Search Results (365)

Sjögren’s Disease (SjD) is an autoimmune disorder characterized by sicca symptoms arising from impaired salivary and lacrimal gland function and accompanying extraglandular involvement. SjD is recognized as an illness of female dominance for which the 2002 American–European Consensus Group Classification Criteria and the American College of Rheumatology/European Alliance of Associations for Rheumatology 2016 classification criteria are utilized for inclusion in clinical trials, and treatment recommendations from countries belonging to the American College of Rheumatology or the European Alliance of Associations for Rheumatology are globally recognized. It is presumed that there are geographical differences among female sufferers, and unique diagnostic criteria and recommendations are used in clinical practice in Japan. In addition to the items included in the classification criteria, several methods to measure saliva secretion, serum biomarkers, and artificial intelligence tools have recently been reported to be useful for the assessment of SjD. While symptomatic therapies including tear drops, artificial saliva, and muscarinic agonists are still the mainstay for treating SjD, several kinds of molecular targeted drugs, such as biological drugs and Janus kinase inhibitors, that are expected to improve the prognosis of SjD have been tested in recent clinical trials. Full article

Background: Despite therapeutic advances, morbidity and mortality remain high in patients with rheumatoid arthritis (RA) and psoriatic arthritis (PsA), primarily due to increased cardiovascular risk. Objectives: Our study aimed to evaluate the cardiovascular risk profile and biomarker dynamics in patients with RA and PsA treated with Janus kinase inhibitors (JAKis). To our knowledge, this is the first study assessing Lp(a) levels in this context. Methods: This prospective, observational study assessed 48 adult patients. The follow-up period was 12 months. Traditional cardiovascular risk factors and biological markers, including lipid profile, lipoprotein(a) [Lp(a)], and uric acid (UA), were assessed at baseline and follow-up. Correlations between JAKi therapy, lipid profile changes, and cardiovascular risk factors were investigated. Cox regression analysis was used to identify predictors of non-major cardiovascular events. Results: A strong positive correlation was observed between baseline and 12-month Lp(a) levels (r = 0.926), despite minor statistical shifts. No major cardiovascular events occurred during follow-up; however, 47.9% of patients experienced non-major cardiovascular events (e.g., uncontrolled arterial hypertension, exertional angina, and new-onset arrhythmias). Active smoking [hazard ratio (HR) 9.853, p = 0.005], obesity (HR 3.7460, p = 0.050), and arterial hypertension (HR 1.219, p = 0.021) were independent predictors of these events. UA (HR 1.515, p = 0.040) and total cholesterol (TC) (HR 1.019, p = 0.034) were significant biochemical predictors as well. Elevated baseline Lp(a) combined with these factors was associated with an increased event rate, particularly after age 60. Conclusions: Traditional cardiovascular risk factors remain highly prevalent and predictive, underscoring the need for comprehensive cardiovascular risk management. Lp(a) remained stable and may serve as a complementary biomarker for risk stratification in JAKi-treated patients. Full article

Ulcerative colitis (UC), a subtype of inflammatory bowel disease (IBD), is a chronic, relapsing inflammatory condition that significantly impairs the patient’s quality of life. While biologics have transformed disease management, a substantial number of patients remain unresponsive or lose efficacy over time. Tofacitinib (TOFA), an oral Janus kinase (JAK) inhibitor, introduces a novel therapeutic class of small-molecule drugs with a unique oral administration route, offering enhanced patient convenience and broader accessibility compared to parenterally administered biologics. As the first oral treatment approved for moderate to severe UC in years, TOFA acts by modulating the JAK/STAT pathway, influencing critical inflammatory mediators such as IL-6, IL-17, and IFN-γ. However, response rates are variable and appear dose-dependent, with up to 60% of patients showing inadequate therapeutic outcomes. This review represents the first comprehensive synthesis focused specifically on biomarkers of TOFA response in UC. Drawing on multi-omics data—epigenomics, transcriptomics, proteomics, and cellular profiling, we highlight emerging predictors of responsiveness, including CpG methylation signatures (e.g., LRPAP1 and FGFR2), transcriptomic regulators (e.g., REG3A and CLDN3), immune and epithelial cell shifts, and the cationic transporter MATE1. TOFA demonstrates a dual mechanism by modulating immune responses while supporting epithelial barrier restoration. Despite being promising, TOFA’s dose-dependent efficacy and interpatient variability underscore the critical need for non-invasive, predictive biomarkers to guide personalized treatment. As the first review of its kind, this work establishes a basis for precision medicine approaches to optimize the clinical utility of TOFA in UC management. Full article

