Ossicular Chain Lesions in Tympanic Perforations and Chronic Otitis Media without Cholesteatoma

OBJECTIVE: The first aim was to determine the prevalence, kind, and functional effects on hearing of ossicular chain suffering (OCS) in chronic otitis without cholesteatoma (NCOM) and tympanic perforations (TP). The second aim was to correlate the findings with clinical parameters and hearing level.MATERIALS AND METHODS: The study group comprised 250 consecutive patients affected by NCOM and who were subjected to tympanoplasty and never operated on before. Each patient underwent preoperative pure tone audiometry. Ossicles were evaluated during surgery. The incidence of OCS in NCOM was reported in 15-62% of the patients.RESULTS: Ossicular chain suffering was found in 26 out of the 250 patients included in the overall sample (10%). It was found in 7% of the patients affected by TP without otorrhea and in 19% of the patients affected by chronic ear discharge with drum perforation. OCS was found most frequently in posterior eardrum perforations and in patients with bilateral disease. The incus was the ossicle most frequently interested by resorption (92% of the patients). The air conduction threshold and air bone gap were more impaired in NCOM than in TP.CONCLUSION: Ossicular chain damages in patients with non-cholesteatomatous middle ear pathologies are not frequent and are present in no more than 10% of the patients, but lesions found were similar to those reported in patients with cholesteatoma. Otorrhea, posterior perforation, and bilateral disease can be considered as good predictors of OCS

ACTA OTORHINOLARYNGOLOGICA ITALICA

Presentiamo un caso di posizionamento di impianto cocleare in un uomo di 50 anni che, dopo aver subito tre anni prima un intervento per via retrosigmoidea per un neurinoma dellacustico in stadio 1, è stato colpito da ipoacusia improvvisa ipsilaterale sviluppando un intenso acufene. Dopo lattivazione dellimpianto lacufene è sceso da un grado 4 ad un grado 2 secondo il THI. Sono migliorate le capacità di localizzazione. Lascolto nel rumore (S/R + 7 dB) con il segnale proveniente dal lato operato è migliorato da 38 a 100%. Abbiamo inoltre verificato un significativo incremento dei punteggi relativi a spazialità e linguaggio del questionario Speech, spatial and qualities of sounds. In conclusione limpianto cocleare è una soluzione praticabile ed efficace in caso di insorgenza di ipoacusia ritardata dopo chirurgia conservativa del neurinoma dellacustico

The treatment of adult-onset Still’s disease with anakinra, a recombinant human IL-1 receptor antagonist: a systematic review of the literature

Adult-onset Still’s disease (AOSD) is a rare, inflammatory disease of unknown aetiology, generally affecting young adults and requiring immunosuppressive treatment. In the last few years, biologic disease-modifying anti-rheumatic drugs (bDMARDs) have been successfully used in refractory cases, based on the pathogenic role of inflammatory cytokines in AOSD. Amongst bDMARDs, several observations confirmed the clinical usefulness of anakinra, a recombinant human non-glycosylated IL-1 receptor antagonist, in AOSD. At present, the treatment is still largely empirical and due to the possible fallacious aspects of clinical judgement, in this work, we performed a systematic review of literature (SRL) to summarise the evidence regarding the treatment with anakinra in AOSD, analysing rate of complete remission, corticosteroids (CCSs)-sparing effect, long-term retention rate, and safety. After screening titles, abstracts and analysis of full text, 15 manuscripts were analysed: 1 open randomised multicentre trial with two parallel groups and 14 observational single-arm retrospective studies. Collectively, results of the present SRL suggest the effectiveness of anakinra in the treatment of patients with AOSD. Furthermore, patients with AOSD are likely to achieve a good clinical response with anakinra and these outcomes are associated with a largely favourable safety profile. Furthermore, the majority of patients treated with anakinra may achieve a complete remission, also in monotherapy. Finally, the treatment with anakinra is associated with an important CCSs-sparing effect, and, a large percentage of these patients may stop CCSs, thus reducing predictable long-term CCSs side effects without the occurrence of new flares. © Copyright CliniCal and Experimental Rheumatology 2021

Trisomic dose of several chromosome 21 genes perturbs haematopoietic stem and progenitor cell differentiation in Down's syndrome

