Circulating Proteins Associated with Anti-IL6 Receptor Therapeutic Resistance in the Sera of Patients with Severe COVID-19.

Circulating proteomes provide a snapshot of the physiological state of a human organism responding to pathogenic challenges and drug interventions. The outcomes of patients with COVID-19 and acute respiratory distress syndrome triggered by the SARS-CoV2 virus remain uncertain. Tocilizumab is an anti-interleukin-6 treatment that exerts encouraging clinical activity by controlling the cytokine storm and improving respiratory distress in patients with COVID-19. We investigate the biological determinants of therapeutic outcomes after tocilizumab treatment. Overall, 28 patients hospitalized due to severe COVID-19 who were treated with tocilizumab intravenously were included in this study. Sera were collected before and after tocilizumab, and the patient's outcome was evaluated until day 30 post-tocilizumab infusion for favorable therapeutic response to tocilizumab and mortality. Hyperreaction monitoring measurements by liquid chromatography-mass spectrometry-based proteomic analysis with data-independent acquisition quantified 510 proteins and 7019 peptides in the serum of patients. Alterations in the serum proteome reflect COVID-19 outcomes in patients treated with tocilizumab. Our results suggested that circulating proteins associated with the most significant prognostic impact belonged to the complement system, platelet degranulation, acute-phase proteins, and the Fc-epsilon receptor signaling pathway. Among these, upregulation of the complement system by activation of the classical pathway was associated with poor response to tocilizumab, and upregulation of Fc-epsilon receptor signaling was associated with lower mortality.

Clinical features and long-term outcomes of patients with systemic polyarteritis nodosa diagnosed since 2005: Data from 196 patients.

BACKGROUND: The landscape of polyarteritis nodosa (PAN) has substantially changed during the last decades. Recent data regarding causes, characteristics, and prognosis of systemic PAN in the modern era are lacking. METHODS: This retrospective study included patients with systemic PAN referred to the French Vasculitis Study Group between 2005 and 2019. Characteristics, associated conditions and outcomes were collected, and predictors of relapse and death were analyzed. RESULTS: 196 patients were included. Main clinical symptoms were constitutional (84%), neurological (59%), skin (58%) and musculoskeletal (58%) manifestations. Secondary PAN accounted for 55 (28%) patients, including myelodysplastic syndrome (9%), solid cancer (7%), lymphoma (4%) and autoinflammatory diseases (4%). No patient had active HBV infection. All treated patients (98.5%) received glucocorticoids (GCs), alone (41%) or in combination with immunosuppressants (59%), with remission achieved in 90%. Relapses were independently associated with age >65 years (HR 1.85; 95% CI1.12-3.08), gastrointestinal involvement (1.95; 95% CI1.09-3.52) and skin necrotic lesions (HR 1.95; 95%CI 1.24-3.05). One-, 5- and 10-year overall survival rates were 93%, 87% and 81%, respectively. In multivariate analyses, age >65 years (HR 2.80; 95%CI 1.23-6.37), necrotic purpura (HR 4.16; 95%CI 1.62-10.70), acute kidney injury (HR 4.89; 95% 1.71-13.99) and secondary PAN (HR 2.98; 95%CI 1.29-6.85) were independently associated with mortality. CONCLUSION: Landscape of PAN has changed during the last decades, with the disappearance of HBV-PAN and the emergence of secondary PAN. Relapse rate remains high, especially in aged patients with gastrointestinal and cutaneous necrosis, as well as mortality.

FIP1L1-PDGFRA-Associated Hypereosinophilic Syndrome as a Treatable Cause of Watershed Infarction.

