Динамика клинико-иммунологических показателей у пациентов, перенесших COVID-19 среднетяжелого течения и получавших терапию с включением ингибитора янус-киназ

The ORAL Surveillance trial showed a potentially higher incidence of malignancy and major adverse cardiovascular events (MACEs) associated with tofacitinib than those associated with tumor necrosis factor (TNF) inhibitors (TNFis). However, few studies have compared the safety of non-TNFis or other Janus kinase (JAK) inhibitors (JAKis). This study was aimed at comparing the incidence rates (IRs) of malignancies and MACEs in patients with rheumatoid arthritis (RA) treated using interleukin-6 (IL-6) inhibitors (IL-6is) or JAKis. We retrospectively analyzed 427 patients with RA who were treated using an IL-6i (n = 273) or a JAKi (n = 154). We determined the IRs of malignancy and MACEs, and the standardized incidence ratio (SIR) of malignancies and investigated factors related to malignancy and MACEs. After adjusting the clinical characteristic imbalance by propensity score matching (PSM), we compared the IRs of adverse events between the JAKi and IL-6i groups. After PSM, the observational period was determined to be 605.27 patient-years (PY), and the median observational period was determined to be 2.28 years. We identified seven cases of malignancy (IR: 2.94 per 100 PY) in the JAKi-treated group and five cases (IR: 1.36 per 100 PY) in the IL-6i-treated group after PSM. The IR of MACEs was 2.56 and 0.83 (per 100 PY) in the JAKi- and IL-6i-treated groups. The IRRs of JAKi-treated patients versus IL-6i-treated patients were 2.13 (95% confidence interval (CI): 0.67-7.42) for malignancy and 3.03 (95% CI: 0.77-15.21) for MACE. There were no significant differences in IRR for malignancy and MACE between both groups after PSM. Univariate and multivariable Cox regression analyses revealed that older age and JAKi use were independent risk factors for malignancy, while older age, hypertension, and JAKi use were independent risk factors for MACEs. The overall malignancy SIR was significantly higher in the JAKi-treated group compared to the general population (2.10/100 PY, 95% CI: 1.23-2.97). The IRs of malignancy and MACE in patients with RA after PSM were comparable between IL-6i-treated and JAKi-treated patients. However, the SIR of malignancy in JAKi treatment was significantly higher than in the general population; therefore, further safety studies comparing JAKi to non-TNFi biologic disease-modifying antirheumatic drugs (bDMARDs) are needed.

Janus kinase (JAK) inhibitors are being increasingly used in inflammatory bowel diseases (IBDs). In the present review we raise a series of practical questions on JAK inhibitors in IBD and provide clear and concise answers. We performed a bibliographic search to identify studies assessing the role of JAK inhibitors in IBD. The key conclusions are summarized as follows. Upadacitinib has shown favorable efficacy outcomes in ulcerative colitis relative to other JAK inhibitors, although this conclusion requires confirmation through randomized trials. Extended induction can benefit patients with partial response. Real-world data support the use of JAK inhibitors in pediatric and older adults with IBD. JAK inhibitor efficacy appears unaffected by body mass index. JAK inhibitors may offer considerably high colectomy-free rates in acute severe ulcerative colitis. Interruption of therapy should be cautious, as maintenance seems key to sustained remission. Dose re-escalation can recapture response in over half of patients with loss of efficacy. Switching between JAK inhibitors, especially from tofacitinib to upadacitinib, is a viable strategy. Upadacitinib appears promising in the treatment of refractory perianal fistulizing Crohn's disease. JAK inhibitors may also be an option in refractory pouchitis. Combination therapy with JAK inhibitors and biologics may be beneficial in refractory IBD, though more studies are needed. JAK inhibitors appear effective in some extraintestinal dermatologic manifestations. Pretreatment screening for latent tuberculosis is advised. JAK inhibitors cause reversible, dose-dependent cholesterol increases without consistent evidence of a clear impact on cardiovascular risk, but monitoring is advised. Use in pregnancy is discouraged due to potential risks, and breastfeeding is contraindicated because of drug excretion in milk.

