Janus Kinase Inhibitors Baricitinib Research Articles

Portrait of a patient with systemic lupus erythematosus for the prescription of the type I interferon inhibitor anifrolumab

In recent years the use of monoclonal antibodies that block activity of type I interferon (IFN) or its receptors has become the new approach in the pharmacotherapy of systemic lupus erythematosus (SLE).Objective: to characterize patients with SLE treated with the type I IFN receptor inhibitor anifrolumab (AFM, Saphnelo®).Material and methods. The prospective 12-month study included 21 patients with SLE who met the 2012 SLICC criteria. Standard laboratory and immunological markers for SLE were examined in all patients. The SLEDAI-2K index was used to determine the activity of SLE and the CLASI index was used to determine the severity of the mucocutaneous syndrome. Organ damage was assessed using the SLICC/ACR Damage Index (DI). The LupusQol and FACIT-Fatigue questionnaires were used to analyze health-related quality of life (HRQoL).Results and discussion. Female patients prevailed in the study, female/male ratio – 17 (81%)/4 (19%), median age – 31 [27; 46] years, disease duration – 9 [6.0; 11.0] years. The majority of patients (86%) had moderate or high disease activity according to the SLEDAI-2K index. Among the clinical manifestations of SLE, skin and mucous membranes lesions predominated (81%). Non-erosive polyarthritis of varying severity was observed in 66% of cases. Serositis showed 24% of patients (pleurisy, pericarditis), 43% had hematological abnormalities (hemolytic anemia, leukopenia, lymphopenia) and 14% - urinary syndrome (daily proteinuria up to 0.5 g/l and/or urinary sediment – leukocytes/erythrocytes/cylinders up to 5 in the field of view in the absence of urinary tract infection). All patients had immunological disorders. 14% of them were diagnosed with antiphospholipid syndrome (APS) and 43% with Sjögren's syndrome.All patients received hydroxychloroquine, 95% received glucocorticoids (GC) from 5 to 60 mg/day, 66% received immunosuppressants (cyclophosphamide, mycophenolate mofetil, azathioprine, methotrexate). 33% of patients had anamnesis of treatment with biologic disease modifying antirheumatic drugs (rituximab, belimumab, dual anti-B-cell therapy) and Janus kinase inhibitor baricitinib. All patients experienced a significant deterioration in HRQoL.Conclusion. The indications for prescribing AFM to 21 patients with SLE were: active SLE according to SLEDAI-2K and/or CLASI with predominant involvement of skin, its appendages and development of polyarthritis with immunological disorders, intolerance/ineffectiveness of previous standard therapy and inability to achieve low average daily doses of oral GCs. Other clinical manifestations in some patients were: serositis, mild hematological disorders (Coombs-positive anemia, leukopenia), urinary syndrome. AFM could be prescribed for a combination of SLE with secondary APS and Sjögren's syndrome as well as for a high DI SLICC.

Comparison of treatment of COVID-19 with inhaled bromhexine, higher doses of colchicine and hymecromone with WHO-recommended paxlovid, molnupiravir, remdesivir, anti-IL-6 receptor antibodies and baricitinib

Millions of publications and thousands of clinical trials have not led to the discovery of an effective treatment for COVID-19. We believe that the reason for this is the inaccurate strategy of inhibiting target molecules involved in the pathogenesis of the disease. The leading cause of death in COVID-19 is the cytokine storm, which is caused by an NLRP3 inflammasome hyperreaction. WHO recommends for the outpatients treatment drugs blocking the replication of SARS-CoV-2. However, viral load and replication are not directly related to NLRP3 inflammasome hyperreactivity. This also explains the partial success of the WHO favorite paxlovid to reduce hospitalizations (51%). For hospital treatment, WHO suggests antibodies against the interleukin-6 receptor and Janus kinase (JAK) inhibition. Although important, IL-6 is one of dozens of cytokines elevated as a consequence of cytokine storm. The JAK inhibitor baricitinib inhibited the effect of not only IL-6 but also other elevated cytokines. But if the NLRP3 inflammasome is inhibited, the cytokines will not be elevated, and there will be no need for baricitinib. All medicines recommended by the WHO are distinguished by their very high prices. Our therapeutic strategy is based on inhibition of SARS-CoV-2 entry into the cell and inhibition of the NLRP3 inflammasome. We offer two readily available, cheap and well-known medications - bromhexine hydrochloride and colchicine. The many studies on the treatment of COVID-19 so far have not produced the expected result. The devil is buried in the details. For bromhexine, the reason is the way and its late application. Bromhexine is most effective when given prophylactically or started by inhalation after contact with a person with COVID-19. Its earliest possible application is crucial for its effect. Increased doses of colchicine are necessary for COVID-19 treatment due to the fact that it accumulates in leukocytes, and this leads to inhibition of NLRP3. The high doses we administer have been given widely in the past and are completely safe. Our highest dose is about 5 times lower per kg of weight than the lowest severe toxic dose of colchicine described. Our results show about a 5-fold decrease in hospital mortality and almost complete prevention of hospitalizations if outpatients are treated with inhaled bromhexine and colchicine.

