Anifrolumab In Refractory Systemic Lupus Erythematosus: A Real-Life, Multicenter Study.

OBJECTIVE: To report the real-world experience on the use of ANI in refractory SLE. METHODS: Multicenter retrospective study involving 9 Italian SLE referral centers participating in a compassionate use program for the use of ANI in active adult SLE patients in whom all the available treatment choices failed, were not tolerated or contraindicated.At baseline, at 1, 3, 6, 9 and 12 months of treatment, overall and organ specific disease activity, flares, daily glucocorticoid (GC) dose, and adverse events were recorded. RESULTS: A total of 26 patients were enrolled. At 4 weeks after starting ANI, a significant decrease in SLEDAI-2K (p=0.005), SLEDAS (p=0.005) and PGA (p=0.001) was recorded, and the same trend was maintained over time. A significant reduction in CLASI-activity (p<0.001) and in tender (p=0.026) and swollen (p=0.017) joint count was also recorded. At 3 months of follow-up, 33% of patients already achieved a remission state, while 46% were in LLDAS; at 6 months, 50% were in remission and 80% in LLDAS. A significant reduction in the mean GC daily dose was observed, starting from week 4 (p=0.04). A total of 4 disease flares according to the SELENA-SLEDAI Flare Index were recorded (three mild-moderate and one severe). Overall, 4 out of 20 patients with at least 24 weeks of follow-up (20%) were considered "non responders". CONCLUSION: This study provides a real-world experience on the use of ANI in refractory SLE patients, confirming its rapid effectiveness and an overall acceptable safety profile.

The impact of environmental factors on aetiopathogenesis and clinical manifestations of Behçet's syndrome.

Behçet's syndrome (BS) is a rare multisystem vasculitis involving blood vessels of any size. BS aetiology is still unclear to date, and the heterogeneity of clinical expression among ethnics and genders make early diagnosis challenging. However, so far, considerable efforts have been made toward the understanding of BS, leading researchers to agree that the coexistence of some environmental triggers and a genetical susceptibility both underlie BS aetiopathogenesis. In particular, viral agents, oral microbial flora, and mucosal microbiota have been widely explored in this regard, but still no specific microorganism has been definitely linked to the disease aetiology. Likewise, the concept that some environmental factors may play a role in BS clinical presentation has emerged based on the growing evidence that disease severity is usually higher in male patients, and that diet and fatigue may be involved in disease recurrence, especially in mucocutaneous manifestations. Moreover, smoke cessation is acknowledged as a risk factor for oral ulcerations, although the underlying mechanism is still not clear. All those environmental factors play their effects through epigenetic mechanisms. The aim of this review is to discuss the evidence on the role of environmental factors in BS aetiopathogenesis and clinical course.

Dupilumab for relapsing or refractory sinonasal and/or asthma manifestations in eosinophilic granulomatosis with polyangiitis: a European retrospective study.

BACKGROUND: Eosinophilic granulomatosis with polyangiitis (EGPA) is often associated with glucocorticoid-dependent asthma and/or ear, nose and throat (ENT) manifestations. When immunosuppressants and/or mepolizumab are ineffective, dupilumab could be an option. We describe the safety and efficacy of off-label use of dupilumab in relapsing and/or refractory EGPA. PATIENTS AND METHODS: We conducted an observational multicentre study of EGPA patients treated with dupilumab. Complete response was defined by Birmingham Vasculitis Activity Score (BVAS)=0 and prednisone dose ≤4 mg/day, and partial response by BVAS=0 and prednisone dose >4 mg/day. Eosinophilia was defined as an eosinophil count >500/mm3. RESULTS: Fifty-one patients were included. The primary indication for dupilumab was disabling ENT symptoms in 92%. After a median follow-up of 13.1 months, 18 patients (35%) reported adverse events (AEs), including two serious AEs. Eosinophilia was reported in 34 patients (67%), with a peak of 2195/mm3 (IQR 1268-4501) occurring at 13 weeks (IQR 4-36) and was associated with relapse in 41%. Twenty-one patients (41%) achieved a complete response and 12 (24%) a partial response. Sixteen (31%) patients experienced an EGPA relapse while on dupilumab, which was associated with blood eosinophilia in 14/16 (88%) patients. The median eosinophil count at the start of dupilumab was significantly lower in relapsers than in non-relapsers, as was the median time between stopping anti-IL-5/IL-5R and switching to dupilumab. CONCLUSION: These results suggest that dupilumab may be effective in treating patients with EGPA-related ENT manifestations. However, EGPA flares occurred in one-third of patients and were preceded by eosinophilia in 88%, suggesting that caution is required.

