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The TP53 gene, encoding tumour suppressor protein p53, is located on the short arm of chromosome 17 (17p). Patients with 17p deletion (del17p) chronic lymphocytic leukaemia have poor responses and survival after chemoimmunotherapy. We assessed the activity and safety of ibrutinib, an oral covalent inhibitor of Bruton's tyrosine kinase, in relapsed or refractory patients with del17p chronic lymphocytic leukaemia or small lymphocytic lymphoma. We did a multicentre, international, open-label, single-arm study at 40 sites in the USA, Canada, Europe, Australia, and New Zealand. Patients (age ≥18 years) with previously treated del17p chronic lymphocytic leukaemia or small lymphocytic lymphoma received oral ibrutinib 420 mg once daily until progressive disease or unacceptable toxicity. The primary endpoint was overall response in the all-treated population per International Workshop on Chronic Lymphocytic Leukaemia 2008 response criteria modified for treatment-related lymphocytosis. Preplanned exploratory analyses were progression-free survival, overall survival, sustained haematological improvement, and immunological improvement. Patient enrolment is complete, but follow-up is ongoing. Treatment discontinuation owing to adverse events, unacceptable toxicity, or death were collected as a single combined category. This study is registered with ClinicalTrials.gov, number NCT01744691. Between Jan 29, 2013, and June 19, 2013, 145 patients were enrolled. The all-treated population consisted of 144 patients with del17p chronic lymphocytic leukaemia or small lymphocytic lymphoma who received at least one dose of study drug, with a median age of 64 years (IQR 57–72) and a median of two previous treatments (IQR 1–3). At the prespecified primary analysis after a median follow-up of 11·5 months (IQR 11·1–13·8), 92 (64%, 95% CI 56–71) of 144 patients had an overall response according to independent review committee assessment; 119 patients (83%, 95% CI 76–88) had an overall response according to investigator assessment. In an extended analysis with median follow-up of 27·6 months (IQR 14·6–27·7), the investigator-assessed overall response was reported in 120 patients (83%, 95% CI 76–89). 24-month progression-free survival was 63% (95% CI 54–70) and 24-month overall survival was 75% (67–81). Sustained haematological improvement was noted in 72 (79%) of 91 patients with any baseline cytopenia. No clinically relevant changes were noted from baseline to 6 months or 24 months in IgA (median 0·4 g/L at baseline, 0·6 g/L at 6 months, and 0·7 g/L at 24 months), IgG (5·0 g/L, 5·3 g/L, and 4·9 g/L), or IgM (0·3 g/L at each timepoint) concentrations. Common reasons for treatment discontinuation were progressive disease in 34 (24%) patients and adverse events, unacceptable toxicity, or death in 24 (17%) patients. Major bleeding occurred in 13 (9%) patients (11 [8%] grade 3–4). Grade 3 or worse infections occurred in 43 (30%) patients, including pneumonia in 19 (13%) patients. In the extended analysis, 38 patients died, 18 as a result of adverse events (four pneumonia, three chronic lymphocytic leukaemia, two Richter's syndrome, two sepsis, and one each of acute myocardial infarction, septic shock, encephalopathy, general deterioration in physical health, abnormal hepatic function, myocardial infarction, and renal infarction). A high proportion of patients had an overall response to ibrutinib and the risk:benefit profile was favourable, providing further evidence for use of ibrutinib in the most difficult subset of patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma. Ibrutinib represents a clinical advance in the treatment of patients with del17p chronic lymphocytic leukaemia and has been incorporated into treatment algorithms as a primary treatment for these patients. Pharmacyclics LLC, an AbbVie Company.

