Search Results (462)

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

Atopic dermatitis (AD) is a chronic, relapsing inflammatory skin disease characterized by substantial clinical and immunological heterogeneity. Once considered primarily a disorder of epidermal barrier dysfunction, AD is now recognized as a complex systemic inflammatory condition involving dysregulated immune responses, epithelial-derived signaling, neuroimmune interactions, and diverse molecular endotypes. Advances in molecular immunology have substantially improved understanding of the cytokine networks underlying disease pathogenesis and have accelerated the transition toward precision medicine approaches in AD. This narrative review summarizes current evidence regarding the immunopathogenesis of AD, focusing on the interplay between classical and emerging cytokine pathways, biomarker development, and recent therapeutic innovations. While interleukin (IL)-4 and IL-13 remain central drivers of type 2 inflammation and barrier impairment, additional mediators including IL-31, IL-33, IL-22, thymic stromal lymphopoietin (TSLP), and OX40/OX40L signaling, and the emerging Th9/IL-9 axis contribute to chronic inflammation, neuroimmune activation, epidermal remodeling, pruritus, and disease heterogeneity. Comparative evaluation of these pathways supports the identification of distinct immunological endotypes relevant to disease stratification and targeted therapy. The review further discusses current and emerging biomarkers associated with disease severity, therapeutic responsiveness, and inflammatory profiling, including cytokine signatures, serum biomarkers, and transcriptomic approaches. Recent advances in biologic therapies, Janus kinase (JAK) inhibitors, and novel cytokine-targeted interventions are discussed within the context of a precision medicine framework integrating immunological profiling, molecular endotyping, and mechanism-based therapeutic innovation. Continued advances in biomarker discovery, multi-omics technologies, and predictive therapeutic algorithms are expected to further refine disease stratification and support increasingly individualized management strategies for patients with AD. Full article

The introduction of biologic disease-modifying antirheumatic drugs (bDMARDs) and targeted synthetic disease-modifying antirheumatic drugs (tsDMARDs) has significantly enhanced the prognosis for patients with rheumatoid arthritis (RA). Nevertheless, improving quality of life remains a major clinical challenge requiring the implementation of multidirectional therapeutic measures. Pain reduction plays a particularly important role in this context, representing one of the primary treatment goals for many patients. Scientific evidence indicates that effective pain management is a crucial predictive factor for the improvement of mental and physical health in patients with RA. The aim of this literature review was to summarise the mechanisms of action of Janus kinase inhibitors (JAKi), with particular emphasis on their modulation of pain generation and transmission. Furthermore, the study aimed to compare the results of clinical studies and assess the actual effectiveness of these drugs in reducing pain in clinical practice. JAKi exhibit peripheral analgesic effects by directly reducing the production of pro-nociceptive cytokines and modulating macrophage polarisation. Moreover, they influence central pain processing mechanisms by modulating the IL-6/JAK/STAT3 pathway and by reducing microglial and astrocyte proliferation in the dorsal horn of the spinal cord. The results of randomised clinical trials confirm that JAKi provide rapid, clinically significant pain reduction. Some studies also point to the persistence of this effect over a longer period, and to their greater efficacy compared with conventional disease-modifying antirheumatic drugs (cDMARDs) and bDMARDs. The efficacy of this group of drugs has also been noted in patients with an inadequate response to prior therapy with biological drugs. A key focus of future research remains determining the optimal timing for introducing JAKi in the treatment of RA and identifying predictive factors to enable the selection of patients most likely to benefit from this class of drugs. Full article

