Selective JAK1 Inhibitor Research Articles

The effect of food on the pharmacokinetics of WXFL10203614, a potential selective JAK1 inhibitor, in healthy Chinese subjects.

Objective: This study was performed to investigate the effect of food on the pharmacokinetics (PK) of WXFL10203614 in healthy Chinese subjects. Methods: This was a randomized, open-label, single-dose, two-treatment (fed vs fasted), two-period, two-sequence, crossover study. 14 eligible subjects were averagely randomized into 2 sequences and then received 10mg WXFL10203614 under fasted or fed condition. In each period, the blood samples were collected from 0h (pre-dose) and serially up to 72h post-dose, and plasma concentrations were detected using the high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method. The effect of food on the PK profile and safety of WXFL10203614 were assessed. Results: 70 subjects were screened, and 14 subjects (10 male and 4 female) were enrolled and completed the study. Under the fasted condition, WXFL10203614 was absorbed rapidly with a Tmax of 0.98h. The absorption rate was slower, Tmax delayed by 2.98h, and the Cmax decreased by 16.3% when WXFL10203614 administered after the high-fat and high-calorie diet, other PK parameters were not affected. The 90% confidence intervals (CIs) for the ratio (fed/fasted) of geometric means of the Cmax, AUC0-t and AUC0-∞ were 0.73-1.01, 0.90-1.03 and 0.90-1.03, indicating that the high-fat and high-calorie diet might impact the absorption process of WXFL10203614. Although the Cmax was slightly decreased, there was no significant difference in the Cmax under fasted and fed conditions. Thus, it was not considered clinically significant owing to the small magnitude of changes in Cmax. All Treatment-emergent adverse events (TEAEs) were mild and resolved spontaneously without treatment. Conclusion: Food had no clinically relevant effects on drug system exposure of WXFL10203614. It was well tolerated under fasted and fed conditions in healthy Chinese subjects, so WXFL10203614 could be administered orally with or without food. Clinical Trial Registration: http://www.chinadrugtrials.org.cn/index.html, identifier CTR20191636.

The Effect of Upadacitinib on Lipid Profile and Cardiovascular Events: A Meta-Analysis of Randomized Controlled Trials

Our aim was to systematically investigate the effect of upadacitinib, an oral JAK-1 selective inhibitor, on lipid profile and cardiovascular disease risk. PubMed, PubMed Central and ClinicalTrials.gov databases were searched for relevant randomized controlled trials (RCTs) up to 31 July 2022. We performed a qualitative synthesis of published RCTs to investigate the associations of upadacitinib with lipoprotein changes, along with a quantitative synthesis of MACE and mean lipoprotein changes where there were available data. Nineteen RCTs were eligible for the present systematic review, which included 10,656 patients with a mean age of 51 years and a follow-up period of 12-52 weeks. Increases in low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) were noted upon upadacitinib administration (3-48 mg/day) in 15 studies, while the LDL-C:HDL-C ratio remained unchanged. The pooled analyses of three placebo-controlled RCTs (n = 2577) demonstrated that upadacitinib at 15 mg increased the LDL-C by 15.18 mg/dL (95% CI: 7.77-22.59) and HDL-C by 7.89 mg/dL (95% CI: 7.08-8.69). According to the pooled analysis of 15 placebo-controlled RCTs (n = 7695), upadacitinib had no effect on MACE (risk ratio, RR: 0.62; 95% CI: 0.24-1.60). A sub-analysis focusing on upadacitinib at 15 mg (12 studies, n = 5395) demonstrated similar results (RR: 0.67; 95% CI: 0.19-2.36). Treatment with upadacitinib increases both LDL-C and HDL-C levels. Nevertheless, upadacitinib had no significant effect on the cardiovascular disease risk during a ≤52-week follow-up.

Immunomodulators in Mechanically Ventilated Patients With COVID-19: Lessons Learned From Underpowered Trials.

Immunomodulators in Mechanically Ventilated Patients With COVID-19: Lessons Learned From Underpowered Trials.

