Objective To report long-term safety from the completed extension trial of baricitinib, an oral selective Janus kinase inhibitor, in patients with active rheumatoid arthritis (RA). Methods Treatment-emergent adverse events are summarised from an integrated database (9 phase III/II/Ib and 1 long-term extension) of patients who received any baricitinib dose (All-bari-RA). Standardised incidence ratio (SIR) for malignancy (excluding non-melanoma skin cancer (NMSC)) and standardised mortality ratio (SMR) were estimated. Additional analysis was done in a subset of patients who had ever taken 2 mg or 4 mg baricitinib. Results 3770 patients received baricitinib (14 744 patient-years of exposure (PYE)). All-bari-RA incidence rates (IRs) per 100 patient-years at risk were 2.6, 3.0 and 0.5 for serious infections, herpes zoster and major adverse cardiovascular events (MACE), respectively. In patients aged ≥50 with ≥1 cardiovascular risk factor, the IR for MACE was 0.77 (95% CI 0.56 to 1.04). The IR for malignancy (excluding NMSC) during the first 48 weeks was 0.6 and remained stable thereafter (IR 1.0). The SIR for malignancies excluding NMSC was 1.07 (95% CI 0.90 to 1.26) and the SMR was 0.74 (95% CI 0.59 to 0.92). All-bari-RA IRs for deep vein thrombosis (DVT)/pulmonary embolism (PE), DVT and PE were 0.5 (95% CI 0.38 to 0.61), 0.4 (95% CI 0.26 to 0.45) and 0.3 (95% CI 0.18 to 0.35), respectively. No clear dose differences were noted for exposure-adjusted IRs (per 100 PYE) for deaths, serious infections, DVT/PE and MACE. Conclusions In this integrated analysis including long-term data of baricitinib from 3770 patients (median 4.6 years, up to 9.3 years) with active RA, baricitinib maintained a similar safety profile to earlier analyses. No new safety signals were identified. Trial registration number NCT01185353, NCT00902486, NCT01469013, NCT01710358, NCT02265705, NCT01721044, NCT01721057, NCT01711359 and NCT01885078.

https://ard.bmj.com/content/annrheumdis/early/2021/10/27/annrheumdis-2021-221276.full.pdf

Safety of baricitinib for the treatment of rheumatoid arthritis over a median of 4.6 and up to 9.3 years of treatment: final results from long-term extension study and integrated database.

Janus kinase (JAK) is a signal transducer and activator of a protein transcription system that transduces signals from cell surface cytokine and growth factor receptors to the nucleus. Recently developed JAK inhibitors (JAKinibs) inhibit JAKs non-selectively or selectively and down-regulate the effects of corresponding ligands (i.e. cytokines and growth factors). JAKinibs are efficacious against rheumatoid arthritis and other immune-mediated inflammatory diseases and are being increasingly prescribed clinically. Regarding safety, JAKinib use is associated with common or unique changes in laboratory parameters; however, incidence rates of serious adverse drug reactions (ADRs) associated with these changes are low. Opportunistic and other infections, including tuberculosis, are the most critical ADRs of treatment with JAKinibs, and screening and monitoring of patients should be carefully performed. Incidence rates of herpes zoster (HZ) in patients receiving JAKinibs are high in Japan and Korea, and modestly high in other countries. Filgotinib may not be associated with an elevated risk for HZ, but long-term safety data are lacking. Data from clinical development programmes and post-marketing surveillance have indicated no increased risk for malignancy or serious cardiac events; however, long-term observational studies are necessary. Despite the non-elevated risk of gastrointestinal perforations, patients with older age and/or a history of diverticulitis or receiving non-steroidal anti-inflammatory drugs should be carefully evaluated to determine the risk-benefit balance. The incidence rates of venous thromboembolism with all approved doses are similar to that expected in the population, although there are discrepancies in the placebo-controlled portion of the baricitinib clinical development programmes. Regulatory agencies in the USA and Europe suggested a higher risk for thrombotic events in patients receiving JAKinibs. Pharmacokinetic studies demonstrated that dose adjustment should be considered for JAKinib use in patients with moderate-to-severe renal or hepatic dysfunction, depending on the metabolism of each drug. Long-term observational studies enrolling patients with diverse clinical backgrounds are required to strike a risk-benefit balance in clinical settings.

/pdf/selectivity-of-janus-kinase-inhibitors-in-rheumatoid-1t3ntuid8j.pdf

Selectivity of Janus Kinase Inhibitors in Rheumatoid Arthritis and Other Immune-Mediated Inflammatory Diseases: Is Expectation the Root of All Headache?