Safety profile of baricitinib in patients with systemic lupus erythematosus: an integrated analysis

ObjectivesTo assess the safety of the oral Janus kinase inhibitor baricitinib in adult patients with systemic lupus erythematosus (SLE) receiving stable background therapy. Topics of special interest included infections and...

Efficacy and safety of tofacitinib in the treatment of rheumatoid arthritis: results of 10 years of use

The article presents a review of the basic data on the efficacy and safety of the drug tofacitinib, the place of the drug in the treatment of rheumatoid arthritis (RA) patients according to current international and Russian recommendations. Data on the mechanism of action of Janus kinase inhibitors, the spectrum of cytokines inhibited by tofacitinib is presented. The results of major randomised controlled trials demonstrating high clinical efficacy in patients who have not responded to methotrexate (MT) and other synthetic classical anti-rheumatic drugs (SCARDs), genetically engineered biologic drugs, are presented, with equal efficacy of tofacitinib when given as monotherapy or in combination with MT or other SCARDs, with adalimumab. The safety of tofacitinib with long-term treatment (up to 9.5 years) is analysed. The cardiovascular tolerability of tofacitinib is presented separately, considering the proposals discussed at the last EULAR 2022 Congress. The low incidence of serious cardiovascular adverse events, including venous thrombosis and thromboembolism over the long-term follow-up period, and the risk of these adverse events, which was no higher than on the selective Janus kinase inhibitor baricitinib, are presented. Changes in laboratory parameters (haemoglobin, neutrophil count, aminotransferase concentration) during tofacitinib administration are described. Domestic data on the use of tofacitinib in the treatment of RA patients is demonstrated. An association was shown between early clinical response to tofacitinib (5 mg twice daily) and a reduction in RA activity after 3 and 6 months in RA patients. Tofacitinib in real clinical practice showed early development of effect (by week 12) in the group of patients who did not respond to MT and in 60% of cases to genetically engineered biologic drugs, with respect to indicators of inflammatory activity of RA and functional status of patients. Domestic authors have noted the high safety of tofacitinib. A domestic generic version of the original drug tofacitinib has been reported to be registered for the same indications: RA, psoriatic arthritis, plaque psoriasis, ulcerative colitis.

AB0414 DRUG PERSISTENCE ON JANUS KINASE (JAK) INHIBITORS COMPARED TO BIOLOGIC DMARDs IN PATIENTS WITH RHEUMATOID ARTHRITIS: RETROSPECTIVE STUDY IN THE AUSTRALIAN POPULATION

