Search Results (120)

C-C motif chemokine ligand 2 (CCL2) interacts with cytokines, adipokines, miRNAs, and multiple synovial cell populations. Experimental studies indicate that these interactions can form a CCL2-associated inflammatory amplification network across cell types. In cellular and animal models, increased CCL2 is associated with monocyte recruitment, synovial fibroblast activation, osteoclast-related bone remodelling, and vascular responses. Therapeutic strategies targeting the CCL2-centered inflammatory network include antagonists of the CCL2/CCR2 axis, natural products, synthetic compounds, conventional antirheumatic drugs, and emerging delivery-based approaches. Notably, direct CCL2/CCR2 inhibition has shown biological activity in experimental models but has not produced consistent clinical benefit in established rheumatoid arthritis (RA). Although these findings do not establish CCL2 as a dominant causal driver of RA, human observational studies suggest that circulating CCL2 may complement established markers in preclinical RA risk assessment, disease activity and remission classification, estimation of treatment response, and evaluation of RA-related complications such as interstitial lung disease. Of note, no validated concentration cut-off or standardized assay currently supports its routine clinical use. This review examines the CCL2-related inflammatory network in RA and evaluates its cellular mechanisms, therapeutic implications, and potential clinical applications. Full article

Background: Janus kinase inhibitors (JAK inhibitors) have expanded therapeutic options for rheumatoid arthritis (RA), although factors associated with treatment response in routine clinical practice remain incompletely defined. Objectives: This study aimed to evaluate clinical, treatment-related and pharmacogenetic factors associated with response to different JAK inhibitors in patients with RA. Methods: An ambispective observational real-world cohort study was conducted in patients with RA treated with tofacitinib, baricitinib, filgotinib, or upadacitinib. Disease activity was assessed at 3 and 6 months using the Disease Activity Score in 28 joints based on C-reactive protein (DAS28-CRP). Clinical response was evaluated according to European Alliance of Associations for Rheumatology (EULAR) response criteria, low disease activity (LDA), and remission thresholds. Clinical, laboratory, and treatment-related variables were collected, and selected single-nucleotide polymorphisms (SNPs) in JAK1, JAK2, and JAK3 genes were genotyped. Bivariate and multivariable analyses were performed to identify variables associated with treatment outcomes. Results: Lower baseline inflammatory burden and lower disease activity were consistently associated with higher probabilities of EULAR response, LDA, and remission across JAK inhibitors. Treatment-related factors were also associated with improved outcomes. Pharmacogenetic associations were heterogeneous and drug-specific, with the most recurrent exploratory signals involving JAK2 variants. However, these genetic findings showed variability across outcomes and time points. Conclusions: In this real-world RA cohort, clinical and treatment-related factors were the most consistent variables associated with response to JAK inhibitors. Pharmacogenetic variation within the JAK pathway, particularly involving JAK2, may contribute to drug-specific variability in response, but these findings should be considered exploratory because of the limited sample size, multiple comparisons, and sparse genotype subgroups. Larger independent studies are required before JAK genotyping can be incorporated into individualized treatment strategies. Full article

Polymyalgia rheumatica (PMR) and giant cell arteritis (GCA) are systemic inflammatory diseases deeply rooted in age-related immunosenescence and inflammaging. Conventional long-term glucocorticoid (GC) therapy poses significant metabolic and infectious risks for older adults, necessitating safer alternatives. This review critically evaluates the pathophysiological rationale and clinical efficacy of small-molecule drugs, including Janus kinase inhibitors (JAKi) and conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), as steroid-sparing treatments for PMR and GCA. By selectively inhibiting intracellular networks like the JAK-STAT pathway and nucleotide biosynthesis, these agents aim to attenuate maladaptive inflammation. Clinical evidence highlights that JAK inhibitors, particularly upadacitinib for GCA and tofacitinib or baricitinib for PMR, demonstrate the potential to induce remission and significantly reduce the required GC burden in a subset of patients. Although methotrexate remains the primary csDMARD, its modest overall efficacy suggests it should be reserved for patients with definitive contraindications or restricted access to JAK inhibitors. Furthermore, novel therapies like clofutriben demonstrate potential in reversing GC-induced morbidities without compromising disease control. Ultimately, integrating targeted small-molecule immunomodulators establishes a crucial therapeutic paradigm that attempts to maximize clinical remission while safeguarding the physiological integrity of geriatric patients against severe GC toxicities. Full article