Background/Objectives: Tofacitinib is a Janus kinase 1 and 3 inhibitor that was developed to treat rheumatoid arthritis. Accordingly, this study aimed to predict plasma tofacitinib concentrations and pharmacokinetic parameters in patients with renal failure through physiologically based pharmacokinetic (PBPK) simulations. Methods: PK-Sim and Simcyp simulators were used, as well as conventional Dedrick plot analysis, employing a single animal extrapolation method. The predictions were compared with previously published data. Results: PBPK simulations of tofacitinib in patients with renal failure closely matched the observed plasma concentration profiles and pharmacokinetic results, including the area under the plasma concentration–time curve (AUC), maximum plasma concentration (C_max), and time to reach C_max (T_max). The ratios of the simulated to observed plasma concentrations and pharmacokinetic parameters for tofacitinib were within a 0.5–2.0-fold error range. Although the results from the Dedrick plot were reasonably good, they were less accurate than those of the PBPK simulations. This was because the Dedrick plot relied solely on preclinical plasma concentration data without incorporating drug physicochemical properties, in vitro data, or physiological and pathophysiological variables. Conclusions: The findings suggest that PBPK simulations using single-species extrapolation effectively provide preliminary estimates of plasma tofacitinib concentration profiles and pharmacokinetic parameters in humans under specific conditions, including renal failure. Furthermore, the results provide a foundation for adjusting tofacitinib dosage and dosing schedules to maintain effective plasma concentrations by considering the pathophysiological characteristics of patients according to their specific diseases. Full article

Objectives: We wished to evaluate the safety profile of the Janus kinase (JAK) inhibitors used in the Spanish population; to study the onset of major adverse cardiovascular events (MACEs) and thrombotic events (arterial and venous); and to analyze the factors associated with the onset of these events. Methods: We conducted a retrospective observational study of a cohort of patients with rheumatoid arthritis (RA), spondyloarthritis (SpA), and psoriatic arthritis (PsA) included in the biological therapy registry of the Rheumatology Department of Virgen Macarena University Hospital (HUVM), Seville, Spain, who started targeted treatment between 2019 and late 2024. We collected data on disease activity, traditional cardiovascular risk factors, the Charlson comorbidity index, previous synthetic or biologic drug therapy, the use of corticosteroids (and their dose), severity data (structural damage, extra-articular manifestations), and adverse events at the end of follow-up (e.g., MACEs, infections, neoplasms, and herpes zoster). We performed a descriptive bivariate analysis and a multivariate logistic regression analysis (dependent variable: MACEs) to identify factors that were independently associated with MACEs. Results: The study population comprised 137 patients (110 with RA, 18 with PsA, and 9 with SpA) who were followed up for a mean of 3.9 (2.6) years. Most patients had received JAK inhibitors as their second-line or subsequent treatment. At the end of the follow-up, 82 patients (66.7%) continued their treatment. Nine patients (6.6%) experienced a MACE, and five experienced a heart attack. All of these patients had RA. We found no differences between JAK inhibitors in terms of the incidence of the adverse events studied. Patients who experienced MACEs were more often male and smokers (current or former) and more often had hypertension and diabetes. No significant differences were found in the association with disease activity or previous or concomitant treatment. The factors that were independently associated with MACEs were a previous cardiovascular event (OR, 10.74; 95%CI, 1.05–113.7; p = 0.036), male sex (OR, 9.7; 95%CI, 1.6–76.5; p = 0.016), diabetes mellitus (OR, 10.3; 95%CI, 1.75–83; p = 0.013), and the duration of treatment with JAK inhibitors (OR, 1.47; 95%CI, 1.13–2.01; p = 0.005). Conclusions: We found no differences in the onset of adverse events, specifically MACEs, between the different JAK inhibitors analyzed. These events are more common in patients who already have cardiovascular risk factors, such as diabetes mellitus, or who have already experienced a cardiovascular event. JAK inhibitors broadly suppress cytokines in patients whose disease is refractory to other treatments. However, we must continue to evaluate their long-term safety in real-world studies. Full article

