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Reduction of clinical symptoms and serum interleukin-6 (IL-6) levels after nighttime (2 am) and morning (7.30 am) administration of 5.0–7.5 mg of prednisolone for five consecutive days in two groups of RA patients (n=13 in each group).
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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 p...
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Background We describe the early experiences of adults with systemic rheumatic disease who received the COVID-19 vaccine.
Methods From 2 April to 30 April 2021, we conducted an online, international survey of adults with systemic rheumatic disease who received COVID-19 vaccination. We collected patient-reported data on clinician communication, bel...
Leflunomide is a recently developed disease modifying antirheumatic drug that may cause acute diarrhea as an adverse effect. This adverse effect is usually mild and develops during the first few weeks of treatment. In this report, we present a case of rheumatoid arthritis patient with severe diarrhea treated with leflunomide for an extended period...
Objectives
Our goal was to investigate whether cardiovascular disease (CVD) risk factors are associated with the retention of biologic disease‐modifying antirheumatic drugs (bDMARDs) or targeted‐synthetic DMARDs (tsDMARDs) in patients with rheumatoid arthritis (RA).
Methods
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Background: While numerous disease-modifying anti-rheumatic drugs (DMARDs) has brought about a dramatic paradigm shift in the management of rheumatoid arthritis (RA), unmet needs remain such as small proportion of achievement drug-free patients. The aim of this study is to explore key molecules for remission at T cell level, which is known to invol...
Objectives
To analyse glucocorticoid (GC) use and trajectories in a real-life cohort of rheumatoid arthritis (RA).
Methods
Patients with RA included in the longitudinal RCVRIC cohort for initiating or changing biological disease-modifying antirheumatic drugs, were compared for the use of GCs at baseline. Among the GC users, the GC dose was analyse...
Citations
... In the quest for effective treatment modalities, the focus has increasingly shifted towards novel approaches, including the use of immune-modulating agents such as Janus kinase (JAK) inhibitors, among which Tofacitinib has emerged as a promising candidate due to its capacity to modulate immune responses, particularly in autoimmune skin conditions (8). Concurrently, low-dose oral steroids have been a longstanding therapeutic option, attributed to their well-documented anti-inflammatory properties (9,10). Although both treatment strategies have individually demonstrated potential, the absence of comparative studies to assess their relative efficacy and safety in vitiligo treatment underscores a significant gap in the current research landscape (11). ...
Background: Vitiligo is a chronic autoimmune condition characterized by depigmented patches on the skin, presenting significant treatment challenges. Recent studies have focused on the immunomodulatory effects of tofacitinib, a Janus kinase inhibitor, and the anti-inflammatory properties of low-dose oral steroids, yet comparative data on their efficacy and safety are scarce. Objective: The aim of this study was to compare the efficacy and safety of tofacitinib tablets with low-dose oral steroids in the treatment of vitiligo over a six-month period. Methods: This descriptive comparative study involved 42 patients with vitiligo, recruited from the Department of Dermatology at the Combined Military Hospital Abbottabad between November 15, 2022, and November 15, 2023. Participants were randomly assigned to receive either tofacitinib tablets (Group A) or low-dose oral steroids (Group B), with adherence monitored through routine follow-ups. The primary outcome measured was the proportion of repigmentation, assessed using standardized photography and Image software, alongside lesion size reduction and the incidence of adverse events. Statistical analyses were performed using SPSS version 25, with p-values ≤0.05 considered significant. Results: Both groups demonstrated comparable efficacy in terms of repigmentation and lesion size reduction, with no significant difference observed between the tofacitinib (55.8% ± 15.2 repigmentation; 100% lesion size reduction) and low-dose steroid groups (50.2% ± 13.5 repigmentation; 85.71% lesion size reduction) at the 6-month follow-up. The incidence of adverse events was similarly low and statistically non-significant between the two groups. Conclusion: Tofacitinib and low-dose oral steroids are both effective and safe for the treatment of vitiligo, offering valuable options for patient management. Further research with larger sample sizes and longer follow-up is necessary to confirm these findings and evaluate the long-term outcomes of these treatments.