Relapsed and refractory multiple myeloma remains the principal cause of myeloma-related mortality despite major advances in therapeutic options, including proteasome inhibitors, immunomodulatory drugs, monoclonal antibodies, and T-cell-based immunotherapies. Conventional resistance models based on linear genetic clonal evolution inadequately explain reversible drug resistance, heterogeneous responses, and relapse after deep remissions. Emerging data from longitudinal genomics, single-cell analyses, and functional studies support a paradigm in which relapsed and refractory multiple myeloma is driven by adaptive plasticity rather than irreversible genetic change alone. Myeloma cells undergo reversible cell state transitions through transcriptional, epigenetic, metabolic, and proteostatic reprogramming, shaped by bone marrow microenvironmental cues and immune pressure. This narrative review integrates current evidence supporting adaptive plasticity as a central driver of therapeutic failure in relapsed and refractory multiple myeloma and discusses clinical and translational implications, highlighting adaptive treatment strategies and approaches targeting phenotypic flexibility to improve durability of response. Full article

Background: In psoriatic arthritis (PsA), clinical tenderness and ultrasound (US) capture distinct yet related aspects of entheseal disease activity. However, their longitudinal relationship after initiation of biologic disease-modifying antirheumatic drugs (bDMARDs), and the clinical significance of early discordance during follow-up remain unclear. Methods: In this retrospective observational cohort study based on routinely collected medical records, patients with CASPAR-defined PsA and clinically and ultrasonographically active enthesitis at baseline (Clin+/US+) who initiated bDMARD therapy underwent paired, same-day, blinded clinical and US assessments at approximately 6 and 12 months. Agreement between clinical and US findings was quantified using Cohen’s kappa. Discordant states (Clin−/US+ and Clin+/US−) were prespecified, and predictors of Clin−/US+ status at 6 months were analyzed using models that accounted for within-patient clustering. Results: Thirty-nine patients contributed 82 entheses and were treated with either tumour necrosis factor inhibitors (53.8%) or interleukin-17 inhibitors (46.2%). At 6 months, agreement between clinical and US assessments was fair (κ = 0.286; 95% confidence interval [CI], 0.080 to 0.492), with 23.2% of entheses classified as Clin−/US+ and 52.4% as concordantly inactive. At 12 months, agreement improved to substantial-to-almost-perfect levels (κ = 0.779; 95% CI, 0.595 to 0.963), with only 1.2% of entheses remaining Clin−/US+ and 80.5% achieving concordant remission. NSAID exposure was the only significant predictor of Clin−/US+ status at 6 months in univariable analysis (odds ratio [OR], 3.82; 95% CI, 1.27 to 11.47; p = 0.017) and remained associated after multivariable adjustment (OR, 6.16; 95% CI, 1.14 to 33.2; p = 0.03). Conclusions: In PsA patients starting bDMARD therapy, clinical and US assessments of enthesitis showed partial discordance at 6 months, followed by greater convergence at 12 months. These findings suggest that clinical and imaging abnormalities may resolve asynchronously during follow-up and should therefore be interpreted in an integrated, time-aware manner. Residual US abnormalities in the setting of clinical improvement should be interpreted cautiously and within the broader clinical context. Full article

Autoimmune hepatitis (AIH) is a chronic immune-mediated liver disorder that, without treatment, can advance to fibrosis and cirrhosis. Although standard regimens with corticosteroids and thiopurines have significantly improved survival, many patients still experience relapses and drug-related toxicity, highlighting the urgent need for alternative strategies. Recent studies underscore AIH’s multifactorial nature, revealing intricate interactions among genetic susceptibility, environmental triggers, and dysregulated immune responses. Next-generation diagnostics, ranging from novel biomarkers to high-resolution imaging, are enhancing early detection and more precise disease classification. At the same time, multi-omics analyses and artificial-intelligence-based models are refining predictions of disease trajectory and therapeutic response. On the treatment horizon, investigational options such as targeted immunomodulators, B-cell–depleting therapies, and cell-based interventions aim to achieve durable remission while minimizing adverse effects. This review critically appraises these advances and explores how integrating epidemiological insights with cutting-edge research in pathogenesis, diagnostics, and therapy could pave the way for more personalized and effective management of AIH. Full article

