Ankylosing spondylitis (AS) is a chronic inflammatory disease primarily affecting the spine and pelvic bones. Recently, many researchers have confirmed that biological therapy is effective for AS patients, which provides a new perspective for the treatment of AS. This study aimed to evaluate the characteristics of scientific research on AS and biological therapy worldwide and investigate research hotspots and the direction of future trends. Global literature on AS and biological therapy published from 2004 to 2023 was searched in the Web of Science, Scopus, and PubMed databases. Visualization and bibliometric analysis were carried out using the VOSviewer and CiteSpace software with the retrieved data regarding countries, institutions, journals, authors, and keywords. A total of 2,243 related articles were included, showing that the number of articles in this field has increased annually. The highest number of articles were from the USA (24.39%), followed by Italy (14.36%), England (12.19%), Germany (10.66%), and Spain (7.86%). Braun J was the most prolific author, with a h-index of 16. The institution with the most articles was Charite Universitatsmedizin Berlin, and the Rheumatology journal had the highest number of publications. "janus kinase inhibitor" and "secukinumab" displayed a notable citation burst in recent years, indicating IL-17i and JAKi are research hotspots. More and more attention has been paid to the association between AS and biological therapy in the past two decades. The USA plays a leading role, and China has made remarkable progress. This study has provided a valuable reference for future research in this field.

Purpose: Livedoid vasculopathy (LV) is a chronic microvascular thrombosis disorder with an unclear pathogenesis, potentially involving hypercoagulability and inflammation. This systematic review aims to evaluate the efficacy and safety of Janus kinase (JAK) inhibitors and biologics in the treatment of LV.

Materials and methods: A comprehensive search was conducted in PubMed, EMBASE, and the Cochrane Library on June 10, 2024, to identify relevant studies evaluating the use of JAK inhibitors and biologics in LV treatment.

Results: A total of 15 articles were included in the review. Among the 41 patients treated with biologics and JAK inhibitors, 36 (87.8%) showed positive clinical responses, including significant improvements in pain relief. TNF-α inhibitors were the most commonly used monotherapy, followed by JAK inhibitors. Adverse events were infrequent, suggesting that these treatments generally have a favorable safety profile.

Conclusions: JAK inhibitors and biologics appear to be safe and effective alternatives for managing refractory LV. These findings provide a foundation for future studies to further validate their clinical effectiveness and long-term safety.

Janus kinase (JAK) inhibitors (JAKinibs) are effective for inflammatory bowel disease (IBD), but their cardiovascular safety is inconclusive. We aim to assess the cardiovascular risks associated with JAKinibs in IBD patients.

Systematic searches of seven databases and ClinicalTrials.gov from inception to February 2024 were conducted. Outcomes included major adverse cardiovascular events (MACE), venous thromboembolism events (VTE) and cardiovascular events (CVE), which were separately evaluated based on whether or not the dose was considered. P-score was applied to rank interventions.

A total of 26 trials involving 10,537 IBD patients were included, and results showed no significantly increased risk of MACE, VTE and CVE was associated with JAKinibs. However, when the dose was considered, Tofacitinib 5 mg BID (versus placebo) showed a trend towards an increased risk of MACE [odds ratio (OR)=1.05, 95% confidence interval (CI): 0.23-4.82], as well as Upadacitinib 30 mg QD (versus placebo) showed a trend towards increased risks of VTE (OR=1.36, 95% CI: 0.23-8.03) and CVE (OR=1.08, 95% CI: 0.24-4.85), and ranked higher than placebo for the risk of VTE [P-score=0.766 (versus 0.722)]. Notably, Deucravacitinib ranked lowest for all cardiovascular risks, and significantly decreased the risks of VTE (OR=0.03, 95% CI: 0.00-0.87) and CVE (OR=0.03, 95% CI: 0.00-0.87) compared with placebo.

Although a trend of increased cardiovascular risks was found considering dose, no significantly increased cardiovascular risk was associated with JAKinibs in IBD patients, and Deucravacitinib significantly decreased the risks of VTE and CVE.

Previous research has revealed a positive correlation between rheumatoid arthritis (RA) and cardiovascular diseases, but the causal relationship is unclear. This study applies Mendelian randomization to examine whether RA causally contributes to the likelihood of various cardiovascular diseases, such as heart failure, coronary artery disease, and atrial fibrillation.

Using genome-wide association data, we conducted a univariable MR (UVMR) analysis to evaluate the causal impact of RA on CVD, primarily utilizing the inverse variance weighted method. Additional MR methods were used to test the robustness of the results. Multivariable MR (MVMR) was applied to explore potential confounders.

In the European population, genetically predicted RA had a harmful causal effect on HF, with the IVW analysis indicating an OR of 1.06 (95% CI: 1.02-1.10, P < 0.01) based on 23 SNPs. No causal relationships were found between RA and other CVDs. The MVMR analysis did not identify significant causal impact of rheumatoid arthritis on HF after controlling for traditional risk factors. In the Asian population, RA was associated with an adverse effect on AF, with the IVW method reporting an OR of 1.20 (95% CI: 1.01-1.41, P = 0.03) for 5 SNPs. No other CVD relationships were found.

Our MR analysis indicates that genetic susceptibility to rheumatoid arthritis increases the likelihood of heart failure in European populations and atrial fibrillation in East Asian populations. However, established CVD risk factors, such as smoking, overweight, and physical inactivity, remain critically important in the management of RA. Key Points • Multiple studies have highlighted a marked increase in the cardiovascular event risk among individuals with RA. However, additional RCTs are needed for confirmation. • We applied Mendelian randomization to explore the potential causal relationship between rheumatoid arthritis and cardiovascular conditions. The findings demonstrated a causal link between RA and heart failure among European populations, as well as an association between RA and atrial fibrillation in East Asian groups. • Further adjustments using multivariable Mendelian randomization to account for the influence of traditional cardiovascular risk factors revealed that the causal association between RA and heart failure disappeared.

Infective and noninfective pulmonary complications occur with biologic agents and targeted small molecule inhibitors used to treat immune-mediated inflammatory conditions. The most common lower respiratory tract infection is bacterial pneumonia. Opportunistic infections including tuberculosis can also occur at increased rates depending on the immunosuppressive agent, specific disease, and epidemiologic background of the patient. The most common noninfectious sequela is drug-induced interstitial lung disease.

Groundbreaking strategies for preventive cardiology were showcased at the 2024 American Society for Preventive Cardiology (ASPC) Congress on Cardiovascular Disease (CVD) Prevention held in Salt Lake City, Utah, from August 2nd to 4th, 2024. The event featured 69 moderators and 13 scientific sessions comprised of 98 topics, 36 satellite events, 133 poster presentations, and 27 lifestyle classes. The conference highlighted innovative strategies focused on integrating cardiovascular, kidney, and metabolic health, presenting a cohesive approach for managing complex, interrelated conditions. Pivotal studies have addressed the role of lipid-lowering therapies, the benefits of early statin initiation, and the importance of precision medicine in preventing CVD. The ASPC's emphasis on translating this research into practical clinical tools has the potential to revolutionize preventive care strategies, making strides toward reducing the burden of CVD globally and improving long-term patient outcomes through personalized and early intervention approaches.

