Conjunctivitis in dupilumab clinical trials Akinlade, B.; Guttman‐Yassky, E.; Bruin‐Weller, M. ...
British journal of dermatology (1951),
September 2019, Letnik:
181, Številka:
3
Journal Article
Recenzirano
Odprti dostop
Summary
Background
Dupilumab blocks the shared receptor component for interleukin (IL)‐4 and IL‐13. It is approved in the U.S.A. for patients aged ≥ 12 years with moderate‐to‐severe atopic dermatitis ...(AD) uncontrolled by topical prescription medicines or who cannot use topical medicines, for patients in Japan whose AD is uncontrolled with existing therapies, for patients with moderate‐to‐severe AD in Europe who are candidates for systemic therapy and for patients aged ≥ 12 years for maintenance treatment of moderate‐to‐severe asthma uncontrolled with their current medicines. AD trials have reported increased incidence of conjunctivitis for dupilumab vs. placebo.
Objectives
To characterize further the occurrence and risk factors of conjunctivitis in dupilumab clinical trials.
Methods
We evaluated randomized placebo‐controlled trials of dupilumab in AD (n = 2629), asthma (n = 2876), chronic rhinosinusitis with nasal polyps (CRSwNP) (n = 60) and eosinophilic oesophagitis (EoE) (n = 47).
Results
In most AD trials, dupilumab‐treated patients had higher conjunctivitis incidence than placebo controls. Higher baseline AD severity and previous history of conjunctivitis were associated with increased conjunctivitis incidence. Conjunctivitis was mostly mild to moderate. Most cases recovered or resolved during the treatment period; two patients permanently discontinued dupilumab due to conjunctivitis or keratitis. Common treatments included ophthalmic corticosteroids, antibiotics, and antihistamines or mast cell stabilizers. Most cases were diagnosed by the investigators. In asthma and CRSwNP trials, the incidence of conjunctivitis was lower for both dupilumab and placebo than in AD trials; dupilumab did not increase the incidence compared with placebo. In the EoE trial, no patients had conjunctivitis.
Conclusions
Conjunctivitis was more frequent with dupilumab treatment in most AD trials. In dupilumab trials in other type 2 diseases, incidence of conjunctivitis was overall very low, and was similar for dupilumab and placebo. In AD, the incidence of conjunctivitis was associated with AD severity and prior history of conjunctivitis. The aetiology and treatment of conjunctivitis in dupilumab‐treated patients require further study.
What's already known about this topic?
Ocular disorders, including allergic conjunctivitis, are common in patients with atopic dermatitis (AD).
In most dupilumab AD trials, dupilumab‐treated patients had higher conjunctivitis incidence than those receiving placebo.
Most cases were mild to moderate and recovered or were recovering during study treatment; study treatment discontinuation due to conjunctivitis was rare.
Conjunctivitis incidence was very low and similar for dupilumab and placebo in clinical trials in asthma, chronic rhinosinusitis with nasal polyps and eosinophilic oesophagitis.
What does this study add?
This analysis confirms and extends the results of the individual clinical trials.
Baseline disease‐related factors, including AD severity, prior conjunctivitis history and certain biomarkers (thymus and activation‐regulated chemokine, IgE, eosinophils), were associated with increased incidence of conjunctivitis.
Patients who responded well to dupilumab had reduced incidence of conjunctivitis.
Further study is needed to elucidate the aetiology and treatment of conjunctivitis in dupilumab‐treated patients with AD.
Linked Editorial: Chia‐Yu Chu. Br J Dermatol 2019; 181:436–437.
