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Background and aims: Tofacitinib is a Janus kinase inhibitor (JAKi) recently approved for the treatment of moderate to severe ulcerative colitis (UC) based on robust efficacy and safety data derived from OCTAVE clinical trials. Evidence on the outcomes of tofacitinib therapy in real-world UC patients is needed, as a number of these patients would be deemed ineligible for clinical trials. We have therefore summarised data derived from observational, real-world evidence (RWE) studies on the effectiveness and safety of tofacitinib in moderate to severe UC patients. Methods: We searched the PubMed, EMBASE, Scopus, Web of Science and Cochrane databases for observational studies on the use of tofacitinib in UC patients, published between 30 May 2018 and 24 January 2021. Pooled induction (8–14 weeks) and maintenance (16–26 weeks) clinical response and remission rates were calculated, as well as the proportion of reported adverse events using random effects models. Results: Nine studies were included, comprising 830 patients, of which 81% were previously treated with anti-tumour necrosis factor (TNF) and 57% with vedolizumab. Induction of clinical response and remission were achieved in 51% (95% confidence interval, 41–60%) and 37% (26–45%) of patients, after a median follow-up of 8 weeks. At the end of a median follow-up of 24 weeks, maintenance of clinical response and remission were met in 40% (31–50%) and 29% (23–36%) of patients, respectively. Thirty-two percent of the patients had at least one adverse event, the most commonly reported being mild infection (13%) and worsening of UC, requiring colectomy (13%). A third of the patients (35%) discontinued tofacitinib, most frequently due to primary non-response (51%). Conclusion: Tofacitinib is a safe and effective therapy in real-world UC patients, as previously reported by clinical trials.

Purpose of ReviewRecognition of the importance of enthesitis as the pivotal pathological process underpinning spondyloarthropathies (SpA) has increased in recent years. Thus, we summarized the current knowledge on the pathogenic role of enthesitis on SpA shown by both animal models and human studies in vivo.Recent FindingsExperimental models have shown several SpA-like diseases that commence at entheses and are linked to nail disease as well as dactylitis, two important entheseal-associated conditions in humans. Frequently, enthesitis is not the primary outcome measure in studies of peripheral PsA and SpA although arguably it is the key parameter being indirectly assessed in spinal disease in ankylosing spondylitis. The use of different agents including JAK, IL-17, and IL-23 inhibitors contributes significantly to our understanding of enthesitis in terms of involved immune pathways.SummaryEnthesitis and enthesis organ inflammation may be the primary pathological process underlying SpA associated skeletal inflammation. Emergent studies are beginning to elucidate the molecular basis for this type of joint inflammatory response.

Baricitinib is a Janus kinase (JAK) 1 and 2 inhibitor approved for treating rheumatoid arthritis (RA). The JAK/STAT system is essential in the intracellular signaling of different cytokines and in the activation process of the monocyte lineage. This study verifies the effects of baricitinib on STAT phosphorylation in monocytes of RA patients and evaluates the correlation between STAT phosphorylation and response to therapy. We evaluated the disease activity of patients (DAS28CRP) at baseline (T0) and after 4 and 12 weeks (T1–T3) of treatment with baricitinib, dividing them into responders (n = 7) and non-responders (n = 7) based on the reduction of DAS28CRP between T0 and T1 of at least 1.2 points. Through flow cytometry, STAT1 phosphorylation was analyzed at T0/T1/T3 in monocytes, at basal conditions and after IL2, IFNα, and IL6 stimulation. We showed that monocyte frequency decreased from T0 to T1 only in responders. Regarding the phosphorylation of STAT1, we observed a tendency for higher basal pSTAT1 in monocytes of non-responder patients and, after 4 weeks, a significant reduction of cytokine-induced pSTAT1 in monocytes of responders compared with non-responders. The single IFNα stimulation only partially recapitulated the differences in STAT1 phosphorylation between the two patient subgroups. Finally, responders showed an increased IFN signature at baseline compared with non-responders. These results may suggest that monocyte frequency and STAT1 phosphorylation in circulating monocytes could represent early markers of response to baricitinib therapy.

Janus kinase inhibitors (JAKis) are the most recent new drug class to arrive to the market for rheumatoid arthritis (RA) treatment. While they have proven to be a very effective treatment option, there remains significant concern regarding the risk of cardiovascular events, thrombosis and malignancy, particularly given the findings of the post-marketing ORAL Surveillance study and FDA black box warnings. This article reviews the key findings of the most impactful cohort of studies and registry data since ORAL Surveillance. It also evaluates the role of JAKis in practice and offers guidance on risk stratifying patients and determining their suitability for a JAKi.

