Efficacy and safety study of targeted small-molecule drugs in the treatment of systemic lupus erythematosus.

BACKGROUND: Targeted small-molecule drugs in the treatment of systemic lupus erythematosus (SLE) have attracted increasing attention from clinical investigators. However, there is still a lack of evidence on the difference in the efficacy and safety of different targeted small-molecule drugs. Therefore, this study was conducted to assess the efficacy and safety of different targeted small-molecule drugs for SLE. METHODS: Randomized controlled trials (RCTs) on targeted small-molecule drugs in the treatment of SLE in PubMed, Web of Science, Embase, and Cochrane Library were systematically searched as of April 25, 2023. Risk of bias assessment was performed for included studies using the Cochrane's tool for evaluating the risk of bias. The primary outcome indicators were SRI-4 response, BICLA response, and adverse reaction. Because different doses and courses of treatment were used in the included studies, Bayesian network meta-regression was used to investigate the effect of different doses and courses of treatment on efficacy and safety. RESULTS: A total of 13 studies were included, involving 3,622 patients and 9 targeted small-molecule drugs. The results of network meta-analysis showed that, in terms of improving SRI-4, Deucravacitinib was significantly superior to that of Baricitinib (RR = 1.32, 95% CI (1.04, 1.68), P < 0.05). Deucravacitinib significantly outperformed the placebo in improving BICLA response (RR = 1.55, 95% CI (1.20, 2.02), P < 0.05). In terms of adverse reactions, targeted small-molecule drugs did not significantly increase the risk of adverse events as compared to placebo (P > 0.05). CONCLUSION: Based on the evidence obtained in this study, the differences in the efficacy of targeted small-molecule drugs were statistically significant as compared to placebo, but the difference in the safety was not statistically significant. The dose and the course of treatment had little impact on the effect of targeted small-molecule drugs. Deucravacitinib could significantly improve BICLA response and SRI-4 response without significantly increasing the risk of AEs. Therefore, Deucravacitinib is very likely to be the best intervention measure. Due to the small number of included studies, more high-quality clinical evidence is needed to further verify the efficacy and safety of targeted small-molecule drugs for SLE.

Comparison of the therapeutic effects of febuxostat combined with a low-purine diet and allopurinol combined with a low-purine diet on the improvement of gout patients.

OBJECTIVE: To compare the clinical efficacy of febuxostat combined with a low-purine diet versus allopurinol combined with a low-purine diet in the treatment of gout. METHODS: In this prospective controlled trial, 98 gout patients admitted to our hospital from February 2021 to December 2022 were enrolled as study subjects. Patients were randomly assigned to the study group (febuxostat combined with a low-purine diet) and the control group (allopurinol combined with a low-purine diet), with 49 patients in each group. The therapeutic effect was evaluated based on joint function and serum uric acid levels after treatment, and classified into three levels: markedly effective, effective, and ineffective. The levels of inflammatory factors, including tumor necrosis factor-a (TNF-a), cytokine interleukin-1beta (IL-1ß), and interleukin (IL)-18 (IL-18), were collected. The Numeric Rating Scale (NRS) was used to assess the degree of pain in patients. Clinical indicators before and 6 months after treatment were compared between the two groups. RESULTS: There was no statistically significant difference in age and gender between the two groups. After 6 months of treatment, the effective rate in the study group (48 cases, 97.96%) was higher than that in the control group (42 cases, 85.71%), with a statistically significant difference (p = .027). At the same time, the study group had significantly lower levels of serum uric acid (162.39 µmol/L ± 17.23 µmol/L vs. S198.32 µmol/L ± 18.34 µmol/L, p < .001), creatinine (87.39 mmol/L ± 9.76 mmol/L vs. 92.18 mmol/L ± 9.27 mmol/L, p = .014), total cholesterol (3.65 mmol/L ± 0.65 mmol/L vs. 4.76 mmol/L ± 0.73 mmol/L, p < .001), and triglycerides (1.76 mmol/L ± 0.32 mmol/L vs. 2.28 mmol/L ± 0.41 mmol/L, p < .001) compared to the control group, with statistically significant differences (p < .05). After treatment, the levels of inflammatory factors and degree of pain in the study group were significantly lower than those in the control group (all p < .05). During the treatment process, the incidence of adverse reactions in the study group (2 cases, 4.08%) was lower than that in the control group (9 cases, 18.37%), with a statistically significant difference (p = .025). CONCLUSION: Febuxostat combined with a low-purine diet can reduce inflammatory factors and alleviate the degree of pain in gout patients, significantly improving their clinical symptoms.