Plain language summary available online
Respond to this article
Early in the 1990s, several case series described adults suffering from dysphagia and children with refractory reflux symptoms, both accompanied by an eosinophil‐predominant infiltration, thereby ...conclusively distinguishing it from gastroesophageal reflux disease. Eosinophilic esophagitis (EoE) was recognized as its own entity in the adult and in the pediatric literature. In the last decade, evidence has accumulated that EoE represents a T‐helper (Th)2‐type inflammatory disease. Remodeling of the esophagus is a hallmark of EoE, leading to esophageal dysfunction and bolus impaction. Familial occurrence and disease association with single‐nucleotide polymorphisms underscore the influence of genetics in this disease. Eosinophilic esophagitis may affect individuals at any age, although the clinical presentation is highly age dependent. There is a significant allergic bias in the EoE population, with the majority of patients having concurrent allergic rhinitis, asthma, eczema, and/or a history of atopy. One noteworthy difference is that in children, EoE seems to be primarily a food antigen–driven disease, whereas in adults, mainly aeroallergen sensitization has been observed. Treatment modalities for EoE include the 3Ds: drugs, diet, and dilation. The crucial question of whether adult and pediatric EoE are different phenotypes of one single entity or whether we are confronted with two different diseases is still open. Here, we review similarities and differences between EoE in adults and children.
Linked ContentThis article is linked to Moaward et al and Molina‐Infante and Lucento papers. To view these articles visit https://doi.org/10.1111/apt.14233 and https://doi.org/10.1111/apt.14123.
Summary
Background
Dysphagia is the hallmark of eosinophilic esophagitis (EoE), but no validated dysphagia instruments in this population exist.
Aim
To develop and field test a patient‐reported ...outcome (PRO) for dysphagia in subjects with EoE.
Methods
This was a multi‐centre/multi‐phase prospective study. The first phase developed a dysphagia questionnaire using qualitative methods. The second phase was a 30‐day field trial to test the instrument and assess content validity. Adolescents and adults with EoE, active symptoms of dysphagia and oesophageal eosinophilia (≥15 eosinophils per high‐power field) were enrolled. Solid‐food‐avoidance days, dysphagia days and actions taken to get relief were recorded. A dysphagia score was calculated and compared to the Straumann Dysphagia Instrument (SDI).
Results
Ten adolescents and 10 adults were included in the first phase and the Dysphagia Symptom Questionnaire (DSQ), a three‐item daily electronic diary, was developed. In the second phase, 35 subjects finished the field trial (18 adults, 17 adolescents, mean age 24, 54% male, 95% white, 54% currently on topical corticosteroids). The median number of dysphagia days per week was 2 for adolescents vs. 4 for adults (P < 0.001), and 2 for those on topical steroids vs. 4 for those not on topical steroids (P < 0.001). The DSQ score strongly correlated with the number of dysphagia days (R = 0.96; P < 0.001) and the SDI (R = 0.77; P < 0.001).
Conclusions
The DSQ, a three‐question patient‐reported outcome, was successfully developed and field tested. The DSQ had content validity and the score accurately measured dysphagia frequency and intensity. The Dysphagia Symptom Questionnaire is suitable for use in clinical trials of EoE patients with dysphagia.
SUMMARY
Eosinophilic esophagitis (EoE) is an important cause of upper gastrointestinal dysfunction in children and adults. The EoE-quality of life (QOL)-A was validated as a disease-specific measure ...of quality of life in EoE. This study characterized the extent of QOL concerns in a cohort of adult EoE patients and delineated the relationships between QOL and other disease activity measures. One hundred sixty-seven patients enrolled in this prospective cohort study. Patients with established and suspected EoE undergoing endoscopy at a single university-based medical center were recruited. EoE was diagnosed on the basis of the clinical criteria and histologic demonstration of ≥15 eos/hpf while on proton pump inhibition therapy. Sixty five patients undergoing repeat endoscopy during the enrollment period participated twice. Patients provided demographic information and completed symptom assessments and the EoE-QOL-A. Analyses included comparisons with overall QOL as well as QOL subscales. Outcome measures included endoscopic activity using a validated instrument, the EoE Endoscopic Reference Score, and histology. Overall QOL was significantly correlated with dysphagia frequency, intensity, and severity (P < 0.001). Patients who experienced a food impaction in the last 30 days had significantly worse overall QOL (P = 0.009). There was no correlation between overall QOL and years since diagnosis, symptom duration, endoscopic features, or histologic findings. Patient symptoms correlated with endoscopic features of edema, rings, and stricture severity. Histologic activity was highly correlated with severity of endoscopic features. Patients who underwent repeat endoscopy with histologic response demonstrated improved eating and social QOL; however, overall QOL was unchanged. In adults with EoE, patient reported QOL is associated with symptom severity but not endoscopic or histologic features. Disease-specific QOL may complement parameters of biologic activity in the assessment of overall disease burden in EoE.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Running is the most popular form of exercise in the United States. Gastroesophageal reflux (GER) is common during exercise and may affect performance. Previous studies have focused on increased ...intra-abdominal pressure as a major determinant of acid reflux during physical exertion. In this issue, Herregods et al. examined the mechanisms of GER in healthy volunteers using simultaneous high-resolution manometry and pH impedance testing performed while running. Novel observations afforded by the utilization of state-of-the-art technology include the importance of transient lower esophageal sphincter relaxation ("belch reflex") and transient formation of hiatal hernia during exercise. The findings are provocative and lend credence to commonsense strategies to minimize the consequences of belching in runners.
