Oral Low-Dose Glucocorticoids Should Be Included in Any Recommendation for the Use of Non-Biologic and Biologic Disease-Modifying Antirheumatic Drugs in the Treatment of Rheumatoid Arthritis

Abstract

At present, growing scientific evidence from the medical literature and expert opinion provides strong consideration for a mandatory role of glucocorticoids (GCs) in the management of rheumatoid arthritis (RA). Earlier application strategies were based on initial high doses, with subsequent tapering schedules, resulting in dose-related side effects. Recent low-dose GC schemes are more feasible in routine care, while providing evidence of clinical, functional and structural efficacy. Thus, initial low-dose GC ‘bridging' treatment on a disease-modifying antirheumatic drug background should be included in any existing recommendations for RA management, as very recently advocated by the EULAR Task Force 2013 updated guidelines. Long-term low-dose therapy appears to provide acceptable safety, leading to long-standing slowing of structural damage, seen even after GC therapy withdrawal. Gaps in knowledge about the optimal method to taper and possibly discontinue GC treatment remain, and this topic should be addressed in clinical trials and observational studies. Recent efforts in GC medication have also included the introduction of a modified-release drug formulation capable of drug delivery consistent with chronobiological pathogenetic rhythms of disease, which has been quite efficacious in controlling the signs and symptoms related to pathways of circadian cytokines. Long-term data will further clarify the add-on benefits of such modified-release formulations.

Astrocytic p75NTR expression provoked by ischemic stroke exacerbates the blood–brain barrier disruption

“…Thus, our results indicate that inhibition of astroglial p75 NTR is beneficial for the BBB integrity after OGD/R. p75 NTR was reported to activate NF-κB signaling (Caporali et al, 2015) and p75 NTR can directly interact with the E3 RING ubiquitin ligase (Siah2) which regulates HIF-1α degradation, thus, stabilizes HIF-1α proteins and upregulates VEGF expression under the HIF-1α promotor in hypoxia conditions (Le Moan et al, 2011). Therefore, we next blocked the NF-κB signaling and HIF-1α signaling separately by using their selective inhibitors, JSH-23 and PX-478, to OGD/R (Figure 8f), but not for the decrease of ZO-1 (JSH-23: p = .4412; PX-478: p = .5613) (Figure 8f).…”

“…p75 NTR was reported to activate NF‐ κ B signaling (Caporali et al, 2015) and p75 NTR can directly interact with the E3 RING ubiquitin ligase (Siah2) which regulates HIF‐1 α degradation, thus, stabilizes HIF‐1 α proteins and upregulates VEGF expression under the HIF‐1 α promotor in hypoxia conditions (Le Moan et al, 2011). Therefore, we next blocked the NF‐ κ B signaling and HIF‐1 α signaling separately by using their selective inhibitors, JSH‐23 and PX‐478, respectively.…”

“…In addition, a gelatin zymography assay (a well-established assay for MMP activity, especially MMP9) showed a decreased MMP9 activity (*p < .05) in brain homogenates of p75 NTR cKD mice than the control mice after MCAO, indicating astrocyte p75 NTR knockdown reduced the expression of MMP9 (Figure S3). The intracellular domain (ICD) of p75 NTR activates NF-κB signaling (Caporali et al, 2015;Yuan et al, 2019), which is involved in many inflammation related biopathological processes, including ischemic stroke (Fann et al, 2018;Sivandzade et al, 2019). Furthermore, MMP9 and VEGF has been shown to be upregulated in inflammatory status via activation of NF-κB signaling pathway (Pan et al, 2020;Qin et al, 2019;Wu et al, 2020).…”

Subclinical atherosclerosis and history of cardiovascular events in Italian patients with rheumatoid arthritis

“…[ 56 – 60 ] Although a growing body of evidence suggests new possible therapeutic targets in rheumatic diseases, [ 61 – 64 ] future specific designed studies are needed to entirely elucidate this issue, considering, even today, the central role of CCSs “bridging” therapy in management of these patients. [ 65 ] Furthermore, due to a higher value of missing data concerning body mass index (BMI), we could not evaluate its impact on CVEs and subclinical atherosclerosis. However, it has been shown that during RA, in which sarcopenia may alter the body composition, BMI may not be considered a valid predictor of CVEs and subclinical atherosclerosis, as in normal population.…”

Efeito de drogas sintéticas inibidoras do fator de necrose tumoral alfa na artrite reumatoide em ratos

“…(CAPORALI et al, 2015;CAPORALI et al, 2013;BIANCHI, 2012), a prednisolona é utilizada aqui como droga padrão, por um lado visando comparar sua ação antiartrítica com a das drogas sob estudo e por outro avaliar se sua ação poderia influenciar a ação antiartrítica dessas drogas.Enfim, considerando-se o conhecimento prévio dos efeitos adversos e das medidas de segurança para minimizá-los, do ponto de vista da importância do envolvimento da síntese de TNF-α na AR, é intrigante que nem todas as características do potencial antiartrítico de PTX, TAL, ROL e RUP tenham sido exploradas sistematicamente e com a devida profundidade em modelos animais, de modo a consubstanciar sua posterior indicação formal para ensaios clínicos, visando seu possível reposicionamento na terapêutica dessa doença. Então, sendo essas drogas sintéticas potencialmente inibidoras de TNF-α, seriam elas realmente pouco eficazes nas doenças autoimunes, ou estariam "esquecidas" como alternativas terapêuticas em estudos esparsos realizados num passado carente de conhecimentos e técnicas consolidadas para uma avaliação experimental mais refinada e segura, com maiores dificuldades para um controle mais eficaz de seus eventuais efeitos colaterais e, em geral, para o enfrentamento dessas doenças?1.6.…”