Phase I Study of SHR0302, a Selective JAK1 Inhibitor, Combined with Prednisone for First-Line Treatment of Chronic Graft-Versus-Host Disease after Allo-HSCT

Background: Chronic graft-versus-host-disease (cGVHD) is a life-threatening complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT) that affects various organs leading to a reduced quality of life, with an incidence of 40% to 70%. The standard first-line therapy for cGVHD is prednisone ± a calcineurin inhibitor, but most patients respond inadequately and prolonged corticosteroid use could cause a variety of side effects. SHR0302 is a Janus kinase (JAK) 1 selective inhibitor which has demonstrated efficacy in preclinical models of GVHD. Herein, we reported the safety and efficacy of SHR0302 plus prednisone as first-line treatment for newly diagnosed cGVHD after allo-SCT. Methods: This was a phase I open-label study. Patients who were aged 18-70, and confirmedly diagnosed with first-episode moderate/severe cGVHD requiring systemic immunosuppressive therapy after allo-HSCT were included in the study. cGVHD was defined according to national institutes of health (NIH) criteria. Patients received SHR0302 plus prednisone daily. For each patient, prednisone was administered at an initial dose of 1 mg/kg/d for two weeks, then tapered according to the response of the patient. A 3 + 3 design was implemented for dose finding of SHR0302 at doses of 1mg/d, 2mg/d, 4mg/d, 6mg/d, and 8mg/d. The primary endpoints were safety and tolerability of the combination therapy of SHR0302 and prednisone assessed by NCI-CTCAE v5.0. And the secondary endpoints included the overall response rate (ORR) at week 4 of treatment and the recommended Phase II dose (RP2D). Dose-limiting toxicities (DLTs) were defined as grade 4 hematologic toxicity or grade 3 non-hematologic toxicity associated with SHR0302 which occurred in the first 28 days of study treatment. Results: As of July 30, 2022, 18 patients were enrolled in the study with 3 patients each in the dose level 1-4, and 6 patients in the dose level 5, with a median follow-up of 27 (4-91) weeks. The median age of the patients was 47 (31-64) years, of which 5 patients (27.8%) had moderate cGVHD, and 13 patients (72.2%) had severe cGVHD. The median cGVHD NIH score was 4 (3-7). The primarily affected organs were skin (61.1%) followed by liver (55.6%), and mouth (50.0%). As of data cutoff, only one patient (5.6%) discontinued therapy due to inadequate response. No DLTs were seen in the first 4 dose levels. Only one DLT, grade ≥3 hypercholesterolemia, was observed among 6 patients who received 8mg/d of SHR0302. The patient who experienced DLT had preexisting hypercholesterolemia. A maximum tolerated dose was not reached. 17 patients (94.4%) experienced adverse events (AEs) related to SHR0302, and 4 patients (22.2%) experienced grade ≥3 AEs related to SHR0302. Hypercholesterolemia (61.1%), hypertriglyceridemia (44.4%), and platelet count decreased (33.3%) were the most common SHR0302 treatment-related AEs. No SHR0302 treatment-related serious adverse events were reported. The ORR at week 4 after the first SHR0302 administration was 94.4%, including 4 patients (22.2%) achieving complete response, and 13 patients (72.2%) achieving partial response. Among 18 evaluable patients, only 1 patient treated at dose level 1 showed no response at week 4. Conclusions: In summary, SHR0302 plus prednisone demonstrated encouraging efficacy with manageable toxicity in patients with steroid-naive cGVHD. Based on the results from the dose-escalation, 6-mg and 8-mg dose were selected for the dose-expansion.

