Citations

Abstract Rationale: The 1-year double-blind period of the MANDARA trial (NCT04157348) demonstrated non-inferiority of benralizumab to mepolizumab for achieving remission, in adults with relapsing/refractory eosinophilic granulomatosis with polyangiitis (EGPA). Here, we report the 2-year combined double-blind and ongoing open-label extension (OLE) data. Methods: On completion of the double-blind period (n=136/140) comparing benralizumab 1x30mg versus mepolizumab 3x100mg subcutaneously every 4 weeks, patients were invited to enter the OLE where they continued benralizumab (benra/benra) or switched from mepolizumab to benralizumab (mepo/benra). Endpoints included remission (Birmingham Vasculitis Activity Score=0 and oral glucocorticoid [OGC[ dose ≤4 mg/day), OGC use, relapse, blood eosinophil count (bEOS), Asthma Control Questionnaire (ACQ-6), pre-bronchodilator forced expiratory volume in 1 second (pre-BD FEV1), and safety. Results: In total, 128 patients entered the OLE (n=66 benra/benra, n=62 mepo/benra; mean age 52.8 years; 60.2% female), and 119 completed OLE Year 1. Baseline characteristics of those entering the OLE were similar to the double-blind period. At Week 104, over 60% in both groups (41 [62.1%] benra/benra and 42 [67.7%] mepo/benra patients) achieved remission. During the OLE, 51 (77.3%) benra/benra and 42 (67.7%) mepo/benra patients had no relapses. The percentage of benra/benra patients who discontinued OGCs was similar at Weeks 49-52 (27 [40.9%]) and Weeks 101-104 (29 [43.9%]), while the percentage increased for mepo/benra patients between Weeks 49-52 (16 [25.8%]) and Weeks 101-104 (27 [43.5%]; Figure). The median (IQR) OGC dose at Weeks 101-104 was 0.5 (0,5) in benra/benra and 1.36 (0,5) mg/day in mepo/benra patients. The median (IQR) bEOS in benra/benra patients was 20 (10,40) cells/µL at both Weeks 52 and 100; bEOS were depleted in mepo/benra patients from 70 (40,90) cells/µL to 20 (10,50) cells/µL by 4 weeks after switching. Mean (SD) ACQ-6 scores were 0.64 (0.78) in benra/benra patients and 0.60 (0.76) in mepo/benra patients at Week 104 compared with 1.39 (1.18) and 1.11 (0.95) at baseline. Mean (SD) pre-BD FEV1 was 2.59 (0.90) L versus 2.62 (0.84) L in benra/benra versus mepo/benra patients at Week 52, and 2.61 (0.90) versus 2.63 (0.81) L, at Week 100. Safety of mepolizumab and benralizumab was consistent with their known profiles. Conclusions: In patients with EGPA receiving benralizumab, remission rates, OGC discontinuation, and bEOS depletion were durable over 104 weeks with low relapse rates, and without loss of asthma control or lung function decline. Additional bEOS depletion and OGC sparing was observed in patients switching from mepolizumab to benralizumab.

Abstract Rationale: The D'Nerva Targeted Lung Denervation (TLD) System uses radiofrequency energy delivered bronchoscopically to the main bronchi to disrupt parasympathetic nerve innervation to the lung. AIRFLOW-3 clinical trial was a randomized, double blind, sham controlled study to determine the impact of TLD on COPD exacerbations. Methods: AIRFLOW-3 patients had symptomatic COPD (CAT ≥10) with moderate to very severe airflow obstruction (GOLD stage II-IV: 25% ≤ FEV1 ≤ 80% predicted, FEV1/FVC<0.70) and GOLD E status (≥2 moderate or ≥1 severe exacerbation in the prior 12 months) despite optimal medical therapy. The primary endpoint was a time-to-first event comparison of the probability of subjects having a moderate or severe exacerbation, between the Treatment arm (TLD + optimal medical therapy) and the Sham Control arm (optimal medical therapy). Results: 388 patients were randomized 1:1 at 32 clinical sites across the US, EU, and UK. Patients were 67.8 (SD 7.1) years of age, ex-smokers with a 46.7 (22.0) pack-year smoking history, and 41.0 (11.8) post bronchodilator FEV1% pred. SGRQ-C and CAT scores were 62.5 (17.0) and 23.6 (6.3), respectively. Over 90% of patients were on triple therapy (LAMA+LABA+ICS) at baseline and through 1 year of follow up. 42% of patients had prior-year COPD hospitalization(s). There was no difference between groups in the analysis of the primary endpoint. At 1 year, the sham arm exhibited a statistical decline in lung function (decrease in FEV1 and FVC) and worsening of gas trapping (increase in RV). Lung function and gas trapping were stable in the treatment arm. The treatment arm exhibited a statistically significant improvement in dyspnea at one year compared to sham (mMRC, and TDI). These observations led to the identification of a subgroup of TLD treatment responders corresponding to an airway predominant phenotype (lung hyperinflation in the absence of significant emphysema) that demonstrated clinically and statistically significant improvements in lung function and exacerbation frequency and severity (Table). Conclusions: The AIRFLOW-3 clinical trial failed to meet its prespecified primary endpoint. Post-hoc analysis of this robust dataset led to the identification of a responder profile that achieved significant and sustained improvements in lung function, and exacerbation reduction. A future clinical study is being designed to confirm these findings.

