Revisiting characteristics, treatment and outcome of cardiomyopathy in eosinophilic granulomatosis with polyangiitis (formerly Churg-Strauss).

OBJECTIVES: Eosinophilic granulomatosis with polyangiitis (EGPA) is a necrotizing eosinophil-rich vasculitis. Specific cardiomyopathy (CM) was described in early studies as the most important predictor of mortality. We aimed to revisit EGPA-related CM and investigate its outcome in recent decades. METHODS: We reviewed all EGPA patients managed from 2000 to 2019 in our vasculitis clinic. Baseline characteristics and outcomes were analysed. EGPA-related CM was defined as clinical or extra-clinical manifestations of patent myocardial involvement, after exclusion of other causes. RESULTS: We included 176 patients. The median age was 47 years [interquartile range (IQR) 36-58 years]. Specific CM was observed in 70 patients (40%). Cardiac symptoms were observed in 81% of CM+ patients, including mainly typical or atypical chest pain and peripheral oedema. Abnormal ECG, transthoracic echocardiography and cardiac MRI (CMRI) were found in 72%, 72% and 99% of CM+ patients, respectively, contrasting with abnormalities in 32%, 38% and 60% of CM-negative patients, respectively. Late gadolinium enhancement (LGE) was the most frequent abnormality on CMRI (70%). CM+ patients were less frequently ANCA-positive, had less frequent peripheral neuropathy and had higher eosinophil count. Major adverse cardiovascular events (MACEs) occurred in 13% of patients, both in CM+ and CM- patients. Abnormal ECG and LGE on CMRI were associated with the occurrence of MACEs. Four patients died, but none from cardiac causes. CONCLUSION: Specific cardiomyopathy is frequent in EGPA, especially in ANCA-negative patients with high eosinophil counts. Long-term outcome was better than previously reported. Abnormal ECG and LGE on CMRI were associated with the occurrence of MACEs.

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.

Use of biologics to treat relapsing and/or refractory polyarteritis nodosa: data from a European collaborative study.

OBJECTIVES: To describe the effectiveness and safety of biologics for the treatment of relapsing and/or refractory polyarteritis nodosa (PAN). METHODS: A retrospective European collaborative study was conducted in patients with PAN who received biologics for relapsing and/or refractory disease. RESULTS: Forty-two patients with PAN received a total of 53 biologic courses, including TNF-α blockers in 15 cases, rituximab (RTX) in 18 cases, tocilizumab (TCZ) in 10 cases and other biologics in 10 cases. TNF-α blockers and TCZ were mainly used for refractory diseases whereas RTX was mainly initiated for relapsing disease. After a median follow-up of 29 (8-50) months, remission, partial response, treatment failure and treatment discontinuation due to severe adverse events occurred in, respectively, 40%, 13%, 40% and 7% of patients receiving TNF-α blockers, 50%, none, 30% and 20% of TCZ recipients, and 33%, 11%, 56% and none of the RTX recipients. No remission was noted in patients treated with other biologics. Severe adverse events were observed in 14 (28%) patients without significant differences between the three biologics, leading to early biologics discontinuation in only three cases. CONCLUSION: These results suggest that TCZ may be effective in relapsing and/or refractory PAN. Our data warrant further study to confirm these findings.

Effectiveness and safety of infliximab dose escalation in patients with refractory Takayasu arteritis: A real-life experience from a monocentric cohort.

