Interleukin-1 Blockers in Recurrent and Acute Pericarditis: State of the Art and Future Directions.

Diseases of the pericardium encompass a spectrum of conditions, including acute and recurrent pericarditis, where inflammation plays a pivotal role in the pathogenesis and clinical manifestations. Anti-inflammatory therapy indeed forms the cornerstone of treating these conditions: NSAIDs, colchicine, and corticosteroids (as a second-line treatment) are recommended by current guidelines. However, these medications come with several contraindications and are not devoid of adverse effects. In recent years, there has been an increased focus on the role of the inflammasome and potential therapeutic targets. Recurrent pericarditis also shares numerous characteristics with other autoinflammatory diseases, in which interleukin-1 antagonists have already been employed with good efficacy and safety. The objective of this review is to summarize the available studies on the use of anti-IL-1 drugs both in acute and recurrent pericarditis.

The Use of Chitotriosidase as a Marker of Active Sarcoidosis and in the Diagnosis of Fever of Unknown Origin (FUO).

Sarcoidosis is a multi-organ inflammatory granulomatosis with a lung-predominant involvement. The aim of this study was to investigate the use of serum chitotriosidase (CHIT1) in patients with fever of unknown origin (FUO); the patients with confirmed diagnosis of active sarcoidosis were compared with ones affected by inactive or treated sarcoidosis. CHIT1 activity was evaluated in 110 patients initially admitted at the hospital as FUOs. The overall performance of CHIT1 for active sarcoidosis diagnosis was assessed by performing an area under the receiver operating characteristic curve analysis (AUROC). The sarcoidosis patients were significantly older than the FUO patients not affected by sarcoidosis (p < 0.01). CHIT1 showed a good accuracy as a biomarker for active sarcoidosis in patients explored for FUO (AUROC 0.955; CI 95% 0.895-0.986; p < 0.001). A CHIT1 value >90.86 showed 96.8% sensitivity (84.2-99.9) and 85.5% specificity (75-92.8) in discriminating active sarcoidosis from other causes of FUO. CHIT1 significantly discriminated active versus inactive/under treatment sarcoidosis patients (with lower enzyme activity) (ROC analysis, sensitivity: 96.9%, specificity: 94.7%, value >83.01 nmol/mL/h, AUROC: 0.958, 0.862-0.994, p < 0.001) compared to ACE (ROC analysis, sensitivity: 25.8%, specificity: 93.7%, value >65 UI/L). In conclusion, CHIT1 is a reliable/sensitive biomarker of active sarcoidosis, with values significantly decreasing in remitted/treated patients. It significantly discriminates active sarcoidosis from FUO patients, providing a useful tool in the diagnosis-assessing process.

Survey about the Quality of Life of Italian Patients with Fabry Disease.

Fabry disease (FD) is a genetic disease included in the group of lysosomal storage disorders, caused by X-linked deficiency of the enzyme alpha-galactosidase A. The aim of this study was to evaluate different aspects related to the quality of life (QoL) of a multicentre cohort of Italian patients with FD. An observational survey was conducted to measure health-related quality of life (HR-QoL) in FD patients using the CAPI (Computer-Assisted Personal Interview) method: 106 patients (mostly women) responded to the questionnaire. Geographically, 53.7% of patients lived in northern Italy, 18.9% in central Italy and 27.4% in southern Italy or the Islands. All data were collected through a five-dimensional EuroQoL questionnaire referring to functional aspects (mobility, personal care, routine activities) and perception of physical/mental well-being (pain or discomfort, anxiety or depression). A descriptive analysis of responses was performed; FD patients were compared in terms of QoL with subjects suffering from other chronic diseases, such as Crohn's disease, chronic hepatitis, cirrhosis and multiple sclerosis. Difficulty in normal daily activities was reported by 47.2% of FD patients. About one third of subjects also had mobility difficulties. Feelings of loneliness and isolation were reported by 33.3% of those being 60-69 years old. Anxiety was equally reported in both oldest and youngest patients (66.7%), while depression, relational problems, fear of other people's judgement increased along with age, reaching 66.7% in the over-70-years group. Male patients were largely troubled about the risk of physical disability, particularly those aged 60 years or over. Furthermore, FD patients had a poorer QoL than people suffering from other chronic inflammatory disorders. Our study upholds that FD patients have a poor QoL, as already known, negatively impacting psychic well-being and social activities. Our survey has also found a worse QoL in FD patients compared with other severe chronic disorders.