Evidence of subclinical atherosclerosis in eosinophilic granulomatosis with polyangiitis.

OBJECTIVES: Patients affected by eosinophilic granulomatosis with polyangiitis (EGPA) display an increased risk of atherothrombotic events compared with the general population. An increased frequency of subclinical markers of atherosclerosis has been observed in other ANCA-associated vasculitis, but no specific study focused on EGPA. We therefore evaluated subclinical atherosclerosis in EGPA patients and in a control population. METHODS: Forty EGPA patients and 80 controls matched by age, sex and traditional cardiovascular risk factors underwent sonographic assessment of common carotid artery (CCA) intima-media thickness (IMT). The presence of plaques of the CCA was also investigated. The correlation between CCA-IMT and clinical and laboratory features was also assessed. RESULTS: Median CCA-IMT was significantly higher in EGPA patients compared with controls (P = 0.002). Also, the proportion of subjects with increased CCA-IMT and with presence of plaques was significantly higher among EGPA patients (P < 0.001 for both). Moreover, within the EGPA cohort, CCA-IMT tended to increase with disease duration (P = 0.034) and corticosteroid cumulative dose (P = 0.004). No significant associations were found between CCA-IMT, ANCA status, other clinical features and therapeutic regimens. Notably, the prevalence of traditional cardiovascular risk factors was comparable in patients with vs without an increased CCA-IMT. CONCLUSION: Ultrasound markers of subclinical atherosclerosis are increased in EGPA patients as compared with controls, independently of traditional cardiovascular risk factors.

Prevalence and clinical associations of ultrasound-confirmed enthesitis in systemic lupus erythematosus.

OBJECTIVES: To assess the prevalence of US-confirmed enthesitis in a cohort of patients with SLE and to analyse the clinical associations to enthesitis during the course of SLE. METHODS: In a retrospective analysis of the SLE cohort of the Lupus Unit of the Careggi University Hospital, US examinations of SLE patients presenting with tender and/or swollen joints were retrieved to assess the presence of enthesitis. Patients with US-proven enthesitis were compared with SLE controls with tender and/or swollen joints who showed no US evidence of enthesitis. Clinical and laboratory features were compared at disease onset and during follow-up. RESULTS: A total of 400 patients fulfilling EULAR/ACR classification criteria for SLE were assessed. Of these, 106 underwent articular US examination. Evidence of enthesitis was found in 31/106 (29.2%) patients. Seventy-one patients without US-enthesitis were included as controls; four were excluded due to lack of follow-up data. Laboratory and clinical features were comparable between cases and controls at disease onset. Throughout a median follow-up of 10.0 (interquartile range [IQR] 8.3-23.3) years for cases and 12.4 (IQR 7.2-13.3) years for controls, patients with enthesitis were less likely to develop renal involvement (22.6% vs 46.5%, P = 0.028) and failed B cell depletion more frequently (75.0% vs 0%). CONCLUSION: In SLE patients with clinically active joints, US-proven enthesitis is a fairly common finding. Enthesitis in SLE could be the hallmark of a distinct disease phenotype with less renal involvement, more arthritis and low response to anti-CD 20 therapy, potentially requiring a tailored treatment.

A unique circulating miRNA profile highlights thrombo-inflammation in Behçet's syndrome.

