Safety of Janus Kinase inhibitors in Patients with Alopecia Areata: A Systematic Review.

BACKGROUND AND OBJECTIVES: Janus kinase (JAK) inhibitors are emerging as a therapeutic option for alopecia areata. The risk of potential adverse events is currently debated. In particular, several safety data for JAK inhibitors are extrapolated from a single study in elderly patients with rheumatoid arthritis treated with tofacitinib or adalimumab/etanercept as a comparator. The population of patients with alopecia areata is clinically and immunologically different from persons with rheumatoid arthritis and tumor necrosis factor (TNF) inhibitors are not effective in these patients. The objective of this systematic review was to analyze available data on the safety of various JAK inhibitors in patients with alopecia areata. METHODS: The systematic review was performed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A literature review was performed by searching PubMed, Scopus and EBSCO databases with the last search on March 13, 2023. RESULTS: In total, 36 studies were included. The frequency and odds ratio (OR) for most common adverse events versus placebo were: for baricitinib hypercholesterolemia (18.2% vs 10.5%, OR = 1.9) and headache (6.1% vs 5.1%, OR = 1.2), for brepocitinib elevated creatinine level (27.7% vs 4.3%, OR = 8.6) and acne (10.6% vs 4.3%, OR = 2.7), for ritlecitinib acne (10.4% vs 4.3%, OR = 2.6) and headache (12.5% vs 10.6%, OR = 1.2) and for deuruxolitinib headache (21.4% vs 9.1%, OR = 2.7) and acne (13.6% vs 4.5%, OR = 3.3). The respective numbers for upper respiratory infections were: baricitinib (7.3% vs 7.0%, OR = 1.0) and brepocitinib (23.4% vs 10.6%, OR = 2.6); for nasopharyngitis: ritlecitinib (12.5% vs 12.8%, OR = 1.0) and deuruxolitinib (14.6% vs 2.3%, OR = 7.3). CONCLUSIONS: The most common side effects of JAK inhibitors in patients with alopecia areata were headache and acne. The OR for upper respiratory tract infections varied from over 7-fold increased to comparable to placebo. The risk of serious adverse events was not increased.

Investigation on the binding behavior of human α1-acid glycoprotein with Janus Kinase inhibitor baricitinib: Multi-spectroscopic and molecular simulation methodologies.

Baricitinib is a Janus Kinase (JAK) inhibitor that is primarily used to treat moderately to severely active rheumatoid arthritis in adults and has recently been reported for the treatment of patients with severe COVID-19. This paper describes the investigation of the binding behavior of baricitinib to human α1-acid glycoprotein (HAG) employing a variety of spectroscopic techniques, molecular docking and dynamics simulations. Baricitinib can quench the fluorescence from amino acids in HAG through a mix of dynamic and static quenching, according to steady-state fluorescence and UV spectra observations, but it is mainly static quenching at low concentration. The binding constant (Kb) of baricitinib to HAG at 298 K was at the level of 104 M-1, indicating a moderate affinity of baricitinib to HAG. Hydrogen bonding and hydrophobic interactions conducted the main effect, according to thermodynamic characteristics, competition studies between ANS and sucrose, and molecular dynamics simulations. For the change in HAG conformation, the results of multiple spectra showed that baricitinib was able to alter the secondary structure of HAG as well as increase the polarity of the microenvironment around the Trp amino acid. Furthermore, the binding behavior of baricitinib to HAG was investigated by molecular docking and molecular dynamics simulations, which validated experimental results. Also explored is the influence of K+, Co2+, Ni2+, Ca2+, Fe3+, Zn2+, Mg2+ and Cu2+plasma on binding affinity.

JAK inhibitors and COVID-19.

