Cigarette smoke silences innate lymphoid cell function and facilitates an exacerbated type I interleukin-33-dependent response to infection.

Cigarette smoking is a major risk factor for chronic obstructive pulmonary disease and is presumed to be central to the altered responsiveness to recurrent infection in these patients. We examined the effects of smoke priming underlying the exacerbated response to viral infection in mice. Lack of interleukin-33 (IL-33) signaling conferred complete protection during exacerbation and prevented enhanced inflammation and exaggerated weight loss. Mechanistically, smoke was required to upregulate epithelial-derived IL-33 and simultaneously alter the distribution of the IL-33 receptor ST2. Specifically, smoke decreased ST2 expression on group 2 innate lymphoid cells (ILC2s) while elevating ST2 expression on macrophages and natural killer (NK) cells, thus altering IL-33 responsiveness within the lung. Consequently, upon infection and release, increased local IL-33 significantly amplified type I proinflammatory responses via synergistic modulation of macrophage and NK cell function. Therefore, in COPD, smoke alters the lung microenvironment to facilitate an alternative IL-33-dependent exaggerated proinflammatory response to infection, exacerbating disease.

Refractory neutrophilic asthma and ciliary genes.

BACKGROUND: Refractory asthma (RA) remains poorly controlled, resulting in high health care utilization despite guideline-based therapies. Patients with RA manifest higher neutrophilia as a result of increased airway inflammation and subclinical infection, the underlying mechanisms of which remain unclear. OBJECTIVE: We sought to characterize and clinically correlate gene expression differences between refractory and nonrefractory (NR) asthma to uncover molecular mechanisms driving group distinctions. METHODS: Microarray gene expression of paired airway epithelial brush and endobronchial biopsy samples was compared between 60 RA and 30 NR subjects. Subjects were hierarchically clustered to identify subgroups of RA, and biochemical and clinical traits (airway inflammatory molecules, respiratory pathogens, chest imaging) were compared between groups. Weighted gene correlation network analysis was used to identify coexpressed gene modules. Module expression scores were compared between groups using linear regression, controlling for age, sex, and body mass index. RESULTS: Differential gene expression analysis showed upregulation of proneutrophilic and downregulation of ciliary function genes/pathways in RA compared to NR. A subgroup of RA with downregulated ciliary gene expression had increased levels of subclinical infections, airway neutrophilia, and eosinophilia as well as higher chest imaging mucus burden compared to other RA, the dominant differences between RA and NR. Weighted gene correlation network analysis identified gene modules related to ciliary function, which were downregulated in RA and were associated with lower pulmonary function and higher airway wall thickness/inflammation, markers of poorer asthma control. CONCLUSIONS: Identification of a novel ciliary-deficient subgroup of RA suggests that diminished mucociliary clearance may underlie repeated asthma exacerbations despite adequate treatment, necessitating further exploration of function, mechanism, and therapeutics.

Baseline type 2 biomarker levels and response to tezepelumab in severe asthma.