OBJECTIVES: To evaluate effectiveness and safety of infliximab dose escalation in Takayasu arteritis (TAK) patients. To identify factors associated with refractoriness to standard-dose infliximab. METHODS: Medical records of infliximab-treated TAK patients from a large single-centre observational cohort were reviewed. Infliximab therapy duration, concomitant therapies, and reasons for dose escalation and therapy suspension were evaluated. Occurrence of adverse events was recorded. A comparison between patients who maintained infliximab standard-dose and those who needed dose-escalation was performed. Factors associated with refractoriness to standard dose were analysed. RESULTS: Forty-one patients were included. Starting infliximab dose was 5 mg/kg 6-weekly and 28 patients (68%) needed dose escalation. Persistence/recurrence of clinical symptoms was the most frequent reason for escalation. Median therapy duration was 39 (IQR, 26-61) months in the standard-dose group and 68 (38-87) months in the intensified-dose group. In the intensified-dose-group, infliximab was suspended in eight patients (29%) after a median of 38 (31-71) months, due to loss of response (n = 7) or patient's request (n = 1). Patients in the intensified-dose group had a higher number of relapses (3.4 vs 0.8 events/patient) and received a higher cumulative steroid dose (1.7 [1.6-2.3] vs 1.3 [1-1.6] g/month of prednisone). Three patients from the intensified-dose group had serious infections; one patient from the standard-dose group developed paradoxical psoriasis. At univariate analysis, age at diagnosis and age at infliximab start were associated with infliximab escalation. CONCLUSION: In TAK, dose escalation is safe and allows to optimise infliximab durability in refractory patients. Younger patients seem to be more refractory to standard dosages.

Prevalence of COVID infections in a population of rheumatic patients from Lombardy and Marche treated with biological drugs or small molecules: A multicentre retrospective study.

OBJECTIVE: The COVID-19 pandemic has raised questions about the management of systemic immunosuppressive treatments for rheumatic conditions. It is well known that rheumatic patients are at risk of developing infections because of their immunocompromised state. Moreover, drugs such as hydroxychloroquine or tocilizumab that are widely used to treat rheumatic diseases are now being used to treat COVID-19. The aim of this multicentre retrospective study of rheumatic patients in the Italian regions of Lombardy and Marche was to determine whether patients receiving biological or small molecules treatment are more susceptible to the development of COVID-19 than the general population. METHODS: The local registry data of 10,260 rheumatic patients being treated with bDMARDs or small molecules were evaluated from 15 March to 23 April 2020. The final analysis was based on the registry data relating to 7.204, telephone contacts and/or outpatient visits. RESULTS: Forty-seven of the 7.204 patients were diagnosed with COVID-19, seven of whom died; the patients who had symptoms resembling those of COVID-19 but had negative swabs were considered negative for the disease. The overall infection rate was 0.65, and the crude case fatality risk (CFR) in the patients with COVID-19 was 14.9%. There was no difference in the mortality rate among the patients receiving the different individual biological drugs or small molecules. CONCLUSIONS: Our findings suggest that the susceptibility of rheumatic patients to COVID-19 is the same as that of the general population, but confirm that age, disease duration, and the number of co-morbidities are associated with an increased risk of a severe form of the disease. It seems that immunosuppressants drugs do not effectively represent a risk factor for COVID- 19.

Failure of first anti-TNF agent in Takayasu's arteritis: to switch or to swap?

OBJECTIVES: Biologic drugs (bDMARD), especially TNF-α-inhibitors (TNFi), are used in refractory Takayasu's arteritis (TAK) patients. Up to 23% of patients are switched to a different bDMARD because of inefficacy. No data are available on which strategy is more efficient after TNFi failure. The aim of our study is to evaluate whether a switch or swap strategy should be preferred in TAK patients failing TNFis. METHODS: TAK patients treated with a second bDMARD after the failure of the first TNFi were identified from 3 referral centres. Patients were classified as switch if treated with a different TNFi, and swap if treated with a non-TNFi bDMARD. Baseline features were evaluated. Efficacy and safety of the second bDMARD at 6 and 12 months were assessed and a comparison between switch and swap patients was made. RESULTS: Twenty-four TAK patients were identified. Eleven patients (46%) were switched and 13 patients (54%) were swapped (12 to tocilizumab, 1 to ustekinumab). Baseline features of patients in the 2 groups were comparable. At 12 months, the second bDMARD was suspended in 4 switch (36%) and in 5 swap (42%) patients. Second biologic drug survival and relapse-free survival were equivalent between the two groups at 6 and 12 months. A vascular worsening was observed in 4 switch (40%) and 2 swap (25%) patients. Severe infections, myocardial infarction, ischemic stroke or cancer were recorded in no patient. CONCLUSIONS: Our retrospective study suggests that in first-line TNFi failure TAK patients both switch and swap strategies can be considered suitable approaches.

