Baricitinib Therapy Research Articles

Improvement in sleep and itch and enhanced quality of life in adult patients with moderate-to-severe atopic dermatitis: results from a phase 3 trial of baricitinib therapy

Background Baricitinib previously demonstrated improvements in itch and sleep disturbance versus placebo in adults with moderate-to-severe atopic dermatitis (AD). Objectives Examine if itch and sleep improvements are associated with better quality of life (QoL) and productivity in patients with AD. Methods Data were drawn from BREEZE-AD5 (NCT03435081). Itch and sleep improvement at Week 16 were defined using ≥4-point improvements in the Itch Numeric Rating Scale and ≥1.5 decreases in the number of nighttime awakenings since baseline, respectively. Patients with and without improvements were compared on Dermatology Life Quality Index (DLQI) and Work Productivity and Activity Impairment-AD scores. Changes from baseline were analyzed using ANCOVA with last observation carried forward. Proportions were analyzed using logistic regression with non-responder imputation. Results Greater proportions of patients with versus without itch improvement indicated no impact of AD on QoL (37.7 vs. 1.8%). Patients with itch improvement had greater decreases in work time impaired (−29.3 vs. −5.6%). More patients with versus without sleep improvement reported no effect of AD on QoL (25.5 vs. 1.1%); patients with better sleep experienced larger reductions in work time spent impaired (−33.3 vs. −6.1%). Conclusions Patients with AD who experienced itch and sleep improvement had significantly better QoL and productivity.

O10 Characteristics of patients who discontinued baricitinib treatment within 12 months and reasons for discontinuation: real-world data

Abstract Background/Aims Baricitinib is an oral targeted synthetic disease-modifying anti-rheumatic drug (tsDMARD) recommended by the National Institute for Health and Care Excellence (NICE) in the UK for severe rheumatoid arthritis (RA) either as mono- or combination therapy. We wanted to observe the frequency of discontinuation in a real-world setting, the characteristics of patients who stop taking baricitinib, and the reasons for discontinuation. Objective: To describe the characteristics of patients who discontinue baricitinib treatment and the reasons for discontinuation. Methods A real-world retrospective observational study of baricitinib use in RA patients at University Hospital Southampton using local advanced therapy database for data collection. We described the characteristics of patients discontinuing baricitinib therapy and divided patients into two groups. Group 1 (those who discontinued therapy within the first 12 months of use) and group 2 (who continued therapy beyond 12 months) Results From October 2017 to July 2020, a total of 83 patients started baricitinib and were recorded in the database, 55 (66.27%) remain on treatment to date. Among 28 (33.74%) patients who stopped baricitinib, 21 had stopped within 12 months. The reasons for discontinuation were lack of efficacy (64.28%) and AEs (28.57% - 1 tooth infection, 1 urinary tract infection, 1 discitis, 2 chest infection, 1 personality change, 1 deranged liver function and 1 lymphoma). In group 1, the mean (±SD) age was 49.00 (13.65) years, 66.67% were female and 85.71% were previously biologic inadequate responders (IR), 42.86% were receiving monotherapy, with 57.14% being on combination therapy with a csDMARD and 9.52% were using a glucocorticoid. In group 2, 82.26% were female, 61.52 (10.94) years of age and 83.87% were previously biologic IR, 41.94% were on monotherapy and 58.06% on combination therapy with a csDMARD. Patients who discontinued appeared more likely to be younger and male. However, there was no significant difference regarding mono- or combination therapy, disease duration or seropositivity (p-value > 0.05) (Table 1). Conclusion In a real-world setting, baricitinib appears efficacious and well-tolerated in the first year of use by two-thirds of patients. Characteristics such as older age and female gender were associated with continued use. Disclosure M. Lwin: None. C. Holroyd: Honoraria; Lily. Member of speakers’ bureau; Lily. C.J. Edwards: Honoraria; Abbvie, Biogen, BMS, Celgene, Fresenius, GSK, Janssen, Lilly, Mundipharma, Pfizer, Roche, Sanofi, UCB. Member of speakers’ bureau; Abbvie, Biogen, BMS, Celgene, Janssen, Lilly, Sanofi, Pfizer, Roche. Grants/research support; Abbvie, Biogen, Pfizer.