OBJECTIVES: Behçet's syndrome (BS) is a rare systemic vasculitis often complicated by thrombotic events. Given the lack of validated biomarkers, BS diagnosis relies on clinical criteria.In search of novel biomarkers for BS diagnosis, we determined the profile of plasmatic circulating microRNAs (ci-miRNAs) in patients with BS compared with healthy controls (HCs). METHODS: ci-miRNA profile was evaluated by microarray in a screening cohort (16 patients with BS and 18 HCs) and then validated by poly(T) adaptor PCR (PTA-PCR) in a validation cohort (30 patients with BS and 30 HCs). Two disease control groups (30 patients with systemic lupus erythematosus (SLE) and 30 patients with giant cell arteritis (GCA) were also analysed. RESULTS: From the microarray screening, 29 deregulated (differentially expressed (DE)) human ci-miRNAs emerged. A hierarchical cluster analysis indicated that DE ci-miRNAs clearly segregated patients from controls, independently of clinical features. PTA-PCR analysis on the validation cohort confirmed the deregulation of miR-224-5p, miR-206 and miR-653-5p. The combined receiver operating characteristic (ROC) curve analyses showed that such ci-miRNAs discriminate BS from HCs (and BS with active vs inactive disease), as well as BS from patients with SLE and GCA.The functional annotation analyses (FAAs) showed that the most enriched pathways affected by DE ci-miRNAs (ie, cell-matrix interaction, oxidative stress and blood coagulation) are related to thrombo-inflammatory mechanisms. Accordingly, the expression of the three ci-miRNAs from the validation cohort significantly correlated with leucocyte reactive oxygen species production and plasma lipid peroxidation. CONCLUSIONS: The ci-miRNA profile identified in this study may represent a novel, poorly invasive BS biomarker, while suggesting an epigenetic control of BS-related thrombo-inflammation.

The management of transitional care of patients affected by phenylketonuria in Italy: Review and expert opinion.

Phenylketonuria (PKU) is a metabolic inherited disorder in which transition from infancy to adult care is particularly difficult and not sufficiently regulated. According to the scientific literature, only few medical centers offer healthcare assistance for adult patients with PKU that are therefore still treated in pediatric settings. This generates psychological, emotional, and organizational discomfort among patients, leading them to discontinue the follow-up. European guidelines and national consensus documents underline this unmet need and the lack of practical recommendations for a structured transitional pathway in PKU. The aim of this review and expert opinion is to propose good practices for managing the transition period of PKU patients, based on the literature and the experience of a panel of Italian experts in PKU. The consensus of the experts was obtained through the administration of three rounds of surveys and one structured interview. The result is the first proposal of a pathway for an efficient transition of PKU patients. Key steps of the proposed pathway are the "a priori" planning involving the pediatric and adult teams, the acceptance of the patient and his/her family to the process, the preliminary definition of appropriate spaces in the structure, the organization of meetings with the joint team, and the appointment of a transition coordinator. For the first time, the involvement of decision makers and patient associations is proposed.

Neutrophil-mediated mechanisms of damage and in-vitro protective effect of colchicine in non-vascular Behçet's syndrome.

Behçet's syndrome (BS) is a systemic vasculitis with several clinical manifestations. Neutrophil hyperactivation mediates vascular BS pathogenesis, via both a massive reactive oxygen species (ROS) production and neutrophil extracellular traps (NETs) release. Here, we investigated neutrophil-mediated mechanisms of damage in non-vascular BS manifestations and explored the in-vitro effects of colchicine in counteracting these mechanisms. NETs and intracellular ROS production was assessed in blood samples from 80 BS patients (46 with active non-vascular BS, 34 with inactive disease) and 80 healthy controls. Moreover, isolated neutrophils were incubated for 1 h with an oxidating agent [2,2'-azobis (2-amidinopropane) dihydrochloride; 250 nM] and the ability of pure colchicine pretreatment (100 ng/ml) to counteract oxidation-induced damage was assessed. Patients with active non-vascular BS showed remarkably increased NET levels [21.2, interquartile range (IQR) = 18.3-25.9 mU/ml] compared to patients with inactive disease (16.8, IQR = 13.3-20.2 mU/ml) and to controls (7.1, IQR = 5.1-8.7 mU/ml, p < 0.001]. Also, intracellular ROS tended to increase in active BS, although not significantly. In active non-vascular BS, NETs correlated with neutrophil ROS production (p < 0.001) and were particularly increased in patients with active mucosal (p < 0.001), articular (p = 0.004) and gastrointestinal symptoms (p = 0.006). In isolated neutrophils, colchicine significantly reduced oxidation-induced NET production and cell apoptosis, although not via an anti-oxidant activity. Neutrophil-mediated mechanisms might be directly involved in non-vascular BS, and NETs, more than ROS, might drive the pathogenesis of mucosal, articular and intestinal manifestations. Colchicine might be effective in counteracting neutrophils-mediated damage in BS, although further studies are needed.

