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Summary Background Mortality in patients with COVID-19 pneumonia and systemic hyperinflammation is high. We aimed to examine whether mavrilimumab, an anti-granulocyte–macrophage colony-stimulating factor receptor-α monoclonal antibody, added to standard management, improves clinical outcomes in patients with COVID-19 pneumonia and systemic hyperinflammation. Methods This single-centre prospective cohort study included patients aged 18 years or older who were admitted to San Raffaele Hospital (Milan, Italy) with severe COVID-19 pneumonia, hypoxia, and systemic hyperinflammation. Patients received a single intravenous dose (6 mg/kg) of mavrilimumab added to standard care given by the hospital at the time. The control group consisted of contemporaneous patients with similar baseline characteristics who received standard care at the same hospital. The main outcome was time to clinical improvement (defined as improvement of two or more points on the seven-point ordinal scale of clinical status). Other outcomes included proportion of patients achieving clinical improvement, survival, mechanical ventilation-free survival, and time to fever resolution. Adverse events were monitored daily. Findings Between March 17 and April 15, 2020, 13 non-mechanically ventilated patients (median age 57 years [IQR 52–58], 12 [92%] men) received mavrilimumab and 26 patients (median age 60 [IQR 53–67], 17 [65%] men) in the control group received standard care. During the 28-day follow-up, no patients in the mavrilimumab group died, and seven (27%) patients in the control group died (p=0·086). At day 28, all patients in the mavrilimumab group and 17 (65%) patients in the control group showed clinical improvement (p=0·030), with earlier improvement in the mavrilimumab than in the control group (mean time to improvement 8 days [IQR 5 to 11] vs 19 days [11 to >28], p=0·0001). By day 28, one (8%) patient in the mavrilimumab group progressed to mechanical ventilation compared with nine (35%) patients in the control group who progressed to mechanical ventilation or died (p=0·14). By day 14, fever resolved in ten (91%) of 11 febrile patients in the mavrilimumab group, compared with 11 (61%) of 18 febrile patients in the control group (p=0·18); fever resolution was faster in mavrilimumab recipients versus controls (median time to resolution 1 day [IQR 1 to 2] vs 7 days [3 to >14], p=0·0093). Mavrilimumab was well tolerated, with no infusion reactions. Three (12%) patients in the control group developed infectious complications. Interpretation Mavrilimumab treatment was associated with improved clinical outcomes compared with standard care in non-mechanically ventilated patients with severe COVID-19 pneumonia and systemic hyperinflammation. Treatment was well tolerated. Confirmation of efficacy requires controlled testing. Funding IRCCS San Raffaele Scientific Institute.

Summary Background Mortality of patients with coronavirus disease 2019 (COVID-19), acute respiratory distress syndrome (ARDS), and systemic inflammation is high. In areas of pandemic outbreak, the number of patients can exceed maximum capacity of intensive care units (ICUs), and, thus, these individuals often receive non-invasive ventilation outside of the ICU. Effective treatments for this population are needed urgently. Anakinra is a recombinant interleukin-1 receptor antagonist that might be beneficial in this patient population. Methods We conducted a retrospective cohort study at the San Raffaele Hospital in Milan, Italy. We included consecutive patients (aged ≥18 years) with COVID-19, moderate-to-severe ARDS, and hyperinflammation (defined as serum C-reactive protein ≥100 mg/L, ferritin ≥900 ng/mL, or both) who were managed with non-invasive ventilation outside of the ICU and who received standard treatment of 200 mg hydroxychloroquine twice a day orally and 400 mg lopinavir with 100 mg ritonavir twice a day orally. We compared survival, mechanical ventilation-free survival, changes in C-reactive protein, respiratory function, and clinical status in a cohort of patients who received additional treatment with anakinra (either 5 mg/kg twice a day intravenously [high dose] or 100 mg twice a day subcutaneously [low dose]) with a retrospective cohort of patients who did not receive anakinra (referred to as the standard treatment group). All outcomes were assessed at 21 days. This study is part of the COVID-19 Biobank study, which is registered with ClinicalTrials.gov , NCT04318366 . Findings Between March 17 and March 27, 2020, 29 patients received high-dose intravenous anakinra, non-invasive ventilation, and standard treatment. Between March 10 and March 17, 2020, 16 patients received non-invasive ventilation and standard treatment only and comprised the comparison group for this study. A further seven patients received low-dose subcutaneous anakinra in addition to non-invasive ventilation and standard treatment; however, anakinra treatment was interrupted after 7 days because of a paucity of effects on serum C-reactive protein and clinical status. At 21 days, treatment with high-dose anakinra was associated with reductions in serum C-reactive protein and progressive improvements in respiratory function in 21 (72%) of 29 patients; five (17%) patients were on mechanical ventilation and three (10%) died. In the standard treatment group, eight (50%) of 16 patients showed respiratory improvement at 21 days; one (6%) patient was on mechanical ventilation and seven (44%) died. At 21 days, survival was 90% in the high-dose anakinra group and 56% in the standard treatment group (p=0·009). Mechanical ventilation-free survival was 72% in the anakinra group versus 50% in the standard treatment group (p=0·15). Bacteraemia occurred in four (14%) of 29 patients receiving high-dose anakinra and two (13%) of 16 patients receiving standard treatment. Discontinuation of anakinra was not followed by inflammatory relapses. Interpretation In this retrospective cohort study of patients with COVID-19 and ARDS managed with non-invasive ventilation outside of the ICU, treatment with high-dose anakinra was safe and associated with clinical improvement in 72% of patients. Confirmation of efficacy will require controlled trials. Funding None.

