Epidemiology and geographic clustering of Erdheim-Chester disease in Italy and France.

This geoepidemiological study, performed in Italy and France, shows that Erdheim-Chester disease is increasingly diagnosed and cases cluster in specific geographic areas, namely southern Italy and central France. Disease frequency inversely correlates with the Human Development Index.

Autoantibody-Mediated Depletion of IL-1RA in Still's Disease and Potential Impact of IL-1 Targeting Therapies.

BACKGROUND: Adult-onset Still's disease (AOSD) and systemic juvenile idiopathic arthritis (sJIA) resemble a continuum of a rare, polygenic IL-1ß-driven disease of unknown etiology. OBJECTIVE: In the present study we sought to investigate a potential role of recently described autoantibodies neutralizing the interleukin-1(IL-1)-receptor antagonist (IL-1-Ra) in the pathogenesis of Still's disease. METHODS: Serum or plasma samples from Still's disease patients (AOSD, n = 23; sJIA, n = 40) and autoimmune and/or inflammatory disease controls (n = 478) were analyzed for autoantibodies against progranulin (PGRN), IL-1Ra, IL-18 binding protein (IL-18BP), and IL-36Ra, as well as circulating IL-1Ra and IL-36Ra levels by ELISA. Biochemical analyses of plasma IL-1Ra were performed by native Western blots and isoelectric focusing. Functional activity of the autoantibodies was examined by an in vitro IL-1ß-signaling reporter assay. RESULTS: Anti-IL-1-Ra IgG were identified in 7 (27%) out of 29 Still's disease patients, including 4/23 with AOSD and 3/6 with sJIA and coincided with a hyperphosphorylated isoform of endogenous IL-1Ra. Anti-IL-36Ra antibodies were found in 2 AOSD patients. No anti-PGRN or anti-IL-18BP antibodies were detected. Selective testing for anti-IL-1Ra antibodies in an independent cohort (sJIA, n = 34) identified 5 of 34 (14.7%) as seropositive. Collectively, 8/12 antibody-positive Still's disease patients were either new-onset active disease or unresponsive to IL-1 blocking drugs. Autoantibody-seropositivity associated with decreased IL-1Ra plasma/serum levels. Seropositive plasma impaired in vitro IL-1Ra bioactivity, which could be reversed by anakinra or canakinumab treatment. CONCLUSION: Autoantibodies neutralizing IL-1Ra may represent a novel patho-mechanism in a subgroup of Still's disease patients, which is sensitive to high-dose IL-1 blocking therapy.

Subclinical giant cell arteritis increases the risk of relapse in polymyalgia rheumatica.

OBJECTIVE: The aim of the present study was to determine the clinical significance of subclinical giant cell arteritis (GCA) in polymyalgia rheumatica (PMR) and ascertain its optimal treatment approach. METHODS: Patients with PMR who fulfilled the 2012 European Alliance of Associations for Rheumatology/American College of Rheumatology Provisional Classification Criteria for PMR, did not have GCA symptoms and were routinely followed up for 2 years and were stratified into two groups, according to their ultrasound results: isolated PMR and PMR with subclinical GCA. The outcomes (relapses, glucocorticoid use and disease-modifying antirheumatic drug treatments) between groups were compared. RESULTS: We included 150 patients with PMR (50 with subclinical GCA) with a median (IQR) follow-up of 22 (20-24) months. Overall, 47 patients (31.3 %) had a relapse, 31 (62%) in the subclinical GCA group and 16 (16%) in the isolated PMR group (p<0.001). Among patients with subclinical GCA, no differences were found in the mean (SD) prednisone starting dosage between relapsed and non-relapsed patients (32.4±15.6 vs 35.5±12.1 mg, respectively, p=0.722). Patients with subclinical GCA who relapsed had a faster prednisone dose tapering in the first 3 months compared with the non-relapsed patients, with a mean dose at the third month of 10.0±5.2 versus 15.2±7.9 mg daily (p<0.001). No differences were found between relapsing and non-relapsed patients with subclinical GCA regarding age, sex, C reactive protein and erythrocyte sedimentation rate. CONCLUSIONS: Patients with PMR and subclinical GCA had a significantly higher number of relapses during a 2-year follow-up than patients with isolated PMR. Lower starting doses and rapid glucocorticoid tapering in the first 3 months emerged as risk factors for relapse.

Efficacy and safety of targeted therapies in VEXAS syndrome: retrospective study from the FRENVEX.

