Search Results (163)

Background: Janus kinase inhibitors (JAKi) are approved for the treatment of rheumatoid arthritis (RA), aiming to achieve clinical remission. Composite scores such as Disease Activity Score in 28 joints with C-reactive protein (DAS28-CRP) are influenced by subjective factors, and JAKi may impact these dimensions beyond inflammation. Ultrasound provides a sensitive and objective assessment of synovial activity. Objective: To evaluate clinical and ultrasound-defined remission in RA patients treated with JAKi under routine care. Methods: This cross-sectional study included all consecutive patients treated with baricitinib, filgotinib, tofacitinib, or upadacitinib between 1 November 2022 and 30 April 2023. Clinical remission was defined as DAS28-CRP and ultrasound remission as absence of power Doppler (PD) signal across a standardized 32-joint evaluation. Results: We include 78 patients with established RA; 87.2% were female, with mean age of 59.5 ± 10.8 years and disease duration of 10.6 ± 8.0 years. Most were seropositive for RF and/or ACPA (74.4%), and comorbidities were highly prevalent (93.6%). Clinical remission was observed in 42.3% and ultrasound remission in 56.4%, with no statistically significant differences between JAKi groups. Among 50 patients meeting remission by either definition, 30 (60%) fulfilled both criteria, 11 (22%) had ultrasound remission only, and 9 (18%) met clinical remission without sonographic confirmation. Discordant cases were often associated with osteoarthritis, fibromyalgia, mood disorders, and elevated inflammatory markers. Conclusions: JAKi were effective in achieving remission in many RA patients. Ultrasound revealed residual synovitis despite clinial remission and, conversely, silent remission in cases not meeting DAS28-CRP criterion, reinforcing its value for accurate monitoring and personalized therapeutic decisions. No meaningful clinical or ultrasonographic differences were observed between the various JAK inhibitors, indicating comparable perfomance across agents in routine practice. Full article

Background/Objectives: The enhancement of antitumor immune responses by radiotherapy (RT) is partially attributed to the activation of the IFN-type-I pathway. However, the loss of HLA-class-I molecules, which occurs in a large percentage of non-small-cell lung cancers (NSCLCs), may block the cytotoxic effect of T-cells and immunotherapy (IO). Moreover, autophagy is also involved in HLA downregulation. We investigated the complex interactions between RT, HLA molecules, autophagy, and IFN-type-I responses. Methods: The A549, H1299, and ATG7-deficient NSCLC cell lines, along with the modified shLC3A H1299 cell line, were used for in vitro experiments. The effect of RT (8 and 3 × 8 Gy) on Interferon beta (IFNβ), IFN-stimulated genes (ISGs), and HLA-class-I expression in combination with IFN-type-I-response inhibitors (Ruxolitinib, Tofacitinib, Amlexanox) targeting the JAK and TBK1 was studied with Flow cytometry and RT-PCR. Results: RT significantly induced HLA-class-I expression. A parallel upregulation of IFNβ and ISGs mRNA levels was also documented. Although the IFN-type-I-response inhibitors suppressed the RT-induced IFNβ and ISGs expression, their effect on HLA-class-I expression was minimal. Blockage of LC3A autophagy (shLC3A cell line) significantly upregulated HLA-class-I basal levels, and RT further enhanced HLA expression. IFN-type-I-response inhibitors blocked the RT-inductive effect in the shLC3A H1299, but had no effect in the ATG7-deficient H1650 cell line. Conclusions: The current study supports the theory that baseline autophagy, RT-induced autophagy blockage, and IFN-type-I response enhancement define the HLA-class-I levels in NSCLC cells. This complex interplay emerges as a promising target for the development of radio-vaccination strategies to enhance the efficacy of radio-immunotherapy. Full article