Preferable treatments for epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) with brain metastasis are elusive. The study intended to estimate the relative efficacy and safety of systemic therapies. Clinical trials about therapies for EGFR-mutant, brain-metastatic NSCLC were identified. Progression-free survival (PFS) and overall survival (OS) were analysed using random effects Bayesian network meta-analyses (NMAs) on the hazard ratio (HR)-scale. Nomogram and Kaplan-Meier plots based on clinical or individual factors are displayed using data obtained from the Surveillance Epidemiology and End Results (SEER) database. Third-generation EGFR- tyrosine kinase inhibitors (EGFR-TKI) (osimertinib), EGFR-TKIs + stereotactic radiosurgery (SRS)/whole brain radiotherapy (WBRT) (gefitinib/erlotinib + SRS/WBRT), and EGFR-TKIs (erlotinib) + anti-vascular endothelial growth factor receptor (anti-VEGFR) (bevacizumab) achieved superior PFS (HR: 0.30 (0.15-0.59); HR: 0.47 (0.31-0.72); HR: 0.50 (0.21-1.21) vs. deferring SRS/WBRT) and acceptability; EGFR-TKIs + SRS/WBRT was top ranking (vs. others) for OS followed by third-generation EGFR-TKI. In the dataset cohort of 1173 brain-metastatic NSCLC patients, the 6-month, 1-year, and 3-year survival rates were 59.8%, 41.3%, and 5.6%, respectively. Race and origin, and year of diagnosis were independent predictors of OS. Survival curves showed that the OS of patients varied significantly by histology and race. Third-generation EGFR-TKI and EGFR-TKIs + SRS/WBRT are more effective and potentially acceptable for EGFR-mutant NSCLC with brain metastases balancing OS and PFS. Surgeries without adjuvant therapies cannot significantly improve the OS of brain-metastatic NSCLC patients. The study highlights importance of osimertinib in these patients and provide a reference for clinical treatments.

Efficacy and safety of therapies for EGFR-mutant non-small cell lung cancer with brain metastasis: an evidence-based Bayesian network pooled study of multivariable survival analyses.

Importance Intracranial metastatic disease (IMD) is a serious and life-altering complication for many patients with cancer. Targeted therapy may address the limitations of current treatments as an additional agent to achieve intracranial disease control in some patients with IMD. Given the paucity of evidence regarding effectiveness, current guidelines have not made recommendations on the use of targeted therapy. Osimertinib mesylate is a mutant epidermal growth factor receptor (EGFR) inhibitor that can penetrate the blood-brain barrier and inhibit tumor cell survival and proliferation in patients with non–small cell lung cancer (NSCLC) with specific EGFR alterations. Objective To assess the effectiveness and safety of osimertinib in the management of IMD. Data Sources Studies were selected from MEDLINE and Embase databases from their inception to September 20, 2019, using the following search query: (osimertinibORmereletinibORtagrissoORtamarixORazd9291) AND (brain metastasesORintracranial metastatic diseaseORcns). Study Selection Studies reporting intracranial outcomes for patients with metastatic EGFR-variant NSCLC and IMD treated with osimertinib were included in this systematic review and meta-analysis. Among 271 records identified in the systematic review, 15 studies fulfilled eligibility criteria for inclusion in the meta-analysis. Data Extraction and Synthesis Data were extracted from published studies and supplements. These data were pooled using a random-effects model. Risk of bias was assessed using the Cochrane risk of bias tool and the modified Newcastle-Ottawa Scale. Main Outcomes and Measures Information extracted included study characteristics, intracranial effectiveness measures, and safety measures. Meta-analyses of proportions were conducted to pool estimates for central nervous system (CNS) objective response rate and CNS disease control rate. Results Fifteen studies reporting on 324 patients were included in the meta-analysis. The CNS objective response rate was 64% (95% CI, 53%-76%; n = 195), and CNS disease control rate was 90% (95% CI, 85%-93%; n = 246). Included studies reported complete intracranial response rates of 7% to 23%, median best decrease in intracranial lesion size of −40% to −64%, and Common Terminology Criteria for Adverse Events (version 3.0) grade 3 or higher adverse event rates of 19% to 39%. Subgroup analyses did not reveal additional sources of heterogeneity. Conclusions and Relevance Findings reported herein support a potential role for osimertinib in the treatment of patients with metastatic EGFR-variant NSCLC and IMD treated with osimertinib. Clinical decision makers would benefit from the inclusion of patients with IMD in future trials to identify factors that predict responses to targeted therapy.

https://jamanetwork.com/journals/jamanetworkopen/articlepdf/2763239/erickson_2020_oi_200086.pdf

Assessment of Effectiveness and Safety of Osimertinib for Patients With Intracranial Metastatic Disease: A Systematic Review and Meta-analysis.