OBJECTIVES: Vacuoles, E1 enzyme, X-linked, autoinflammatory and somatic (VEXAS) syndrome is an adult-onset autoinflammatory disease associated with somatic ubiquitin-like modifier-activating enzyme 1 (UBA1) mutations. We aimed to evaluate the efficacy and safety of targeted therapies. METHODS: Multicentre retrospective study including patients with genetically proven VEXAS syndrome who had received at least one targeted therapy. Complete response (CR) was defined by a clinical remission, C-reactive protein (CRP) ≤10 mg/L and a ≤10 mg/day of prednisone-equivalent therapy, and partial response (PR) was defined by a clinical remission and a 50% reduction in CRP levels and glucocorticoid dose. RESULTS: 110 patients (median age 71 (68-79) years) who received 194 targeted therapies were included: 78 (40%) received Janus kinase (JAK) inhibitors (JAKi), 51 (26%) interleukin (IL)-6 inhibitors, 33 (17%) IL-1 inhibitors, 20 (10%) tumour necrosis factor (TNFα) blockers and 12 (6%) other targeted therapies. At 3 months, the overall response (CR and PR) rate was 24% with JAKi, 32% with IL-6 inhibitors, 9% with anti-IL-1 and 0% with TNFα blockers or other targeted therapies. At 6 months, the overall response rate was 30% with JAKi and 26% with IL-6 inhibitors. Survival without treatment discontinuation was significantly longer with JAKi than with the other targeted therapies. Among patients who discontinued treatment, causes were primary failure, secondary failure, serious adverse event or death in 43%, 14%, 19% and 19%, respectively, with JAKi and 46%, 11%, 31% and 9%, respectively, with IL-6 inhibitors. CONCLUSIONS: This study shows the benefit of JAKi and IL-6 inhibitors, whereas other therapies have lower efficacy. These results need to be confirmed in prospective trials.

Prevalence and characteristics of subclinical giant cell arteritis in polymyalgia rheumatica.

OBJECTIVE: The main objective of this study was to analyse the prevalence and characteristics of subclinical GCA in patients with PMR. METHODS: This was a cross-sectional multicentre international study of consecutive patients with newly diagnosed PMR without symptoms or signs suggestive of GCA. All patients underwent US of the temporal superficial, common carotid, subclavian and axillary arteries. Patients with halo signs in at least one examined artery were considered to have subclinical GCA. The clinical, demographic and laboratory characteristics of the PMR group without subclinical vasculitis were compared with subclinical GCA, and the pattern of vessel involvement was compared with that of a classical single-centre GCA cohort. RESULTS: We included 346 PMR patients, 267 (77.2%) without subclinical GCA and 79 (22.8%) with subclinical GCA. The PMR patients with subclinical GCA were significantly older, had a longer duration of morning stiffness and more frequently reported hip pain than PMR without subclinical GCA. PMR with subclinical GCA showed a predominant extracranial large vessel pattern of vasculitic involvement compared with classical GCA, where the cranial phenotype predominated. The patients with PMR in the classical GCA group showed a pattern of vessel involvement similar to classical GCA without PMR but different from PMR with subclinical involvement. CONCLUSION: More than a fifth of the pure PMR patients had US findings consistent with subclinical GCA. This specific subset of patients showed a predilection for extracranial artery involvement. The optimal screening strategy to assess the presence of vasculitis in PMR remains to be determined.

Rituximab retention rate in systemic sclerosis: a long term real-life multicenter study.