Telemedicine in myocarditis: Evolution of a mutidisciplinary "disease unit" at the time of COVID-19 pandemic.

Myocarditis Disease Unit (MDU) is a functional multidisciplinary network designed to offer multidisciplinary assistance to patients with myocarditis. More than 300 patients coming from the whole Country are currently followed up at a specialized multidisciplinary outpatient clinic. Following the pandemic outbreak of the SARS-CoV-2 infection in Italy, we present how the MDU rapidly evolved to a "tele-MDU", via a dedicated multitasking digital health platform.

Efficacy and safety of mycophenolate mofetil in patients with virus-negative lymphocytic myocarditis: A prospective cohort study.

BACKGROUND: virus-negative lymphocytic myocarditis (VNLM) is a severe inflammatory heart disease with elusive therapies. We aimed to assess the efficacy of mycophenolate-mofetil (MMF) in patients with VNLM. METHODS: patients were enrolled in this prospective cohort study and were treated with MMF, as the initial treatment in case of concomitant systemic immune diseases (SIDs), or as rescue therapy in isolated myocarditis intolerant/resistant to azathioprine. All were initially evaluated for endomyocardial biopsy; ECG, 24-h Holter, echocardiography, troponin T and NT-proBNP were obtained in all patients at baseline and after 6 months. The primary end-point was the change in left-ventricular ejection-fraction (LVEF) on echocardiogram after 6 months. SECONDARY OUTCOMES: decrease in serum NT-proBNP and troponin-T levels, reduction of LV end-diastolic-volume (LVEDV), amelioration of regional wall motion abnormalities (RWMA), and modification of clinical status. RESULTS: 20 patients (10 females, median age at diagnosis 32 [41-59] years) were enrolled. Baseline echocardiography revealed a reduced LVEF (<55%) in 11 patients (55%) and a median LV-EF of 53.5 [44-60.5]%. Baseline median troponin T and NT-proBNP were 50.5 (14.4-288.5)ng/L and 257.0 (90.5-912.0)pg/ml, respectively. After 6 months, the median LVEF significantly improved (57 [50-61]%,p = 0.016), irrespective of concomitant steroid dose. Consistently, after 6 months LVEDV decreased from 135 ±â€¯50 ml to 114 ±â€¯38 ml (p < 0.001), and only 6 patients had RWMA, compared to 14 at baseline (p = 0.016). The amelioration of cardiac function was paralleled by a reduction of median troponin T (12.0 [10.0-24.0],p = 0.02) and NT-proBNP(79.5 [74.5-223-2],p = 0.007) and by a reduction in the number of patients with dyspnea NYHA class II-III(p = 0.02). None of the patients required drug discontinuation. CONCLUSIONS: MMF migh be a safe and effective therapeutic option in VNLM, both as first-line agent and as a rescue therapy.

Systemic sclerosis myocarditis has unique clinical, histological and prognostic features: a comparative histological analysis.