... This can also lead to cost savings and a reduced need for further animal testing in the drug repurposing process. For example, prednisone is a corticosteroid commonly used in humans to treat inflammation and immune-related disorders [74]. It has also been used in dogs to treat various conditions such as allergies, inflammatory diseases, and cancer [75]. ...
The process of discovering small molecule drugs involves screening numerous compounds and optimizing the most promising ones, both in vitro and in vivo. However, approximately 90% of these optimized candidates fail during trials due to unexpected toxicity or insufficient efficacy. Current concepts with respect to drug–protein interactions suggest that each small molecule interacts with an average of 6–11 targets. This implies that approved drugs and even discontinued compounds could be repurposed by leveraging their interactions with unintended targets. Therefore, we developed a computational repurposing framework for small molecules, which combines artificial intelligence/machine learning (AI/ML)-based and chemical similarity-based target prediction methods with cross-species transcriptomics information. This repurposing methodology incorporates eight distinct target prediction methods, including three machine learning methods. By using multiple orthogonal methods for a “dataset” composed of 2766 FDA-approved drugs targeting multiple therapeutic target classes, we identified 27,371 off-target interactions involving 2013 protein targets (i.e., an average of around 10 interactions per drug). Relative to the drugs in the dataset, we identified 150,620 structurally similar compounds. The highest number of predicted interactions were for drugs targeting G protein-coupled receptors (GPCRs), enzymes, and kinases with 10,648, 4081, and 3678 interactions, respectively. Notably, 17,283 (63%) of the off-target interactions have been confirmed in vitro. Approximately 4000 interactions had an IC50 of <100 nM for 1105 FDA-approved drugs and 1661 interactions had an IC50 of <10 nM for 696 FDA-approved drugs. Together, the confirmation of numerous predicted interactions and the exploration of tissue-specific expression patterns in human and animal tissues offer insights into potential drug repurposing for new therapeutic applications.
... Previous studies demonstrated that moxibustion could regulate circadian rhythms of REV-ERBα in RA rats, coupled with the fact that REV-ERBα is involved in the CLOCK/BMAL1 core feedback loop and is a transcriptional repressor of the biological clock cycle [14]. Modified-release prednisone given at bedtime could effectively treat RA [23]. Therefore, we investigated the effects of chrono-moxibustion on the expression of the core clock genes CLOCK and BMAL1 in RA rats and provided a reliable basis for the clinical treatment of RA with moxibustion at the chronotherapeutic level. ...
Objective:
The clinical symptoms of rheumatoid arthritis (RA) have significant circadian rhythms, with morning stiffness and joint pain. Moxibustion is effective in the treatment of RA, while the underlying therapeutic mechanisms remain limited. Thus, we explored whether moxibustion could adjust the circadian rhythm of RA by modulating the core clock genes CLOCK and BMAL1 at the molecular level.
Methods:
144 Sprague Dawley rats were randomly divided into four groups: control group (group A), model group (group B), 7-9 am moxibustion treatment group (group C), and 5-7 pm moxibustion treatment group (group D). Each group was divided into 6 time points (0 am, 4 am, 8 am, 12 N, 6 pm, and 8 pm) with an equal number of rats at each time point. Except for group A, all rats were injected with Freund's Complete Adjuvant (FCA) 0.15 ml on the right foot pad to establish the RA model. The rats of the two moxibustion treatment groups were respectively subjected to moxibustion at 7-9 am and 5-7 pm. After 3 weeks of treatment, the tissues were collected at 6 time points during the next 24 hours. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was used to test the mRNA expression of CLOCK and BMAL1 in the hypothalamus and synovial tissues. CLOCK and BMAL1 protein expression in synovial tissues were detected with western blot.
Results:
Compared to group A, group B showed significantly down-regulated expression levels of CLOCK and BMLA1 at synovial tissue (P < 0.05), while no statistically significant difference was found in the hypothalamus (P > 0.05). The expression levels of CLOCK and BMLA1 were up-regulated in the moxibustion treatment groups in different tissues, especially in synovial tissue (P < 0.05) compared to group B. Nevertheless, no difference was observed between groups C and D (P > 0.05).