•Upadacitinib was evaluated in children with moderate to severe atopic dermatitis.•Apparent oral clearance of upadacitinib was associated with pediatric body weight.•The evaluated upadacitinib pediatric regimen was generally safe and effective. This study aims to characterize the pharmacokinetics, safety, tolerability, and exploratory efficacy of upadacitinib, an oral Janus kinase inhibitor approved for treating moderate to severe atopic dermatitis (AD) in adults and adolescents, in children with severe AD. In an open-label, multiple-dose, Phase 1 study, pediatric patients with severe AD from two age groups (2 to <6 years and 6 to <12 years) received bodyweight-based dosing regimens of upadacitinib using either twice-daily immediate-release (IR) oral solution or once-daily extended-release (ER) tablets. A pharmacokinetic assessment was conducted on Day 7 of the study, which was followed by a long-term safety and exploratory efficacy evaluation for up to 108 weeks. The results reported here are based on an interim analysis when the study had completed enrollment and pharmacokinetic assessment. A total of 35 patients were enrolled and received upadacitinib. The maximum upadacitinib plasma concentration was attained within a median time of 0.5 to 2 hours and 2 to 2.5 hours for the IR oral solution and ER tablet formulations, respectively. Upadacitinib functional half-life was generally shorter with IR oral solution relative to ER tablets. Upadacitinib apparent oral clearance decreased with decreasing body weight in the pediatric patients enrolled in this study. Upadacitinib was generally safe and well tolerated. The most common (≥3 patients) adverse events were upper respiratory tract infection, COVID-19 infection, headache, abdominal discomfort, vomiting, asthma, and cough. No new safety risks were identified compared to the known safety profile for upadacitinib in adults and adolescents. In the 30 patients with available exploratory efficacy data at Week 12, 36.7% achieved validated Investigator's Global Assessment scale for AD score of 0 or 1 (Validated Investigator Global Assessment for AD 0/1), and 70.0% had Eczema Area and Severity Index (EASI) improvement of at least 75% (EASI 75). The characterized pharmacokinetic profiles in this study, together with the observed safety and exploratory efficacy results, support further investigation of the current upadacitinib dosing regimen in future confirmatory Phase 3 clinical trials in children with AD. Clinical Trial Number: NCT03646604, registered 2018-08-23

Upadacitinib is an oral Janus kinase (JAK) inhibitor with greater inhibitory potency for JAK1 than JAK2, JAK3, and tyrosine kinase 2. We aimed to assess the efficacy and safety of upadacitinib compared with placebo for the treatment of moderate-to-severe atopic dermatitis. Measure Up 1 and Measure Up 2 were replicate multicentre, randomised, double-blind, placebo-controlled, phase 3 trials; Measure Up 1 was done at 151 clinical centres in 24 countries across Europe, North and South America, Oceania, and the Asia-Pacific region; and Measure Up 2 was done at 154 clinical centres in 23 countries across Europe, North America, Oceania, and the Asia-Pacific region. Eligible patients were adolescents (aged 12–17 years) and adults (aged 18–75 years) with moderate-to-severe atopic dermatitis (≥10% of body surface area affected by atopic dermatitis, Eczema Area and Severity Index [EASI] score of ≥16, validated Investigator's Global Assessment for Atopic Dermatitis [vIGA-AD] score of ≥3, and Worst Pruritus Numerical Rating Scale score of ≥4). Patients were randomly assigned (1:1:1) using an interactive response technology system to receive upadacitinib 15 mg, upadacitinib 30 mg, or placebo once daily for 16 weeks, stratified by baseline disease severity, geographical region, and age. Coprimary endpoints were the proportion of patients who had achieved at least a 75% improvement in EASI score from baseline (EASI-75) and