Background and Purpose: Ischemic stroke has been reported in various conditions associated with eosinophilia. FIP1L1-PDGFRA fusion ([Fip1-like 1-platelet-derived growth factor receptor alpha]; F/P) leads to the proliferation of the eosinophilic lineage and thus to a clonal hypereosinophilic syndrome that is highly responsive to imatinib. Methods: We previously reported on a nationwide retrospective study of 151 patients with F/P-associated clonal hypereosinophilic syndrome. Patients from this cohort with a clinical history of ischemic stroke (as well as 2 additional cases) were further analyzed to better define their clinical picture and outcomes. Results: Sixteen male patients (median age, 51 [43­59] years) with low-to-intermediate cardiovascular risk were included. Median National Institutes of Health Stroke Scale was 4 (range, 1­6). Most cerebral imaging disclosed multiple bilateral infarctions of watershed distribution (69%). Despite frequent cardiac involvement (50%), cardiac thrombus was evidenced in a single patient and, according to the TOAST classification (Trial of ORG 10172 in Acute Stroke Treatment), 62.5% of strokes were presumably of undetermined etiology. Among the 15 patients treated with imatinib, and after a median follow-up of 4.5 years, stroke recurred in only 3 patients (consisting of either cardio embolic or hemorrhagic events, unrelated to the first episode). Conclusions: F/P+ clonal hypereosinophilic syndrome is a diagnosis to consider in patients with unexplained ischemic stroke and hypereosinophilia (especially in the setting of multiple cortical borderzone distribution) and warrants prompt initiation of imatinib.

Tocilizumab for Severe Worsening COVID-19 Pneumonia: a Propensity Score Analysis.

BACKGROUND: High levels of serum interleukin-6 (IL-6) correlate with disease severity in COVID-19. We hypothesized that tocilizumab (a recombinant humanized anti-IL-6 receptor) could improve outcomes in selected patients with severe worsening COVID-19 pneumonia and high inflammatory parameters. METHODS: The TOCICOVID study included a prospective cohort of patients aged 16-80 years with severe (requiring > 6 L/min of oxygen therapy to obtain Sp02 > 94%) rapidly deteriorating (increase by ≥ 3 L/min of oxygen flow within the previous 12 h) COVID-19 pneumonia with ≥ 5 days of symptoms and C-reactive protein levels > 40 mg/L. They entered a compassionate use program of treatment with intravenous tocilizumab (8 mg/kg with a maximum of 800 mg per infusion; and if needed a second infusion 24 to 72 h later). A control group was retrospectively selected with the same inclusion criteria. Outcomes were assessed at D28 using inverse probability of treatment weighted (IPTW) methodology. RESULTS: Among the 96 patients included (81% male, mean (SD) age: 60 (12.5) years), underlying conditions, baseline disease severity, and concomitant medications were broadly similar between the tocilizumab (n = 49) and the control (n = 47) groups. In the IPTW analysis, treatment with tocilizumab was associated with a reduced need for overall ventilatory support (49 vs. 89%, wHR: 0.39 [0.25-0.56]; p < 0.001). Albeit lacking statistical significance, there was a substantial trend towards a reduction of mechanical ventilation (31% vs. 45%; wHR: 0.58 [0.36-0.94]; p = 0.026). However, tocilizumab did not improve overall survival (wHR = 0.68 [0.31-1.748], p = 0.338). Among the 85 (89%) patients still alive at D28, patients treated with tocilizumab had a higher rate of oxygen withdrawal (82% vs. 73.5%, wHR = 1.66 [1.17-2.37], p = 0.005), with a shorter delay before being weaned of oxygen therapy (mean 11 vs. 16 days; p < 0.001). At D28, the rate of patients discharged from hospital was higher in the tocilizumab group (70% vs. 40%, wHR = 1.82 [1.22-2.75]; p = 0.003). The levels of CRP and fibrinogen post therapy (p < 0.001 for both variables) were significantly lower in the tocilizumab group (interaction test, mixed model). Rates of neutropenia (35% vs. 0%; p < 0.001) were higher in the tocilizumab group, yet rates of infections (22% vs. 38%, p = 0.089) including ventilator-acquired pneumonia (8% vs. 26%, p = 0.022) were higher in the control group. CONCLUSION: These data could be helpful for the design of future trials aiming to counter COVID-19-induced inflammation, especially before patients require admission to the intensive care unit.

Monocyte/Macrophage Abnormalities Specific to Rheumatoid Arthritis Are Linked to miR-155 and Are Differentially Modulated by Different TNF Inhibitors.

