Identification of distinct subgroups of Sjögren's disease by cluster analysis based on clinical and biological manifestations: data from the cross-sectional Paris-Saclay and the prospective ASSESS cohorts.

BACKGROUND: Sjögren's disease is a heterogenous autoimmune disease with a wide range of symptoms-including dryness, fatigue, and pain-in addition to systemic manifestations and an increased risk of lymphoma. We aimed to identify distinct subgroups of the disease, using cluster analysis based on subjective symptoms and clinical and biological manifestations, and to compare the prognoses of patients in these subgroups. METHODS: This study included patients with Sjögren's disease from two independent cohorts in France: the cross-sectional Paris-Saclay cohort and the prospective Assessment of Systemic Signs and Evolution of Sjögren's Syndrome (ASSESS) cohort. We first used an unsupervised multiple correspondence analysis to identify clusters within the Paris-Saclay cohort using 26 variables comprising patient-reported symptoms and clinical and biological manifestations. Next, we validated these clusters using patients from the ASSESS cohort. Changes in disease activity (measured by the European Alliance of Associations for Rheumatology [EULAR] Sjögren's Syndrome Disease Activity Index [ESSDAI]), patient-acceptable symptom state (measured by the EULAR Sjögren's Syndrome Patient Reported Index [ESSPRI]), and lymphoma incidence during follow-up were compared between clusters. Finally, we compared our clusters with the symptom-based subgroups previously described by Tarn and colleagues. FINDINGS: 534 patients from the Paris-Saclay cohort (502 [94%] women, 32 [6%] men, median age 54 years [IQR 43-64]), recruited between 1999 and 2022, and 395 patients from the ASSESS cohort (370 [94%] women, 25 [6%] men, median age 53 years [43-63]), recruited between 2006 and 2009, were included in this study. In both cohorts, hierarchical cluster analysis revealed three distinct subgroups of patients: those with B-cell active disease and low symptom burden (BALS), those with high systemic disease activity (HSA), and those with low systemic disease activity and high symptom burden (LSAHS). During follow-up in the ASSESS cohort, disease activity and symptom states worsened for patients in the BALS cluster (67 [36%] of 186 patients with ESSPRI score <5 at month 60 vs 92 [49%] of 186 at inclusion; p<0·0001). Lymphomas occurred in patients in the BALS cluster (five [3%] of 186 patients; diagnosed a median of 70 months [IQR 42-104] after inclusion) and the HSA cluster (six [4%] of 158 patients; diagnosed 23 months [13-83] after inclusion). All patients from the Paris-Saclay cohort with a history of lymphoma were in the BALS and HSA clusters. This unsupervised clustering classification based on symptoms and clinical and biological manifestations did not correlate with a previous classification based on symptoms only. INTERPRETATION: On the basis of symptoms and clinical and biological manifestations, we identified three distinct subgroups of patients with Sjögren's disease with different prognoses. Our results suggest that these subgroups represent different heterogeneous pathophysiological disease mechanisms, stages of disease, or both. These findings could be of interest when stratifying patients in future therapeutic trials. FUNDING: Fondation pour la Recherche Médicale, French Ministry of Health, French Society of Rheumatology, Innovative Medicines Initiative 2 Joint Undertaking, Medical Research Council UK, and Foundation for Research in Rheumatology.

Systemic lupus erythematosus associated with HIV infection: a retrospective case-control study.

OBJECTIVES: The association of systemic lupus erythematosus (SLE) and human immunodeficiency virus (HIV) remains scarcely described in the literature. Our objectives were to describe the characteristics of SLE in patients living with HIV (SLE-PLHIV) and compare it with SLE characteristics in patients without HIV infection. METHODS: We performed a retrospective study of 13 patients with SLE-PLHIV diagnosed between 1975 and 2020 in four different French hospitals. These patients were compared in a case-control study with a 1:5 ratio to age-, sex- and year of diagnosis- matched patients with SLE without HIV infection. RESULTS: Median (IQR) age at SLE diagnosis for patients with SLE and HIV infection was 43 years (36-53). There were 77% women. Main clinical manifestations were polyarthrtitis (84%), cutaneous lupus (69%), kidney disease (54%), serositis (15%) and autoimmune cytopenias (auto-immune haemolytic anaemia and/or immune thrombocytopenia) (31%). There were no neuropsychiatric manifestations. All patients had positive antinuclear antibody test with a titre ≥1:160. Anti-dsDNA antibodies were present in 75% of patients, and anti-Sm antibodies in 33%. SLE-PLHIV had more frequently renal manifestations (54 vs. 16%, p=0.006) and autoimmune cytopenia (31 vs 8%, p=0.04) than patients without HIV infection. CONCLUSIONS: SLE and HIV infection appear to be a rare association. Patients with SLE-PLHIV seem to have more renal manifestations and autoimmune cytopenias than patients with SLE without HIV infection.