Treatment of Myeloproliferative Neoplasms with Janus Kinase Inhibitors: A Meta-Analysis of Cardiovascular Safety

Background Three types of Janus kinase (JAK) inhibitors are currently available for the treatment of ulcerative colitis (UC) in Japan. Although several studies have reported their efficacy and safety in clinical practice, real-world data remain limited. Therefore, we investigated treatment outcomes across multiple local medical institutions. Methods This was a multicentre, retrospective study including patients with UC who were prescribed a JAK inhibitor between July 2007 and December 2025. The primary outcomes were clinical remission and response at 4 weeks, 52 weeks, and at the most recent follow-up. The efficacy and safety profiles of each JAK inhibitor were compared descriptively. Results A total of 74 patients with UC were treated with JAK inhibitors during the study period: 23 with tofacitinib, 29 with filgotinib, and 22 with upadacitinib. Clinical remission rates at 4 and 52 weeks were 70.0% and 47.6% for tofacitinib, 86.2% and 60.7% for filgotinib, and 95.2% and 72.2% for upadacitinib, respectively. Among patients who underwent JAK inhibitor intraclass switching, tofacitinib was used in 4.4% (1/23), filgotinib in 6.9% (2/29), and upadacitinib in 68.2% (15/22). Upadacitinib demonstrated higher efficacy than the other JAK inhibitors, including in patients who had previously received a different JAK inhibitor. One case of herpes zoster infection occurred in a patient treated with tofacitinib; however, there was no significant difference in the incidence of adverse events among the three JAK inhibitors. No cases of death, malignancy, or major acute cardiovascular events were observed. In this study, JAK inhibitors were more frequently prescribed for patients intolerant to 5-aminosalicylic acid (5-ASA) (35.1%). Conclusion Upadacitinib demonstrated favourable therapeutic efficacy even in community-based medical settings. The accumulation of further detailed real-world data will help optimise the selection of the most appropriate JAK inhibitor for individual patients with ulcerative colitis. Conflict of interest: Dr. Mori, Statoshi: No conflict of interest Maeda, Nobuhisa: No conflict of interest Kuwazuru, Kosuke: No conflict of interest Sameshima, Yoichi: No conflict of interest Tanaka, Akihito: No conflict of interest Komaki, Yuga: No conflict of interest Kanmura, Shuji: No conflict of interest

Janus kinase 2 (JAK2) inhibitors in the treatment of multiple myeloma: modulating the myeloma immune microenvironment.

Gastrointestinal perforations have been reported in a small number of rheumatoid arthritis (RA) patients treated with Janus kinase (JAK) inhibitors in clinical trials. However, large-scale postmarketing data repositories are needed to further investigate this potentially rare but serious adverse event. A retrospective, pharmacovigilance study of the FDA adverse event reporting system (July 2014 to September 2023) assessing the reporting of gastrointestinal perforations following JAK inhibitors compared to biological disease-modifying antirheumatic drugs (bDMARDs) in RA patients. The adjusted reporting odds ratio (adj.ROR) was calculated using a multivariable logistic regression model. Of 399,983 RA patients included in the study, 76,446 were treated with JAK inhibitors (tofacitinib, n=52,365; upadacitinib, n=21,856; baricitinib, n=2225) and 323,537 were treated with bDMARDs (TNF inhibitors, rituximab, and abatacept). Overall, 230 cases of gastrointestinal perforation following JAK inhibitors were identified, with a median time of 9 (IQR: 4-22) months from treatment initiation. Compared with bDMARDs, JAK inhibitors were associated with a higher-than-expected reporting of gastrointestinal perforations (adj.ROR=1.98[1.69-2.31]). Increased reporting of gastrointestinal perforations was observed among recipients of JAK inhibitors or bDMARDs who used steroids or non-steroidal anti-inflammatory drugs concurrently (adj.ROR=2.82 [2.41-3.31]). Perforations of both the upper and lower gastrointestinal tract were significantly over-reported (n=51, adj.ROR=1.55 [1.12-2.14], n=143, adj.ROR=1.78 [1.46-2.17], respectively). Furthermore, the safety signal was significant across all JAK inhibitors: tofacitinib (n=125, adj.ROR=1.52 [1.25-1.85]), upadacitinib (n=84, adj.ROR=2.73 [2.17-3.44]), and baricitinib (n=21, adj.ROR=5.38 [3.46-8.37]). In this global pharmacovigilance study, all JAK inhibitors were associated with increased reporting of gastrointestinal perforations compared with bDMARDs in RA patients. Until more data on IBD patients emerge, careful surveillance and increased clinicians' awareness should also be advocated for this population.