Background: Tinnitus is believed to cause significant psychological distress leading to impairment in quality of life (QOL). Purpose: To assess the negative impact of tinnitus on patient’s QOL and discuss the management approach of tinnitus patient. Method: A cross-sectional study was conducted within one year duration on 88 patients who experienced tinnitus. Patients from Otorhinolaryngology clinic, Universiti Kebangsaan Malaysia Medical Centre (UKMMC) were evaluated based on socio-demographic data, clinical data and QOL. QOL was assessed using Tinnitus Handicap Inventory (THI), a self-report questionnaire measuring 3 domains of QOL: functional, emotional and catastrophic scales. Result: Respondents consisted of 35 males (39.8%) and 53 females (60.2%), with mean age of 57.9±13.9 years old. Pure tone audiometry should be done at least once during the follow up period. Patients with persistent tinnitus had significantly higher mean THI total scores (p=0.042) and emotional subscale score (p=0.037) compared to patients with intermittent tinnitus. However, there were no significant associations between gender, duration of tinnitus and laterality of tinnitus with patient’s THI score. Discussion: All patients should have good history taking, proper physical examination and investigation. Those without the primary cause of tinnitus would be given tinnitus activity treatment by good counselling on tinnitus. Patient with vascular disorder would be given conservative treatment. Conclusion: Magnetic resonance imaging was indicated in asymmetrical hearing loss with tinnitus. Computed tomography scan with contrast was indicated when there is pulsatile tinnitus with/without abnormal ear finding. Patients with high grades THI questionnaire would be referred to psychiatrist for further assessment. ABSTRAK Latar belakang: Tinitus diyakini dapat menyebabkan stress psikologi yang signifikan sehingga mengakibatkan penurunan kualitas hidup seseorang ( Quality of Life / QOL). Tujuan: Menilai dampak negatif tinitus pada kualitas hidup penderita dan merencanakan penatalaksanaannya. Metode: Penelitian ini merupakan studi potong lintang pada 88 penderita tinitus selama satu tahun. Penderita yang datang ke unit rawat jalan Telinga Hidung Tenggorok Bedah Kepala dan Leher (THT-KL), Universiti Kebangsaan Malaysia Medical Centre (UKMMC) dilakukan evaluasi berdasarkan data demografi, data klinis dan QOL. Quality of life dinilai menggunakan Tinnitus Handicap Inventory (THI), kuesioner tentang penderita yang mengukur 3 domain QOL: skala fungsional, emosional dan katastropik. Hasil: Responden terdiri dari 35 laki-laki (39,8%) dan 53 perempuan (60,2%), dengan rerata usia 57.9±13.9 tahun. Audiometri nada murni perlu dilakukan minimal satu kali selama periode penelitian. Penderita dengan tinitus persisten secara signifikan memiliki nilai rata-rata THI yang lebih tinggi (p=0.042) dan nilai emotional subscale (p=0.037) dibandingkan dengan penderita tinitus intermiten. Tidak ada hubungan yang signifikan antara jenis kelamin, durasi tinitus dan lateralisasi tinitus dengan nilai THI penderita. Diskusi: Semua penderita diperlukan anamnesis yang baik dan pemeriksaan fisik yang menyeluruh. Penderita tanpa penyebab primer dari tinitusnya akan diberikan terapi konseling tinitus yang baik. Penderita dengan gangguan pembuluh darah akan diberikan pengobatan konservatif. Kesimpulan: Magnetic resonance imaging perlu dilakukan pada gangguan pendengaran satu sisi dengan tinitus. Computed tomography scan dengan kontras dilakukan pada tinitus pulsatil dengan atau tanpa kelainan pada telinga. Pada pendertita dengan nilai kuesioner THI yang tinggi akan dirujuk ke psikiater untuk penilaian lebih lanjut.