the proportion of patients who had achieved a vIGA-AD response (defined as a vIGA-AD score of 0 [clear] or 1 [almost clear] with ≥2 grades of reduction from baseline) at week 16. Efficacy was analysed in the intention-to-treat population and safety was analysed in all randomly assigned patients who received at least one dose of study drug. These trials are registered with ClinicalTrials.gov, NCT03569293 (Measure Up 1) and NCT03607422 (Measure Up 2), and are both active but not recruiting. Between Aug 13, 2018, and Dec 23, 2019, 847 patients were randomly assigned to upadacitinib 15 mg (n=281), upadacitinib 30 mg (n=285), or placebo (n=281) in the Measure Up 1 study. Between July 27, 2018, and Jan 17, 2020, 836 patients were randomly assigned to upadacitinib 15 mg (n=276), upadacitinib 30 mg (n=282), or placebo (n=278) in the Measure Up 2 study. At week 16, the coprimary endpoints were met in both studies (all p<0·0001). The proportion of patients who had achieved EASI-75 at week 16 was significantly higher in the upadacitinib 15 mg (196 [70%] of 281 patients) and upadacitinib 30 mg (227 [80%] of 285 patients) groups than the placebo group (46 [16%] of 281 patients) in Measure Up 1 (adjusted difference in EASI-75 response rate vs placebo, 53·3% [95% CI 46·4–60·2] for the upadacitinib 15 mg group; 63·4% [57·1–69·8] for the upadacitinib 30 mg group) and Measure Up 2 (166 [60%] of 276 patients in the upadacitinib 15 mg group and 206 [73%] of 282 patients in the upadacitinib 30 mg group vs 37 [13%] of 278 patients in the placebo group; adjusted difference in EASI-75 response rate vs placebo, 46·9% [39·9–53·9] for the upadacitinib 15 mg group; 59·6% [53·1–66·2] for the upadacitinib 30 mg group). The proportion of patients who achieved a vIGA-AD response at week 16 was significantly higher in the upadacitinib 15 mg (135 [48%] patients) and upadacitinib 30 mg (177 [62%] patients) groups than the placebo group (24 [8%] patients) in Measure Up 1 (adjusted difference in vIGA-AD response rate vs placebo, 39·8% [33·2–46·4] for the upadacitinib 15 mg group; 53·6% [47·2–60·0] for the upadacitinib 30 mg group) and Measure Up 2 (107 [39%] patients in the upadacitinib 15 mg group and 147 [52%] patients in the upadacitinib 30 mg group vs 13 [5%] patients in the placebo group; adjusted difference in vIGA-AD response rate vs placebo, 34·0% [27·8–40·2] for the upadacitinib 15 mg group; 47·4% [41·0–53·7] for the upadacitinib 30 mg group). Both upadacitinib doses were well tolerated. The incidence of serious adverse events and adverse events leading to study drug discontinuation were similar among groups. The most frequently reported treatment-emergent adverse events were acne (19 [7%] of 281 patients in the upadacitinib 15 mg group, 49 [17%] of 285 patients in the upadacitinib 30 mg group, and six [2%] of 281 patients in the placebo group in Measure Up 1; 35 [13%] of 276 patients in the upadacitinib 15 mg group, 41 [15%] of 282 patients in the upadacitinib 30 mg group, and six [2%] of 278 patients in the placebo group in Measure Up 2), upper respiratory tract infection (25 [9%] patients, 38 [13%] patients, and 20 [7%] patients; 19 [7%] patients, 17 [16%] patients, and 12 [4%] patients), nasopharyngitis (22 [8%] patients, 33 [12%] patients, and 16 [6%] patients; 16 [6%] patients, 18 [6%] patients, and 13 [5%] patients), headache (14 [5%] patients, 19 [7%] patients, and 12 [4%] patients; 18 [7%] patients, 20 [7%] patients, and 11 [4%] patients), elevation in creatine phosphokinase levels (16 [6%] patients, 16 [6%] patients, and seven [3%] patients; nine [3%] patients, 12 [4%] patients, and five [2%] patients), and atopic dermatitis (nine [3%] patients, four [1%] patients, and 26 [9%] patients; eight [3%] patients, four [1%] patients, and 26 [9%] patients). Monotherapy with upadacitinib might be an effective treatment option and had a positive benefit–risk profile in adolescents and adults with moderate-to-severe atopic dermatitis. AbbVie.

