Efficacy and Safety of Baricitinib Combined With Topical Corticosteroids for Treatment of Moderate to Severe Atopic Dermatitis: A Randomized Clinical Trial.

Importance: Baricitinib, an oral selective Janus kinase 1 and 2 inhibitor, effectively reduced disease severity in moderate to severe atopic dermatitis (AD) in 2 phase 3 monotherapy studies. Objective: To assess the efficacy and safety of 4 mg and 2 mg of baricitinib in combination with background topical corticosteroid (TCS) therapy in adults with moderate to severe AD who previously had an inadequate response to TCS therapy. Design, Setting, and Participants: This double-blind, placebo-controlled, phase 3 randomized clinical trial, BREEZE-AD7 (Study of Baricitinib [LY3009104] in Combination With Topical Corticosteroids in Adults With Moderate to Severe Atopic Dermatitis) was conducted from November 16, 2018, to August 22, 2019, at 68 centers across 10 countries in Asia, Australia, Europe, and South America. Patients 18 years or older with moderate to severe AD and an inadequate response to TCSs were included. After completing the study, patients were followed up for up to 4 weeks or enrolled in a long-term extension study. Interventions: Patients were randomly assigned (1:1:1) to receive 2 mg of baricitinib once daily (n = 109), 4 mg of baricitinib once daily (n = 111), or placebo (n = 109) for 16 weeks. The use of low-to-moderate potency TCSs was allowed. Main Outcomes and Measures: The primary end point was the proportion of patients achieving a validated Investigator Global Assessment for Atopic Dermatitis (vIGA-AD) score of 0 (clear) or 1 (almost clear), with a 2-point or greater improvement from baseline at week 16. Results: Among 329 patients (mean [SD] age, 33.8 [12.4] years; 216 [66%] male), at week 16, a vIGA-AD score of 0 (clear) or 1 (almost clear) was achieved by 34 patients (31%) receiving 4 mg of baricitinib and 26 (24%) receiving 2 mg of baricitinib compared with 16 (15%) receiving placebo (odds ratio vs placebo, 2.8 [95% CI, 1.4-5.6]; P = .004 for the 4-mg group; 1.9 [95% CI, 0.9-3.9]; P = .08 for the 2-mg group). Treatment-emergent adverse events were reported in 64 of 111 patients (58%) in the 4-mg group, 61 of 109 patients (56%) in the 2-mg group, and 41 of 108 patients (38%) in the placebo group. Serious adverse events were reported in 4 patients (4%) in the 4-mg group, 2 (2%) in the 2-mg group, and 4 (4%) in the placebo group. The most common adverse events were nasopharyngitis, upper respiratory tract infections, and folliculitis. Conclusions and Relevance: A dose of 4 mg of baricitinib in combination with background TCS therapy significantly improved the signs and symptoms of moderate to severe AD, with a safety profile consistent with previous studies of baricitinib in AD. Trial Registration: ClinicalTrials.gov Identifier: NCT03733301.

Long-term safety of brodalumab in Japanese patients with plaque psoriasis: An open-label extension study.