Axial spondyloarthritis (axSpA) and psoriatic arthritis (PsA) are chronic inflammatory diseases that often cause joint damage, potentially leading to joint replacement surgery. We assessed whether Janus kinase (JAK) inhibitors reduce the risk of total knee or hip replacement compared to nonsteroidal anti-inflammatory drugs (NSAIDs). Using the Merative™ MarketScan® Commercial Database, we conducted a nested case-control study of adults aged 18-65years with axSpA and/or PsA from October 2015 to December 2021. Medication exposure was categorized hierarchically using pharmacy and procedure claims, including JAK inhibitors, non-tumor necrosis factor inhibitor biologics (non-TNFi biologics), TNF inhibitors (TNFi), DMARDs, NSAIDs (referent), and none. Logistic regression with confounder adjustment assessed associations between medication class and joint replacement risk. Among 8855 eligible adults, 1771 cases of joint replacement were identified. JAK inhibitor use was not significantly associated with reduced odds of joint replacement compared to NSAIDs (odds ratio [OR] 0.67, 95% confidence interval [CI] 0.41-1.08). Non-TNFi biologic users (OR 0.66, 95% CI 0.53-0.82), TNFi users (OR 0.63, 95% CI 0.52-0.76), and DMARD users (OR 0.65, 95% CI 0.53-0.80) had lower odds of joint replacement than NSAID users. We did not find conclusive evidence that relative to NSAIDs, JAK inhibitors prevent end-stage arthritis requiring surgery in axSpA and PsA; however, risk was reduced with use of non-TNFi biologics, TNFi, or DMARDs. Longer-term data are needed to understand the optimal utilization of JAK inhibitors in preventing end-stage arthritis in these conditions. Key Points • Axial spondyloarthritis (axSpA) and psoriatic arthritis (PsA) are chronic inflammatory diseases that often cause joint damage, potentially leading to joint replacement surgery. •In our study, although there was not conclusive evidence that JAK inhibitors prevent end-stage arthritis requiring surgery in axSpA and PsA relative to NSAIDs, we did find that risk was reduced with use of non-TNFi biologics, TNFi, or DMARDs. • Understanding the impacts of different medication classes, including Janus kinase (JAK) inhibitors and tumor necrosis factor inhibitors (TNFi) relative to nonsteroidal anti-inflammatory drugs (NSAIDs) may guide treatment decisions.

This review explores the link between immune interactions and chronic pain, offering new perspectives on treatment. It focuses on Janus kinase (JAK) inhibitors' potential in pain management. Immune cells' communication with neurons shapes neuroinflammatory responses, and JAK inhibitors' effects on pain pathways are discussed, including cytokine suppression and microglial modulation. This review integrates studies from rheumatoid arthritis (RA) pain and central sensitization to highlight connections between immune interactions and pain. Studies on RA joint pain reveal the shift from cytokines to sensitization. Neurobiological investigations into central sensitization uncover shared pathways in chronic pain. Clinical evidence supports JAK inhibitors' efficacy on pain-related outcomes and their effects on neurons and immune cells. Challenges and future directions are outlined, including interdisciplinary collaboration and dosing optimization. Overall, this review highlights JAK inhibitors' potential to target immune-mediated pain pathways, underscoring the need for more research on immune-pain connections.

Janus kinase (JAK) inhibitors have emerged as an effective class of therapies for various inflammatory diseases such as rheumatoid arthritis (RA). JAK inhibitors function intracellularly by modulating the catalytic activity of JAKs and disrupting the receptor‐mediated signaling of multiple cytokines and growth factors, including those with pro‐inflammatory activity. Understanding the inhibition profiles of different JAK inhibitors, based on the associated cytokine receptors and downstream inflammatory pathways affected, is important to identify the potential mechanisms for observed differences in efficacy and safety. This study applied an integrated modeling approach, using in vitro whole blood cytokine inhibition potencies and plasma pharmacokinetics, to determine JAK‐dependent cytokine receptor inhibition profiles, in the context of doses estimated to provide a similar clinical response in RA clinical trials. The calculated profiles of cytokine receptor inhibition for the JAK inhibitors tofacitinib, baricitinib, upadacitinib, and filgotinib and its metabolite, were generally similar when clinically efficacious doses for RA were considered. Only minor numerical differences in percentage cytokine receptor inhibition were observed, suggesting limited differentiation of these inhibitors based on JAK pharmacology, with each showing a differential selectivity for JAK1 heterodimer inhibition. Nevertheless, only robust clinical testing involving head‐to‐head studies will ultimately determine whether there are clinically meaningful differences between these JAK inhibitors. Furthermore, ongoing and future research into inhibitors with alternative JAK selectivity remains of clinical importance. Thus, all JAK inhibitors should be characterized via thorough preclinical, metabolic and pharmacological evaluation, adequate long‐term clinical data, and when available, real‐world experience.