OBJECTIVES: to report real-life data on rituximab retention-rate as indicator of safety and efficacy in a multicentric national cohort of systemic sclerosis patients. METHODS: SSc patients treated with rituximab and followed for at least 36 months were included, clinically characterized, and longitudinally monitored. A competing risk analysis with sub-Hazard Ratio(sHR) definition was performed to explore the clinical variables linked to specific cause of rituximab discontinuation. RESULTS: One-hundred-fifty-two SSc-patients (mean age 47.3 ± 12.3 years; females 79.6%; diffuse disease 77.6%; anti-topoisomerase-I positivity 63.2%) were evaluated over a median(IQR) time of 3.3(1.7-5.0) years. The primary indication for rituximab were interstitial lung disease (ILD)(38.8%), worsening skin fibrosis(36.8%), and arthritis(13.8%); 138 patients(90.8%) received more than one rituximab course. The 5-years rituximab retention rate was 59.9%(44.6-64.7%). Clinical response was the most common reason for rituximab discontinuation[5.7(3.7-8.4) per 100 patient-year] and was associated with a shorter disease duration[sHR 0.8(0.7-0.9)], anti-topoisomerase-I negativity[sHR 0.4(0.2-0.9)], previous digital ulcers[sHR 2.6(1.1-6.2] and no history of arthritis[sHR 0.3 (0.1-0.8)]. Treatment failure was the second cause of rituximab discontinuation[3.7(2.2-6.0) per 100 patient-year] and was associated with anti-centromere antibody positivity[sHR 2.8(1.1-7.4)] and anti-topoisomerase-I negativity[sHR 0.2(0.1-0.6)]. Adverse events(AEs) were the less common cause of discontinuation[3.1(1.7-5.2) per 100 patient-year], associated with limited cutaneous subset[sHR 3.4(1.2-9.7)] and previous mycophenolate mofetil treatment[sHR 4.5(1.2-16.3)]. CONCLUSION: rituximab is a safe and effective treatment in SSc: clinical response emerged as the primary reason for rituximab discontinuation, and AEs had a limited impact on treatment persistence. The identification of specific disease features associated with a response to rituximab will be useful in the management of SSc-patients.

Diagnostic capabilities, clinical features, and longitudinal UBA1 clonal dynamics of a nationwide VEXAS cohort.

VEXAS is a prototypic hemato-inflammatory disease combining rheumatologic and hematologic disorders in a molecularly defined nosological entity. In this nationwide study, we aimed at screenshotting the current diagnostic capabilities and clinical-genomic features of VEXAS, and tracked UBA1 longitudinal clonal dynamics upon different therapeutics, including allogeneic hematopoietic cell transplant. We leveraged a collaboration between the Italian Society of Experimental Hematology and of Rheumatology and disseminated a national survey to collect clinical and molecular patient information. Overall, 13/29 centers performed UBA1 genomic testing locally, including Sanger sequencing (46%), next-generation sequencing (23%), droplet digital polymerase chain reaction (8%), or combination (23%). A total of 41 male patients were identified, majority (51%) with threonine substitutions at Met41 hotspot, followed by valine and leucine (27% and 8%). Median age at VEXAS diagnosis was 67 years. All patients displayed anemia (median hemoglobin 9.1 g/dL), with macrocytosis. Bone marrow vacuoles were observed in most cases (89%). The most common rheumatologic association was polychondritis (49%). A concomitant myelodysplastic neoplasm/syndrome (MDS) was diagnosed in 71% of patients (n = 28), chiefly exhibiting lower Revised International Prognostic Scoring System risk profiles. Karyotype was normal in all patients, except three MDS cases showing -Y, t(12;16)(q13;q24), and +8. The most frequently mutated gene was DNMT3A (n = 10), followed by TET2 (n = 3). At last follow-up, five patients died and two patients progressed to acute leukemia. Longitudinal UBA1 clonal dynamics demonstrated mutational clearance following transplant. We collected a nationwide interdisciplinary VEXAS patient cohort, characterized by heterogeneous rheumatologic manifestations and treatments used. MDS was diagnosed in 71% of cases. Patients exhibited various longitudinal UBA1 clonal dynamics.

Age at diagnosis influences the clinical phenotype, treatment strategies and outcomes in patients with giant cell arteritis: results from the observational GCAGE study on a large cohort of 1004 patients.

BACKGROUND: Immune and vascular ageing are proposed risk factors for giant cell arteritis (GCA). Data on the impact of age at diagnosis of GCA on the clinical presentation and course of the disease are scarce. METHODS: Patients with GCA followed at referral centres within the Italian Society of Rheumatology Vasculitis Study Group were enrolled up to November 2021. Patients were grouped according to age at diagnosis: ≤64, 65-79 and ≥80 years old. RESULTS: The study included 1004 patients, mean age 72.1±8.4, female 70.82%. Median follow-up duration was 49 (IQR 23-91) months. Patients in the oldest group (≥80 years) had significantly more cranial symptoms, ischaemic complications and risk for blindness compared with the groups 65-79 and ≤64 years (blindness: 36.98% vs 18.21% vs 6.19%; p<0.0001). Large-vessel-GCA was more frequent in the youngest group (65% of patients). Relapses occurred in 47% of patients. Age did not influence the time to first relapse, nor the number of relapses. Older age was negatively associated with the number of adjunctive immunosuppressants. Patients >65 years old had 2-3 fold increased risk for aortic aneurysm/dissection up to 60 months follow-up. Serious infections, but not other treatment-related complications (hypertension, diabetes, osteoporotic fractures), were significantly associated with older age. Mortality occurred in 5.8% of the population with age >65, cranial and systemic symptoms as independent risk factors. CONCLUSIONS: The highest risk of ischaemic complications, aneurysm development, serious infections and the possible undertreatment make of GCA a very challenging disease in the oldest patients.