Durable renal response and safety with add-on belimumab in patients with lupus nephritis in real-life setting (BeRLiSS-LN). Results from a large, nationwide, multicentric cohort.

BACKGROUND: Belimumab was recently approved for treatment of lupus glomerulonephritis (LN). AIM: To evaluate renal response and its predictors in LN patients receiving belimumab in real-life. PATIENTS AND METHODS: We considered all patients fulfilling the SLEDAI-2K renal items and/or having estimated glomerular filtration rate (eGFR)≤60 ml/min/1.73 m2, with positive anti-dsDNA and/or low C3/C4 enrolled in the multicentre Italian lupus cohort BeRLiSS (BElimumab in Real LIfe Setting Study), treated with monthly IV Belimumab 10 mg/kg over standard treatment. Primary efficacy renal response (PERR), defined as proteinuria ≤0.7 g/24 h, eGFR≥60 ml/min/1.73 m2 without rescue therapy, was considered as primary outcome. Complete renal response (CRR; proteinuria <0.5 g/24 h, eGFR≥90 ml/min/1.73 m2) was considered as secondary outcome. Prevalence and predictors of PERR were evaluated at 6, 12, 24 months by multivariate logistic regression. RESULTS: Among the 466 SLE patients of BeRLiSS, 91 fulfilled the inclusion criteria, 79 females, median age 41.0 (33.0-47.0) years, median follow-up 22.0 (12.0-36.0) months. Sixty-four (70.3%) achieved PERR, of whom 38.4% reached CRR. Among patients achieving PERR at 6 months, 86.7% maintained response throughout the follow-up. At multivariable analysis, hypertension (OR [95%CI]: 0.28 [0.09-0.89], p = 0.032), high baseline serum creatinine (0.97 [0.95-0.99], p = 0.01) and high baseline proteinuria (0.37, [0.19-0.74], p = 0.005) negatively predicted PERR. Positive predictors of PERR at 12 and 24 months were baseline anti-Sm positivity (OR [95%CI]: 6.2 [1.21-31.7], p = 0.029; 19.8 [2.01-186.7], p = 0.009, respectively) and having achieved PERR at 6 months (14.4 [3.28-63.6]; 11.7 [2.7-48.7], p = 0.001 for both). CONCLUSIONS: Add-on therapy with belimumab led to durable renal response in patients with LN in a real-life setting.

Significance of PR3-ANCA positivity in eosinophilic granulomatosis with polyangiitis (Churg-Strauss).

OBJECTIVES: Only a third of patients with eosinophilic granulomatosis with polyangiitis (EGPA) are ANCA-positive, mainly directed against MPO. ANCA directed against PR3 are rarely found in EGPA. We aimed to examine the significance of PR3-ANCA in EGPA. METHODS: We set up a retrospective European multicentre cohort including 845 patients. Baseline characteristics and outcomes were analysed and compared according to ANCA status. RESULTS: ANCA status was available for 734 patients: 508 (69.2%) ANCA-negative, 210 (28.6%) MPO-ANCA and 16 (2.2%) PR3-ANCA. At baseline, PR3-ANCA patients, compared with those with MPO-ANCA and ANCA-negative, less frequently had active asthma (69% vs 91% and 93%, P = 0.003, respectively) and peripheral neuropathy (31% vs 71% and 47%, P < 0.0001), more frequently had cutaneous manifestations (63% vs 38% and 34%, P = 0.03) and pulmonary nodules (25% vs 10% and 8%, P = 0.046), and lower median eosinophil count (1450 vs 5400 and 3224/mm3, P < 0.0001). Vasculitis relapse-free survival was shorter for PR3-ANCA (hazard ratio 6.05, P = 0.005) and MPO-ANCA patients (hazard ratio 1.88, P = 0.0002) compared with ANCA-negative patients. CONCLUSION: PR3-ANCA EGPA patients differ from those with MPO-ANCA and negative ANCA, and share clinical features with granulomatosis with polyangiitis. This suggests that PR3-ANCA EGPA could be a particular form of PR3-ANCA-associated vasculitis.

Prevalence and clinical course of SARS-CoV-2 infection in patients with Behçet's syndrome.