Janus kinase (JAK) inhibitors have emerged as a promising oral therapeutic option for alopecia areata (AA), an autoimmune condition characterized by hair loss. These therapies demonstrate clinical efficacy with hair regrowth even in long-standing cases of AA. However, their broad immunomodulatory effects raise concerns about long-term safety. JAK inhibitors disrupt multiple signalling pathways used by type I and type II cytokines, leading to significant reductions in T cells, natural killer cells and macrophage activation. Although short-term clinical trials support their efficacy and tolerability, the long-term safety profile in AA remains poorly understood, necessitating an evaluation of potential risks. A literature review of clinical trials evaluating the safety profile of JAK inhibitors in AA was conducted. Relevant studies were identified through a structured search of PubMed, using keywords such as ‘alopecia areata’, ‘side effects’ and ‘JAK inhibitors’. Inclusion criteria encompassed randomized controlled trials reporting treatment-emergent adverse events (AEs) and serious AEs. Exclusion criteria included nonhuman trials, case reports and lack of full-text availability. Using these selection criteria, 15 studies were identified. Data extraction focused on length of follow-up of AEs, treatment-emergent AEs and serious AEs. The findings were synthesized to provide an overview of the safety profiles of baricitinib, ritlecitinib, deuruxolitinib, ivarmacitinib and other JAK inhibitors. Long-term safety data were scarce, with only one study (the phase IIb/III ALLEGRO trial on ritlecitinib) extending to 2 years, while others had follow-ups of 52 weeks or shorter. The most common treatment-emergent AEs included upper-respiratory-tract infections, acne and headache. The incidence of serious AEs remained low across trials. In trials involving baricitinib and ritlecitinib, there were isolated reports of malignancies, particularly squamous cell carcinoma, melanoma and breast cancer. There was a single report of thromboembolic events and one case of myocardial infarction in a patient with pre-existing cardiovascular risk factors. JAK inhibitors were generally well tolerated, with most AEs being mild to moderate within a period of 2 years. Serious infections and malignancies were rare, and no increased risk of thromboembolism or cardiovascular events was observed beyond isolated cases. While the short-term safety profile (24–52 weeks) appears favourable, data on long-term effects remain limited beyond 2 years. Given the chronic nature of AA and the potential for extended use of JAK inhibitors, further long-term studies are necessary to better assess the risks of malignancies, cardiovascular events and other rare but serious AEs associated with this drug class. Although short-term studies indicate efficacy and tolerability, the absence of longitudinal research underpins the need for cautious clinical use and informed patient decision making.

Background:Psoriatic arthritis (PsA) affects 4-30 percent of patients with psoriasis. PsA can affect peripheral joints, axial joints, and entheses. PsA has been linked to an increased risk of several comorbidities,...

Background:Janus kinase (JAK) inhibitors block the signaling of multiple JAK-dependent cytokines. A number of studies have reported on the clinical efficacy of JAK inhibitors in patients with rheumatoid arthritis (RA)....