BACKGROUND: Tezepelumab is a human monoclonal antibody that blocks activity of thymic stromal lymphopoietin (TSLP). In the phase IIb PATHWAY study (NCT02054130), tezepelumab significantly reduced annualized asthma exacerbation rates (AAERs) versus placebo in adults with severe, uncontrolled asthma. We evaluated the effects of tezepelumab in reducing type 2 (T2) inflammatory biomarker levels in the PATHWAY population, and the relationship between baseline T2 biomarker levels and AAER. METHODS: Adults with severe, uncontrolled asthma (n = 550) were randomized to tezepelumab (70 mg or 210 mg every 4 weeks, or 280 mg every 2 weeks) or placebo for 52 weeks. Blood eosinophil count, fractional exhaled nitric oxide (FeNO), and serum total immunoglobulin (Ig)E, interleukin (IL)-5, IL-13, periostin, thymus and activation-regulated chemokine (TARC), and TSLP were measured at baseline and over 52 weeks. AAERs were analyzed by baseline threshold (high/low) biomarker levels. RESULTS: Positive correlations were observed between T2 inflammatory biomarkers (blood eosinophil count, FeNO, IL-5, IL-13 and periostin) at baseline. At Week 52, treatment with tezepelumab 210 mg reduced all biomarker levels measured from baseline versus placebo. Exacerbations were reduced by 55-83% in the pooled tezepelumab cohort versus placebo, irrespective of baseline blood eosinophil count, FeNO, or serum total IgE, IL-5, IL-13, periostin, TARC, or TSLP, when these biomarkers were assessed individually. CONCLUSION: At baseline, positive correlations between specific T2 inflammatory biomarkers were observed. Tezepelumab reduced multiple T2 inflammatory biomarkers, which indicates decreased airway inflammation, and reduced exacerbations irrespective of baseline T2 biomarker profiles in patients with severe asthma.

The relationship between airway immunoglobulin activity and eosinophils in COPD.

In chronic obstructive pulmonary disease (COPD), the effects of inhaled corticosteroids are predicted by blood eosinophil counts. We previously briefly reported increased immunoglobulin (Ig)A and IgM levels in bronchoalveolar lavage (BAL) of COPD patients with higher (eosinophilhigh ) compared to lower (eosinophillow ) blood eosinophils (>250/µL versus < 150/µL), suggesting differences in adaptive immune function. An inverse relationship exists between eosinophil counts and airway pathogenic bacteria levels. The mechanistic reasons for these associations between eosinophils, corticosteroids and pathogenic bacteria are unclear. IgA, IgM and IgG levels were assessed in BAL, bronchial biopsies and epithelium collected from eosinophilhigh (n = 20) and eosinophillow (n = 21) patients. Bronchial B-cell numbers were measured by immunohistochemistry. B-cell activity was assessed in bronchial samples and following exposure to BAL from eosinophilhigh and eosinophillow patients. BAL levels of non-typeable Haemophilus influenza (NTHi)-specific immunoglobulins were quantified. Results showed airway expression of IgA, IgG1 and IgM were lower in eosinophillow compared to eosinophilhigh patients, with lower levels of NTHi-specific IgA and IgM. Bronchial B-cell numbers were similar in both groups, but B-cell activity was lower in eosinophillow patients. In conclusion, COPD eosinophillow patients show differences in adaptive immune function compared to COPD eosinophilhigh patients. These differences may cause different microbiomes in these COPD phenotypes.

Modulation of blood inflammatory markers by benralizumab in patients with eosinophilic airway diseases.