Severe cases of COVID-19 are characterized by hyperinflammation induced by cytokine storm, ARDS leading to multiorgan failure and death. JAK-STAT signaling has been implicated in immunopathogenesis of COVID-19 infection under different stages such as viral entry, escaping innate immunity, replication, and subsequent inflammatory processes. Prompted by this fact and prior utilization as an immunomodulatory agent for several autoimmune, allergic, and inflammatory conditions, Jakinibs have been recognized as validated small molecules targeting the rapid release of proinflammatory cytokines, primarily IL-6, and GM-CSF. Various clinical trials are under investigation to evaluate Jakinibs as potential candidates for treating COVID-19. Till date, there is only one small molecule Jakinib known as baricitinib has received FDA-approval as a standalone immunomodulatory agent in treating critical COVID-19 patients. Though various meta-analyses have confirmed and validated the safety and efficacy of Jakinibs, further studies are required to understand the elaborated pathogenesis of COVID-19, duration of Jakinib treatment, and assess the combination therapeutic strategies. In this review, we highlighted JAK-STAT signalling in the pathogenesis of COVID-19 and clinically approved Jakinibs. Moreover, this review described substantially the promising use of Jakinibs and discussed their limitations in the context of COVID-19 therapy. Hence, this review article provides a concise, yet significant insight into the therapeutic implications of Jakinibs as potential anti-COVID agents which opens up a new horizon in the treatment of COVID-19, effectively.

With an epidemic spread, metabolic syndrome represents an increasingly emerging risk for the population globally, and is currently recognized as a pathological entity. It is represented by a cluster of different conditions including increased blood pressure, high blood sugar, excess body fat around the waist and abnormal cholesterol or triglyceride levels. These conditions lead directly to several disorders, including obesity, dyslipidemia, hyperglycaemia, insulin resistance, impaired glucose tolerance and hypertension causing an increase in cardiovascular risk and in particular atherosclerotic disease. Despite efforts to promote healthier lifestyles through exercise, reduced caloric intake, and improved dietary choices, the incidence and prevalence of metabolic syndrome continue to rise worldwide. Recent research has highlighted the involvement of signaling pathways in chronic inflammatory conditions like obesity and type 2 diabetes mellitus, revealing the significance of the JAK/STAT pathway in atherosclerotic events. This pathway serves as a rapid membrane-to-nucleus signaling module that regulates the expression of critical mediators. Consequently, JAK inhibitors (JAKi) have emerged as potential therapeutic options for metabolic diseases, offering a promising avenue for intervention. The aim of this review is to shed light on the emerging indications of JAK inhibitors in metabolic syndrome, emphasizing their potential role in attenuating associated inflammatory processes, improving insulin sensitivity, and addressing cross-talk with the insulin pathway, with the intention of contributing to efforts in the field of inflammation pharmacology.

Upadacitinib is a selective Janus kinase inhibitor approved for the treatment of severe atopic dermatitis (AD). This systematic review aims to summarize the most recent data in terms of effectiveness and safety of upadacitinib in the treatment of severe AD in a real-world setting. The review included a comprehensive search of databases, including PubMed, Google Scholar and Web of Science, according to Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines. The literature search initially identified 242 studies. Of these, 214 were excluded after reviewing their titles and abstracts. We then conducted a full-text review of 25 studies, of which 17 met our inclusion criteria and were therefore included in our systematic review. The analysis of real-world studies showed high effectiveness of upadacitinib, in terms of both clinical signs and subjective symptoms, in different patient populations, including those resistant to other treatments. No new significant safety concerns have emerged as compared to randomized clinical trials.

Glucocorticoid (GC) use in rheumatoid arthritis (RA) remains concerning due to adverse effects. Janus kinase inhibitors (JAKi) may enable GC reduction or discontinuation. This study examined factors associated with GC use and the role of JAKi in achieving GC-free status using the 2022 National Database of Rheumatic Diseases in Japan (NinJa). Data from 8,555 RA patients were analyzed. Patient characteristics, disease activity, functional status, and treatments were compared between GC users and non-users. Multivariate logistic regression and propensity score–matched analyses assessed associations between GC use and disease-modifying anti-rheumatic drugs (DMARDs). Predictors of GC use in JAKi-treated patients were also evaluated, including causal mediation analysis. GC was used in 25% of patients (mean 3.77 mg/day). Users were more often male, with higher disease activity and disability. Methotrexate, TNF inhibitors, IL-6 inhibitors, and JAKi were linked to lower GC use. JAKi-treated patients had significantly less GC use and lower doses than biological (b)DMARD-free or bDMARD-treated groups. In JAKi users, higher Clinical Disease Activity Index (CDAI) predicted GC use and correlated with GC dose. Disease activity strongly influences GC use in RA. JAKi treatment is associated with lower GC use and may facilitate tapering in real-world practice.