Validation of the 2022 American College of Rheumatology/EULAR classification criteria for Takayasu arteritis.

OBJECTIVES: The present study validates the 2022 ACR/European Alliance of Associations for Rheumatology (EULAR) classification criteria for Takayasu's arteritis (TAK), compared with the 1990 ACR TAK classification criteria. METHODS: The fulfilment of 2022 ACR/EULAR and 1990 ACR TAK criteria from four referral centres was assessed for TAK compared with extracranial giant cell arteritis (EC-GCA) and other controls. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), likelihood ratio of a positive test (LR+) or negative test (LR-), and area under receiver operating characteristics curve (AUC) were calculated. RESULTS: Among 504 patients with TAK (404 females) and 222 controls (151 females, 144 patients with EC-GCA), the 2022 ACR/EULAR criteria had better sensitivity (95.83% vs 82.94%) and NPV, but poorer specificity (63.51% vs 90.54%), PPV, LR+, LR- and AUC at the pre-determined cut-offs than the 1990 ACR criteria. The 2022 ACR/EULAR criteria had greater specificity (76.06% vs 57.62%) and AUC (0.845 vs 0.771), with similar sensitivity (93% vs 96.53%) in males as in females. The 2022 ACR/EULAR criteria performed similarly with only EC-GCA as controls (sensitivity 95.83%, specificity 60.42%, AUC 0.781). Sensitivity remained similar, whereas specificity was higher for 40-60 years vs <40 years. Cut-offs of ≥6 (sensitivity 91.87%, specificity 82.88%) and ≥7 (sensitivity 86.71%, specificity 86.49%), or removing the point for female sex (sensitivity 92.64%, specificity 81.08%) greatly improved the balance between sensitivity and specificity. CONCLUSION: The poor specificity of the 2022 ACR/EULAR TAK criteria in real-life settings was improved by increasing the cut-off to 6 or 7, or removing the point for female sex.

Myocarditis in anti-synthetase syndrome: clinical features and diagnostic modalities.

OBJECTIVES: Myocarditis is an overlooked manifestation of anti-synthetase syndrome (ASS). Our study describes the clinical and instrumental features of ASS-myocarditis and evaluates the diagnostic performance of cardiac magnetic resonance (CMR) with mapping techniques. METHODS: Data from ASS-patients were retrospectively analyzed. CMR data of patients diagnosed with myocarditis, including late gadolinium enhancement (LGE), T2-ratio, T1-mapping, extra-cellular volume (ECV) and T2-mapping, were reviewed. Myocarditis was defined by the presence of symptoms of heart involvement with increased high-sensitive troponin T (hs-TnT) and/or NT-proBNP and at least an instrumental abnormality. Clinical features of ASS patients with and without myocarditis were compared. A p value<0.05 was considered. RESULTS: Among a cohort of 43 ASS-patients (median age 58[48.0-66.0] years; females 74.4%; anti-Jo1 53.5%), 13(30%) were diagnosed with myocarditis. In 54% of patients, myocarditis was diagnosed at clinical onset. All ASS-myocarditis patients had at least one CMR abnormality: increased ECV in all cases, presence of LGE, increased T1 and T2-mapping in 91%. The 2009-Lake Louis criteria (LLC) were satisfied by 6 patients, the 2018-LLC by 10. With the updated LLC, the sensitivity for myocarditis improved from 54.6% to 91.0%. ASS-patients with myocarditis were more frequently males(53% vs 13%;p=0.009) with fever(69% vs 17%;p=0.001), and had higher hs-TnT (88.0[23.55-311.5] vs 9.80[5.0-23.0]ng/L; p < 0.001), NT-proBNP(525.5[243.5-1575.25] vs 59.0[32.0-165.5;p=0.013]pg/ml;p=0.013) and C-reactive protein(CRP)(7.0[1.7-15.75] vs 1.85[0.5-2.86]mg/L;p=0.011) compared to those without myocarditis. CONCLUSION: In ASS, myocarditis is frequent, even at clinical onset. ASS-patients with myocarditis frequently presented with fever and increased CRP, suggesting the existence of an inflammatory phenotype. The use of novel CMR mapping techniques may increase the diagnostic sensitivity for myocarditis in ASS.