BACKGROUND: Benralizumab, a humanized, afucosylated, monoclonal antibody that targets interleukin-5 receptor α, depletes eosinophils and basophils by enhanced antibody-dependent cell-mediated cytotoxicity. It demonstrated efficacy for patients with moderate to severe asthma and, in a Phase IIa trial, for chronic obstructive pulmonary disease (COPD) with eosinophilic inflammation. We investigated effects of benralizumab 100 mg every 8 weeks (first three doses every 4 weeks) subcutaneous on blood inflammatory markers through proteomic and gene-expression analyses collected during two Phase II studies of patients with eosinophilic asthma and eosinophilic COPD. METHODS: Serum samples for proteomic analysis and whole blood for gene expression analysis were collected at baseline and 52 weeks (asthma study) or 32 weeks (COPD study) post-treatment. Proteomic analyses were conducted on a custom set of 90 and 147 Rules-Based Medicine analytes for asthma and COPD, respectively. Gene expression was profiled by Affymetrix Human Genome U133 plus 2 arrays (~ 54 K probes). Gene set variation analysis (GSVA) was used to determine transcriptomic activity of immune signatures. Treatment-related differences between analytes, genes, and gene signatures were analyzed for the overall population and for patient subgroups stratified by baseline blood eosinophil count (eosinophil-high [≥300 cells/µL] and eosinophil-low [< 300 cells/µL]) via t-test and repeated measures analysis of variance. RESULTS: Eosinophil chemokines eotaxin-1 and eotaxin-2 were significantly upregulated (false discovery rate [FDR] < 0.05) by approximately 2.1- and 1.4-fold in the asthma study and by 2.3- and 1.7-fold in the COPD study following benralizumab treatment. Magnitude of upregulation of these two chemokines was greater for eosinophil-high patients than eosinophil-low patients in both studies. Benralizumab was associated with significant reductions (FDR < 0.05) in expression of genes associated with eosinophils and basophils, such as CLC, IL-5Rα, and PRSS33; immune-signaling complex genes (FCER1A); G-protein-coupled receptor genes (HRH4, ADORA3, P2RY14); and further immune-related genes (ALOX15 and OLIG2). The magnitude of downregulation of gene expression was greater for eosinophil-high than eosinophil-low patients. GSVA on immune signatures indicated significant treatment reductions (FDR < 0.05) in eosinophil-associated signatures. CONCLUSIONS: Benralizumab is highly selective, modulating blood proteins or genes associated with eosinophils or basophils. Modulated protein and gene expression patterns are most prominently altered in eosinophil-high vs. eosinophil-low patients. TRIAL REGISTRATION: NCT01227278 and NCT01238861 .

Airway and serum biochemical correlates of refractory neutrophilic asthma.

BACKGROUND: Despite progress in the diagnosis and management of asthma, many patients have poorly controlled or refractory asthma (RA). The mechanism of this RA is not well understood. OBJECTIVE: We sought to explore the relationship between neutrophils and other biomarkers of RA. METHOD: Sixty patients with RA, 30 patients with nonrefractory asthma (NRA), and 20 healthy subjects were enrolled. We performed a comprehensive characterization of these study subjects, which included laboratory and pulmonary function studies, chest computed tomography, and bronchoscopy with bronchoalveolar lavage (BAL). We analyzed BAL fluid and serum for a total of 244 biomolecules using a multiplex assay and correlated them with clinical and other laboratory parameters. RESULTS: RA was significantly different from NRA with regard to pulmonary function indices, bronchial basement membrane thickness, and BAL fluid neutrophil and lymphocyte counts but not eosinophil counts. BAL fluid neutrophil counts negatively and positively correlated with forced vital capacity and age, respectively. Of the 244 biomolecules studied, 52 and 14 biomolecules from BAL fluid and serum, respectively, were significantly different among the study groups. Thirteen of these 52 molecules correlated with BAL fluid neutrophil counts. BAL fluid from 40% of patients with RA was positive for a pathogenic microbe. Infection-negative neutrophilic RA was associated with an increase in levels of select biomarkers of inflammation in the serum, suggesting the presence of systemic inflammation. CONCLUSIONS: RA was associated with increased numbers of neutrophils and proneutrophilic biomolecules in the airways. Subclinical infection was present in 40% of patients with RA, which likely contributed to neutrophilic inflammation. A subgroup of patients with noninfected neutrophilic RA was associated with systemic inflammation.

A Sputum Proteomic Signature That Associates with Increased IL-1ß Levels and Bacterial Exacerbations of COPD.