During SARS-CoV-2 infection, the innate immune response can be inhibited or delayed, and the subsequent persistent viral replication can induce emergency signals that may culminate in a cytokine storm contributing to the severe evolution of COVID-19. Cytokines are key regulators of the immune response and virus clearance, and, as such, are linked to the-possibly altered-response to the SARS-CoV-2. They act via a family of more than 40 transmembrane receptors that are coupled to one or several of the 4 Janus kinases (JAKs) coded by the human genome, namely JAK1, JAK2, JAK3, and TYK2. Once activated, JAKs act on pathways for either survival, proliferation, differentiation, immune regulation or, in the case of type I interferons, antiviral and antiproliferative effects. Studies of graft-versus-host and systemic rheumatic diseases indicated that JAK inhibitors (JAKi) exert immunosuppressive effects that are non-redundant with those of corticotherapy. Therefore, they hold the potential to cut-off pathological reactions in COVID-19. Significant clinical experience already exists with several JAKi in COVID-19, such as baricitinib, ruxolitinib, tofacitinib, and nezulcitinib, which were suggested by a meta-analysis (Patoulias et al.) to exert a benefit in terms of risk reduction concerning major outcomes when added to standard of care in patients with COVID-19. Yet, only baricitinib is recommended in first line for severe COVID-19 treatment by the WHO, as it is the only JAKi that has proven efficient to reduce mortality in individual randomized clinical trials (RCT), especially the Adaptive COVID-19 Treatment Trial (ACTT-2) and COV-BARRIER phase 3 trials. As for secondary effects of JAKi treatment, the main caution with baricitinib consists in the induced immunosuppression as long-term side effects should not be an issue in patients treated for COVID-19.We discuss whether a class effect of JAKi may be emerging in COVID-19 treatment, although at the moment the convincing data are for baricitinib only. Given the key role of JAK1 in both type I IFN action and signaling by cytokines involved in pathogenic effects, establishing the precise timing of treatment will be very important in future trials, along with the control of viral replication by associating antiviral molecules.

Integrated safety analysis of baricitinib in adults with severe alopecia areata from two randomized clinical trials.

BACKGROUND: Baricitinib, an oral, selective, reversible Janus kinase (JAK)1/JAK2 inhibitor, is an approved treatment for adults with severe alopecia areata (AA) in the USA, European Union and Japan. OBJECTIVES: To report safety data for baricitinib in patients with severe AA from two clinical trials including long-term extension periods. METHODS: This analysis includes pooled patient-level safety data from two trials, an adaptive phase II/III trial (BRAVE-AA1) and a phase III trial (BRAVE-AA2) (ClinicalTrials.gov, NCT03570749 and NCT03899259). Data are reported in three datasets: (i) the placebo-controlled dataset (up to week 36): baricitinib 2 mg and 4 mg vs. placebo; (ii) the extended dataset (up to the data cutoff): patients remaining on continuous treatment with baricitinib 2 mg or 4 mg from baseline; and (iii) the all-baricitinib dataset (all-BARI, up to the data cutoff): all patients receiving any dose of baricitinib at any time during the trials. Safety outcomes include treatment-emergent adverse events (TEAEs), adverse events of special interest and abnormal laboratory changes. Proportions of patients with events and incidence rates (IR) were calculated. RESULTS: Data were collected for 1303 patients who were given baricitinib, reflecting 1868 patient-years of exposure (median 532 days). The most frequently reported TEAEs during the placebo-controlled period (based on the baricitinib 4-mg group) were upper respiratory tract infection, nasopharyngitis, headache, acne and elevated blood creatine phosphokinase (CPK). During the placebo-controlled period, the frequency of acne was higher with baricitinib than placebo, and elevated CPK was higher with baricitinib 4 mg than placebo and baricitinib 2 mg. In all-BARI, the IR of serious infections was low (n = 16, IR 0.8). There was one opportunistic infection (IR 0.1), and 34 cases of herpes zoster (IR 1.8). There was one positively adjudicated major adverse cardiovascular event (myocardial infarction) (IR 0.1), one pulmonary embolism (IR 0.1), three malignancies other than nonmelanoma skin cancer (IR 0.2) and one gastrointestinal perforation (IR 0.1). No deaths were reported. CONCLUSIONS: This integrated safety analysis in patients with severe AA is consistent with the overall safety profile of baricitinib. Some differences with atopic dermatitis were noted that may be attributable to the disease characteristics of AA.

The third dose of mRNA SARS-CoV-2 vaccines enhances the spike-specific antibody and memory B cell response in myelofibrosis patients.