Introduction: Still’s disease is a systemic, non-monogenic autoinflammatory condition affecting both children and adolescents (systemic juvenile idiopathic arthritis, sJIA) and adults (adult-onset Still’s disease, AOSD). Its clinical spectrum ranges from mild forms to life-threatening cases. Glucocorticoids represent the first-line therapy, but their chronic use is burdened with significant side effects. Hence, add-on therapy with disease modifying anti-rheumatic drugs and biologic anti-cytokine agents is frequently required, especially in patients with severe and recalcitrant clinical phenotypes. Among the targetable cytokines with a primary role in the pathogenesis of Still’s disease, interleukin-1 has a leading position. Areas covered: This review presents the available controlled evidence and observational studies regarding the efficacy and safety of canakinumab, a monoclonal antibody targeting interleukin-1β, in the treatment of Still’s disease. Expert opinion: Controlled studies fully support the clinical efficacy of canakinumab in the treatment of patients affected by sJIA. Conversely, strong evidences are still lacking in AOSD patients; nevertheless, its use in the adult population is legitimated by an increasing number of cases series and case reports and by preclinical data linking the pathogenesis of these two diseases. In addition, canakinumab has an excellent safety profile. Its role in preventing and treating macrophage activation syndrome is still debated.

Introduction: Adult onset Still disease (AOSD) is a rare systemic inflammatory condition. The clinical spectrum of this disease ranges from self-limiting forms with mild symptoms to life-threatening cases. Glucocorticoids and non-steroidal anti-inflammatory drugs (NSAIDs) represent the first line of therapy for AOSD, with add-on therapy with second-line drug reserved to steroid-dependent patients and in life-threatening cases. Currently, early treatment with conventional disease modifying anti-rheumatic drugs (DMARDs) and biologic agents blocking causal cytokines is advocated in patients with severe and recalcitrant clinical manifestations. Areas covered: This review analyzes the available controlled evidence and observational data regarding the efficacy and safety of conventional and biological pharmacological agents in the treatment of AOSD. Expert opinion: Non-steroidal anti-inflammatory drugs (NSAIDs) and glucocorticoids are effective in controlling clinical manifestations in the majority of AOSD patients. Conventional DMARDs can be 20 effective in some severe and steroid-dependent cases of AOSD; however, anti-cytokine agents represent an effective and overall more suitable alternative in this specific subset of patients. IL-1 and IL-6 blockade are effective in treating systemic and articular inflammation of AOSD patients. IL-1 blockade also has an excellent safety profile and therefore represent the first choice of biologic treatment in this clinical scenario.

