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We aimed to apply and compare the QRISK3 and the adjusted Global AntiPhospholipid Syndrome (APS) Score (aGAPSS) in a cohort of systemic lupus erythematosus (SLE) patients, with and without a concomitant diagnosis of APS, in order to assess their augmented risk of developing cardiovascular diseases (CVDs).Patients (25-85 yo) with a diagnosis of SLE and/or of Secondary APS (SAPS) were included. QRISK3 was calculated using the official online calculator; aGAPSS using the validated point-values based on aPL-profile and independent risk factors.The cohort included 142 SLE patients: 34 SAPS (23.9%) and 108 SLE patients without APS (76.1%).When considering all the cohort, patients with cerebrovascular/coronary events showed higher values of aGAPSS (10.1 ± 6.2 vs. 5.8 ± 6.1; p = 0.007), but not of the QRISK3. Furthermore, a significant association was observed between the occurrence of these events and high-risk aGAPSS: p = 0.03 for aGAPSS≥8, p = 0.01 for aGAPSS ≥9, p = 0.008 for aGAPSS ≥10. aGAPSS strongly correlated with the occurrence of any thrombotic event, both at the uni- and multivariate analysis (p = 0.012 and p = 0.009). Male gender also resulted to positively correlate with the occurrence of any thrombotic event at both uni- and multivariate analysis (p = 0.017 and p = 0.03). Focusing on aPL-profile, regardless the diagnosis, we found a statistical significance only for aGAPSS (aPL+ =9.6 ± 6.3 vs. aPL- = 4.1 ± 5.1; p 0.001).Despite QRISK3 being more accurate than traditional risk score in predicting CVD risk in SLE patients, aGAPSS appears to be the most valuable tool for this purpose.

Background Patients on B-cell depleting agents may have a suboptimal response to vaccination, placing them at a higher risk of contracting SARS-CoV-2 or suffering from a more severe prognosis. Indeed, available data on pre-exposure prophylaxis with tixagevimab/cilgavimab (Evusheld) in subjects with glomerular diseases (GD) who received rituximab is limited. Methods We conducted a prospective study analyzing the safety and efficacy of tixagevimab/cilgavimab for pre-exposure prophylaxis in patients with GD who received rituximab in the previous 12 months. Rate of symptomatic infections and hospitalizations were compared to patients with GD treated with rituximab who refused to receive tixagevimab/cilgavimab. Results Tixagevimab/cilgavimab was administered to 22 patients (12 females, mean age 58,4 ± 19,6 years) with GD diagnoses including membranous nephropathy, lupus nephritis, ANCA-associated vasculitis and focal segmental glomerulosclerosis. No patient treated with tixagevimab/cilgavimab experienced symptomatic infection with SARS-CoV-2 during the follow-up (mean observation time follow-up was 112 ± 23 days), while 11 out 28 controls (39,3%) reported a symptomatic infection (p = 0001), requiring hospitalization in 2 cases. Reported adverse events were mild, namely self-limiting headache (4), discomfort at the injection site (3), flu-like symptoms/myalgia (3), and fever (1). No serious adverse event, (e.g. cardiac events, anaphylaxis) was reported. Conclusion Pre-exposure prophylaxis with tixagevimab/cilgavimab (Evusheld) seems safe and lowering of about 40% the risk of symptomatic SARS-CoV-2 infection in vaccinated subjects with GD who received anti-CD20 therapy. Possible applications in the subset of patients who need immunosuppressive therapy, especially with Rituximab, in a pandemic setting might be envisaged.

