Diagnosis and management of primary heart involvement in systemic sclerosis.

PURPOSE OF REVIEW: In systemic sclerosis (SSc) primary heart involvement (pHI) is frequent, even though often unrecognized due to its occult nature and to the lack of a specific diagnostic algorithm. The purpose of this review is to report the state of the art of the evidence in the current literature, as well as the overall diagnostic modalities and therapeutic strategies for primary heart involvement in SSc. RECENT FINDINGS: SSc-pHI is defined by the presence of cardiac abnormalities that are predominantly attributable to SSc rather than other causes and/or complications; it may be sub-clinical and must be confirmed through diagnostic investigations. Novel electrocardiographic analysis and cardiac magnetic resonance (CMR) with mapping techniques have been recently proposed, showing a great utility in the early identification of SSc-pHI and in the noninvasive characterization of myocardial tissue. Immunosuppressive therapy emerged as fundamental to curb myocardial inflammation, and recent preclinical and clinical data support the role of antifibrotic drugs to treat SSc-pHI. SUMMARY: our review will help clinicians to properly integrate the available diagnostic modalities for the assessment of SSc-pHI. The ultimate goal is to propose a feasible diagnostic algorithm for the early identification of patients with SSc-pHI, and a schematic therapeutic approach to manage SSc-pHI.

Distinctive clinical traits of lupus-related myocarditis: a multicentre retrospective study.

OBJECTIVES: Cardiovascular involvement in systemic lupus erythematosus (SLE) is frequent but little is known about possible distinctive traits of SLE-related myocarditis (myoSLE) in comparison to patients with SLE (onlySLE) or myocarditis alone (onlyMyo). METHODS: A retrospective analysis was performed comparing patients with myoSLE (n = 25) from three centres with consecutive patients with onlySLE (n = 279) and onlyMyo (n = 88). SLE patients were dichotomised by disease duration ≤1 vs >1 year into recent onlySLE/early myoSLE vs longstanding onlySLE/late myoSLE. Further stratification into disease duration of 1-5, 5-10 and >10 years was also performed. SLE disease activity index 2000 (SLEDAI-2K) was used to estimate disease activity. Myocarditis was diagnosed through biopsy or magnetic resonance. RESULTS: Women were significantly more frequent among myoSLE than among onlyMyo (72% vs 43%; p= 0.013). Compared with onlyMyo, myoSLE patients had a higher frequency of conduction abnormalities (22% vs 5%; p= 0.046) and presented with numerically higher frequencies of left ventricular function compromise (48% vs 30%), along with higher pro-brain natriuretic peptide levels. Inflammation markers were higher in myoSLE compared with onlyMyo and to patients with onlySLE with >10 years of disease duration. SLEDAI-2K was significantly higher in late myoSLE than in longstanding onlySLE. Antiphospholipid syndrome was more frequent in myoSLE than in onlySLE. Multivariate analysis showed an association among myoSLE, anti-beta-2-glycoprotein I antibodies (aB2GPI, p= 0.014) and a higher number of involved British Isles Lupus Assessment Group domains in patient history (p= 0.003). CONCLUSION: myoSLE has unique clinical traits compared with other forms of myocarditis and is associated with aB2GPI and a more severe SLE course.

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.

Long-term retention rate, adverse event temporal patterns and rescue treatment strategies of mycophenolate mofetil in systemic sclerosis: insights from real-life.

BACKGROUND: Mycophenolate mofetil (MMF) is a mainstay for the treatment of systemic sclerosis (SSc). The occurrence and implications of MMF-related adverse events on drug retention rates in real life remain poorly defined. We aimed to determine the MMF retention rate and to investigate the causes and patterns of discontinuation, adverse events (AEs) and treatment options used after discontinuation. METHODS: SSc patients who started MMF treatment underwent a retrospective longitudinal assessment for up to 5 years. We documented the incidence, predictors, and impacts of MMF treatment on gastrointestinal intolerance, infections, laboratory abnormalities, and cancer. Rescue strategies implemented after MMF discontinuation were recorded. RESULTS: The 5-year MMF retention rate of 554 patients stood at 70.7% and 19.6% of them stopped MMF due to AEs. One out of every four patients experienced a dose reduction or discontinuation of MMF due to AEs, with gastrointestinal intolerance being the predominant cause. The 5-year cumulative incidence rates for gastrointestinal intolerance, cancer, severe infections, and laboratory toxicity leading to MMF discontinuation were 6.4%, 4.1%, 3.1%, and 2.1%, respectively. Lower respiratory tract was the most affected, with bacteria being the predominant causative agent. Intestinal and pulmonary circulation involvement were tied to elevated AE rates and MMF discontinuation. The most common approaches post-MMF cessation were "watch and wait" and switch to rituximab. CONCLUSIONS: MMF use in SSc appears to be limited by the occurrence of AEs, both in terms of persistence and dosing of the drug. Rescue options after MMF discontinuation are limited and many patients remain without immunosuppressant.

Cardiovascular magnetic resonance parametric mapping in the risk stratification of patients affected by chronic myocarditis.