Background Treatment of rheumatoid arthritis (RA) frequently requires Janus kinase inhibitors (JAKi) and biologic DMARDs (bDMARDs) with other mechanisms of action (OMA) after tumour necrosis factor inhibitors (TNFi) failure. Comparative safety data between JAKis and OMA in TNFi-inadequate responders (TNFi-IR) remain limited. Objectives To evaluate and compare safety profiles of JAKis versus OMA in TNFi-IR RA patients. Methods A retrospective cohort study followed 305 RA patients (163 JAKis; 142 OMA) previously treated with TNFi for up to 24 months. Incidence rates (IR) of adverse events (AEs) per 100 patient-years (PY) and incidence rate ratios (IRR) adjusted for disease activity and previous bDMARD exposure were calculated using Poisson regression. Results At baseline, OMA patients had higher disease activity (DAS28-CRP = 4.5 vs. 3.8), whereas comorbidities and other baseline characteristics were similar. Overall, AE incidence was higher with OMA (IR 111.6/100 PY) compared to JAKis (IR 65.3/100 PY; adjusted IRR 1.67, 95% CI 1.22–2.31). Serious AEs occurred more frequently with OMA (IR 11.7/100 PY) versus JAKis (IR 7.9/100 PY; adjusted IRR 0.41, 95% CI 0.18–0.95). Infection rates were comparable; herpes zoster occurred exclusively in the JAKi group during the initial year. Venous thromboembolism, cardiovascular events, and malignancies were rare and similar between groups. Conclusion In RA patients with inadequate response to TNFis, JAKis and OMA showed comparable safety profiles over 24 months. Serious AEs were numerically higher with OMA; herpes zoster was more frequent with JAKis. No new significant safety signals emerged. Key messages What is already known on this topic • Janus kinase inhibitors (JAKis) and non-TNF biologic DMARDs (OMA) are increasingly prescribed for RA patients who have an inadequate response to TNF inhibitors, though comparative safety data between these drug classes are limited. What this study adds • This study provides direct comparative evidence on the safety profiles of JAKis versus OMA in RA patients with inadequate response to TNFi, demonstrating similar overall safety outcomes, albeit highlighting differences in the timing and frequency of specific adverse events, such as herpes zoster infections with JAKis and serious adverse events with OMA. How this study might affect research, practice, or policy • These results reinforce existing guidelines advocating for individualised therapeutic choices based on patient-specific risk factors and suggest the continued need for careful patient monitoring, particularly for infections and serious adverse events, guiding clinicians in selecting appropriate therapies after TNFi failure.

A number of studies have demonstrated a key role of miRNA isolated from cells, tissue or body fluids as disease-specific biomarkers of autoimmune rheumatic diseases including rheumatoid arthritis (RA) and systemic sclerosis (SSc). Also, the expression level of miRNA is changing during disease development, therefore miRNA can be used as biomarkers monitoring RA progression and treatment response. In this study we have investigated the monocytes-specific miRNA that could serve as potential biomarkers of disease progression observed in sera and synovial fluids (SF) in early (eRA) and advanced (aRA) RA and in RA patients before and 3 months after selective JAK inhibitor (JAKi) -baricitinib treatment. Samples from healthy control (HC) (n=37), RA (n=44) and SSc (n=10) patients were used. MiRNA-seq of HC, RA, and SSc monocytes was performed to find versatile miRNA present in different rheumatic diseases. Selected miRNAs were validated in body fluids in eRA (<2 years disease onset) and aRA (>2 years disease onset) and RA patients receiving baricitinib. Using miRNA-seq, we selected top 6 miRNA out of 95 that were significantly changed in both RA and SSc monocytes compared to HC. To identify circulating miRNA predicting RA progression, these 6 miRNA were measured in eRA and aRA sera and SF. Interestingly, miRNA (-19b-3p, -374a-5p, -3614-5p) were significantly increased in eRA sera vs HC and even further upregulated in SF vs aRA sera. In contrast, miRNA-29c-5p was significantly reduced in eRA sera vs HC and even further decreased in SF vs aRA sera. Kegg pathway analysis predicted that miRNA were involved in inflammatory-mediated pathways. ROC analysis demonstrated that miRNA-19b-3p (AUC=0.85, p=0.04) can be used as biomarker predicting JAKi response. In conclusion, we identified and validated miRNA candidates which were present simultaneously in monocytes, sera, SF and that can be used as biomarkers predicting joint inflammation and monitoring therapy response to JAKi in RA patients.