Brodalumab, an interleukin-17 receptor A inhibitor, demonstrated rapid and robust efficacy with a favorable safety profile in patients with moderate to severe plaque psoriasis. Here, we present data from a multicenter, open-label extension study in patients with plaque psoriasis with/without psoriatic arthritis who completed 64 weeks of treatment with brodalumab (140 or 210 mg, every 2 weeks [Q2W]). Patients were enrolled to evaluate the long-term safety and efficacy of a modified dose of brodalumab. Eligible patients were switched to a reduced dose of brodalumab (140 mg every 4 weeks on day 1) in the extension study; the dose and dosing interval were modified sequentially at the physician's discretion (minimum 140 mg every 8 weeks and maximum 210 mg Q2W) until drug approval, after which all patients were switched to 210 mg Q2W for postmarketing surveillance. Of the 129 patients enrolled, 107 (82.9%) completed the 108-week or more extension study. All patients had psoriasis that was well controlled with brodalumab treatment on day 1. Improvement in psoriasis-related symptoms, evaluated with the Psoriasis Area and Severity Index, Psoriasis Scalp Severity Index, Dermatology Life Quality Index, Nail Psoriasis Severity Index, and American College of Rheumatology 20, 50 and 70, was maintained during the 108-week extension study. Brodalumab treatment was well tolerated throughout, and no new safety signals were identified. The most commonly reported treatment-related adverse event was nasopharyngitis, followed by influenza and oral candidiasis. No cases of serious candida infection or Crohn's disease were observed in this study. Serious treatment-related adverse events, such as appendicitis, brain abscess, bacterial meningitis, colon cancer, immunoglobulin A nephropathy and tubulointerstitial nephritis, were reported in one patient each. No anti-brodalumab-binding antibodies or brodalumab-neutralizing antibodies were detected in any patient throughout the extension study. Overall, the long-term efficacy and safety of brodalumab were demonstrated over 108 weeks.

Correlation between IL-17A expression in nasopharyngeal carcinoma tissues and cells and pathogenesis of NPC in endemic areas.

OBJECTIVE: We investigated the correlation between the expression of IL-17A in nasopharyngeal carcinoma tissues and cells and the occurrence and development of NPC was also investigated. METHODS: Forty-five NPC biopsy specimens from January 2014 to January 2016 were selected. Forty-five NPC tissue specimens and 45 chronic nasopharyngitis tissue samples were detected by immunohistochemistry. Statistical methods were used to analyze the correlation between IL-17A expression and the clinicopathological variables of NPC. The NPC patients were followed up. The levels of IL-17A mRNA in 40 NPC tissue specimens and 45 chronic nasopharyngitis tissue samples were detected by real-time PCR. IL-17A expression in 15 NPC tissue specimens and chronic nasopharyngitis tissue samples was further detected by Western blotting assays. RESULTS: IL-17A expression in NPC tissues was significantly higher than that of chronic nasopharyngitis tissues (P < 0.05). IL-17A was expressed in the nucleus and cytoplasm of both NPC tissues and chronic nasopharyngitis tissues. Stage III + IV NPC, tumor volume ≥ 50 mm, and hepatic envelope invasion and cervical lymph node metastasis were associated with significantly higher IL-17A levels versus stage I + II NPC, tumor size < 50 mm, no membrane invasion and lack of cervical lymph node metastasis (P < 0.05). IL-17A was statistically associated with tissue differentiation, serum EBV-lgA levels, and EBV infection. IL-17A-positive patients had significantly longer median survival versus IL-17A-negative patients (21.0 vs. 13.0 months, log-rank test: P < 0.05). Furthermore, 65% (26/40) of NPC tissue samples had significantly higher IL-17A mRNA levels than chronic nasopharyngitis (P < 0.05). IL-17A expression was significantly higher in NPC ≥ 50 mm, stage III + IV NPC and NPC with cervical lymph node invasion than its corresponding chronic nasopharyngitis tissue. CONCLUSION: IL-17A may be involved in the regulation of various malignant biological behaviors of NPC, which is closely related to the occurrence and development of NPC.

Are new variants of psoriasis therapy (IL-17 inhibitors) safe?