Background: Although previous studies have confirmed that Janus kinase (JAK) inhibitors have good efficacy and safety in the treatment of atopic dermatitis, the U.S. Food and Drug Administration has issued a black box warning for all JAKs. Therefore, it is necessary for us to further pay attention to their safety. Method: The medical literature data bases were searched from database creation until August 26, 2023. Randomized controlled trials of moderate-to-severe atopic dermatitis treated with JAK1-selective inhibitors (upadacitinib and abrocitinib) were included. Results: In this meta-analysis, which included 12 studies (one of which reported two outcomes), we collected data at 2, 4, 8, 12, and 16 weeks. Almost all results showed that JAK1-selective inhibitors were more efficacious than controls and had an onset of action at week 2. There was no significant difference in the incidence of serious adverse events and adverse events, leading to discontinuation, whereas, for treatment-associated adverse events, the JAK1-selective inhibitors were higher than the control group (RR 1.16 [95% confidence interval, 1.11-1.21]; p < 0.00001). Conclusion: Overall, the treatment of atopic dermatitis with JAK1-selective inhibitors has a rapid onset of action. However, we need to be aware of the treatment-associated adverse events, more studies need to be conducted to provide better decisions on clinical medications for patients with moderate-to-severe atopic dermatitis.

The use of Janus kinase inhibitors (JAKis) in immune-mediated inflammatory diseases (IMIDs) beyond licence is expanding rapidly. The aim of this scoping review was to identify and present the available evidence on the efficacy of JAKis in all conditions without marketing authorisation.

Through a systematic literature search we identified studies including 5 or more patients that assessed the use of any JAKi for any efficacy outcome. Quantitative analyses in the form of pairwise meta-analyses were performed for eligible data from randomised controlled trials (RCTs) only.

Eighty-three (n = 83) studies in total were included in our review, assessing efficacy of JAKis in 34 IMIDs. In most conditions, JAKis exhibited generally positive effects, though the majority of evidence came from observational, non-comparative studies. Pairwise meta-analyses were possible for hidradenitis suppurativa and systemic lupus erythematosus (SLE). For hidradenitis suppurativa, we found a clear benefit of treatment with JAKis compared with placebo in achieving clinical response [OR 2.35, 95 % CI (1.24 to 4.46)]. For treatment-resistant SLE, the results were equivocal; JAKi showed some benefit over placebo but statistical significance was only reached for one of the two meta-analysed outcome measures [SLE Responder Index 4, OR 1.41, 95 % CI (1.01 to 1.98); SLE Disease Activity Index 2000; OR 1.36, 95 % CI (0.99 to 1.88)].

There is a rapidly increasing use of JAKis beyond current licencing in most IMIDs. Large comparative trials are necessary to confirm efficacy and guide future licencing decisions.

There is accumulating evidence that inflammation is a key driver of atherosclerosis development and thrombotic complications. This pathophysiological mechanism explains, at least in part, the increased cardiovascular risk of patients with immune-mediated arthritis. Experimental and clinical studies have shown that tumour necrosis factor (TNF) plays a pathological role in both vascular and joint diseases, suggesting that TNF inhibitors (TNFis) may limit cardiovascular events in patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA) or spondyloarthritis (SpA). This review summarizes studies exploring the effects of TNFis on cardiovascular outcomes in patients with RA, PsA or SpA. Clinical studies suggest that TNFis reduce vascular inflammation and may improve (or prevent worsening of) endothelial dysfunction and arterial stiffness. There is evidence that TNFis reduce the incidence of cardiovascular events in patients with inflammatory arthritis compared with non-biological treatments, particularly in patients with rheumatoid arthritis. Fewer studies have compared the effects of different classes of biological therapy on outcomes, but found no significant difference in the risk of cardiovascular events between patients taking TNFis and other biological therapy. In contrast, patients at high cardiovascular risk may derive greater benefit from a TNFi than from a Janus kinase inhibitor (JAKi). The cardiovascular impact of JAKis is still under debate, with a recent safety warning. Targeted control of inflammation is a key strategy to reduce the risk of major adverse cardiovascular events in patients with inflammatory arthritis. Cardiovascular evaluation and risk stratification, using a multidisciplinary approach involving rheumatology and cardiology teams, are recommended to guide optimal immunomodulatory treatment.

Janus kinase inhibitors (JAKi) have been associated with an increased risk of venous thromboembolism (VTE) limiting the use of JAKi-based therapy. To improve risk stratification and drug development, it is crucial to understand the implication of dysregulated JAK-Signal Transducers and Activators of Transcription (STAT) signaling in the pathogenesis of VTE. The objective of this study is to clarify the putative genomic vulnerability to dysregulated JAK-STAT signaling in VTE through systematic mining of large-scale datasets generated from studies comparing VTE patients with healthy controls. Particularly, we assess the representation of entities of the JAK-STAT signaling pathway including STAT target genes among sets of miRNA, mRNA, and proteins differentially abundant in VTE patients, and we explore the putative cumulative genetic association of JAK-STAT signaling gene sets to VTE. Genes related to the JAK-STAT pathway were found significantly altered in VTE patients compared to healthy controls, indicating that genes under transcriptional control of STAT may be dysregulated in VTE. In support of this notion, we find a significant overrepresentation of predicted STAT target genes among genes downregulated in VTE patients, and promoter sequences of differentially regulated genes were significantly enriched with STAT transcription factor binding site motifs. Further linking STAT signaling to the molecular signature of VTE, genes targeted by miRNAs differentially regulated in patients are significantly enriched with STAT target genes and genes acting in the JAK-STAT signaling pathway. Together, our findings indicate that disruptions in the JAK-STAT pathway contribute to the molecular profile of VTE. This offers hope for identifying ways to interact with the JAK-STAT pathway that do not carry the risk of VTE.

To assess safety of baricitinib in Japanese patients with rheumatoid arthritis (RA) in real-world clinical practice.

This all-case postmarketing surveillance study included patients initiating baricitinib for RA from September 2017 to April 2019. Treatment duration was recorded. Safety data were collected for up to 3 years from initiation (up to 4 weeks postdiscontinuation in discontinuing patients).

Safety analyses included 4720 patients; 2580 (54.7%) were ≥65 years old. Baricitinib persistence rate was 45.4% (3-year Kaplan-Meier analysis); the most common discontinuation reason was insufficient effectiveness (n = 1005, 21.3%). Serious adverse events occurred in 600 patients [incidence rate (IR) 10.42/100 patient-years (PY); 95% confidence interval, 9.76-11.09]. There were 39 deaths [IR 0.43 (0.30-0.57)/100 PY]. Adverse events of special interest IRs per 100 PY were herpes zoster 4.68 (4.22-5.14), serious infection 3.05 (2.68-3.41), malignancy 1.09 (0.87-1.30), major adverse cardiovascular events 0.35 (0.23-0.48), and venous thromboembolism 0.25 (0.15-0.36). IRs did not increase with prolonged exposure.

No new safety concerns were identified during this 3-year postmarketing surveillance study of baricitinib in Japanese patients with RA. Patients and clinicians should be cognizant of herpes zoster and other serious infection risks during baricitinib treatment, especially in the first 6 months.

JAK inhibitors (JAKi) have emerged as effective treatments for chronic inflammatory diseases, including gastrointestinal, dermatological, and rheumatological conditions. Despite their efficacy, concerns about their safety profile necessitate a comprehensive framework for their optimal use. This study aimed to establish an expert consensus (the JAK-ERA [Janus Kinase-inhibitors Evidence-based Risk Analysis] Multidisciplinary Expert Consensus) on the principles guiding JAKi therapy to maximize therapeutic benefits while mitigating risks.

A Delphi method was employed, gathering opinions from experts across multiple disciplines. This iterative process involved rounds of surveys and feedbacks to synthesize diverse expert knowledge into a cohesive set of principles and consensus statements. The multidisciplinary panel included specialists in cardiology, oncology, hematology, gastroenterology, dermatology, and rheumatology.