SYK Kinase As a Master Regulator of Netosis

Background NETosis is a key neutrophil response to tissue damage and pathogens. It is a form of programmed cell death resulting in chromatin decondensation, histone citrullination and controlled extracellular release of chromosomal DNA. This DNA complexed to a variety of noxious proteins such as elastase, myeloperoxidase and citrullinated histones is called neutrophil extracellular traps (NETs). NETs are largely responsible for anti-viral and anti-microbial effects of neutrophils during infection. NETs can cause significant tissue damage in various pathological conditions such as severe infections (COVID-19 and others) and multiple autoimmune and autoinflammatory diseases characterized by hyperactivation of innate and adaptive immune systems. Together with concurrent platelet and coagulation cascade activation, NETs formation is known to drive coagulopathy and thrombosis often associated with sterile inflammation in autoimmune and autoinflammatory diseases and in severe COVID-19 (Y. Zhou et al.). Strong correlation between NETosis biomarkers and thrombosis has been established in patients with many thrombogenic diseases (Mołek et al.; Martos et al.). Inhibition of NETs using DNAse treatment, protein arginine deiminase 4 (PAD4) inhibitors, or PAD4 knockout results in decrease in thrombi formation in vitro and in vivo (Franck et al.; Martinod et al.; Yan et al.). NETs release induced by plasma from severe COVID-19 patients in normal human neutrophils can be blocked in the presence of the highly selective SYK inhibitor R406, an active metabolite of the immune thrombocytopenia drug fostamatinib (Strich et al.). The inhibitor is thought to block antibody- and viral particle-mediated neutrophil activation through FcgRIIA and C-type lectin receptors (CLRs) controlled by SYK. Methods/Results To further elucidate the role of SYK kinase in NETosis, we have analyzed healthy human neutrophil responses to various stimuli in the presence of multiple commercially available SYK inhibitors using the Incucyte Live-Cell Analysis System. As expected, R406 potently inhibited immune complex induced NETosis mediated by FcgRIIA. To our surprise, every SYK inhibitor we've tested selectively blocked seemingly unrelated LPS-mediated TLR4-dependent NETs release. The effect was clearly specific as SYK inhibition had no effect on SYK-independent LPS-induced cytokine secretion or on cell proliferation at concentrations far exceeding those fully blocking NETosis. In contrast to SYK inhibitors, neither a selective JAK inhibitor nor dexamethasone had a significant effect on NETs release under the same assay conditions. Moreover, R406 potently inhibited NETs production in response to hydrogen peroxide and monosodium urate (MSU) crystal treatment of healthy neutrophils. The mechanisms behind the ability of SYK inhibitors to block NETs formation in response to such a plethora of unrelated stimuli will be further discussed. Conclusions The ability of SYK inhibitors to block both NETosis and platelet activation (in case of platelets, via CLEC2 and GPVI - two receptors involved in thrombosis yet dispensable for hemostasis) is consistent with possibility that, in addition to anti-inflammatory properties, SYK inhibition has potential anti-thrombotic effects (Harbi et al.). Indeed, the latter might be behind the lower than expected rates of thrombotic events in ITP patients observed in clinical trials of fostamatinib (Cooper et al.). References Yilu Zhou et al. Front Cardiovasc Med. 2021 Dec 2;8:786387. Laura Martos et al. Int J Mol Sci. 2020 Aug 6;21(16):5651. Patrycja Mołek et al. Thromb Res. 2022 May;213:1-7. Grégory Franck et al. Circ Res. 2018 June 22;123(1): 33-42. Kimberly Martinod et al. Proc Natl Acad Sci U S A. 2013 May 21;110(21):8674-8679. Yanyan Yan et al. Aging (Albany NY). 2019 Sep 15;11(17):6951-6959. Jeffrey R Strich et al. J Infect Dis. 2021 Mar 15;223(6):981-984. Maan H. Harbi et al. Int J Mol Sci. 2022 Jul;23(13):6982. Nichola Cooper et al. Ther Adv Hematol. 2021 Apr 30;12:20406207211010875

Efficacy of WWQ-131, a highly selective JAK2 inhibitor, in mouse models of myeloproliferative neoplasms

Hyperactivation of the Janus kinase 2 (JAK2) signaling pathway leads to myeloproliferative neoplasms (MPNs) and targeting JAK2 can be used as an effective strategy for the treatment of MPNs. Here, our study indicated that WWQ-131 was a highly selective JAK2 inhibitor (IC50 =2.36 nM), with 182-fold and 171-fold more selective to JAK1 and JAK3, respectively. In JAK2V617F-dependent cell lines, WWQ-131 efficaciously inhibited cell proliferation, induced cell cycle arrest at the G2/M phase and apoptosis, and blocked the aberrant activation of JAK2 signaling pathway. In a mouse Ba/F3_JAK2V617F driven disease model, WWQ-131 effectively suppressed STAT5 phosphorylation in spleen and liver, and inhibited Ba/F3_JAK2V617F cells spreading and proliferation in vivo. In addition, WWQ-131 suppressed rhEPO-induced extramedullary erythropoiesis and polycythemia in mice, as well as hematocrits and spleen sizes, especially had no effect on white blood cell count. Furthermore, WWQ-131 (75 mg/kg) exhibited stronger therapeutic effects than fedratinib (120 mg/kg) in these two MPN models. Taken together, this study suggests that WWQ-131 will be a promising candidate for the treatment of MPNs.