ObjectiveA dysregulated immune response is involved in the pathogenesis of polymyalgia rheumatica (PMR) and giant cell arteritis (GCA). These diseases have been reported as immune‐related adverse events in patients with cancer treated with immune checkpoints inhibitors. In this cross‐sectional study, the relationship between soluble immune checkpoint molecules (sICMs) and clinical/imaging features of PMR and GCA was investigated.MethodsConsecutive patients with PMR diagnosed according to the criteria by Bird et al were compared with age‐ and sex‐matched healthy controls. Patients with PMR and overlapping GCA had to also satisfy the 1990 ACR classification criteria for GCA. All patients underwent standardized clinical, laboratory examination, and 18F‐fluorodeoxyglucose positron emission tomography/computed tomography scans. The sICM anticytotoxic T Ly‐4, the programmed cell death protein 1 (PD‐1), and PD‐1 ligands PD‐L1 and PD‐L2 were measured by enzyme‐linked immunosorbent assay.ResultsForty patients (80% women, mean age 76 years, and mean disease duration 88 days) were assessed. Of these, 30 had isolated PMR and 10 had PMR with GCA. Patients showed significantly higher concentrations of all sICMs compared with controls (P < 0.001). Conditional logistic regression revealed the strong discriminative capacity of these molecules between patients and healthy controls, with PD‐1 showing complete separation among groups (effect size = 0.78) and PD‐L1 (odds ratio [OR] 134.33, P < 0.001) and PD‐L2 (OR 63.00, P < 0.001) demonstrating the strongest ability to distinguish patients from controls. Correlations between sICM levels and clinical features were generally weak or absent, with no significant differences based on disease phenotype or glucocorticoid exposure. Results were similar in glucocorticoid‐naive patients.ConclusionsICMs are significantly elevated in PMR and GCA and strongly differentiate patients from healthy controls. Although they do not correlate with clinical or imaging features, their consistent elevation in active disease might suggest a complex interplay between innate and adaptive immunity.image

Objective To develop and validate classification criteria for pediatric chronic nonbacterial osteomyelitis (CNO) jointly supported by EULAR and the American College of Rheumatology (ACR). Methods This international initiative had 4 phases: (1) candidate items were proposed in a survey of pediatric rheumatologists, (2) criteria definition and reduction by Delphi and nominal group technique exercises, (3) criteria weighting using multicriteria decision analysis, and (4) refinement of weights and threshold score in a development cohort of 441 patients and validation in another cohort of 514 patients. Results The new EULAR/ACR classification criteria for CNO require typical radiographic or magnetic resonance imaging findings and bone pain as an obligatory entry criterion and exclusion criteria of malignancy, infection, vitamin C deficiency, and hypophosphatasia, followed by additive weighted criteria in 5 clinical (site of bone lesions, pattern of bone lesions, age at onset, coexisting conditions, fever) and 4 pathology/laboratory domains (bone biopsy findings if done, anemia, C‐reactive protein level, and erythrocyte sedimentation rate). A total score ≥55 is required for classification as CNO. The new criteria had a sensitivity of 82% and specificity of 98% in the validation cohort. Conclusion These new classification criteria for pediatric CNO developed with international input reflect current views about CNO, have high specificity and good sensitivity, and provide a key foundation for future CNO research.