Psoriasis is a chronic, recurrent, inflammatory, and proliferative skin disease. Its etiology has not yet been fully assessed, but undoubtedly it is a multifaceted disease. The key role in its pathomechanism is played by genetic, immunologic, and environmental factors and stress. If traditional methods of psoriasis treatment (phototherapy, methotrexate, retinoids, cyclosporine A) fail, we reach for the following biopharmaceuticals - infliximab, etanercept, adalimumab, or ustekinumab. However, genetic engineering progress discovers new possibilities - the pending clinical trials involve IL-17, IL-23 antagonists, PDE4 and -3 and -1. Psoriasis etiopathogenesis mainly involves the IL-17A, IL-17F, and IL-17A/F subtypes, which affect the keratinocytes. The biological therapy molecularly oriented with the antagonists of interleukin 17 is based mainly on the influence onto the cytokine in the manner that prevents it from binding with the receptor. Three biopharmaceuticals are currently under third phase studies: two fully humanized antibodies neutralizing IL-17 - ixekizumab and secukinumab, and one human monoclonal antibody, brodalumab. The below work will be devoted to the analysis of possible undesirable symptoms, which were observed during the studies. We will try to review the latest literature concerning the most important clinical trials conducted in many centers.

Nasopharyngeal Infection of Mice with Streptococcus pyogenes and In Vivo Detection of Superantigen Activity.

Streptococcus pyogenes is a globally prominent human-specific pathogen that is responsible for an enormous burden of infectious disease. Despite intensive experimental efforts to understand the molecular correlates that contribute to invasive infections, there has been less focus on S. pyogenes carriage and local infection of the nasopharynx. This chapter describes an acute nasopharyngeal infection model in mice that is utilized in our laboratory to study the role of superantigen toxins in the biology of S. pyogenes. We also describe a method to detect superantigen-specific T cell activation in vivo.

[The rehabilitative treatment of the frequently ill children presenting with chronic infectious foci in the nasopharynx].

AIM: The objective of the present study was to elucidate the influence of the combined physiotherapeutic remedial treatment on the effectiveness of rehabilitation of the frequently ill children (FIC) and children presenting with chronic infectious foci inthe nasopharynx taking into consideration their microelemental and immunological status. MATERIALS AND METHODS: A total of 80 frequently ill children and children presenting with chronic infectious foci inthe nasopharynx were available for the observation with special reference to dynamics of clinical conditions, immunological processes, and microelement composition. CONCLUSION: The combined treatment including the intake of "Asonovklyuch" mineral water enhanced the resistance of the children to the causative factors of respiratory infections and increased selenium content in their body. It is concluded that the treatment of the children presenting with chronic infectious foci inthe nasopharynx with the use of the specialized dietary product "Clinutren Junior" produces an anti-inflammatory and immunoregulatory effect and thereby promotes the correction of disorders of microelement nutrition.

Ribosomal therapy in the treatment of recurrent acute adenoiditis.

The aim of this study was to evaluate the efficacy of an oral ribosomal immunotherapy in the management of children with recurrent acute adenoiditis (RAA). 60 children with RAA were included and randomly assigned into two groups (group A and B). Group A children underwent ribosomal prophylaxis, while group B received a placebo. Before, at the end and 6 months after start of the therapy, children underwent medical history, ENT examination, plasma levels of immunoglobulins class E, A, G, M (IgE, IgA, IgG, IgM), tympanometry, active anterior rhinomanometry and VAS scores by children' parents. After the treatment and at the end of the study, in the group A, the serum concentration of IgE was significantly (P < 0.05) lower than in group B (77.34 +/- 6.23 vs. 95.49 +/- 7.07 mg/dl; 74.82 +/- 6.26 vs. 94.44 +/- 7.44 mg/dl), IgA titers were significantly (P < 0.05) higher than in group B (312.04 +/- 18.41 vs. 213.20 +/- 11.82; 309.07 +/- 18.33 vs. 211.73 +/- 11.54 mg/dl) as well as serum concentration of IgG (1401.12 +/- 118.81 vs. 1101.81 +/- 109.64 mg/dl; 1412.19 +/- 116.43 vs. 1144.06 +/- 103.58 mg/dl). At the end of the study, comparison between the two groups showed, in group A: 77% of children (n = 23), versus 23% (n = 7) of group B, with a type A tympanogram; significant (P < 0.05) nasal flow decrease at the rhinomanometric measures; VAS scores were significantly (P < 0.05) improved (1.8 +/- 0.22 vs. 5.1 +/- 0.59) and frequency, severity and social impact of RAA episodes were significantly (P < 0.05) lower than group B. Our results show the therapeutic effectiveness of this approach in the prophylaxis of recurrent acute adenoiditis.