Microneedle array-based drug delivery offers a minimally invasive and safe approach for breaching the skin barrier, enabling localized and targeted treatment—an advantage particularly valuable in chronic condition management, such as rheumatoid arthritis (RA). RA presents a multifaceted pathophysiology, often necessitating long-term pharmacological management. However, conventional oral administration may lead to systemic drug distribution, increasing the likelihood of adverse effects, and ultimately undermining therapeutic efficacy. In this study, a hollow microneedle array was employed for effective delivery of Tofacitinib and the antioxidant N-acetylcysteine (NAC). A comprehensive evaluation was conducted across multiple levels, in which inflammation and cartilage degradation were assessed histologically using hematoxylin-eosin (H&E) and Safranin O–Fast Green staining. Radiologically, micro-computed tomography (micro-CT) was employed to visualize bone structure alterations. On the molecular level, enzyme-linked immunosorbent assay (ELISA) was used to quantify inflammatory cytokines and oxidative stress markers. Furthermore, differentially expressed genes and enriched signaling pathways were identified through transcriptomic profiling pre- and post-treatment. And the potential regulatory targets and mechanistic insights into the therapeutic response were elucidated through correlation analyses between gene expression profiles and pathological indicators. This study provides a mechanistic and computational basis for precision targeted therapy, validates the efficacy and safety of microneedle delivery in a rheumatoid arthritis (RA) model, and demonstrates its potential application in local drug delivery strategies. Full article

Background/Objectives: GPA is a PR3-ANCA–predominant small vessel vasculitis with organ involvement. Real-world, single-centre data are needed to interpret evolving therapies and phenotype patterns in national conditions. Material and Methods: Retrospective cohort study of consecutive GPA patients managed at the National Institute of Geriatrics, Rheumatology and Rehabilitation (Warsaw, Poland) from 1 September 2010 to 1 September 2025. Data included demographics, phenotype, BVAS, organ involvement, PR3/MPO-ANCA serology, and induction/maintenance therapies. Results: Fifty patients were included (54.0% men). Mean age was 52.5 years; mean BMI was 26.15 kg/m². Ear-nose-throat (ENT) disease was frequent: rhinosinusitis 76.0%, nasal cartilage destruction 64.0%, subglottic stenosis 34.0%. Pulmonary nodules occurred in 52.0%, cavitation in 28.0%, and diffuse alveolar haemorrhage in 34.0%. Renal involvement included haematuria in 42.0%, chronic kidney disease (CKD) in 32.0%, and rapidly progressive kidney disease in 22.0%. Orbital inflammation was 36.0%, and PR3-ANCA was positive in 70.0%. All patients received glucocorticoids for induction; cyclophosphamide 28/50 (56.0%), rituximab 6/50 (12.0%), and mycophenolate with methotrexate 6/50 (32%). Maintenance therapy included methotrexate (78.0%), mycophenolate (64.0%), rituximab (52.0%), and azathioprine (12.0%). Conclusions: This Polish single-centre cohort shows an ear-nose-throat-lung-kidney (ELK)-dominant, PR3-predominant GPA phenotype and frequent but variable kidney involvement. Over 2010–2025, practice changed toward rituximab-based strategies, steroid minimisation, selective use of plasma exchange, and early avacopan uptake, with tofacitinib for maintenance therapy as a possible new therapeutic option. Full article

Background: This study aimed to explore whether differences exist between males and females in a cohort of bio-experienced UC patients treated with vedolizumab (VDZ), ustekinumab (UST), or tofacitinib (TOFA) in a 48-week retrospective study. Methods: We evaluated intra- and inter-treatment sex-specific differences regarding clinical response, remission, steroid-free remission, sustained clinical response, late remission, and changes in faecal calprotectin and inflammatory markers at 8, 24, and 48 weeks, as well as endoscopic response and remission at 48 weeks. Results: Among 602 patients (50.2% female), males treated with UST had higher rates of clinical (p = 0.029) and steroid-free clinical remission (p = 0.013) at 24 weeks. Conversely, females on TOFA showed higher clinical remission at 8 weeks (p = 0.043). In males, VDZ demonstrated a superior clinical response over time (p < 0.05), while TOFA showed the highest remission rate at 48 weeks. In females, TOFA was superior for clinical remission at 8 and 24 weeks (p < 0.05). Males had a higher late remission rate (p = 0.04) with an increased likelihood (aOR 1.958, 95%CI 1.088–3.524, p = 0.025). Endoscopic outcomes and faecal calprotectin levels showed no significant sex-specific differences. Conclusions: Sex-based profiling may guide individualised therapeutic strategies in UC patients in this setting. Full article