A total of 6 overarching principles and 13 expert consensus statements were developed. The percentage of agreement ranged between 78 and 100 %. The principles highlight the importance of rapid intervention to prevent complications and alleviate psychological burdens. Detailed risk assessments for cardiovascular (CV), thromboembolic, and cancer risks were deemed essential. Recommendations included using validated tools for CV risk evaluation, comprehensive thromboembolic risk assessment, and routine cancer screenings based on standard protocols. Multidisciplinary collaboration was stressed to ensure precise risk management and optimal therapeutic outcomes.

The consensus provides a structured approach to JAKi therapy, balancing efficacy with safety considerations. The overarching principles and expert consensus statements offer a robust framework for clinical practice, ensuring that JAKi use is tailored to individual patient profiles, thereby enhancing outcomes and minimizing risks. Ongoing validation through prospective studies and real-world data is essential to further refine these recommendations.

The complex pathophysiology of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) is reflected in the heterogeneity of the presenting clinical syndromes caused by these diseases but also provides a variety of conceivable molecular and cellular targets that can be therapeutically manipulated. The last decade has seen an expansion of established and potential therapies for treating AAV, some of which target the dysfunctional autoreactive immune response and others aim to ameliorate the downstream consequences of local vascular inflammation and necrosis. The success and widespread adoption of the anti-CD20 monoclonal antibody, rituximab, as an agent to both induce and maintain remission, has heralded a change in the standard-of-care management of AAV, replacing the "old guard" combination of cyclophosphamide and high-dose corticosteroids established in the 1970s. The development and approval of avacopan, a first-in-class small-molecule antagonist to the main receptor for the complement anaphylatoxin C5a, has the potential to reduce the corticosteroid burden experienced by patients with AAV and may also improve outcomes for those with AAV kidney disease. It marks the culmination of almost 20 years of international collaboration, from understanding the pathological role of complement in basic murine models of AAV through to a phase III clinical trial, and emphasises the importance of following promising translational discoveries through to drug development and clinical deployment. This article summarises how recent progress in our understanding of the basic pathophysiology of AAV has resulted in the development of new and effective treatments and, reciprocally, how studying the impact of these treatments in patients has advanced our understanding of dysfunctional immunobiology in disease.

To investigate rates of key safety outcomes in patients with rheumatoid arthritis (RA) initiating biologic/targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) and in reference cohorts, presented over time since the market entry of each b/tsDMARD class and over calendar period at treatment start.

This was a nationwide register-based cohort study conducted from 2006 to 2022. From the Swedish Rheumatology Quality Register and national registers, we identified treatment initiators of b/tsDMARDs (n = 33,550 initiations), an early bionaive RA cohort (n = 16,011), and a matched general population cohort (n = 111,074). The main outcome was first of either major adverse cardiovascular event, venous thromboembolism, cancer, or serious infection. We stratified rates by time since market entry of each b/tsDMARD class at treatment start, and by calendar year of treatment start. We calculated incidence rates (IRs) and hazard ratios (HRs) using Cox regression and adjusted for patient characteristics.

Overall, 5862 events were observed in the b/tsDMARD initiator cohort. b/tsDMARD treatments initiated >5 (vs <2) years since market entry of that class were associated with lower outcome rates (unadjusted HR = 0.74; 95% CI = 0.67-0.81). This association was attenuated once adjusting for patient characteristics (adjusted HR = 0.93; 95% CI = 0.84-1.03). By contrast, during our study period, adjusted rates declined (adjusted HR = 0.74 and 95% CI = 0.69-0.80 for b/tsDMARDs initiated 2016-2021 vs 2006-2010), despite a constant rate in the background population.

Modest channelling makes the safety profile of b/tsDMARDs appear worse when new on the market. Declining incidences of typical RA comorbidities in b/tsDMARD initiators during recent years suggest that the bar defining an "acceptable" safety profile for new b/tsDMARDs for use in RA should be lower(ed).

Atopic dermatitis is the most common chronic inflammatory skin disease globally. Key features include an eczematous eruption accompanied by intense itch, which can have an enormous negative effect on patients' quality of life, especially in those with moderate-to-severe disease. Atopic dermatitis is part of a spectrum of atopic conditions that can also include several non-cutaneous organs such as respiratory (eg, allergic rhinitis and asthma) and gastrointestinal (eg, food allergy) systems. For decades, long-term disease control and maintenance were particularly challenging given that treatment options were limited to broad topical and systemic immunosuppressive agents. However, better insights into the pathophysiology of this condition over the past decade have led to the development and approval of safe and efficacious novel targeted treatment approaches. The updated pathophysiological understanding and the evolving therapeutic landscape of atopic dermatitis are discussed in this Seminar.

Anti-melanoma differentiation-associated gene 5 (MDA-5) antibody-positive dermatomyositis is associated with rapidly progressive interstitial lung disease (RP-ILD). We encountered a man in his 40s who presented with a history of a fever and dry cough. Based on laboratory tests and computed tomography scans of his chest, he was diagnosed with anti-MDA-5 antibody-positive dermatomyositis with RP-ILD refractory to antimicrobial agents. Although the patient was treated with glucocorticoids, calcineurin inhibitors, intravenous cyclophosphamide, and plasma exchange, ventilatory management was still required. The patient survived additional therapy with tofacitinib; however, he developed a catheter-related pulmonary embolism as a complication.

The combination of different biological and targeted synthetic DMARDs (i.e., combotherapy) has recently emerged in the management of immune-mediated inflammatory diseases (IMID). However, real-life data across specialities and prognostic factors related to combotherapy are lacking.

Multicenter observational study conducted using the Clinical Data Warehouse from Paris Hospitals' Public Assistance including IMID patients under combotherapy, and a matched monotherapy control group. The primary endpoint was the occurrence of serious adverse events (SAE), defined by severe infections, major cardiovascular events, neoplasia and mortality (all-cause).

From 42,071 subjects having an IMID, 131 combotherapy lines were identified among 125 patients (median age of 36 years, 58 % females) between 2017 and 2022. The most frequent IMIDs were inflammatory bowel disease (48.8 %), connective tissue diseases (23.2 %), inflammatory myopathies (14.4 %) and vasculitis (11.2 %). After a median follow-up of 15 months [IQR 19], 30 (24 %) patients presented severe infections, 5 (4 %) neoplasia, 4 (3.2 %) venous thromboembolism, 3 (2.4 %) acute coronary syndromes and 7 (5.6 %) deaths. The 1-year cumulative incidence of SAE and severe infections were 29 % (95 %CI 21-38), and 24 % (95 %CI 16-32), respectively. The survival, incidence of SAE and severe infections were not statistically different from combotherapy patients compared to monotherapy controls (n=251) after adjustment for confounders. In multivariate analyses, we found abatacept + JAKi (HR 6.81, 95 %CI 1.88-24.68), anti-IL-1-based (HR 4.82, 95 %CI 1.17-19.89) and anti-CD20-based (HR 4.03, 95 %CI 1.22-13.31) combotherapies to be independently associated with an increased risk of SAE.

The overall risk of SAE under combotherapy does not seem greatly increased compared to monotherapy, but certain combinations warrant caution. The combotherapy composition seems predictive of safety outcomes.

Patients Acceptable Symptom State (PASS) is a single dichotomized question assessing health satisfaction. We aimed to investigate PASS achievement within 4 weeks of treatment with Janus kinase (JAK) inhibitors (Jakinibs) and its association with treatment response after 4 and 12 weeks in rheumatoid arthritis (RA) patients.

We recruited consecutive RA patients starting baricitinib or tofacitinib. At baseline, 4 and 12 weeks, we calculated disease activity [Disease Activity Score on 28 joints (DAS28), Clinical Disease Activity Index, Simplified Disease Activity Index], disease status [remission and low-disease activity (LDA)], percentage of patients achieving PASS, and the time to attain PASS. We assessed the impact of clinically relevant variables on PASS achievement by logistic regression analysis.