Vaccination against SARS-CoV-2 using mRNA-based vaccines has been highly recommended for fragile subjects, including myelofibrosis patients (MF). Available data on the immune responsiveness of MF patients to mRNA SARS-CoV-2 vaccination, and the impact of the therapy with the JAK inhibitor ruxolitinib, are still fragmented. Here, we profile the spike-specific IgG and memory B-cell response in MF patients, treated or not with ruxolitinib, after the second and the third dose of SARS-CoV-2 BNT162b2 (BioNTech) and mRNA-1273 (Moderna) vaccines. Plasma and peripheral blood mononuclear cells samples were collected before vaccination, post the second and the third doses and tested for spike-specific antibodies, ACE2/RBD antibody inhibition binding activity and spike-specific B cells. The third vaccine dose significantly increased the spike-specific IgG titers in both ruxolitinib-treated and untreated patients, and strongly enhanced the percentage of subjects with antibodies capable of in vitro blocking ACE2/RBD interaction, from 50% up to 80%. While a very low frequency of spike-specific B cells was measured in blood 7 days after the second vaccination dose, a strong and significant increase was elicited by the third dose administration, generating a B cell response similar to the one detected in healthy controls. Despite the overall positive impact of the third dose in MF patients, two patients that were under active concomitant immunosuppressive treatment at the time of vaccination, and a patient that received lymphodepleting therapies in the past, remained low responders. The third mRNA vaccine dose strongly increases the SARS-CoV-2 specific humoral and B cell responses in MF patients, promoting a reactivation of the immune response similar to the one observed in healthy controls.

Etrasimod as induction and maintenance therapy for ulcerative colitis (ELEVATE): two randomised, double-blind, placebo-controlled, phase 3 studies.

BACKGROUND: Etrasimod, a once-daily, oral, sphingosine 1-phosphate (S1P) receptor modulator that selectively activates S1P receptor subtypes 1, 4, and 5, with no detectable activity on S1P2,3, is in development for the treatment of immune-mediated diseases, including ulcerative colitis. In these two phase 3 trials, we aimed to evaluate the safety and efficacy of etrasimod in adult patients with moderately to severely active ulcerative colitis. METHODS: In two independent randomised, multicentre, double-blind, placebo-controlled, phase 3 trials, ELEVATE UC 52 and ELEVATE UC 12, adults with active moderate-to-severe ulcerative colitis and an inadequate or loss of response or intolerance to at least one approved ulcerative colitis therapy were randomly assigned (2:1) to once-daily oral etrasimod 2 mg or placebo. Patients in ELEVATE UC 52 were enrolled from 315 centres in 40 countries. Patients in ELEVATE UC 12 were enrolled from 407 centres in 37 countries. Randomisation was stratified by previous exposure to biologicals or Janus kinase inhibitor therapy (yes vs no), baseline corticosteroid use (yes vs no), and baseline disease activity (modified Mayo score [MMS]; 4-6 vs 7-9). ELEVATE UC 52 comprised a 12-week induction period followed by a 40-week maintenance period with a treat-through design. ELEVATE UC 12 independently assessed induction at week 12. The primary efficacy endpoints were the proportion of patients with clinical remission at weeks 12 and 52 in ELEVATE UC 52 and week 12 in ELEVATE UC 12. Safety was evaluated in both trials. ELEVATE UC 52 and ELEVATE UC 12 were registered with ClinicalTrials.gov, NCT03945188 and NCT03996369, respectively. FINDINGS: Patients in ELEVATE UC 52 were enrolled between June 13, 2019, and Jan 28, 2021. Patients in ELEVATE UC 12 were enrolled between Sept 15, 2020, and Aug 12, 2021. ELEVATE UC 52 and ELEVATE UC 12 screened 821 patients and 606 patients, respectively, with 433 and 354 subsequently undergoing random assignment. The full analysis set of ELEVATE UC 52 comprised 289 patients assigned to etrasimod and 144 to placebo. In ELEVATE UC 12, 238 patients were assigned to etrasimod and 116 to placebo. In ELEVATE UC 52, a significantly greater proportion of patients in the etrasimod group achieved clinical remission compared with patients in the placebo group at completion of the 12-week induction period (74 [27%] of 274 patients vs ten [7%] of 135 patients; p<0·0001) and at week 52 (88 [32%] of 274 patients vs nine [7%] of 135 patients; p<0·0001). In ELEVATE UC 12, 55 (25%) of 222 patients in the etrasimod group had clinical remission compared with 17 (15%) of 112 patients in the placebo group at the end of the 12-week induction period (p=0·026). Adverse events were reported in 206 (71%) of 289 patients in the etrasimod group and 81 (56%) of 144 patients in the placebo group in ELEVATE UC 52 and 112 (47%) of 238 patients in the etrasimod group and 54 (47%) of 116 patients in the placebo group in ELEVATE UC 12. No deaths or malignancies were reported. INTERPRETATION: Etrasimod was effective and well tolerated as an induction and maintenance therapy in patients with moderately to severely active ulcerative colitis. Etrasimod is a treatment option with a unique combination of attributes that might address the persistent unmet needs of patients with ulcerative colitis. FUNDING: Arena Pharmaceuticals.