OBJECTIVES: We aimed to assess the prevalence of SARS-CoV-2 infection among Behçet's syndrome (BS) patients, evaluating the possible association between demographic and clinical features and the risk of infection. Moreover, we aimed to evaluate the possible association between BS disease activity and treatment, and the risk of SARS-CoV-2 infection. METHODS: A survey was conducted on BS patients followed at the Behçet's Centre of the Careggi University Hospital, Florence, Italy. We further evaluated the possible association between BS disease activity and treatment, and the risk of SARS-CoV-2 infection. RESULTS: Out of 335 BS patients contacted, fourteen cases of SARS-CoV-2 were identified between April 1st, 2020 and February 9th, 2021, suggesting a prevalence of SARS-CoV-2 infection among BS patients of 4.2%, in line with the data of the general population in Italy (4.4%). When comparing clinical features between SARS-CoV-2 cases and matched SARS-CoV-2 negative BS patients, we found that the presence of different disease manifestations did not significantly differ between the two groups. SARS-CoV-2 cases and controls were also comparable in terms of immunosuppressive therapy, with the only exception of corticosteroids (71.4% vs. 35.7%, p=0.030), whose daily dose was significantly higher in cases than controls [5mg/day (IQR 0-10,) vs. 0 mg/day (IQR 0-5), p=0.005], suggesting that the right timing of usage and the more appropriate dosage of corticosteroid are a key question for the better management of these patients. CONCLUSIONS: Based on our results, patients with BS do not seem to be at a greater risk of SARS-CoV-2 infection or severe complications compared with the general population.

Long-term effectiveness and safety of secukinumab for treatment of refractory mucosal and articular Behçet's phenotype: a multicentre study.

OBJECTIVE: To evaluate the effectiveness and safety of secukinumab in patients with a mucosal and articular Behçet's phenotype resistant to conventional and biologic treatment. METHODS: A multicentre retrospective study was performed on 15 patients with a mucosal and articular phenotype of Behçet's syndrome fulfilling the International Criteria for Behçet's Disease and refractory to treatment with colchicine, disease-modifying antirheumatic drugs and at least one antitumour necrosis factor-α agent. Minimum follow-up was set at 6 months. Six patients with a polyarticular involvement were treated with secukinumab 300 mg/month, while all other cases received secukinumab 150 mg/month. Dose increase from 150 to 300 mg per month and shortening of administration frequency were allowed for poor disease control. Response evaluation was based on the number of oral ulcers in the previous 28 days and Disease Activity Score-28 for articular manifestations. RESULTS: At 3 months of follow-up, nine (66.7%) patients achieved a response (complete or partial), and this proportion further increased to 86.7% at 6 months, 76.9% at 12 months, 90.0% at 18 months and 100.0% after 24 months. Notably, all patients who started with secukinumab 300 mg/month achieved complete response by month 6. Seven (46.7%) patients could achieve a response only after switching to a higher dosage. CONCLUSIONS: Our study suggests that secukinumab at a dose of 150 and 300 mg per month is safe and effective for the long-term treatment of patients with Behçet's syndrome with a mucosal and articular phenotype refractory to previous treatments. Notably, secukinumab 300 mg/month resulted in superior complete mucosal and articular responses with no serious or dose-related adverse effects.

Obstetric antiphospholipid syndrome is not associated with an increased risk of subclinical atherosclerosis.