Biotechnological Agents for Patients With Tumor Necrosis Factor Receptor Associated Periodic Syndrome-Therapeutic Outcome and Predictors of Response: Real-Life Data From the AIDA Network.

Objective: To describe the role of biotechnological therapies in patients with tumor necrosis factor receptor associated periodic syndrome (TRAPS) and to identify any predictor of complete response. Methods: Clinical, laboratory, and therapeutic data from 44 Caucasian TRAPS patients treated with biologic agents were retrospectively collected in 16 Italian tertiary Centers. Results: A total of 55 biological courses with anakinra (n = 26), canakinumab (n = 16), anti-TNF-α agents (n = 10), and tocilizumab (n = 3) were analyzed. A complete response was observed in 41 (74.5%) cases, a partial response in 9 (16.4%) cases and a treatment failure in 5 (9.1%) cases. The frequency of TRAPS exacerbations was 458.2 flare/100 patients-year during the 12 months prior to the start of biologic treatment and 65.7 flare/100 patients-years during the first 12 months of therapy (p < 0.0001). The median duration of attacks was 5.00 (IQR = 10.50) days at the start of biologics and 1.00 (IQR = 0.00) days at the 12-month assessment (p < 0.0001). Likewise, a significant reduction was observed in the Autoinflammatory Disease Activity Index during the study period (p < 0.0001). A significant corticosteroid sparing effect was observed as early as the first 12 months of treatment both in the number of patients requiring corticosteroids (p = 0.025) and in the dosages employed (p < 0.0001). A significant reduction was identified in the erythrocyte sedimentation rate (p < 0.0001), C reactive protein (p < 0.0001), serum amyloid A (p < 0.0001), and in the 24-h proteinuria dosage during follow-up (p = 0.001). A relapsing-remitting disease course (OR = 0.027, C.I. 0.001-0.841, p = 0.040) and the frequency of relapses at the start of biologics (OR = 0.363, C.I. 0.301-0.953, p = 0.034) were significantly associated with a complete response. No serious adverse events were observed. Conclusions: Treatment with biologic agents is highly effective in controlling clinical and laboratory TRAPS manifestations. Patients with a relapsing-remitting course and a lower frequency of flares at the start of treatment show more likely a complete response to biologic agents.

Drug survival of anakinra and canakinumab in monogenic autoinflammatory diseases: observational study from the International AIDA Registry.

OBJECTIVES: To investigate survival of IL-1 inhibitors in monogenic autoinflammatory disorders (mAID) through drug retention rate (DRR) and identify potential predictive factors of drug survival from a real-life perspective. PATIENTS AND METHODS: Multicentre retrospective study analysing patients affected by the most common mAID treated with anakinra or canakinumab. Survival curves were analysed with the Kaplan-Meier method. Statistical analysis included a Cox-proportional hazard model to detect factors responsible for drug discontinuation. RESULTS: Seventy-eight patients for a total of 102 treatment regimens were enrolled. The mean treatment duration was 29.59 months. The estimated DRR of IL-1 inhibitors at 12, 24 and 48 months of follow-up was 75.8%, 69.7% and 51.1%, respectively. Patients experiencing an adverse event had a significantly lower DRR (P=0.019). In contrast, no significant differences were observed between biologic-naïve patients and those previously treated with biologic drugs (P=0.985). Patients carrying high-penetrance mutations exhibited a significantly higher DRR compared with those with low-penetrance variants (P=0.015). Adverse events were the only variable associated with a higher hazard of treatment withdrawal [hazard ratio (HR) 2.573 (CI: 1.223, 5.411), P=0.013] on regression analysis. A significant glucorticoid-sparing effect was observed (P<0.0001). CONCLUSIONS: IL-1 inhibitors display an excellent long-term effectiveness in terms of DRR, and their survival is not influenced by the biologic line of treatment. They display a favourable safety profile, which deserves, however, a close monitoring given its impact on treatment continuation. Special attention should be paid to molecular diagnosis and mutation penetrance, as patients carrying low-penetrance variants are more likely to interrupt treatment.