Model of Chronic Itch in Aged Mice: Beneficial Effects of Drugs Affecting Descending Modulatory Systems.

Pruritus in the elderly, particularly those cases without skin dryness or other identifiable causes, makes treatment challenging due to the lack of evidence regarding the therapeutic effects of antipruritics. This study proposes an age-related alloknesis mouse model for an evaluation system for such cases, and aimed to investigate the effectiveness and mechanisms of action of several drugs commonly used as antipruritics in Japan, utilizing this model. Mice 69-80 weeks old were used as aged mice, and the level of mechanical alloknesis was counted as the number of scratching behaviours in response to innocuous stimuli. Bepotastine, neurotropin, pregabalin, baricitinib, and abrocitinib were used as antipruritics, and yohimbine and methysergide as inhibitors of the descending inhibitory pathway. The findings suggest that mechanical alloknesis in aged mice is a suitable animal model for assessing pruritus in the elderly without xerosis, and pregabalin, neurotropin, baricitinib, and abrocitinib may be effective antipruritics in the elderly through activating both the noradrenergic and serotonergic descending inhibitory pathways. These findings may be useful for the selection of antipruritics for pruritus in the elderly without skin lesions or dryness.

JAK inhibitors in the treatment of adult patients with juvenile idiopathic arthritis: a retrospective monocentric experience.

OBJECTIVES: This study aims to evaluate the efficacy and safety of JAK inhibitors (JAKi) in a monocentric cohort of adult patients with juvenile idiopathic arthritis (JIA). METHODS: Patients attending a rheumatology transition clinic were retrospectively included in case of: i) JIA diagnosis according to current classification criteria (1); ii) age ≥18 years and iii) treatment with JAKi for at least 3 months. RESULTS: Seventeen adult patients with JIA were treated with JAKi (as first JAKi, 9 patients (52.9%) received tofacitinib and 8 (47.1%) baricitinib). At 3 months after JAKi initiation, 8 patients (47%) achieved a response and 4 patients (23.5%) achieved disease remission (3 patients with baricitinib and 1 with tofacitinib, 37.5% vs. 16.7%, p=0.294). None of those with systemic JIA and enthesitis-related arthritis obtained remission; the remission rate at 3 months was higher, although not significantly, in the oligoarticular subset compared to the polyarticular subset (37.5% vs. 20%). Patients with ≤1 active joint involvement at JAKi start had a higher remission rate (50% vs. 22.2%). Subjects who achieved remission on JAKi had a significantly lower pre-treatment DAS28-CRP compared to those with still active disease (p=0.010, Mann-Whitney U=4). A pre-treatment DAS28-CRP <3.76 predicted response to JAKi with 100% sensitivity and 84.6% specificity (p=0.023). The remission rate was lower among patients who had been treated with ≥2 biological drugs before JAKi start (9% vs. 66.7%; p=0.05). One patient in concomitant treatment with leflunomide developed severe arterial hypertension. CONCLUSIONS: JAKi may represent an effective and safe treatment option for adult JIA patients with low/moderate disease activity, particularly in case of oligoarticular involvement.

The effects of low HER2 expression on survival in patients with metastatic breast cancer treated with CDK 4/6 inhibitors: a multicenter retrospective study.