PURPOSE: Activation of the interleukin-1ß (IL-1ß) signaling pathway has been implicated in COPD, but the proportion of COPD subjects whose disease is principally driven by activation of this pathway is poorly understood. In this study, we sought to differentiate an IL-1ß-associated sputum signature from other inflammation-associated COPD phenotypes. METHODS: Luminex-multiplex assays were used to study IL-1ß-mediated signature proteins within airway epithelium, smooth muscle, and vascular endothelial cell cultures. The IL-1ß-mediated signature was tested in a longitudinal study comprising of 35 paired stable-COPD and acute exacerbation (AECOPD) sputum samples. The presence of respiratory pathogens (H. influenzae, M. catarrhalis, S. pneumoniae, and P. aeruginosa) was evaluated by sputum cultures. RESULTS: Five proteins namely TNF-α, GCSF, IL-6, CD-40L, and MIP-1ß were found to be IL-1ß-regulated across all donors and cell types. All five of these IL-1ß-mediated proteins were significantly increased (p < 0.05) in sputum corresponding to AECOPD events showing at least a twofold increase in IL-1ß (IL-1ß(+) events, 18 of 35 total events), relative to preceding stable-COPD state. Sputum IL-1ß levels showed no significant association (p > 0.05, spearman) with known markers of other major COPD inflammation phenotypes. In addition, there was a significant association with bacterial presence in sputum culture with an odds ratio of 9 (95 % CI 1.56, 51.9) in IL-1ß(+) events versus IL-1ß(-) events. CONCLUSION: Our findings provide insights into potential markers of IL-1ß-associated AECOPD, and reaffirm association between IL-1ß pathway activation and airway bacterial infection in COPD. Taken together, our findings could help identify COPD patient subsets who may benefit from therapies targeting IL-1ß pathway.

CD40 ligand antagonist dazodalibep in Sjögren's disease: a randomized, double-blinded, placebo-controlled, phase 2 trial.

Sjögren's disease (SjD) is a chronic, systemic autoimmune disease with no approved disease-modifying therapies. Dazodalibep (DAZ), a novel nonantibody fusion protein, is a CD40 ligand antagonist that blocks costimulatory signals between T and B cells and antigen-presenting cells, and therefore may suppress the wide spectrum of cellular and humoral responses that drive autoimmunity in SjD. This study was a phase 2, randomized, double-blinded, placebo (PBO)-controlled trial of DAZ with a crossover stage in two distinct populations of participants with SjD. Population 1 had moderate-to-severe systemic disease activity and population 2 had an unacceptable symptom burden and limited systemic organ involvement. All participants had a diagnosis of SjD, with 21.6% and 10.1% having an associated connective tissue disease (rheumatoid arthritis or systemic lupus erythematosus) in populations 1 and 2, respectively. The remaining participants would be considered as having primary Sjögren's syndrome. The primary endpoint for population 1 (n = 74) was the change from baseline in the European League Against Rheumatism Sjögren's Syndrome Disease Activity Index at day 169. The primary endpoint for population 2 (n = 109) was the change from baseline in the European League Against Rheumatism Sjögren's Syndrome Patient Reported Index at day 169. The primary endpoints (least squares mean ± standard error) were achieved with statistical significance for both population 1 (DAZ, -6.3 ± 0.6; PBO, -4.1 ± 0.6; P = 0.0167) and population 2 (DAZ, -1.8 ± 0.2; PBO, -0.5 ± 0.2; P = 0.0002). DAZ was generally safe and well tolerated. Among the most frequently reported adverse events were COVID-19, diarrhea, headache, nasopharyngitis, upper respiratory tract infection, arthralgia, constipation and urinary tract infection. In summary, DAZ appears to be a potential new therapy for SjD and its efficacy implies an important role for the CD40/CD40 ligand pathway in its pathogenesis. ClinicalTrials.gov identifier: NCT04129164 .

Impact of anti-interleukin-6 receptor blockade on circulating T and B cell subsets in patients with systemic lupus erythematosus.