Candida dubliniensis is an opportunistic yeast closely related to Candida albicans and an uncommon cause of central nervous system (CNS) infection. While isolates are often susceptible to azoles, reduced susceptibility or acquired resistance may occur, making species identification and antifungal susceptibility testing clinically relevant. We report a 3-year-old boy with Philadelphia chromosome-positive B-cell precursor acute lymphoblastic leukemia (ALL) in hematologic remission who developed chronic meningitis during maintenance chemotherapy. The initial presentation was non-specific (marked somnolence without fever or meningeal signs) and lumbar puncture performed to exclude CNS relapse revealed neutrophil-predominant pleocytosis and elevated protein; the cerebrospinal fluid (CSF) culture grew C. dubliniensis. Treatment with intravenous liposomal amphotericin B followed by prolonged fluconazole led to clinical improvement and sterile CSF. Six months later, progressive gait disturbance, limb pain, and episodic severe headaches recurred; repeat CSF cultures again yielded C. dubliniensis, with a changed susceptibility profile. Spine MRI demonstrated leptomeningeal enhancement involving the cauda equina nerve roots. Intravenous voriconazole with therapeutic drug monitoring was initiated and combined with intrathecal liposomal amphotericin B (seven doses, dose-escalated up to 3 mg), which was well tolerated and associated with rapid neurologic improvement, CSF sterilization, and radiologic resolution. At 12 months of follow-up, the patient remained infection-free and in leukemia remission. This case highlights that C. dubliniensis chronic meningitis may present subtly yet progress, requiring repeated CSF cultures with susceptibility testing; intrathecal liposomal amphotericin B can be a safe and effective adjunct to systemic therapy in refractory or recurrent disease. Full article

Thyroid disorders are among the most common endocrine disorders worldwide and are classified as noncommunicable diseases. These disorders are associated with significant morbidity, impaired quality of life, and considerable socioeconomic burden. Like other noncommunicable diseases, thyroid disorders arise from complex interactions between genetic susceptibility and environmental factors, including diet and lifestyle. Despite growing interest in lifestyle-based approaches to noncommunicable disease prevention and management, thyroid disorders have received comparatively limited attention in this context. Graves’ disease, the most common cause of hyperthyroidism, is a relevant condition for exploring dietary interventions. Current treatment strategies—anti-thyroid drugs, radioactive iodine and thyroidectomy—have remained largely unchanged for decades. Long-term remission following drug therapy is achieved in no more than approximately 50% of patients, while all treatment modalities carry potential adverse effects. These limitations underscore the need for alternative or adjunctive therapeutic strategies. Iodine intake plays a central role in thyroid hormone synthesis. Indeed, observational studies have shown inverse associations between iodine intake and remission rates, as well as achievement of euthyroidism, medication requirements and thyroid autoantibody titers. These findings suggest that dietary iodine restriction may enhance treatment efficacy and reduce medication-related risks. Beyond its direct effects on thyroid hormone synthesis, iodine may influence Graves’ disease through indirect mechanisms involving the lipid profile and the gut–thyroid axis. Autoimmune thyroid diseases are associated with a dyslipidemic profile and with gut microbiota dysbiosis; the latter characterized by increased potentially pathogenic bacteria and reduced beneficial bacteria such as Lactobacillus and Bifidobacterium. Full article

