Anti-IL-4/IL-13 for the treatment of asthma: the story so far.

Introduction: Severe asthma is a global health concern with high morbidity and mortality. Understanding of its complex pathophysiology continues to increase, providing specific immune targets for therapeutic intervention.Areas covered: In this review, we focus on the role of IL-4 and IL-13 in severe asthma and on the biologic therapies developed to target them, particularly dupilumab, a monoclonal antibody against the IL-4 receptor α subunit and IL-4/IL-13 receptor complex. A literature search was undertaken for all studies of monoclonal antibodies against IL-4 and IL-13.Expert Opinion: Dupilumab decreases the rate of severe asthma exacerbations and improves symptoms, lung function, and quality of life. Importantly, these effects are also observed during reduction of maintenance oral corticosteroid doses. Those with the highest T2 biomarkers derive the greatest benefit and the presence of atopic dermatitis or chronic rhinosinusitis with or without nasal polyposis may recommend dupilumab as the preferred biologic treatment for a patient.

Sarilumab monotherapy or in combination with non-methotrexate disease-modifying antirheumatic drugs in active rheumatoid arthritis: A Japan phase 3 trial (HARUKA).

Objectives: To determine long-term safety and efficacy of sarilumab as monotherapy or with non-methotrexate (MTX) conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) in Japanese patients with active rheumatoid arthritis (RA).Methods: In this double-blind, randomized study (NCT02373202), patients received subcutaneous sarilumab 150 mg q2w (S150) or 200 mg q2w (S200) as monotherapy or with non-MTX csDMARDs for 52 weeks. The primary endpoint was safety.Results: Sixty-one patients received monotherapy (S150, n = 30; S200, n = 31) and 30 received combination therapy (S150 + csDMARDs, n = 15; S200 + csDMARDs, n = 15). Rates of treatment-emergent adverse events (TEAEs) were 83.3%/90.3%/93.3%/86.7% for S150/S200/S150 + csDMARDs/S200 + csDMARDs, respectively. Nasopharyngitis and neutropenia were the most frequently reported TEAEs. One serious infection was reported in each monotherapy group and in the S200 + csDMARDs group. There were no cases of grade 4 neutropenia; no patients with grade 3 neutropenia experienced associated serious infection. Improvements in ACR20/50/70 response rates were generally similar between the two monotherapy groups and between the two combination groups; improvements in physical function (Health Assessment Questionnaire-Disability Index, HAQ-DI) and DAS28-CRP were observed at weeks 24 and 52 (all groups).Conclusion: The safety profile of sarilumab was consistent with known class effects of interleukin-6 signaling blockade therapeutics. Sarilumab as mono- or combination therapy improved clinical signs/symptoms and physical function in Japanese RA patients.

Efficacy, safety, and pharmacokinetics of emicizumab prophylaxis given every 4 weeks in people with haemophilia A (HAVEN 4): a multicentre, open-label, non-randomised phase 3 study.