Effectiveness and tolerance of Janus kinase inhibitors for the treatment of recalcitrant atopic dermatitis in a real-life French multicenter adult cohort

Effectiveness and tolerance of Janus kinase inhibitors for the treatment of recalcitrant atopic dermatitis in a real-life French multicenter adult cohort

Inflammatory Bowel Disease and Pregnancy

Inflammatory Bowel Disease and Pregnancy

Management of Axial Spondyloarthritis - Insights into Upadacitinib.

Although the pathogenesis of spondyloarthritis (SpA) has still not been elucidated our options to treat SpA have definitely improved in the last decades. There are two main types of SpA: (i) axial spondyloarthritis (axSpA), also covering the classical ankylosing spondylitis (AS) which is largely equivalent to radiographic (r)-axSpA but different from non-radiographic (nr)-axSpA, and (ii) peripheral SpA (pSpA) also covering psoriatic arthritis (PsA) as the main subtype. The subtype nr-axSpA has historically developed because the approval of drugs for AS did not cover forms without structural changes in the sacroiliac joints which is mandatory in the 1984 New York criteria. The definitions for axSpA are based on the 2009 Assessments in AxSpA International Society (ASAS) classification criteria. Several biologic disease modifying anti-rheumatic drugs (bDMARDs) such as the tumor necrosis factor alpha inhibitors (TNFi) and the interleukin-17-inhibitors (IL-17i) are approved mostly for the whole spectrum of SpA including axSpA and PsA but L-17i does not work in inflammatory bowel disease (IBD). Targeted synthetic (ts) DMARDs cover mainly the janus kinase (JAK)-inhibitors which have recently been developed to inhibit inflammation in several rheumatic and other immune mediated diseases such as IBD. Indeed, the physiologic mechanism of JAK-mediated signal transduction has been recognized as an important target because the inhibition of its actions was shown to successfully work as a therapeutic mechanism. There are now 4 small molecule JAK inhibitors (JAKi) that currently play a role in rheumatology with variable selectivity for the four different JAK isoforms: tofacitinib, baricitinib, upadacitinib and filgotinib. In this review, we summarize current clinical trial data and evaluate the use of the JAK1 selective inhibitor upadacitinib in the treatment of axSpA, including nr-axSpA and r-axSpA. Even though the efficacy and safety of upadacitinib over shorter periods of time has been convincing to date, long-term trials are needed to fully establish its performance and also evaluate the safety at higher doses, and its use in PsA.

S2254 Use of Upadacitinib in Refractory Esophageal Lichen Planus: Endoscopic Improvement in "Planus" Sight

Introduction: Lichen planus (LP) is an inflammatory skin condition that affects oropharyngeal and esophageal mucosa. Esophageal LP (ELP) has a prevalence of 0.19% but is thought to be underdiagnosed. It presents with ulceration, exudates, rings and/or strictures. Although pathogenesis of LP is incompletely understood, the JAK signaling pathway is thought to play a role. Upadacitinib is a selective JAK1 inhibitor approved for use in ulcerative colitis. We present a case of refractory ELP with endoscopic and histologic response to upadacitinib after failing standard treatment. Case Description/Methods: A 68-year-old female with history of Sjogren’s syndrome, LP, and prior peptic stricture at the gastroesophageal junction presented with dysphagia to both liquids and solids, intermittent reflux, regurgitation, and self-limited impactions. An EGD showed esophageal stenosis, severe esophagitis, and mucosal ulceration (Figure A). Passage of the scope resulted in dilation; however, formal dilation of stenosis was not performed due to severity of esophagitis. Esophageal biopsies revealed squamous mucosa with parakeratosis, dyskeratotic cells and scattered lymphocytes consistent with ELP. Subsequently, the patient recalled having a remote history of oral lichen planus. She was started on pantoprazole 40 mg twice daily and budesonide oral slurry with limited response. With co-management by gastroenterology and dermatology, she was initiated on mycophenolate 500 mg daily and increased to 2000 mg twice a day. She continued to lack both histologic and symptomatic improvement remaining limited to a soft and liquid diet resulting in a 20lb weight loss. She was started on monotherapy with upadacitinib 30 mg twice daily. This resulted in marked symptomatic recovery with repeat endoscopy 3 months later showing dramatic macroscopic and histologic improvement (Figure B), with only some residual fibrostenotic disease remaining (Figure C). Discussion: Multimodal treatment is typically employed in ELP with medical therapy and endoscopic dilation. Systemic or topical steroids are first line, with efficacy estimated at 60-70%. Other therapies include tacrolimus, cyclosporine, mycophenolate, rituximab, adalimumab, and tofacitinib, however data for these therapies are limited. To date, there are only 2 cases reported in the literature of successful treatment of oro-esophageal LP with upadacitinib. Given profound improvement seen in our patient, upadacitinib may offer another alternative for these difficult-to-treat patients.Figure 1.: 1a. ELP on initial diagnostic endoscopy before initiation of therapy. 1b. Follow up endoscopy performed after 12 weeks of upadacitinib treatment. 1c. Lichenoid esophagitis: lymphocytic infiltrates, focal histiocytic aggregate (blue arrow) and dyskeratosis (Civatte body, red arrow).