OBJECTIVE: To outline the clinical, histological and prognostic features of systemic sclerosis (SSc) endomyocardial biopsy-proven myocarditis with respect to those of diverse endomyocardial biopsy-proven virus-negative myocarditis (VNM). METHODS: We retrospectively analysed data from three cohorts of endomyocardial biopsy-proven myocarditis: SSc-related VNM (SSc-VNM); isolated VNM (i-VNM); and VNM related to other systemic autoimmune diseases (a-VNM). The degree of myocardial fibrosis was expressed as relative percentage and fibrotic score (0-3). Clinical data, cardiac enzymes, echocardiogram, 24 h ECG Holter and cardiac magnetic resonance were obtained at baseline and during follow-up. Non-parametric tests were used. RESULTS: We enrolled 12 SSc-VNM [11 females, mean age 49.3 (14.2) years; seven diffuse-SSc, five early-SSc], 12 i-VNM [12 females, mean age 47.7 (10.8) years] and 10 a-VNM [four females, mean age 48.4 (16.3) years] patients. SSc patients had higher degrees of myocardial fibrosis as assessed by both percentage [SSc-VNM: 44.8 (18.8)%; a-VNM: 28.6 (16.5)%; i-VNM: 24.9 (10.3)%; P = 0.019] and score [SSc-VNM: 2.3 (0.8); a-VNM: 1.4 (1.1); i-VNM: 1.2 (0.7); P = 0.002]. Myocardial fibrosis directly correlated with skin score (r = 0.625, P = 0.03) and number of ventricular ectopic beats on 24 h ECG Holter in SSc patients (r = 0.756, P = 0.01). Dyspnoea class was higher at presentation in SSc-VNM patients (P = 0.041) and we found heart failure only in SSc patients (25%) (P = 0.05). At cardiac magnetic resonance, myocardial oedema was nearly undetectable in SSc-VNM patients compared with others (P = 0.02). All patients received immunosuppressive treatment. The number of patients who died during follow-up due to cardiac complications was significantly higher in SSc-VNM patients (50%), as compared with a-VNM (0%) and i-VNM (8.3%) patients (P = 0.006). Patients who died during follow-up had higher degrees of myocardial fibrosis [52.2 (11.6)% vs 27.5 (12.9)%, P = 0.024; fibrotic score: 2.83 (0.41) vs 1.4 (0.9), P < 0.001]. CONCLUSION: SSc has unique clinical and histological features, as it tends to present more frequently with heart failure and a higher dyspnoea class and to show higher degrees of myocardial fibrosis. These specific features are paralleled by a worse cardiac prognosis.

18F-FDG PET reveals unique features of large vessel inflammation in patients with Takayasu's arteritis.

PURPOSE: The object of this study was to assess whether 18F-fluorodeoxyglucose PET/CT (FDG PET/CT) provides novel information in patients with Takayasu's arteritis (TA) in addition to that provided by current activity assessment, to analyse the effects of possible confounders, such as arterial grafts, and to verify whether PET/CT could be informative in lesions <4 mm thick. METHODS: We studied 30 patients with TA, evaluated from October 2010 to April 2014 by both PET/CT and magnetic resonance imaging (MRI). All arterial lesions were evaluated by PET both qualitatively (positive/negative) and semiquantitatively (maximum standardized uptake value, SUVmax), and the thickness of lesions in the MRI field of view was evaluated. In a per-patient analysis, the relationships between the PET data and acute-phase reactants and NIH criteria for active TA were evaluated. In a per-lesion analysis, the relationships between the PET features of each lesion and MRI morphological data were evaluated. The effects of the presence of arterial grafts were also evaluated. RESULTS: Increased FDG uptake was seen in 16 of 30 patients (53%) and in 46 of 177 vascular lesions (26%). Significant periprosthetic FDG uptake was seen in 6 of 7 patients (86%) with previous vascular surgery and in 10 of 11 of grafts (91%). Graft-associated uptake influenced the PET results in three patients (10%) and the SUVmax values in five patients (17%). Of 39 lesions with significant FDG uptake, 15 (38%) were <4 mm thick. Lesion thickness was correlated with lesion SUVmax in FDG-avid lesions only. FDG arterial uptake was not associated with systemic inflammation or NIH criteria. CONCLUSIONS: PET/CT reveals unique and fundamental features of arterial involvement in TA. PET/CT may be useful in the assessment of local inflammatory and vascular remodelling events independent of systemic inflammation during follow-up, even in lesions in which the arterial wall is <4 mm. The presence of arterial grafts is a potential confounder. Prospective studies are required to correlate PET findings with relevant clinical outcomes.