Background/Objectives: Patients with rheumatoid arthritis (RA) and psoriatic arthritis (PsA) exhibit increased cardiovascular risk, partly attributed to persistent systemic inflammation. Janus kinase inhibitors (JAKi) effectively reduce inflammation, but their impact on cardiovascular risk remains unclear. This pilot study aimed to evaluate the effect of JAKi therapy on systemic inflammation and lipid markers, correlate traditional cardiovascular risk factors with biological parameters, and quantify subclinical atherosclerosis progression. Methods: We conducted a prospective, single-center study including 48 patients receiving JAKi. Clinical, inflammatory, lipid, and vascular parameters were assessed at baseline (T0) and after 12 months (T1). Primary endpoints included changes in carotid intima-media thickness (cIMT), ankle-brachial index (ABI), and carotid plaque presence. Results: Mean cIMT significantly decreased from 0.29 mm to 0.125 mm (p = 0.019), while ABI improved modestly, but not significantly (0.125 to 0.04, p = 0.103). Carotid plaque prevalence increased slightly from 39.6% to 47.9%, p = 0.159. C-reactive protein (CRP) levels declined significantly, while interleukin (IL)-1β levels increased. Lipoprotein(a) [Lp(a)] levels decreased significantly (mean reduction −7.96 mmol/L, p = 0.001). Multivariate regression identified Lp(a) as an independent predictor of carotid plaque at both T0 (p = 0.011) and T1 (p = 0.005). Baseline ABI was a significant predictor of acute cardiovascular events [hazard ratio (HR): 4.614, 95% CI: 1.034–20.596, p = 0.045]. Conclusions: JAKi therapy significantly reduced systemic inflammation and cIMT in patients with autoimmune rheumatic diseases, suggesting a potential benefit in attenuating early vascular changes. However, residual cardiovascular risk remains in patients with low ABI and elevated Lp(a), warranting close monitoring. Full article

Janus kinase 2 (JAK2) inhibitors have gained regulatory approval for treating various human diseases. While the JAK2/signal tranducer and activator of transcription 3 (STAT3) pathway plays a role in tumorigenesis, JAK2/STAT3 inhibitors have shown limited therapeutic efficacy in triple-negative breast cancer (TNBC). In this study, we assessed the antiproliferative effects of clinically approved JAK2 inhibitors in TNBC cell lines (MDA-MB-231 and HS578T) using the MTT assay. Among the four JAK2 inhibitors evaluated (fedratinib, cerdulatinib, peficitinib, and filgotinib), fedratinib significantly inhibited the proliferation of TNBC cells with IC₅₀ values below 2 μM. Fedratinib also demonstrated superior efficacy in inhibiting long-term colony formation compared to other JAK2 inhibitors. Western blot analyses showed that fedratinib uniquely inhibits the phosphoinositide 3-kinase (PI3K)/AKT pathway and moderately affects the MAP kinase/ERK kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway, in addition to targeting JAK2/STAT3 signaling. Moreover, fedratinib distinctly decreased MYC and cyclin D1 protein levels while inducing poly (ADP-ribose) polymerase (PARP) cleavage and apoptotic cell death more effectively than other JAK2 inhibitors. We next investigated the effects of simultaneously inhibiting JAK2/STAT3 together with the MEK/ERK or PI3K/AKT pathways, as well as the impact of triple pathway inhibition. Notably, combining ceduratinib with either cobimetinib (MEK inhibitor) and ipatasertib (AKT inhibitor) or trametinib (MEK inhibitor) and alpelisib (PI3K inhibitor) mimicked the effects of fedratinib on the cell proliferation, MYC and cyclin D1 suppression, and pro-apoptotic protein induction. These finding suggest that JAK2 inhibition enhances the anticancer effects of concurrent MEK/ERK and PI3K/AKT pathway inhibition, while JAK2 inhibition alone shows minimal efficacy in TNBC cells. Full article