Systemic therapies are typically combined with topical corticosteroids for the management of moderate-to-severe atopic dermatitis. Upadacitinib is an oral Janus kinase (JAK) inhibitor with greater inhibitory potency for JAK1 than JAK2, JAK3, or tyrosine kinase 2 that is being tested for atopic dermatitis. We aimed to assess the efficacy and safety of upadacitinib plus topical corticosteroids compared with placebo for the treatment of moderate-to-severe atopic dermatitis. In this randomised, double-blind, placebo-controlled, phase 3 trial (AD Up) adults (aged 18–75 years) and adolescents (aged 12–17 years) with chronic atopic dermatitis that was moderate to severe (≥10% of body surface area affected, Eczema Area and Severity Index [EASI] score of ≥16, validated Investigator's Global Assessment for atopic dermatitis [vIGA-AD] score of ≥3, and weekly average Worst Pruritus Numerical Rating Scale score of ≥4 at baseline) were enrolled at 171 clinical centres across 22 countries in the Asia-Pacific region, Europe, the Middle East, North America, and Oceania. Patients were randomly assigned (1:1:1) to receive upadacitinib 15 mg, upadacitinib 30 mg, or placebo once daily, all in combination with topical corticosteroids for 16 weeks. Randomisation was done using an interactive response technology system, stratified by baseline disease severity, geographical region, and age. Study investigators, study site personnel, and patients were masked to study treatment. The coprimary endpoints were the proportion of patients who had achieved at least a 75% reduction in EASI score from baseline (EASI-75) and the proportion of patients who had achieved a vIGA-AD response (defined as a vIGA-AD score of 0 [clear] or 1 [almost clear] with ≥2 grades of improvement from baseline) at week 16. Efficacy was analysed in the intention-to-treat population and safety was analysed in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, NCT03568318, and is active, but not recruiting. Between Aug 9, 2018, and Dec 20, 2019, 901 patients were randomly assigned to receive upadacitinib 15 mg plus topical corticosteroids (n=300), upadacitinib 30 mg plus topical corticosteroids (n=297), or placebo plus topical corticosteroids (n=304). At week 16, the proportion of patients who had achieved EASI-75 was significantly higher in the upadacitinib 15 mg plus topical corticosteroid group (194 [65%] of 300 patients) and the upadacitinib 30 mg plus topical corticosteroids group (229 [77%] of 297 patients) than the placebo group (80 [26%] of 304 patients; adjusted difference in EASI-75 response rate vs placebo, 38·1% [95% CI 30·8–45·4] for the upadacitinib 15 mg group and 50·6% [43·8–57·4] for the upadacitinib 30 mg group; p<0·0001 for both doses). The proportion of patients who had achieved a vIGA-AD response at week 16 was significantly higher in the upadacitinib 15 mg plus topical corticosteroid group (119 [40%] patients) and upadacitinib 30 mg plus topical corticosteroid group (174 [59%] patients) than the placebo group (33 [11%] patients; adjusted difference in vIGA-AD response vs placebo, 28·5% [22·1–34·9] for the upadacitinib 15 mg group and 47·6% [41·1–54·0] for the upadacitinib 30 mg group; p<0·0001 for both doses). During the double-blind period, upadacitinib 15 and 30 mg were well tolerated in combination with topical corticosteroids. The most frequently reported treatment-emergent adverse events (≥5% in any treatment group) were acne, nasopharyngitis, upper respiratory tract infection, oral herpes, elevation of blood creatine phosphokinase levels, headache, and atopic dermatitis. The incidence of acne was higher in the upadacitinib 15 mg (30 [10%] of 300 patients) and upadacitinib 30 mg (41 [14%] of 297 patients) groups than the placebo group (six [2%] of 304 patients). The incidence of adverse events leading to discontinuation of study drug (four [1%] patients in the upadacitinib 15 mg plus topical corticosteroids group, four [1%] patients in the upadacitinib 30 mg plus topical corticosteroids group, and seven [2%] patients in the placebo plus topical corticosteroids group) and serious adverse events (seven [2%] patients, four [1%] patients, and nine [3%] patients) were similar among treatment groups. No deaths were reported in any treatment group. Upadacitinib plus topical corticosteroids was well tolerated and superior to placebo plus topical corticosteroids. Upadacitinib as combination therapy had a positive benefit–risk profile in adults and adolescents with moderate-to-severe atopic dermatitis. AbbVie.