Drug-Drug Interactions Involving Dexamethasone in Clinical Practice: Myth or Reality?

Concomitant administration of multiple drugs frequently causes severe pharmacokinetic or pharmacodynamic drug-drug interactions (DDIs) resulting in the possibility of enhanced toxicity and/or treatment failure. The activity of cytochrome P450 (CYP) 3A4 and P-glycoprotein (P-gp), a drug efflux pump sharing localization and substrate affinities with CYP3A4, is a critical determinant of drug clearance, interindividual variability in drug disposition and clinical efficacy, and appears to be involved in the mechanism of numerous clinically relevant DDIs, including those involving dexamethasone. The recent increase in the use of high doses of dexamethasone during the COVID-19 pandemic have emphasized the need for better knowledge of the clinical significance of drug-drug interactions involving dexamethasone in the clinical setting. We therefore aimed to review the already published evidence for various DDIs involving dexamethasone in vitro in cell culture systems and in vivo in animal models and humans.

Infliximab for the Treatment of Inflammatory Labyrinthitis: A Retrospective Cohort Study.

Inflammatory labyrinthitis is defined as a fluctuant vestibulo-cochlear syndrome associated with an impairment of the blood-labyrinthine barrier (BLB) on delayed FLAIR MRI sequences. Systemic and intratympanic corticosteroids are the gold standard treatment but their effect is frequently insufficient. The objective is here to determine whether infliximab could be of value in the treatment of bilateral inflammatory labyrinthitis. A retrospective monocentric study was conducted between January 2013 and December 2021. All patients included in the study were affected with a bilateral vestibulo-cochlear syndrome associated with bilateral blood-labyrinthine barrier impairment. Patients were administered infliximab at the dose of 5 mg/kg every 6 weeks for 6 months. Audiometry, MRI with delayed FLAIR sequences on the labyrinth, and corticosteroid doses still required were assessed both before and after treatment with infliximab was completed. Pure-tone average (PTA) was the primary outcome. The secondary outcomes were the speech recognition threshold (SRT), the Dizziness Handicap Inventory (DHI) score, and the corticosteroid (CS) dose. A total of nine patients including five men and four women were enrolled in the study. Thirteen ears were analyzed. After a 6-month period of treatment, the mean PTA (54 ± 24 db versus 66 ± 22 db; p = 0.027), SRT (54 ± 37 db versus 66 ± 32 db; p = 0.041) and DHI score (27 ± 15 versus 9 ± 2; p = 0.032) significantly improved. After the 6-month treatment period, the mean CS dose decreased from 38 ± 33 to 6 ± 5 mg/day (p = 0.003). We conclude that infliximab substantially improves the vestibulo-cochlear function in patients with bilateral inflammatory labyrinthitis and could be of value in corticosteroid-dependent cases.

Relapsing Polychondritis With Palmoplantar Pustulosis.

Palmoplantar pustulosis (PPP) is a very rare cutaneous manifestation observed during relapsing polychondritis (RP),1,2 not found in other conditions associated with saddle nose (eg, granulomatosis with polyangiitis, sarcoidosis, VEXAS [vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic] syndrome, congenital syphilis, leprosy, septal abscess).

A 24-Year-Old Woman With Cough, Arthralgia, and Skin Ulcerations.

CASE PRESENTATION: A 24-year-old Senegalese woman without remarkable history except anemia and iron deficiency related to excessive menstrual bleeding and sickle cell trait was admitted to our internal medicine department with 4-month fever, weight loss (-13 kg), dyspnea for limited efforts, intermittent productive cough, and bilateral metacarpophalangeal (MCP) and interphalangeal arthralgia. She was born and lived in France. She traveled previously to Senegal in 2015. She had no history of tobacco, alcohol, or drug use nor proximity with animals. She was taking no medication.

Autoantibodies Neutralizing Type I IFNs in the Bronchoalveolar Lavage of at Least 10% of Patients During Life-Threatening COVID-19 Pneumonia.

