Long-term Efficacy and Tolerability of RPC4046 in an Open-Label Extension Trial of Patients With Eosinophilic Esophagitis.

BACKGROUND & AIMS: The short-term efficacy of RPC4046, a monoclonal antibody against interleukin-13, has been shown in patients with eosinophilic esophagitis (EoE). We investigated the long-term efficacy and safety of RPC4046 in an open-label, long-term extension (LTE) study in adults with EoE. METHODS: We analyzed data from 66 patients who completed the 16-week, double-blind, induction portion of a phase 2 study of RPC4046 (180 mg or 360 mg/wk) vs placebo and then completed a 52-week LTE, receiving open-label RPC4046 360 mg/wk. The study was conducted at 28 centers in 3 countries; patients were enrolled between September 2014 and January 2017. Outcomes were stratified by double-blind dose group and included esophageal eosinophil counts, EoE endoscopic reference score, EoE histologic scoring system score, symptom-based EoE activity index score, and safety. RESULTS: By week 12 of the LTE, esophageal eosinophil mean and peak counts, total EoE endoscopic reference scores, and EoE histologic scoring system grade and stage scores did not differ considerably between patients who originally received placebo vs RPC4046. Most patients maintained responses through week 52. Symptom remission (symptom-based EoE activity index score, ≤20) increased from 14% at LTE entry to 67% at LTE week 52 in placebo‒RPC4046 patients and from 30% to 54% in RPC4046‒RPC4046 (either dose) patients. Of the 28 patients who did not have a histologic response to RPC4046 during the double-blind induction phase, 10 patients (36%) achieved response during the LTE. The most common adverse events were upper respiratory tract infection (21%) and nasopharyngitis (14%). CONCLUSIONS: One year of treatment with RPC4046 is generally well tolerated and results in continued improvement and/or maintenance of endoscopic, histologic, and clinical measures of EoE disease activity relative to baseline. TRIAL REGISTRATION: NCT02098473.

Efficacy of Dupilumab in a Phase 2 Randomized Trial of Adults With Active Eosinophilic Esophagitis.

BACKGROUND & AIMS: Eosinophilic esophagitis (EoE) is an allergen-mediated inflammatory disease with no approved treatment in the United States. Dupilumab, a VelocImmune-derived human monoclonal antibody against the interleukin (IL) 4 receptor, inhibits IL4 and IL13 signaling. Dupilumab is effective in the treatment of allergic, atopic, and type 2 diseases, so we assessed its efficacy and safety in patients with EoE. METHODS: We performed a phase 2 study of adults with active EoE (2 episodes of dysphagia/week with peak esophageal eosinophil density of 15 or more eosinophils per high-power field), from May 12, 2015, through November 9, 2016, at 14 sites. Participants were randomly assigned to groups that received weekly subcutaneous injections of dupilumab (300 mg, n = 23) or placebo (n = 24) for 12 weeks. The primary endpoint was change from baseline to week 10 in Straumann Dysphagia Instrument (SDI) patient-reported outcome (PRO) score. We also assessed histologic features of EoE (peak esophageal intraepithelial eosinophil count and EoE histologic scores), endoscopically visualized features (endoscopic reference score), esophageal distensibility, and safety. RESULTS: The mean SDI PRO score was 6.4 when the study began. In the dupilumab group, SDI PRO scores were reduced by a mean value of 3.0 at week 10 compared with a mean reduction of 1.3 in the placebo group (P = .0304). At week 12, dupilumab reduced the peak esophageal intraepithelial eosinophil count by a mean 86.8 eosinophils per high-power field (reduction of 107.1%; P < .0001 vs placebo), the EoE-histologic scoring system (HSS) severity score by 68.3% (P < .0001 vs placebo), and the endoscopic reference score by 1.6 (P = .0006 vs placebo). Dupilumab increased esophageal distensibility by 18% vs placebo (P < .0001). Higher proportions of patients in the dupilumab group developed injection-site erythema (35% vs 8% in the placebo group) and nasopharyngitis (17% vs 4% in the placebo group). CONCLUSIONS: In a phase 2 trial of patients with active EoE, dupilumab reduced dysphagia, histologic features of disease (including eosinophilic infiltration and a marker of type 2 inflammation), and abnormal endoscopic features compared with placebo. Dupilumab increased esophageal distensibility and was generally well tolerated. ClinicalTrials.gov, Number: NCT02379052.

RPC4046, a Monoclonal Antibody Against IL13, Reduces Histologic and Endoscopic Activity in Patients With Eosinophilic Esophagitis.

