose reduction resulted in small, statistically significant increases in disease activity at 12, 24 and 48 weeks. Dose reduction also produced earlier and more frequent relapse (loss of step-down criteria) over 48 weeks compared with 4 mg maintenance (23% 4 mg vs 37% 2 mg, p=0.001). Rescue rates were 10% for baricitinib 4 mg and 18% for baricitinib 2 mg. Dose reduction was associated with a numerically lower rate of non-serious infections (30.6 for baricitinib 4 mg vs 24.9 for 2 mg). Rates of serious adverse events and adverse events leading to discontinuation were similar across groups.
In a large randomised, blinded phase 3 study, maintenance of RA control following induction of sustained LDA/REM with baricitinib 4 mg was greater with continued 4 mg than after taper to 2 mg. Nonetheless, most patients tapered to 2 mg could maintain LDA/REM or recapture with return to 4 mg if needed.
Pheochromocytomas and paragangliomas (PPGLs) provide some of the clearest genetic evidence for the critical role of metabolism in the tumorigenesis process. Approximately 40% of PPGLs are caused by ...driver germline mutations in 16 known susceptibility genes, and approximately half of these genes encode members of the tricarboxylic acid (TCA) cycle. Taking as a starting point the involvement of the TCA cycle in PPGL development, we aimed to identify unreported mutations that occurred in genes involved in this key metabolic pathway and that could explain the phenotypes of additional individuals who lack mutations in known susceptibility genes. To accomplish this, we applied a targeted sequencing of 37 TCA-cycle-related genes to DNA from 104 PPGL-affected individuals with no mutations in the major known predisposing genes. We also performed omics-based analyses, TCA-related metabolite determination, and 13C5-glutamate labeling assays. We identified five germline variants affecting DLST in eight unrelated individuals (∼7%); all except one were diagnosed with multiple PPGLs. A recurrent variant, c.1121G>A (p.Gly374Glu), found in four of the eight individuals triggered accumulation of 2-hydroxyglutarate, both in tumors and in a heterologous cell-based assay designed to functionally evaluate DLST variants. p.Gly374Glu-DLST tumors exhibited loss of heterozygosity, and their methylation and expression profiles are similar to those of EPAS1-mutated PPGLs; this similarity suggests a link between DLST disruption and pseudohypoxia. Moreover, we found positive DLST immunostaining exclusively in tumors carrying TCA-cycle or EPAS1 mutations. In summary, this study reveals DLST as a PPGL-susceptibility gene and further strengthens the relevance of the TCA cycle in PPGL development.
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