Background:Exposure to severe or chronic life stressors may alter immune function and high levels of subsequent distress have been implicated in autoimmune disease pathogenesis. Post-traumatic stress disorder (PTSD) is a debilitating psychiatric condition affecting 1-12% of the general population1, occurring in response to traumatic events. Growing evidence supports an association between trauma exposure and PTSD with systemic lupus erythematosus (SLE) onset2.Objectives:To cross-sectionally assess PTSD prevalence in a cohort of patients with SLE and to examine its correlation with quality of life.Methods:A 189-item anonymous questionnaire including demographics, disease features, the 9-domain Trauma and Loss Spectrum – Self Report (TALS-SR) and the 8-domain Lupus Quality of Life (Lupus QoL) was administered via web to a cohort of patients with SLE. Patients were classified as PTSD cases based on TALS-SR items corresponding to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria for PTSD.Results:Ninety-nine (95% female and 5% male) patients with a median follow-up of 16.5 years completed the questionnaire. Self-reported fatigue prevalence was 75%. Fifteen patients (15%) reportedly were on psychological and/or psychiatric support. Thirty-one patients (31%) met the DSM-5 criteria for PTSD. The average LupusQoL interdomain score was 80/100. PTSD cases reported significantly lower scores compared to non-cases in three LupusQoL domains: planning (83 vs. 100, p=0.035), body image (85 vs. 95, p=0.031), and fatigue (67 vs. 92, p=0.001). An inverse correlation between TALS-SR scores and Lupus QoL subscales was found (Table1). In particular, the degree of stress secondary to losses or upsetting events was strongly correlated to fatigue intensity (rho= -0.458, pConclusion:PTSD prevalence might be higher in SLE than in the general population and have a detrimental influence on quality of life. Fatigue perception might be more significantly affected by PTSD. Intervention studies are needed to assess the therapeutical effects of psychological support in patients with SLE.References:[1]Shalev A et al. Post-Traumatic Stress Disorder. New England Journal of Medicine, June 2017.[2]Roberts AL et al. Association of Trauma and Posttraumatic Stress Disorder With Incident Systemic Lupus Erythematosus in a Longitudinal Cohort of Women. Arthritis & Rheumatology, November 2017.Table 1.Spearman rho coefficients outlining correlation across Lupus QoL and TALS-SR domains. The highest negative correlation has been found between fatigue and reaction to traumatic events. Significant correlations boxes are coloured in yellow (weak, rho 0.20-0.39) and red (moderate, rho 0.40-0.59). * pLupusQoL DomainsLupus QoL Total ScorePhysical healthPainPlanningIntimate relationshipsBurden to othersEmotional healthBody imageFatigueTALS-SR DomainsLoss events-.217-.217-.096-.031.047-.022.076-.009-.061Grief reactions-.145-.104-.041-.018-.124-.172-.192-.149-.107Potentially traumatic events.039-.082-.169-.167-.207-.185-.046-.229-.096Reaction to losses or upsetting events-.221-.256*-.289*-.218-.290*-.369**-.371**-.458**-.341**Re-experiencing-.139-.215-.245*-.228-.320**-.275*-.287*-.342**-.274*Avoidance and numbing-.176-.246*-.279*-.257*-.337**-.405**-.413**-.406**-.338**Maladaptive coping-.190-.238-.294*-.282*-.324**-.340**-.358**-.405**-.327**Arousal-.134-.177-.263*-.320**-.283*-.279*-.321**-.397**-.282*Personal characteristics / risk factors-.044-.115-.266*-.189-.409**-.231-.197-.253*-.199Disclosure of Interests:Luca Moroni: None declared, Martina Mazzetti: None declared, Giuseppe Alvise Ramirez: None declared, Simone Zuffada: None declared, Nicola Farina: None declared, Enrica Bozzolo: None declared, Valentina Di Mattei: 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

Systemic sclerosis (SSc) patients may develop severe coronavirus disease 2019 (COVID-19) (1), but no reports are available on disease progression following a severe acute respiratory syndrome coron...

Objectives To assess drug retention rates (DRRs) and reasons for discontinuation of biologic disease-modifying antirheumatic drugs (bDMARDs) in a large monocentric cohort of patients with adult onset Still's disease (AOSD). Methods Clinical data of AOSD patients treated with at least one bDMARD and followed up at our Center were retrospectively evaluated. Data about disease duration, number of previous bDMARDs, concomitant treatments, and reasons for therapy discontinuation were collected. Survival curves were examined by the Kaplan-Meier method and compared using a stratified log-rank test. 24-month DRRs were calculated for each bDMARD. Hazard ratio (HR) for previous bDMARD use was evaluated. Results Forty-two AOSD patients received a total of 79 bDMARD-courses. Anakinra (ANK; n = 41) was the most frequently used bDMARD, followed by tocilizumab (TCZ; n = 21) and Tumor Necrosis Factor inhibitors (TNFi; n = 17). Biologic agents were administered concomitantly with prednisone in all cases (mean dose, 23 ± 18 mg/day) and with csDMARD therapy in 54 (68%) of courses. Thirty-six (46%) treatment courses were discontinued by 24 months. DRRs at 24 months were 62.5% for TCZ, 53.1% for ANK, and 11.8% for TNFi. ANK and TCZ DRRs were similar (p = 0.576), but significantly higher than TNFi (p = 0.015). Previous biologic therapies did not impact DRR (HR 0.73, 95% CI = 0.40 - 1.31, p = 0.288). Conclusions In our AOSD study population, 24 months DRRs of TCZ and ANK were similar and significantly higher than the TNFi DRR. Previous use of biologic agents did not affect DRRs.