[The colonization resistance of the tonsils in healthy and frequently ill children]. / Stan kolonizatsiinoï rezystentnosti mihdalykiv u zdorovykh ta chasto khvoriiuchykh ditei.

State of colonization resistance was studied in healthy children and those presenting with recurring infectious and inflammatory diseases of the upper respiratory tract. Identification of representatives of tonsil anaerobic and aerobic floras was carried out. Lactic acid bacteria (LAB), alpha-Streptococcus, were present in tonsil flora of healthy children. Pathogenic microorganisms and opportunistic pathogens were recoverable from always ailing children with tonsillitis, with alpha-streptococcus being recoverable very seldom and no decrease in LAB levels being seen. In patients--candidates for tonsillectomy, pathogenic microorganisms were identifiable, with LAB levels decrease by a factor of 10(3-4). The above findings suggest development of dysbacteriosis, decrement of tonsil colonization resistance in always ailing children, which fact is to be considered in designing and implementing therapeutic measures.

Studies on haemagglutination and serum resistance status of strains of Moraxella catarrhalis isolated from the elderly.

A total of 40 strains of Moraxella catarrhalis, isolated from the sputum of elderly persons with respiratory tract infections and from nasopharyngeal swabs from healthy elderly, were examined for haemagglutination of human red blood cells and resistance to bactericidal activity in normal human serum (NHS). 15 of 20 strains isolated from the infected elderly and 3 of 20 strains isolated from the healthy elderly showed haemagglutinating properties (p < 0.001). Similarly, 13 of 20 strains from the infected group and 2 of 20 strains from the healthy group were found to be resistant to the bactericidal activity of NHS (p < 0.001). Strains of M. catarrhalis which were associated with respiratory tract infections in the elderly, in contrast to strains colonizing the healthy elderly, were found to be predominantly haemagglutinating for human red blood cells and resistant to complement killing in NHS.

Nasopharyngeal antibodies to pneumococcal pneumolysin in children with acute otitis media.

Pneumolysin, an intracellular protein toxin of all clinically relevant pneumococcal serotypes, is released in vivo during the autolysis of pneumococci and is believed to pave the way for intact pneumococci to invade and cause disease. Therefore, antibodies to pneumolysin should prevent its destructive function. We measured antibodies to pneumococcal pneumolysin in acute- and convalescent-phase nasopharyngeal aspirate samples of 120 children (median age, 2.5 years) with acute otitis media by enzyme immunoassay. Nasopharyngeal immunoglobulin M (IgM) and IgG class antibodies to pneumolysin were rarely detectable, whereas IgA class antibody was detected often, occurred independently of serum IgA antibody in serum, and correlated with the presence of the secretory component in pneumococcal antibody, indicating local production of IgA antibodies. Nasopharyngeal IgA antibody to pneumolysin was detected in 93% of the children already in the acute phase of otitis. Twenty percent of the children developed at least a threefold rise in the pneumolysin-specific IgA antibody concentration by the convalescent phase of otitis, with the youngest at 6 months of age, regardless of the pneumococcal findings in the nasopharynx or middle ear fluid. We suggest that nasopharyngeal IgA antibody to pneumolysin can be produced early in life by pneumococcal colonization.

[The value of polymerase chain reaction on Epstein-Barr virus subtypes in the differentiation of benign and malignant nasopharyngeal biopsies].