Background: Atopic dermatitis (AD) is a chronic inflammatory skin disease with substantial impact on quality of life. The introduction of biologics and Janus kinase (JAK) inhibitors has markedly transformed systemic treatment strategies. However, long-term prospective real-world registries evaluating drug survival, safety, phenotype-specific treatment response, and post-discontinuation outcomes remain limited, particularly in Asian populations. Methods: The Western Japan Atopic Dermatitis Registry (WJADR) is a multicenter, prospective, observational registry coordinated by Kyushu University and collaborating institutions across western Japan. Patients initiating or currently receiving systemic therapy for AD are enrolled. Longitudinal data collection includes clinical phenotype classification, disease course classification, treatment exposure, physician-assessed severity scores, patient-reported outcomes, biomarkers, and safety information. The primary outcome is drug survival, while secondary outcomes include clinical improvement, adverse events, phenotype–treatment interactions, biomarker–treatment correlations, and treatment-switch patterns. Results: WJADR was designed as a phenotype-integrated real-world registry to evaluate comprehensive systemic treatment strategies and post-discontinuation outcomes in AD prior to the completion of patient enrollment and outcome analyses. Unlike existing registries primarily focused on biologic initiator cohorts or treatment burden, WJADR integrates clinical phenotypes, biomarkers, and longitudinal outcomes to support precision medicine approaches. Conclusions: WJADR represents the first large-scale multicenter prospective AD registry in western Japan and may provide ethnicity-specific real-world evidence to support long-term safety evaluation, treatment optimization, and phenotype-guided therapeutic strategies in AD. Full article

Rheumatoid arthritis (RA) is a systemic rheumatic disease. Its most prominent characteristic is synovitis, which manifests clinically as arthritis, resulting in joint damage. Interstitial lung disease (ILD) is an extraarticular manifestation of RA that hinders therapeutic goals, affects life prognosis, and can be worsened by the administration of disease-modifying antirheumatic drugs (DMARDs). Therefore, proper management of ILD, including consideration of risk factors such as the systemic disease activity of RA and autoantibodies, and early detection with high-resolution computed tomography are required at the introduction of DMARDs. Methotrexate, a class of DMARD used as the anchor drug for RA treatment, has been recognized as likely to worsen RA-ILD. However, there are currently reports suggesting that methotrexate may have beneficial effects on RA-ILD. Conversely, several studies have also shown exacerbations of ILD with the administration of biological DMARDs, which are thought of as tolerable for patients with RA-ILD. Rheumatologists should be wary of emergence or changes in the activity of ILD and arthritis during treatment of any kind with DMARDs. Further studies are warranted to clarify underlying ethnic factors, such as the possible effects of antimelanoma differentiation-associated gene 5 antibodies on RA-ILD. Full article

Ovarian cancer (OVC) is a leading cause of gynecological cancer mortality due to late-stage diagnosis and chemoresistance. Among the multiple molecular mediators, oncogenic epidermal growth factor receptor (EGFR) signaling has emerged as a key regulator of tumor progression and drug resistance, ultimately governing cancer survival. Therefore, this review focused on the molecular mechanisms of aberrant EGFR signaling to promote chemoresistance in ovarian cancer through multiple interlinking pathways, including the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of the rapamycin (mTOR), mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK), and Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling cascades. These pathways act in concert to confer resistance, including proliferation, antiapoptotic effects, cancer stem cell maintenance, and facilitating epithelial-mesenchymal transition (EMT), which function together to decrease sensitivity towards platinum-based and taxane chemotherapies. Furthermore, we incorporate novel evidence regarding EGFR cross-talk with extracellular matrix (ECM) and metabolic reprogramming, especially their relevance to immune evasion mechanisms, hypoxia, and extracellular vesicles (EVs)-mediated signaling. In addition, we elaborated on the limitation of the current EGFR targeting therapy, which will be beneficial for further designing new combinatorial treatment approaches by using EGFR inhibitors with immunotherapy, nanocarriers, and microbiota modulators. Overall, this review highlights the updated role of EGFR signaling as a key regulator of chemoresistance in ovarian cancer, providing insights for developing targeted therapies to overcome drug resistance and improve patient survival. Full article