Acute severe ulcerative colitis (ASUC) is a medical emergency affecting up to 25% of patients with ulcerative colitis (UC), with colectomy required in approximately 25–30% of cases during the initial admission. Intravenous corticosteroids remain the first-line therapy, though one-third of patients do not respond, necessitating rescue with infliximab or calcineurin inhibitors, which are both supported by randomized trials and guideline recommendations. Comparative studies and meta-analyses have shown similar efficacy between these agents, while sequential use is associated with higher adverse event rates and should be restricted to specialized centers. Recent data have refined infliximab use, with the PREDICT-UC trial showing no superiority of intensified dosing over standard regimens. Emerging therapies are under investigation: vedolizumab has been used as maintenance following calcineurin induction; ustekinumab has shown benefits in retrospective UC cohorts, particularly after cyclosporine; and Janus kinase (JAK) inhibitors represent the most recent addition. The randomized TACOS trial and the prospective TRIUMPH study demonstrated an improved short-term response with tofacitinib in steroid-refractory ASUC, and real-world reports suggest promising outcomes with upadacitinib. While infliximab and cyclosporine remain as standard rescue therapies, ongoing trials with novel agents are likely to broaden treatment options. This review summarizes the clinical features, initial management, and the role of advanced therapies in ASUC. Full article

Background and Objective: Tofacitinib (TOF), an oral Janus kinase inhibitor used to treat rheumatoid arthritis (RA), is extensively metabolized by cytochrome P450 (CYP) 3A4. Ritonavir (RTV), a protease inhibitor, is commonly used as a pharmacokinetic (PK) enhancer due to its potent CYP3A4 inhibitory effects. Considering the prevalence of comorbidities in RA patients, it is possible to use TOF and RTV concurrently, raising concerns about potential drug–drug interactions (DDIs). The current study aims to assess the potential DDIs between RTV and TOF. Methods: An in vivo rat study was conducted to investigate the impacts of RTV on the PK of TOF. Rats were randomly divided into three groups: vehicle, RTV 10 mg/kg, and RTV 20 mg/kg, each undergoing four days of pretreatment. On the test day, TOF (10 mg/kg) was administered following co-administration of the respective RTV doses. Blood samples were collected at the pre-specified time points. Plasma concentrations of TOF were quantified using liquid chromatography coupled with mass spectrometry, and PK parameters were analyzed using non-compartmental analysis. Results: RTV (10 and 20 mg/kg) increased the area under the curve of TOF by 2.53-fold (95% CI: 1.64–3.43) and 5.39-fold (95% CI: 4.47–6.33), respectively, and the maximum concentration by 1.47-fold (95% CI: 0.99–2.00) and 2.86-fold (95% CI: 2.39–3.37), respectively. Whereas the half-life (t_1/2) remained unchanged. Conclusions: RTV substantially increased TOF exposure in rats. These results suggest the need for dose adjustments of TOF during co-administration with RTV in clinical settings. Further clinical research is needed to confirm these findings. Full article