Graft-versus-host disease (GVHD) remains a significant barrier to the success of allogeneic hematopoietic stem cell transplantation (allo-HSCT), contributing to long-term morbidity and non-relapse mortality in both pediatric and adult populations. Central to GVHD pathophysiology is the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway, where JAK2 mediates key pro-inflammatory cytokines, including IL-6, IFN-γ, and GM-CSF. These cytokines promote donor T cell activation, effector differentiation, and target organ damage. The introduction of ruxolitinib, a selective JAK1/2 inhibitor, has transformed the treatment landscape for steroid-refractory acute and chronic GVHD, leading to improved response rates and durable symptom control. However, its limitations—such as cytopenias, infectious complications, and incomplete responses—have catalyzed the development of next-generation agents. In 2024, the FDA approved axatilimab, a CSF-1R inhibitor that targets monocyte-derived macrophages in fibrotic chronic GVHD, and remestemcel-L, an allogeneic mesenchymal stromal cell therapy, for pediatric steroid-refractory acute GVHD. Both agents offer mechanistically distinct and clinically meaningful additions to the therapeutic armamentarium. In parallel, emerging combination strategies involving JAK2 inhibitors and novel biologics show promise in enhancing immune tolerance while preserving graft-versus-leukemia (GvL) effects. Recent advances in biomarker development, such as the MAGIC Algorithm Probability (MAP), are enabling early risk stratification and response prediction. The integration of these tools with organ-specific and personalized approaches marks a shift toward more precise, durable, and tolerable GVHD therapy. This review highlights the current state and future direction of JAK2 inhibition and complementary therapies in the evolving GVHD treatment paradigm. Full article

Background: Numerous novel medications are being developed to treat moderate to severe atopic dermatitis (AD), notably biologics and Janus kinase inhibitors (JAKis). However, the exact guideline for the first determination of which medication has not been established yet. This study was conducted to identify patients who would show favorable clinical results from using JAKis. Methods: Based on the degree of improvement in EASI at 16 weeks, 43 patients were divided into three groups: Group 1 (EASI-90), Group 2 (EASI-75), and Group 3 (EASI-50). Results: Compared to Group 1 and Group 2, Group 3 exhibited a significantly higher rate of multiple positive results in MAST (p-value = 0.005, p-value = 0.004), a greater proportion of individuals with higher IgE levels exceeding 1000 (p-value = 0.003, p-value = 0.027), and the presence of allergic comorbidities (p-value = 0.049, p-value = 0.026). However, baseline laboratory test results, such as eosinophil counts, LDH, and so on, showed no significant differences among the three groups. Conclusions: JAKis might provide prompt clinical improvement, especially in patients with relatively low serum Ig E levels who do not have multiple allergen positivities and allergic comorbidities. Full article