Conclusions:
Moxibustion could treat RA by modulating clock core genes CLOCK and BMAL1 to regulate the circadian rhythm. However, there was no significant difference between the 7-9 am moxibustion treatment group and the 5-7 pm moxibustion treatment group. This study provides a basis for research on moxibustion in the treatment of RA.
... Modified-Release (MR) prednisone taken at night (administration at 10 pm and release from the capsule after 4 h at 3-4 am) was shown to be highly effective in abolishing the IL-6 morning peak, with improvement in morning stiffness that was substantially greater than what was observed with conventional immediaterelease prednisolone [31][32][33]. Similar to the glucocorticoid chronotherapy results, Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) taken at night have been reported to be more effective in controlling morning signs and symptoms of RA than either morning or daytime dosing. ...
... Modified-release prednisone, by taking advantage of the circadian fluctuations of inflammatory cytokines, cortisol, and morning symptoms, can be given at bedtime to be released approximately 4 hours later. Clinical trials have shown that modified-release prednisone was more effective than a long-term, low-dose glucocorticoid treatment in patients with RA. 117,118 As a result, it has been proposed that biological disease-modifying antirheumatic drugs and nonsteroidal anti-inflammatory drugs should be administered based on similar chronotherapy rules. 119 In an animal model using serum from MRL/lpr mice, TNF-α mRNA levels showed a 24-hour rhythm with a peak at 22 hours after light was turned on (HALO) and a trough at 18 HALO after RA had developed. ...
Pancreatitis, in both acute and chronic forms, poses a major therapeutic challenge and is associated with great morbidity and several complications. The nature of pancreatic injury in chronic pancreatitis (CP) and the wide range of causative processes that lead to CP have made effective therapy a true unmet need. Multiple physiological, genetic, environmental, and behavioral factors contribute to the development of CP. As a result, several fields of research are aimed at identifying and addressing the factors that contribute to pancreatic injury. In this article, we review the current understanding of the pathogenesis and natural history of CP. We focus on the autonomous nervous system, immune system, and role of a chronobiological therapeutic approach to alleviate symptoms and prevent or reverse pancreatic injury associated with CP. We aim to demonstrate that individualizing chronopharmacological treatments for CP is a promising direction for future treatment using immune, nervous, and circadian systems.
... Le pourcentage de patients pouvant interrompre la corticothérapie varie de 12,6 à 33,3% avec une dose nulle ou < 7,5 mg/j. De façon générale, l'épargne cortisonique doit être atteinte le plus rapidement possible avec une gestion adaptée à l'état clinique et à la disponibilité des traitements de fond (Berthelot et al., 2002, Bressolle et al., 1998, Wolde et al., 1996, Beltrametti et al., 2016. ...
Objectif : Evaluer la gestion et l’efficacité des DMARDs conventionnels chez les patients souffrant de PR au Bénin. Patients et Méthode : Etude transversale et analytique portant sur les patients suivis pour une PR et traitée par DMARDs. Le diagnostic de PR a été retenu sur la base des critères EULAR/ACR 2010. Les données recueillies ont été analysées grâce au logiciel SPSS17.0 Résultats : 156 patients souffrant de PR ont été évalués. L'âge moyen des patients était de 44,6 ± 14,1 [15-69] ans et le sex- ratio était de 0,14. Le facteur rhumatoïde était présent chez 88%, les anticorps anti-CCP étaient présents chez 69.20%. L’âge moyen de début de la maladie était 32,7 ± 7.03 [18-50]. La durée moyenne d’évolution était de 10,3 ± 7,1 [0,5-25] ans. Le DAS28 moyen au début était 5,71± 2.04. Au plan radiologique, le score moyen de Larsen était de 38,55 ± 16,94. La dose moyenne de Prednisone était de 15 mg/jour. Les DMARDs utilisés étaient : Méthotrexate 15 à 20mg/semaine (150 cas), le léflunomide (6 cas), la salazopyrine 2g/j (27cas), hydroxychloroquine 400 mg / jour (24 cas). A 24 mois, le DAS28 moyen était de 3, 91±2,01 et 23,7% des patients avaient une PR active. Conclusion : La disponibilité des DMARDs pose