BackgroundIn rheumatoid arthritis (RA) persistence on disease modifying anti-rheumatic drugs (DMARDs) can be interpreted as a composite measure of effectiveness, safety, and tolerability. There is limited data available on real-life use of the newest class of drugs, the Janus Kinase (JAK) inhibitors. JAK inhibitors are small-molecule treatments which are administered orally on a daily basis and offer a long-term option in RA treatment.ObjectivesTo compare drug persistence on JAK inhibitors tofacitinib, baricitinib and upadacitinib to tumor necrosis factor-α (TNF) inhibitors and other DMARDs in RA patients in Australia.MethodsA retrospective observational study was conducted among RA patients in the Australian Medicare Database (from January 2006 till October 2021), aged ≥18 and for whom a JAK inhibitor or biologic DMARDs were dispensed. Data were provided by the Australian Department of Health and Aging through PROSPECTION, an Australian healthcare consulting company. A deidentified 10% sample of the database was taken as a random representation of RA patients in Australia.Kaplan-Meier analysis was used to calculate drug persistence rates, defined as the time from treatment initiation until the date of the last dose when there had not been a script dispensed for 6 months; except for rituximab, where a 12-month gap was applied.ResultsData from 5,455 patients were analysed. For all patients the 12-month persistence rates were 61% for JAK inhibitors (baricitinib, tofacitinib, upadacitinib), 62% for tocilizumab, 52% for TNF inhibitors (adalimumab, certolizumab, etanercept, golimumab, infliximab), and 51% for abatacept. The JAK inhibitors baricitinib (64%) and upadacitinib (78%) were superior to tofacitinib (54%). Median treatment persistence for upadacitinib was not reached (n = 430); was 27.1 months for baricitinib and 15.2 months for tofacitinib. For TNF inhibitors, treatment persistence was 15.1 months for adalimumab, 14.1 months for certolizumab, 14.0 months for etanercept, 11.1 months for golimumab and 4.5 months for infliximab.Persistence rates on first-line JAK inhibitors were 70% for baricitinib and 57% for tofacitinib; persistence rates dropped to 63% for baricitinib and 47% for tofacitinib in the second-line setting. First-line persistence rates were 54% for TNF inhibitors and 65% for tocilizumab, rates were sustained for tocilizumab, but dropped to 48% for TNF inhibitors in the second-line setting.ConclusionThis real-world data highlights that in an Australian clinical practice setting treatment persistence rates on 12 months on JAK inhibitors, in particular baricitinib and upadacitinib, were superior to TNF inhibitors, but not to tocilizumab. Suggesting that persistence rates might differ according to biologics mode of action and line of treatment.Table 1.Persistence rates at 12 months post treatment initiationAll patientsFirst lineSecond lineJAK inhibitorsOverall61% (2155)60% (616)60% (554)Baricitinib64% (537)70% (158)63% (124)Tofacitinib54% (1188)57% (441)47% (294)Upadacitinib78% (430)28% (17)84% (136)TNF inhibitorsOverall52% (6339)54% (4227)48% (1561)Adalimumab55% (2710)56% (2030)48% (590)Certolizumab51% (593)54% (251)47% (147)Etanercept52% (2079)55% (1354)47% (623)Golimumab49% (814)49% (506)47% (174)Infliximab35% (143)23% (86)53% (27)Other DMARDsAbatacept51% (952)56% (263)46% (310)Rituximab49% (284)41% (70)65% (79)Tocilizumab62% (1156)65% (279)65% (351)In brackets are number of patients.

Janus Kinase Inhibitors in the Treatment of Type I Interferonopathies: A Case Series From a Single Center in China.

ObjectiveThis study aimed to assess the efficacy and safety of 2 Janus kinase (JAK) inhibitors (jakinibs) tofacitinib and ruxolitinib in the treatment of type I interferonopathies patients including STING-associated vasculopathy with onset in infancy (SAVI), Aicardi-Goutières syndrome (AGS), and spondyloenchondrodysplasia with immune dysregulation (SPENCD).MethodsA total of 6 patients were considered in this study: 2 patients with SAVI, 1 patient with AGS1, 1 patient with AGS7, and 2 patients with SPENCD. Clinical manifestations, laboratory investigations, radiology examinations, treatment, and outcomes were collected between November 2017 and November 2021 in Peking Union Medical College Hospital. The disease score for patients with SAVI and AGS scale for patients with AGS were documented. The expression of 6 interferon-stimulated genes (ISGs) was assessed by real-time PCR.ResultsThree patients (1 patient with SAVI, 2 patients with AGS) were treated with ruxolitinib and 3 patients (1 patient with SAVI, 2 patients with SPENCD) were treated with tofacitinib. The mean duration of the treatment was 2.5 years (1.25–4 years). Upon treatment, cutaneous lesions and febrile attacks subsided in all affected patients. Two patients discontinued the corticoid treatment. Two patients with SAVI showed an improvement in the disease scores (p < 0.05). The erythrocyte sedimentation rate normalized in 2 patients with AGS. The interferon score (IS) was remarkably decreased in 2 patients with SPENCD (p < 0.01). Catch-ups with growth and weight gain were observed in 3 and 2 patients, respectively. Lung lesions improved in 1 patient with SAVI and remained stable in 3 patients. Lymphopenia was found in 3 patients during the treatment without severe infections.ConclusionThe JAK inhibitors baricitinib and tofacitinib are promising therapeutic agents for patients with SAVI, AGS, and SPENCD, especially for the improvement of cutaneous lesions and febrile attacks. However, further cohort studies are needed to assess the efficacy and safety.