Autoantibodies (auto-Abs) neutralizing type I interferons (IFNs) are found in the blood of at least 15% of unvaccinated patients with life-threatening COVID-19 pneumonia. We report here the presence of auto-Abs neutralizing type I IFNs in the bronchoalveolar lavage (BAL) of 54 of the 415 unvaccinated patients (13%) with life-threatening COVID-19 pneumonia tested. The 54 individuals with neutralizing auto-Abs in the BAL included 45 (11%) with auto-Abs against IFN-α2, 37 (9%) with auto-Abs against IFN-ω, 54 (13%) with auto-Abs against IFN-α2 and/or ω, and five (1%) with auto-Abs against IFN-ß, including three (0.7%) with auto-Abs neutralizing IFN-α2, IFN-ω, and IFN-ß, and two (0.5%) with auto-Abs neutralizing IFN-α2 and IFN-ß. Auto-Abs against IFN-α2 also neutralize the other 12 subtypes of IFN-α. Paired plasma samples were available for 95 patients. All seven patients with paired samples who had detectable auto-Abs in BAL also had detectable auto-Abs in plasma, and one patient had auto-Abs detectable only in blood. Auto-Abs neutralizing type I IFNs are, therefore, present in the alveolar space of at least 10% of patients with life-threatening COVID-19 pneumonia. These findings suggest that these auto-Abs impair type I IFN immunity in the lower respiratory tract, thereby contributing to hypoxemic COVID-19 pneumonia.

Pachymeningitis associated with IgG4-related disease and ANCA positivity: Case report and review of the literature.

OBJECTIVE: Hypertrophic pachymeningitis is a rare clinical disorder involving localized or diffuse thickening of the dura mater. Considering pachymeningitis is both in the clinical spectrum of IgG4-RD and ANCA vasculitis (specifically granulomatosis with polyangiitis), an overlap syndrome is discussed. METHODS: We report a case of hypertrophic pachymeningitis revealed by headache and cranial nerve dysfunction, and coexistence of biopsy-proven IgG4-RD pachymeningitis and MPO-ANCA positivity. Furthermore, all cases previously reported in the literature of pachymeningitis with IgG4-RD and presence of ANCA were analyzed. RESULTS: Thirteen patients with pachymeningitis, IgG4-RD and ANCA were analyzed. Patients with HP-related IgG4 and ANCA are mainly male (8, 62%). Median age at diagnosis was 64 years. Main clinical manifestations at diagnosis were localized to the head and neck with headaches (10, 77%), cranial nerve dysfunction (7, 54%), hearing impairment (6, 46%) and vertigo (4, 31%). Except 1 patient with diffuse aortitis, no other systemic manifestation was observed at diagnosis and during follow-up. Serum IgG4 was often elevated (11, 85%) and ANCA was mainly with myeloperoxidase specificity (11, 85%). Seven patients had cerebrospinal fluid analyse with lymphocytic pleocytosis in 5 cases (71%), elevated proteins in 4 cases (57%), positive oligoclonal bands in 3 cases (42%) and decreased glucose in one case (14%). On the MRI, the thickening of the dura mater concerned most often the posterior fossa, in 7 cases (54%). Among 10 cases with histological findings, all showed increased IgG4-positivity of plasma cells, 50% lymphocytic infiltrate but none presented the three major histological criteria of IgG4-related disease. Three (30%) showed histological signs of vasculitis with vascular wall damage and/or giant cells. Among the 12 patients treated with steroid therapy, a clinical improvement was noted in 11 cases (92%). Relapse occurred during tapering in 4 patients (33%). An immunosuppressive drug was added in 2nd line for 7 cases (54%), with a clinical improvement in all. CONCLUSION: Pachymeningitis with IgG4 and ANCA seems a localized disease to the head and neck. Leptomeningeal biopsy commonly found IgG4 criteria and no vasculitis. All patients responded well to steroid therapy and immunosuppressive drugs, especially rituximab, with clinical and radiological improvement but relapse and/or sequelae are not uncommon.

18-Fluorodeoxyglucose positron emission tomography/computed tomography for large vessel vasculitis in clinical practice.