Sex influence on outcomes of patients with systemic sclerosis-associated interstitial lung disease: a EUSTAR database analysis.

OBJECTIVE: Interstitial lung disease (ILD) is the leading cause of morbidity and mortality in systemic sclerosis (SSc) patients. We aimed to investigate the impact of sex on SSc-ILD. METHODS: EUSTAR SSc patients with radiologically confirmed ILD and available percentage predicted forced vital capacity (%pFVC) were included. Demographics and disease features were recorded. A change in %pFVC over 12 months (s.d. 6) (cohort 1) was classified into stable (≤4%), mild (5-9%) and large progression (≥10%). In those with 2-year longitudinal %pFVC (cohort 2), the %pFVC change at each 12-month (s.d. 6) interval was calculated. Logistic regression analyses [odds ratio (OR) and 95% CI] and Cox proportional hazards models adjusted for age and %pFVC were applied. RESULTS: A total of 1136 male and 5253 female SSc-ILD patients were identified. Males were significantly younger, had a shorter disease duration, had a higher prevalence of CRP elevation and frequently had diffuse cutaneous involvement. In cohort 1 (1655 females and 390 males), a higher percentage of males had stable ILD (74.4% vs 69.4%, P = 0.056). In multivariable analysis, disease duration and %pFVC [OR 0.99 (95% CI 0.98, 0.99) and OR 0.97 (95% CI 0.95, 0.99), respectively] in males and age, %pFVC and anti-centromere [OR 1.02 (95% CI 1.00, 1.04), OR 0.97 (95% CI 0.96, 0.98) and OR 0.39 (95% CI 0.245, 0.63), respectively] in females were associated with large progression. The 1-year mortality rate was higher in males (5.1% vs 2.5%, P = 0.013). In cohort 2 (849 females and 209 males), a higher percentage of females showed periods of large progression (11.7% vs 7.7%, P = 0.023), the percentage of patients with none, one or two periods of worsening was not different. The overall death rate was 30.9% for males and 20.4% in females (P < 0.001). In the survival analysis, male sex was a predictor of mortality [OR 1.95 (95% CI 1.66, 2.28)]. CONCLUSIONS: Male SSc-ILD patients have a poorer prognosis and sex-specific predictors exist in SSc-ILD.

Systemic pharmacological treatment of digital ulcers in systemic sclerosis: a systematic literature review.

OBJECTIVE: To evaluate the evidence concerning systemic pharmacological treatments for SSc digital ulcers (DUs) to inform the development of evidence-based treatment guidelines. METHODS: A systematic literature review of seven databases was performed to identify all original research studies of adult patients with SSc DUs. Randomized controlled trials (RCTs) and prospective longitudinal observational studies (OBSs) were eligible for inclusion. Data were extracted, applying the patient, intervention, comparison, outcome framework, and risk of bias (RoB) was assessed. Due to study heterogeneity, narrative summaries were used to present data. RESULTS: Forty-seven studies that evaluated the treatment efficacy or safety of pharmacological therapies were identified among 4250 references. Data from 18 RCTs of 1927 patients and 29 OBSs of 661 patients, at various RoB (total 2588 patients) showed that i.v. iloprost, phosphodiesterase-5 inhibitors and atorvastatin are effective for the treatment of active DUs. Bosentan reduced the rate of future DUs in two RCTs (moderate RoB) and eight OBSs at low to high RoB. Two small studies (moderate RoB) indicate that Janus kinase inhibitors may be effective for the treatment of active DUs, otherwise there are no data to support the use of immunosuppression or anti-platelet agents in the management of DUs. CONCLUSION: There are several systemic treatments, across four medication classes, that are effective therapies for the management of SSc DUs. However, a lack of robust data means it is not possible to define the optimal treatment regimen for SSc DUs. The relatively low quality of evidence available has highlighted further areas of research need.

Myelomonocytic cells in giant cell arteritis activate trained immunity programs sustaining inflammation and cytokine production.