Abstract Background and Aims Tyrosine kinase 2 is a downstream intracellular mediator of interleukin-23 signaling, which has a key role in the pathogenesis of inflammatory bowel disease. Deucravacitinib is a novel, oral, selective, allosteric tyrosine kinase 2 inhibitor currently approved for the treatment of adults with moderate to severe plaque psoriasis. Methods Here we describe 3 randomized, double-blind, placebo-controlled phase 2 studies of deucravacitinib in patients with moderately to severely active Crohn’s disease (LATTICE-CD [NCT03599622]) or ulcerative colitis (LATTICE-UC [NCT03934216] and IM011-127 [NCT04613518]). Patients were randomized to receive placebo or twice-daily deucravacitinib 3 or 6 mg (LATTICE-CD), 6 mg (LATTICE-UC), or 12 mg (IM011-127) for 12 weeks. Coprimary endpoints for LATTICE-CD were clinical remission and endoscopic response at week 12. The primary endpoint was clinical remission (per modified Mayo score) at week 12 for LATTICE-UC and clinical response (per modified Mayo score) at week 12 for IM011-127. Results A total of 239 (LATTICE-CD), 131 (LATTICE-UC), and 38 (IM011-127) patients were randomized. The primary endpoints were not met for all 3 studies, which resulted in early study termination for LATTICE-CD and IM011-127. High efficacy rates were observed in placebo groups throughout the studies. In all studies, the safety profile of deucravacitinib was consistent with the known safety profile observed in patients with psoriasis, and no new safety signals were observed. Conclusions Deucravacitinib at multiple doses did not demonstrate significant clinical benefit vs placebo in moderately to severely active Crohn’s disease or ulcerative colitis. Deucravacitinib was safe and well tolerated.

ABSTRACT LYRM7‐associated mitochondrial complex III deficiency has classically been described in the literature as a childhood‐onset episodic leukoencephalopathy with neuroimaging findings of cavitating periventricular and subcortical white matter loss. We describe the heterogeneous clinical and neuroimaging profile of six individuals from south India with the specific homozygous pathogenic variant in the LYRM7 gene (c.2T>C, (p.Met1?)). This is a retrospective case series featuring six cases (four pediatric, one adult, and one adolescent‐onset) with the pathogenic start loss LYRM7 variant. The spectrum of neurologic manifestations and brain imaging findings documented over multiple clinic visits was analyzed and described. Vision loss and lactic acidosis were seen in all but one individual. A novel phenotype with adult‐onset isolated bilateral simultaneous optic neuropathy was noted. Characteristic cavitating leukoencephalopathy in supratentorial white matter was seen in the brain MRI of three out of six individuals. A comprehensive description of our cases along with the previously published cases is provided in the table highlighting the clinical and imaging variability and the disease course. The phenotype of adult‐onset isolated acute optic neuropathy can be a manifestation of LYRM7‐related mitochondrial disorder. LYRM7‐associated Mitochondrial Complex III deficiency should be considered in the differential diagnosis of para‐ and post‐infectious demyelinating/inflammatory disorders, especially if there is a background of variable developmental delay, recurrence of the episodes, family history, cystic changes in cerebral white matter on imaging, or poor response to immunomodulation. The case series also exemplifies the intra‐and inter‐familial variability seen with this rare disorder.

Background The Woven EndoBridge (WEB) device is a prevalent treatment for intracranial aneurysms. While many studies have assessed the obliteration rate post-WEB embolization, few have focused on long-term outcomes in partially thrombosed aneurysms. Objective To assess whether partially thrombosed aneurysms are at higher risk of recurrence or retreatment following WEB embolization compared with non-thrombosed aneurysms. Methods We evaluated data from 22 academic institutions, focusing on previously untreated cerebral aneurysms treated with the WEB device. Logistic regression was utilized to analyze factors predicting long-term aneurysm obliteration and retreatment necessity. Results Among 1303 patients, 26 presented with a partially thrombosed aneurysm. In the partially thrombosed group, the mean aneurysm maximal diameter was 10.7±4 mm with a neck ratio of 1.99±1.19 mm, larger than in the control group where the mean aneurysm maximal diameter was 6.81±2.37 mm with a neck ratio of 1.64±0.51 mm (P<0.001 for both maximal diameter and neck ratio). At the final follow-up, partially thrombosed aneurysms treated by the WEB device had a 38.5% retreatment rate, compared with 7.0% for non-thrombosed aneurysms (P<0.001). Among partially thrombosed aneurysms, the Raymond-Roy type IIIa/b occlusion rate was higher (38.5% vs 9.9%, P<0.001). On multivariate analysis, partially thrombosed aneurysms compared with non-thrombosed aneurysms had an increased rate of retreatment (OR 3.64, 95% CI 1.28 to 10.1). Conclusion Partially thrombosed aneurysms are associated with a poorer occlusion rate and a higher rate of retreatment following WEB embolization. For partially thrombosed aneurysms, the WEB device appears suboptimal as a first-line treatment, and therefore alternative techniques should be prioritized.