Host-modifying drugs against COVID-19: some successes, but not yet the breakthrough.

SummaryAfter reviewing antiviral drugs (Brüssow Environmental Microbiology 2021) the present review summarizes the results of clinical trials with host‐modifying drugs in COVID‐19 patients. Clinical benefits were observed with different immunomodulators. The variable outcomes of trials with the interleukin 6 receptor inhibitor tocilizumab demonstrated that treatment benefits might only be present in specific subgroups of patients or in specific infection stages. A meta‐analysis of trials with the interleukin 1 receptor antagonist anakinra showed a survival benefit only in patients with hyperinflammation. The Janus kinase inhibitor baricitinib is an anti‐inflammatory treatment that showed a clinical benefit in hospitalized patients who do not yet need supplementary oxygen. In contrast, the corticosteroid dexamethasone showed mortality reducing effects that were limited to patients on ventilation or in need of supplementary oxygen. Therapeutic dose of anticoagulation met the criteria for inferiority in severe cases, but showed a small survival benefit in non‐severe COVID‐19 patients. Large trials with colchicine showed a small or no survival benefit. Azithromycin, an antibiotic with immunomodulatory activity, showed no effects in numerous clinical trials. The trials showed a clear need for new drugs instead of repurposed drugs and drugs that specifically target the SARS‐CoV‐2 virus or the pathology developing in COVID‐19 patients.

Efficacy and safety of the oral Janus kinase inhibitor baricitinib in the treatment of adults with alopecia areata: Phase 2 results from a randomized controlled study

There are no treatments approved by the Food and Drug Administration for alopecia areata. To evaluate the efficacy and safety of baricitinib in patients with ≥50% scalp hair loss in a phase 2 study of adults with alopecia areata (BRAVE-AA1). Patients were randomized 1:1:1:1 to receive placebo or baricitinib 1mg, 2mg, or 4mg once daily. Two consecutive interim analyses were performed after all patients completed weeks 12 and 36 or had discontinued treatment prior to these time points. The primary endpoint was the proportion of patients achieving a Severity of Alopecia Tool (SALT) score ≤20 at week 36. Logistic regression was used with nonresponder imputation for missing data. A total of 110 patients were randomized (placebo, 28; baricitinib 1-mg, 28; 2-mg, 27; 4-mg, 27). The baricitinib 1-mg dose was dropped after the first interim analysis based on lower SALT30 response rate. At week 36, the proportion of patients achieving a SALT score of ≤20 was significantly greater in baricitinib 2-mg (33.3%, P=.016) and 4-mg (51.9%, P = .001) groups versus placebo (3.6%). Baricitinib was well tolerated with no new safety findings. Small sample size limits generalizability of results. These results support the efficacy and safety of baricitinib in patients with ≥50% scalp hair loss.

JAK inhibitors dampen activation of interferon-stimulated transcription of ACE2 isoforms in human airway epithelial cells

SARS-CoV-2 infection of human airway epithelium activates genetic programs leading to progressive hyperinflammation in COVID-19 patients. Here, we report on transcriptomes activated in primary airway cells by interferons and their suppression by Janus kinase (JAK) inhibitors. Deciphering the regulation of the angiotensin-converting enzyme 2 (ACE2), the receptor for SARS-CoV-2, is paramount for understanding the cell tropism of SARS-CoV-2 infection. ChIP-seq for activating histone marks and Pol II loading identified candidate enhancer elements controlling the ACE2 locus, including the intronic dACE2 promoter. Employing RNA-seq, we demonstrate that interferons activate expression of dACE2 and, to a lesser extent, the genuine ACE2 gene. Interferon-induced gene expression was mitigated by the JAK inhibitors baricitinib and ruxolitinib, used therapeutically in COVID-19 patients. Through integrating RNA-seq and ChIP-seq data we provide an in-depth understanding of genetic programs activated by interferons, and our study highlights JAK inhibitors as suitable tools to suppress these in bronchial cells.

Baricitinib and dexamethasone for hospitalized patients with COVID-19.