Efficacy and Safety of Baricitinib in Patients with Severe Alopecia Areata over 52 Weeks of Continuous Therapy in Two Phase III Trials (BRAVE-AA1 and BRAVE-AA2).

BACKGROUND: The oral Janus kinase (JAK) inhibitor baricitinib has demonstrated efficacy for severe alopecia areata (AA) over 36 weeks. There are limited data on the longer-term treatment of AA. OBJECTIVE: The aim of this study was to evaluate the efficacy and safety of baricitinib for AA in adults with ≥50% scalp hair loss through 52 weeks of continuous therapy in two phase III trials (BRAVE-AA1 and BRAVE-AA2). METHODS: Patients randomized to baricitinib at baseline in BRAVE-AA1 (N = 465) and BRAVE-AA2 (N = 390) retained their treatment allocation through Week 52. Efficacy outcomes included the proportion of patients achieving a Severity of Alopecia Tool (SALT) score ≤ 20 (≤ 20% scalp hair loss). Data were censored after permanent treatment discontinuation or if collected remotely due to the coronavirus disease 2019 (COVID-19) pandemic. RESULTS: Response rates for hair regrowth increased over the 52-week period. Of patients treated with baricitinib 4 mg and 2 mg, respectively, 40.9% and 21.2% in BRAVE-AA1 and 36.8% and 24.4% in BRAVE-AA2 achieved a SALT score ≤ 20 at Week 52. The most frequent treatment-emergent adverse events included upper respiratory tract infection, headache, nasopharyngitis, acne, urinary tract infection, creatine phosphokinase elevation, and COVID-19 infection. LIMITATION: There were no comparisons with placebo. CONCLUSION: Efficacy of baricitinib for adults with severe AA continuously improved over 52 weeks, indicating that long-term treatment may be necessary to observe maximum clinical benefit. There were no new safety signals. CLINICALTRIALS REGISTRATION: ClinicalTrials.gov NCT03570749 and NCT03899259. Efficacy and Safety of Baricitinib in Patients with Severe Alopecia Areata: Week-52 Results from BRAVE-AA1 and BRAVE-AA2.

Alopecia areata (AA) is an autoimmune disease that causes patchy hair loss on the scalp, face, and body. Baricitinib is a Janus kinase inhibitor that is approved to treat AA in several countries, based on results from two studies, BRAVE-AA1 and BRAVE-AA2. In these studies, adults with at least 50% scalp hair loss were treated with baricitinib for 36 weeks. Long-term therapy is important in AA, and hair regrowth can take longer in some patients with severe disease. Therefore, we assessed outcomes from a longer course of therapy. In this study, we report the results after 52 weeks of continuous treatment with baricitinib 4 mg or 2 mg in 465 patients in BRAVE-AA1 and 390 patients BRAVE-AA2. The goal was to reduce scalp hair loss to 20% or less by Week 52. In BRAVE-AA1, 40.9% of patients who took baricitinib 4 mg and 21.2% of patients who took baricitinib 2 mg had 20% or less missing scalp hair by Week 52. Similarly, in BRAVE-AA2, 36.8% of patients who took baricitinib 4 mg and 24.4% of patients who took baricitinib 2 mg had 20% or less missing scalp hair by Week 52. The most common adverse effects that were reported during the study period were upper respiratory tract infection, headache, nasopharyngitis, acne, urinary tract infection, creatine phosphokinase elevation, and coronavirus disease 2019 (COVID-19) infection. The results of longer-term treatment indicate that hair regrowth continues to improve without any new safety concerns for adults with severe AA taking baricitinib.

