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Chronotherapy with low-dose modified-release prednisone for the management of rheumatoid arthritis: a review.

ABSTRACT: To date, rheumatoid arthritis (RA) remains a debilitating, life-threatening disease. One major concern is morning symptoms (MS), as they considerably impair the patients' quality of life and ability to work. MS change in a circadian fashion, resembling the fluctuations of inflammatory cytokines such as interleukin-6, whose levels are higher in RA patients compared to healthy donors. Conversely, serum levels of the potent anti-inflammatory glucocorticoid cortisol are similar to that of healthy subjects, suggesting an imbalance that sustains a pro-inflammatory state. From a therapeutic point of view, administering synthetic glucocorticoids (GCs) to RA patients represents an optimal strategy to provide for the inadequate levels of cortisol. Indeed, due to their high efficacy in RA, GCs remain a cornerstone more than 60 years after their first introduction, and despite the development of a wide range of targeted agents. However, to improve safety, low-dose GCs have been introduced, that have demonstrated high efficacy in reducing disease activity, radiological progression, and improving patients' signs and symptoms especially in early RA when added to conventional disease-modifying antirheumatic drugs. A further improvement has been provided by the development of modified-release prednisone, which, by taking advantage of the circadian fluctuations of inflammatory cytokines, cortisol and MS, is given at bedtime to be released approximately 4 hours later. Several studies have already demonstrated the efficacy of this agent on disease activity, MS, and quality of life in the setting of established RA. Moreover, preliminary studies have shown that this new formulation not only has no impact on the adrenal function, but likely improves it. This review is a comprehensive, updated summary of the current evidence on the use of GCs in RA, with focus on the efficacy and safety of low-dose prednisone and modified-release prednisone, the latter representing a rational, cost-effective, and tailored approach to maximize the benefit/risk ratio in RA patients.

SUBMITTER: Beltrametti SP

PROVIDER: S-EPMC5123661 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Chronotherapy with low-dose modified-release prednisone for the management of rheumatoid arthritis: a review.

Beltrametti Stefano Paolo SP Ianniello Aurora A Ricci Clara C

Therapeutics and clinical risk management 20161121

To date, rheumatoid arthritis (RA) remains a debilitating, life-threatening disease. One major concern is morning symptoms (MS), as they considerably impair the patients' quality of life and ability to work. MS change in a circadian fashion, resembling the fluctuations of inflammatory cytokines such as interleukin-6, whose levels are higher in RA patients compared to healthy donors. Conversely, serum levels of the potent anti-inflammatory glucocorticoid cortisol are similar to that of healthy su ...[more]

PMID: 27920546

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Project description:IntroductionRheumatoid arthritis (RA) produces debilitating morning stiffness. Exogenous glucocorticoids can help with these symptoms when timed appropriately. Bedtime dosing of delayed-release prednisone (DR-prednisone) matches the rise of inflammatory cytokines before awakening and can improve stiffness and other RA symptoms. A prospective open-label study was conducted in patients currently on stable doses of immediate-release prednisone (IR-prednisone) who were switched to DR-prednisone to analyze the incremental benefit of better timed and lower dose glucocorticoid therapy.MethodsTwelve US sites enrolled patients with moderate-severe RA into a 12-week prospective study. Patients were switched from IR- to DR-prednisone while maintaining other existing background therapies. Change from baseline in morning stiffness severity, morning stiffness duration, swollen and tender joint counts (S-TJC), 28 joint disease activity score (DAS28), and patient/physician global assessment (PGA/PhGA), among others, were measured. Post-hoc analyses were performed on those completing 10 weeks of treatment and those with >60 min of morning stiffness at baseline.ResultsFifty-six patients had at least one follow-up visit and were similar in demographics to previous controlled trials with DR-prednisone with regard to baseline age and DAS28-CRP but had lower morning stiffness and RA duration. DR-prednisone produced a trend toward lower morning stiffness severity and duration with a reduction in daily prednisone dose of almost 1 mg. Patients treated with DR-prednisone for ≥10 weeks demonstrated significant reductions in morning stiffness duration, SJC, TJC, DAS28-CRP, and PhGA (all p ≤ 0.04). Patients treated for ≥10 weeks with >60 min of baseline morning stiffness produced similar results in these measures as well as a 21% reduction in morning stiffness severity (p = 0.02).ConclusionPatients switched to DR-prednisone from IR-prednisone in this practice-based study maintained or improved their outcomes across a variety of domains, and results were comparable to previous controlled trials in which patients completed at least 10 weeks of treatment.FundingHorizon Pharma USA, Inc.Trial registrationClinicalTrials.gov identifier, NCT02287610.