The glucocorticoid dexamethasone is the standard of care in critically ill patients with COVID-19 to suppress the inappropriately heightened inflammatory response (cytokine storm), but the Janus kinase inhibitor baricitinib combined with remdesivir has received emergency use authorization for the same indication. As of this writing, in a hospitalized patient with COVID-19 who has evidence of pneumonitis or hypoxia, we recommend using either regimen, but not both together. Both regimens have shown benefit in randomized controlled trials, but we cannot state with certainty that either is superior to the other, nor whether they should be used together. Further trials are underway.

Janus kinase inhibitors for the therapy of atopic dermatitis

The JAK-STAT pathway is involved in the signaling of multiple cytokines driving cutaneous inflammation in atopic dermatitis (AD). Janus kinase (JAK) inhibitors target individual receptor-associated kinases, thereby preventing the mediation of inflammatory signals. Several JAK inhibitors with varying mechanism of action, potency, and safety represent potential therapeutic options for AD in both topical and systemic application. The JAK1/2 selective JAK inhibitor baricitinib was the first substance from this class of drugs approved by the EMA for the systemic oral treatment of AD. The clinical development program of the JAK1 selective inhibitors upadacitinib and abrocitinib is finalized with positive results for AD. The PAN-JAK inhibitor delgocitinib was the first substance being approved for the treatment of AD (in Japan). This review article covers the rising data on investigational and approved JAK inhibitors in the context of the treatment of AD.

Covid-19: Acts of omission

<h3>Background</h3> Baricitinib is a Janus kinase (JAK)1/JAK2 inhibitor approved for the treatment of rheumatoid arthritis (RA)^1-2. STAT proteins bind JAK kinase dimers coupled with cytokine receptors and regulate gene transcription. The JAK/STAT system is responsible for the intracellular signaling of different cytokines contributing to the activation process of the monocyte lineage, therefore the use of JAK inhibitors can affect cell functionality^3-6. <h3>Objectives</h3> The aim of the present study was to verify the effects of baricitinib on STAT phosphorylation in peripheral mononuclear cells (PBMCs) of RA patients and to evaluate any correlation between STAT phosphorylation and response to therapy. <h3>Methods</h3> At baseline (BL) and after 4 weeks (w4) of treatment, we evaluated patients’ disease activity (DAS28_PCR, CDAI and SDAI), dividing them into responders and non-responders according to the Minimal Clinically Important Difference for DAS28_PCR (1.2 points) at w4. The phosphorylation of STAT1, STAT4 and STAT5 was analyzed at BL and w4 in gated monocytes, Treg, CD8 + and CD4 + lymphocytes from 4 responder and 4 non-responder patients through flow cytometry, at basal conditions and after IL2, IFNα and IL6 stimulation. <h3>Results</h3> Baseline clinical and demographic characteristics of patients are reported in Table 1. We showed that monocyte count decreased from BL to w4 mostly in responders. Basal pSTAT1 phosphorylation tent to be higher in monocytes of non-responder patients; after 4 weeks of treatment, the reduction of the cytokine-induced pSTAT1 was significantly greater in monocytes from responders compared to non-responders (Figure 1). The phosphorylation of STAT4 and STAT5 was not affected by treatment in any cell type and at any time point. We further studied the STAT1 phosphorylation pathway isolating the effect of stimulation with IFNα and stratifying monocytes according to their surface marker expression of CD14 and CD16 in classical, intermediate and non-classical. We observed the same pattern with a significant greater reduction of pSTAT1 in monocytes from responder patients, compared to non-responders, after the treatment with baricitinib. <h3>Conclusion</h3> These results may suggest that monocyte count and STAT1 phosphorylation in circulating monocytes could represent early markers of response to baricitinib therapy. <h3>References</h3> [1]Gadina M, et al. Janus kinases to jakinibs: from basic insights to clinical practice. Rheumatology (Oxford). 2019 [2]Gadina M, et al. Translating JAKs to Jakinibs. J Immunol. 2020 [3]Kubo S, et al. The JAK inhibitor, tofacitinib, reduces the T cell stimulatory capacity of human monocyte-derived dendritic cells. Ann Rheum Dis. 2014 [4]Kubo S, et al. Janus Kinase Inhibitor Baricitinib Modulates Human Innate and Adaptive Immune System. Front Immunol. 2018 [5]Ikari Y, et al. Peficitinib Inhibits the Chemotactic Activity of Monocytes via Proinflammatory Cytokine Production in Rheumatoid Arthritis Fibroblast-Like Synoviocytes. Cells. 2019 [6]Yang X, et al. Tofacitinib inhibits ox-LDL-induced adhesion of THP-1 monocytes to endothelial cells. Artif Cells Nanomed Biotechnol. 2019 <h3>Disclosure of Interests</h3> Cristina Garufi Consultant of: Lilly, Gloria Tucci: None declared, Ilenia Pacella: None declared, Marta Zagaglioni: None declared, Alessandra Pinzon Grimaldos: None declared, Fulvia Ceccarelli: None declared, Silvia Piconese: None declared, Francesca Romana Spinelli Consultant of: Lilly, Fabrizio Conti Consultant of: Lilly