BACKGROUND: Circulating plasmablasts/plasma cells and activated B and T cells are increased in systemic lupus erythematosus (SLE). Interleukin (IL)-6 induces differentiation of B cells into antibody-forming cells and of T cells into effector cells. OBJECTIVE: To examine the hypothesis that blocking IL-6 would reverse some of the immune abnormalities present in SLE. METHODS: Fifteen patients with SLE with mild-to moderate disease activity were treated with biweekly infusions of tocilizumab, a humanised anti-IL-6 receptor monoclonal antibody for 12 weeks. Lymphocyte subsets (analysed by flow cytometry) and serum immunoglobulin levels were compared at baseline and at weeks 6 and 12. RESULTS: Tocilizumab decreased activated T and B cells, the frequency of CD27(high)CD38(high)IgD- plasmablasts/plasma cells and IgD-CD27+ post-switched memory B cells as well as IgG+ memory B cell, whereas it increased the frequency of IgD+CD27- antigen-inexperienced B cells. Among antigen-inexperienced IgD+CD27- B cells, CD38(low) mature naïve B cells increased significantly and CD38(Intermediate)CD5+ pre-naïve B cells showed a decreasing trend, whereas CD38(high)CD5+ transitional type 1 B cells did not change. Most of the changes occurred in patients who had abnormal values at baseline. IgG, IgA, IgG1 and IgG3 serum levels decreased albeit within the normal range. The frequency of CD4+CD45RA+CCR7+ naïve T cells increased. CONCLUSIONS: In vivo blockade of the IL-6 receptor decreases lymphocyte activation and restores B and T cell homoeostasis by either blocking differentiation and/or trafficking in patients with SLE and leads to normalisation of the abnormal B and T cell subsets seen at baseline.

An autoinflammatory disease with deficiency of the interleukin-1-receptor antagonist.

BACKGROUND: Autoinflammatory diseases manifest inflammation without evidence of infection, high-titer autoantibodies, or autoreactive T cells. We report a disorder caused by mutations of IL1RN, which encodes the interleukin-1-receptor antagonist, with prominent involvement of skin and bone. METHODS: We studied nine children from six families who had neonatal onset of sterile multifocal osteomyelitis, periostitis, and pustulosis. Response to empirical treatment with the recombinant interleukin-1-receptor antagonist anakinra in the first patient prompted us to test for the presence of mutations and changes in proteins and their function in interleukin-1-pathway genes including IL1RN. RESULTS: We identified homozygous mutations of IL1RN in nine affected children, from one family from Newfoundland, Canada, three families from The Netherlands, and one consanguineous family from Lebanon. A nonconsanguineous patient from Puerto Rico was homozygous for a genomic deletion that includes IL1RN and five other interleukin-1-family members. At least three of the mutations are founder mutations; heterozygous carriers were asymptomatic, with no cytokine abnormalities in vitro. The IL1RN mutations resulted in a truncated protein that is not secreted, thereby rendering cells hyperresponsive to interleukin-1beta stimulation. Patients treated with anakinra responded rapidly. CONCLUSIONS: We propose the term deficiency of the interleukin-1-receptor antagonist, or DIRA, to denote this autosomal recessive autoinflammatory disease caused by mutations affecting IL1RN. The absence of interleukin-1-receptor antagonist allows unopposed action of interleukin-1, resulting in life-threatening systemic inflammation with skin and bone involvement. (ClinicalTrials.gov number, NCT00059748.)

A novel mutation of IL1RN in the deficiency of interleukin-1 receptor antagonist syndrome: description of two unrelated cases from Brazil.