Cancer metastasis and chemoresistance are primary reasons for cancer-related mortality. Current therapeutic options rely mostly on single-target drugs, which often fail to exhibit long-lasting remission of the disease progression due to the complexity of metastasis and resistance mechanisms. Natural products (NPs) possess inherent structural diversity, rendering them suitable as multi-target agents. The utilization of NPs is often impeded in treating complex diseases such as cancer, even though approximately 65% of approved anticancer drugs are NP derivatives, or synthetic derivatives containing NP-pharmacophores, due to various factors, including poor aqueous solubility and variable oral bioavailability, structural complexity, synthetic inaccessibility, and stereochemical diversity that confounds structure–activity relationship analyses. This review discusses how integrating artificial intelligence (AI) and machine learning (ML) with chemoinformatics can identify, prioritize, and experimentally validate NPs, potentially paving the way for new drugs that address intricate processes such as metastasis and resistance. We summarize the recent computational advances in the field, including graph neural networks, attention mechanisms, Siamese networks, virtual screening, and network pharmacology. These advancements address ADMET optimization, molecular representation, virtual screening, network pharmacology, and experimental validation. We emphasize how each of these approaches tackles the unique challenges associated with NPs. We contextualize our review within the specific challenges presented by the chemical space of NPs. Additionally, we analyze real-world case studies of successful AI-assisted NP discovery and categorize the quality of evidence into three levels: Level A, which includes in vivo efficacy with mechanistic details; Level B, which consists of in vitro validation of mechanisms and phenotypes; and Level C, which represents computational hypotheses that are awaiting experimental verification. Additionally, we propose an operational framework for selecting suitable AI methodologies based on available data, target characterization, and validation resources. Finally, we emphasize the limitations and future directions in AI-facilitated NP discovery. Full article

Background: Treating depression and anxiety in adolescents can be challenging due to interindividual variability in medication response. With current trial-and-error prescribing practices, adolescents may undergo multiple medication changes over months or years before an effective and tolerated drug and dose are identified. Pharmacogenomic (PGx) testing can identify interindividual differences in drug metabolism, and evidence supporting PGx-guided prescribing in adults with mental disorders is growing. However, its impact on pediatric psychotropic prescribing remains underexplored. Methods: This is a protocol for a parallel-arm, multicentre, randomized controlled trial. Canadian adolescents aged 12–17 years who are initiating or switching a selective serotonin reuptake inhibitor (SSRI) for depression and/or an anxiety disorder under physician care are eligible. A total of 452 participants will be randomized 1:1 to PGx-guided SSRI prescribing (experimental) or SSRI prescribing based on current practice guidelines (control). Participants, caregivers, prescribing clinicians, outcome assessors, and investigators will be blinded to treatment allocation. Dual primary outcomes are symptom remission at 12 weeks, measured with the Quick Inventory of Depressive Symptomatology–Adolescent (QIDS-A17-SR) and the Screen for Child Anxiety Related Disorders (SCARED). Secondary outcomes, assessed at 4, 8, and 12 weeks, include participant- and physician-rated changes in depressive and anxiety symptoms, role functioning, health-related quality of life, health care utilization, cost-effectiveness, side-effect burden, medication burden, and adherence. Multiple testing will be addressed using the Hochberg method, and a parallel gated analysis will account for non-actionable genotypes. Secondary analysis will estimate minimal clinically important differences for symptom and role-functioning change with PGx-guided therapy. Discussion: At the time of writing, 36 participants have consented and been randomized to an intervention. This trial will evaluate whether PGx-guided prescribing improves symptom remission in adolescents treated with SSRIs. If efficacious, results should be interpreted with existing pediatric pharmacokinetic, observational, and adult trial data to inform PGx use in managing pediatric anxiety and depressive disorders. Full article