BACKGROUND: Emicizumab, a subcutaneously administered, humanised, bispecific, monoclonal antibody, is approved to treat people with haemophilia A of all ages with and without coagulation factor VIII (FVIII) inhibitors. HAVEN 4 assessed emicizumab prophylaxis administered as one dose every 4 weeks in adults and adolescents with haemophilia A, regardless of FVIII inhibitor status. METHODS: In this phase 3, multicentre, open-label, two-stage study, patients aged 12 years and older with severe congenital haemophilia A (<1% of normal FVIII activity in blood) or haemophilia A with FVIII inhibitors, undergoing treatment with either FVIII concentrates or bypassing agents were recruited from three sites in Japan and Spain for a run-in cohort, and from 17 sites in Australia, Belgium, Japan, Poland, Spain, and the USA for a subsequent expansion cohort. Participants in the run-in and expansion cohorts were given emicizumab subcutaneously 6 mg/kg every 4 weeks for 24 weeks or more; for patients in the expansion cohort this regimen was preceded by four loading doses of 3 mg/kg once weekly. In the run-in cohort, we assessed pharmacokinetics after single and multiple (every 4 weeks) subcutaneous administration of 6 mg/kg emicizumab and safety. In the expansion cohort, the efficacy endpoint was efficacy of prophylactic emicizumab in maintaining adequate bleed prevention, assessed in all patients who received at least one dose of emicizumab and reported as annualised bleed rates for treated bleeds, all bleeds (treated and untreated), treated spontaneous bleeds, treated joint bleeds, and treated target joint bleeds. Safety was assessed in all participants given emicizumab. This study is registered with ClinicalTrials.gov, number NCT03020160, and is ongoing. FINDINGS: Between Jan 30, 2017, and Feb 27, 2017, seven patients were enrolled into the initial run-in cohort, which confirmed the expected pharmacokinetic profile and safety of the regimen based on model-based simulations, providing sufficient evidence for opening of the expansion cohort (n=41), which was recruited and enrolled between May 24, 2017, and June 30, 2017. The annualised rate of treated bleeds was 2·4 (95% CI 1·4-4·3). 23 (56·1%; 95% CI 39·7-71·5) of 41 reported no treated bleeds and 37 (90%; 76·9-97·3) reported zero to three treated bleeds. The annualised bleed rate was 4·5 (95% CI 3·1-6·6) for all bleeds, 0·6 (0·3-1·5), for treated spontaneous bleeds, 1·7 (0·8-3·7) for treated joint bleeds, and 1·0 (0·3-3·3) for treated target joint bleeds. The most frequent treatment-related adverse event was injection-site reaction (nine [22%] of 41 patients). We observed no thrombotic events or development of de-novo antidrug antibodies with neutralising potential or FVIII inhibitors. INTERPRETATION: Emicizumab given once every 4 weeks showed clinically meaningful bleed control while being well tolerated. This regimen could improve patient care by decreasing treatment burden and increasing adherence to effective prophylaxis, potentially decreasing the development of secondary complications for people with haemophilia A. FUNDING: F Hoffmann-La Roche and Chugai Pharmaceutical.

An evaluation of mepolizumab for the treatment of severe asthma.

Introduction: Asthma is considered one of the most common chronic conditions globally, characterized by variable airflow obstruction and symptoms. Severe asthma is diagnosed when asthma control requires high-intensity therapy or continues to remain uncontrolled despite treatment. Eosinophilic inflammation is known to be perpetuated by the activity of IL-5 in a proportion of severe asthma subjects, and targeting IL-5 may offer a therapeutic option. Areas covered: In this review, we discuss the role and pathogenesis of IL-5 and eosinophils in asthma and rationale of antagonizing IL-5 in severe eosinophilic asthma. Mepolizumab is the first of three anti-IL-5 biologics licensed in 2015 for use in this subgroup of patients. We discuss clinical and real-life studies leading up to its approval and post-marketing outcomes in terms of efficacy and safety to-date, as well as its pros and cons. Expert opinion: IL-5 antagonism has paved the way for an additional personalized therapeutic opportunity for use in severe asthma with eosinophilic inflammation, though there is limited evidence on the long-term implications of suppressing/depleting eosinophils and the duration for which they should be administered.

Tofacitinib for the treatment of psoriasis and psoriatic arthritis.

INTRODUCTION: Psoriasis and psoriatic arthritis (PsA) are inflammatory immune-mediated conditions which can cause considerable disability and reduced quality of life. Management can be complex as clinical heterogeneity may lead to different treatment pathways. Tofacitinib is a novel, oral Janus Kinase (JAK) inhibitor with proven efficacy in rheumatoid arthritis. Areas covered: This review analyzes recent studies of tofacitinib in psoriatic disease treatment. The relevant literature was identified using clinicaltrials.gov, PubMed, and Google Scholar. Tofacitinib efficacy was demonstrated in PsA by the OPAL Broaden and OPAL Beyond phase-III studies, and received FDA and EMA approval. Tofacitinib was superior to placebo for the treatment of moderate-to-severe plaque psoriasis in the OPT Pivotal 1 and 2, OPT Retreatment studies, but FDA approval was declined for this indication based on issues of clinical efficacy and long-term safety. Expert commentary: Tofacitinib is an important oral drug for the treatment of PsA. However, the long-term safety data require further evaluation. Tofacitinib and other JAK inhibitors show potential to broaden the treatment options in PsA and other inflammatory conditions.