Many immune cells and effector molecules (e.g. cytokines, Interferons, growth factors) utilize different combinations of Janus kinase (JAK) and signal transducer and activator of transcription (STAT) molecules to transduce signals from the cell surface to the nucleus, where they regulate transcription. This pathway is basically involved in almost all inflammatory diseases and also in the interleukin (IL)-23/IL-17 cascade, which is an essential part of the pathogenesis of spondyloarthropathies (SpA). Upon evidence from in vitro and in vivo experiments indicating disease-modifying effects of JAK inhibition in inflammatory joint disease, numerous inhibitors of the JAK/STAT pathway (= JAKinibs) with different selectivity against the four members of the JAK family [JAK1, JAK2, JAK3, and tyrosine kinase 2 (TYK2)] were developed. Trials in rheumatoid arthritis were successful with respect to efficacy and safety, and currently, three JAKinibs are approved for the treatment of rheumatoid arthritis in the European Union. Although new treatment options (anti-IL-23, anti-IL-17, and phosphodiesterase 4 inhibitors) have become available for spondyloarthritis and especially psoriatic arthritis (PsA) within the last years, most of them are biologics and do not address all disease manifestations equally. Therefore, multiple trials were initiated to evaluate JAKinibs in PsA and axial spondyloarthritis (axSpA). A trial of Tofacitinib (OPAL) was successful in PsA and has led to the inclusion of JAKinibs into the treatment algorithm. Currently many trials with JAKinibs are ongoing for PsA and axSpA, with one phase III trial of upadacitinib (selective JAK1 inhibitor) showing good therapeutic response in active radiographic axSpA.

/pdf/impact-of-janus-kinase-inhibition-on-the-treatment-of-axial-qh9gmxcsz4.pdf

Impact of Janus Kinase Inhibition on the Treatment of Axial Spondyloarthropathies.