Background: Young-onset rheumatoid arthritis (YORA), defined by disease onset between 16–40 years, raises distinct clinical challenges related to long-term disease burden, fertility, and prolonged exposure to immunomodulatory therapy. Despite its relevance, evidence regarding treatment outcomes in this population remains limited and heterogeneous, largely due to inconsistent definitions of YORA across studies. Methods: This systematic review was conducted in accordance with the PRISMA 2020 guidelines to synthesize contemporary evidence on the efficacy and safety of biologic and targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) in younger rheumatoid arthritis populations. A structured search of PubMed and Embase was performed to identify studies published between 2020 and 2025 that evaluated advanced therapies in patients with young-onset rheumatoid arthritis or in rheumatoid arthritis cohorts reporting age-stratified outcomes for younger adults. Results: From the screened literature, 16 studies met the predefined inclusion criteria, including 6 studies explicitly defining YORA based on age at disease onset and 10 studies reporting outcomes in younger adult subgroups (<40–45 years). Across studies, younger patients demonstrated higher remission rates, greater reductions in disease activity, and superior treatment persistence compared with older-onset rheumatoid arthritis cohorts. Tumor necrosis factor inhibitors, interleukin-6 receptor antagonists, and Janus kinase inhibitors showed consistent clinical efficacy. Structural outcomes, reported in a limited number of studies, suggested low rates of radiographic progression in younger patients. Safety profiles were generally favorable, with infections and laboratory abnormalities representing the most reported adverse events and no age-specific safety signals being identified. Conclusions: Biologic and targeted therapies provide substantial clinical benefit in YORA and younger adult RA populations, with outcomes being generally superior to those observed in older-onset RA. However, heterogeneity in YORA definitions and limited long-term data highlight the need for prospective, age-at-onset-defined studies and extended pharmacovigilance to better inform lifelong treatment strategies. Full article

Background: Tumor necrosis factor-α (TNFα) inhibitors have significantly improved outcomes in children with non-systemic juvenile idiopathic arthritis (JIA), achieving long-term clinical remission for many patients. However, the optimal strategy for TNF-α inhibitor withdrawal remains unknown, whether through abrupt discontinuation, gradual dose reduction, or interval extension. Objective: We aim to identify patient-, disease-, and treatment-related predictors of successful TNF-α inhibitor withdrawal in children with non-systemic JIA. Methods: In this prospective, randomized, open-label, single-center study, 76 children with non-systemic JIA in stable remission for ≥24 months on etanercept or adalimumab were enrolled. At the time of TNF-α inhibitor discontinuation, all patients underwent a comprehensive evaluation, including a clinical examination, laboratory tests (serum calprotectin [S100 proteins] and high-sensitivity C-reactive protein [hsCRP]), and advanced joint imaging (musculoskeletal ultrasound and magnetic resonance imaging [MRI]) to assess subclinical disease activity. Patients were randomized (1:1:1, sealed-envelope allocation) to one of three predefined tapering strategies: (I) abrupt discontinuation; (II) extension of dosing intervals (etanercept 0.8 mg/kg every 2 weeks; adalimumab 24 mg/m² every 4 weeks); or (III) gradual dose reduction (etanercept 0.4 mg/kg weekly; adalimumab 12 mg/m² every 2 weeks). Follow-up visits were scheduled at 3, 6, 9, 12, and 18 months to monitor for disease relapse. Results: Higher baseline Childhood Health Assessment Questionnaire (CHAQ) scores (≥2), elevated serum calprotectin [S100 proteins] and hsCRP levels at withdrawal, imaging evidence of subclinical synovitis, and a history of uveitis were all significantly associated with increased risk of flare. No significant associations were found for other clinical or demographic characteristics. Conclusions: Early significant clinical response, absence of subclinical disease activity, and concomitant low-dose methotrexate therapy were key predictors of sustained drug-free remission. These findings may inform personalized strategies for biologic tapering in pediatric JIA. Full article

Background: Idiopathic intracranial hypertension (IIH), also known as primary pseudotumor cerebri, is characterized by increased intracranial pressure (ICP) without an identifiable cause. It can lead to significant morbidity, including permanent vision loss, especially in younger children. The exact cause of IIH is still unclear, but excess adiposity seems to be a key risk factor. Current treatment options are unsatisfactory, but research is exploring novel therapies targeting obesity-related mechanisms. Methods: Narrative review of the literature aimed at summarizing current knowledge regarding the epidemiology, pathophysiology, clinical features, treatment options and long-term outcomes for pediatric IIH, with a particular focus on the link with obesity. Results: The incidence of IIH is rising, mirroring the obesity epidemic. Excess adiposity, predominantly visceral, might cause IIH through several factors such as decreased venous return, hormone dysregulation, inflammation, obstructive sleep apnea, and dysfunction of the glymphatic system. The extent of weight loss required and the most appropriate strategy to achieve it are still uncertain. Given the difficulty in achieving and maintaining weight loss with dietary strategies, bariatric surgery and weight loss medications are emerging as effective options for long-term remission of both obesity and IIH. Conclusions: IIH is a rare and poorly understood disease. At present, weight loss represents the only treatment that addresses the pathophysiology of IIH. The role and potential as standalone or synergistic therapies of weight loss drugs and bariatric surgery for IIH in adolescents require future research. Full article