Proinflammatory macrophages and miR-155 are increased in patients with rheumatoid arthritis (RA). We studied membrane TNF (mTNF) expression on blood monocytes, polarization into macrophages, miR-155 expression, and the effect of anti-TNF on these biomarkers in RA patients. Sixty-seven RA patients and 109 controls (55 healthy, 54 with spondyloarthritis and connective tissue diseases) were studied. Monocytes were isolated and differentiated into macrophages with or without anti-TNF. mTNF expression was increased on monocytes from RA patients, but not from other inflammatory diseases, correlated with disease activity. Under human serum AB or M-CSF, only monocytes from RA had a defect of differentiation into M2-like macrophages and had a propensity for preferential maturation toward M1-like macrophages that contributed to synovial inflammation. This defect was correlated to mTNF expression and was partially reversed by monoclonal anti-TNF Abs but not by the TNF soluble receptor. miR-155 was increased in M2-macrophages except in adalimumab-treated patients. Transfection of healthy monocytes with miR-155 induced a decrease in M2-like markers, and transfection of RA monocytes with antagomir-155 allowed restoration of M2-like polarization. Defect in differentiation of monocytes into M2-like-macrophages linked to increased miR-155 and correlated with increased mTNF on monocytes could play a key role in RA pathogenesis. Monoclonal anti-TNF Abs but not the TNF soluble receptor partially restored this defect.

Epidemiology, clinical picture and long-term outcomes of FIP1L1-PDGFRA-positive myeloid neoplasm with eosinophilia: Data from 151 patients.

FIP1L1-PDGFRA-positive myeloid neoplasm with eosinophilia (F/P+ MN-eo) is a rare disease: robust epidemiological data are lacking and reported issues are scarce, of low sample-size and limited follow-up. Imatinib mesylate (IM) is highly efficient but no predictive factor of relapse after discontinuation has yet been identified. One hundred and fifty-one patients with F/P+ MN-eo (143 males; mean age at diagnosis 49 years; mean annual incidence: 0.18 case per million population) were included in this retrospective nationwide study involving all French laboratories who perform the search of F/P fusion gene (study period: 2003-2019). The main organs involved included the spleen (44%), skin (32%), lungs (30%), heart (19%) and central nervous system (9%). Serum vitamin B12 and tryptase levels were elevated in 74/79 (94%) and 45/57 (79%) patients, respectively, and none of the 31 patients initially treated with corticosteroids achieved complete hematologic remission. All 148 (98%) IM-treated patients achieved complete hematologic and molecular (when tested, n = 84) responses. Forty-six patients eventually discontinued IM, among whom 20 (57%) relapsed. In multivariate analysis, time to IM initiation (continuous HR: 1,01 [0.99-1,03]; P = .05) and duration of IM treatment (continuous HR: 0,97 [0,95-0,99]; P = .004) were independent factors of relapse after discontinuation of IM. After a mean follow-up of 80 (56) months, the 1, 5- and 10-year overall survival rates in IM-treated patients were 99%, 95% and 84% respectively. In F/P+ MN-eo, prompt initiation of IM and longer treatment durations may prevent relapses after discontinuation of IM.

Iron deficiency, an unusual cause of thrombocytopenia: results from a multicenter retrospective case-controlled study.

Iron deficiency anemia (IDA) is often associated with mild to moderate thrombocytosis, and iron deficiency-associated thrombocytopenia (IDAT) is much more uncommon and often misdiagnosed as immune thrombocytopenia (ITP). To better describe the features of IDAT, we conducted a retrospective multicenter case-control study. We identified 10 patients (9 women) with a definite diagnosis IDAT, with a median age of 43.5 [range, 16-72] years and a median platelet count of 30.5 × 109/L [range, 21-80], and 7 patients with a possible diagnosis of IDAT. Bleeding manifestations were absent in all patients but one. All the patients recovered (platelet count ≥ 150 × 109/L) upon iron therapy ± red blood cell transfusion after a median time of 6 [4-39] days. When compared with 30 randomly newly diagnosed ITP patients matched on age, the baseline platelet count was significantly lower in ITP (median = 7 × 109/L [4-59], p < 0.001) whereas MPV was higher (10.5 fL [9,4-13,8] vs 8.2 fL, for IDAT p < 0.001). The median platelet count on day 7 was 337 × 109/L [113-1000] for IDAT cases vs 72 × 109/L [13-212] for ITP controls (p < 0.001). IDAT is potentially an under-recognized cause of thrombocytopenia that may be easily managed with iron therapy.