Sustainability in Internal Medicine: A Year-Long Ward-Wide Observational Study.

Population aging and multimorbidity challenge health system sustainability, but the role of assistance-related variables rather than individual pathophysiological factors in determining patient outcomes is unclear. To identify assistance-related determinants of sustainable hospital healthcare, all patients hospitalised in an Internal Medicine Unit (n = 1073) were enrolled in a prospective year-long observational study and split 2:1 into a training (n = 726) and a validation subset (n = 347). Demographics, comorbidities, provenance setting, estimates of complexity (cumulative illness rating scale, CIRS: total, comorbidity, CIRS-CI, and severity, CIRS-SI subscores) and intensity of care (nine equivalents of manpower score, NEMS) were analysed at individual and Unit levels along with variations in healthcare personnel as determinants of in-hospital mortality, length of stay and nosocomial infections. Advanced age, higher CIRS-SI, end-stage cancer, and the absence of immune-mediated diseases were correlated with higher mortality. Admission from nursing homes or intensive care units, dependency on activity of daily living, community- or hospital-acquired infections, oxygen support and the number of exits from the Unit along with patient/physician ratios were associated with prolonged hospitalisations. Upper gastrointestinal tract disorders, advanced age and higher CIRS-SI were associated with nosocomial infections. In addition to demographic variables and multimorbidity, physician number and assistance context affect hospitalisation outcomes and healthcare sustainability.

Validation of the Italian version of the ANCA-associated vasculitis patient-reported outcome (AAV-PRO) questionnaire.

Objectives: The primary objective of this study was the translation and validation of the ANCA-associated vasculitis patient-reported outcome (AAV-PRO) questionnaire into Italian, denoted as AAV-PRO_ita. The secondary objective was to evaluate the impact of ANCA-associated vasculitis (AAV) on quality of life (QoL) and work impairment in a large cohort of Italian patients. Methods: The study design took a prospective cohort study approach. First, the AAV-PRO was translated into Italian following the step guidelines for translations. The new AAV-PRO_ita questionnaire covered three disease domains: organ-specific and systemic symptoms and signs; physical function; and social and emotional impact. Second, Italian-speaking AAV patients were recruited from 17 Italian centres belonging to the Italian Vasculitis Study Group. Participants completed the AAV-PRO_ita questionnaire at three time points. Participants were also requested to complete the work productivity and activity impairment: general health questionnaire. Results: A total of 276 AAV patients (56.5% women) completed the questionnaires. The AAV-PRO_ita questionnaire demonstrated a good internal consistency and test-retest reliability. Female AAV patients scored higher (i.e. worse) in all thee domains, especially in the social and emotional impact domain (P < 0.001). Patients on glucocorticoid therapy (n = 199) had higher scores in all domains, especially in the physical function domain (P < 0.001), compared with patients not on glucocorticoid therapy (n = 77). Furthermore, patients who had at least one relapse of disease (n = 114) had higher scores compared with those who had never had one (n = 161) in any domain (P < 0.05). Finally, nearly 30% of the patients reported work impairment. Conclusion: The AAV-PRO_ita questionnaire is a new 29-item, disease-specific patient-reported outcome measuring tool that can be used in AAV research in the Italian language. Sex, glucocorticoids and relapsing disease showed the greatest impact on QoL.

Clinical Applications of FDG-PET Scan in Arrhythmic Myocarditis.