Polymerase chain reaction (PCR) of Epstein-Barr virus (EBV) EBNA-2 type A (PCR-A) along with dot blot hybridization using EBV DNA Bam-W and EBNA-2 type A and B fragment as the probes (DBH-W, -A, and -B) was performed in the nasopharyngeal biopsies. The positive rates of PCR-A, DBH-W, -A and -B were 83.9%, 80.6%, 74.2% and 0.0% in 31 cases of nasopharyngeal, respectively, and 12.0%, 40.0%, 92.0% and 0.0% in 25 cases of chronic nasopharyngitis (NP), respectively. There were significant differences between NPC and NP or non-NPC (P < = 0.0001) detected by PCR-A. The results indicated that positive PCR-A would be valuable for early diagnosis of nasopharyngeal carcinoma. The reasons which might make those differences were discussed.

Respiratory syncytial virus group-specific antibody response in nasopharyngeal secretions from infants and children after primary infection.

Respiratory syncytial virus (RSV) group-specific immunoglobulin A (IgA) and IgG enzyme-linked immunosorbent assay antibody and neutralizing antibody responses were determined for nasopharyngeal secretions (NPS) from 27 infants and children (6 to 18 months of age) undergoing primary infection with RSV group A or B strain. IgA and IgG antibody responses against RSV envelope glycoproteins (fusion [F] and large [G] glycoprotein) in NPS were also analyzed. Most subjects examined developed moderate levels of NPS IgA and IgG antibodies and neutralizing antibody activity to both group A and B strains in convalescent phase; however, the levels of antibodies to homologous strains were significantly higher than to the heterologous strains. Patients infected with group A developed antibodies in both F and G glycoproteins of A2 strains (group A). Patients infected with group B developed levels of antibody activity to F glycoprotein of A2 strain similar to those of patients infected with group A. However, these subjects developed little or no antibody response to G glycoprotein of A2 strain. These data suggest that the IgA and IgG antibody responses to G glycoprotein in the respiratory tract are group specific. It is suggested that lack of antibody response to the G glycoprotein of the heterologous group in the respiratory tract may determine the outcome of reinfection with other RSV strains.

Role of IgE-mediated hypersensitivity in otitis media with effusion: pathophysiologic considerations.

A pathophysiologic model of otitis media with effusion secondary to IgE-mediated hypersensitivity is described. Specific mediators of inflammation are released by mucosal mast cells in the nasal mucosa following the interaction of antigen and specific IgE antibody. These mediators increase vascular permeability, mucosal blood flow, and, most important, mucus production. Furthermore, accessory cell types are recruited by colony-stimulating factors that in turn provide an autocrine-positive feedback for the influx of further inflammatory cells. The eustachian tube is then effectively obstructed by both intrinsic venous engorgement and extrinsic mucus plugs, isolating the middle ear space from the ambient environment. The net result is the increased exchange of nitrogen into the middle ear mucosa from the middle ear cavity. This causes the development of a significant middle ear underpressure that disrupts tight junctions and allows for transudation of fluids into the middle ear space. The prolonged obstruction of the eustachian tube with mucus results in middle ear inflammation, mucosal metaplasia, and increased glandular activities, all of which are hallmarks of chronic otitis media with effusion.

[Immunohistochemical and cytochemical analysis of lymphocytes and plasma cells in nasopharyngeal carcinoma].

Cytoplasmic IgA+, IgG+ and IgM+ in plasma cells, present in biopsy tissue of 68 patients with nasopharyngeal carcinoma (NPC) and 40 patients with chronic nasopharyngitis (CN), were studied by immunoperoxidase (PAP) technique. EB virus VCA-IgA serum antibody in all these patients was determined. At the same time, the activity of T lymphocytes of 41 patients (23 with NPC and 18 with CN) was investigated by alpha-naphthyl acetate esterase (ANAE) method. The number of T lymphocytes in NPC was far less than that in CN. This suggests that the impediment or deficiency in cellular immunity may promote the development and growth of tumor. The number of IgA+ plasma cells in NPC was obviously more than that in CN. As the increase in the level of VCA-IgA serum antibody in NPC patients corresponded to the increase in the number of IgA+ plasma cells in the tumor tissue, it was presumed that part of the IgA+ plasma cells might participate in the production and introduction of VCA-IgA antibody. We suggest that the examination of VCA-IgA serum antibody be a reliable screening test for NPC. No significant difference was found in the numbers of IgG+ plasma cells between NPC and CN. IgM+ plasma cells were rare in both.