P36 Crohn’s-associated inflammatory arthritis treated successfully with upadacitinib

Introduction/BackgroundEnteropathic arthritis is inflammatory arthritis which is associated with inflammatory bowel disease such as Crohn’s disease and ulcerative colitis. The optimal treatment for patients is one which is effective for both arthritis and bowel disease. First line treatments include DMARDs such as methotrexate and sulfasalazine. Second line options include anti-TNF biologics such as infliximab and adalimumab, and the anti-IL-12/23 biologic ustekinumab. There is currently little guidance on choice of treatment if these options fail. We present a case of Crohn’s-associated inflammatory arthritis which did not respond to two anti-TNFs but was successfully treated with the JAK inhibitor upadacinitib.Description/MethodA 30-year-old male was referred to gastroenterology with a 4 month history of diarrhoea and weight loss. His faecal calprotectin was raised at 982µg/g. He had a history of seronegative inflammatory arthritis diagnosed 5 years previously. He had been treated initially with methotrexate and sulfasalazine, which were discontinued due to side effects and inefficacy, and his arthritis was subsequently well-controlled on etanercept for the last year.Colonoscopy showed patchy colitis at the rectum which was continuous in the transverse and ascending colon and caecum. The appearances and mucosal biopsy were consistent with moderately active Crohn’s colitis. In view of this, etanercept was switched to adalimumab, which was administered using the accelerated loading regimen used in IBD.Five weeks after switching the patient developed a flare of arthritis with knee and ankle inflammation and CRP 30. He was given oral steroids and reviewed in a combined rheumatology/gastroenterology clinic. The frequency of adalimumab was increased to 40mg weekly and subcutaneous methotrexate 10mg weekly was introduced.Despite this, the patient’s arthritis remained active, although with some improvement in his bowel symptoms and a fall in faecal calprotectin to 117µg/g. Adalimumab was switched to certolizumab and methotrexate increased to 15mg weekly with intra-muscular steroids. On certolizumab he developed progressively more active arthritis with CRP 83, bilateral ankle inflammation and large knee effusions requiring aspiration and steroid injection.After 8 weeks of certolizumab, there was no improvement and the decision was made to switch to upadacitinib 15mg daily. Within 4 weeks of treatment with upadacitinib he noticed a significant improvement in his arthritis and after 12 weeks was in clinical remission with normal CRP and faecal calprotectin. Methotrexate was later discontinued due to nausea. Over 12 months later the patient remains in remission for both bowel disease and arthritis on upadacitinib monotherapy.Discussion/ResultsIn enteropathic arthritis, joint symptoms may precede or follow bowel disease. Etanercept, a recombinant TNF-receptor fusion protein, is not an effective treatment for IBD. Indeed, there are case reports and observational data to suggest that etanercept may be associated with an increased risk of developing IBD in some patients. In our case the patient developed Crohn’s disease while taking etanercept and the switch to adalimumab precipitated a flare of his arthritis which was not controlled by treatment intensification. The failure of two anti-TNF biologics, adalimumab and certolizumab, may point to the activation of alternative cytokine inflammatory pathways as the driver of the patient’s disease.Our patient was managed in a combined rheumatology/gastroenterology clinic which enabled an inter-specialty approach to managing both aspects of his disease. After the failure of certolizumub we made the decision to trial upadacitinib, a selective JAK1 inhibitor, owing to our experience of its effectiveness in rheumatoid and psoriatic arthritis, and its promising results in Phase 3 trials in Crohn’s disease. We considered ustekinumab but opted against it as in our experience it may be suboptimal in patients in whom arthritis is the most troublesome symptom. Upadacitinib worked quickly and effectively to control our patient’s arthritis alongside his bowel disease and was well tolerated.There are currently limited treatments which are effective for both IBD and arthritis, and there is little guidance on treatment strategies in enteropathic arthritis if anti-TNF and ustekinumab are unsuccessful. Tofacitinib, a JAK1/3 inhibitor, is licensed for rheumatoid and psoriatic arthritis and ulcerative colitis, but is not effective for Crohn’s disease. Upadacitinib is undergoing Phase 3 trials in Crohn’s disease and our case highlights its potential role in the treatment of patients with Crohn’s disease and inflammatory arthritis in whom anti-TNF therapy is unsuccessful.Key learning points/Conclusion1. Etanercept is not an effective treatment for inflammatory bowel disease and may necessitate a change to another anti-TNF biologic such as infliximab or adalimumab.2. Upadacitinib, a selective JAK1 inhibitor, was successfully used in our case to treat both arthritis and bowel disease. Although this was just one case, the results of Phase 3 trials suggest a promising role for upadacitinib in Crohn’s disease and it is already used in the treatment of rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis.3. Patients with enteropathic arthritis may be best managed in a specialist combined gastroenterology and rheumatology clinic where a holistic approach to the management of both aspects of their disease can be undertaken.