Hidradenitis suppurativa (HS) and atopic dermatitis (AD) are both inflammatory dermatoses that can significantly impact patient quality of life, however, limited research exists regarding their association. The purpose of this comprehensive review is to compare the inflammatory pathogenesis of HS and AD, explore the associations between these diseases, and discuss standalone and concomitant disease treatment options. Although HS and AD are understood to be primarily driven by the Th1 and Th2 inflammation pathways, respectively, these conditions both utilize the Janus Kinase/Signal transducer and activator of transcription (JAK/STAT) pathway to promote inflammation. Newer research also suggests that IL-36 and IL-1 receptor-associated kinase 4 (IRAK4) may be two additional inflammatory signals shared between the HS and AD disease pathways. These shared mechanisms are reflected in patient presentations as HS and AD are often concomitantly present and demonstrate a bidirectional association in the current literature. Treatment options for concomitant disease are limited, but leverage the shared immune pathogenesis of both diseases. Dupilumab has been reported to improve both HS and AD symptoms in select patients. JAK inhibitors are currently FDA-approved for the treatment of AD, and early trials have suggested benefits from JAK inhibitors such as upadacitinib, povorcitinib, and topical ruxolitinib for HS. Possible future avenues for research on treating both HS and AD include IRAK-4 inhibitors such as zabedosertib and BAY1830839, and diet and gut microbiome modifications. Full article

Lichen planus (LP) is a chronic inflammatory disorder affecting approximately 1% of the population. It presents with a wide range of clinical manifestations, mainly involving the skin, mucosal surfaces, and skin appendages, and is often characterized by a relapsing course and variable response to treatment. Although several therapeutic strategies are available, many are off-label and show limited efficacy in resistant forms. Increasing evidence points to the central role of the JAK/STAT signaling pathway in the immunopathogenesis of LP, with cytokines such as interferon-gamma and interleukin-21 playing key roles in sustaining chronic inflammation. Based on this rationale, Janus kinase (JAK) inhibitors have recently been proposed as potential therapeutic agents in LP. This review explores the biological basis for their use and systematically summarizes the existing clinical evidence on the use of JAK inhibitors in cutaneous, mucosal, appendageal, and nail variants of LP. The preliminary data suggests favorable outcomes in many patients with difficult-to-treat disease, with an acceptable safety profile. Further prospective trials are needed to establish their definitive role in the management of LP. Full article

This review aimed to provide a comprehensive overview of the current landscape of etrasimod. Etrasimod is an oral, once-daily selective modulator of sphingosine 1-phosphate receptors (S1PR), developed for the treatment of moderately to severely active ulcerative colitis and currently being explored for its potential in other immune-mediated inflammatory diseases. It selectively targets the S1PR subtypes S1PR₁, S1PR₄, and S1PR₅, with limited activity on S1PR₃ and no activity on S1PR₂. Clinical trials have demonstrated that etrasimod significantly reduces symptoms and induces endoscopic improvement in patients with moderate to severe ulcerative colitis who are refractory or intolerant to at least one conventional therapy, biologic agent, or Janus kinase inhibitor, while maintaining a favourable safety profile. At the end of 2023, etrasimod was approved in the United States and Europe, and it is currently under review for ulcerative colitis in several other regions. Etrasimod offers a novel therapeutic option with unique characteristics that may help address the persistent unmet needs of real-world patients with moderately to severely active ulcerative colitis. Full article

Janus kinase inhibitors, including tofacitinib, filgotinib, and upadacitinib, have emerged as effective therapeutic options for the management of inflammatory bowel diseases (IBDs). By targeting the JAK-STAT signaling pathway, these agents modulate immune responses and reduce inflammation. However, concerns regarding the potential risk of malignancy associated with their use have gained significant attention. The JAK-STAT pathway is not only critical for inflammatory signaling but also plays a pivotal role in cellular growth, differentiation, and tumor surveillance. Observational studies and clinical trial data in rheumatoid arthritis have reported malignancies, including non-melanoma skin cancer and solid tumors, in patients receiving JAK inhibitors, with evidence suggesting variable risks depending on the selectivity of the agent. Current evidence does not suggest an increased risk of oncogenesis in patients with IBDs. Balancing therapeutic efficacy with long-term safety requires ongoing vigilance; patient stratification based on risk factors; and tailored monitoring strategies to mitigate potential adverse effects, including malignancies, during JAK inhibitor therapy. Long-term follow-up data of up to 10 years offer reassuring evidence that JAK inhibitor therapy in IBD patients does not confer an increased risk of malignancies, supporting their continued use within appropriate clinical settings. Full article