Limb arteries involvement assessed by FDG/PET CT at diagnosis of giant cell arteritis and risk of relapse: An observational study.

INTRODUCTION: Steroids and anti-IL6 biotherapy are highly effective in obtaining remission in patients with giant cell arteritis (GCA) but the risk of relapses remains high. We aimed to identify predictors of relapse in GCA. METHODS: All consecutive patients admitted with a new diagnosis of GCA - according to the 2022 American College of Rheumatology/EULAR (ACR/EULAR) classification criteria - between May 2011 and May 2022 were eligible for this study. The primary outcome was the GCA relapse rate over the 36-months follow up. Factors associated with the primary outcome and time to first relapse were analyzed. RESULTS: One hundred and eight patients (74 [69-81] years, 64.8% women) with a new diagnosis of GCA were studied. GCA was biopsy-proven in 65 (60.2%) cases. Ninety-eight (90.7%) FDG/PET CT scans performed at diagnosis were available for review. All patients received steroids given for 21.0 [18.0-28.5] months, associated with methotrexate (n=1, 0.9%) or tocilizumab (n=2, 1.9%). During a median follow-up of 27.5 [11.4-35.0] months, relapse occurred in 40 (37%) patients. Multivariable Cox regression model, including general signs, gender, aortic wall thickness, FDG uptake in arterial wall and IV steroid pulse as covariates, showed that both general signs (HR 2.0 [1.0-4.0, P<0.05) and FDG uptake in limb arteries (HR 2.7 [1.3-5.5], P<0.01) at diagnosis were associated with GCA relapse. CONCLUSION: FDG uptake in limb arteries at diagnosis is a predictor of relapse in newly diagnosed GCA.

French guidelines for the etiological workup of eosinophilia and the management of hypereosinophilic syndromes.

Eosinophilic-related clinical manifestations are protean and the underlying conditions underpinning eosinophilia are highly diverse. The etiological workup of unexplained eosinophilia/hypereosinophilia can be challenging, and can lead sometimes to extensive, inappropriate, costly and/or invasive investigations. To date, guidelines for the etiological workup and management of eosinophilia are mainly issued by hematologists, and thus mostly cover the scope of clonal hypereosinophilic syndromes (HES). Here, thanks to an extensive literature review, and thanks to the joint work of a large panel of experts involving physicians from both adult and pediatric medicine and from various subspecialties (as well as a representative of a patients' association representative), we provide recommendations for both the step-by step diagnostic workup of eosinophilia (whether unexplained or within specific contexts) as well as the management and follow-up of the full spectrum of eosinophilic disorders (including clonal, reactive, lymphocytic and idiopathic HES, as well as single-organ diseases). Didactic prescription summaries intended to facilitate the prescription of eosinophil-targeted drugs are also provided, as are practical diagnostic and therapeutic algorithms. Lastly, this set of recommendations also includes a summary intended for general practitioners, as well as an overview of the therapeutic patient education program set up by the French reference center for HES. Further updates will be mandatory as new validated information emerges.

Clinical presentation, outcome, and prognostic markers in patients with intravascular large B-cell lymphoma, a lymphoma study association (LYSA) retrospective study.

BACKGROUND: Intravascular large B-cell lymphoma (lVLBCL) is a very rare type of large B-cell lymphoma. METHODS: We conducted a retrospective study on IVLBCL patients treated from 2000 to 2016 in LYSA cooperative group centers. RESULTS: Sixty-five patients were identified in 23 centers. Median age at diagnosis was 69 years (range 23-92). Thirty-four patients (64%) had an IPI score >3 and 40 patients (67%) had a performance status ≥2. The most frequent extra-nodal locations were bone marrow (n = 34; 52%), central nervous system (n = 25; 39%), and skin (n = 21; 33%). Nodal involvement and endocrine system were observed in 34% (n = 22) and 18% (n = 12) of all cases, respectively. Twenty-six patients (41%) had macrophage activation syndrome. Tumor cells were frequently CD5 positive (52%) with a non-germinal center origin (86%). BCL2 was expressed in 87% of all samples analyzed (n = 20) and 43% of patients had a MYC/BCL2 double expression. Fifty-six patients were treated with a regimen of chemotherapy containing rituximab, among whom 73% reached complete remission. The median progression-free survival (PFS) and median overall survival (OS) were 29.4 months and 63.8 months, respectively. History of autoimmune disorder (Hazard ratio [HR] 3.3 [1.4-7.8]; p < 0.01), nodal involvement (HR 2.6 [1.4-5.1]; p < 0.01), lack of anthracycline (HR 0.1 [0-0.4] for use; p < 0.001), or no intensification at first-line regimen (p = 0.02) were associated with worse PFS. High-dose methotrexate use was not associated with better PFS or OS. CONCLUSIONS: Our study highlights the aggressive clinical picture of IVLBCL, in particular the frequency of macrophage activation syndrome, and the need for new therapies despite a response to R-CHOP-like regimen similar to non-intravascular diffuse large B-cell lymphomas.