OBJECTIVES: The persistent positivity of aPLs, either isolated or associated with thrombotic and/or obstetric events (APS), has been associated with the increase of intima-media thickness (IMT) and carotid plaques. Despite the fact that aPLs can promote both thrombotic and obstetric complications, some pathogenic differences have been documented between the two entities. This study aimed to evaluate whether the atherosclerotic risk differs between subjects with obstetric and thrombotic APS. METHODS: A total of 167 APS women (36 obstetric and 131 thrombotic) were compared with 250 aPLs negative controls. IMT of the common carotid artery (CCA) and of the bulb and the prevalence of carotid plaques were assessed. RESULTS: CCA- and bulb-IMT were significantly higher in women with thrombotic APS, while being similar between the obstetric APS and the controls [CCA-IMT: mean (s.d.) 0.97 (0.49), 0.78 (0.22) and 0.81 (0.12) mm for the thrombotic, obstetric and control groups, respectively, P < 0.001 between thrombotic and controls, P = 0.002 between thrombotic and obstetric; bulb-IMT: mean (s.d.) 1.38 (0.79), 0.96 (0.27) and 0.96 (0.51) mm for the thrombotic, obstetric and control groups, P < 0.001]. Women with thrombotic APS had significantly increased risk of presenting carotid plaques. This risk was significantly lower in obstetric APS. CONCLUSION: Unlike thrombotic APS, obstetric APS is not associated with an increase of markers of subclinical atherosclerosis. If confirmed on wider populations, these results could suggest different pathogenetic role of aPLs in promoting atherosclerosis in vascular and obstetric APS, and raise questions on the risk-benefit profile of thromboprophylaxis in obstetric APS outside pregnancy periods.

Adalimumab effectively controls both anterior and posterior noninfectious uveitis associated with systemic inflammatory diseases: focus on Behçet's syndrome.

BACKGROUND: To compare the efficacy of Adalimumab (ADA) in noninfectious anterior uveitis (AU) and posterior segment (PS) involvement, associated with different conditions, with a focus on Behçet's syndrome (BS). METHODS: In this retrospective, multicenter post-hoc study, we evaluated the efficacy of ADA in terms of ocular control and relapses in 96 patients with AU and PS uveitis, either idiopathic (IU) or associated with BS or with other systemic disorders (OSD) (Juvenile Idiopathic Arthritis, Psoriatic Arthritis, Ankylosing Spondylitis, Vogt-Koyanagi-Harada, Inflammatory Bowel Disease), followed in three tertiary referral centers. RESULTS: Ninety-six patients (45 AU; 51 PS uveitis) were included. Eleven had IU, 58 BS, and 27 OSD. All patients with AU achieved complete long-term ocular control. In PS uveitis, 89%, 67% and 100% of patients with BS, IU and OSD achieved ocular control at the last follow-up (> 12 months), respectively. The lowest ocular relapse rate occurred in patients with AU with BS (1/13) or IU (0/2). ADA accounted for long-term disease control, and no predictors of ocular control and relapse were identified; particularly, ocular relapses seemed not related to systemic ones. Macular edema resolved in 75% and 67% of PS uveitis with BS and IU, respectively. CONCLUSIONS: ADA controls both anterior and posterior uveitis, with an efficacy similar in IU, BS and OSD patients. In BS, the efficacy of ADA seems to be independent of demographic and clinical characteristics, and ocular relapses mostly occurred independently from systemic ones. Based on our results, ADA may represent a valid alternative in anterior refractory uveitis.

Unveiling the Efficacy, Safety, and Tolerability of Anti-Interleukin-1 Treatment in Monogenic and Multifactorial Autoinflammatory Diseases.

Autoinflammatory diseases (AIDs) are heterogeneous disorders characterized by dysregulation in the inflammasome, a large intracellular multiprotein platform, leading to overproduction of interleukin-1(IL-1)ß that plays a predominant pathogenic role in such diseases. Appropriate treatment is crucial, also considering that AIDs may persist into adulthood with negative consequences on patients' quality of life. IL-1ß blockade results in a sustained reduction of disease severity in most AIDs. A growing experience with the human IL-1 receptor antagonist, Anakinra (ANA), and the monoclonal anti IL-1ß antibody, Canakinumab (CANA), has also been engendered, highlighting their efficacy upon protean clinical manifestations of AIDs. Safety and tolerability have been confirmed by several clinical trials and observational studies on both large and small cohorts of AID patients. The same treatment has been proposed in refractory Kawasaki disease, an acute inflammatory vasculitis occurring in children before 5 years, which has been postulated to be autoinflammatory for its phenotypical and immunological similarity with systemic juvenile idiopathic arthritis. Nevertheless, minor concerns about IL-1 antagonists have been raised regarding their employment in children, and the development of novel pharmacological formulations is aimed at minimizing side effects that may affect adherence to treatment. The present review summarizes current findings on the efficacy, safety, and tolerability of ANA and CANA for treatment of AIDs and Kawasaki vasculitis with a specific focus on the pediatric setting.