Background/Objectives: Lichen planus (LP) is a chronic inflammatory disease of autoimmune origin, affecting the skin and mucous membranes. While corticosteroids and immunosuppressants are traditionally used, many cases remain refractory or intolerant to standard therapies. Recent advances in immunopathogenesis have led to the exploration of targeted therapies, including biologic agents and small-molecule inhibitors. Methods: This review synthesizes current evidence from case reports, case series, and observational studies on the use of monoclonal antibodies (anti-TNF-α, anti-IL-17, anti-IL-23, anti-IL-6) and JAK inhibitors in LP. A structured literature search was conducted across PubMed, Scopus, and Web of Science, focusing on studies published between 2010 and 2025. Data on mechanisms, clinical efficacy, safety, and research limitations were extracted and summarized. Results: Promising therapeutic responses were reported for IL-17 inhibitors (secukinumab, ixekizumab) and JAK inhibitors (tofacitinib, baricitinib) in mucosal and recalcitrant LP. Anti-TNF agents showed variable efficacy, while emerging targets such as BTK and IFN-γ are under investigation. Adverse events were generally mild to moderate, but long-term safety data are lacking. The absence of randomized controlled trials and standardized outcome measures limits generalizability. Conclusions: Biologic and small-molecule therapies represent a potential paradigm shift in the treatment of LP, offering targeted immunomodulation with promising efficacy in refractory cases. Further collaborative research, including randomized studies and biomarker-driven approaches, is urgently needed to validate these treatments and establish personalized care strategies. Full article

Rheumatoid arthritis (RA) is an autoimmune disease affecting the synovium. Mitochondrial dysfunction is considered a critical factor in the pathogenesis of RA. The aim of the study was to determine the effect of methotrexate and tofacitinib on mitochondrial function and oxidative stress in an in vitro study on the model synovial cell line SW982. TNF-alpha-stimulated SW982 cells, as well as control untreated cells, were incubated with methotrexate and tofacitinib. A metabolic test was performed to assess mitochondrial function. The oxidative stress generated after the application of the therapeutics was determined by a chromatographic analysis. The results obtained showed an increase in ATP levels (p < 0.0001) and a decrease in proton leak (p < 0.0003) after treatment with tofacitinib. The opposite trend was observed—reduced ATP production (p < 0.0096) and increased levels of proton leak (p < 0.0001)—after treatment with methotrexate. A two-fold increase in 8-ISOPGF2A was measured in comparison to TNF-alpha-stimulated and untreated cells. The dynamics of mitochondrial activity and oxidative stress were monitored in a certified RA model cell line after the administration of two different therapeutics. Methotrexate was found to induce mitochondrial dysfunction and oxidative stress in vitro, while tofacitinib partially improved mitochondrial parameters. 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

The B-cell adapter for PI3K (BCAP) is a protein that connects membrane receptor signaling to the PI3K pathway. In fibroblasts or dendritic cells, priming the cGAS nucleic-acid-sensing pathway increases BCAP expression and enhances type I interferon (IFN-I) production upon lipopolysaccharide (LPS) stimulation. These findings corroborate the idea that BCAP may bias cytokine production toward IFN during inflammation, indicating its potential involvement in IFN-driven diseases like systemic lupus erythematosus (SLE). We investigate the role of BCAP in regulating the inflammatory response in SLE and its relationship with IFN-mediated inflammation. BCAP gene expression and IFN signature were analyzed in 36 subjects with SLE and 20 healthy controls. Two cellular models were used to assess BCAP’s role in LPS response and IFN signaling after cGAS stimulation. We found a correlation between BCAP and interferon-stimulated gene (ISG) expression in SLE. In a cellular model, tofacitinib and anifrolumab, acting as IFN signaling “inhibitors”, blocked BCAP overexpression triggered by cGAS, confirming BCAP as an ISG. Additional studies in BCAP^−/− cells revealed that, in the absence of BCAP, these cells exhibited diminished IFN production upon LPS stimulation following prior exposure to cGAMP. Overall, BCAP is an ISG that acts as a positive regulator of Toll-like receptor 4-mediated IFN production. We speculate that its increased expression in SLE may contribute to a positive feedback loop, enhancing IFN production during bacterial infections. 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