Right ventricular strain in Anderson-Fabry disease.

BACKGROUND: 2D speckle tracking echocardiography (2DSTE) is superior to standard echocardiography in the assessment of subtle right ventricle (RV) systolic dysfunction. In this study we aimed to: 1) test the hypothesis that 2DSTE may unveil subtle RV systolic dysfunction in patients with Fabry disease; 2) investigate whether the physiologic difference between the 3-segment (RV-FWS) and the 6-segment (RV-GLS) RV strain (∆RV strain) is preserved in Fabry patients. METHODS AND RESULTS: Standard echocardiography and 2DSTE were performed in 49 Fabry patients and 49 age- and sex-matched healthy controls. Fabry patients were divided in two groups according to the presence/absence of left ventricular hypertrophy (LVH+: left ventricular wall thickness > 12 mm, 49% of total Fabry patients). RV systolic function assessed by standard echocardiography was normal in the majority of Fabry patients (92%) while RV-GLS and RV-FWS were impaired in about 40%. RV-GLS and RV-FWS were significantly worse in patients LVH+ vs LVH- and vs controls (RV-GLS: LVH+ vs LVH-: -18.4 ± -4.3% vs -23.8 ± -3.1% p<0.001; LVH+ vs controls: -18.4 ± -4.3% vs -23.9 ± -2.8% p<0.001; RV-FWS: LVH+ vs LVH-: -21.8 ± -5.3% vs -26.7 ± -3.8% p = 0.002, LVH+ vs controls -21.8 ± -5.3% vs -26.8 ± -3.9% p<0.001). No difference was found between LVH- patients and controls in both RV-GLS (p = 0.65) and RV-FWS (p = 0.79). ∆RV strain was similar among the groups. CONCLUSIONS: In Fabry cardiomyopathy impaired RV-GLS and RV-FWS is a common finding, while RV strain is preserved in Fabry patients without overt cardiac involvement. The physiologic difference between RV-FWS and RV-GLS is maintained in Fabry patients, regardless of the presence of cardiomyopathy.

Early introduction of anakinra improves acute pericarditis and prevents tamponade in Staphylococcal sepsis.

The clinical response to anakinra observed by this patient concurrently treated with antibiotics indirectly confirms the potentially pathogenic role of IL-1 in maintaining the pericardial disease and shows how IL-1 blockade might allow avoiding the pericardiocentesis procedure. The report supports the hypothesis that anakinra is an effective and safe tool in the early treatment of acute pericarditis of presumed bacterial origin nonresponding to targeted antibiotic therapy.

Children and Adults with PFAPA Syndrome: Similarities and Divergences in a Real-Life Clinical Setting.