OBJECTIVES: Chronic myocardial inflammation is the substrate for arrhythmias and dilated cardiomyopathy onset, causing morbidity and mortality. Cardiovascular magnetic resonance (CMR) is the noninvasive gold standard for myocardial inflammation detection, due to the high sensitivity of the parametric mapping techniques. However, the potential prognostic capabilities of CMR mapping have not been studied in the setting of chronic myocarditis. METHODS: This is a retrospective study on consecutive patients undergoing CMR with suspicion of chronic myocarditis from September 2017 to November 2021. CMR was acquired according to 2018 Lake Louise Criteria recommendations. The outcome (chronic heart failure, recurrent chronic myocarditic chest pain, ICD/PM implantation, arrhythmias [Lown class ≥ 2]) was collected at follow-up. The extent and degree of native T1, T2, and extracellular volume fraction alterations were used to create multivariate binary logistic regression models for outcome prediction, with or without left ventricle ejection fraction; their AUCs were compared with DeLong test. Differences between other parameters were assessed using Chi-square test, Fisher's exact test, or Mann-Whitney U-test. RESULTS: The population included 88 patients (age 43 [32-52] yo), mostly male (53/88, 60%). After a median follow-up of 21 (17-34) months, 31/88 (35%) patients experienced the outcome. The model based on the extension of mapping alterations and LV dysfunction reached a good predictability (AUC 0.71). The model based on the intensity of mapping alterations and LV dysfunction had a very good performance (AUC 0.80). CONCLUSION: The quantitative analysis of CMR mapping parameters indicative of myocardial damage severity may improve risk stratification in patients with chronic myocarditis. CLINICAL RELEVANCE STATEMENT: The intensity of myocardial damage, assessed as the degree of native T1, T2, and ECV alteration, together with left ventricle dysfunction, improved patient risk stratification. Further prospective studies will be necessary for validation before clinical application. KEY POINTS: Risk stratification of patients affected by chronic myocarditis is an unmet clinical need. Cardiovascular MRI (CMR) can role in risk stratification thanks to its multiparametric capabilities of tissue characterization. A model based on CMR parametric mapping and left ventricle ejection fraction can predict arrhythmia, heart failure, and recurrent symptoms.

Agreement between local and central anti-synthetase antibodies detection: results from the Classification Criteria of Anti-Synthetase Syndrome project biobank.

OBJECTIVES: The CLASS (Classification Criteria of Anti-Synthetase Syndrome) project is a large international multicentre study that aims to create the first data-driven anti-synthetase syndrome (ASSD) classification criteria. Identifying anti-aminoacyl tRNA synthetase antibodies (anti-ARS) is crucial for diagnosis, and several commercial immunoassays are now available for this purpose. However, using these assays risks yielding false-positive or false-negative results, potentially leading to misdiagnosis. The established reference standard for detecting anti-ARS is immunoprecipitation (IP), typically employed in research rather than routine autoantibody testing. We gathered samples from participating centers and results from local anti-ARS testing. As an "ad-interim" study within the CLASS project, we aimed to assess how local immunoassays perform in real-world settings compared to our central definition of anti-ARS positivity. METHODS: We collected 787 serum samples from participating centres for the CLASS project and their local anti-ARS test results. These samples underwent initial central testing using RNA-IP. Following this, the specificity of ARS was reconfirmed centrally through ELISA, line-blot assay (LIA), and, in cases of conflicting results, protein-IP. The sensitivity, specificity, positive likelihood ratio and positive and negative predictive values were evaluated. We also calculated the inter-rater agreement between central and local results using a weighted κ co-efficient. RESULTS: Our analysis demonstrates that local, real-world detection of anti-Jo1 is reliable with high sensitivity and specificity with a very good level of agreement with our central definition of anti-Jo1 antibody positivity. However, the agreement between local immunoassay and central determination of anti-non-Jo1 antibodies varied, especially among results obtained using local LIA, ELISA and "other" methods. CONCLUSIONS: Our study evaluates the performance of real-world identification of anti-synthetase antibodies in a large cohort of multi-national patients with ASSD and controls. Our analysis reinforces the reliability of real-world anti-Jo1 detection methods. In contrast, challenges persist for anti-non-Jo1 identification, particularly anti-PL7 and rarer antibodies such as anti-OJ/KS. Clinicians should exercise caution when interpreting anti-synthetase antibodies, especially when commercial immunoassays test positive for non-anti-Jo1 antibodies.

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.

Glucocorticoids prescribing practices in systemic sclerosis: an analysis of the EUSTAR database.

OBJECTIVES: To estimate the prevalence of long-term exposure to glucocorticoids (GCs) and to identify factors associated with, and variations in prescribing practices over time and across recruiting countries. METHODS: We included patients with SSc having a visit recorded in the EUSTAR database from January 2013 onward. We analysed the prevalence and the main features of GCs users, their exposure to GCs over time, and their GCs dosages. Multivariable linear regression was used to analyse the factors identified as associated with GCs intake duration. Time trends, and variations in GCs utilization across recruiting countries were explored. Missing data were imputed using multiple imputation with chained equations. RESULTS: The 9819 patients included were mostly females (85%), the majority had lcSSc (73%), and the median age was 58 years. At baseline, 34% of patients (n = 2769/8109) (48% dcSSc vs 29% lcSSc) were on GCs, and the median dose was 7.5 mg/day. GCs users were more frequently males and anti-Scl70 positive, and more commonly had dcSSc and more severe disease. On average, GCs users spent 25% of their follow-up time (median 33.2 months) on GCs, with no significant between-subsets difference. Notably, 33% (n = 971/2959) and 22% (n = 647/2959) of patients followed up for >1 year had received GCs for >6 and >12 months, respectively. Multivariable analysis showed that patient and disease characteristics poorly explained the variability in GCs exposure (adjusted-R2 = 0.06, P < 0.001). GCs utilization varied within and across countries, and gradually decreased over time (36% in 2013 vs 23% in 2018). CONCLUSIONS: GCs are widely and long-term prescribed in SSc, with significant between-countries and within-country differences. A gradual decrease in their utilization has been observed.

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.