PURPOSE: Endocrine therapy (ET) in combination with CDK 4/6 inhibitors (CDK 4/6i) is the standard treatment modality for hormone receptor (HR)-positive and HER2-negative metastatic breast cancer (mBC). There is uncertainty about the prognostic and predictive value of HER2-low status and whether HER2-low BC is an individual biologic subtype. In this study, we aimed to investigate the prognostic effect of HER2 expression status on survival in mBC patients treated with first-line ET plus CDK 4/6i. METHODS: This multicenter retrospective study included patients with HR + /HER2-negative mBC cancer who were treated with first-line CDK 4/6i in combination with ET from January 2016 to March 2023. Patients were divided into two groups (HER2-low and zero), and survival and safety analyses were performed. RESULTS: A total of 201 patients were included in this study; of these, 73 (36.3%) had HER2-low disease and 128 (63.7%) had HER2-zero. There were 135 patients (67.2%) treated with ribociclib and 66 (32.8%) with palbociclib. Most of the patients (75.1%) received aromatase inhibitors as combination-endocrine therapy. Baseline characteristics were similar between the two groups. The median follow-up was 19.1 months (range: 2.5-78.4). The most common side effect was neutropenia (22.4%). The frequency of grade 3-4 toxicity was similar between the HER2-zero and low patients (32% vs 31.5%; p = 0.939). Visceral metastases were present in 44.8% of patients. Between the HER2-low and zero groups, median PFS (25.2 vs 22.6 months, p = 0.972) and OS (not reached vs 37.5 months, p = 0.707) showed no statistically significant differences. CONCLUSION: The prognostic value of HER2-low status remains controversial. Our study showed no significant effect of HER2 low expression on survival in patients receiving CDK 4/6i plus ET.

Inhibition of mitochondrial folate metabolism drives differentiation through mTORC1 mediated purine sensing.

Supporting cell proliferation through nucleotide biosynthesis is an essential requirement for cancer cells. Hence, inhibition of folate-mediated one carbon (1C) metabolism, which is required for nucleotide synthesis, has been successfully exploited in anti-cancer therapy. Here, we reveal that mitochondrial folate metabolism is upregulated in patient-derived leukaemic stem cells (LSCs). We demonstrate that inhibition of mitochondrial 1C metabolism through impairment of de novo purine synthesis has a cytostatic effect on chronic myeloid leukaemia (CML) cells. Consequently, changes in purine nucleotide levels lead to activation of AMPK signalling and suppression of mTORC1 activity. Notably, suppression of mitochondrial 1C metabolism increases expression of erythroid differentiation markers. Moreover, we find that increased differentiation occurs independently of AMPK signalling and can be reversed through reconstitution of purine levels and reactivation of mTORC1. Of clinical relevance, we identify that combination of 1C metabolism inhibition with imatinib, a frontline treatment for CML patients, decreases the number of therapy-resistant CML LSCs in a patient-derived xenograft model. Our results highlight a role for folate metabolism and purine sensing in stem cell fate decisions and leukaemogenesis.

Ribociclib plus Endocrine Therapy in Early Breast Cancer.

BACKGROUND: Ribociclib has been shown to have a significant overall survival benefit in patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer. Whether this benefit in advanced breast cancer extends to early breast cancer is unclear. METHODS: In this international, open-label, randomized, phase 3 trial, we randomly assigned patients with HR-positive, HER2-negative early breast cancer in a 1:1 ratio to receive ribociclib (at a dose of 400 mg per day for 3 weeks, followed by 1 week off, for 3 years) plus a nonsteroidal aromatase inhibitor (NSAI; letrozole at a dose of 2.5 mg per day or anastrozole at a dose of 1 mg per day for ≥5 years) or an NSAI alone. Premenopausal women and men also received goserelin every 28 days. Eligible patients had anatomical stage II or III breast cancer. Here we report the results of a prespecified interim analysis of invasive disease-free survival, the primary end point; other efficacy and safety results are also reported. Invasive disease-free survival was evaluated with the use of the Kaplan-Meier method. The statistical comparison was made with the use of a stratified log-rank test, with a protocol-specified stopping boundary of a one-sided P-value threshold of 0.0128 for superior efficacy. RESULTS: As of the data-cutoff date for this prespecified interim analysis (January 11, 2023), a total of 426 patients had had invasive disease, recurrence, or death. A significant invasive disease-free survival benefit was seen with ribociclib plus an NSAI as compared with an NSAI alone. At 3 years, invasive disease-free survival was 90.4% with ribociclib plus an NSAI and 87.1% with an NSAI alone (hazard ratio for invasive disease, recurrence, or death, 0.75; 95% confidence interval, 0.62 to 0.91; P = 0.003). Secondary end points - distant disease-free survival and recurrence-free survival - also favored ribociclib plus an NSAI. The 3-year regimen of ribociclib at a 400-mg starting dose plus an NSAI was not associated with any new safety signals. CONCLUSIONS: Ribociclib plus an NSAI significantly improved invasive disease-free survival among patients with HR-positive, HER2-negative stage II or III early breast cancer. (Funded by Novartis; NATALEE ClinicalTrials.gov number, NCT03701334.).