Diagnosis, prognostic assessment, and monitoring disease activity in patients with large vessel vasculitis (LVV) can be challenging. Early recognition of LVV and treatment adaptation is essential because vascular complications (aneurysm, dilatations, ischemic complications) or treatment related side effects can occur frequently in these patients. 18-fluorodeoxyglucose positron emission tomography/computed tomography (2-[18F]FDG-PET/CT) is increasingly used to diagnose, follow, and evaluate treatment response in LVV. In this review, we aimed to summarize the current evidence on the value of 2-[18F]FDG-PET/CT for diagnosis, follow, and treatment monitoring in LVV.

Tocilizumab-treated convalescent COVID-19 patients retain the cross-neutralization potential against SARS-CoV-2 variants.

Although tocilizumab treatment in severe and critical coronavirus disease 2019 (COVID-19) patients has proven its efficacy at the clinical level, there is little evidence supporting the effect of short-term use of interleukin-6 receptor blocking therapy on the B cell sub-populations and the cross-neutralization of SARS-CoV-2 variants in convalescent COVID-19 patients. We performed immunological profiling of 69 tocilizumab-treated and non-treated convalescent COVID-19 patients in total. We observed that SARS-CoV-2-specific IgG1 titers depended on disease severity but not on tocilizumab treatment. The plasma of both treated and non-treated patients infected with the ancestral variant exhibit strong neutralizing activity against the ancestral virus and the Alpha, Beta, and Delta variants of SARS-CoV-2, whereas the Gamma and Omicron viruses were less sensitive to seroneutralization. Overall, we observed that, despite the clinical benefits of short-term tocilizumab therapy in modifying the cytokine storm associated with COVID-19 infections, there were no modifications in the robustness of B cell and IgG responses to Spike antigens.

Impairment of central retinal artery hemodynamics in affected and fellow eyes in giant cell arteritis patients with unilateral vision loss.

OBJECTIVES: Permanent visual impairment is a major complication of giant cell arteritis (GCA). We investigated the added value of color Doppler imaging (CDI) of the central retinal artery (CRA) in patients with suspected GCA for early risk evaluation before temporal artery biopsy (TAB) results become available. METHODS: We conducted a non-interventional observational study of 30 consecutive patients hospitalized for suspected GCA, including a comprehensive analysis of clinical, laboratory, imaging, CDI and pathology data. GCA was diagnosed or excluded (GCA+, GCA-, respectively) according to American College of Rheumatology (ACR) criteria and TAB findings. Three patients not meeting ACR criteria were excluded secondarily. The GCA- group contained ten patients, and the GCA+ group contained 17 patients, including eight with unilateral, transient or permanent clinical visual impairment (CVI). RESULTS: Mean blood flow velocity (mBFV) in the CRA was impaired in the affected eyes of GCA + CVI+ patients (1.9 ± 0.9 cm.s-1, p < 0.001) relative to controls (4.1 ± 1.0 cm.s-1), GCA- patients (3.6 ± 0.7 cm.s-1) and GCA + CVI- patients (3.8 ± 0.8 cm.s-1). The mBFVs of the CRA was similar for affected and fellow eyes (right or left). CRA mBFV measurements effectively differentiated between patients with and without CVI (ROC-curve analysis, AUC = 0.925 [95%CI: 0.700 to 0.996], p < 0.0001, 88% sensitivity, 89% specificity, and cutoff of ≤2.7 cm.s-1 for affected eyes; 75% sensitivity, 100% specificity and cutoff of ≤2.2 cm.s-1 for fellow eyes). CONCLUSION: CDI facilities the early detection of visual ischemia risk in GCA+ patients, justifying urgent high-dose corticosteroid administration to save at least the fellow eye before pathology results become available.

Cluster analysis reveals eosinophilia and fibrosis as poor prognostic markers in 128 patients with eosinophilic fasciitis.