We enrolled 113 patients [98 (86.7%) females; median age 59.6 (interquartile range 16.9), median disease duration 144 (132) months]. 90 (79.6%) patients achieved PASS after 10 (8) days. A similar percentage of PASS achievers and non-achievers was in remission/LDA at weeks 4 and 12, but the reduction of disease activity was significantly greater in PASS achievers. All patients achieving Boolean remission at weeks 4 and 12 had achieved PASS within 4 weeks. The impact of Patients Global Assessment (PGA) on DAS28 was significantly greater in PASS non-achievers compared to PASS achievers; inversely, the impact of C-reactive protein was more relevant in PASS achievers. At multivariate analysis, pain and PGA were significantly associated with PASS.

In our cohort, Jakinibs allowed an early achievement of PASS in a great percentage of RA patients. PASS is strictly dependent on PGA and pain and could suggest, early in the management of RA patients, therapeutic success.

Rheumatoid arthritis (RA) is a chronic multisystem common autoimmune disease. Joints and the whole musculoskeletal system bear the brunt of the disease. Proper adequate treatment at the early stage is the foremost necessity to protect the patients from long term disabilities and reduce patient systemic morbidities including atherosclerosis and coronary artery disease. New biologic and non-biologic antirheumatic drugs in the last two decades have brought new dimensions for treat to target strategy and array of novel therapies for RA are in the horizon. Here in this systematic review our objective is to provide an overview of current developments and potentially available therapeutic options for RA. Novel immune-based therapies has the potential to change the treatment for RA. We have discussed in detail about the new drugs for RA in the horizon and provided analyses of the future drugs in pipeline for the management of RA.

This systematic literature review (SLR) on efficacy outcomes was performed to inform the 2024 update of the expert consensus statement on the treatment of immune-mediated inflammatory diseases (IMIDs) with Janus kinase inhibitors (JAKi).

An update of the 2019 SLR was performed in MEDLINE, Embase, and the Cochrane Library. For efficacy, randomised, placebo (PLC)- or active-controlled trials on all JAKi investigated in IMIDs, as well as cohort and claims data for conditions where such studies were not available, were included.

In total, 10,556 records were screened, and 182 articles were included in the final analysis, investigating 21 JAKi in 51 IMIDs. Forty-three phase 2 and 59 phase 3 trials as well as 9 strategic trials and 72 pilot or cohort studies and case series were considered. JAKi demonstrated efficacy both in PLC-controlled trials as well as in head-to-head comparisons against active comparators, with 93 of 102 randomised controlled trials (RCTs) meeting their primary endpoints. Since 2019, 8 JAKi have received approval by the Federal Drug Agency and the European Medicine Agency for treatment of 11 IMIDs; of these, for 2, no approved disease-modifying antirheumatic drug (DMARD) therapy had previously been available.

JAKi are effective for treating IMIDs, and various compounds have recently been approved. The impact of Janus kinase (JAK) selectivity for distinct JAK-STAT pathways needs further investigation, and few data are also available on sustained disease control upon tapering or withdrawal or on the optimal strategic placement of JAKi in international treatment algorithms.

This systematic literature review (SLR) on safety outcomes was performed to inform the 2024 update of the expert consensus statement on the treatment of immune-mediated inflammatory diseases (IMIDs) with Janus kinase inhibitors (JAKi).

An update of the 2019 SLR was performed in MEDLINE, Embase, and the Cochrane Library. For safety, randomised, placebo-controlled or active-controlled trials on all JAKi investigated in IMIDs, long-term extension (LTE) studies, pooled trial data analyses, and cohort and claims studies were included.

We screened 13,905 records, of which 209 were finally included. Three safety trials and 13 post hoc analyses, 83 efficacy randomised controlled trials (RCTs) with adequate safety reporting, 56 integrated safety analyses and LTE of RCTs, 20 additional conference abstracts on RCT data, as well as 37 real-world cohort studies were presented to the task force. Safety profiles of JAKi were overall consistent across compounds and indications, but impacts of patient profiles, treatment dosing, and other cofactors like background medications on drug safety could be observed. Furthermore, differential effects of variously selective JAKi on distinct adverse events of special interest (AESI) and laboratory outcomes were discerned.

A substantial amount of literature was published on JAKi safety since 2019. A comprehensive overview of these data supports the optimal use of JAKi in patients with IMIDs, by consideration and balance of their benefits as well as risks in every patient.

This systematic review and meta-analysis evaluated the incidence of serious adverse events (SAEs) in patients with Crohn's disease (CD) and ulcerative colitis (UC) treated with upadacitinib and examined secondary adverse events.

A comprehensive search of PubMed, Embase and Cochrane Library was conducted to identify randomized controlled trials (RCTs) comparing upadacitinib with placebo in adults with inflammatory bowel disease (IBD). The primary outcome was the incidence of SAEs, while secondary outcomes included specific adverse events. Risk ratios (RR) with 95% confidence intervals (CI) were calculated.

Six RCTs, including 2611 patients, were analyzed. The incidence of SAEs did not significantly differ between upadacitinib (6.1%) and placebo (7%) (RR = 0.77; 95% CI: 0.50-1.20; p = 0.25). Secondary outcomes showed no significant differences in serious infections, hepatic disorders, nasopharyngitis or herpes zoster. However, neutropenia (RR = 5.63; 95% CI: 1.90-16.65; p = 0.0002) and creatine kinase elevation (RR = 2.34; 95% CI: 1.22-4.47; p = 0.01) were higher with upadacitinib, while anemia (RR = 0.36; 95% CI: 0.27-0.48; p < 0.00001) and arthralgia (RR = 0.47; 95% CI: 0.30-0.75; p = 0.001) were reduced.

Upadacitinib did not increase the overall risk of SAEs in IBD patients, with a notable reduction in anemia and arthralgia. However, the higher risks of neutropenia and CK elevation underscore the importance of monitoring. Further research is necessary to assess long-term safety, particularly regarding rare but serious events such as thromboembolism.

Recombinant GH16B β-agarase-catalyzed liquefaction of 5-7 %(w/v) melted agarose at 50 °C completely hydrolyzed agarose into neoagarohexaose (NA6) and neoagarotetraose (NA4). Subsequent saccharification by recombinant GH50A β-agarase or recombinant GH50A β-agarase/recombinant GH117A α-neoagarobiose hydrolase at 35 °C converted NA6/NA4 into neoagarobiose (NA2) or 3,6-anhydro-L-galactose (L-AHG)/D-galactose, respectively. Purification of NA6/NA4 and NA2 was achieved by Sephadex G-15 column chromatography, while L-AHG was purified by Sephadex G-10, achieving ≥ 98 % purity. L-AHG (25-200 μg/mL), but not NA2, NA4, or NA6, inhibited the proliferation of immobilized anti-CD3/anti-CD28-activated T cells and immobilized anti-CD40 + soluble anti-IgM + interleukin (IL)-4-activated B cells. This inhibition impacted the G1-S traverse in the cell cycle without influencing CD69 expression and p27Kip1 down-regulation, markers of the exit from G0 into G1 phase in activated lymphocytes. L-AHG impeded cyclin-dependent kinases (CDKs)-driven retinoblastoma phosphorylation, necessary for the G1-S traverse, by reducing the activating phosphorylation of CDKs (CDK4, CDK2, and CDK1) and lowering cyclin D3, cyclin A2 and cyclin B1 levels. Furthermore, L-AHG diminished the production of growth factors, including IL-2 in activated T cells and IL-6 in activated B cells. The antiproliferative effect of L-AHG on T cells was partially restored by exogenous IL-2 but was unaffected by exogenous IL-6 on B cells. L-AHG inhibited the activating phosphorylation of Janus kinase 1 (JAK1), affecting signal transducer and activator of transcription 1 (STAT1) and STAT3 signaling. These results demonstrate that L-AHG may serve as a novel immunosuppressant by impairing JAK-STAT growth factor signaling and G1-S cell cycle progression in T and B lymphocytes.