Cyclin-dependent kinase 4/6 inhibitors in the treatment of advanced or metastatic breast cancer.

OBJECTIVE: Despite the relatively high cure rates in early-stage breast cancer, advanced and metastatic breast cancer cases are associated with more inauspicious patient outcomes. Fortunately, with the advent of cyclin-dependent kinase (CDK)4/6 inhibitors (e.g. palbociclib, ribociclib, and abemaciclib) with endocrine therapy, survival in advanced and metastatic breast cancer has appreciably improved. In the current review, we discuss these distinctions and the concomitant implications associated with the individual CDK4/6 inhibitors. DATA SOURCES: We conducted an extensive PubMed search comprising several review articles on the topic of advanced or metastatic breast cancer treatment, with specific terms that included CDK4/6 inhibitors, treatment, and breast cancer. DATA SUMMARY: Palbociclib, ribociclib, and abemaciclib have exhibited superior progression-free survival differences compared to endocrine therapy alone. However, there are differences among the various CDK4/6 inhibitors with regard to overall survival, tolerability and quality of life. CONCLUSIONS: Ribociclib may be indicated for pre/perimenopausal patients, whereas abemaciclib is potentially recommended to address endocrine-resistant or visceral disease. Alternatively, palbociclib is associated with lower discontinuation rates than abemaciclib and unlike ribociclib, QTc prolongation is not observed with palbociclib.

Duvelisib: A comprehensive profile.

Duvelisib (DUV) is chemically named as (S)-3-(1-((9H-Purin-6-yl)amino)ethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one. It is a novel drug with a small molecular weight and characterized by dual phosphoinositide-3-kinase (PI3K)- and PI3K-inhibitory activity. The Food and Drug Administration (FDA) recently approved DUV for the management of small lymphocytic lymphoma (SLL) and relapsed or refractory chronic lymphocytic leukemia (CLL) in adult patients. DUV is marketed under the brand name of Copiktra® (Verastem, Inc., Needham, MA, USA). This chapter provides a critical extensive review of the literature, the description of DUV in terms of its names, formulae, elemental composition, appearance, and use in the treatment of CLL, SLL, and follicular lymphoma. The chapter also describes the methods for preparation of DUV, its physical-chemical properties, analytical methods for its determination, pharmacological properties, and dosing information.

Therapeutic drug monitoring in inflammatory bowel disease: A practical approach.

The global burden of inflammatory bowel diseases (IBD) is estimated at 4.9 million and the global prevalence exceeds 0.3%. Multiple newer therapeutic agents have broadened the options for the therapy of IBD in the last three decades. Thiopurines, however, have retained their place as maintenance therapy in IBD, especially in resource-constrained setting. But thiopurines have narrow therapeutic range, often needing discontinuation due to side effects or lack of efficacy. Biologic agents revolutionized the treatment of IBD, but the efficacy is lost in 50% of patient after one year. These outcomes are often due to inadequate drug concentrations that may lead to the development of antibodies as well as pharmacodynamic failure. Therapeutic drug monitoring (TDM) was proposed to reduce loss of response and to optimize the therapy in patients on thiopurine and biologic therapy. TDM is based on exposure-response relationship, suggesting a positive correlation between elevated serum anti-TNF concentrations and favorable therapeutic outcomes. TDM has multiple facets. This article discusses the benefits, evidence and limitations of TDM. The practical use of TDM in clinical practice is highlighted. Newer developments in the field and their relevance in practice are discussed.

Infliximab for maintenance of medically-induced remission in Crohn's disease.