BACKGROUND: Eosinophilic fasciitis (EF) is an extremely rare disease with polymorphic presentation and prognosis. OBJECTIVE: To further investigate EF features. METHODS: We performed a retrospective multicentre study of EF patients from 2013 to 2019, clustered patients using multivariate correspondence analysis, and sought prognosis factors. RESULTS: One hundred twenty-eight patients were included. Sixty-nine (50%) patients had skin sclerosis, and eosinophil count was increased in 71 (55%) patients. Multivariate correspondence analysis identified 3 clusters: a "mild," a "late-onset and hypereosinophilic," and a "fibrotic" cluster. Of 109 patients who followed up for more than 1 year, 49 (45%) presented a relapse, and 48 (44%) had sequelae. Multivariate analysis revealed that eosinophilia (hazard ratio = 1.56; P = .02) and fibrosis (hazard ratio = 4.02; P = .002) were predictive factors of relapse, whereas edema (odds ratio = 0.31; P = .03), relapse (odds ratio = 3.00; P = .04) and fibrosis (odds ratio = 1) were predictive factors of sequelae. Following relapse, treatment modifications consisted of an increase in glucocorticoids in 40 (82%) patients and the addition of methotrexate in 31 (63%) patients. These modifications led to clinical improvement and glucocorticoid withdrawal in 37 (76%) and 22 (45%) patients. LIMITATIONS: Retrospective study. CONCLUSION: EF patients can be divided into 3 homogenous clusters, which, along with fibrosis and eosinophilia, are prognosis factors of relapse and sequelae.

In vivo confocal microscopic study of corneal innervation in Sjögren's Syndrome with or without small fiber neuropathy.

PURPOSE: To study changes in the subbasal nerve plexus by In vivo confocal microscopy (IVCM) in Sjögren's Syndrome (SS) with or without associated Small Fiber Neuropathy (SFN), in order to prevent diagnostic delay. METHODS: Seventy-one patients with SS, including 19 with associated SFN, 20 healthy volunteers and 20 patients with Meibomian gland dysfunction (MGD) were included in this retrospective case-control study. IVCM was used to investigate subbasal nerve plexus density and morphology. RESULTS: Corneal sensitivity as evaluated with the Cochet-Bonnet aesthesiometer was significantly reduced in the SS group versus the control group (P = 0.026) and the MGD group (P = 0.037). The number of inflammatory cells was significantly increased in the SS group to 86.2 ± 82.1 cells/mm2 compared to the control group (P < 0.001). The density of the subbasal nerve plexus was significantly reduced to 16.7 ± 6.5 mm/mm2 in the SS group compared to the control group (P < 0.005) and the MGD group (P = 0.042). The tortuosity of the nerves in the SS group was significantly increased compared to the control group (P < 0.001) and the MGD group (P = 0.025). The average number of subbasal nerve plexus neuromas was significantly increased in the SS group compared to the control group (P = 0.001), with a significant increase in the average number of neuromas in SS patients with associated SFN compared to SS patients without SFN (P = 0.008). CONCLUSION: IVCM can be useful to detect corneal nerve changes in SS patients and may allow earlier diagnosis of the disease and to consider new therapeutic approaches.

The risk of COVID-19 death is much greater and age dependent with type I IFN autoantibodies.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection fatality rate (IFR) doubles with every 5 y of age from childhood onward. Circulating autoantibodies neutralizing IFN-α, IFN-ω, and/or IFN-ß are found in ∼20% of deceased patients across age groups, and in ∼1% of individuals aged <70 y and in >4% of those >70 y old in the general population. With a sample of 1,261 unvaccinated deceased patients and 34,159 individuals of the general population sampled before the pandemic, we estimated both IFR and relative risk of death (RRD) across age groups for individuals carrying autoantibodies neutralizing type I IFNs, relative to noncarriers. The RRD associated with any combination of autoantibodies was higher in subjects under 70 y old. For autoantibodies neutralizing IFN-α2 or IFN-ω, the RRDs were 17.0 (95% CI: 11.7 to 24.7) and 5.8 (4.5 to 7.4) for individuals <70 y and ≥70 y old, respectively, whereas, for autoantibodies neutralizing both molecules, the RRDs were 188.3 (44.8 to 774.4) and 7.2 (5.0 to 10.3), respectively. In contrast, IFRs increased with age, ranging from 0.17% (0.12 to 0.31) for individuals <40 y old to 26.7% (20.3 to 35.2) for those ≥80 y old for autoantibodies neutralizing IFN-α2 or IFN-ω, and from 0.84% (0.31 to 8.28) to 40.5% (27.82 to 61.20) for autoantibodies neutralizing both. Autoantibodies against type I IFNs increase IFRs, and are associated with high RRDs, especially when neutralizing both IFN-α2 and IFN-ω. Remarkably, IFRs increase with age, whereas RRDs decrease with age. Autoimmunity to type I IFNs is a strong and common predictor of COVID-19 death.

Characterization and outcomes of 414 patients with primary SS who developed haematological malignancies.