Regression of Coronary Aneurysms With Intravenous Immunoglobulins and Steroids for COVID-19 Adult Multisystem Inflammatory Syndrome.

A multisystem inflammatory syndrome mimicking Kawasaki disease has been increasingly reported, mainly in children, in the context of coronavirus disease-2019 (COVID-19). We report on the first case of coronary aneurysm resolution after treatment with steroids and intravenous immunoglobulins in an adult patient with multisystem inflammatory syndrome temporally associated with COVID-19. (Level of Difficulty: Beginner.).

Lymphocyte Immunophenotyping and CD4/CD8 Ratio in Cerebrospinal Fluid for the Diagnosis of Sarcoidosis-related Uveitis.

Background: This study aimed to assess the diagnostic relevance of CD4/CD8 ratio in cerebrospinal fluid (CSF) for the etiological diagnosis work-up of uveitis.Methods: We consecutively included patients who were referred to our department for the diagnostic workup of intermediate and/or posterior uveitis. Etiological diagnoses were established in a blind manner regarding CD4/CD8 ratio.Results: Fifty-two patients were included. A diagnosis of ocular sarcoidosis was made in 15 (29%) patients, 21% had another determined diagnosis while 50% remained of undetermined origin. Median CD4/CD8 ratio in CSF was 4.57 (IQR 3.39-5.47) in ocular sarcoidosis, 1.74 (1.60-3.18) in uveitis due to other determined cause (P = .008), and 2.83 (2.34-3.54) in those with uveitis of undetermined origin (P = .007). CD4/CD8 ratio >3.23 was associated with a diagnosis of ocular sarcoidosis.Conclusion: Determination of CD4/CD8 ratio in CSF can be useful for diagnosis work-up since a CD4/CD8 ratio >3.23 in CSF is associated with ocular sarcoidosis.

Venous thrombosis and predictors of relapse in eosinophil-related diseases.

Eosinophils have widespread procoagulant effects. Eosinophilic cardiovascular toxicity mostly consists of endomyocardial damage or eosinophilic vasculitis, while reported cases of venous thrombosis (VT) are scarce. We aimed to report on the clinical features and treatment outcomes of patients with unexplained VT and eosinophilia, and to identify predictors of relapse. This retrospective, multicenter, observational study included patients aged over 15 years with VT, concomitant blood eosinophilia ≥ 1G/L and without any other moderate-to-strong contributing factors for VT. Fifty-four patients were included. VT was the initial manifestation of eosinophil-related disease in 29 (54%) patients and included pulmonary embolism (52%), deep venous thrombosis (37%), hepatic (11%) and portal vein (9%) thromboses. The median [IQR] absolute eosinophil count at VT onset was 3.3G/L [1.6-7.4]. Underlying eosinophil-related diseases included FIP1L1-PDGFRA-associated chronic myeloid neoplasm (n = 4), Eosinophilic Granulomatosis with Polyangiitis (n = 9), lymphocytic (n = 1) and idiopathic (n = 29) variants of hypereosinophilic syndrome. After a median [IQR] follow-up of 24 [10-62] months, 7 (13%) patients had a recurrence of VT. In multivariate analysis, persistent eosinophilia was the sole variable associated with a shorter time to VT relapse (HR 7.48; CI95% [1.94-29.47]; p = 0.015). Long-term normalization of eosinophil count could prevent the recurrence of VT in a subset of patients with unexplained VT and eosinophilia ≥ 1G/L.