Guselkumab for the treatment of psoriasis.

INTRODUCTION: Psoriasis is a chronic immune mediated disease in which the interplay of T cells and keratinocytes seems to play a key role. In this context, the interleukin (IL)-23/IL-17 axis is currently considered to be crucial in the pathogenesis of psoriasis and the selective inhibition of IL-23 may be viewed as an improvement of treatments blocking both IL-23 and IL-12, since its upstream actions. Areas covered: The authors performed a thorough and updated review on guselkumab, a fully human IgG1λ monoclonal antibody that blocks the p19 subunit of IL-23, analyzing efficacy and safety data from phase I, II and III trials. Expert opinion: Guselkumab represents a very promising therapy, providing an alternative mechanism of action with high efficacy and safety profiles, sustained total skin clearance, and rapid onset of effect also to psoriasis patients who previously failed or experienced an inadequate response to anti-TNF-α or anti-IL12/23. Guselkumab will definitively shift therapeutic goals of psoriasis management from PASI 75 to PASI 90 and 100 due to its exciting trials results, also favored by its increased treatment adherence due to its administering regimen (100 mg injection at week 0, 4 and then every 8 weeks).

Characterization of the nasopharyngeal and middle ear microbiota in gastroesophageal reflux-prone versus gastroesophageal reflux non-prone children.

Otitis media (OM) is one of the most common pediatric infections worldwide, but the complex microbiology associated with OM is poorly understood. Previous studies have shown an association between OM and gastroesophageal reflux (GER) in children. Therefore, in order to bridge the gap in our current understanding of the interaction between GER and OM, we investigated the nasopharyngeal and middle ear microbiota of children suffering from GER-associated OM and OM only, using culture-independent 16S rRNA gene sequencing. Middle ear fluid, nasopharyngeal swabs, and clinical data were collected as part of a prospective pilot study conducted at the Department of Otorhinolaryngology of the Erasmus MC-Sophia Children's Hospital, Rotterdam, the Netherlands. A total of 30 children up to 12 years of age who suffered from recurrent acute otitis media (AOM) (5), chronic otitis media with effusion (OME) (23), or both (2), and who were listed for tympanostomy tube placement, were included in the study. Nine children were included in the GER-associated OM cohort and 21 in the OM-only cohort. We found no obvious effect of GER on the nasopharyngeal and middle ear microbiota between the two groups of children. However, our results highlight the need to assess the true role of Alloiococcus spp. and Turicella spp. in children presenting with a high prevalence of recurrent AOM and chronic OME.

[The possibilities for the rational pharmacotherapy of adenoiditis in the children]. / Vozmozhnosti ratsional'noi farmakoterapii adenoidita u detei.

The available literature data give evidence that viral infection is the main cause underlying the development of inflammatory nasopharyngeal pathology in the children. According to ICD-10, nether acute nor chronic adenoiditis should be considered as a self-consistent nosological entity. Acute adenoiditis is usually regarded as a form of acute nasopharyngitis (J02) or acute respiratory viral infection (J06.9) whereas chronic adenoiditis is commonly referred to as representing other chronic diseases of the tonsils and adenoids (J 35.8). The reactive changes in the nasopharyngeal tonsils begin to be manifested on days 3-5 after the onset of acute respiratory viral infection; thereafter, they persist and gradually disappear within the next 2-3 weeks. In the majority of the cases, acute adenoiditis is actually a physiological reaction of the nasopharyngeal tonsils as the organs of regional mucosal immunity to antigenic stimulation. There is no universally accepted opinion as regards the duration of the inflammatory process which would allow these pathological changes to be considered as turned into chronic ones. This condition is actually not a serious pathology provided it is not associated with the concomitant complications and produces no clinically significant effect on the child's quality of life. Under practical conditions, such children are most frequently treated with the use of irrigation therapy. Taking into account that otorhinolaryngologists all over the world do not consider chronic adenoiditis as an independent nosological entity but distinguish only hypertrophy of adenoid vegetations or chronic rhinosinusitis (in the presence of inflammatory changes in the nasopharynx), it appears correct to speak about chronic adenoiditis provided the clinical manifestations of the disease persist for more than 12 weeks. Based on the predominant etiological component, the viral, bacterial, and allergic forms of nasopharyngeal adenoiditis can be distinguished even though it is rather difficult to actually determine which etiological factor prevails in each concrete case. The aforedescribed situation poses a large number of questions pertaining to the choice of either systemic or topical antibacterial therapy.