Children with Down's syndrome (DS) have 20–50-fold higher incidence of all leukaemias (lymphoid and myeloid), for reasons not understood. As incidence of many solid tumours is much lower in DS, we speculated that disturbed early haematopoietic differentiation could be the cause of increased leukaemia risk. If a common mechanism is behind the risk of both major leukaemia types, it would have to arise before the bifurcation to myeloid and lymphoid lineages. Using the transchromosomic system (mouse embryonic stem cells (ESCs)) bearing an extra human chromosome 21 (HSA21)) we analyzed the early stages of haematopoietic commitment (mesodermal colony formation) in vitro. We observed that trisomy 21 (T21) causes increased production of haemogenic endothelial cells, haematopoietic stem cell precursors and increased colony forming potential, with significantly increased immature progenitors. Transchromosomic colonies showed increased expression of Gata-2, c-Kit and Tie-2. A panel of partial T21 ESCs allowed us to assign these effects to HSA21 sub-regions, mapped by 3.5 kbp-resolution tiling arrays. The Gata-2 increase on one side, and c-Kit and Tie-2 increases on the other, could be attributed to two different, non-overlapping HSA21 regions. Using human-specific small interfering RNA silencing, we could demonstrate that an extra copy of RUNX1, but not ETS-2 or ERG, causes an increase in Tie-2/c-Kit levels. Finally, we detected significantly increased levels of RUNX1, C-KIT and PU.1 in human foetal livers with T21. We conclude that overdose of more than one HSA21 gene contributes to the disturbance of early haematopoiesis in DS, and that one of the contributors is RUNX1. As the observed T21-driven hyperproduction of multipotential immature precursors precedes the bifurcation to lymphoid and myeloid lineages, we speculate that this could create conditions of increased chance for acquisition of pre-leukaemogenic rearrangements/mutations in both lymphoid and myeloid lineages during foetal haematopoiesis, contributing to the increased risk of both leukaemia types in DS

POS1247 CLINICAL FEATURES AND OUTCOMES OF COVID-19 IN PATIENTS WITH IGG4-RELATED DISEASE. A COLLABORATIVE EUROPEAN MULTI-CENTRE STUDY

Background:Coronavirus disease 2019 (COVID-19) is a pandemic-spread systemic infectious disease with prominent respiratory manifestations and significant associated morbidity and mortality. Elderly people are most significantly affected with mortality ranging from 2.4% (age 60-69) to 19.6% (age>80) in European Countries. The prevalence of COVID-19 and of its complications in patients with immune-mediated disorders, remains unclear. The frequency and impact of COVID-19 on patients with IgG4-related diease (IgG4-RD), many of whom are on concurrent immunosuppression has not been addressed.Objectives:To assess the epidemiological and clinical relevance of COVID-19 in patients with IgG4-RD.Methods:This is a multi-centre retrospective observational study of IgG4-RD patients from France, Italy, Spain and the United Kingdom. Demographics, comorbidities, IgG4-RD features, current and past treatment along with COVID-19-suggestive symptoms and COVID-19 diagnoses from February 2020 to January 2021 were recorded by means of direct or phone interviews. Patients with reverse-transcriptase polymerase chain reaction-confirmed (cCOVID) or presumed COVID-19 based on clinical, serological or imaging features (pCOVID) were pooled for analysis (totCOVID) and compared to patients who were not diagnosed with COVID-19. Inter-group comparison of categorical and quantitative variables were performed by using the chi-square test with Fisher's correction and the Mann-Whitney's test respectively. Data are expressed as median (interquartile range) unless otherwise specified.Results:A total of 305 patients [71% males, median age 64 (54-74) years] were studied. Pancreato-biliary disease was the most frequently observed IgG4-RD phenotype (39%). Fifty-one percent of patients were taking corticosteroids at time of interview and 30% were on biological or conventional immunosuppressants. Thirty-two totCOVID cases (23 cCOVID, nine pCOVID) were identified: 11/32 were hospitalised, two needed intensive care and four (13%; 3/4 aged >80 years) died. Having one or more infected family members was a risk factor for COVID-19 in patients with IgG4-RD (OR=19.9; p20mg) or rituximab administration.Conclusion:The prevalence and course of COVID-19 in IgG4-RD patients are similar to those of the general population of the same age, with no evident impact of disease- or treatment-related factors to the basal infectious risk. Effective public health countermeasures might be beneficial for patients with IgG4RD.References:[1]European Centre for Disease Prevention and Control (ECDC): https://covid19-surveillance-report.ecdc.europa.eu/[2]Yang H, Ann Rheum Dis, 2021Disclosure of Interests:Giuseppe Alvise Ramirez: None declared, Marco Lanzillotta: None declared, Mikael Ebbo: None declared, Andreu Fernandez-Codina Consultant of: consulting fees from Atheneum Consulting, Gaia Mancuso: None declared, Fernando Martínez-Valle: None declared, Olimpia Orozco-Galvez: None declared, Nicolas Schleinitz: None declared, Lorenzo Dagna Consultant of: Abbvie, Amgen, Biogen, BristolMyers Squibb, Celltrion, Galapagos, GlaxoSmithKline, Novartis, Pfizer, Roche, Sanofi-Genzyme, and SOBI, Grant/research support from: The Unit of Immunology, Rheumatology, Allergy and Rare Diseases (UnIRAR) received unresctricted research/educational grants from Abbvie, Bristol-Myers Squibb, Celgene, GlaxoSmithKline,Janssen, Merk Sharp & Dohme, Mundipharma Pharmaceuticals, Novartis, Pfizer, Roche, Sanofi Genzyme, and SOBI, Emma L. Culver: None declared, Emanuel Della Torre: None declare