INTRODUCTION: Analogies or differences of periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome in children and adults are barely known. The aim of our study was to compare the overall characteristics of a large cohort of patients, both children and adults, diagnosed with PFAPA syndrome. METHODS: In the last decade, we identified 120 children and 63 adults with periodically recurring fevers, who fulfilled the criteria for PFAPA diagnosis. The two subcohorts were analyzed according to demographic features, clinical manifestations, laboratory data, and responses to therapies. RESULTS: The mean age of onset was 2.4 ± 1.5 and 19.7 ± 10.3 years, respectively, in children and adults, while attacks occurred every 3.8 ± 0.8 and every 4.3 ± 2.3 weeks, respectively, in children and adults. A higher prevalence of exudative pharyngitis was observed in children (58.8%), and the majority of children had only two cardinal signs during flares. In adults, there was a higher interpersonal variability of the intercritical periods. Inflammatory markers measured during non-febrile periods were normal in children but altered in the totality of adults during febrile periods. A strong efficacy of corticosteroids in controlling the pediatric syndrome was observed, but response rates to steroids were less brilliant in adults. Colchicine and interleukin-1 inhibitors were used in the management of the steroid-resistant adult syndrome. Conversely, tonsillectomy was performed in a very low number of children, but was effective in 60.7% of adults when treated after 16 years. The mean age of disappearance of PFAPA symptoms has been 6.4 ± 2.4 years in children, while only 27% of adults have shown a complete drug-free symptom regression. CONCLUSIONS: A linear conformity of the PFAPA syndrome has been observed between pediatric and adult patients. PFAPA symptoms tended to disappear with no sequelae in 94.1% of children, while the disease was still active in almost 3/4 of adults at the time of our assessment.

Evidence of evolution towards left midventricular obstruction in severe Anderson-Fabry cardiomyopathy.

AIMS: In Fabry cardiomyopathy, left ventricular outflow tract obstruction mimicking hypertrophic cardiomyopathy is a very rare finding, with few cases reported and successfully treated with cardiac surgery. In our population of patients with Fabry disease and severe left ventricular hypertrophy (LVH) at the time of diagnosis, we observed an evolution towards a midventricular obstructive phenotype. METHODS AND RESULTS: We present a case series of three classically affected Fabry male patients with significant diagnostic delay and severe cardiac involvement (maximal wall thickness >20 mm) at first evaluation. All patients developed midventricular obstructive form over time despite prompt initiation and optimal compliance to enzyme replacement therapy. The extension and distribution of the LVH, involving the papillary muscles, was the main mechanism of obstruction, unlike the asymmetric septal basal hypertrophy and the mitral valve abnormalities commonly seen as substrate of left ventricular outflow tract obstruction in hypertrophic cardiomyopathy. CONCLUSIONS: Fabry cardiomyopathy can evolve over time towards a midventricular obstructive form due to massive LVH in classically affected men with significant diagnostic delay and severe LVH before enzyme replacement therapy initiation. This newly described cardiac phenotype could represent an adverse outcome of the disease.

Clinical Features at Onset and Genetic Characterization of Pediatric and Adult Patients with TNF-α Receptor-Associated Periodic Syndrome (TRAPS): A Series of 80 Cases from the AIDA Network.

This study explores demographic, clinical, and therapeutic features of tumor necrosis factor receptor-associated periodic syndrome (TRAPS) in a cohort of 80 patients recruited from 19 Italian referral Centers. Patients' data were collected retrospectively and then analyzed according to age groups (disease onset before or after 16 years) and genotype (high penetrance (HP) and low penetrance (LP) TNFRSF1A gene variants). Pediatric- and adult-onset were reported, respectively, in 44 and 36 patients; HP and LP variants were found, respectively, in 32 and 44 cases. A positive family history for recurrent fever was reported more frequently in the pediatric group than in the adult group (p < 0.05). With reference to clinical features during attacks, pericarditis and myalgia were reported more frequently in the context of adult-onset disease than in the pediatric age (with p < 0.01 and p < 0.05, respectively), while abdominal pain was present in 84% of children and in 25% of adults (p < 0.01). Abdominal pain was significantly associated also to the presence of HP mutations (p < 0.01), while oral aphthosis was more frequently found in the LP variant group (p < 0.05). Systemic amyloidosis occurred in 25% of subjects carrying HP variants. As concerns laboratory features, HP mutations were significantly associated to higher ESR values (p < 0.01) and to the persistence of steadily elevated inflammatory markers during asymptomatic periods (p < 0.05). The presence of mutations involving a cysteine residue, abdominal pain, and lymphadenopathy during flares significantly correlated with the risk of developing amyloidosis and renal impairment. Conversely, the administration of colchicine negatively correlated to the development of pathologic proteinuria (p < 0.05). Both NSAIDs and colchicine were used as monotherapy more frequently in the LP group compared to the HP group (p < 0.01). Biologic agents were prescribed to 49 (61%) patients; R92Q subjects were more frequently on NSAIDs monotherapy than other patients (p < 0.01); nevertheless, they required biologic therapy in 53.1% of cases. At disease onset, the latest classification criteria for TRAPS were fulfilled by 64/80 (80%) patients (clinical plus genetic items) and 46/80 (57.5%) patients (clinical items only). No statistically significant differences were found in the sensitivity of the classification criteria according to age at onset and according to genotype (p < 0.05). This study describes one of the widest cohorts of TRAPS patients in the literature, suggesting that the clinical expression of this syndrome is more influenced by the penetrance of the mutation rather than by the age at onset itself. Given the high phenotypic heterogeneity of the disease, a definite diagnosis should rely on both accurate working clinical assessment and complementary genotype.