BARICITINIB: NEW PHARMACOTHERAPY OPTIONS FOR RHEUMATOID ARTHRITIS AND OTHER IMMUNE-MEDIATED INFLAMMATORY RHEUMATIC DISEASES

Deciphering the mechanisms of the pathogenesis of immune-mediated inflammatory rheumatic diseases (IMIRDs) in conjunction with designing a wide range of biological agents is one of the major medical advances in the 21st century. A new promising area of pharmacotherapy for IMIRDs is associated with the design of the so-called targeted oral medications that primarily include Janus kinase (JAK) inhibitors. The review presents new data on the efficacy and safety of the new JAK inhibitor baricitinib in treating rheumatoid arthritis and other IMIRDs.

Hypereosinophilic syndrome—a rare adverse event of anti-cytokine treatment in rheumatoid arthritis resolved after Janus kinase inhibitor therapy

Eosinophilia is uncommon in early rheumatoid arthritis (RA). The most frequent causes of hypereosinophilia during RA treatment are atopic eczema, allergy, helminth infection, haematological malignancy and drug-associated complications. The pathogenesis of this abnormality associated with anti-cytokine therapy is still unknown. We report the case of a young woman with RA and eosinophilia accompanied by systemic symptoms such as dyspnoea, fluid retention and eosinophilic vasculitis. An interesting observation was the persistence of eosinophilia during treatment with various biologics and its normalization after switching to the Janus kinase inhibitor baricitinib.

Antibody-drug conjugates targeting CD45 plus Janus kinase inhibitors permit allogeneic hematopoietic stem cell transplantation with minimal treatment-related toxicity

Abstract Allogeneic hematopoietic stem cell transplantation (alloHSCT) is a potentially curative therapy for hematologic diseases. However, toxicities from chemotherapy- or irradiation-based transplant conditioning, as well as graft-versus-host disease (GvHD), limit the use of alloHSCT to the most severe diseases. Novel conditioning regimens able to achieve donor engraftment with minimal adverse effects for the patient could greatly expand the safe applicability of alloHSCT to a wider variety of diseases. Antibody-drug conjugates targeting CD45 (CD45-ADC) have been shown previously to permit engraftment in murine syngeneic HSCT models. We set out to extend this approach to the allogeneic setting, developing CD45-ADC-based regimens able to both make marrow space for donor stem cells and overcome immune barriers to their engraftment. CD45-ADC combined with CD4+ and CD8+ T cell depletion was sufficient for engraftment in MHC-matched (BALB to DBA/2) and MHC-mismatched (CB6F1 to B6) murine alloHSCT models. The selective Janus kinase inhibitor baricitinib, shown by our lab to prevent GvHD, also inhibited host-versus-graft responses and allowed allogeneic engraftment when combined with CD45-ADC. In our alloHSCT models, up to 90% donor chimerism was achieved in over 70% of mice treated with CD45-ADC plus baricitinib. Finally, unlike mice conditioned with irradiation, mice treated with CD45-ADC did not develop GvHD when infused with allogeneic splenocytes. In conclusion, CD45-ADC plus baricitinib provides a safe, effective approach to alloHSCT conditioning in mice. These studies demonstrate the promise of immunotherapeutic strategies to achieve transplant tolerance while minimizing treatment-related morbidity and mortality.

Janus kinase inhibitor baricitinib is not an ideal option for management of COVID-19

The Wuhan outbreak of novel Corona virus infection has been the global focus since December 2019. This infection has become a global pandemic. It is highly important to understand the virology of the pathogen and to explore the therapeutic options for management of this pandemic. Drug repurposing strategies are being considered for management of COVID 19. Among the identified drugs, Baricitinib has become a keen interest for researchers because of its ability to inhibit the viral assembly by the prevention of Clarithrin associated endocytosis. We tried to explore the reasons on why Baricitinib is not an ideal option for COVID 19.