Summary
Ambulatory pH monitoring detects abnormal levels of acid reflux in the oesophagus and can be used to correlate patients’ symptoms with oesophageal acid exposure. Catheter‐based pH testing has ...several limitations, including issues of sensitivity, specificity, tolerability and the inability to record non‐acid reflux events.
In an effort to improve upon these drawbacks, several devices have been introduced, including the Bilitec system for measuring duodenogastro‐oesophageal reflux; intraluminal impedance monitoring, which detects the distribution, composition and clearing of both acid and non‐acid oesophageal reflux; and a wireless pH monitoring device, the Bravo capsule.
Initial investigations using the Bilitec system demonstrated that duodenogastro‐oesophageal reflux tracked very closely with acid reflux and decreased with proton‐pump inhibitor (PPI) therapy, casting doubt on the clinical utility of Bilitec monitoring. Recent evidence revealed a possible role for duodenogastro‐oesophageal reflux in a subset of patients who continue to report reflux symptoms in the setting of normalized oesophageal acid exposure on high‐dose PPI therapy.
When combined with pH monitoring, impedance monitoring enhances the detection and characterization of gastro‐oesophageal reflux and may have a role in the evaluation of certain specific gastro‐oesophageal reflux disease (GERD) symptoms that persist despite acid suppression therapy.
The utility of the Bravo wireless technology for GERD diagnosis has been validated in several studies, with improvements over catheter‐based pH monitoring in tolerability, accuracy and sensitivity, as well as the ability to record periods both off and on PPI therapy in a single study.
All three diagnostic modalities have advanced the understanding of GERD pathogenesis, but their impact on the clinical management of GERD is still the focus of active investigation.
Background Although most of the patients with eosinophilic esophagitis (EoE) have mucosal and structural changes that could potentially explain their symptoms, it is unclear whether EoE is ...associated with abnormal esophageal motor function. The aims of this study were to evaluate the esophageal pressure topography (EPT) findings in EoE and to compare them with controls and patients with gastro‐esophageal disease (GERD).
Methods Esophageal pressure topography studies in 48 EoE patients, 48 GERD patients, and 50 controls were compared. The esophageal contractile pattern was described for ten 5‐mL swallows for each subject and each swallow was secondarily characterized based on the bolus pressurization pattern: absent, pan‐esophageal pressurization, or compartmentalized distal pressurization.
Key Results Thirty‐seven percent of EoE patients were classified as having abnormal esophageal motility. The most frequent diagnoses were of weak peristalsis and frequent failed peristalsis. Although motility disorders were more frequent in EoE patients than in controls, the prevalence and type were similar to those observed in GERD patients (P = 0.61, chi‐square test). Pan‐esophageal pressurization was present in 17% of EoE and 2% of GERD patients while compartmentalized pressurization was present in 19% of EoE and 10% of GERD patients. These patterns were not seen in control subjects.
Conclusions & Inferences The prevalence of abnormal esophageal motility in EoE was approximately 37% and was similar in frequency and type to motor patterns observed in GERD. Eosinophilic esophagitis patients were more likely to have abnormal bolus pressurization patterns during swallowing and we hypothesize that this may be a manifestation of reduced esophageal compliance.
PDF