OBJECTIVE: Trained immunity (TI) is a de facto memory program of innate immune cells, characterized by immunometabolic and epigenetic changes sustaining enhanced production of cytokines. TI evolved as a protective mechanism against infections; however, inappropriate activation can cause detrimental inflammation and might be implicated in the pathogenesis of chronic inflammatory diseases. In this study, we investigated the role of TI in the pathogenesis of giant cell arteritis (GCA), a large-vessel vasculitis characterized by aberrant macrophage activation and excess cytokine production. METHODS: Monocytes from GCA patients and from age- and sex-matched healthy donors were subjected to polyfunctional studies, including cytokine production assays at baseline and following stimulation, intracellular metabolomics, chromatin immunoprecipitation-qPCR, and combined ATAC/RNA sequencing. Immunometabolic activation (i.e. glycolysis) was assessed in inflamed vessels of GCA patients with FDG-PET and immunohistochemistry (IHC), and the role of this pathway in sustaining cytokine production was confirmed with selective pharmacologic inhibition in GCA monocytes. RESULTS: GCA monocytes exhibited hallmark molecular features of TI. Specifically, these included enhanced IL-6 production upon stimulation, typical immunometabolic changes (e.g. increased glycolysis and glutaminolysis) and epigenetic changes promoting enhanced transcription of genes governing pro-inflammatory activation. Immunometabolic changes of TI (i.e. glycolysis) were a feature of myelomonocytic cells in GCA lesions and were required for enhanced cytokine production. CONCLUSIONS: Myelomonocytic cells in GCA activate TI programs sustaining enhanced inflammatory activation with excess cytokine production.

Oncogene-induced maladaptive activation of trained immunity in the pathogenesis and treatment of Erdheim-Chester disease.

Trained immunity (TI) is a proinflammatory program induced in monocyte/macrophages upon sensing of specific pathogens and is characterized by immunometabolic and epigenetic changes that enhance cytokine production. Maladaptive activation of TI (ie, in the absence of infection) may result in detrimental inflammation and development of disease; however, the exact role and extent of inappropriate activation of TI in the pathogenesis of human diseases is undetermined. In this study, we uncovered the oncogene-induced, maladaptive induction of TI in the pathogenesis of a human inflammatory myeloid neoplasm (Erdheim-Chester disease, [ECD]), characterized by the BRAFV600E oncogenic mutation in monocyte/macrophages and excess cytokine production. Mechanistically, myeloid cells expressing BRAFV600E exhibit all molecular features of TI: activation of the AKT/mammalian target of rapamycin signaling axis; increased glycolysis, glutaminolysis, and cholesterol synthesis; epigenetic changes on promoters of genes encoding cytokines; and enhanced cytokine production leading to hyperinflammatory responses. In patients with ECD, effective therapeutic strategies combat this maladaptive TI phenotype; in addition, pharmacologic inhibition of immunometabolic changes underlying TI (ie, glycolysis) effectively dampens cytokine production by myeloid cells. This study revealed the deleterious potential of inappropriate activation of TI in the pathogenesis of human inflammatory myeloid neoplasms and the opportunity for inhibition of TI in conditions characterized by maladaptive myeloid-driven inflammation.

High-dose anakinra in addition to standard of care including corticosteroids in patients with severe COVID-19 treated with non-invasive ventilation.

Management of COVID-19 patients experiencing persisting respiratory failure despite corticosteroids remains challenging. Data on high-dose intravenous anakinra (HD-ANK) in this context are lacking. We aimed to investigate the impact of HD-ANK on mortality in COVID-19 patients progressing to non-invasive ventilation (NIV) while receiving corticosteroids. We retrospectively analyzed the impact of HD-ANK on 28-day mortality in individuals hospitalized with COVID-19 necessitating NIV after corticosteroid initiation. A total of 256 patients were identified: 146 received standard-of-care only (SOC), and 110 received HD-ANK+SOC. The groups were well-balanced at baseline. In-hospital mortality at 28 days did not differ between the two groups. HD-ANK is not beneficial in patients with severe COVID-19 deteriorating despite corticosteroids.

Cardiac magnetic resonance findings in acute and post-acute COVID-19 patients with suspected myocarditis.