Recent concerns regarding the safety of Janus kinase inhibitors (JAKis) have prompted investigation into their impact on immune cell subsets in rheumatoid arthritis (RA) patients. This study aims to analyse alterations in immune cell populations induced by JAKis that may contribute to adverse events, such as infections or malignancies. This study included 78 RA patients meeting ACR/EULAR criteria with an established treatment with JAKis (tofacitinib, baricitinib, upadacitinib, or filgotinib), 20 healthy donors, and 20 RA patients treated with biological disease-modifying antirheumatic drugs (bDMARDs). Peripheral blood mononuclear cells (PBMCs) were immunophenotyped directly after isolation using multiparametric flow cytometry to characterise innate and adaptive immune-cell subsets. JAKi-treated patients showed a significant reduction in cytotoxic NK Dim (CD3−CD56+CD16+) cells and in the percentage of NK Dim cells expressing the activation marker Nkp30. In CD4+ T cells, the percentage of Th17 (CD3+CD4+CD45RA+CCR6+CXCR3−), Th1-17 (CD3+CD4+CD45RA+CCR6+CXCR3+), and central memory (CM, CD3+CD4+CD45RA+CD62L+) cells was lower in the JAKi group, while effector memory (EM, CD3+CD4+CD45RA−CD62L−) and terminally differentiated CD45RA (TEMRA, CD3+CD4+CD45RA+CD62L−) T helper cells were increased compared to healthy and bDMARD-treated controls. The reduction in NK Dim and Th1-17 cells and the increase in exhausted Th subsets suggest a potential compromise in antiviral immunity and balanced immune responses in JAKi-treated RA patients. These alterations may contribute to an increased risk of infections or malignancies. Full article

Background and Objectives: Several biologics and oral Janus kinase (JAK) inhibitors have been developed and shown in clinical trials and real-world studies to be effective and safe in moderate-to-severe atopic dermatitis (AD). In this study, we aimed to evaluate the real-world outcomes of patients with moderate-to-severe AD treated with dupilumab and JAK inhibitors in our facility, focusing on their short-term effect on serum galectin-7 levels, a biomarker reflecting skin barrier impairment, and one-year stability based on patient-oriented outcomes. Materials and Methods: In a single-center, retrospective study of AD patients treated with dupilumab or JAK inhibitors between January 2018 and December 2024, we assessed physician-oriented outcomes until 16 weeks and patient-oriented outcomes until 52 weeks. Serum galectin-7 levels at baseline and 4 and/or 16 weeks after treatment were measured in 14 patients. Results: A total of 45 patients starting dupilumab and 10 patients starting JAK inhibitors were enrolled. Percentage reductions in EASI scores from baseline at 4, 8, and 16 weeks were 58.36 ± 22.09, 69.59 ± 20.96, and 75.98 ± 19.70, with no significant differences between patients treated with dupilumab and JAK inhibitors. Serum galectin-7 levels were significantly reduced after treatment at 4 and 16 weeks in the entire population. Both DLQI and POEM scores were reduced at 4 weeks and gradually decreased until 52 weeks. The reduction was faster with JAK inhibitors than with dupilumab. Visits with unstable effectiveness, defined as a visit with a three-point or greater increase in the POEM score at 28, 40, and 52 weeks, were more frequent in JAK inhibitor patients. Conclusions: Both dupilumab and JAK inhibitors showed high effectiveness on skin inflammation and decreased a marker of skin barrier dysfunction within 16 weeks. JAK inhibitors improved patient-reported outcomes more quickly than dupilumab, but instability of effectiveness during 16 and 52 weeks was higher with JAK inhibitors. Full article