OBJECTIVE: To characterize 414 patients with primary SS who developed haematological malignancies and to analyse how the main SS- and lymphoma-related features can modify the presentation patterns and outcomes. METHODS: By January 2021, the Big Data Sjögren Project Consortium database included 11 966 patients fulfilling the 2002/2016 classification criteria. Haematological malignancies diagnosed according to the World Health Organization (WHO) classification were retrospectively identified. RESULTS: There were 414 patients (355 women, mean age 57 years) with haematological malignancies (in 43, malignancy preceded at least one year the SS diagnosis). A total of 376 (91%) patients had mature B-cell malignancy, nearly half had extranodal marginal zone lymphoma (MZL) of mucosa-associated lymphoid tissue (MALT lymphoma) (n = 197), followed by diffuse large B-cell lymphoma (DLBCL) (n = 67), nodal MZL lymphoma (n = 29), chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) (n = 19) and follicular lymphoma (FL) (n = 17). Rates of complete response, relapses and death were 80%, 34% and 13%, respectively, with a 5-year survival rate of 86.5% after a mean follow-up of 8 years. There were significant differences in age at diagnosis (younger in MALT, older in CLL/SLL), predominant clinical presentation (glandular enlargement in MALT lymphoma, peripheral lymphadenopathy in nodal MZL and FL, constitutional symptoms in DLBCL, incidental diagnosis in CLL/SLL), therapeutic response (higher in MALT lymphoma, lower in DLBCL) and survival (better in MALT, nodal MZL and FL, worse in DLBCL). CONCLUSION: In the largest reported study of haematological malignancies complicating primary SS, we confirm the overwhelming predominance of B-cell lymphomas, especially MALT, with the salivary glands being the primary site of involvement. This highly-specific histopathological scenario is linked with the overall good prognosis with a 5-year survival rate of nearly 90%.

Tocilizumab plus dexamethasone versus dexamethasone in patients with moderate-to-severe COVID-19 pneumonia: A randomised clinical trial from the CORIMUNO-19 study group.

Background: In moderate-to-severe COVID-19 pneumonia, dexamethasone (DEX) and tocilizumab (TCZ) reduce the occurrence of death and ventilatory support. We investigated the efficacy and safety of DEX+TCZ in an open randomized clinical trial. Methods: From July 24, 2020, through May 18, 2021, patients with moderate-to-severe COVID-19 pneumonia requiring oxygen (>3 L/min) were randomly assigned to receive DEX (10 mg/d 5 days tapering up to 10 days) alone or combined with TCZ (8 mg/kg IV) at day 1, possibly repeated with a fixed dose of 400 mg i.v. at day 3. The primary outcome was time from randomization to mechanical ventilation support or death up to day 14, analysed on an intent-to-treat basis using a Bayesian approach. ClinicalTrials.gov number, NCT04476979. Findings: A total of 453 patients were randomized, 3 withdrew consent, 450 were analysed, of whom 226 and 224 patients were assigned to receive DEX or TCZ+DEX, respectively. At day 14, mechanical ventilation or death occurred in 32/226 (14%) and 27/224 (12%) in the DEX and TCZ+DEX arms, respectively (hazard ratio [HR] 0·85, 90% credible interval [CrI] 0·55 to 1·31). At day 14, the World health Organization (WHO) clinical progression scale (CPS) was significantly improved in the TCZ+DEX arm (OR 0·69, 95% CrI, 0·49 to 0.97). At day 28, the cumulative incidence of oxygen supply independency was 82% in the TCZ+DEX arms and 72% in the DEX arm (HR 1·36, 95% CI 1·11 to 1·67). On day 90, 24 deaths (11%) were observed in the DEX arm and 18 (8%) in the TCZ+DEX arm (HR 0·77, 95% CI 0·42-1·41). Serious adverse events were observed in 25% and 21% in DEX and TCZ+DEX arms, respectively. Interpretation: Mechanical ventilation need and mortality were not improved with TCZ+DEX compared with DEX alone. The safety of both treatments was similar. However, given the wide confidence intervals for the estimate of effect, definitive interpretation cannot be drawn. Funding: Programme Hospitalier de Recherche Clinique [PHRC COVID-19-20-0151, PHRC COVID-19-20-0029], Fondation de l'Assistance Publique - Hôpitaux de Paris (Alliance Tous Unis Contre le Virus) and from Fédération pour la Recherche Médicale" (FRM). Tocilizumab was provided by Roche.