BACKGROUND: 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) scan has no recognized role in diagnosis, prognosis, and disease monitoring in patients with arrhythmic myocarditis. OBJECTIVES: The purpose of this study was to investigate the value of FDG-PET scan in arrhythmic myocarditis. METHODS: The authors enrolled 75 consecutive patients (age 47 ± 14 years, 65% men) undergoing FDG-PET scan for arrhythmic myocarditis. Myocarditis was diagnosed by endomyocardial biopsy (EMB) and, whenever applicable, cardiac magnetic resonance (CMR). RESULTS: Indications for FDG-PET scan included either contraindication to CMR (n = 50) or mismatch between CMR and EMB (n = 25). Overall, 50 patients (67%) had positive FDG-PET. Sensitivity was 75% referring to EMB, and 73% to CMR. Specificity was 67% referring to EMB, and 59% to CMR. FDG-PET accuracy was lower in the presence of borderline myocarditis, and either late (>30 days) or on-immunosuppression FDG-PET scanning. Anteroseptal distribution pattern, found in 12 of 50 (24%) patients including 7 of 7 cardiac sarcoidosis cases, was associated with greater occurrence of ventricular arrhythmias and atrioventricular blocks in 4.2 ± 1.7 years of follow-up (10 of 12 vs 7 of 38, and 7 of 12 vs 0 of 38, respectively; both P < 0.001). In 39 patients (52%), FDG-PET was repeated by 13 ± 2 months, allowing immunosuppression withdrawal after FDG uptake normalization either by first (76%) or second reassessment (24%). CONCLUSIONS: FDG-PET scan may be a clinically useful diagnostic technique in arrhythmic myocarditis, in particular when CMR is unsuitable because of irregular heartbeat or implantable cardioverter-defibrillator-related artifacts. Anteroseptal FDG distribution is associated with a worse arrhythmic outcome and should raise the suspicion of cardiac sarcoidosis. During follow-up, repeated FDG-PET allows myocarditis monitoring to guide immunosuppression withdrawal.

A Prospective Observational Study on the Efficacy and Safety of Infliximab-Biosimilar (CT-P13) in Patients With Takayasu Arteritis (TAKASIM).

Objectives: Infliximab (IFX) is widely used in patients with refractory Takayasu arteritis (TAK). Recently, the IFX-biosimilar CT-P13 has been introduced for the treatment of inflammatory diseases. The aim of this study was to assess the efficacy and safety of CT-P13 in patients with refractory TAK. Methods: In this prospective, open-label, single-center trial, TAK patients either already on treatment with IFX-originator (switch group) or never treated with IFX (naïve group) received CT-P13 for 52 weeks. The primary outcomes of the study were: (i) number of patients with active disease at month 6; (ii) incidence of treatment-emergent adverse events at month 12. Disease activity was assessed at month 6 and month 12 by clinical evaluation (ITAS-2020, ITAS-ESR, and ITAS-CRP scores) and imaging assessment [magnetic resonance angiography (MRA) and (18F)-FDG-PET]. Results: 23 patients were recruited (21 switch, 2 naïve). At baseline, 7 patients (32%) were classified as active. At month 6, one patient voluntarily dropped out and 7 patients were still active (30%), including one patient started on a different bDMARD at month 2 due to poor disease control. Mean daily dose of prednisone equivalent was significantly lower than baseline (4.2 ± 1.9 mg vs. 4.8 ± 2.1 mg, p = 0.009). At month 12, another patient was excluded because of pregnancy desire. Five patients were classified as active (24%), including two patients started on a different bDMARD at month 2 and month 6. Mean daily dose of prednisone equivalent was significantly lower than baseline (3.3 ± 2.6, p = 0.034). No patient experienced side effects during CT-P13 infusion. Overall, one patient experienced grade 1 adverse event and 9 patients experienced grade 2 adverse events. In no case hospitalization was required. CT-P13 retention rate was 90.9% at month 6 and 90.4% at month 12. Conclusion: In this study, the use of IFX-biosimilar CT-P13 in patients with refractory TAK showed satisfying efficacy and safety profile.