BACKGROUND & AIMS: Eosinophilic esophagitis (EoE) is a chronic, esophageal, type 2 inflammatory response associated with increased serum levels of interleukin 13 (IL13), which might contribute to its pathogenesis. RPC4046, a recombinant humanized monoclonal antibody against IL13, prevents its binding to the receptor subunits IL13RA1 and IL13RA2. We performed a phase 2 trial to evaluate the efficacy and safety of RPC4046 in patients with EoE. METHODS: We performed a multicenter, double-blind trial of 99 adults with active EoE randomly assigned (1:1:1) to groups given RPC4046 (180 or 360 mg) or placebo once weekly for 16 weeks, from September 2014 through December 2015. Patients were seen at day 1 (baseline) and weeks 2, 4, 8, 12, and 16. They underwent esophagogastroduodenoscopy and biopsies were collected at baseline and week 16. Patients completed a daily dysphagia symptom diary through week 16 and patient-reported outcome data were collected. The primary outcome was change in mean esophageal eosinophil count in the 5 high-power fields (hpfs) with the highest level of inflammation. RESULTS: At week 16, mean changes in esophageal eosinophil count per hpf were a reduction of 94.8 ± 67.3 in patients who received 180 mg RPC4046 (P < .0001) and a reduction of 99.9 ± 79.5 in patients who received 360 mg RPC4046 (P < .0001) compared with a reduction of 4.4 ± 59.9 in patients who received placebo. The 360-mg RPC4046 group, compared with the placebo group, showed significant reductions in validated endoscopic severity score at all esophageal locations (P < .0001), validated histologic grade and stage scores (both P < .0001), and clinician's global assessment of disease severity (P = .0352); they had a numerical reduction in scores from the dysphagia symptom diary (P = .0733). Significant reductions in esophageal eosinophil counts and histologic and endoscopic features were observed in patients with steroid-refractory EoE who received RPC4046. The most common adverse events were headache and upper respiratory tract infection. CONCLUSIONS: In a phase 2 trial of patients with EoE, we found RPC4046 (a monoclonal antibody against IL13) to reduce histologic and endoscopic features compared with placebo. RPC4046 was well tolerated. ClinicalTrials.gov no: NCT02098473.

The preference for an endoscopist specific sex: a link between ethnic origin, religious belief, socioeconomic status, and procedure type.

BACKGROUND AND AIM: The sex of the physician performing the endoscopic procedure is one of the parameters influencing patient satisfaction. Our aim was to characterize patients' preferences according to their sex, socioeconomic status, and religious beliefs and according to procedure-related variables. METHODS: All patients undergoing an endoscopic procedure at Sheba Hospital between April 2012 and September 2012 were asked to complete a questionnaire regarding their sex, ethnic background, socioeconomic status, religious practice, and preference for an endoscopist of a specific sex. Questionnaires were included for analysis only when more than 95% of the items were addressed. RESULTS: A total of 1,009 patients agreed to complete the questionnaires; of these 946 (94% [59% male]) were eligible for inclusion. Most patients (675 [70%]) expressed no preference for sex of the endoscopist, while 234 patients (25%) preferred a same-sex endoscopist, and only 55 (6%) preferred an other-sex endoscopist. Stepwise logistic regression analysis showed that in female patients, lower education (odds ratio [OR] = 1.28), non-Jewish religion (OR = 4.86), orthodox religious practice (OR = 2.28), African or Asian ethnic origin (OR = 2.44), scheduled for colonoscopy (OR = 1.90), and no previous endoscopy experience (OR = 1.88) were all associated with a preference for a same-sex endoscopist. CONCLUSION: One-quarter of patients preferred the physician performing their examination to be of particular sex. Most of these patients preferred a same-sex endoscopist. Education level, intensity of religious practice, ethnic origin, and type of endoscopic examination were associated with a preference for a same-sex endoscopist. Addressing patients' preferences may improve the atmosphere in the clinical environment, reduce stress, and facilitate better treatment and adherence to endoscopic surveillance programs.

Pathogenesis and natural history of osteonecrosis.

BACKGROUND AND OBJECTIVES: Osteonecrosis (avascular necrosis) is a relatively common disorder seen by both rheumatologists and orthopedic surgeons. The vast majority of cases are secondary to trauma. However, for non-traumatic cases, there often remains a diagnostic challenge in defining the cause of bone death. The goal of this article is to review data extensively in the medical literature with respect to the pathogenesis of osteonecrosis, its natural history, and treatment. METHODS: A review of 524 studies on osteonecrosis was performed, of which 213 were selected and cited. RESULTS: Non-traumatic osteonecrosis has been associated with corticosteroid usage, alcoholism, infections, hyperbaric events, storage disorders, marrow infiltrating diseases, coagulation defects, and some autoimmune diseases. However, a large number of idiopathic cases of osteonecrosis have been described without an obvious etiologic factor. Although corticosteroids can produce osteonecrosis, careful history is always warranted to identify other risk factors. The pathogenesis of non-traumatic osteonecrosis appears to involve vascular compromise, bone and cell death, or defective bone repair as the primary event. Our understanding of the pathogenesis of osteonecrosis is now much better defined and skeletal scintigraphy and magnetic resonance imaging have enhanced diagnosis greatly. Early detection is important because the prognosis depends on the stage and location of the lesion, although the treatment of femoral head osteonecrosis remains primarily a surgical one. CONCLUSIONS: Osteonecrosis has been associated with a wide range of conditions. Many theories have been proposed to decipher the mechanism behind the development of osteonecrosis but none have been proven. Because osteonecrosis may affect patients with a variety of risk factors, it is important that caregivers have a heightened index of suspicion. Early detection may affect prognosis because prognosis is dependent on the stage and location of the disease. In particular, the disease should be suspected in patients with a history of steroid usage, especially in conjunction with other illnesses that predispose the patient to osteonecrosis. RELEVANCE: A better understanding of the pathophysiology, diagnosis and treatment of osteonecrosis will help the physician determine which patients are at risk for osteonecrosis, facilitating early diagnosis and better treatment options.