The JAK pathway is a potential therapeutic target in ankylosing spondylitis. This study assessed the efficacy and safety of upadacitinib, a selective JAK1 inhibitor, in patients with ankylosing spondylitis. This multicentre, randomised, double-blind, placebo-controlled, two-period, parallel-group, phase 2/3 study, SELECT-AXIS 1, enrolled adults in 62 sites in 20 countries. Eligible patients had active ankylosing spondylitis, fulfilled modified New York criteria, were previously untreated with biological disease-modifying antirheumatic drugs, and had inadequate response to at least two or intolerance or contraindication to non-steroidal anti-inflammatory drugs. Patients were randomly assigned 1:1 using interactive response technology to take oral upadacitinib 15 mg once daily or oral placebo for the 14-week period 1; only period 1 data are reported here. The primary endpoint was the composite outcome measure of the Assessment of SpondyloArthritis international Society 40 response at week 14. Analyses were done in the full analysis set of patients who were randomly assigned and received at least one dose of study drug. This study is registered with ClinicalTrials.gov, NCT03178487. Between Nov 30, 2017, and Oct 15, 2018, 187 patients were randomly assigned to upadacitinib 15 mg (93 patients) or to placebo (94 patients), and 178 (95%) patients (89 in the upadacitinib group and 89 in the placebo group) completed period 1 on study drug (by the completion date of Jan 21, 2019). Significantly more patients had an Assessment of SpondyloArthritis international Society 40 response in the upadacitinib group versus in the placebo group at week 14 (48 [52%] of 93 patients vs 24 [26%] of 94 patients; p=0·0003; treatment difference 26% [95% CI 13–40]). Adverse events were reported in 58 (62%) of 93 patients in the upadacitinib group versus 52 (55%) of 94 in the placebo group. The most common adverse event in the upadacitinib group was increased creatine phosphokinase (eight [9%] of 93 patients in the upadacitinib group vs two [2%] of 94 patients with placebo). No serious infections, herpes zoster, malignancy, venous thromboembolic events, or deaths were reported; one serious adverse event was reported in each group. Upadacitinib 15 mg was efficacious and well tolerated in patients with active ankylosing spondylitis who had an inadequate response or contraindication to non-steroidal anti-inflammatory drugs. These data support the further investigation of upadacitinib for the treatment of axial spondyloarthritis. AbbVie.

A hallmark of SLE is the production of high-titer, high-affinity, isotype-switched IgG autoantibodies directed against nucleic acid-associated antigens. Several studies have established a role for both type I IFN (IFN-I) and the activation of TLRs by nucleic acid-associated autoantigens in the pathogenesis of this disease. Here, we demonstrate that 2 IFN-I signaling molecules, IFN regulatory factor 9 (IRF9) and STAT1, were required for the production of IgG autoantibodies in the pristane-induced mouse model of SLE. In addition, levels of IgM autoantibodies were increased in pristane-treated Irf9 -/- mice, suggesting that IRF9 plays a role in isotype switching in response to self antigens. Upregulation of TLR7 by IFN-alpha was greatly reduced in Irf9 -/- and Stat1 -/- B cells. Irf9 -/- B cells were incapable of being activated through TLR7, and Stat1 -/- B cells were impaired in activation through both TLR7 and TLR9. These data may reveal a novel role for IFN-I signaling molecules in both TLR-specific B cell responses and production of IgG autoantibodies directed against nucleic acid-associated autoantigens. Our results suggest that IFN-I is upstream of TLR signaling in the activation of autoreactive B cells in SLE.

Natural killer (NK) cells from NOD mice have numeric and functional abnormalities, and restoration of NK cell function prevents autoimmune diabetes in NOD mice. However, little is known about the number and function of NK cells in humans affected by type 1 diabetes. Therefore, we evaluated the phenotype and function of NK cells in a large cohort of type 1 diabetic children. Peripheral blood mononuclear blood cells were obtained from subjects whose duration of disease was between 6 months and 2 years. NK cells were characterized by flow cytometry, enzyme-linked immunosorbent spot assays, and cytotoxicity assays. Signaling through the activating NK cell receptor, NKG2D, was assessed by immunoblotting and reverse-phase phosphoprotein lysate microarray. NK cells from type 1 diabetic subjects were present at reduced cell numbers compared with age-matched, nondiabetic control subjects and had diminished responses to the cytokines interleukin (IL)-2 and IL-15. Analysis before and after IL-2 stimulation revealed that unlike NK cells from nondiabetic control subjects, NK cells from type 1 diabetic subjects failed to downregulate the NKG2D ligands, major histocompatibility complex class I-related chains A and B, upon activation. Moreover, type 1 diabetic NK cells also exhibited decreased NKG2D-dependent cytotoxicity and interferon-γ secretion. Finally, type 1 diabetic NK cells showed clear defects in NKG2D-mediated activation of the phosphoinositide 3-kinase-AKT pathway. These results are the first to demonstrate that type 1 diabetic subjects have aberrant signaling through the NKG2D receptor and suggest that NK cell dysfunction contributes to the autoimmune pathogenesis of type 1 diabetes.