Effective treatment of low-risk acute GVHD with itacitinib monotherapy

AbstractThe standard primary treatment for acute graft-versus-host disease (GVHD) requires prolonged, high-dose systemic corticosteroids (SCSs) that delay reconstitution of the immune system. We used validated clinical and biomarker staging criteria to identify a group of patients with low-risk (LR) GVHD that is very likely to respond to SCS. We hypothesized that itacitinib, a selective JAK1 inhibitor, would effectively treat LR GVHD without SCS. We treated 70 patients with LR GVHD in a multicenter, phase 2 trial (NCT03846479) with 28 days of itacitinib 200 mg/d (responders could receive a second 28-day cycle), and we compared their outcomes to those of 140 contemporaneous, matched control patients treated with SCSs. More patients responded to itacitinib within 7 days (81% vs 66%, P = .02), and response rates at day 28 were very high for both groups (89% vs 86%, P = .67), with few symptomatic flares (11% vs 12%, P = .88). Fewer itacitinib-treated patients developed a serious infection within 90 days (27% vs 42%, P = .04) due to fewer viral and fungal infections. Grade ≥3 cytopenias were similar between groups except for less severe leukopenia with itacitinib (16% vs 31%, P = .02). No other grade ≥3 adverse events occurred in >10% of itacitinib-treated patients. There were no significant differences between groups at 1 year for nonrelapse mortality (4% vs 11%, P = .21), relapse (18% vs 21%, P = .64), chronic GVHD (28% vs 33%, P = .33), or survival (88% vs 80%, P = .11). Itacitinib monotherapy seems to be a safe and effective alternative to SCS treatment for LR GVHD and deserves further investigation.

Partial human Janus kinase 1 deficiency predominantly impairs responses to interferon gamma and intracellular control of mycobacteria.

PurposeJanus kinase-1 (JAK1) tyrosine kinase mediates signaling from multiple cytokine receptors, including interferon alpha/beta and gamma (IFN-α/β and IFN-γ), which are important for viral and mycobacterial protection respectively. We previously reported autosomal recessive (AR) hypomorphic JAK1 mutations in a patient with recurrent atypical mycobacterial infections and relatively minor viral infections. This study tests the impact of partial JAK1 deficiency on cellular responses to IFNs and pathogen control.MethodsWe investigated the role of partial JAK1 deficiency using patient cells and cell models generated with lentiviral vectors expressing shRNA.ResultsPartial JAK1 deficiency impairs IFN-γ-dependent responses in multiple cell types including THP-1 macrophages, Epstein-Barr Virus (EBV)-transformed B cells and primary dermal fibroblasts. In THP-1 myeloid cells, partial JAK1 deficiency reduced phagosome acidification and apoptosis and resulted in defective control of mycobacterial infection with enhanced intracellular survival. Although both EBV-B cells and primary dermal fibroblasts with partial JAK1 deficiency demonstrate reduced IFN-α responses, control of viral infection was impaired only in patient EBV-B cells and surprisingly intact in patient primary dermal fibroblasts.ConclusionOur data suggests that partial JAK1 deficiency predominantly affects susceptibility to mycobacterial infection through impact on the IFN-γ responsive pathway in myeloid cells. Susceptibility to viral infections as a result of reduced IFN-α responses is variable depending on cell type. Description of additional patients with inherited JAK1 deficiency will further clarify the spectrum of bacterial and viral susceptibility in this condition. Our results have broader relevance for anticipating infectious complications from the increasing use of selective JAK1 inhibitors.