Background: No studies investigated the prevalence of arrhythmias among clinically-stable patients affected by COVID-19 infection. Methods: We assessed prevalence, type, and burden of arrhythmias, by a single-day snapshot in seven non-intensive COVID Units at a third-level center. Results: We enrolled 132 inhospital patients (mean age 65±14y; 66% males) newly diagnosed with COVID-19 infection. Arrhythmic episodes were detected in 12 patients (9%). In detail, 8 had atrial fibrillation, and 4 self-limiting supraventricular tachyarrhythmias. There were no cases of ventricular arrhythmias or new-onset atrioventricular blocks. In addition, we report no patients with QTc interval >450ms. Conclusions: Our single-day snapshot survey suggests that the prevalence of arrhythmias among clinically stable COVID-19 patients is low. In particular, no life-threatening arrhythmic events occurred.

Coronavirus disease 2019 (COVID-19) is a condition caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Severe cases of COVID-19 result in acute respiratory distress syndrome and death. A detrimental, hyper-inflammatory immune response with excess release of cytokines is the main driver of disease development and of tissue damage in these patients. Thus, repurposing of biologic agents and other pharmacological inhibitors of cytokines used for the treatment of various inflammatory conditions emerged as a logical therapeutic strategy to quench inflammation and improve the clinical outcome of COVID-19 patients. Evaluated agents include the interleukin one receptor blocker anakinra, monoclonal antibodies inhibiting IL-6 tocilizumab and sarilumab, monoclonal antibodies inhibiting granulocyte-monocyte colony stimulating factor and tumor necrosis factor, and Janus kinase inhibitors. In this review, we discuss the efficacy and safety of these therapeutic options based on direct personal experience and on published evidence from observational studies and randomized clinical trials.

In the last decade, interest has been growing in the relationship between obesity and several other clinical conditions, besides the well-established links between body mass index (BMI) and cardiovascular diseases or cancer. A particular focus has been put on the impact of a higher BMI on immune-mediated diseases such as rheumatoid arthritis (RA) and psoriatic arthritis (PsA). Obesity has been found to be associated with greater arthritis activity and a reduced probability of response to anti-tumor necrosis factor (TNF) agents. On the other hand, weight loss increases the chances of treatment success. Although the direct effect of a higher body mass on drug clearance might in part account for this obesity-related effect, other biological mechanisms could be involved. The evidence of a negative influence of obesity on arthritis treatment is particularly strong as far as anti-TNF inhibition is concerned; on the contrary, the response to biologic agents targeting interleukin-6, cytotoxic T lymphocyte antigen 4, or CD20 seems not to be negatively affected by a higher BMI. In this review, we will consider the main studies investigating the influence of obesity on anti-rheumatic treatment in RA and PsA patients. We will also try to hypothesize about a possible pathogenic explanation of this phenomenon and its role in the choice of an appropriate and personalized therapy.

Graphical abstract, Coronavirus Disease 2019 (COVID-19) is a pandemic disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The clinical spectrum of COVID-19 is broad and varies from mild to severe forms complicated by acute respiratory distress and death. This heterogeneity might reflect the ability of the host immune system to interact with SARS-CoV2 or the characteristics of the virus itself in terms of loads or persistence. Information on this issue might derive from interventional studies. However, results from high-quality trials are scarce. Here we evaluate the level of evidence of available published interventional studies, with a focus on randomised controlled trials and the efficacy of therapies on clinical outcomes. Moreover, we present data on a large cohort of well-characterized patients hospitalized at a single University Hospital in Milano (Italy), correlating viral clearance with clinical and biochemical features of patients.

We have read with interest the article by Cohen-Aubart et al 1 reporting the efficacy of infliximab in the treatment of Erdheim-Chester disease (ECD), a rare non-Langerhans histiocytosis. The anti-Tumor Necrosis Factor-α agent demonstrated a variable degree of efficacy, suggesting that infliximab might represent a therapeutic option for moderately severe ECD cases; similar results had been observed with anakinra.2 3 Nonetheless, following the identification of causative mutations along the mitogen-activated protein kinase(MAPK) pathway,4 severe forms of ECD are currently treated with targeted small molecule agents. Specifically, the BRAF inhibitor vemurafenib and the MAPK or extracellular-signal regulated kinase (MEK) inhibitor cobimetinib have been successfully used to treat life-threatening forms of ECD. Although life-saving, these drugs are associated with severe toxicity, which often mandates treatment discontinuation.5 …