Baricitinib in patients with severe pneumonia due to COVID-19 in Veracruz, Mexico

Background: Patients affected by COVID-19 pneumonia who present severe symptoms with manifest hypoxemia and cytokine storm have a high mortality rate, which is why therapies focused on reducing inflammation and improving lung function have been used, being one of them Baricitinib Material and methods: Patients who presented data of severe pneumonia due to COVID-19 with data of severe hypoxemia and cytokine storm were selected, from June to August 2020, to whom the SaO2/FiO2 ratio is measured at the beginning, intermediate and end of treatment. Results: We included data from 30 patients, 22 (73%) men, with a median age of 58.5 years. 77% had comorbidities: hypertension (43%), obesity (30%), diabetes (27%). The medians of D-Dimer 982ng/mL, Ferritin 1,375ng/mL and CRP 10mg/dL. 97% patients had treatment: azithromycin (77%), ivermectin (53%) and dexamethasone (47%). The initial pulseoximetry (SaO2) with room air had a median of 80.5% and the median SaO2/FiO2 (SAFI) was 134; 90% had moderate ARDS and 10% had severe ARDS. All received Baricitinib 4 mg/day by 14 days. SaO2 at 7 days had a median of 93.0% and the median SAFI was 310; the median SaO2 at 14 days was 95% and the median SAFI was 452. In comparative analysis, baseline SaO2/SAFI was significantly lower compared to 7 and 14 days (p = 0.001 for both comparisons). 90% patients improved and 10% died. Conclusion: Baricitinib therapy in these patients presented good results by improving clinical status and pulmonary failure, with patients being cared for at home and avoiding mechanical ventilation.

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

Efficacy of baricitinib in treating rheumatoid arthritis: Modulatory effects on fibrotic and inflammatory biomarkers in a real-life setting

BackgroundBaricitinib is a JAK inhibitor that blocks intracellular signalling pathways of inflammatory cytokines recommended for Rheumatoid arthritis (RA) patients not responding to initial treatment. Among RA extrareticular features, interstitial lung involvement is primarly characterized by fibrotic evolution. The aim of the present study was to analyse the effects of baricitinib in a population of RA and RA-ILD patients in a real-life setting, describing any changes in lung function parameters, serum inflammatory biomarkers and fibrotic biomarkers after 6 months of treatment. Materials and methods15 patients (median (IQR) 65 (55–66); 13% males and 74% smokers) treated with baricitinib were enrolled. 4 patients (27%) were classified as RA-ILD before baricitinib therapy. Our study is the first to evaluate adipokine levels in RA patients (including a small population with RA-ILD) after six months of baricitinib treatment with a novel multiplex method. ResultsThe modulatory effects of baricitinib on lipid mediators were associated with clinical and functional improvement, demonstrated by the significant increase in DLco and KCO percentages after six months of treatment. Baricitinib decreased the systemic inflammation by lowering expression of IL-6 and CRP and reducing ESR and serum concentrations of adiponectin. A significant reduction of KL-6 levels in RA-ILD patients after six months of baricitinib therapy reflects the stability of interstitial lung involvement in these patients. ConclusionBaricitinib was demonstrated to be a safe immune modulator that reduces the concentrations biomarkers of lung fibrosis and inflammation in RA patients, including a subgroup with interstitial lung involvement.

New alternative in the treatment of rheumatoid arthritis: clinical utility of baricitinib.

Baricitinib is an innovative small-molecule drug that reversibly inhibits continuous activation of JAK/STAT pathway, thus reducing joint inflammation. The drug was approved for use as monotherapy or in combination with methotrexate (MTX) in the treatment of adults with moderately to severely active rheumatoid arthritis (RA). The aim of this paper was to review the studies on pharmacology, mode of action, pharmacokinetics, efficacy, and safety of baricitinib in patients with RA. Baricitinib provides an innovative approach to modulating the immune and inflammatory response in patients with RA, which is especially important in individuals who do not respond to disease-modifying antirheumatic drugs or standard biologic drugs (tumor necrosis factor inhibitors) or who lose response over time. Baricitinib therapy reduces symptoms of RA and improves the quality of life. Moreover, it has shown high efficacy and an acceptable safety profile in Phase III randomized controlled trials (RCTs) and become another JAK inhibitor approved for RA treatment, providing a useful alternative option. RCTs have revealed a significant benefit of baricitinib over placebo, MTX, and adalimumab in terms of standard efficacy outcomes, especially the American College of Rheumatology ACR20, ACR50, and ACR70 response rates. Additionally, a clinically meaningful improvement in patient-reported outcomes, including the quality of life, compared with placebo has been reported. The safety profile seems acceptable, although some rare but potentially severe adverse events have been observed, such as serious infections, opportunistic infections (eg, herpes zoster), malignancies, and cardiac or hepatic disorders. Baricitinib administered at an approved dose of 2 or 4 mg once daily offers a novel and promising alternative to parenterally administered biologic drugs used in RA treatment.