IRF7 expression correlates with HIV latency reversal upon specific blockade of immune activation.

The persistence of latent HIV reservoirs allows for viral rebound upon antiretroviral therapy interruption, hindering effective HIV-1 cure. Emerging evidence suggests that modulation of innate immune stimulation could impact viral latency and contribute to the clearing of HIV reservoir. Here, the latency reactivation capacity of a subclass of selective JAK2 inhibitors was characterized as a potential novel therapeutic strategy for HIV-1 cure. Notably, JAK2 inhibitors reversed HIV-1 latency in non-clonal lymphoid and myeloid in vitro models of HIV-1 latency and also ex vivo in CD4+ T cells from ART+ PWH, albeit its function was not dependent on JAK2 expression. Immunophenotypic characterization and whole transcriptomic profiling supported reactivation data, showing common gene expression signatures between latency reactivating agents (LRA; JAK2i fedratinib and PMA) in contrast to other JAK inhibitors, but with significantly fewer affected gene sets in the pathway analysis. In depth evaluation of differentially expressed genes, identified a significant upregulation of IRF7 expression despite the blockade of the JAK-STAT pathway and downregulation of proinflammatory cytokines and chemokines. Moreover, IRF7 expression levels positively correlated with HIV latency reactivation capacity of JAK2 inhibitors and also other common LRAs. Collectively, these results represent a promising step towards HIV eradication by demonstrating the potential of innate immune modulation for reducing the viral reservoir through a novel pathway driven by IRF7.

A highly selective JAK3 inhibitor is developed for treating rheumatoid arthritis by suppressing γc cytokine-related JAK-STAT signal.

Janus kinases (JAKs) play a critical role in immune responses by relaying signals from more than 50 cytokines, making them attractive therapeutic targets for autoimmune diseases. Although approved JAK inhibitors have demonstrated clinical efficacy, they target a broad spectrum of cytokines, which results in side effects. Therefore, next-generation inhibitors maintain efficacy, while sparing adverse events need to be developed. Among members of the JAK family, JAK3 only regulates a narrow spectrum of γc cytokines and becomes a potentially ideal target. Here, a highly JAK3-selective inhibitor Z583 is developed, which showed a potent inhibition of JAK3 with an IC50 of 0.1 nM and exhibited a 4500-fold selectivity for JAK3 than other JAK subtypes. Furthermore, Z583 completely inhibited the γc cytokine signaling and sufficiently blocked the development of inflammatory response in RA model, while sparing hematopoiesis. Collectively, the highly selective JAK3 inhibitor Z583 is a promising candidate with significant therapeutic potential for autoimmune diseases.

Efficacy and Safety of Ivarmacitinib in Patients With Moderate-to-Severe, Active, Ulcerative Colitis: A Phase II Study

Current therapies for ulcerative colitis (UC) fail to achieve satisfactory disease control. Selective inhibition of Janus kinase (JAK) type 1 may improve clinical outcomes in patients with UC while avoiding the side effects associated with pan-JAK inhibition. The safety and efficacy of the selective JAK1 inhibitor ivarmacitinib (formerly SHR0302) were evaluated in patients with moderate-to-severe, active UC. AMBER2 was a double-blind, placebo-controlled, phase II trial conducted at 63 clinical centers in China, the United States, and Europe. Patients (N= 164) were randomized 1:1:1:1 to receive oral ivarmacitinib 8 mg once daily (QD), 4 mg twice daily (BID), or 4 mg QD, or placebo for 8 weeks, followed by an 8-week extension period. The primary endpoint was clinical response rate at week 8. Hochberg's procedure was used to control the study-wise type 1 error at alpha=0.1. A total of 146 (89.0%) patients completed 8 weeks of treatment. Week 8 clinical response rates were significantly higher in the 8 mg QD (46.3%; P= .066), 4 mg BID (46.3%; P= .059), and 4 mg QD (43.9%; P= .095) groups vs placebo (26.8%). Week 8 rates of clinical remission were 22.0% (P= .020), 24.4% (P= .013), and 24.4% (P= .011) in the 3 ivarmacitinib treatment groups, respectively, vs 4.9% for placebo. During the initial 8-week period, treatment-emergent adverse events occurred in 43.9% to 48.8% of ivarmacitinib-treated patients and in 39.0% of the placebo group, and were predominantly mild. There were no deaths, or major adverse cardiovascular or thromboembolic events. Ivarmacitinib demonstrated clinical efficacy and was well tolerated in patients with moderate-to-severe, active, UC. Ivarmacitinib represents a promising new treatment for moderate-to-severe UC. gov number, NCT03675477.