OBJECTIVE: Monogenic autoinflammatory diseases are disorders of Mendelian inheritance that are characterized by mutations in genes that regulate innate immunity and whose typical features are systemic inflammation without high-titer autoantibodies or antigen-specific T cells. Skin and bone inflammation in the newborn period have been described in 3 of these autoinflammatory disorders: neonatal-onset multisystem inflammatory disease, Majeed syndrome, and deficiency of interleukin-1 (IL-1) receptor antagonist (DIRA) syndrome. This study was undertaken to present the characteristics of the DIRA syndrome in 2 cases from Brazil, and describe a novel mutation in IL1RN. METHODS: Two unrelated Brazilian patients were evaluated for the clinical signs and symptoms of these 3 disorders, and peripheral blood samples were assessed for mutations in NLRP3, LPIN2, and IL1RN by DNA resequencing analysis. A mutation in IL1RN that encodes a mutant protein was identified, and the expression and function of this mutant protein were compared to those of the wild-type protein. RESULTS: Both patients presented with pustular dermatitis resembling generalized pustular psoriasis, recurrent multifocal aseptic osteomyelitis, and elevation in the levels of acute-phase reactants, all of which are features most consistent with the DIRA syndrome. Chronic lung disease was observed in 1 of the patients, and jugular venous thrombosis was observed in the other patient. Both patients showed a partial response to corticosteroid therapy, and 1 patient experienced an initial improvement of dermatitis with the use of acitretin. Both patients were homozygous for a novel 15-bp (in-frame) deletion on the IL1RN gene. The mutated protein expressed in vitro had no affinity with the IL-1 receptor, and stimulation of the patients' cells with recombinant human IL-1α or IL-1ß led to oversecretion of proinflammatory cytokines, similar to the findings obtained in previously reported patients. CONCLUSION: The presence of the same homozygous novel mutation in IL1RN in 2 unrelated Brazilian patients suggests that this genetic variant may be a founder mutation that has been introduced in the Brazilian population.

Increased mast cell activation in eosinophilic chronic obstructive pulmonary disease.

Objectives: A subset of chronic obstructive pulmonary disease (COPD) patients have increased numbers of airway eosinophils associated with elevated markers of T2 inflammation. This analysis focussed on mast cell counts and mast cell-related gene expression in COPD patients with higher vs lower eosinophil counts. Methods: We investigated gene expression of tryptase (TPSAB1), carboxypeptidase A3 (CPA3), chymase (CMA1) and two mast cell specific gene signatures; a bronchial biopsy signature (MCbb) and an IgE signature (MCIgE) using sputum cells and bronchial epithelial brushings. Gene expression analysis was conducted by RNA-sequencing. We also examined bronchial biopsy mast cell numbers by immunohistochemistry. Results: There was increased expression of TPSAB1, CPA3 and MCbb in eosinophilhigh than in eosinophillow COPD patients in sputum cells and bronchial epithelial brushings (fold change differences 1.21 and 1.28, respectively, P < 0.01). Mast cell gene expression was associated with markers of T2 and eosinophilic inflammation (IL13, CLCA1, CST1, CCL26, eosinophil counts in sputum and bronchial mucosa; rho = 0.4-0.8; P < 0.05). There was no difference in MCIgE gene expression between groups. There was no difference in the total number of bronchial biopsy mast cells between groups. Conclusion: These results demonstrate that eosinophilic inflammation is associated with altered mast cell characteristics in COPD patients, implicating mast cells as a component of T2 inflammation present in a subset of COPD patients.

Comparison of Tripterygium wilfordii Hook F versus sulfasalazine in the treatment of rheumatoid arthritis: a randomized trial.