Background: Atopic dermatitis (AD) is associated with neuropsychiatric comorbidity, yet no study has directly compared neuropsychiatric outcomes across all three major systemic treatment classes. This study examined neuropsychiatric outcomes among patients with AD receiving Janus kinase (JAK) inhibitors, dupilumab, or conventional immunosuppressants. Methods: This retrospective cohort study utilized the TriNetX global health research network. Three propensity score-matched cohorts were constructed based on demographics, comorbidities, and concomitant medications. The primary outcome was incident neuropsychiatric disorder within 24 months. Results: After matching, cohorts included 608 (JAK inhibitors vs. dupilumab), 502 (JAK inhibitors vs. conventional), and 2322 patients (dupilumab vs. conventional). In the largest cohort, conventional immunosuppressants were associated with a significantly higher incidence of neuropsychiatric disorders compared with dupilumab (hazard ratio [HR] 1.26, 95% confidence interval [CI] 1.00–1.59; p = 0.042). A similar directional trend was observed for conventional immunosuppressants compared with JAK inhibitors (HR 1.97, 95% CI 1.13–3.42; p = 0.015). The comparison between JAK inhibitors and dupilumab did not reach statistical significance (HR 0.62, 95% CI 0.37–1.03; p = 0.063). Findings regarding rare outcomes, such as autism spectrum disorders, were based on very low event counts and should be interpreted with extreme caution. Conclusions: In this large propensity-matched cohort, dupilumab was associated with significantly lower neuropsychiatric disorder incidence compared with conventional systemic immunosuppressants, with a similar directional trend observed for JAK inhibitors. These hypothesis-generating findings suggest potential neuropsychiatric outcome differences among systemic therapies for AD, warranting further investigation to establish whether the associations reflect treatment effects or residual confounding. 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

Background: A significant proportion of individuals with Takayasu arteritis (TA) experience relapses notwithstanding standard treatment with glucocorticoids, and conventional synthetic or biologic disease-modifying antirheumatic drugs (DMARDs). As the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway contributes to the pathogenesis of TA, JAK inhibitors (JAKi) could represent a viable therapeutic alternative. This study assessed the effectiveness of JAKi in patients with relapsing TA within a real-world setting in a country with a low incidence of TA such as Spain and included a comprehensive review of the literature. Methods: we conducted a retrospective analysis of TA patients managed with JAKi for recurrent disease across three Spanish centers. Evaluated outcomes comprised clinical remission, clinical and analytical remission, glucocorticoid-sparing effect, improvement in imaging techniques, and adverse events. A systematic literature search was performed to identify further cases of TA treated with JAKi. Results: six patients (83.3% females) with a mean age 48.5 years and relapsing TA received JAKi therapy: baricitinib (n = 2); tofacitinib (n = 2), and upadacitinib (n = 2). Before JAKi therapy, all (100%) patients had received conventional synthetic immunosuppressants, and four (66.7%) biologics. Clinical remission was achieved in 2/6 (33.3%), 3/5 (60%), 3/5 (60%), 2/3 (66.7%), and 2/2 (100%) patients at 1, 3, 6, 12 and 18 months, respectively. Clinical + analytical remission was observed in 1/6 (16.7%), 2/5 (40%), 2/5 (40%), 2/3 (66.7%), and 2/2 (100%) patients, respectively. Two patients who underwent a follow-up PET/CT imaging showed partial improvement in both. After a median (IQR) follow-up of 9.5 (6.0–16.7) months, one (16.7%) patient discontinued the initial JAKi due to no improvement and one patient discontinued it because was diagnosed with tonsillar neoplasia. The literature search identified another 166 JAKi-treated TA cases with clinical improvement reported for the majority of them. Conclusions: this real-world analysis and literature review suggest that JAKi could be effective in the management of TA, including for those patients who have failed established glucocorticoid-sparing strategies. Full article

Patients with myeloproliferative neoplasms (MPN) are at increased risk of herpes zoster, particularly during Janus kinase inhibitor (JAKi) therapy, yet the immunogenicity of recombinant zoster vaccine (RZV) in this setting remains incompletely characterized. We performed a prospective pilot translational study including 18 patients with MPN and a small age-matched healthy donor group (n = 4, descriptive reference only). Samples were collected at baseline, 21 days after the first dose, and 21 days after the second dose. Humoral response was assessed by anti-varicella-zoster virus (VZV) immunoglobulin G (IgG) enzyme-linked immunosorbent assay (ELISA), whereas antigen-specific cellular responses were evaluated after ex vivo stimulation with recombinant VZV glycoprotein E followed by flow cytometry and cytokine quantification. IgG levels increased over time in MPN patients, while cellular responses remained limited, heterogeneous, and not consistently enhanced. Cytokine production was low and variable across time points. Overall, RZV in MPN under JAKi was associated with detectable humoral responses but limited cellular activation, supporting an apparent discordance between humoral and cellular immune readouts under the experimental conditions used. Full article