un problème dans notre pays. Leur utilisation rationnelle associée à une faible dose de prednisone permet d’épargner aux patients une biothérapie dont le coût reste hors de la portée des patients de notre pays à faible revenu. Aim: To evaluate the management and efficacy of conventional DMARDs in RA patients in Benin. Patients and Method: Transversal and analytical study of patients followed for RA and treated with DMARDs. The diagnosis of RA was selected on the basis of EULAR/ACR 2010 criteria. The data collected were analysed using SPSS17.0 software. Results: 156 RA patients were evaluated. The mean age of the patients was 44.6 ± 14.1 [15-69] years and the sex ratio was 0.14. The mean age of the patients was 44.6 ± 14.1 [15-69] and the sex ratio was 0.14. Rheumatoid factor was present in 88%, anti-CCP antibodies were present in 69.20%. The mean age of disease onset was 10.3 ± 7.1 [0.5-25] years. The mean time to progression was 8.9 ± 7.7 [1-30]. The mean DAS28 at onset was 5.71± 2.04 [1-30]. Radiologically, the mean feedback score was 38.55 ± 16.94 [1-30]. The mean dose of Prednisone was 15 mg/day. The DMARDs used were: methotrexate 15-20 mg/week (150 cases), leflunomide (6 cases), salazopyrin 2g/day (27 cases), hydroxychloroquine 400 mg/day (24 cases). At 24 months, mean DAS28 was 3.91±2.01 and 23.7% of patients had active RA. Conclusion: Availability of DMARDs is a problem in our country. Their rational use associated with a low dose of prednisone saves patients from biotherapy, the cost of which remains out of reach for low-income patients in our country.
... To obtain sufficient cells for analysis, as we were limited in sampling frequency, we selected dawn and dusk (06:00 and 18:00); these time points had previously been found to show the greatest difference in multiple animal models of circadian control of inflammation [21]. Additionally, the peak of clinical RA disease activity is at 06:00 [22] at the end of the rest phase. Comparing gene expression between RA patients and healthy controls, we found 1547 genes (Fig. 2a) to be differentially expressed at 06:00, but in marked contrast, only 287 genes (Fig. 2b) at 18:00, emphasising the magnitude of the circadian effect. ...
Objective
We applied systems biology approaches to investigate circadian rhythmicity in rheumatoid arthritis (RA).
Methods
We recruited adults (age 16–80 years old) with a clinical diagnosis of RA (active disease [DAS28 > 3.2]). Sleep profiles were determined before inpatient measurements of saliva, serum, and peripheral blood mononuclear leukocytes (PBML). Transcriptome and proteome analyses were carried out by RNA-SEQ and LC-MS/MS. Serum samples were analysed by targeted lipidomics, along with serum from mouse collagen induced-arthritis (CIA). Bioinformatic analysis identified RA-specific gene networks and rhythmic processes differing between healthy and RA.
Results
RA caused greater time-of-day variation in PBML gene expression, and ex vivo stimulation identified a time-of-day-specific RA transcriptome. We found increased phospho-STAT3 in RA patients, and some targets, including phospho-ATF2, acquired time-of-day variation in RA. Serum ceramides also gained circadian rhythmicity in RA, which was also seen in mouse experimental arthritis, resulting from gain in circadian rhythmicity of hepatic ceramide synthases.
Conclusion
RA drives a gain in circadian rhythmicity, both in immune cells, and systemically. The coupling of distant timing information to ceramide synthesis and joint inflammation points to a systemic re-wiring of the circadian repertoire. Circadian reprogramming in response to chronic inflammation has implications for inflammatory co-morbidities and time-of-day therapeutics.
Electronic supplementary material
The online version of this article (10.1186/s13075-019-1825-y) contains supplementary material, which is available to authorized users.
... In fact, DR/MR has demonstrated considerable improvement in morning stiffness in comparison with IR [234][235][236]. Morning stiffness in RA patients is a function of the imbalance between IL-6 (a pro-inflammatory cytokine involved in RA pathogenesis [237]) and cortisol (anti-inflammatory) in the mornings (a circadian routine) [238]. DR/ MR administration at bedtime modifies this imbalance, thereby mitigating morning stiffness [238,239]. ...