BACKGROUND: Extracts of the medicinal plant Tripterygium wilfordii Hook F (TwHF) have been used in China for centuries to treat a spectrum of inflammatory diseases. OBJECTIVE: To compare the benefits and side effects of TwHF extract with those of sulfasalazine for the treatment of active rheumatoid arthritis. DESIGN: Randomized, controlled trial. A computer-generated code with random, permuted blocks was used to assign treatment. SETTING: 2 U.S. academic centers (National Institutes of Health, Bethesda, Maryland, and University of Texas, Dallas, Texas) and 9 rheumatology subspecialty clinics (in Dallas and Austin, Texas; Tampa and Fort Lauderdale, Florida; Arlington, Virginia; Duncanville, Pennsylvania; Wheaton and Greenbelt, Maryland; and Lansing, Michigan). PATIENTS: 121 patients with active rheumatoid arthritis and 6 or more painful and swollen joints. INTERVENTION: TwHF extract, 60 mg 3 times daily, or sulfasalazine, 1 g twice daily. Patients could continue stable doses of oral prednisone or nonsteroidal anti-inflammatory drugs but had to stop taking disease-modifying antirheumatic drugs at least 28 days before randomization. MEASUREMENTS: The primary outcome was the rate of achievement of 20% improvement in the American College of Rheumatology criteria (ACR 20) at 24 weeks. Secondary end points were safety; radiographic scores of joint damage; and serum levels of interleukin-6, cholesterol, cortisol, and adrenocorticotropic hormone. RESULTS: Outcome data were available for only 62 patients at 24 weeks. In a mixed-model analysis that imputed data for patients who dropped out, 65.0% (95% CI, 51.6% to 76.9%) of the TwHF group and 32.8% (CI, 21.3% to 46.0%) of the sulfasalazine group met the ACR 20 response criteria (P=0.001). Patients receiving TwHF also had significantly higher response rates for ACR 50 and ACR 70 in mixed-model analyses. Analyses of only completers showed similar significant differences between the treatment groups. Significant improvement was demonstrated in all individual components of the ACR response, including the Health Assessment Questionnaire disability score. Interleukin-6 levels rapidly and significantly decreased in the TwHF group. Although not statistically significant, radiographic progression was lower in the TwHF group. The frequency of adverse events was similar in both groups. LIMITATIONS: Only 62% and 41% of patients continued receiving TwHF extract and sulfasalazine, respectively, during the 24 weeks of the study. Long-term outcome data were not collected on participants who discontinued treatment. CONCLUSION: In patients who continued treatment for 24 weeks and could also use stable oral prednisone and nonsteroidal anti-inflammatory drugs, attainment of the ACR 20 response criteria was significantly greater with TwHF extract than with sulfasalazine.

Neonatal-onset multisystem inflammatory disease responsive to interleukin-1beta inhibition.

BACKGROUND: Neonatal-onset multisystem inflammatory disease is characterized by fever, urticarial rash, aseptic meningitis, deforming arthropathy, hearing loss, and mental retardation. Many patients have mutations in the cold-induced autoinflammatory syndrome 1 (CIAS1) gene, encoding cryopyrin, a protein that regulates inflammation. METHODS: We selected 18 patients with neonatal-onset multisystem inflammatory disease (12 with identifiable CIAS1 mutations) to receive anakinra, an interleukin-1-receptor antagonist (1 to 2 mg per kilogram of body weight per day subcutaneously). In 11 patients, anakinra was withdrawn at three months until a flare occurred. The primary end points included changes in scores in a daily diary of symptoms, serum levels of amyloid A and C-reactive protein, and the erythrocyte sedimentation rate from baseline to month 3 and from month 3 until a disease flare. RESULTS: All 18 patients had a rapid response to anakinra, with disappearance of rash. Diary scores improved (P<0.001) and serum amyloid A (from a median of 174 mg to 8 mg per liter), C-reactive protein (from a median of 5.29 mg to 0.34 mg per deciliter), and the erythrocyte sedimentation rate decreased at month 3 (all P<0.001), and remained low at month 6. Magnetic resonance imaging showed improvement in cochlear and leptomeningeal lesions as compared with baseline. Withdrawal of anakinra uniformly resulted in relapse within days; retreatment led to rapid improvement. There were no drug-related serious adverse events. CONCLUSIONS: Daily injections of anakinra markedly improved clinical and laboratory manifestations in patients with neonatal-onset multisystem inflammatory disease, with or without CIAS1 mutations. (ClinicalTrials.gov number, NCT00069329 [ClinicalTrials.gov].).

Treating moderate-to-severe atopic dermatitis with benralizumab: results from the HILLIER study, a plain language summary.