Inflammaging is defined as chronic low-grade inflammation associated with aging and is increasingly recognized as a dynamic and mechanistically driven biological process rather than a state adequately described by circulating biomarkers alone. Traditional inflammatory markers alone, including interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and C-reactive Protein (CRP), fail to capture the complexity, tissue specificity, and causal architecture of inflammaging. Recent experimental evidence has demonstrated that diverse upstream drivers, including immunosenescence, gut microbiome dysbiosis, metabolic dysfunction, and cellular senescence, converge on a limited number of central inflammatory hubs, including nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome, GMP–AMP synthase–stimulator of interferon genes (cGAS–STING), Janus kinase/signal transducer and activator of transcription (JAK/STAT), and p38 mitogen-activated protein kinase (p38 MAPK) signaling. These mechanistic nodes represent promising therapeutic targets, potentially modifiable biological processes, and support the emerging concept of ‘druggable inflammaging’, whereby senotherapeutics, inflammasome inhibitors, innate immune modulators, and metabolic interventions may actively modify aging-associated inflammatory biology rather than simply monitor it through biomarkers. This review highlights a paradigm shift from biomarker-based assessment toward mechanism-based intervention, where inflammaging can be characterized as a modifiable biological process and a central target for precision pharmacological strategies in aging-related diseases. Full article

Janus kinase 2 (JAK2) occupies a central position in cytokine signaling and plays essential roles in hematopoiesis, immune regulation, and cancer. Although recent advances in structural biology, cryo-EM, receptor modeling, and biophysical analysis have substantially expanded current views of JAK2 function, key mechanistic questions remain regarding how receptor geometry, JH2-mediated autoinhibition, and disease-associated mutations are structurally integrated. In this review, we discuss the multidomain organization of JAK2 and examine how the FERM–SH2 module, the pseudokinase domain (JH2), and the catalytic kinase domain (JH1) cooperate to govern receptor specificity, allosteric control, and cytokine-induced activation. We further analyze how pathogenic mutations rewire this regulatory system by weakening autoinhibitory contacts, altering linker-mediated communication, or stabilizing active dimeric conformations. Finally, we assess current and emerging therapeutic strategies, from ATP-competitive inhibitors to macrocyclic and JH2-selective allosteric modulators, with emphasis on how structural insight can guide next-generation drug design. These advances support a more integrated view of JAK2 regulation and define new opportunities for selective therapeutic intervention. Full article

Sarcoidosis is a multisystem granulomatous disorder of uncertain origin which still presents major therapeutic dilemmas. Longstanding dependence on corticosteroids, while effective for acute inflammation, carries considerable adverse effects over time. Advances in deciphering sarcoidosis pathobiology—including aberrant Janus kinase (JAK)- signal transducer and activator of transcription (STAT) signaling, mechanistic target of rapamycin (mTOR)-driven metabolic shifts, Th1/Th17.1 immune skewing, effector T-cell exhaustion, and granuloma-centered cytokine circuits—have revealed several targets for intervention. The treatment options are rapidly changing: the SARCORT trial showed that low-dose prednisolone is non-inferior to higher prednisolone doses; the pivotal PREDMETH trial validated methotrexate as a feasible first-line steroid-sparing option; efzofitimod, a novel immunomodulator targeting neuropilin-2, produced steroid-reducing effects in Phase IIbut not in Phase III trials; and JAK inhibitors are accumulating evidence across cutaneous and systemic presentations. The 2025 World Association for Sarcoidosis and Other Granulomatoses (WASOG) statement supports a move toward earlier steroid-sparing approaches. This review methodically connects sarcoidosis molecular and pathophysiological mechanisms to new targeted treatments, examines clinical trial evidence, and proposes future directions toward biomarker-driven individualized care. Full article