Metabolomic analyses of COVID-19 patients unravel stage-dependent and prognostic biomarkers.

The circulating metabolome provides a snapshot of the physiological state of the organism responding to pathogenic challenges. Here we report alterations in the plasma metabolome reflecting the clinical presentation of COVID-19 patients with mild (ambulatory) diseases, moderate disease (radiologically confirmed pneumonitis, hospitalization and oxygen therapy), and critical disease (in intensive care). This analysis revealed major disease- and stage-associated shifts in the metabolome, meaning that at least 77 metabolites including amino acids, lipids, polyamines and sugars, as well as their derivatives, were altered in critical COVID-19 patient's plasma as compared to mild COVID-19 patients. Among a uniformly moderate cohort of patients who received tocilizumab, only 10 metabolites were different among individuals with a favorable evolution as compared to those who required transfer into the intensive care unit. The elevation of one single metabolite, anthranilic acid, had a poor prognostic value, correlating with the maintenance of high interleukin-10 and -18 levels. Given that products of the kynurenine pathway including anthranilic acid have immunosuppressive properties, we speculate on the therapeutic utility to inhibit the rate-limiting enzymes of this pathway including indoleamine 2,3-dioxygenase and tryptophan 2,3-dioxygenase.

Extensive DVT and Pulmonary Embolism Leading to the Diagnosis of Coronavirus Disease 2019 in the Absence of Severe Acute Respiratory Syndrome Coronavirus 2 Pneumonia.

There is growing evidence that coronavirus disease 2019 (COVID-19) is associated with a hypercoagulable state. To date, all patients reported with venous thromboembolic disease and COVID-19 have shown evidence of viral pneumonia. Here, we report the case of a 31-year-old patient with unexplained extensive DVT and bilateral pulmonary embolism in the absence of COVID-19 pneumonia, leading to the diagnosis of otherwise asymptomatic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. In the context of the COVID-19 pandemic, given the high rates of otherwise asymptomatic patients, testing for SARS-CoV-2 should be performed in all patients with unexplained VTE occurring in COVID-19-endemic areas, even in the absence of other disease manifestations suggestive of SARS-CoV-2 infection.

Serum 1,25(OH)2 Vitamin D and 25(OH) Vitamin D Ratio for the Diagnosis of Sarcoidosis-Related Uveitis.

Purpose: The diagnostic workup of uveitis is challenging, with 30 to 50% of cases remaining of undetermined etiology despite multiple investigations. Sarcoid granuloma-related increase of 1,25(OH)2D levels could be helpful for the diagnosis of ocular sarcoidosis.Methods: Monocentric retrospective cohort study of patients for whom serum 25(OH)D and 1,25(OH)2D levels were measured during the etiologic workup of unexplained uveitis in a tertiary referral center. The diagnoses of uveitis' underlying diseases were established according to international diagnostic criteria.Results: Fifty-nine patients were included. The diagnosis of defined, presumed or probable sarcoidosis was made in 37% of patients while 41% of cases remained of undetermined origin. The median serum levels of 25(OH)D in patients with ocular sarcoidosis and in those with uveitis due to another cause were 34.50 [21.2-40.8] and 43.20 [32.2-58.3] nmol/L (P=0.02), respectively. In the same subgroups of patients, the median serum levels of 1,25(OH)2D were 132.4 [107.4-163.9] and 108.0 [84.30-130.5] pmol/l (P=0.02), and the median 1,25(OH)2D/25(OH)D ratio was 4.17 [3.11-5.09] and 2.56 [1.54-3.37] (P=0.0007) respectively. A 1,25(OH)2D/25(OH)D ratio >3.5 was associated with the diagnosis of sarcoidosis with a 68 % sensitivity and a 78% specificity and, in univariate analysis, was associated with an abnormal chest CT-scan (OR=5.7, P=0.003), granulomas on bronchial biopsy (OR=14.7, P=0.007) and bronchoalveolar lavage fluid lymphocytosis (OR=12.4, P=0.0006).Conclusion: The measurement of serum 25(OH)D and 1,25(OH)2D levels is a useful tool in the etiological workup of patients with unexplained uveitis, since a high 1,25(OH)2D/25(OH)D ratio is suggestive of ocular sarcoidosis.