A systematic review on the effect of upadacitinib on lipid profile

Background and Aims : To systematically address the association between upadacitinib, an oral JAK-1 selective inhibitor, and its effect on lipid profile, as well as the role of this association in cardiovascular risk.

Abrocitinib in atopic dermatitis: review of the current literature and clinical trials.

Atopic dermatitis (AD) is an inflammatory chronic-relapsing skin disease affecting approximately 15% to 20% of children and 10% of adults in industrialized countries. Both loss of epidermal barrier permeability and immune dysregulation seem to be the most important actors in AD pathogenesis. Several studies have demonstrated the role of Janus kinase (JAK) enzymes in AD pathogenesis suggesting oral and topical JAK inhibitors as new emerging therapies for AD. Among the JAK inhibitors, abrocitinib is an oral JAK1-selective inhibitor. The aim of this study is reviewing current literature about the efficacy and safety of abrocitinib in AD. The literature search was carried out considering the main search engines relating to medical literature and clinical trials. The efficacy and safety of abrocitinib have been confirmed in several studies suggesting this drug as a valuable treatment for moderate to severe AD.

Synthesis and evaluation of hydrazinyl-containing pyrrolo[2,3-d]pyrimidine series as potent, selective and oral JAK1 inhibitors for the treatment of rheumatoid arthritis

Selective inhibition of JAK kinases within the JAK family has been a desired goal of research in order to maximize efficacy while reducing undesired off target effect. Aiming to minimize adverse effects such as anemia, a promising new class of pyrrolo[2,3-d]pyrimidine series containing a hydrazinyl moiety were synthesized and profiled. Among them compound 8m and 8o showed the best enzymatic activity against JAK1 with IC50 value of 0.16 nM and 0.3 nM respectively, and with selectivity over JAK2 by 40.6 and 10 folds respectively. In addition, 8o had an improved PK profile and demonstrated better in vivo efficacy than Tofacitinib in CIA model.

IL-7 Promotes the Expansion of Circulating CD28- Cytotoxic T Lymphocytes in Patients With IgG4-Related Disease via the JAK Signaling.

ObjectivesThis study aimed to elucidate the changes and associated mechanisms of circulating CD28- cytotoxic T lymphocytes (CTLs) in patients with IgG4-related disease (IgG4-RD).MethodsFifty IgG4-RD patients and 15 healthy controls (HCs) were recruited. Peripheral blood mononuclear cells (PBMCs) were isolated, the levels of circulating CD28- CTLs were detected by flow cytometry, and the proportions of CD127lo or GZMB+CD28- CTL subsets were analyzed in the meantime. Mechanistically, PBMCs isolated from IgG4-RD patients were stimulated with IL-7 in the presence or absence of the JAK inhibitor tofacitinib. Flow cytometry was used to analyze the proliferation of CD28- CTLs and the changes in related subpopulations.ResultsCirculating CD4+CD28- CTLs and CD8+CD28- CTLs were significantly increased in IgG4-RD patients compared with HCs, accompanied by an elevation of CD127lo or GZMB+ CTL subsets. The ex vivo culture of PBMCs showed that IL-7 could induce the amplification of CD4+CD28- CTLs and CD8+CD28- CTLs in IgG4-RD. Furthermore, IL-7 promotes the proliferation and functional subset changes of these CD28- CTLs in this disease. The selective JAK inhibitor tofacitinib significantly inhibited the effects of IL-7 on CD4+CD28- CTLs and CD8+CD28- CTLs.ConclusionIL-7 can affect the immune balance of IgG4-RD patients by promoting the expansion and function of CD4+CD28- and CD8+CD28- CTLs in IgG4-RD through the JAK pathway. Blockade of the IL-7 signaling pathway may be a new therapeutic strategy for IgG4-RD.