AB0370 UTILITY OF CRP AND ESR IN THE DIAGNOSIS OF GIANT CELL ARTERITIS RELAPSE IN A PHASE 2 TRIAL OF MAVRILIMUMAB

Background:No universally accepted definition of flare currently exists in giant cell arteritis (GCA). Although relapses are defined mostly on clinical grounds (recurrence of GCA-related signs/symptoms), C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) help clinicians assess disease activity. In fact, >70% of patients on glucocorticoids (GCs) alone have increased CRP or ESR when the disease is active. In contrast, tocilizumab, given its IL-6-blockade effect in the liver, rapidly reduces CRP and ESR levels, rendering them unreliable for disease activity monitoring. Mavrilimumab – a GM-CSF receptor α inhibitor with demonstrated efficacy in a Phase 2 GCA trial1 – downregulates inflammation upstream of IL-6. We hypothesized that mavrilimumab would not interfere with the utility of CRP and ESR in monitoring disease activity and in identifying GCA relapse.Objectives:To analyze the relationship between CRP/ESR and clinical disease activity in GCA patients treated with mavrilimumab.Methods:New-onset and relapsing GCA patients with active disease were recruited. GC-induced remission (no GCA symptoms and CRP <1 mg/dL or ESR <20 mm/hr) was required by baseline. Patients were randomized 3:2 to mavrilimumab 150 mg or placebo subcutaneously every 2 weeks plus a protocol-defined 26-week prednisone taper. The primary efficacy endpoint was time to relapse by Week 26. Relapse (adjudicated) was defined as recurrent GCA-related signs/symptoms, including new/worsening vasculitis on imaging, concurrent with CRP ≥1 mg/dL and/or ESR ≥30 mm/hr. CRP and ESR were also measured periodically during the trial.This post hoc analysis assessed the association of recurrent GCA-related signs/symptoms with concurrent CRP or ESR elevation post-randomization by treatment arm. We also assessed the proportion of patients with CRP or ESR elevation without GCA-related signs/symptoms up to Week 26.Results:Seventy patients were enrolled (mavrilimumab, N=42; placebo, N=28). The association of CRP or ESR elevation with unequivocal GCA-related signs/symptoms post-randomization was consistent regardless of treatment arm: 8/8 in the mavrilimumab group and 13/13 in the placebo group (Table 1). During relapse, median (range) CRP was 1.8 (1.4 – 8.4) mg/dL (mavrilimumab group) and 1.8 (1.1 – 9.0) mg/dL (placebo group). Corresponding ESR values were 39.5 (30 – 102) mm/hr (mavrilimumab group) and 49 (31 – 101) mm/hr (placebo group). Four mavrilimumab recipients had self-limited, equivocal GCA-related signs/symptoms without concurrent CRP or ESR elevation; all 4 completed the prespecified GC taper by Week 26 without need for rescue GCs, so relapse was not confirmed. At least 1 elevated CRP or ESR value in the absence of GCA-related signs/symptoms was observed in 58.8% of mavrilimumab recipients and 93.3% of placebo recipients by Week 26.Conclusion:The observed association of CRP or ESR elevation with GCA-related signs/symptoms is consistent with the upstream mechanism and supports the utility of the stringent protocol definition of relapse. The frequency and magnitude of CRP and ESR elevations at relapse were similar in both treatment groups, suggesting that CRP and ESR remain useful in assessments of disease activity in mavrilimumab-treated patients. CRP and ESR elevations without GCA-related signs/symptoms occurred more often in placebo recipients.References:[1]Cid, Unizony et al. Arthritis Rheumatol. 2020; 72 (suppl 10)Table 1.CRP and ESR levels in patients with or without GCA relapseAssessment§MavrilimumabPlaceboMavrilimumabPlaceboN=42N=28N=42N=28With RelapseWithout Relapse# of patients8 (19.1)13 (46.4)34 (81.0)15 (53.6) Elevated CRP* or ESR†8 (100.0)13 (100.0)20 (58.8)14 (93.3)  Elevated CRP*7 (87.5)10 (76.9)10 (29.4)11 (73.3)   Median (range) mg/dL1.8 (1.4 - 8.4)1.8 (1.1 - 9.0)2.6 (1.3 – 7.0)2.0 (1.0 – 6.6) Elevated ESR†6 (75.0)9 (69.2)16 (47.1)10 (66.7)  Median (range) mm/hr39.5 (30 - 102)49.0 (31 - 101)41.5 (30 - 110)53.5 (30 - 82)§# (%), except where indicated otherwise.*CRP ≥ 1 mg/dL†ESR ≥ 30 mm/hrDisclosure of Interests:Sebastian Unizony Consultant of: Janssen and Kiniksa, Grant/research support from: Genentech, Maria C. Cid Speakers bureau: Roche and Kiniksa, Paid instructor for: GSK and Vifor, Consultant of: Janssen, GSK, and Abbvie, Grant/research support from: Kiniksa, Elisabeth Brouwer Speakers bureau: Dr. E.Brouwer as an employee of the UMCG received speaker fees and consulting fees from Roche in 2017 2018 which were paid to the UMCG., Consultant of: Dr. E.Brouwer as an employee of the UMCG received speaker fees and consulting fees from Roche in 2017 2018 which were paid to the UMCG., Lorenzo Dagna Speakers bureau: Abbvie, Amgen, Biogen, BMS, Celltrion, Galapagos, Glaxo SmithKline, Novartis, Pfizer, Roche, Sanofi-Genzyme, SOBI, Consultant of: Abbvie, Amgen, Biogen, BMS, Celltrion, Galapagos, Glaxo SmithKline, Novartis, Pfizer, Roche, Sanofi-Genzyme, SOBI; clinical trial for Kiniksa, Grant/research support from: Abbvie, Amgen, BMS, Celltrion, Galapagos, Novartis, Pfizer, Roche, Sanofi-Genzyme, SOBI, Merk Sharp &Dohme, Janssen, Kiniksa, Bhaskar Dasgupta Paid instructor for: Educational grant symposium/workshop for Roche-chugai, Sanofi, and Abbvie, Consultant of: CI UK for the Kiniksa trial, Grant/research support from: Educational grant symposium/workshop for Roche-chugai, Sanofi, and Abbvie, Bernhard Hellmich Consultant of: Honoraria paid to the institution for participation in the clinical trial, Eamonn Molloy: None declared, Carlo Salvarani: None declared, Bruce C. Trapnell Consultant of: Consultant member of DSMB for Kiniksa., Kenneth J Warrington Consultant of: Clinical trial support from Eli Lilly and Kiniksa, Ian Wicks: None declared, Manoj Samant Shareholder of: Kiniksa Pharmaceuticals, Employee of: Kiniksa Pharmaceuticals, Teresa Zhou Shareholder of: Kiniksa Pharmaceuticals, Employee of: Kiniksa Pharmaceuticals, Lara Pupim Shareholder of: Kiniksa Pharmaceuticals, Employee of: Kiniksa Pharmaceuticals, John F. Paolini Shareholder of: Kiniksa Pharmaceuticals, Employee of: Kiniksa Pharmaceutical