Choanal bleeding due to nasopharyngitis.

Twenty-two patients with bleeding from the nasopharynx which due to secondary changes in acute nasopharyngitis were treated at the Fujisaki Hospital. The titers of IgG, IgM and IgA of the viral capsid antigen (VCA), IgG and IgA of the early antigen (EA), and EB nuclear antigen (EBNA) were measured. There was no correlation between season of coryza or changes in season and the onset of nasopharyngitis, except for a slightly greater occurrence during mid summer and mid winter. One of three patients with severe bleeding, underwent posterior nasal packing using a rolled 10 X 10 cm gauze sponge. The majority of cases of bleeding from the nasopharynx were most satisfactorily treated by administration of the ranitidine hydrochloride (Zantac) of a selective antagonist for the H2-receptor of histamine.

[Cross-reacting intraspecies antigens of Neisseria meningitidis. II. The dynamics of antimeningococcal antibodies to cross-reacting antigens in different forms of meningococcal infection]. / Perekrestno reagiruiushchie vnutrividovye antigeny Neisseria meningitidis. Soobshchenie II. Dinamika protivomeningokokkovykh antitel k perekrestno reagiruiushchim antigenam pri razlichnykh formakh meningokokkovoi infektsii.

The presence of antibodies to meningococci has been determined in the sera of 203 patients with meningococcal infection and 234 healthy persons by means of the indirect hemagglutination tests with the use of polyvalent erythrocyte diagnosticum. The tests have shown that antibodies to cross-reacting antigens can be detected both in patients with generalized forms of meningococcal infection and in healthy persons; the level and occurrence of these antibodies depend on the age of the subjects under examination and the form taken by the course of meningococcal infection. The study has revealed that the background level of antibodies to meningococci in healthy persons is mainly formed due to meningococcal carriership. Antibodies to cross-reacting meningococcal antigens have been shown to be capable of being transferred transplacentally.

[Changes in specific and nonspecific immunity factors in saliva and serum of patients with different clinical variants of meningococcal infection]. / Dinamika spetsificheskikh i nespetsificheskikh faktorov immuniteta v sliune i syvorotke krovi bol'nykh s razlichnymi klinicheskimi formami meningokokkovoi infektsii.

Local and humoral immunity factors have been studied in 152 patients with different forms of meningococcal infection. The peculiar pattern of the time course of changes in these factors, depending on the clinical form of the disease, has been revealed. In the generalized form of infection changes in the immunological characteristics of the saliva and blood serum (lysozyme, secretory immunoglobulin, immunoglobulins of the main classes and specific antimeningococcal antibodies) have been shown to be more essential than in the localized form.

[Serologic studies of patients with meningococcal nasopharyngitis]. / Serologicheskie issledovaniia u bol'nykh meningokokkovymi nazofaringitami.

The results of the serological examination of 156 patients with bacteriologically confirmed meningococcal nasopharyngitis are presented. For control 221 patients with acute respiratory diseases and 345 healthy persons from groups having no registered cases of meningococcal infection were examined. The passive hemagglutination test with serogroup A and C polysaccharides revealed the presence of antibody titers between 1:20 and 1:640 in 67.3% of nasopharyngitis patients and antibody titers not exceeding 1:40 in 11.3-11.6% of persons in the control groups. The time course of antibody formation in nasopharyngitis was similar to that in generalized forms, but response was less pronounced: the maximum response was observed on days 5-10, and the decrease of the antibody level by day 20. In 47 foci of meningococcal infection the etiology of the disease was serologically confirmed on the first day of an epidemiologist's visit to the focus in 62.2% of 162 nasopharyngitis patients and in 36% of patients with acute respiratory diseases.