CD45-ADC Plus Janus Kinase (JAK) Inhibitors As Conditioning for MHC-Mismatched Murine Hematopoietic Stem Cell Transplantation Is Associated with Minimal Toxicity and Graft Versus Host Disease

INTRODUCTION: Allogeneic hematopoietic stem cell transplantation (alloHSCT) provides the best chance for disease control in acute myeloid leukemia (AML). The known anti-leukemia benefit of alloHSCT is attributable to pre-transplant conditioning with chemotherapy and/or radiation and the graft-versus-leukemia (GvL) effect. However, the utility of alloHSCT is limited by significant treatment-related morbidity and mortality resulting from conditioning regimen-related toxicities and graft versus host disease (GvHD). AML is primarily diagnosed in elderly patients, for whom alloHSCT may be contraindicated due to an inability to tolerate these adverse effects. Therefore, an unmet clinical need exists for novel alloHSCT conditioning regimens that minimize toxicity without sacrificing therapeutic efficacy. Previously, we and others (Palchaudhuri et al. (2016), Nat Biotech; Persaud et al. (2018), Blood) have shown that antibody-drug conjugates (ADCs) composed of a CD45.2-specific antibody linked to the ribosome-inactivating protein saporin (CD45-SAP) permitted stable, high-level engraftment in murine syngeneic HSCT. We hypothesize that such targeted, immunotherapeutic strategies can be applied to the setting of alloHSCT, enhancing its safety and applicability to the treatment of hematologic diseases. METHODS: For engraftment studies, recipient mice were conditioned with 3 mg/kg CD45-SAP 7 days prior to infusion of 10-20 x 106 whole bone marrow cells. The following alloHSCT models were used: MHC-matched (BALB/c→DBA/2), F1-to-parent (CB6F1→B6), and F1-to-F1 (B6CBAF1→CB6F1). In some experiments, CD45-SAP treatment was combined with CD4+ and CD8+ T cell depletion and/or the Janus kinase (JAK) inhibitor, baricitinib. For GvHD studies, a parent-to-F1 (B6→CB6F1) model was used in which recipients were infused with 25 x 106 donor splenocytes after CD45-SAP treatment or sublethal irradiation. For studies with human CD45-SAP, MOLM13 AML cell line viability was measured with XTT assays, and cord-blood CD34+cell colony formation was assessed using methylcellulose assays. RESULTS: CD45-SAP combined with CD4+ and CD8+ T cell depletion allowed high-level engraftment in MHC-matched and F1-to-parent alloHSCT models (Figure 1A-B). Baricitinib, previously shown by our lab to prevent GvHD while preserving the GvL effect (Choi et al. (2018), Leukemia), permitted short-term HSC engraftment in F1-to-parent alloHSCT when mice were dosed daily with the drug during the first 21 days post-HSCT (Figure 1C). Graft stability in baricitinib-treated mice was improved by either combining daily baricitinib treatment with pre-transplant T cell depletion (Figure 1D), or by delivering baricitinib via continuous infusion (Figure 1E). In parent-to-F1 GvHD models, CD45-SAP conditioned mice showed minimal morbidity or mortality when infused with allogeneic splenocytes, whereas mice conditioned with sublethal irradiation succumbed within 3 weeks to severe GvHD (Figure 1F). That alloreactive T cells did not cause GvHD in CD45-SAP treated mice prompted us to use donor lymphocyte infusions to enhance engraftment in a fully haploidentical (F1-to-F1) HSCT model. Our results suggest that addition of donor T cells to the bone marrow graft promotes donor engraftment without eliciting clinically apparent GvHD (Figure 1G). Finally, anti-human CD45 (clone BC8), when conjugated to saporin, inhibited MOLM13 cell growth and cord blood CD34+ cell colony formation in vitro (Figure 1H-I), consistent with both an anti-stem cell and anti-leukemic effect. CONCLUSIONS: Combining CD45-SAP with T cell depletion and/or pharmacologic immunomodulation with the JAK inhibitor baricitinib effectively conditions mice for engraftment of MHC-matched and haploidentical HSCs without causing significant toxicity. Strikingly, mice conditioned with CD45-SAP, unlike mice conditioned with irradiation, did not develop GvHD when infused with allogeneic splenocytes. Finally, we have demonstrated that human CD45-SAP is cytotoxic to both the MOLM13 AML cell line and cord-blood derived stem cells. Taken together, these studies provide key proof-of-principle evidence that targeted immunotherapeutics (CD45-SAP plus JAK inhibitors) can accomplish the goals of alloHSCT - creating marrow space for donor HSCs, overcoming immune barriers to engraftment, and eliminating leukemia cells - with limited toxicity or GvHD. Disclosures Cooper: Wugen: Consultancy, Equity Ownership, Patents &amp; Royalties. Rettig:WashU: Patents &amp; Royalties: Patent Application 16/401,950. DiPersio:Incyte: Consultancy, Research Funding; Celgene: Consultancy; Amphivena Therapeutics: Consultancy, Research Funding; Cellworks Group, Inc.: Membership on an entity's Board of Directors or advisory committees; RiverVest Venture Partners Arch Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; NeoImmune Tech: Research Funding; Macrogenics: Research Funding, Speakers Bureau; WUGEN: Equity Ownership, Patents &amp; Royalties, Research Funding; Magenta Therapeutics: Equity Ownership; Karyopharm Therapeutics: Consultancy; Bioline Rx: Research Funding, Speakers Bureau.

