Gradual tapering TNF inhibitors versus conventional synthetic DMARDs after achieving controlled disease in patients with rheumatoid arthritis: first-year results of the randomised controlled TARA study

Mulligen, Elise van; Jong, Pascal H P de; Kuijper, M.; Ven, Myrthe van der; Appels, Cathelijne; Bijkerk, C.; Harbers, J.B.; Man, Y. de; Molenaar, T.H.E.; Tchetverikov, I.; Goekoop-Ruiterman, Yvonne P M; Zeben, J. van; Hazes, J. M. W.; Weel, A.; Luime, Jolanda J.

doi:10.1136/annrheumdis-2018-214970

Cited by 50 publications

(31 citation statements)

References 30 publications

(41 reference statements)

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“…The recent STRASS study of RA-patients in remission (DAS28 < 2.6) found that relapse was observed more frequently in patients placed on a progressively increased spacing of TNF-blockers injections than those maintained on their previous dosing regimen (76.6% vs 46.5%, p = 0.0004), however the equivalence of the two strategies could not be demonstrated due to an underpowered trial [23]. Most recently, the TARA (TApering strategies in Rheumatoid Arthritis) study, the first randomized controlled study comparing a de-escalation strategy with reduction and discontinuation of synthetic DMARDs versus TNF-blockers, highlighted the importance of first reducing treatment with bDMARDs prior to initiation of synthetic DMARDs therapy [24]. Concerning TCZ tapering, several strategies have been tried, including discontinuation TCZ infusions [12,13], and gradually increasing the RTI to a fixed interval (eg.…”

Section: Discussionmentioning

confidence: 99%

Successful long-term remission through tapering tocilizumab infusions: a single-center prospective study

Ladhari

Blay

Vincent³

et al. 2020

BMC Rheumatol

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Background: Strategic drug therapy for rheumatoid arthritis (RA) patients with prolonged remission is not well defined. According to recent guidelines, tapering biological Disease-Modifying Anti-Rheumatic Drugs (bDMARDs) may be considered. We aimed to evaluate the effectiveness of long-term maintenance of tocilizumab (TCZ) treatment after the progressive tapering of infusions. Methods: We conducted an exploratory, prospective, single-center, open-label study, on RA patients with sustained remission of at least 3 months and treated with TCZ infusions every 4 weeks. The initial re-treatment interval was extended to 6 weeks for the first 3 months. Thereafter, the spacing between infusions was determined by the clinician. Successful long-term maintenance following the tapering of TCZ infusions was defined by patients still treated after two years by TCZ with a minimum dosing interval of 5 weeks. Results: Thirteen patients were enrolled in the study. Eight out of thirteen were still treated by TCZ after two years. Successful long-term maintenance was possible in six patients, with four patients maintaining a re-treatment interval of 8-weeks or more. We observed 5 patients with TCZ withdrawal: one showing adverse drug reaction (neutropenia) and four with secondary failure. Patients achieving successful long-term maintenance with TCZ were significantly younger than those with secondary failure (p < 0.05). In addition, RA patients with positive rheumatoid factor and anti-citrullinated peptide antibodies, experienced a significantly greater number of flares during our 2year follow-up (p < 0.01). Conclusions: A progressive tapering of TCZ infusions may be possible for many patients. However, larger studies, including more patients, are needed to confirm this therapeutic option.

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Section: Discussionmentioning

confidence: 99%

Successful long-term remission through tapering tocilizumab infusions: a single-center prospective study

Ladhari

Blay

Vincent³

et al. 2020

BMC Rheumatol

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“…Доводом в пользу подобной практики может служить и тот факт, что ГИБП или таргетные БПВП чаще всего назначают пациентам, у которых стандартные БПВП оказываются недостаточно эффективными. В рандомизированном исследовании TARA были сопоставлены результаты постепенной отмены (в течение 6 мес) стандартных БПВП или ингибиторов ФНОα у 189 больных РА, у которых была достигнута ремиссия заболевания на фоне комбинированной терапии двумя препаратами [29]. Полной отмене БПВП предшествовало последовательное двукратное снижение дозы в два раза под контролем активности РА, в то время как ингибитор ФНО-α отменяли после увеличения интервала между введениями в два раза и последующего снижения дозы.…”

Section: исследование Oral-shiftunclassified

Janus-kinase inhibitors in rheumatoid and psoriatic arthritis and other rheumatic disease

Novikov¹,

Moiseev²

2020

CPT

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янускиназ: перспективы применения при ревматоидном и псориатическом артрите и других ревматических заболеваниях. Клин фармакол тер 2020;29(1):41-47. [Novikov PI, Moiseev SV. Janus-kinase inhibitors in rheumatoid and psoriatic arthritis and other rheumatic diseases. Klinicheskaya farmakologiya i terapiya = Clin Pharmacol Ther 2020; 29(1):41-47 (In Russ.)].