INTRODUCTION: Cardiac injury is commonly reported in COVID-19 patients, resulting associated to pre-existing cardiovascular disease, disease severity, and unfavorable outcome. Aim is to report cardiac magnetic resonance (CMR) findings in patients with myocarditis-like syndrome during the acute phase of SARS-CoV-2 infection (AMCovS) and post-acute phase (cPACS). METHODS: Between September 2020 and January 2022, 39 consecutive patients (24 males, 58%) were referred to our department to perform a CMR for the suspicion of myocarditis related to AMCovS (n = 17) and cPACS (n = 22) at multimodality evaluation (clinical, laboratory, ECG, and echocardiography). CMR was performed for the assessment of volume, function, edema and fibrosis with standard sequences and mapping techniques. CMR diagnosis and the extension and amount of CMR alterations were recorded. RESULTS: Patients with suspected myocarditis in acute and post-COVID settings were mainly men (10 (59%) and 12 (54.5%), respectively) with older age in AMCovS (58 [48-64]) compared to cPACS (38 [26-53]). Myocarditis was confirmed by CMR in most of cases: 53% of AMCovS and 50% of cPACS with negligible LGE burden (3 [IQR, 1-5] % and 2 [IQR, 1-4] %, respectively). Myocardial infarction was identified in 4/17 (24%) patients with AMCovS. Cardiomyopathies were identified in 12% (3/17) and 27% (6/22) of patients with AMCovS and cPACS, including DCM, HCM and mitral valve prolapse. CONCLUSIONS: In patients with acute and post-acute COVID-19 related suspected myocarditis, CMR improves diagnostic accuracy characterizing ischemic and non-ischemic injury and unraveling subclinical cardiomyopathies.

Cardiovascular involvement in Erdheim-Chester diseases is associated with myocardial fibrosis and atrial dysfunction.

PURPOSE: Erdheim-Chester disease (ECD) is a rare multisystem histiocytosis, whose cardiovascular involvement has not been systematically characterized so far. We aimed to systematically (qualitatively and quantitatively) describe the features of cardiovascular involvement in a large cohort of ECD patients and to evaluate its impact on myocardial fibrosis extension and cardiac function. MATERIAL AND METHODS: Among 54 patients with biopsy-proven ECD, 29 patients (59 ± 12 years, 79% males) underwent 1.5-T CMR using a standardized protocol for qualitative and quantitative assessment of disease localization, evaluation of atrial and ventricular function, and assessment of non-dense and dense myocardial fibrosis. RESULTS: The right atrioventricular (AV) groove was the most commonly affected cardiac site (76%) followed by the right atrial walls (63%), thoracic aorta (59%), and superior vena cava (38%). Right AV groove involvement, encasing the right ventricular artery, was associated with non-dense myocardial fibrosis in the infero-septal (20/26 patients) and the inferior (14/26 patients) mid-basal left ventricular (LV) wall. In two patients with right AV groove localization, LGE revealed myocardial infarction in the same myocardial segments. Three out of five patients with left AV groove involvement had non-dense LGE on the lateral LV mid-basal wall. Bulky right atrial pseudomass was associated with atrial dysfunction and superior and inferior vena cava stenosis. CONCLUSIONS: In ECD patients, AV groove localization is associated with LV wall fibrosis in the downstream coronary territories, suggesting hemodynamic alterations due to coronary encasement. Conversely, atrial pseudomass ECD localizations impact on atrial contractility causing atrial dysfunction and are associated with atrio-caval junction stenosis.

Cardiac magnetic resonance in systemic sclerosis myocarditis: the value of T2 mapping to detect myocardial inflammation.

OBJECTIVES: Myocarditis in SSc is associated with a poor prognosis. Cardiac magnetic resonance (CMR) is the non-invasive diagnostic modality of choice for SSc myocarditis. Our study investigates the performance of the mapping techniques included in the revised Lake Louise criteria (LLC) for the identification of SSc myocarditis. METHODS: CMR data (right and left ventricular function and morphology, early and late gadolinium enhancement [LGE], T2 ratio, and T1 mapping, extracellular volume [ECV] and T2 mapping) of SSc patients diagnosed with myocarditis were reviewed. Myocarditis was defined by the presence of symptoms of SSc heart involvement with increased high-sensitive troponin T (hs-TnT) and/or NT-proBNP and at least an abnormality at 24 h ECG Holter and/or echocardiography and/or CMR. A P-value < 0.05 was considered as statistically significant. RESULTS: Nineteen patients (median age 54 [46-70] years; females 78.9%; diffuse SSc 52.6%; anti-Scl70+ 52.6%) were identified: 11 (57.9%) had echocardiographic, and 8 (42.8%) 24 h ECG Holter abnormalities. All patients had at least one CMR abnormality: LGE in 18 (94.7%), increased ECV in 10 (52.6%) and T2 mapping >50 ms in 15 (78.9%). Median T1 and T2 mapping were 1085 [1069-1110] ms and 53.1 [52-54] ms, respectively. T1 mapping directly correlated with NT-proBNP (r = 0.620; P = 0.005), ESR (r = 0.601; P = 0.008), CRP (r = 0.685; P = 0.001) and skin score (r = 0.507; P = 0.027); ECV correlated with NT-proBNP serum levels (r = 0.702; P = 0.001). No correlations emerged between T2 mapping and other parameters. Ten patients satisfied the 2009 LLC, 17 the 2018 LLC. With the new criteria including T2 mapping, the sensitivity improved from 52.6% to 89.5%. CONCLUSION: The CMR mapping techniques improve the sensitivity to detect myocardial inflammation in patients with SSc heart involvement. The evaluation of T2 mapping increases diagnostic accuracy for the recognition of myocardial inflammation in SSc.