Omicron-induced interferon signaling prevents influenza A H1N1 and H5N1 virus infection.

Recent findings in permanent cell lines suggested that SARS-CoV-2 Omicron BA.1 induces a stronger interferon response than Delta. Here, we show that BA.1 and BA.5 but not Delta induce an antiviral state in air-liquid interface cultures of primary human bronchial epithelial cells and primary human monocytes. Both Omicron subvariants caused the production of biologically active types I (α/ß) and III (λ) interferons and protected cells from super-infection with influenza A viruses. Notably, abortive Omicron infection of monocytes was sufficient to protect monocytes from influenza A virus infection. Interestingly, while influenza-like illnesses surged during the Delta wave in England, their spread rapidly declined upon the emergence of Omicron. Mechanistically, Omicron-induced interferon signaling was mediated via double-stranded RNA recognition by MDA5, as MDA5 knockout prevented it. The JAK/STAT inhibitor baricitinib inhibited the Omicron-mediated antiviral response, suggesting it is caused by MDA5-mediated interferon production, which activates interferon receptors that then trigger JAK/STAT signaling. In conclusion, our study (1) demonstrates that only Omicron but not Delta induces a substantial interferon response in physiologically relevant models, (2) shows that Omicron infection protects cells from influenza A virus super-infection, and (3) indicates that BA.1 and BA.5 induce comparable antiviral states.

Upadacitinib treatment in patients with moderate to severe atopic dermatitis: A retrospective single-centre Australian review of 14 patients post phase 3 clinical trial.

Recent phase 2b and phase 3 clinical trials support the safety and efficacy of the selective Janus kinase (JAK)-1 inhibitor upadacitinib (UPA) in the treatment of moderate to severe atopic dermatitis (AD). However, to date, there is little experience with UPA therapy for AD in Australia. We report findings from a retrospective study to better understand the therapeutic response and side effects noted in a single-centre Australian cohort.

Clinical Implications of Targeting the JAK-STAT Pathway in Psoriatic Disease: Emphasis on the TYK2 Pathway.

Cytokines in the interleukin (IL)-23/IL-17 axis are central to psoriasis pathogenesis. Janus kinase (JAK) signal transducer and activator of transcription (STAT) regulates intracellular signalling of several cytokines (including IL-12, 23, 22, 6, 17, and interferon (IFN)-γ) in the IL-23/IL-17 axis, and, as a result, has become a therapeutic target for psoriasis treatment. Although several JAK1-3 inhibitors, with varying degrees of selectivity, have been developed for immune-mediated inflammatory diseases, use in psoriasis is limited by a low therapeutic index as anticipated by signals from other disease indications. More selective inhibition of the JAK family is an area of interest. Specifically, selective tyrosine kinase (TYK)2 inhibition suppresses IL-23/IL-17 axis signalling, and at therapeutic doses, has a favorable safety profile compared to therapeutic doses of JAK1-3 inhibitors. Phase III efficacy and safety data for the selective allosteric TYK2-inhibitor, deucravacitinib, in adult patients with moderate-to-severe plaque psoriasis is promising. Furthermore, phase II clinical trials for ropsacitinib (PF-06826647), a selective TYK2 inhibitor, and brepocitinib (PF-06700841), a JAK1/TYK2 inhibitor, have also demonstrated efficacy and an acceptable safety profile in adult patients with moderate-to-severe plaque psoriasis. Other novel TYK2 allosteric inhibitors, NDI-034858 and ESK-001, are currently being investigated in adult patients with plaque psoriasis. This article reviews the details of the JAK-STAT pathway in psoriasis pathophysiology, the rationale for selective targeting of JAKs in the treatment of psoriasis, and provides clinical perspective on clinical trial data for JAK and TYK2 inhibitors.

The infection risks of JAK inhibition.