Janus kinase (JAK), a class of non-receptor tyrosine kinases, are essential in modulating the cytokine signaling cascade of cytokines associated with immune responses. Despite their potential in the treatment of autoimmune diseases, JAK inhibitors are associated with safety concerns, regarding cytokine suppression and significant side effects. Tyrosine kinase 2 (TYK2), a prominent member of the JAK family, is central to the signaling of interleukins (ILs) and interferons (IFNs), such as IL-12, IL-23 and IFNs. Targeted TYK2 inhibitors that specifically target the Janus Homology 1 (JH1) and pseudokinase (JH2) domains show enhanced specificity. JH1 acts as an ATP-competitive inhibitor, while JH2 acts as an allosteric regulator, contributing to reduced systemic side effects and improved therapeutic outcomes in clinical settings. This review summarizes the recent advances on the synthetic strategies of TYK2 inhibitors and their applications in the treatment of autoimmune diseases.

Myocardial injury is common after brain injury; however, few studies have reported serial cardiac troponin (cTn) measurements to distinguish whether the myocardial injury is acute or chronic. The fourth Universal Definition of Myocardial Infarction introduced for the first time the criteria for acute myocardial injury (AMI). We aimed to investigate the prevalence and prognostic implications of AMI in primary intracerebral hemorrhage.

We retrospectively analyzed patients with primary intracerebral hemorrhage within 48 hours after symptom onset. All patients included had at least 2 cTn measurements: 1 obtained at the time of emergency admission and at least 1 more within the first 2 days of hospitalization. AMI was defined as an elevated cTn above the upper-reference limit (14 ng/L) along with a rise/fall >20%. Patients were followed for up to 5 years. Outcomes included major adverse cardiac events (MACEs; a composite of vascular death, nonfatal coronary events, and nonfatal stroke) and 90-day unfavorable outcomes (modified Rankin scale score ≥4). Cox proportional hazards models, multivariable logistic regression models, and Kaplan-Meier analyses were used to evaluate the association between AMI and outcomes. Of 600 patients included, 115 had AMI (19.2%). AMI independently conferred an increased risk for major adverse cardiac events (adjusted hazard ratio, 1.69 [95% CI, 1.12-2.53]) and 90-day unfavorable outcomes (adjusted odds ratio, 2.15 [95% CI, 1.26-3.67]) compared with patients without AMI.

AMI is relatively common in patients with intracerebral hemorrhage and is associated with both long-term major adverse cardiac events and 90-day unfavorable outcomes.

Bullous pemphigoid (BP) is the most common autoimmune subepidermal blistering disorder, primarily presenting with tense bullae and severe pruritus. Diagnosing and treating BP can be challenging due to its variable clinical presentations. We will briefly discuss these phenotypes, highlight diagnostic basics, and briefly summarize recent laboratory advancements that have improved diagnostic sensitivity and accuracy. The treatment landscape for BP has evolved significantly. Newer therapies, including biologics such as rituximab, omalizumab, dupilumab, and Janus kinase inhibitors target the immunopathogenesis of BP and can reduce the adverse effects associated with cumulative corticosteroid exposure and conventional immunosuppressants. This article provides a comprehensive overview of BP's clinical features, diagnostic approaches, and emerging therapeutic options, emphasizing personalized medicine, and improved patient outcomes.

Axial spondyloarthritis is an immune-mediated inflammatory condition involving the sacroiliac joints, spine, and peripheral joints. It affects approximately 1% of adults in the US and is associated with impaired physical function and reduced quality of life.

Inflammatory chronic back pain characterized by gradual onset starting before age 45 years, prolonged morning stiffness, improvement with exercise, and lack of improvement with rest is the most common symptom of axial spondyloarthritis and affects more than 80% of patients. Patients with axial spondyloarthritis may also have inflammatory arthritis in large peripheral joints (most commonly knees) in an oligoarticular, asymmetric fashion; inflammation at tendon insertions (enthesitis); inflammatory eye disease (uveitis); psoriasis; and inflammatory bowel disease. The pathogenesis of axial spondyloarthritis may involve genetic predisposition, gut microbial dysbiosis, and entheseal trauma, with immune cell infiltration of the sacroiliac joints and entheseal insertion areas in the spine. There are currently no diagnostic criteria for axial spondyloarthritis. The diagnosis, often delayed 6 to 8 years after symptom onset, is based on history (ie, inflammatory back pain [sensitivity, 74%-81%; specificity, 25%-44%]), laboratory findings (human leukocyte antigen B27-positive [sensitivity, 50%; specificity, 90%] and elevated C-reactive protein level [sensitivity, 35%; specificity, 91%]), and imaging findings consisting of sacroiliitis on plain radiography (sensitivity, 66%; specificity, 68%) or magnetic resonance imaging (sensitivity, 78%; specificity, 88%). First-line treatments are physical therapy and nonsteroidal anti-inflammatory drugs (NSAIDs). However, less than 25% of patients achieve complete symptom control with NSAIDs. Approximately 75% of patients require biologic drugs (tumor necrosis factor inhibitors [anti-TNF agents], interleukin 17 inhibitors [anti-IL-17 agents]) or targeted synthetic disease-modifying antirheumatic agents (Janus kinase [JAK] inhibitors) to reduce symptoms, prevent structural damage, and improve quality of life. Clinical trials reported that anti-TNF agents significantly improved ASAS20 (measure of pain, function, and inflammation) in 58% to 64% of patients compared with 19% to 38% for placebo. Similar outcomes were attained with anti-IL-17 agents (48%-61%, vs 18%-29% with placebo) and JAK inhibitors (52%-56%, vs 26%-29% with placebo). Anti-TNF agents, anti-IL-17 agents, and JAK inhibitors have been associated with reduced radiographic progression of axial spondyloarthritis.

Axial spondyloarthritis predominantly affects the sacroiliac joints and spine but is also associated with extraskeletal manifestations such as uveitis, psoriasis, and inflammatory bowel disease. Physical therapy and NSAIDs are first-line treatments, but most patients require therapy with biologics (anti-TNF or anti-IL-17 agents) or JAK inhibitors to achieve improvement in signs and symptoms, inflammation control, and reduced progression of structural damage.

The purpose of this review is to outline considerations for treating older adults with rheumatoid arthritis-associated interstitial lung disease (RA-ILD) as it relates to infection, comorbidities, cancer, and quality of life.

The recent 2023 American College of Rheumatology/American College of Chest Physicians guideline conditionally recommended specific disease-modifying antirheumatic drugs (DMARDs), antifibrotics, and short-term glucocorticoids to treat RA-ILD. Since RA-ILD often affects older adults, we contextualize these pharmacologic options related to infection, gastrointestinal (GI) effects, cancer, cardiovascular disease, and quality of life. Nearly all DMARDs and glucocorticoids are immunosuppressive and increase infection risk. Rituximab, mycophenolate, cyclophosphamide, and glucocorticoids may have particularly high infection risk. Many therapies recommended for treating RA-ILD have potential GI side effects. Antifibrotics have a high rate of nausea and diarrhea. Janus kinase inhibitors may increase risk of cancer and cardiovascular disease in older people. In older individuals, decisions must weigh the risks and benefits of drug options while considering clinical and social factors such as polypharmacy, adherence, cost, convenience, and social support. Management of RA-ILD in older individuals is complex and should consider risks and benefits, while optimizing quality and quantity of life through a shared decision-making process.