Response to baricitinib therapy in patients with rheumatoid arthritis with inadequate response to csDMARDs as a function of baseline characteristics

ObjectiveWe analysed the effects of baseline characteristics on the safety and efficacy of baricitinib in patients with rheumatoid arthritis (RA) with inadequate response to conventional synthetic disease-modifying antirheumatic drugs (csDMARDs)...

Translational Positioning of Janus Kinase (JAK) Inhibitors in Alopecia Areata

Alopecia areata (AA) is an autoimmune disease due to T cell attack of the hair follicles and breakdown of their immune privilege resulting in transient non-scarring hair loss which may last from weeks to decades and which presents an enormous psychological burden. As so far no FDA approved successful treatments for AA are available, new hope and light arose on the horizon with the recently published genome wide association studies in AA patients revealing new molecular pathways disrupted in AA including autophagy/apoptosis, transforming growth factor beta/Tregs and JAK (Janus family of non-receptor protein tyrosine kinase) signaling (Petukhova et al., 2010, Betz et al., 2015). Thus, today it is assumed that CD8 + NKG2D + T effector memory cells mediate alopecia areata in part through Janus kinase (JAK) signaling and that alopecia areata might be treated with JAK inhibitors. This assumption has been supported by clinical use of JAK inhibitors within a clinical study setting (Xing et al., 2014) or observed as a “side effect”, when JAK inhibitor treatment of another underlying disease resulted in regrowth of longstanding patchy or universal alopecia areata (Craiglow and King, 2014, Pieri et al., 2015). Xing et al., 2014 demonstrated that the interferon-γ (IFNγ)-signaling pathway is upregulated in AA-lesional skin, and that the use of JAK inhibitors was able to reverse symptoms of the disorder in mice and in three humans with AA. While different groups (Craiglow and King, 2014, Pieri et al., 2015, Higgins et al., 2015) reported successful use of ruxolitinib, a JAK1/2 inhibitor licensed for treating myelofibrosis, others reported successful use of the JAK 1/3 inhibitor tofacitinib in AA while using it for treating psoriasis (Craiglow and King, 2014). In this issue of EBioMedicine, Jabbari et al. followed up on hair growth observed in a patient under baricitinib therapy, also a JAK1/2 inhibitor and studied JAK inhibitor action in the C3H/HeJ graft-recipient mouse model of AA (Jabbari et al., 2015). Under JAK inhibitor treatment, CD8 + cell infiltrates and MHC class I and II expressions were markedly reduced in C3H/HeJ mice grafted with alopecic skin, both in a preventive and a therapeutic setting. In addition, gene expression profiling using the Alopecia Areata Disease Activity Index (ALADIN) biomarker for response to treatment confirmed the assumed normalization of the IFN-gamma gene expression signature. The approach of Jabbari et al. represents an excellent model for translational work, where a specific clinical observation made in a special patient is complemented with mechanistic work, which nicely allows to link macroscopic appearance, immunohistochemistry and gene expression profiles with the current idea of how JAK inhibitors could be beneficial in AA (Jabbari et al., 2015). However, all euphoria should not let forget that JAK inhibitors inhibit multiple pathogenic pathways simultaneously. A broad spectrum of side effects already limits their use in the different licensed indications. Similarly, clinical studies on response rates in larger groups of patients will have to take into account the heterogeneity among AA patients. Maintenance of hair growth and relapse rates after cessation of therapy will have to be monitored carefully. Also, we have to be very aware of the fact that despite its tremendous psychosocial burden, AA is a benign lifelong genetic predisposition, with one third of AA patients being affected before 30 years of age. Safety aspects will have to be carefully considered especially in this young population. With this regard, the small molecule JAK inhibitors do not only offer advantages for effective oral delivery, but are also highly interesting candidate molecules for topical treatment. While overall penetration rates in skin especially via the transfollicular route should not be a problem, a focus of research should be put on ways to increase follicular penetration and reduce systemic absorption. Incorporation in particle-based formulations or even the design of functionalized nanocarriers capable of targeting inflammatory infiltrates along the hair follicle could be one option for future developments in AA management strategies. Such targeted delivery may help increase local drug concentration and efficacy with reduced systemic side-effects. This translational exemplary research may pave the way to further target-oriented strategies based on insights in the disease pathogenesis rather than empiric observation, even in such complex autoimmune mediated diseases as alopecia areata.