Background and Objectives: Janus kinase (JAK) inhibitors have expanded the therapeutic options for moderate-to-severe atopic dermatitis (AD). The possibility of dose modulation with abrocitinib (100 and 200 mg) and upadacitinib (15 and 30 mg), both selective JAK1 inhibitors, represents a potential clinical advantage, allowing dose escalation in cases of insufficient response and dose de-escalation in the setting of poor tolerability or during maintenance treatment. However, real-world data remain limited, and the rationale for dose adjustment is not always standardized. This study aimed to describe, using a real-world database, the frequency, timing, and reasons for dose modifications of these agents. Materials and Methods: We retrospectively analyzed the clinical data of 212 patients with moderate-to-severe AD treated with abrocitinib (n = 47) or upadacitinib (n = 165). Dose adjustments, including dose escalation and dose de-escalation, were recorded together with their timing and clinical reasons. Results: In the abrocitinib group, 34/47 patients (72.3%) initiated treatment at 100 mg, whereas 13/47 patients (27.7%) started at 200 mg. Six patients (12.8%) underwent a dose adjustment. One patient (2.1%) switched from 200 to 100 mg because of complete AD remission and concomitant menstrual cycle alterations, whereas five patients (10.6%) underwent dose escalation from 100 to 200 mg because of incomplete disease control. Among the six abrocitinib-treated patients who underwent dose adjustment, achievement of IGA 0/1 after dose modification was documented in all cases. In the upadacitinib group, 93/165 patients (56.4%) started at 15 mg, whereas 72/165 patients (43.6%) started at 30 mg. Overall, 44/165 patients (26.7%) underwent at least one dose adjustment, accounting for a total of 50 dose modifications: 27 escalations from 15 to 30 mg and 23 de-escalations from 30 to 15 mg. Among patients initiating treatment at 15 mg, 23/93 patients (24.7%) increased the dose to 30 mg after a median of 33.1 weeks because of suboptimal disease control. Among those starting at 30 mg, 21/72 patients (29.2%) reduced the dose to 15 mg after a median of 44.3 weeks. Of these, 12/21 patients (57.1%) reduced the dose because of adverse events, including herpetic infections and acne, whereas the remaining patients de-escalated because of optimal disease control. Some patients underwent multiple dose modifications: four followed a 30→15→30 mg sequence, with re-escalation after 13.2 weeks because of suboptimal disease control, and two followed a 15→30→15 mg sequence, with dose reduction after approximately 26.7 weeks because of herpes zoster. Overall, 29/44 patients achieved IGA 0/1 within 16 weeks and 38/44 within 32 weeks after dose modification. Conclusions: In this real-world cohort, dose adjustments of selective JAK1 inhibitors were frequently performed in patients with moderate-to-severe AD, particularly among those treated with upadacitinib. Dose escalation was mainly used to address suboptimal disease control, whereas dose de-escalation was performed in the setting of adverse events or optimal disease control. The availability of two dosing regimens may allow treatment intensity to be adapted to individual disease severity, response, and tolerability, supporting a personalized approach to AD management. Full article

Background: Difficult-to-treat anatomical areas in atopic dermatitis (AD), including the head and neck, hands, genital and intertriginous regions, are frequently associated with therapeutic refractoriness, persistent pruritus, and substantial functional and psychosocial burden. Real-world evidence (RWE) regarding the effectiveness of Janus kinase (JAK) inhibitors in these site-dominant phenotypes remains fragmented. This structured narrative review aimed to synthesize available RWE on abrocitinib, baricitinib, and upadacitinib in AD involving difficult-to-treat areas. Methods: A comprehensive search of PubMed, Ovid MEDLINE, Scopus, Embase, and the Cochrane Library was conducted up to 31 December 2025. Real-world observational studies reporting site-specific outcomes in patients with AD treated with JAK inhibitors were included. Primary randomized controlled trial efficacy analyses were excluded, while relevant post hoc regional analyses were considered. A total of 22 studies met eligibility criteria for qualitative synthesis. Results: Across heterogeneous real-world cohorts, JAK inhibitors demonstrated clinically meaningful improvement in difficult anatomical regions, particularly the head and neck and hands. Rapid pruritus reduction was a consistent and clinically relevant finding. Safety profiles were broadly aligned with clinical trial data. Conclusions: Real-world data support JAK inhibitors as effective options for anatomically complex AD phenotypes, warranting further standardized regional assessment. Full article