BACKGROUND: Infliximab is a monoclonal antibody that binds and neutralises tumour necrosis factor-alpha (TNF-α) which is present in high levels in the blood serum, mucosa and stool of patients with Crohn's disease. OBJECTIVES: To determine the efficacy and safety of infliximab for maintaining remission in patients with Crohn's disease. SEARCH METHODS: On 31 August, 2021 and 23 June, 2023, we searched CENTRAL, Embase, MEDLINE, ClinicalTrials.gov, and WHO ICTRP. SELECTION CRITERIA: Randomised controlled trials (RCTs) in which infliximab was compared to placebo or another active comparator for maintenance, remission, or response in patients with Crohn's disease. DATA COLLECTION AND ANALYSIS: Pairs of review authors independently selected studies and conducted data extraction and risk of bias assessment. We expressed outcomes as risk ratios and mean differences with 95% confidence intervals. We assessed the certainty of the evidence using GRADE. Our primary outcome was clinical relapse. Secondary outcomes were loss of clinical response, endoscopic relapse, and withdrawal due to serious and adverse events. MAIN RESULTS: Nine RCTs with 1257 participants were included. They were conducted between 1999 and 2022; seven RCTs included biologically-naive patients, and the remaining two included a mix of naive/not naive patients. Three studies included patients in clinical remission, five included patients with a mix of activity scores, and one study included biologic responders with active disease at baseline. All studies allowed some form of concomitant medication during their duration. One study exclusively included patients with fistulating disease. The age of the participants ranged from 18 to 69 years old. All but one single-centre RCT were multicentre RCTs. Four studies were funded by pharmaceutical companies, two had a mix of commercial and public funding, and two had public funding. Infliximab is probably superior to placebo in preventing clinical relapse in patients who have mixed levels of clinical disease activity at baseline, and are not naive to biologics (56% vs 75%, RR 0.73, 95% CI 0.63 to 0.84, NNTB = 5, moderate-certainty evidence). We cannot draw any conclusions on loss of clinical response (RR 0.59, 95% CI 0.37 to 0.96), withdrawals due to adverse events (RR 0.66, 95% CI 0.37 to 1.19), or serious adverse events (RR 0.60, 95% CI 0.36 to 1.00) because the evidence is very low certainty. Infliximab combined with purine analogues is probably superior to purine analogues for clinical relapse (12% vs 59%, RR 0.20, 95% CI 0.10 to 0.42, NNTB = 2, moderate-certainty evidence), for patients in remission, and who are not naive to biologics. We cannot draw any conclusions on withdrawals due to adverse events (RR 0.47, 95% CI 0.15 to 1.49), and serious adverse events (RR 1.19, 95% CI 0.54 to 2.64) because the evidence is very low certainty. We cannot draw any conclusions about the effects of infliximab on serious adverse events compared to purine analogues (RR 0.79, 95% CI 0.37 to 1.68) for a population in remission at baseline because the evidence is very low certainty. There was no evidence available for the outcomes of clinical relapse, loss of clinical response, and withdrawal due to adverse events. Infliximab may be equivalent to biosimilar for clinical relapse (47% vs 40% RR 1.18, 95% CI 0.82 to 1.69), and it may be slightly less effective in averting loss of clinical response (49% vs 32%, RR 1.50, 95% CI 1.01 to 2.23, low-certainty evidence), for a population with mixed/low disease activity at baseline. Infliximab may be less effective than biosimilar in averting withdrawals due to adverse events (27% vs 0%, RR 20.73, 95% CI 2.86 to 150.33, low-certainty evidence). Infliximab may be equivalent to biosimilar for serious adverse events (10% vs 10%, RR 0.99, 95% CI 0.39 to 2.50, low-certainty evidence). We cannot draw any conclusions on the effects of subcutaneous biosimilar compared with intravenous biosimilar on clinical relapse (RR 1.01, 95% CI 0.65 to 1.57), loss of clinical response (RR 0.94, 95% CI 0.70 to 1.25), and withdrawals due to adverse events (RR 0.77, 95% CI 0.30 to 1.97) for an active disease population with clinical response at baseline because the evidence is of very low certainty. We cannot draw any conclusions on the effects of infliximab compared to adalimumab on loss of clinical response (RR 0.68, 95% CI 0.29 to 1.59), withdrawals due to adverse events (RR 0.10, 95% CI 0.01 to 0.72), serious adverse events (RR 0.09, 95% CI 0.01 to 1.54) for an active disease population with clinical response at baseline because the evidence is of very low certainty. There was no evidence available for the outcome of clinical relapse. AUTHORS' CONCLUSIONS: Infliximab is probably more effective in preventing clinical relapse than placebo (moderate-certainty evidence). Infliximab in combination with purine analogues is probably more effective in preventing clinical and endoscopic relapse than purine analogues alone (moderate-certainty evidence). No conclusions can be drawn regarding prevention of loss of clinical response, occurrence of withdrawals due to adverse events, or total adverse events due to very low-certainty evidence for both of these comparisons. There may be little or no difference in prevention of clinical relapse, withdrawal due to adverse events or total adverse events between infliximab and a biosimilar (low-certainty evidence). Infliximab may lead to more loss of clinical response than a biosimilar (low-certainty evidence). We were unable to draw meaningful conclusions about other comparisons and outcomes related to missing data or very low-certainty evidence due to serious concerns about imprecision and risk of bias. Further research should focus on comparisons with other active therapies for maintaining remission, as well as ensuring adequate power calculations and reporting of methods.