INTRODUCTION: Janus Kinase inhibitors (JAKi) have shown to be highly effective in the treatment of immune-mediated inflammatory diseases. As with all immunomodulatory therapies, careful assessment of any treatment-associated infection risk is essential to inform clinical decision-making. AREAS COVERED: We summarize current literature on infection rates among the licensed JAKi using published phase II/III trial results, post-licensing and registry data. EXPERT OPINION: licensed JAKi show increased risk of infection across the class compared to placebo, most commonly affecting respiratory and urinary tracts, nasopharynx and skin. This risk is dose-dependent. Risks are similar at licensed JAKi doses to that seen with biologic therapies. The risk is compounded by other risk factors for infection, such as age and steroid co-prescription. Herpes zoster reactivation is more common with JAKi compared to other targeted immune modulation, making screening for varicella exposure and vaccination in appropriate cohorts an advisable strategy. Crucially, these small risk increases must be balanced against the known harms (including infection) of uncontrolled autoimmune disease. JAKi are a safe and potentially transformative treatment when used for appropriately selected patients.

Immunogenicity and risks associated with impaired immune responses following SARS-CoV-2 vaccination and booster in hematologic malignancy patients: an updated meta-analysis.

Patients with hematologic malignancies (HM) have demonstrated impaired immune responses following SARS-CoV-2 vaccination. Factors associated with poor immunogenicity remain largely undetermined. A literature search was conducted using PubMed, EMBASE, Cochrane, and medRxiv databases to identify studies that reported humoral or cellular immune responses (CIR) following complete SARS-CoV-2 vaccination. The primary aim was to estimate the seroconversion rate (SR) following complete SARS-CoV-2 vaccination across various subtypes of HM diseases and treatments. The secondary aims were to determine the rates of development of neutralizing antibodies (NAb) and CIR following complete vaccination and SR following booster doses. A total of 170 studies were included for qualitative and quantitative analysis of primary and secondary outcomes. A meta-analysis of 150 studies including 20,922 HM patients revealed a pooled SR following SARS-CoV-2 vaccination of 67.7% (95% confidence interval [CI], 64.8-70.4%; I2 = 94%). Meta-regression analysis showed that patients with lymphoid malignancies, but not myeloid malignancies, had lower seroconversion rates than those with solid cancers (R2 = 0.52, P < 0.0001). Patients receiving chimeric antigen receptor T-cells (CART), B-cell targeted therapies or JAK inhibitors were associated with poor seroconversion (R2 = 0.39, P < 0.0001). The pooled NAb and CIR rates were 52.8% (95% CI; 45.8-59.7%, I2 = 87%) and 66.6% (95% CI, 57.1-74.9%; I2 = 86%), respectively. Approximately 20.9% (95% CI, 11.4-35.1%, I2 = 90%) of HM patients failed to elicit humoral and cellular immunity. Among non-seroconverted patients after primary vaccination, only 40.5% (95% CI, 33.0-48.4%; I2 = 87%) mounted seroconversion after the booster. In conclusion, HM patients, especially those with lymphoid malignancies and/or receiving CART, B-cell targeted therapies, or JAK inhibitors, showed poor SR after SARS-CoV-2 vaccination. A minority of patients attained seroconversion after booster vaccination. Strategies to improve immune response in these severely immunosuppressed patients are needed.

Janus kinase inhibitors for the treatment of COVID-19.