There is a need for efficacious therapies for patients with Crohn's disease that are better tolerated and more durable than available treatments. We aimed to evaluate the efficacy and safety of filgotinib, an oral Janus kinase 1 preferential inhibitor, for treating Crohn's disease.

This phase 3, double-blind, randomised, placebo-controlled trial was conducted in 371 centres in 39 countries. Eligible patients were aged 18-75 years with moderately to severely active Crohn's disease for at least 3 months before enrolment. Patients were enrolled into one of two induction studies on the basis of their experience with biological agents (induction study A included biologic-naive and later biologic-experienced patients and induction study B included biologic-experienced patients). In both induction studies, patients were randomly assigned (1:1:1), using an interactive web response system, to receive oral filgotinib 200 mg, filgotinib 100 mg, or placebo once daily for 11 weeks. Patients who received filgotinib and had two-item patient-reported outcome (PRO2) clinical remission or an endoscopic response at week 10 were re-randomised (2:1) to receive their induction dose or placebo orally, once daily to the end of week 58 in the maintenance study. Co-primary endpoints were PRO2 clinical remission and an endoscopic response at week 10 (induction studies) and week 58 (maintenance study). PRO2 clinical remission was defined as an abdominal pain subscore of not more than 1 and a liquid or very soft stool frequency subscore of not more than 3 (from eDiary data) and endoscopic response was defined as a reduction of at least 50% in Simple Endoscopic Score for Crohn's disease from induction baseline (from central reading of endoscopy). For the induction studies, efficacy was assessed in all randomly assigned patients who received at least one dose of study drug. For the maintenance study, efficacy was assessed in all patients from either filgotinib treatment group in the induction studies who reached PRO2 clinical remission or an endoscopic response at week 10, and who were re-randomised and received at least one dose of study drug in the maintenance study. Patients who received placebo throughout the induction and maintenance studies were not included in the full analysis set for the maintenance study. Safety was assessed in all patients who received at least one dose of study drug. This trial is complete and is registered with ClinicalTrials.gov, NCT02914561.

Between Oct 31, 2016, and Nov 11, 2022, 2634 patients were screened, of whom 1372 were enrolled (induction study A: n=707, induction study B: n=665, and maintenance study: n=481). There were 346 (49%) women and 358 (51%) men in induction study A, 356 (54%) women and 303 (46%) men in induction study B, and 242 women (51%) and 236 men (49%) in the maintenance study. Significantly more patients had PRO2 clinical remission at week 10 with filgotinib 200 mg than with placebo in induction study B (29·7% vs 17·9%, difference 11·9%; 95% CI 3·7 to 20·2, p=0·0039) but not induction study A (32·9% vs 25·7%, 6·9%; -1·4 to 15·2, p=0·0963); there was no significant difference for endoscopic response (induction study A: 23·9% vs 18·1%, difference 5·5%; 95% CI -2·0 to 12·9, p=0·1365; induction study B: 11·9% vs 11·4%, 0·1%; -6·5 to 6·6, p=0·9797). At week 58, both co-primary endpoints were reported in greater proportions of patients who received filgotinib 200 mg than in those who received placebo (PRO2 clinical remission: 43·8% vs 26·4%, difference 16·8%; 95% CI 2·0 to 31·6, p=0·0382; endoscopic response: 30·4% vs 9·4%, difference 20·6%; 95% CI 8·2 to 33·1, p=0·0038). Co-primary endpoints were not met for filgotinib 100 mg in any study. In the induction studies, the most frequently reported treatment-emergent adverse events (TEAEs; ≥5% of patients in any group) were abdominal pain; arthralgia; an exacerbation, flare, or worsening of Crohn's disease; headache; nasopharyngitis; nausea; and pyrexia. In the maintenance study, the most frequently reported TEAEs (≥5% of patients in any filgotinib or associated placebo group) were those reported in the induction studies (except for headache) and abdominal distension, upper abdominal pain, anaemia, and flatulence. Serious TEAEs were reported in 49 patients in induction study A (18 [8%]) of 222 patients in the filgotinib 200 mg group, 16 [7%] of 245 patients in the filgotinib 100 mg group, and 15 [6%] of 237 patients in the placebo group), 81 patients in induction study B (19 [9%] of 202 patients in the filgotinib 200 mg group, 36 [16%] of 228 patients in the filgotinib 100 mg group, and 26 [11%] of 229 patients in the placebo group), and 49 patients in the maintenance study (13 [11%] of 118 patients in the filgotinib 200 mg-filgotinib 200 mg group, five [9%] of 56 patients in the filgotinib 200 mg-placebo group, 14 [13%] of 104 patients in the filgotinib 100 mg-filgotinib 100 mg group, three [5%] of 55 patients in the filgotinib 100 mg-placebo group, and 14 [10%] of 145 patients in the placebo-placebo group). No deaths were reported during the induction and maintenance studies.

Filgotinib 200 mg did not meet the co-primary endpoints of clinical remission and an endoscopic response at week 10, but did meet the co-primary endpoints at week 58. Filgotinib treatment was well tolerated, and no new safety signals were reported.

Galapagos.

We evaluated the efficacy and safety profiles of JAK inhibitors (JAKi) and biologic disease-modifying antirheumatic drugs (bDMARDs) when used with or without methotrexate (MTX) for the treatment of nonsystemic forms of juvenile idiopathic arthritis (nsJIA).

Randomized clinical trials (RCTs) investigating efficacy and safety outcomes of JAKi or bDMARDs for the nsJIA population up to 2023 were searched in ClinicalTrial.gov, PubMed, EMBASE, and Cochrane databases. Bayesian arm-based network meta-analysis compared efficacy as measured by Juvenile Idiopathic Arthritis-American College of Rheumatology 70 (JIA-ACR70) improvement and safety based on rates of serious adverse events (SAEs) among all therapies.

Eligible studies included 45 citations from 16 RCTs (7 parallel and 9 withdrawal trials) with a total of 1,821 participants that investigated nine bDMARDs, three with and six without MTX co-treatment, and two JAKis (tofacitinib and baricitnib). The reported SAE incidence rates ranged from 0 to 0.3 per person-year of follow-up; none of the pairwise comparisons were statistically significant. The JIA-ACR70 improvement by 16 weeks of treatment ranged from 11.3% to 89.5%. Compared with controls, significant JIA-ACR70 improvements were observed for etanercept, golimumab, and all three combination therapies (adalimumab+MTX, etanercept+MTX, and infliximab+MTX), with odds ratios ranging from 2.97 to 3.99. No significant pairwise comparisons between bDMARDs and JAKi versus bDMARDs were noted.

Overall, no significant evidence was found for efficacy and safety profiles in pairwise comparisons of JAKis and bDMARDs. Future studies will expand the meta-analysis by including non-RCT studies and individual participant data.

Janus kinase (JAK) molecules are involved in important cellular activation pathways. Over the past decade, many targeted therapies have emerged, including the increasingly promising role of JAK inhibitors (JAKi) in the treatment of inflammatory and autoimmune diseases. The spectrum of use of these small molecules is increasingly broader. JAKi have been approved in several autoimmune diseases. Currently, four molecules (tofacitinib, baricitinib, upadacitinib and filgotinib) have been labeled for moderate to severe rheumatoid arthritis (RA) with failure or poor tolerance of one or more conventional disease-modifying antirheumatic drug (csDMARDS), or biologics (bDMARDS). JAKi are now also commonly used in other diseases such as psoriatic arthritis, ankylosing spondylitis, and ulcerative colitis. They have also shown promising results in clinical trials for the treatment of other autoimmune conditions. We present here their mechanisms of action, and the main data about JAKi use on systemic and autoimmune diseases.