The recent approval of the biologic therapy, belimumab, for treatment of systemic lupus erythematosus (SLE) by the US FDA has shifted the developmental landscape of therapeutics for this autoimmune disease. Promising therapies are currently in development for the treatment of SLE, with trials designed to emphasize clinically relevant end points. This article will discuss outcome measures that have been utilized including disease activity indices, definitions of flare, measures of damage, global assessments of disease activity and measures of health-related quality of life. Application of these outcome measures in recent trials are highlighted as illustrative examples. Contributions to the recent success of randomized controlled trials in SLE have included use of evidence-based responder indices, clear definitions of treatment failure, predefined management strategies for use of immunosuppressive agents and corticosteroids, sufficient sample sizes and efforts to identify responsive patient populations. Each completed study in SLE promises to better inform trial design and offer further opportunities for success in a field with a continuing unmet therapeutic need.

Significance Patients with the autoimmune disease systemic lupus erythematosus (SLE) develop pathogenic antibodies against their own “self”-antigens. The development of such autoantibodies is thought in part to require help from CD4 ⁺ T cells that also recognize the same self-antigens and direct autoantibody production. In this study, antigen-specific CD4 ⁺ T cells in lupus are identified and tracked for the first time using tetramers containing peptides from the spliceosomal protein U1-70. The proportion of circulating, tetramer-positive CD4 ⁺ cells correlates with the presence of U1-70–specific autoantibodies, and antigen-specific T cells are directly implicated in disease activity by their production of the proinflammatory cytokine IL-17. The role of these cells in disease pathology makes them candidate targets for therapeutic intervention. Antigen-specific CD4 ⁺ T cells are implicated in the autoimmune disease systemic lupus erythematosus (SLE), but little is known about the peptide antigens that they recognize and their precise function in disease. We generated a series of MHC class II tetramers of I-E ᵏ–containing peptides from the spliceosomal protein U1-70 that specifically stain distinct CD4 ⁺ T-cell populations in MRL/ lpr mice. The T-cell populations recognize an epitope differing only by the presence or absence of a single phosphate residue at position serine ¹⁴⁰. The frequency of CD4 ⁺ T cells specific for U1-70(131-150):I-E ᵏ (without phosphorylation) correlates with disease severity and anti–U1-70 autoantibody production. These T cells also express RORγt and produce IL-17A. Furthermore, the U1-70–specific CD4 ⁺ T cells that produce IL-17A are detected in a subset of patients with SLE and are significantly increased in patients with mixed connective tissue disease. These studies provide tools for studying antigen-specific CD4 ⁺ T cells in lupus, and demonstrate an antigen-specific source of IL-17A in autoimmune disease.

In this trial, patients with previously treated and relapsed chronic lymphoid leukemia who received ibrutinib had significantly improved progression-free survival, overall survival, and response rate, as compared with those who received ofatumumab. Chronic lymphoid leukemia (CLL) is characterized by a variable natural history that is partly predicted by clinical and genomic features. 1 Therapy for CLL has evolved from monotherapy with alkylating agents to chemoimmunotherapy. 2 , 3 Each of the combination regimens has shown prolonged rates of progression-free survival, as compared with similar regimens that do not contain antibodies. Treatment of patients with relapsed CLL often includes regimens such as bendamustine and rituximab, 4 ofatumumab, 5 or investigational agents. 6 – 8 Ofatumumab was approved by the Food and Drug Administration (FDA) and the European Medicines Agency on the basis of a single-group study involving patients who had . . .