Prognostic significance of right ventricular hypertrophy and systolic function in Anderson-Fabry disease.

AIMS: Right ventricular hypertrophy (RVH) is a common finding in Anderson-Fabry disease (AFD), but the prognostic role of right ventricular (RV) involvement has never been assessed. The aim of our study was to evaluate the prognostic significance of RVH and RV systolic function in AFD. METHODS AND RESULTS: Forty-five AFD patients (56% male patients) with extensive baseline evaluation, including assessment of RVH and RV systolic function, were followed-up for an average of 51.2 ± 11.4 months. RV systolic function was assessed by standard and tissue Doppler echocardiography. Cardiovascular events were defined as new-onset atrial fibrillation (AF), sustained ventricular arrhythmias, heart failure, or pacemaker/implantable cardioverter defibrillator implantation; renal events were defined as progression to dialysis and/or renal transplantation or significant worsening of glomerular filtration rate; and cerebrovascular events were defined as transient ischaemic attack or stroke. Fourteen patients (31.1%) presented RVH, while RV systolic function was normal in all cases. During the follow-up period, 13 patients (28.8%, 11 male) experienced 18 major events, including two deaths. Cardiovascular events occurred in eight patients (17.7%). The most common event was pacemaker/implantable cardioverter defibrillator implantation (six patients, 13.3%), followed by AF (three cases, 6.6%). Only one case of worsening New York Heart Association class (from II to III and IV) was observed. Ischaemic stroke occurred in three cases (6.6%). Renal events were recorded in three patients (6.6%). At univariate analysis, several variables were associated with the occurrence of events, including RVH (HR: 7.09, 95% CI: 2.17 to 23.14, P = 0.001) and indexes of RV systolic function (tricuspid annular plane systolic excursion HR: 0.77, 95% CI: 0.62 to 0.96, P = 0.02; and RV tissue Doppler systolic velocity HR: 0.76, 95% CI: 0.61 to 0.93, P = 0.01). At multivariate analysis, proteinuria (HR:8.3, 95% CI: 2.88 to 23.87, P < 0.001) and left ventricular mass index (HR: 1.02, 95% CI: 1.00 to 1.03, P = 0.03) emerged as the only independent predictors of outcome. CONCLUSIONS: RVH and RV systolic function show significant association with clinical events in AFD, but only proteinuria and left ventricular mass index emerged as independent predictors of outcome. Our findings suggest that RV involvement does not influence prognosis in AFD and confirm that renal involvement and left ventricular hypertrophy are the main determinant of major cardiac and non-cardiac events.

Rare missense variants in the ALPK1 gene may predispose to periodic fever, aphthous stomatitis, pharyngitis and adenitis (PFAPA) syndrome.