Background: Due to the lack of comprehensive evidence based on prospective studies, the efficacy and safety of Janus Kinase (JAK) inhibitors (including tofacitinib, ruxolitinib, baricitinib, ritlecitinib and brepocitinib) for alopecia areata (AA) are yet to be proved.Methods: The systematic review and meta-analysis was performed pursuant to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guideline and registered on PROSPERO (CRD42022303007).Results: Fourteen prospective studies (5 RCTs and 9 non-RCTs), enrolling a total of 1845 patients with AA, were included for quantitative analysis. In RCTs, oral JAK inhibitors resulted in higher good response rate compared with control (RR: 6.86, 95% CI: 2.91–16.16); topical JAK inhibitors did not show any difference compared with control (RR: 1.00, 95% CI: 0.31–3.18). In non-RCTs, the pooled rate of good response to oral, topical and sublingual JAK inhibitors were 63% (95% CI: 44%–80%), 28% (95% CI: 1%–72%) and 11% (95% CI: 1%–29%), respectively. The pooled recurrence rate in patients treated with JAK inhibitors was 54% (95% CI: 39%–69%), mainly due to the withdrawal of JAK inhibitors. In RCTs, no difference was found in the risk of experiencing most kind of adverse events; in non-RCTs, the reported adverse events with high incidence rate were mostly mild and manageable.Conclusion: JAK inhibitors are efficacious and generally well-tolerated in treating AA with oral administration, whereas topical or sublingual administration lacks efficacy. Subgroup analyses indicate that baricitinib, ritlecitinib and brepocitinib seem to have equal efficacy for AA in RCTs; ruxolitinib (vs. tofacitinib) and AA (vs. AT/AU) are associated with better efficacy outcomes in non-RCT. Due to the high recurrence rate after withdrawal of JAK inhibitors, continuous treatment should be considered to maintain efficacy.Systematic Review Registration: PROSPERO: CRD 42022303007

Introduction and purpose: Insufficient efficacy and adverse effects of classical therapies for inflammatory bowel disease (IBD), such as ulcerative colitis and Crohn's disease, have prompted the search for new, more targeted treatment methods. Janus kinase (JAK) inhibitors are a new group of oral drugs that modulate the proinflammatory cytokine signaling pathway. The aim of this review is to present the state of knowledge on the efficacy and safety of currently registered JAK inhibitors in the treatment of IBD. Review Methods: A systematic search of the PubMed database was conducted, focusing on publications from the last five years as well as selected key earlier studies. The search strategy included relevant keywords related to Janus kinase (JAK) inhibitors and inflammatory bowel disease (IBD). The most pertinent articles aligned with the study objective were reviewed and included. State of knowledge: JAK inhibitors, such as tofacitinib, upadacitinib, and filgotinib, have shown high efficacy in the treatment of moderate to severe UC and CD, especially in patients with insufficient biological therapy response. Clinical studies confirm their efficacy in inducing and maintaining remission and improving endoscopic findings. The most common adverse events are infections (including herpes zoster), and elevation of creatine kinase and lipids. The safety profile remains acceptable, although it requires monitoring, especially at higher doses, and further investigation. Summary: JAK inhibitors are an effective and promising therapeutic option for IBD, offering a rapid onset of action and good symptom control. Despite the favorable clinical effects, an individual approach to treatment and monitoring for adverse effects are necessary, especially with long-term use.

Janus kinase (JAK) inhibitors are promising treatments for atopic dermatitis (AD). The aim of this study was to assess the efficacy and safety of JAK inhibitors for AD treatment via the “Grading of Recommendations Assessment, Development, and Evaluation” approach. We identified 15 randomized controlled trials comparing oral or topical JAK inhibitors against placebo to treat AD. A random-effects meta-analysis was performed, and the numbers-needed-to-treat (NNTs)/numbers-needed-to-harm (NNHs) were calculated. Patients treated with JAK inhibitors were associated with higher rates of achieving eczema area and severity index-75 (rate ratio (RR): 2.84; 95% confidence interval (CI): 2.20–3.67; I2: 38.9%; NNT = 3.97), Investigator’s Global Assessment response (RR: 2.99; 95% CI: 2.26–3.95; I2: 0%; NNT = 5.72), and pruritus numerical rating scale response (RR: 2.52; 95% CI: 1.90–3.35; I2: 39.4%; NNT = 4.91) than those treated with placebo. Moreover, patients treated with JAK inhibitors had a higher risk of treatment-emergent adverse events (RR: 1.14; 95% CI: 1.02–1.28; I2: 52%; NNH = 14.80) but not adverse events leading to drug discontinuation. According to the evidence-based results, JAK inhibitors are potentially effective strategies (certainty of evidence: “moderate”) for treating AD with tolerable side effects (certainty of evidence: “low”). Nevertheless, long-term follow-up is required.