The role of chest CT in deciphering interstitial lung involvement: systemic sclerosis versus COVID-19.

OBJECTIVE: The aim of this study was to identify the main CT features that may help in distinguishing a progression of interstitial lung disease (ILD) secondary to SSc from COVID-19 pneumonia. METHODS: This multicentric study included 22 international readers grouped into a radiologist group (RADs) and a non-radiologist group (nRADs). A total of 99 patients, 52 with COVID-19 and 47 with SSc-ILD, were included in the study. RESULTS: Fibrosis inside focal ground-glass opacities (GGOs) in the upper lobes; fibrosis in the lower lobe GGOs; reticulations in lower lobes (especially if bilateral and symmetrical or associated with signs of fibrosis) were the CT features most frequently associated with SSc-ILD. The CT features most frequently associated with COVID- 19 pneumonia were: consolidation (CONS) in the lower lobes, CONS with peripheral (both central/peripheral or patchy distributions), anterior and posterior CONS and rounded-shaped GGOs in the lower lobes. After multivariate analysis, the presence of CONs in the lower lobes (P < 0.0001) and signs of fibrosis in GGOs in the lower lobes (P < 0.0001) remained independently associated with COVID-19 pneumonia and SSc-ILD, respectively. A predictive score was created that was positively associated with COVID-19 diagnosis (96.1% sensitivity and 83.3% specificity). CONCLUSION: CT diagnosis differentiating between COVID-19 pneumonia and SSc-ILD is possible through a combination of the proposed score and radiologic expertise. The presence of consolidation in the lower lobes may suggest COVID-19 pneumonia, while the presence of fibrosis inside GGOs may indicate SSc-ILD.

Efficacy and safety of TNF-α antagonists and tocilizumab in Takayasu arteritis: multicentre retrospective study of 209 patients.

OBJECTIVE: To assess the safety and the efficacy of TNF-α antagonists and tocilizumab in patients with Takayasu arteritis (TAK). METHODS: A total of 209 patients with TAK [median age 29 years (interquartile range 7-62)], 186 (89%) females] were included. They received either TNF-α antagonists [n = 132 (63%) with 172 lines; infliximab (n = 109), adalimumab (n = 45), golimumab (n = 8), certolizumab (n = 6) and etanercept (n = 5)] or tocilizumab [n = 77 (37%) with 121 lines; i.v. and s.c. in 95 and 26 cases, respectively]. RESULTS: A complete response at 6 months was evidenced in 101/152 (66%) patients on TNF-α antagonists and 75/107 (70%) patients on tocilizumab. Age ≥30 years [odds ratio 2.09 (95% CI 1.09, 3.99)] was associated with complete response, whereas vascular signs [OR 0.26 (95% CI 0.1, 0.65)], baseline prednisone ≥20 mg/day [OR 0.51 (95% CI 0.28, 0.93)] were negatively associated with the complete response to TNF-α antagonists or tocilizumab. During a median follow-up of 36 months, 103 relapses were noted. Supra-aortic branches and thoracic aorta involvement [HR 2.44 (95% CI 1.06, 5.65) and 3.66 (1.18, 11.4), respectively] and systemic signs at baseline [HR 2.01 (95% CI 1.30, 3.11)] were significantly associated with relapse. The cumulative incidence of treatment discontinuation and relapse were similar in TNF-α antagonists and tocilizumab. Fifty-eight (20%) adverse effects occurred on biologic targeted therapies [37 (21%) on TNF-α antagonists and 21 (17%) on tocilizumab (P = 0.4), respectively]. CONCLUSION: This large multicentre study shows high efficacy of biologic targeted treatments in refractory TAK. Efficacy, relapse and drug retention rate were equivalent with TNF-α antagonists and tocilizumab.