Acute myeloid leukemia (AML) continues to carry a dismal prognosis in older adults and those with secondary or high-risk disease, where conventional 7 + 3 chemotherapy has long delivered complete remission rates below 40% and median overall survival often under 6 months. CPX-351 (Vyxeos), a liposomal co-encapsulation of cytarabine and daunorubicin at a fixed synergistic 5:1 molar ratio, was designed to overcome the pharmacokinetic mismatch that undermines the traditional regimen. This review critically examines the preclinical rationale and clinical evidence for CPX-351, with particular attention to whether its nanoparticle platform truly represents a breakthrough or merely an incremental refinement of decades-old cytotoxics. Across phase I–III trials and real-world cohorts, CPX-351 consistently outperformed standard 7 + 3 in its approved populations of newly diagnosed therapy-related AML (t-AML) and AML with myelodysplasia-related changes (AML-MRC) in patients aged 60–75 years. In the pivotal phase III study (n = 309), CPX-351 improved median overall survival from 5.95 to 9.56 months (HR 0.69, 95% CI 0.52–0.90; p = 0.005) and raised the complete remission rate from 33.3% to 47.7%, while facilitating allogeneic transplantation in 34% as opposed to 25% of patients. A five-year follow-up sustained the separation in survival curves, and post-hoc analyses of responders showed median overall survival exceeding 25 months with CPX-351 versus approximately 10 months with 7 + 3 (HR 0.49). Real-world series have reported composite remission rates of 53–60%, measurable residual disease negativity in up to 65% of responders, and median overall survival of 12–20 months, depending on transplant utilization. Despite these gains, the absolute survival benefit remains modest, prolonged cytopenias are universal, and outcomes in TP53-mutated or younger adverse-risk patients are still poor, raising legitimate questions about cost-effectiveness and generalizability. Nonetheless, CPX-351 stands as the first clinically validated example of ratiometric nanomedicine in oncology, proving that reformulating established drugs can yield meaningful progress where novel agents have often failed. Full article

Acute lymphoblastic leukemia (ALL) is the most common pediatric malignancy, characterized by the clonal proliferation of immature lymphoid precursors. The distinction between B-cell ALL (B-ALL) and T-cell ALL (T-ALL) is fundamental, as each subtype exhibits distinct cytomorphological, genetic, and clinical features influencing prognosis and therapeutic strategies. Conventional multi-phase chemotherapy has significantly improved survival rates, yet its efficacy is limited by severe short- and long-term toxicities, highlighting the need for more selective therapeutic approaches. Advances in molecular profiling have enabled the identification of key oncogenic pathways, paving the way for targeted therapies such as tyrosine kinase inhibitors (TKIs), JAK-STAT pathway inhibitors, BCL-2 antagonists, and agents modulating epigenetic and cell cycle regulators. Concurrently, immunotherapeutic strategies have transformed the therapeutic landscape of pediatric ALL. Bispecific antibodies such as blinatumomab (anti-CD19), antibody–drug conjugates like inotuzumab ozogamicin (anti-CD22), and monoclonal antibodies such as daratumumab (anti-CD38) have demonstrated efficacy in relapsed or refractory disease with improved safety profiles. Moreover, CAR-T-cell therapy, particularly CD19-directed products, has shown unprecedented remission rates in refractory B-ALL. The integration of targeted and immune-based therapies into conventional regimens represents a decisive step toward precision medicine, aiming to enhance survival outcomes while reducing treatment-related toxicity and improving quality of life in ALL children. This review aims to provide a comprehensive overview of the current understanding of ALL pathobiology and therapeutic approaches, with particular emphasis on the expanding role of immunotherapeutic strategies in pediatric disease. Full article