Synthesis and Characterization of Compounds Potentially Related to the Janus Kinase Inhibitor Baricitinib

Nine compounds potentially related to the Janus kinase inhibitor Baricitinib have been identified, synthesized by conventional methods, and characterized by IR, 1H and 13C NMR, and mass spectral data.

Novel systemic drugs in treatment of atopic dermatitis: results from phase II and phase III studies published in 2017/2018

The present review will give an update of recently published clinical studies on novel systemic treatment approaches in atopic dermatitis. Until 2017 immunosuppressive drugs such as cyclosporine had to be used in atopic dermatitis when the disease could not sufficiently be treated with topical drugs. Several new substances specifically targeting inflammation in atopic dermatitis are currently studied. In 2017, dupilumab was approved in the United States and in Europe for first-line biologic treatment of moderate to severe atopic dermatitis in adults. The antibody blocks a subunit of the interleukin (IL)-4 and IL-13 receptor, thus inhibiting effects of two key cytokines in type 2 polarized inflammation. In addition to the studies on dupilumab recent clinical investigations on the effects on anti-IL-13 (lebrikizumab, tralokinumab), anti-IL-31 receptor (nemolizumab), anti-IL-22 (fezakinumab), and on small molecules targeting the histamine-4-receptor (ZPL389) and the Janus kinase inhibitor baricitinib have been published as full papers in the last 2 years. A couple of promising novel therapeutical targets have recently been investigated and published in clinical trials on atopic dermatitis.

Emerging treatment options for spondyloarthritis.

The management of spondyloarthritis (SpA) has substantially changed as a consequence of the introduction of biologic disease-modifying antirheumatic drugs (bDMARDs). However, the treatment options in patients with axial SpA (axSpA) not responding to nonsteroidal anti-inflammatory drugs (NSAIDs) had been restricted to tumor necrosis factor alpha (TNFα) inhibitors for almost 15 years. With the approval of secukinumab, an interleukin (IL)-17A inhibitor, there is a new alternative in the treatment of axial SpA. In patients with psoriatic arthritis (PsA) not responding to conventional therapy with NSAIDs and conventional synthetic DMARDs, therapeutic options are more diverse. In addition to TNFα inhibitors and secukinumab, another IL-17A inhibitor ixekizumab, IL-12/23 blocker ustekinumab, phosphodiesterase-4 inhibitor apremilast, T-cell-mediated pathway inhibitor abatacept, and Janus kinase (JAK) inhibitor tofacitinib are the approved treatment. Nevertheless, there is still an unmet need for further treatment options in both axSpA and PsA. Further therapeutics, such as the dual IL-17A and F inhibitor bimekizumab, IL-17 receptor blocker brodalumab, and JAK inhibitors baricitinib, filgotinib and upadacitinib are in development for these indications. IL-23 inhibitors risankizumab, tildrakizumab, and guselkumab are further emerging drugs for PsA. Thus, the number of treatment options in SpA is likely to be increased over the next few years that make identification of optimal treatment strategies essential.