... Morning stiffness in RA patients is a function of the imbalance between IL-6 (a pro-inflammatory cytokine involved in RA pathogenesis [237]) and cortisol (anti-inflammatory) in the mornings (a circadian routine) [238]. DR/ MR administration at bedtime modifies this imbalance, thereby mitigating morning stiffness [238,239]. In terms of safety profiles, no significant difference was observed between the DR/MR and IR modes of therapy [240]. ...
... Rheumatoid arthritis (RA), an autoimmune disorder which affects about 0.5-1% people results in significant morbidity and mortality because of extra articular problems and associated comorbidities [1][2][3]. Similarly, articular mobility and disability is also a major concern in RA. Glucocorticoids (GCs) and Disease Modifying Anti-Rheumatic Drugs (DMARDs) are common medicines used in the management of RA. ...
... These drugs also exert disease-modifying effect, especially when used in the early stage of the disease [6,7] and may avoid development of severe consequences in patients with severe clinical presentation at the beginning [8]. Even after their presence for more than six decade and introduction of other therapies, GCs remain the cornerstone therapy for management of RA [2,6,9]. Despite wide experience, several questions about use of GCs still remain unanswered. ...
... As documented in literature [2,4,13,14], GCs are widely used and are an important therapy for the management of RA in India. About three forth physicians use GC "sometimes to always" in the initial treatment of RA. ...
Background: Several questions about use of glucocorticoids in rheumatoid arthritis are unanswered.
Objective: Understanding perspectives of physicians regarding use of glucocorticoids in rheumatoid arthritis management.
Material and methods: Rheumatologists were interviewed to understand their perspectives and experiences on use of glucocorticoids in rheumatoid arthritis treatment.
Results: Of the enrolled 150 physicians, 74% reported using glucocorticoids "sometimes to always" in the initial treatment whereas 143 (95.4%) reported it using "sometimes to always" in acute exacerbations; 40% sometimes as an adjuvant to disease modifying antirheumatic drugs therapy. Oral low dose prednisolone or equivalent (<15 mg/day) is used by 101 (67.3%) physicians in up to 50% patients. Intra-articular low dose and high dose steroid injections are used by 98 (65.3%) and 55 (36.7%) physicians in up to 50% patients respectively. All physicians used oral methylprednisolone whereas prednisone, triamcinolone and hydrocortisone was used by 98.7%, 98.7% and 97.3% physicians respectively. For short term course, 92 (61.3%) physicians prescribe 5-10 mg/day of prednisone or equivalent. Clinical improvement is excellent and very good according to 36.7% and 44.0% physicians. Functional improvement is excellent and very good according to 26.7% and 38.7% respectively. Weight gain, puffiness of face, fluid retention, osteoporosis, hyperglycemia, hypertension, nausea, weakness, infection, cataract, sleep disturbances, psychosis and glaucoma were the adverse events reported by 121 (80.7%), 115 (76.7%), 100 (66.7%), 87 (58%), 81 (54%), 56 (37.3%), 51 (34.4%),46 (30.7%),44 (29.3%), 36 (24%),29 (19.3%), 23 (15.3%) and 19 (12.7%) physicians in past six months respectively.
Conclusion: Steroids usage for the treatment of rheumatoid arthritis in adult patients is very common among rheumatologists in India. According to this physicians´s opinion based survey, overall tolerability, safety and patient compliance with oral GCs is fair to excellent. Short term use is not a major concern from safety point of view.
The study of the multifaceted interactions between neuroscience and cancer is an emerging field with significant implications for understanding tumor biology and the innovation in therapeutic approaches. Increasing evidence suggests that neurological functions are connected with tumorigenesis. In particular, the peripheral and central nervous systems, synapse, neurotransmitters, and neurotrophins affect tumor progression and metastasis through various regulatory approaches and the tumor immune microenvironment. In this review, we summarized the neurological functions that affect tumorigenesis and metastasis, which are controlled by the central and peripheral nervous systems. We also explored the roles of neurotransmitters and neurotrophins in cancer progression. Moreover, we examined the interplay between the nervous system and the tumor immune microenvironment. We have also identified drugs that target the nervous system for cancer treatment. In this review we present the work supporting that therapeutic agent targeting the nervous system could have significant potential to improve cancer therapy.