BACKGROUND: With potential antiviral and anti-inflammatory properties, Janus kinase (JAK) inhibitors represent a potential treatment for symptomatic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. They may modulate the exuberant immune response to SARS-CoV-2 infection. Furthermore, a direct antiviral effect has been described. An understanding of the current evidence regarding the efficacy and safety of JAK inhibitors as a treatment for coronavirus disease 2019 (COVID-19) is required. OBJECTIVES: To assess the effects of systemic JAK inhibitors plus standard of care compared to standard of care alone (plus/minus placebo) on clinical outcomes in individuals (outpatient or in-hospital) with any severity of COVID-19, and to maintain the currency of the evidence using a living systematic review approach. SEARCH METHODS: We searched the Cochrane COVID-19 Study Register (comprising MEDLINE, Embase, ClinicalTrials.gov, World Health Organization (WHO) International Clinical Trials Registry Platform, medRxiv, and Cochrane Central Register of Controlled Trials), Web of Science, WHO COVID-19 Global literature on coronavirus disease, and the US Department of Veterans Affairs Evidence Synthesis Program (VA ESP) Covid-19 Evidence Reviews to identify studies up to February 2022. We monitor newly published randomised controlled trials (RCTs) weekly using the Cochrane COVID-19 Study Register, and have incorporated all new trials from this source until the first week of April 2022. SELECTION CRITERIA: We included RCTs that compared systemic JAK inhibitors plus standard of care to standard of care alone (plus/minus placebo) for the treatment of individuals with COVID-19. We used the WHO definitions of illness severity for COVID-19. DATA COLLECTION AND ANALYSIS: We assessed risk of bias of primary outcomes using Cochrane's Risk of Bias 2 (RoB 2) tool. We used GRADE to rate the certainty of evidence for the following primary outcomes: all-cause mortality (up to day 28), all-cause mortality (up to day 60), improvement in clinical status: alive and without need for in-hospital medical care (up to day 28), worsening of clinical status: new need for invasive mechanical ventilation or death (up to day 28), adverse events (any grade), serious adverse events, secondary infections. MAIN RESULTS: We included six RCTs with 11,145 participants investigating systemic JAK inhibitors plus standard of care compared to standard of care alone (plus/minus placebo). Standard of care followed local protocols and included the application of glucocorticoids (five studies reported their use in a range of 70% to 95% of their participants; one study restricted glucocorticoid use to non-COVID-19 specific indications), antibiotic agents, anticoagulants, and antiviral agents, as well as non-pharmaceutical procedures. At study entry, about 65% of participants required low-flow oxygen, about 23% required high-flow oxygen or non-invasive ventilation, about 8% did not need any respiratory support, and only about 4% were intubated. We also identified 13 ongoing studies, and 9 studies that are completed or terminated and where classification is pending. Individuals with moderate to severe disease Four studies investigated the single agent baricitinib (10,815 participants), one tofacitinib (289 participants), and one ruxolitinib (41 participants). Systemic JAK inhibitors probably decrease all-cause mortality at up to day 28 (95 of 1000 participants in the intervention group versus 131 of 1000 participants in the control group; risk ratio (RR) 0.72, 95% confidence interval (CI) 0.57 to 0.91; 6 studies, 11,145 participants; moderate-certainty evidence), and decrease all-cause mortality at up to day 60 (125 of 1000 participants in the intervention group versus 181 of 1000 participants in the control group; RR 0.69, 95% CI 0.56 to 0.86; 2 studies, 1626 participants; high-certainty evidence). Systemic JAK inhibitors probably make little or no difference in improvement in clinical status (discharged alive or hospitalised, but no longer requiring ongoing medical care) (801 of 1000 participants in the intervention group versus 778 of 1000 participants in the control group; RR 1.03, 95% CI 1.00 to 1.06; 4 studies, 10,802 participants; moderate-certainty evidence). They probably decrease the risk of worsening of clinical status (new need for invasive mechanical ventilation or death at day 28) (154 of 1000 participants in the intervention group versus 172 of 1000 participants in the control group; RR 0.90, 95% CI 0.82 to 0.98; 2 studies, 9417 participants; moderate-certainty evidence). Systemic JAK inhibitors probably make little or no difference in the rate of adverse events (any grade) (427 of 1000 participants in the intervention group versus 441 of 1000 participants in the control group; RR 0.97, 95% CI 0.88 to 1.08; 3 studies, 1885 participants; moderate-certainty evidence), and probably decrease the occurrence of serious adverse events (160 of 1000 participants in the intervention group versus 202 of 1000 participants in the control group; RR 0.79, 95% CI 0.68 to 0.92; 4 studies, 2901 participants; moderate-certainty evidence). JAK inhibitors may make little or no difference to the rate of secondary infection (111 of 1000 participants in the intervention group versus 113 of 1000 participants in the control group; RR 0.98, 95% CI 0.89 to 1.09; 4 studies, 10,041 participants; low-certainty evidence). Subgroup analysis by severity of COVID-19 disease or type of JAK inhibitor did not identify specific subgroups which benefit more or less from systemic JAK inhibitors. Individuals with asymptomatic or mild disease We did not identify any trial for this population. AUTHORS' CONCLUSIONS: In hospitalised individuals with moderate to severe COVID-19, moderate-certainty evidence shows that systemic JAK inhibitors probably decrease all-cause mortality. Baricitinib was the most often evaluated JAK inhibitor. Moderate-certainty evidence suggests that they probably make little or no difference in improvement in clinical status. Moderate-certainty evidence indicates that systemic JAK inhibitors probably decrease the risk of worsening of clinical status and make little or no difference in the rate of adverse events of any grade, whilst they probably decrease the occurrence of serious adverse events. Based on low-certainty evidence, JAK inhibitors may make little or no difference in the rate of secondary infection. Subgroup analysis by severity of COVID-19 or type of agent failed to identify specific subgroups which benefit more or less from systemic JAK inhibitors. Currently, there is no evidence on the efficacy and safety of systemic JAK inhibitors for individuals with asymptomatic or mild disease (non-hospitalised individuals).