The Janus kinase (JAK) inhibitors are treatment options for autoimmune diseases. Numerous safety concerns have been raised. The European Medicines Agency updated the product information of tofacitinib to include the risk of fractures-but not for other JAK inhibitors. We conducted a global pharmacovigilance analysis of previously investigated JAK inhibitors to investigate a potential class effect.

Individual case safety reports (ICSRs) for all licensed JAK inhibitors were identified from the global WHO pharmacovigilance database. The primary outcome of interest was a bone fracture. Disproportionality analyses using reporting odds ratios (RORs) were conducted.

We identified 122,037 ICSRs for tofacitinib, 27,786 ICSRs for upadacitinib, 14,616 ICSRs for baricitinib, 830 for filgotinib, and 350 for abrocitinib. Among the ICSRs, we identified 2198 (1.8%), 634 (2.3%), and 144 (1.0%) reports, where a bone fracture was reported for tofacitinib, upadacitinib, and baricitinib, respectively. Few reports were available for the newest drugs filgotinib (10) and abrocitinib (1). JAK inhibitors were associated with increased reporting for fracture: tofacitinib (ROR 3.34, 95% confidence interval [CI] 3.20-3.48), upadacitinib (ROR 4.23, 95% CI 3.80-4.48), baricitinib (ROR 1.80, 95% CI 1.52-2.11) and filgotinib (ROR 2.24, 95% CI 1.11-3.94). Patients with bone fractures were more often female, older and had a higher number of co-reported medications. They were more likely to use glucocorticoids, opioids, and bisphosphonates.

The results from this pharmacovigilance analysis, based on a spontaneous reporting database associated with inherent limitations, suggest a potential risk of fractures with JAK inhibitors, indicating that a class effect cannot be ruled out.

Considering the diverse aetiologies and immunodysregulatory statuses observed in each patient with rheumatoid arthritis (RA), stratification based on peripheral blood immunophenotyping holds the potential to enhance therapeutic responses to molecular targeted therapies, biological/targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs).

Immunophenotype analysis was conducted on a cohort of over 500 b/tsDMARDs-naïve patients using flow cytometry. Patients with RA were stratified based on their immunophenotypes, and the treatment response to each targeted therapy was evaluated. Validation was performed using an additional cohort of 183 b/tsDMARDs-naïve patients with RA.

Patients with RA were stratified into five clusters, two of which exhibited distinct RA phenotypes compared with controls, characterised by significant increases in CD4+ effector memory T cells re-expressing CD45RA. Notably, the effectiveness of different b/tsDMARDs varied across clusters. The group using promising b/tsDMARDs was labelled as 'expected' whereas the 'non-expected' group comprised those using others. The expected group outperformed the non-expected group with higher 26-week remission rates (39.9% vs 24.6%, p=0.0004) and low disease activity achievement (80.8% vs 60.2%, p<0.0001). Trajectory analysis showed the non-expected group's 26-week disease activity was influenced by Clinical Disease Activity Index at baseline unlike the expected group. Additionally, different molecular targeted therapies influenced the proportions of each immune cell subset variably. To validate, immunophenotyping was performed on a validation cohort. When 183 cases were grouped based on their b/tsDMARDs usage into expected/non-expected groups, the expected group had a higher remission rate (p=0.0021), further confirming the observed trend.

Our findings offer valuable insights into the diversity of RA and potential therapeutic strategies grounded in the molecular underpinnings.

We conducted a retrospective study to identify incidence rates and potential risk factors of major adverse cardiac events (MACE) in Japanese patients with ulcerative colitis (UC), as existing data are scarce, inconsistent, and provide limited representation of the real-world situation of MACE in Japan.

We utilized administrative claims data, collected between January 2013 and December 2022, from Medical Data Vision, Japan. Patients (aged ≥ 20 years) diagnosed with UC within ± 1 month of the prescription date during the study period were included in the incident cohort. Exclusions comprised patients diagnosed with UC in the first 365 days or with myocardial infarction, heart failure, stroke, or other ischemic heart diseases within 30 days pre-index. The cumulative incidence rate of MACE was calculated using the Kaplan-Meier method. Multivariate Cox regression models were used to calculate hazard ratios (HRs) for all relevant potential risk factors.

Of 11 407 patients in the incident cohort, 91 (0.8%) experienced incident MACE. Over 120 months, the cumulative incidence rate of MACE was 2.86% (95% confidence interval [CI]: 1.89-4.32). Significant HRs (95% CI) were found for age category (≥ 65 years) (4.557 [2.786-7.452]), diabetes (1.709 [1.030-2.835]), and atrial fibrillation (AF) (2.759 [1.188-6.405]) (all p < 0.05). Patients with a history of stroke showed numerically increased risk (1.871 [0.508-6.886]) of MACE.

The cumulative incidence rate of MACE was 2.86% over 120 months. Age, comorbidities of diabetes and AF, and history of stroke were the major risk factors for MACE in Japanese UC patients.

Deucravacitinib, an oral, selective, allosteric tyrosine kinase 2 inhibitor, is approved in multiple countries for adults with moderate to severe plaque psoriasis who are candidates for systemic therapy. The safety and efficacy of deucravacitinib in psoriasis has been demonstrated through 3 years in the phase 3 POETYK PSO-1, PSO-2, and long-term extension (LTE) trials enrolling adults with moderate to severe plaque psoriasis.

To review the effect of deucravacitinib treatment on adverse events of interest (AEIs) over 3 years in POETYK PSO-1, PSO-2, and LTE, cumulative exposure-adjusted incidence rates (EAIRs) of AEIs were recorded through 3 years.

AEIs and 3-year EAIRs of select infections included serious infections (2.5/100 person-years [PY]), COVID-19 (1.6/100 PY), and herpes zoster (0.6/100 PY). Excluding COVID-19, the serious infections EAIR was 0.9/100 PY. Major adverse cardiovascular event (MACE) and venous thromboembolism EAIRs were 0.3/100 PY and 0.1/100 PY, respectively. The EAIRs for malignancies were 0.9/100 PY overall and 0.5/100 PY, excluding nonmelanoma skin cancer (NMSC). Cutaneous events included acne (EAIR, 1.3/100 PY) and folliculitis (EAIR, 1.1/100 PY). Three-year cumulative EAIRs generally remained stable or decreased relative to 1-year rates. EAIRs of non-COVID-19 serious infections, malignancies excluding NMSC, and MACE through 3 years were consistent with rates for other antipsoriatic agents from clinical trials, disease registries, and real-world claims data.

In adults with plaque psoriasis treated with deucravacitinib, the cumulative incidence of AEIs remained comparable or decreased over 3 years of follow-up and aligned with comparison data for other antipsoriatic therapies.

To compare effectiveness of tofacitinib versus tumor necrosis factor inhibitors (TNFi), and across tofacitinib lines of therapy, in patients with rheumatoid arthritis (RA), using US CorEvitas RA Registry data.

Analysis included patients with RA initiating tofacitinib or TNFi with a 12-month follow-up visit between November 2012-February 2021. Primary (Clinical Disease Activity Index-defined low disease activity [CDAI-LDA: CDAI ≤ 10]) and secondary (clinical/disease activity/patient-reported) effectiveness outcomes were assessed at month 12. Outcomes were stratified by treatment regimen (overall tofacitinib vs overall TNFi/tofacitinib monotherapy vs tofacitinib combination therapy/TNFi monotherapy vs TNFi combination therapy/tofacitinib monotherapy vs TNFi combination therapy/tofacitinib combination therapy vs TNFi combination therapy), or tofacitinib line of therapy (2nd/3rd/ ≥ 4th line).