Project description:Angiogenesis plays an essential role in the progression of rheumatoid arthritis (RA). RGD peptide shows high affinity and selectivity for integrin ?v?3, which is one of the most extensively examined target of angiogenesis. Nimesulide could improve the anti-rheumatic profile of methotrexate. But the clinical application was limited due to water-insolubility of both methotrexate and nimesulide and lacking targeting ability. Therefore, this study aimed to design a targeted drug delivery system of micelles mediated by RGD plus the passive targeting of micelles to solve the application problems of methotrexate and nimesulide (M/N), and thus enhance their combined therapeutic effect on RA. Methods: RGD was conjugated with NHS-PEG-PLA to form RGD-PEG-PLA for the preparation of RGD-modified drug-loaded micelles (R-M/N-PMs). The size and zeta potential of micelles were measured by dynamic light scattering. Morphology was detected by transmission electron microscopy. The inhibition effect of R-M/N-PMs on angiogenesis was assessed by the chick chorioallantoic membrane assay. The real-time fluorescence imaging analysis was conducted to examine the in vivo distribution of the fluorescence-labeled R-M/N-PMs. Rats arthritis model induced by Freund's adjuvant was used to evaluate the in vivo anti-inflammatory efficacy of R-M/N-PMs. Results: The in vitro study indicated successful development of R-M/N-PMs. R-M/N-PMs could markedly suppress the angiogenesis of chick embryos. The fluorescence-labeled R-M/N-PMs mainly accumulated in arthritic joints. RGD enhanced the targeting ability of micelles and thus promoted retention of micelles in arthritic joints. Moreover, R-M/N-PMs significantly alleviated the joint swelling while reducing bone erosion and serum levels of inflammatory cytokines. It helped to recover the bone microstructure of arthritic rats. Conclusion: Our results confirmed that the targeted delivery of the combination of a low dose of methotrexate and nimesulide mediated by RGD-modified polymeric micelles could enhance the therapeutic effect on rheumatoid arthritis. These findings provide a promising potential for the clinical therapy of rheumatoid arthritis.

Project description:IntroductionAlthough bDMARDs are effective in the treatment of RA, they are associated with dose-dependent side effects, patient burden, and high costs. Recently, many studies have investigated the possibility of discontinuing or tapering bDMARDs when patients have reached their treatment goal. The aim of this review is to provide a narrative overview of the existing evidence on bDMARD dose reduction and to provide answers to specific dose-reduction-related questions that are of interest to clinicians.MethodsWe systematically searched for relevant studies in four scientific databases. Furthermore, we screened the references of reviews and relevant studies.ResultsOur searches resulted in 45 original studies of bDMARD dose reduction in RA patients (15 RCTs and 30 observational studies). Current evidence shows that bDMARD dose reduction can be considered in all RA patients who achieve stable (e.g., ≥6 months) low disease activity or remission. The best strategies seem to be disease-activity-guided dose optimization and fixed dose reduction, since direct bDMARD discontinuation (without restarting) results in a high flare rate, worse physical functioning, and more joint damage. When tapering the bDMARD treatment of a patient, disease activity should be monitored closely, and if a flare occurs, the dose should be increased to the lowest effective dose. Current evidence shows that restarting bDMARD treatment is effective and safe. Unfortunately, no clear predictors of successful dose reduction have been identified so far.ConclusionThe current evidence and rising healthcare costs urge that dose reduction should be considered for eligible patients. However, the decision to start dose reduction should be made in shared decision-making. Future research should focus not only on a better understanding of the effects of dose reduction on clinical outcomes but also on the perspectives of patients and physicians as well as the implementation of this new treatment principle.

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Chronotherapy with low-dose modified-release prednisone for the management of rheumatoid arthritis: a review.

Publications

Chronotherapy with low-dose modified-release prednisone for the management of rheumatoid arthritis: a review.

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