Secukinumab for the treatment of psoriatic arthritis.

INTRODUCTION: Secukinumab (Cosentyx) is an interleukin-17A (IL-17A) inhibitor administered subcutaneously. Through 2016, it had received approval in a number of countries, including the USA, Japan and in the EU for the treatment of plaque psoriasis, psoriatic arthritis (PsA) and ankylosing spondylitis (AS). AREAS COVERED: This review addresses the mechanism of action, efficacy and safety of secukinumab observed in clinical studies of patients with PsA. Data from recent studies of secukinumab in psoriasis, PsA and AS are included. Expert commentary: Secukinumab appears to be effective in improving various aspects of PsA, including improvements in psoriatic skin, enthesitis and dactylitis, as well as inhibition of the radiographic progression of peripheral arthritis. Secukinumab was in general well tolerated; the most common adverse events were nasopharyngitis, headache, and upper respiratory tract infection.

Nonacog alfa: an analysis of safety data from six prospective clinical studies in different patient populations with haemophilia B treated with different therapeutic modalities.

Nonacog alfa is a recombinant factor IX (FIX) product indicated for treatment and prevention of bleeding episodes in patients with haemophilia B. This posthoc analysis evaluated the safety of nonacog alfa in key clinical studies across 15 years. Data were pooled from six prospective studies that utilized on-demand, prophylactic and preventive nonacog alfa regimens: three open-label, nonrandomized studies that assessed efficacy and safety; a bioequivalence study of original and reformulated nonacog alfa; an open-label, randomized study that compared on-demand and prophylactic treatment; and a noninterventional observational registry study that evaluated safety. Safety assessments included adverse events, serious adverse events (SAEs) and events of special interest. In total, 412 patients received nonacog alfa treatment. Adverse events occurred in 220 patients (53.4%), the most common being pyrexia (n = 63), nasopharyngitis (n = 53) and cough (n = 52). Forty-eight patients (11.7%) experienced treatment-related adverse events; the most common were hypersensitivity (n = 6), urticaria (n = 6), FIX inhibition (n = 5) and pyrexia (n = 4). Seventy-four patients (18.0%) developed SAEs. Thirty-seven events of special interest occurred in 31 (7.5%) patients. Events of special interest included allergic-type manifestations (n = 15), inhibitor development (n = 5), lack of effect (n = 8), red blood cell agglutination in tubing or syringe (n = 7), and thrombogenicity (n = 2). Six patients (1.5%) withdrew due to seven adverse events: hypersensitivity (n = 3), drug eruption, pruritic rash, urticaria and decreased therapeutic response (n = 1 each). Four patients died during the study; no deaths were related to study medication. This pooled safety analysis in haemophilia B patients confirmed the safety of nonacog alfa across various patient populations.

Clinical efficacy and safety of anti-IL-17 agents for the treatment of patients with psoriasis.