Efficacy and safety of mavrilimumab in giant cell arteritis:a phase 2, randomised, double-blind, placebo-controlled trial

OBJECTIVES: Granulocyte-macrophage colony-stimulating factor (GM-CSF) is implicated in pathogenesis of giant cell arteritis. We evaluated the efficacy of the GM-CSF receptor antagonist mavrilimumab in maintaining disease remission. METHODS: This phase 2, double-blind, placebo-controlled trial enrolled patients with biopsy-confirmed or imaging-confirmed giant cell arteritis in 50 centres (North America, Europe, Australia). Active disease within 6 weeks of baseline was required for inclusion. Patients in glucocorticoid-induced remission were randomly assigned (3:2 ratio) to mavrilimumab 150 mg or placebo injected subcutaneously every 2 weeks. Both groups received a 26-week prednisone taper. The primary outcome was time to adjudicated flare by week 26. A prespecified secondary efficacy outcome was sustained remission at week 26 by Kaplan-Meier estimation. Safety was also assessed. RESULTS: Of 42 mavrilimumab recipients, flare occurred in 19% (n=8). Of 28 placebo recipients, flare occurred in 46% (n=13). Median time to flare (primary outcome) was 25.1 weeks in the placebo group, but the median was not reached in the mavrilimumab group (HR 0.38; 95% CI 0.15 to 0.92; p=0.026). Sustained remission at week 26 was 83% for mavrilimumab and 50% for placebo recipients (p=0.0038). Adverse events occurred in 78.6% (n=33) of mavrilimumab and 89.3% (n=25) of placebo recipients. No deaths or vision loss occurred in either group. CONCLUSIONS: Mavrilimumab plus 26 weeks of prednisone was superior to placebo plus 26 weeks of prednisone for time to flare by week 26 and sustained remission in patients with giant cell arteritis. Longer treatment is needed to determine response durability and quantify the glucocorticoid-sparing potential of mavrilimumab. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov number: NCT03827018, Europe (EUdraCT number: 2018-001003-36), and Australia (CT-2018-CTN-01 865-1)