What is this summary about? Atopic dermatitis (AD) is a chronic (long-lasting) skin disease that leads to dry, itchy, and swollen red spots, which can also be painful and flare up at any time. Some people with AD have a high number of eosinophils, a type of white blood cell, which are associated with worse disease. Medicated creams and lotions, prescribed by health care providers, are meant to reduce the symptoms of AD. For some people, these creams and lotions do not work. Benralizumab injection is a medication that reduces and removes eosinophils. A clinical trial called HILLER tested benralizumab to see if there was a difference in symptoms of AD after reducing or removing eosinophils. This article explains how benralizumab reduced eosinophils and the effect it had on AD symptoms in the HILLIER study.What were the main conclusions reported by the researchers? Benralizumab reduced blood eosinophil numbers. However, benralizumab showed no evidence of treatment benefit on signs, symptoms, or severity of AD, as measured by three skin assessments compared with placebo. Benralizumab was well tolerated and had a safety profile that was consistent with previous studies. The five most commonly reported side effects were COVID-19 infection, upper respiratory tract infection, headache, swelling of the lymph nodes, and pink eye (conjunctivitis) in patients who received either benralizumab or placeboWhat are the key takeaways? Benralizumab lowered the number of blood eosinophils without improving AD symptoms and was well tolerated.

Periostin and Dipeptidyl Peptidase-4: Potential Biomarkers of Interleukin 13 Pathway Activation in Asthma and Allergy.

Periostin and dipeptidyl peptidase-4 (DPP-4) are proteins induced by type 2 cytokines interleukin (IL)-4 and IL-13 and show increased expression in asthma and diseases with type 2 inflammation, including atopic dermatitis and chronic rhinosinusitis. Both proteins can also be induced by other stimuli, such as profibrotic factors, which may confound their specificity as biomarkers of IL-13 pathway activation and type 2-driven disease. DPP-4 is important in glucose metabolism; therefore, serum concentrations may be confounded by the presence of concomitant metabolic disease. This review evaluates the potential of these biomarkers for anti-IL-13-directed therapy in asthma and diseases with type 2 inflammation.

Reductions in eosinophil biomarkers by benralizumab in patients with asthma.

BACKGROUND: Eosinophilic inflammation is frequently associated with increased asthma severity. Benralizumab is a humanized, afucosylated, anti-interleukin-5Rα monoclonal antibody that selectively depletes eosinophils and basophils through enhanced antibody-dependent cell-mediated cytotoxicity. OBJECTIVE: To study effects of benralizumab on eosinophil counts and activity following administration to asthma patients. METHODS: Sera were collected from asthma patients enrolled in two clinical studies. Placebo or benralizumab was subcutaneously administered to patients in Phase I (100 or 200 mg, multiple doses; N = 14; NCT00659659) and Phase IIa (25, 100, or 200 mg every 4 weeks; N = 24; NCT00783289) studies. Sera were also collected from healthy volunteers (N = 20) for comparison. Blood eosinophils, IL-5, eosinophil-derived neurotoxin (EDN), eosinophil cationic protein (ECP), eotaxin/chemokine (C-C motif) 11 (CCL11), eotaxin-2/CCL24, tumor necrosis factor (TNF), and interferon-γ (IFN-γ) were measured at baseline and post-treatment. RESULTS: Increased EDN concentrations were observed in sera of patients from both studies relative to healthy volunteers (p < 0.05). At baseline, sera EDN concentrations correlated with blood eosinophil counts (rs = 0.5; p < 0.05). Benralizumab reduced blood eosinophil numbers and sera EDN and ECP relative to baseline (p < 0.05). No changes in TNF or IFN-γ were observed, while serum IL-5, eotaxin/CCL11, and eotaxin-2/CCL24 increased after benralizumab administration vs. placebo (p < 0.05). CONCLUSIONS: In two independent studies, serum IL-5, EDN, and ECP were modulated following benralizumab. Eosinophil depletion after benralizumab also resulted in significant reductions in EDN and ECP concentrations, suggesting that cytotoxic granule proteins were not released after eosinophil reduction.