Enhancing anti-AML activity of venetoclax by isoflavone ME-344 through suppression of OXPHOS and/or purine biosynthesis in vitro.

Venetoclax (VEN), in combination with low dose cytarabine (AraC) or a hypomethylating agent, is FDA approved to treat acute myeloid leukemia (AML) in patients who are over the age of 75 or cannot tolerate standard chemotherapy. Despite high response rates to these therapies, most patients succumb to the disease due to relapse and/or drug resistance, providing an unmet clinical need for novel therapies to improve AML patient survival. ME-344 is a potent isoflavone with demonstrated inhibitory activity toward oxidative phosphorylation (OXPHOS) and clinical activity in solid tumors. Given that OXPHOS inhibition enhances VEN antileukemic activity against AML, we hypothesized that ME-344 could enhance the anti-AML activity of VEN. Here we report that ME-344 enhanced VEN to target AML cell lines and primary patient samples while sparing normal hematopoietic cells. Cooperative suppression of OXPHOS was detected in a subset of AML cell lines and primary patient samples. Metabolomics analysis revealed a significant reduction of purine biosynthesis metabolites by ME-344. Further, lometrexol, a purine biosynthesis inhibitor, synergistically enhanced VEN-induced apoptosis in AML cell lines. Interestingly, AML cells with acquired AraC resistance showed significantly increased purine biosynthesis metabolites and sensitivities to ME-344. Furthermore, synergy between ME-344 and VEN was preserved in these AraC-resistant AML cells. In vivo studies revealed significantly prolonged survival upon combination therapy of ME-344 and VEN in NSGS mice bearing parental or AraC-resistant MV4-11 leukemia compared to the vehicle control. This study demonstrates that ME-344 enhances VEN antileukemic activity against preclinical models of AML by suppressing OXPHOS and/or purine biosynthesis.

The Effect of Renal Replacement Therapy in a Patient with Mercaptopurine Toxicity: Time to Revise Guidelines.

INTRODUCTION: Mercaptopurine, a thiopurine, is used in various disorders of immune regulation, such as autoimmune hepatitis. Thiopurine metabolism is complex with risk for overdosing, especially when metabolism is impaired by liver dysfunction. Hepatotoxicity may be due to mercaptopurine overdose and is often reversible after prompt cessation of the drug. CASE PRESENTATION: Treatment of thiopurine toxicity is mainly supportive and literature on enhanced elimination by renal replacement therapy is ambiguous. CONCLUSION: In this case of thiopurine toxicity, a patient with autoimmune hepatitis presents with abdominal pain, nausea, vomiting, and diarrhea. We show in this case report that renal replacement therapy had no effect on total body clearance of mercaptopurine.