Efficacy and safety of mavrilimumab in giant cell arteritis: a phase 2, randomised, double-blind, placebo-controlled trial

OBJECTIVES: Granulocyte-macrophage colony-stimulating factor (GM-CSF) is implicated in pathogenesis of giant cell arteritis. We evaluated the efficacy of the GM-CSF receptor antagonist mavrilimumab in maintaining disease remission. METHODS: This phase 2, double-blind, placebo-controlled trial enrolled patients with biopsy-confirmed or imaging-confirmed giant cell arteritis in 50 centres (North America, Europe, Australia). Active disease within 6 weeks of baseline was required for inclusion. Patients in glucocorticoid-induced remission were randomly assigned (3:2 ratio) to mavrilimumab 150 mg or placebo injected subcutaneously every 2 weeks. Both groups received a 26-week prednisone taper. The primary outcome was time to adjudicated flare by week 26. A prespecified secondary efficacy outcome was sustained remission at week 26 by Kaplan-Meier estimation. Safety was also assessed. RESULTS: Of 42 mavrilimumab recipients, flare occurred in 19% (n=8). Of 28 placebo recipients, flare occurred in 46% (n=13). Median time to flare (primary outcome) was 25.1 weeks in the placebo group, but the median was not reached in the mavrilimumab group (HR 0.38; 95% CI 0.15 to 0.92; p=0.026). Sustained remission at week 26 was 83% for mavrilimumab and 50% for placebo recipients (p=0.0038). Adverse events occurred in 78.6% (n=33) of mavrilimumab and 89.3% (n=25) of placebo recipients. No deaths or vision loss occurred in either group. CONCLUSIONS: Mavrilimumab plus 26 weeks of prednisone was superior to placebo plus 26 weeks of prednisone for time to flare by week 26 and sustained remission in patients with giant cell arteritis. Longer treatment is needed to determine response durability and quantify the glucocorticoid-sparing potential of mavrilimumab. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov number: NCT03827018, Europe (EUdraCT number: 2018-001003-36), and Australia (CT-2018-CTN-01 865-1)

Effectiveness of Golimumab as Second Anti-TNFα Drug in Patients with Rheumatoid Arthritis, Psoriatic Arthritis and Axial Spondyloarthritis in Italy: GO-BEYOND, a Prospective Real-World Observational Study

In this prospective observational study, data were collected from 34 rheumatology clinics in Italy in patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA) and axial spondyloarthritis (axSpA) who started golimumab (GLM) as a second anti-TNFα drug. The primary objective was to evaluate the effectiveness of GLM after 6 months. Changes in quality of life using the EQ-5D-5L were also assessed. A total of 194 patients aged 53.2 ± 12 years started GLM as a second anti-TNF drug: 39 (20.1%) with RA, 91 (46.9%) with PsA and 64 (32.9%) with axSpA. After 6 months of GLM treatment, 68% of RA patients achieved low disease activity (LDA; DAS28-CRP ≤ 3.2), 31.9% of PsA patients achieved minimal disease activity and 32.5% of axSpA patients achieved LDA (ASDAS-CRP &lt; 2.1). Good/moderate EULAR response was achieved in 61.9% and 73.8% of patients with RA and PsA, respectively, and 16% of axSpA patients achieved a 50% improvement in BASDAI. Across all indications, improvements in disease activity measures and EQ-5D-5L domains were observed over 6 months. The main reasons for GLM interruption were lack/loss of efficacy (7.2%) or adverse events (2%). This study confirms the effectiveness of GLM as a second-line anti-TNF for the treatment of RA, PsA and axSpA in a real-world setting in Italy