Changing patterns in clinical-histological presentation and renal outcome over the last five decades in a cohort of 499 patients with lupus nephritis.

OBJECTIVES: To evaluate changes in demographic, clinical and histological presentation, and prognosis of lupus nephritis (LN) over time. PATIENTS AND METHODS: We studied a multicentre cohort of 499 patients diagnosed with LN from 1970 to 2016. The 46-year follow-up was subdivided into three periods (P): P1 1970-1985, P2 1986-2001 and P3 2002-2016, and patients accordingly grouped based on the year of LN diagnosis. Predictors of patient and renal survival were investigated by univariate and multivariate proportional hazards Cox regression analyses. Survival curves were compared using the log-rank test. RESULTS: A progressive increase in patient age at the time of LN diagnosis (p<0.0001) and a longer time between systemic lupus erythematosus onset and LN occurrence (p<0.0001) was observed from 1970 to 2016. During the same period, the frequency of renal insufficiency at the time of LN presentation progressively decreased (p<0.0001) and that of isolated urinary abnormalities increased (p<0.0001). No changes in histological class and activity index were observed, while chronicity index significantly decreased from 1970 to 2016 (p=0.023). Survival without end-stage renal disease (ESRD) was 87% in P1, 94% in P2% and 99% in P3 at 10 years, 80% in P1 and 90% in P2 at 20 years (p=0.0019). At multivariate analysis, male gender, arterial hypertension, absence of maintenance immunosuppressive therapy, increased serum creatinine, and high activity and chronicity index were independent predictors of ESRD. CONCLUSIONS: Clinical presentation of LN has become less severe in the last years, leading to a better long-term renal survival.

Association of a polymorphism of the Fcγ-receptor 2A (FCGR2A) gene with chronic periaortitis.

OBJECTIVES: Chronic periaortitis (CP) is an inflammatory disease associated in 20-60% of the cases with IgG4 related disease. Current evidence supports an autoimmune nature for CP. Fc gamma receptors (FcγRs) are involved in several immune system activities and are associated with autoimmunity in general. We explored the influence of genetic variants within this region on susceptibility to CP. METHODS: Genotyping of 4 candidate single nucleotide polymorphisms (SNPs) of the FCGR region was performed in CP patients and controls. RESULTS: One hundred and eighty-three cases and 181 controls were included. An association between the SNP rs1801274 of the FCGR2A and CP was detected (OR 1.6, 95%CI 1.18-2.16;corrected p-value, pcorr=0.0085). After stratification of the population according to clinical characteristics, the association was restricted to cases of idiopathic retroperitoneal fibrosis (OR 1.66, 95%CI 1.21-2.29;pcorr=0.028), without involvement of the thoracic aorta (OR 1.77, 95%CI 1.21-2.57;pcorr=0.043), with deep vein thrombosis at onset (OR 3.96, 95%CI 1.81-8.66;pcorr=0.0021) and with normal IgG4 levels (OR 2.67, 95%CI 1.39-5.12;pcorr=0.031). CONCLUSIONS: In the largest candidate gene approach study performed so far in CP, we demonstrated an association for CP with a gene hallmark of autoimmunity. The association appears restricted to typical cases of CP without increase of IgG4 levels.

Use of Interleukin-1 Blockers in Pericardial and Cardiovascular Diseases.

PURPOSE OF REVIEW: This review aims to summarize the role of the interleukin-1 (IL-1) blocking agents in cardiovascular diseases, briefly describing the pathogenetic rationale and the most relevant clinical studies. RECENT FINDINGS: IL-1 is a pivotal cytokine of the innate immune system. Anti-IL-1 agents are currently used for the treatment of several autoimmune and autoinflammatory conditions. Recently, the role of IL-1 has also emerged in cardiovascular diseases. Indeed, two recent randomized controlled trials have shown that the IL-1 receptor antagonist anakinra is effective for the treatment of idiopathic recurrent pericarditis and the IL-1ß blocking agent canakinumab is effective in reducing myocardial infarction in people at risk. Interestingly, interfering with IL-1 has proved to be also effective in other cardiovascular manifestations, such as myocarditis, arrhythmias, and heart failure. Blocking the IL-1 pathway is a possible new therapeutic strategy, potentially leading to innovative therapies in many acute and chronic cardiovascular diseases.