Background: In recent years, musculoskeletal ultrasonography (MSUS) has established itself as a reliable method for evaluating disease activity in combination with clinical examination and laboratory tests. Objectives: In this pilot study, we aimed to evaluate the ultrasound response to treatment with tofacitinib and upadacitinib on tendons and joints in comparison to clinical and laboratory results in patients with RA who have shown inadequate response to conventional synthetic and/or biologic disease-modifying antirheumatic drugs (cs/b DMARDs). Methods: This study presents the MSUS assessment of therapeutic response in RA patients treated with tofacitinib or upadacitinib over a 24-week period. In a prospective, single-center study, patients were treated with upadacitinib 15 mg/daily or tofacitinib 2 × 5 mg/daily or 11 mg/daily, in combination with or without methotrexate or another conventional DMARDs. Disease activity was assessed by DAS28-CRP, CDAI, and SDAI, as well as MSUS. Patients were evaluated at baseline for ultrasound measures and at weeks 2, 4, 8, 12, and 24 for the rest of the indicators. For each patient, we used two ultrasound (US) scores (gray-scale, GS, and power Doppler, PD scores) and the system of European Alliance of Associations for Rheumatology outcome measures in rheumatology (EULAR-OMERACT) US scoring (combined GS and PD). We also calculated the tenosynovitis score (GS and PD) according to OMERACT recommendations. Results: A total of 53 patients were recruited. A total of 25 patients with a mean age of 56 ± 11.6 SD were followed in the upadacitinib group, and 22 patients with a mean age of 56.9 ± 11.3 were followed in the tofacitinib group. At baseline, DAS28-CRP for the upadacitinib group was 5.57 ± 1.24, and for tofacitinib, it was 4.77 ± 1.47. The baseline visit (GS, PD, and combined—US) and tendon US scores (GS and PD) were, respectively, 23 ± 2.96, 15 ± 2.56, 24.08 ± 3.36, 11.04 ± 2.21, and 8.44 ± 1.65 for the upadacitinib group. USGS-J—23 ± 3.55, USPD-J—13.36 ± 2.44, OMERACT composite—23.4 ± 3.84, USGS-T—12.18 ± 2.23, and USPD-T—9.5 ± 1.92 were found in the patients treated with tofacitinib. In both groups of patients, a significant reduction was found in both DAS28-CRP and the described MSUS scores at weeks 8, 12, and 24 (p < 0.05). Conclusions: Upadacitinib managed to produce lower echography scores much faster than tofacitinib; however, the differences in effectiveness evened out at weeks 12 and 24, with all patients being adequately controlled. Full article

Crohn’s disease is a chronic inflammatory granulomatous disease of the gastrointestinal tract. The global incidence and prevalence of Crohn’s disease have significantly increased, largely due to genetic susceptibility, environmental changes, and advancements in diagnostic technology. In recent years, the pharmacologic treatment of Crohn’s disease has been rapidly changing, and although biologics have improved the prognosis of patients to a certain extent, they still have certain limitations. Oral small molecule drugs like JAK inhibitors have become a research hotspot because of their advantages of targeting and regulating the JAK/STAT pathway, convenient administration, and rapid onset of action. JAK inhibitors exhibit divergent therapeutic profiles. Clinical trials have shown that tofacitinib demonstrates limited efficacy in Crohn’s disease management. Filgotinib initially showed clinical remission in phase 2 trials; while its subsequent phase 3 studies failed to demonstrate consistent endoscopic improvement. In contrast, upadacitinib achieved notable clinical remission rates during both induction and maintenance phases of phase 2 trials. However, long-term safety concerns, including thromboembolic events, cardiovascular events, opportunistic infections, and potential malignancy risks, warrant cautious clinical application. This article systematically reviews the pathophysiology of Crohn’s disease, and the evidence for the efficacy and safety of JAK inhibitors to guide clinical practice and research. 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