Background Baricitinib (BARI) is a selective inhibitor of Janus kinase (JAK) 1 and JAK2, approved for the treatment of moderately to severely active rheumatoid arthritis (RA) in adults in over 50 countries, including the United States, Europe and Japan. Due to their disease and associated therapy with disease-modifying anti-rheumatic drugs (DMARDs), RA patients (pts) have an increased risk of herpes zoster (HZ) compared with the general population.1 Furthermore, the incidence of HZ is increased in RA pts treated with BARI versus placebo (PBO).2 Objectives To determine the long-term overall and geographical incidence, time to first event and risk factors for HZ in BARI-treated RA pts. Methods Data were pooled from nine completed Phase 1, 2, and 3 studies of BARI in RA pts, including six randomised, PBO-controlled studies (0–24 weeks in DMARD-inadequate responders, including RA-BUILD, RA-BEACON and the long-term extension study, RA-BEYOND [data cut off February 13, 2018]), and active-controlled studies with methotrexate (MTX; RA-BEGIN study in DMARD-naive pts) and adalimumab (RA-BEAM study in MTX-inadequate responders). The HZ incidence was evaluated for all RA pts who had ever received BARI (any dose) and the HZ incidence rate (IR) was calculated as the number of pts with an HZ event per 100 patient–years of observation (PYO). Exposure included up to 28 days after treatment cessation, and was censored at the HZ event date. Univariate and multivariate Cox proportional hazard regression models were used to evaluate risk factors for HZ. Results Of 3770 RA pts treated with BARI, median age at study entry was 54 years (range 20–90 years), approximately one-quarter were each from North America (n=840; 22%), EU (783; 21%), Asia (959; 25%) and Central America (760; 20%), median time from RA diagnosis was 5 years, 2938 (78%) and 1754 (47%) were on concomitant MTX or corticosteroids (CS; mean dose 6.2 mg/day), respectively. HZ was reported in 323 (9%) pts over 9892 PYO, with median BARI exposure of 1115 days. Of these pts, 12 (4%) had a history of HZ, and 256 (79%) and 168 (52%) were on concomitant MTX and CS, respectively. The median time to first HZ event was 538 days and the overall IR of HZ was 3.3/100 PYO, which did not increase significantly over time (Fig 1). Twenty-six (8%) cases were multidermatomal, and no visceral disease was reported. Eight (2%) pts showed involvement of the ophthalmic division of the Vth cranial nerve and 9 (3%) experienced recurrent HZ during observation. Only 11 HZ pts (4%) had received prior HZ vaccination. Multivariate analyses showed that older age (hazard ratio [HR] 1.30, 95% confidence interval [CI] 1.17, 1.43) and geographical region (Asia, especially Japan, Taiwan and South Korea; HR 1.82, 95% CI 1.28, 2.58; Fig 2) were associated with a higher risk of HZ. Conclusion HZ incidence in BARI-treated RA pts did not increase over time and the majority of HZ events were monodermatomal and uncomplicated. Pts who were older and those from Asia were at increased risk of a HZ event. Reference [1] Smitten AL, et al. Arthritis Rheum 2007;57:1431–1438. 2. Smolen JS, et al. J Rheumatol 2019;46:7–18. Disclosure of Interests Yi-Hsing Chen: None declared, Yi-Ming Chen Grant/research support from: GSK, Pfizer, BMS, Astra & Zeneca, Consultant for: Pfizer, Novartis, Abbvie, Johnson & Johnson, BMS, Roche, Sanofi, MSD, Guigai, Astellas, Inova Diagnostics, UCB, Agnitio Science Technology, United Biopharma, Thermo Fisher, Paid instructor for: Pfizer, Novartis, Abbvie, Johnson & Johnson, BMS, Roche, Astra& Zeneca, Sanofi, MSD, Guigai, Astellas, UCB, Thermo Fisher, Speakers bureau: Pfizer, Novartis, Abbvie, Johnson & Johnson, BMS, Roche, Lilly, GSK, Astra& Zeneca, Sanofi, MSD, Guigai, Astellas, UCB, Thermo Fisher, Josef S. Smolen Grant/research support from: AbbVie, Eli Lilly, Janssen, MSD, Pfizer Inc, Roche, Consultant for: AbbVie, Amgen, AstraZeneca, Astro, Celgene, Celtrion, Eli Lilly, GlaxoSmithKline, ILTOO, Janssen, Medimmune, MSD, Novartis-Sandoz, Pfizer Inc, Roche, Samsung, Sanofi, UCB, Speakers bureau: AbbVie, Amgen, AstraZeneca, Astro, Celgene, Celtrion, Eli Lilly, GlaxoSmithKline, ILTOO, Janssen, Medimmune, MSD, Novartis-Sandoz, Pfizer Inc, Roche, Samsung, Sanofi, UCB, Tsutomu Takeuchi Grant/research support from: Astellas Pharma Inc, Chugai Pharmaceutical Co, Ltd., Daiichi Sankyo Co., Ltd., Takeda Pharmaceutical Co., Ltd., AbbVie GK, Asahikasei Pharma Corp., Mitsubishi Tanabe Pharma Co., Pfizer Japan Inc., Eisai Co., Ltd., AYUMI Pharmaceutical Corporation, Nipponkayaku Co. Ltd., Novartis Pharma K.K., Grant/research support from: AbbVie, Asahi Kasei, Astellas, AstraZeneca, AYUMI, Bristol-Myers Squibb, Chugai, Daiichi Sankyo, Eisai, Eli Lilly Japan, Janssen, Mitsubishi Tanabe, Nippon Kayaku, Novartis, Pfizer Japan Inc, Taiho, Taisho Toyama, Takeda, Teijin, Grant/research support from: Astellas Pharma Inc., Bristol Myers Squibb, Chugai Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Co., Pfizer Japan Inc., Santen Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Teijin Pharma Ltd., AbbVie GK, Asahi Kasei Pharma Corp., Taisho Toyama Pharmaceutical Co., Ltd., SymBio Pharmaceuticals Ltd., Janssen Pharmaceutical K.K., Celltrion Inc., Nipponkayaku Co. Ltd., and UCB Japan, Consultant for: Astra Zeneca K.K., Eli Lilly Japan K.K., Novartis Pharma K.K., Mitsubishi Tanabe Pharma Co., Abbivie GK, Nipponkayaku Co.Ltd, Janssen Pharmaceutical K.K., Astellas Pharma Inc., Taiho Pharmaceutical Co. Ltd., Chugai Pharmaceutical Co. Ltd., Taisho Toyama Pharmaceutical Co. Ltd., GlaxoSmithKline K.K., UCB Japan Co. Ltd., Consultant for: AbbVie, Asahi Kasei, Astellas, AstraZeneca, AYUMI, Bristol-Myers Squibb, Chugai, Daiichi Sankyo, Eisai, Eli Lilly Japan, Janssen, Mitsubishi Tanabe, Nippon Kayaku, Novartis, Pfizer Japan Inc, Taiho, Taisho Toyama, Takeda, Teijin, Consultant for: Astra Zeneca K.K., Eli Lilly Japan K.K., Novartis Pharma K.K., Mitsubishi Tanabe Pharma Co., Asahi Kasei Medical K.K., AbbVie GK, Daiichi Sankyo Co., Ltd., Bristol Myers Squibb, and Nipponkayaku Co. Ltd., Speakers bureau: Astellas Pharma Inc., Bristol Myers Squibb, Chugai Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Co., Pfizer Japan Inc., Santen Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Teijin Pharma Ltd., AbbVie GK, Asahi Kasei Pharma Corp., Taisho Toyama Pharmaceutical Co., Ltd., SymBio Pharmaceuticals Ltd., Janssen Pharmaceutical K.K., Celltrion Inc., Nipponkayaku Co. Ltd., and UCB Japan, Speakers bureau: AbbVie, Asahi Kasei, Astellas, AstraZeneca, AYUMI, Bristol-Myers Squibb, Chugai, Daiichi Sankyo, Eisai, Eli Lilly Japan, Janssen, Mitsubishi Tanabe, Nippon Kayaku, Novartis, Pfizer Japan Inc, Taiho, Taisho Toyama, Takeda, Teijin, Speakers bureau: AbbVie GK., Bristol–Myers K.K., Chugai Pharmaceutical Co. Ltd., Mitsubishi Tanabe Pharma Co., Pfizer Japan Inc., Astellas Pharma Inc, Diaichi Sankyo Co. Ltd., Eisai Co. Ltd., Sanofi K.K., Teijin Pharma Ltd., Takeda Pharmaceutical Co. Ltd., Novartis Pharma K.K., Rudiger Muller: None declared, David Walker Consultant for: Lilly, Pfizer, Roche, Novartis and Gilead, Speakers bureau: Lilly, Pfizer, Janssen., Ran Liao Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Clementine Perrier Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Wen-Shuo Wu Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Kevin Winthrop Consultant for: Gilead, Galapagos, Eli Lilly and Company, Abbvie, Pfizer, GSK