To evaluate the therapeutic efficacy and safety of anti-IL-17 agents in the treatment of psoriasis, we performed a systemic review and meta-analysis of the relevant published clinical trials, collectively referred to as secukinumab, ixekizumab and brodalumab. 2668 patients in eight eligible trials with psoriasis were selected for the present meta-analysis. The estimated pooled PASI75, PSAI90, physician's global assessment (PGA; clear) showed significant improvements for psoriasis patients who received biotherapy compared with placebo. The results of headache, upper respiratory tract infection and infections demonstrated that there was no significant difference between the biotherapy and placebo groups. But the results of nasopharyngitis demonstrated that there was a significant difference for biotherapy group. The results showed that anti-IL-17 agents were effective and safe for psoriasis patients.

An unusual rhino-pharyngeal foreign body.

BACKGROUND: Foreign bodies of the upper aerodigestive tract are commonly seen in the paediatric population; however adult patients with nasal foreign bodies in particular are much less common and when sharp foreign bodies are present there is a great risk of developing complications. STUDY DESIGN: This is a case report of a 20-year-old male magician with impacted rhino-pharyngeal foreign body. He intentionally inserted two long sewing needles into the right nasal cavity during a magical act. RESULTS: The impacted foreign bodies were located in his nose/pharynx and removal was achieved per orally under general anaesthesia. Only a minimal evidence of retropharyngeal abscess was noted despite the prolonged stay of the foreign bodies. CONCLUSION: This case highlights the fact that both a deliberate and an accidental foreign body in an adult nasal cavity can get impacted as well as the significance for its early removal.

Chronic middle ear disease and gastroesophageal reflux disease: a causal relation?

OBJECTIVE: To describe one patient with a puzzling therapy-resistant unilateral chronic otitis media, analyze his diagnosis, and describe three similar patients with the same symptoms and signs, i.e., a chronic ear problem together with gastroesophageal reflux disease (GERD). STUDY DESIGN: Thorough analysis of one patient with a chronic ear problem and GERD, both of which responded favorably after antireflux therapy consisting of omeprazole and conservative antireflux measures (raising the head of the bed by 20 to 25 cm, avoiding meals and drinks 3 hours before retiring, and other dietary and lifestyle modifications), and a search for more patients with similar coexisting conditions. SETTING: Tertiary referral center. METHODS: Patients with chronic ear problems and GERD were thoroughly analyzed by the otorhinolaryngologist and the gastroenterologist. The latter used endoscopy and Savary-Miller's classification of esophagitis, a 24-hour ambulatory dual esophageal pH monitoring, and esophageal manometry. RESULTS: Four patients were identified who had a chronic ear problem and simultaneous GERD. It is reasoned that the GERD leads to nasopharyngitis and this to a chronic ear problem. All the patients responded favorably to anti-GERD therapy. CONCLUSIONS: GERD may manifest itself as an extraesophageal manifestation, such as nasopharyngitis, leading to ear disease. Therapy-resistant chronic middle ear disease may be caused by GERD.

[Variations of nasopharyngeal pH in nasopharyngitis in children]. / Variations du pH rhinopharyngé dans les rhinopharyngites de l'enfant.

In view of the well-known relationship between gastro-oesophageal reflux (GOR) and inflammatory diseases of the bronchi, trachea and larynx, the possibility of a pathogenic acid reflux reaching the pharynx has sometimes been suspected but never demonstrated. Paediatric E.N.T. specialists are often confronted with chronic inflammatory rhinopharyngitis of no obvious origin. In order to test the hypothesis of rhinopharyngeal contamination by gastric acid, the nycthemeral local pH was recorded in children presenting with chronic rhinopharyngitis and gastro-oesophageal reflux, and in two groups of controls without rhinopharyngitis and with or without GOR. Falls in rhinopharyngeal pH were found to be more frequent and to last longer in the 18 patients than in controls. The most significant criterion was the time during which the pH was lower than 6 compared with the total time of recording in these cases where pharyngeal pH measurements were recorded over 15 to 26 hours. It seemed most probable that this acidity resulted from the gastro-oesophageal reflux. Such variations in acid-base balance at the surface of a respiratory mucosa might be instrumental in the genesis or maintenance of the nasopharyngeal inflammatory reaction. However, these two hypotheses must be confirmed or infirmed by further studies.