PFAPA is an autoinflammatory syndrome characterized by periodic fever, aphthous stomatitis, sterile pharingitis, and adenitis, with an onset usually before the age of five. While the condition is most commonly sporadic, a few cases are familial and are usually compatible with an autosomal dominant (AD) transmission pattern, with reduced penetrance in some pedigrees. We performed exome analysis in a family where PFAPA was present in three relatives in two generations showing apparent AD segregation, identifying several rare and/or novel heterozygous variants in genes involved in the autoinflammatory pathway. Following segregation analysis of candidate variants, only one, c. 2770T>C p.(S924P) in the ALPK1 gene, was found to be consistently present in affected family members. ALPK1 is broadly expressed in different tissues and its protein is the intracellular kinase activated by the bacterial ADP-heptose bisphosphate that phosphorylates and activates TRAF-Interacting protein with Forkhead-Associated domain (TIFA) and triggers the immediate response to Gram-negative bacterial invasion. Sequencing analysis of 13 additional sporadic cases and 10 familial PFAPA cases identified two additional heterozygous missense variants c.1024G>C p.(D342H) and c.710C>T p.(T237M) in two sporadic patients, suggesting that rare variants in ALPK1 may represent a predisposing factor for recurrent periodic fever in a pediatric population.

Diagnostic Criteria for Adult-Onset Periodic Fever, Aphthous Stomatitis, Pharyngitis, and Cervical Adenitis (PFAPA) Syndrome.

OBJECTIVE: To identify a set of variables that could discriminate patients with adult-onset periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome from subjects with fever of unknown origin (FUO). METHODS: We enrolled 74 adults diagnosed with PFAPA syndrome according to the currently used pediatric diagnostic criteria and 62 additional patients with FUO. After having collected clinical and laboratory data from both groups, univariate and multivariate analyses were performed to identify the variables associated with PFAPA diagnosis. Odds ratio (OR) values, their statistical significance, and corresponding 95% confidence interval (CI) were evaluated for each diagnostic factor both at the univariate and multivariate analyses. Diagnostic accuracy was evaluated by the area under receiver operating characteristic (ROC) curve, while the leave-one-out cross-validation procedure was used to ensure that the model maintains the same diagnostic power when applied to new data. RESULTS: According to the multivariate analysis, the clinical variables that discriminated PFAPA patients were: fever episodes associated with cervical lymphadenitis (OR = 92; p < 0.0001), fever attacks associated with erythematous pharyngitis (OR = 231; p < 0.0001), increased inflammatory markers during fever attacks (OR = 588; p = 0.001), and the lack of clinical and laboratory signs of inflammation between flares (OR = 1202; p < 0.0001). These variables were considered for a diagnostic model which accounted for their OR values. The diagnostic accuracy of the proposed set of criteria corresponded to an area under ROC curve of 0.978 (95% CI 0.958-0.998), with a model sensitivity and specificity equal to 93.4% (95% CI 87.5-96.5%) and 91.7% (95% CI 82.8-96.7%), respectively. CONCLUSION: we have provided herein a set of clinical diagnostic criteria for adult-onset PFAPA syndrome. Our criteria represent an easy-to-use diagnostic tool aimed at identifying PFAPA patients among subjects with FUO with a high-predictive potential, as shown by its very high sensitivity and specificity.

[Pulmonary-renal syndromes]. / Sindromi pneumo-renali.

Pulmonary-renal syndromes (PRS) are characterized by the simultaneous presence of diffuse alveolar hemorrhage and acute glomerulonephritis. The most common causes of PRS are ANCA-associated vasculitides, Goodpasture's syndrome and systemic lupus erythematosus. The clinical picture of PRS includes hemoptysis (not always present), acute-onset anemia and renal abnormalities ranging from isolated urinary abnormalities to rapidly progressive glomerulonephritis. The severity of the pulmonary involvement determines the mortality risk as well as the need for mechanical ventilation in intensive care. The diagnosis of PRS is based upon clinical, serological, radiological and histological findings. Immunosuppressive therapy, along with an adequate support therapy (especially aimed at avoiding microbial infection), needs to be started promptly and effectively to reduce both the mortality risk and long-term complications such as end-stage renal disease.