3,481 eligible patients initiated tofacitinib (n = 805) or TNFi (n = 2,676). Improvements in effectiveness at month 12 were generally similar across treatment regimens; 25.1% and 30.1% of overall tofacitinib and TNFi initiators achieved CDAI-LDA, respectively (odds ratio 1.29 [95% confidence interval (CI) 0.94, 1.76]). Odds ratios (95% CIs) for achieving CDAI-LDA at 12 months were 0.70 (0.36, 1.37) for 3rd- versus 2nd-line, and 1.09 (0.63, 1.88) for 3rd- versus ≥ 4th-line tofacitinib initiators. At month 12, mean change from baseline in CDAI was greater among 3rd- versus ≥ 4th-line tofacitinib initiators, and mean Health Assessment Questionnaire and patient-reported pain were greater in 3rd- versus 2nd-line and ≥ 4th- versus 3rd-line tofacitinib initiators.

Generally, there were no differences in effectiveness between tofacitinib versus TNFi regimens. Few differences were observed between tofacitinib lines of therapy; sample sizes were small for 2nd/3rd-line initiators.

NCT01402661 (ClinicalTrials.gov; July 25, 2011). Key Points • Using data from the US CorEvitas rheumatoid arthritis (RA) Registry, this study compared the effectiveness of tofacitinib versus tumor necrosis factor inhibitors (TNFi) and across tofacitinib lines of therapy. • Effectiveness of tofacitinib was similar to TNFi regimens up to month 12, while differences in some effectiveness outcomes at month 12 were observed with tofacitinib across different lines of therapy. • The findings of this study may inform future treatment decision-making in patients with RA.

Current literature regarding cancer risk in rheumatic and musculoskeletal diseases (RMDs) is particularly poor and controversial, even though the incidence of malignancy in some patients with RMDs is considered to be increased compared with the general population. Malignancy may be a major comorbidity in subjects with spondyloarthritis (SpA) as the result of multifactorial mechanisms, from disease pathogenesis to the iatrogenic effect of immunomodulating drugs. Several recommendations for screening and management of cancer risk have been developed in recent years with the aim of improving the different outcomes in these patients. The goal of this narrative review is to provide an overview of the currently available evidence on the risk of malignancy connected with RMDs and examine the association of SpA with cancer and the potential impact of its treatment with biologic and targeted synthetic disease-modifying anti-rheumatic drugs on development of malignancy.

Janus kinase (Jak) inhibitors may have increased risk of thromboembolism compared to tumor necrosis factor (TNF) inhibitors. This study investigates the association between Jak inhibitor use and retinal vein occlusion.

This retrospective, non-randomized cohort study used a federated health research network. Propensity-score matched risk ratios with 95% CI were calculated for central and branch retinal vein occlusion (CRVO, BRVO) in patients with immune-mediated inflammatory diseases (IMIDs) treated with Jak inhibitors versus TNF inhibitors.

Jak and TNF inhibitor cohorts each had 5,249 patients. Risk ratio for CRVO with Jak inhibitors (n = 11) versus TNF inhibitors (n = 18) was 0.61 [CI (0.29,1.29)]. Risk ratio for BRVO with Jak inhibitors (n = 17) compared to TNF inhibitors (n = 19) was 0.89 [CI (0.47,1.72)].

This study did not find evidence of increased risk of RVO with the use of Jak inhibitors compared to TNF inhibitors among patients with IMIDs, contributing to literature on Jak inhibitor safety. [Ophthalmic Surg Lasers Imaging Retina 2025;56:72-78.].

Real-world data for filgotinib, a Janus kinase (JAK)1 inhibitor, are limited in patients with rheumatoid arthritis (RA).

To explore real-world filgotinib use in patients with RA in Germany.

This retrospective chart review included patients aged ≥ 18 years with confirmed moderate to severe RA who initiated filgotinib before December 1, 2021, with ≥ 6 months of medical records available prior to filgotinib initiation or after initial diagnosis. Patient characteristics, prior treatments, reasons for initiating/discontinuing filgotinib, disease activity, dose adjustments and concomitant treatments were recorded.

In total, 301 patients from 20 German rheumatology outpatient units were included. One-third were aged ≥ 65 years and almost half had ≥ 1 cardiovascular (CV) risk factor. Most patients initiated filgotinib as monotherapy (83.7%; 12.7% of whom with glucocorticoids) and at the 200 mg dose (84.7%); higher proportions of those initiating the 100 versus 200 mg dose were aged ≥ 65 years and had renal impairment or ≥ 1 CV risk factor. Oral administration (78.4%), fast onset of action (66.8%) and administration as monotherapy (65.4%) were the most common reasons for initiating filgotinib. At 12 months, 41 (18.4%) patients had discontinued filgotinib, most commonly due to lack of effectiveness. After 6‑months of follow-up, 36.8% of patients had achieved Clinical Disease Activity Index (CDAI) remission and 45.6% had achieved CDAI low disease activity.

In clinical practice in Germany, reasons for initiating filgotinib in patients with RA were related to dosing flexibility and general JAK inhibitor attributes. Filgotinib was used predominantly as monotherapy and was effective and generally well tolerated; however, longer-term data in larger, prospective cohorts are needed.

Small molecule Janus kinase (JAK) inhibitors have revolutionized the management of ulcerative colitis (UC) and Crohn's disease (CD) through their low immunogenicity, safety, and consistent pharmacologic response that are superior to existing therapeutic options. In this perspective, we highlight existing evidence supporting the use of currently approved JAK inhibitors (upadacitinib, tofacitinib, and filgotinib) for UC or CD, additionally emphasizing the evidence for their use in related autoimmune conditions such as rheumatoid arthritis and spondyloarthropathies. Our perspective concludes with a review of the existing comparative effectiveness literature, which positions JAK inhibitors, particularly upadacitinib, favorably compared with other biologic therapies. This perspective is paired with a companion publication highlighting the origins and development of JAK inhibitors and a more in-depth review of their pathophysiologic mechanisms.

In the last decades, consisting evidence supported a close relationship between both innate and adaptive immune systems and the accelerated cardiovascular (CV) disease characterizing autoimmune diseases, such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). Indeed, several cell lines involved in the pathogenesis of these autoimmune diseases, such as macrophages and dendritic cells, as well as different T and B lymphocyte subsets, and inflammatory cytokines, have been demonstrated to be directly involved in the mechanisms underlying early atherosclerotic arterial wall damage. Traditional CV risk factors play a concomitant role but do not sufficiently account for the increased prevalence of CV disease in these patients. Indeed, the pathophysiological link between RA and SLE and atherosclerosis is based on complex inflammatory pathways that interconnect these conditions and may explain the significant morbidity and mortality rates demonstrated in these patients, with consequent significant negative effects on quality of life and long-term survival. Consequently, it is intriguing to hypothesize that immunosuppressive drugs commonly used in the treatment of these pathologies may also exert an immunomodulatory and anti-inflammatory effect in mitigating the atherosclerotic damage that has been demonstrated to occur early in the initial stages of the disease. Recognizing risk factors, predicting occurrences and early intervention to prevent CV disease development have emerged as critical objectives in RA and SLE treatment. In this review, we aimed to provide an updated overview of the atherogenic effects exerted by the immune and inflammatory pathways involved in the pathogenesis of RA and SLE. Moreover, we examined the available evidence which may support the potential effects of immunosuppressive therapies in reducing CV damage and, consequently, CV disease risk in these patients.