https://ard.bmj.com/content/annrheumdis/78/Suppl_2/755.full.pdf

Fri0164 incidence rate and characterization of herpes zoster in patients with moderate-to-severe rheumatoid arthritis: an update from baricitinib clinical studies

1353PCNS response to osimertinib in Asian-Pacific patients (pts) with T790M-positive advanced NSCLC: data from an open-label Phase II trial (AURA17)

OBJECTIVE The prevalence and associations of leucopenia in SLE remain incompletely understood. We evaluated associations of disease activity and medication use with leucopenia (lymphopenia and neutropenia) in a multinational, prospectively followed SLE cohort. METHODS Data from the Asia Pacific Lupus Collaboration cohort, in which disease activity and medications were prospectively captured from 2013 to 2018, were used. Predictors of lymphopenia (lymphocyte count <0.8 × 109/l) and neutropenia (neutrophil count <1.5 × 109/l) were examined using multiple failure, time-dependent survival analyses. RESULTS Data from 2330 patients and 18 287 visits were analysed. One thousand and eighteen patients (43.7%) had at least one episode of leucopenia; 867 patients (37.2%) had lymphopenia, observed in 3065 (16.8%) visits, and 292 (12.5%) patients had neutropenia, in 622 (3.4%) visits. After multivariable analyses, lymphopenia was associated with overall disease activity, ESR, serology, prednisolone, AZA, MTX, tacrolimus, CYC and rituximab use. MTX and ciclosporin were negatively associated with neutropenia. Lupus low disease activity state was negatively associated with both lymphopenia and neutropenia. CONCLUSION Both lymphopenia and neutropenia were common in SLE patients but were differentially associated with disease and treatment variables. Lymphopenia and neutropenia should be considered independently in studies in SLE.

Independent associations of lymphopenia and neutropenia in patients with systemic lupus erythematosus: a longitudinal, multinational study

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Papers

Fri0164 incidence rate and characterization of herpes zoster in patients with moderate-to-severe rheumatoid arthritis: an update from baricitinib clinical studies

1353PCNS response to osimertinib in Asian-Pacific patients (pts) with T790M-positive advanced NSCLC: data from an open-label Phase II trial (AURA17)

Independent associations of lymphopenia and neutropenia in patients with systemic lupus erythematosus: a longitudinal, multinational study