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“…IL-17 and TNF-α levels were reported to have correlation with RA activity and thus were currently selected as therapy targets (13,14). We analyzed the presence of possible correlation between AMPK levels with IL-17 and TNF-α in the serum samples.…”

Section: Serum P-ampk-α1 Levels Positively Correlated With Disease Acmentioning

confidence: 99%

Adenosine monophosphate-activated protein kinase activator inhibits activation of fibroblast-like synoviocytes but promotes hyaluronan and proteoglycan link protein 1 secretion

Chen

Fujuan

Beijia

et al. 2020

Preprint

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Objectives: To determine whether any correlation exists between disease activity and AMPK levels in rheumatoid arthritis (RA) patients and investigate the effects of AMPK activator treatment on RA fibroblast-like synoviocytes (RA-FLS).Methods: Serum AMPK-α1, p-AMPK-α1, TNF-α and IL-17 levels between osteoarthritis (OA) and RA patients having different disease activities were compared by ELISA. Differentially expressed genes (DEGs) between RA and OA synovium from NCBI GEO Profiles (accession numbers: GSE1202112, GSE55235, GSE5545713) were identified and the genes intersecting in all the three datasets were selected for enrichment analysis. Immunohistochemical staining was done with synovium obtained from OA and RA patients for p-AMPK-α1. AMPK gene expression in synovium was semi-quantified by RT-qPCR. RNA sequencing of FLS was performed and DEGs were selected for KEGG enrichment analysis. AMPK activator, metformin, treated RA-FLS were tested for proliferation and migration by MTT and scratch test, respectively. Expression of IL-6, AMPK-α1, PKA-α, RAPTOR, mTOR, HAPLN1, RUNX1 and RUNX2 genes were determined by qPCR. Phosphorylated AMPK-α1 and HAPLN1 levels were determined by an automated electrophoresis-western blot analysis method.Results: In RA sera, a positive correlation between p-AMPK-α1 levels and DAS28 (r = 0.270, 95%CI: 0.142-0.492, p < 0.0001) as well as CRP levels (r = 0.259, 95%CI: 0.009-0.478, p < 0.05) was found. Similarly, a positive correlation was observed between AMPK-α1 and TNF-α levels (r = 0.460, 95% CI: 0.241-0.640, p = 0.0002). DEGs between OA and RA synovium from NCBI GEO profiles and our RNA sequencing data suggested activation of metabolic pathways specific to RA-FLS. AMPK-α1 was highly expressed in the synovium of RA but not OA patients. Metformin at higher concentrations inhibited RA-FLS proliferation in a dose dependant manner, however, at lower concentrations it has an opposite effect. On the other hand, AMPK inhibitor, dorsmophin, promoted the proliferation of RA-FLS significantly. Interestingly, both metformin and dorsmophin substantially inhibited the migration of RA-FLS. In FLS, relative expression level of IL-6 mRNA was significantly decreased after metformin treatment, while the expression of AMPK-α1, PKA-α and HAPLN1 genes were significantly increased. Western blot analysis confirmed increased expression of p-AMPK-α1 and HAPLN1 genes in the metformin treated FLS.Conclusions: Inflammatory stress in RA synovium leads to an increase in AMPK levels, possibly as a protective mechanism. AMPK activator but not metformin per se could be a potential therapeutic for RA by promoting HAPLN1 secretion to protect the joints.

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Gradual tapering TNF inhibitors versus conventional synthetic DMARDs after achieving controlled disease in patients with rheumatoid arthritis: first-year results of the randomised controlled TARA study

Cited by 50 publications

References 30 publications

Successful long-term remission through tapering tocilizumab infusions: a single-center prospective study

Successful long-term remission through tapering tocilizumab infusions: a single-center prospective study

Janus-kinase inhibitors in rheumatoid and psoriatic arthritis and other rheumatic disease

Adenosine monophosphate-activated protein kinase activator inhibits activation of fibroblast-like synoviocytes but promotes hyaluronan and proteoglycan link protein 1 secretion

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