JAK: Not Just Another Kinase.

The JAK/STAT axis is implicated in cancer, inflammation, and immunity. Numerous cytokines/growth factors affect JAK/STAT signaling. JAKs (JAK1, JAK2, JAK3, and TYK2) noncovalently associate with cytokine receptors, mediate receptor tyrosine phosphorylation, and recruit ≥1 STAT proteins (STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b, and STAT6). Tyrosine-phosphorylated STATs dimerize and are then transported into the nucleus to function as transcription factors. Signaling is attenuated by specific suppressor of cytokine signaling proteins, creating a negative feedback loop. Both germline mutations and polymorphisms of JAK family members correlate with specific diseases: Systemic lupus erythematosus (TYK2 polymorphisms); severe combined immunodeficiency (JAK3 mutations); pediatric acute lymphoblastic leukemia (TYK2 mutations); and hereditary thrombocytosis (JAK2 mutations). Somatic gain-of-function JAK mutations mainly occur in hematologic malignancies, with the activating JAK2 V617F being a myeloproliferative disorder hallmark; it is also seen in clonal hematopoiesis of indeterminate potential. Several T-cell malignancies, as well as B-cell acute lymphoblastic leukemia, and acute megakaryoblastic leukemia also harbor JAK family somatic alterations. On the other hand, JAK2 copy-number loss is associated with immune checkpoint inhibitor resistance. JAK inhibitors (jakinibs) have been deployed in many conditions with JAK activation; they are approved in myeloproliferative disorders, rheumatoid and psoriatic arthritis, atopic dermatitis, ulcerative colitis, graft-versus-host disease, alopecia areata, ankylosing spondylitis, and in patients hospitalized for COVID-19. Clinical trials are investigating jakinibs in multiple other autoimmune/inflammatory conditions. Furthermore, dermatologic and neurologic improvements have been observed in children with Aicardi-Goutieres syndrome (a genetic interferonopathy) treated with JAK inhibitors.

JAK-STAT signaling as an ARDS therapeutic target: Status and future trends.

Acute respiratory distress syndrome (ARDS) is characterized by noncardiogenic pulmonary edema. It has a high mortality rate and lacks effective pharmacotherapy. With the outbreak of COVID-19 worldwide, the mortality of ARDS has increased correspondingly, which makes it urgent to find effective targets and strategies for the treatment of ARDS. Recent clinical trials of Janus kinase (JAK) inhibitors in treating COVID-19-induced ARDS have shown a positive outcome, which makes the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway a potential therapeutic target for treating ARDS. Here, we review the complex cause of ARDS, the molecular JAK/STAT pathway involved in ARDS pathology, and the progress that has been made in strategies targeting JAK/STAT to treat ARDS. Specifically, JAK/STAT signaling directly participates in the progression of ARDS or colludes with other pathways to aggravate ARDS. We summarize JAK and STAT inhibitors with ARDS treatment benefits, including inhibitors in clinical trials and preclinical studies and natural products, and discuss the side effects of the current JAK inhibitors to reveal future trends in the design of JAK inhibitors, which will help to develop effective treatment strategies for ARDS in the future.

[Janus kinase inhibitors in immunoinflammatory rheumatic diseases].

Despite great advances in the diagnosis and treatment of immunoinflammatory rheumatic diseases, which have led to a significant improvement in the prognosis in many patients, the fundamental medical problems of this pathology the restoration of the quality of life and the reduction of mortality to the population level are far from being resolved. This served as a stimulus for the study of new approaches to the pharmacotherapy of IVRD, one of which is associated with the use of low molecular weight chemically synthesized drugs that inhibit intracellular "signaling" molecules Janus kinase. Modern advances regarding the use of Janus kinase inhibitors in the treatment of immunoinflammatory rheumatic diseases and COVID -19 are considered.