We aimed to investigate the epidemiology, the clinical and laboratory characteristics of the pediatric involvement of antiphospholipid syndrome (APS), by performing a review of the current evidence and reviewing local experience in the Northwest Italy. To achieve this, we performed a detailed literature search to identify articles describing clinical and laboratory characteristics of pediatric APS. In concomitance, we conducted a registry-based study collecting data from the Piedmont and Aosta Valley Rare Disease Registry including pediatric patients diagnosed with APS in the last 11 years. The literature review led to inclusion of six articles with a total of 386 pediatric patients (65% females, 50% with systemic lupus erythematosus (SLE) as concomitant diagnosis). Rates of venous and arterial thrombosis were 57 and 35%, respectively. “Extra-criteria manifestations” included mostly hematologic and neurologic involvement. Almost one-quarter of patients (19%) reported recurrent events and 13% manifested as catastrophic APS. A total of 17 pediatric patients (mean age 15.1 ± 2.8, 76% female) developed APS in the Northwest of Italy. In 29% of cases, SLE was a concomitant diagnosis. Deep vein thrombosis was the most frequent manifestation (28%) followed by catastrophic APS (6%). The estimated prevalence of pediatric APS in Piedmont and Aosta Valley Region is 2.5/100,000 people, whereas the estimated annual incidence is 0.2/100,000 inhabitants. In conclusion, clinical manifestations of pediatric APS seem to be more severe and with a high prevalence of noncriteria manifestations. International efforts are needed to better characterize this condition and to develop new specific diagnostic criteria to avoid missed/delayed diagnosis in children with APS.

(1) Background: Immunological laboratory testing is known to be complex, and it is usually performed in tertiary referral centers. Many criticalities affect diagnostic immunological testing, such as limited availability, the need for specifically trained laboratory staff, and potential difficulties in collecting blood samples, especially in the most vulnerable patients, i.e., the elderly and children. For this reason, the identification of a new feasible and reliable methodology for autoantibody detection is urgently needed. (2) Methods: We designed a systematic review to investigate the available literature on the utilization of saliva samples for immunological testing. (3) Results: A total of 170 articles were identified. Eighteen studies met the inclusion criteria, accounting for 1059 patients and 671 controls. The saliva collection method was mostly represented by passive drooling (11/18, 61%), and the most frequently described methodology for antibody detection was ELISA (12/18, 67%). The analysis included 392 patients with rheumatoid arthritis, 161 with systemic lupus erythematosus, 131 with type 1 diabetes mellitus, 116 with primary biliary cholangitis, 100 with pemphigus vulgaris, 50 with bullous pemphigoids, 49 with Sjogren syndrome, 39 with celiac disease, 10 with primary antiphospholipid syndromes, 8 with undifferentiated connective tissue disease, 2 with systemic sclerosis, and 1 with autoimmune thyroiditis. The majority of the reviewed studies involved adequate controls, and saliva testing allowed for a clear distinction of patients (10/12 studies, 83%). More than half of the papers showed a correlation between saliva and serum results (10/18, 55%) for autoantibody detection, with varying rates of correlation, sensitivity, and specificity. Interestingly, many papers showed a correlation between saliva antibody results and clinical manifestations. (4) Conclusions: Saliva testing might represent an appealing alternative to serum-based testing for autoantibody detection, considering the correspondence with serum testing results and the correlation with clinical manifestations. Nonetheless, standardization of sample collection processing, maintenance, and detection methodology has yet to be fully addressed.

AimTo apply thrombin generation assay (TGA) in a large cohort of antiphospholipid antibodies (aPL)-positive patients.Material and methods108 patients were tested with TGA and lupus anticoagulant (LA) testing and divided according to their aPL profile. Briefly, 21 patients were positive for anti-phosphatidylserine (aPS)/prothrombin (PT) IgG/IgM (group1), 29 for anti-ß2-glycoprotein-I (aβ2GPI) and anti-cardiolipin (aCL) IgG/IgM (group2), 31 for aPS/PT, aβ2GPI and aCL IgG/IgM (group3), 27 for aPS/PT and/or aβ2GPI+aCL IgM at low-titres (group4). 31 healthy donors (HDs) and 24 controls treated with vitamin K antagonists (VKA) were included.ResultsThe most deranged TGA and LA profiles were observed in tetra-positive patients (group3) that differed significantly to the other groups, thus those with isolated, double or triple aPL-positivity. Moreover, when comparing the TGA profile of all antiphospholipid syndrome (APS) patients, aPL-carriers, HDs and VKA controls, we observed that the aPL+ patients (especially APS) showed a distinctive profile that allowed to distinguish them from the other groups with significantly higher tLag and tPeak, and lower Peak and area under the curve.When focusing on APS clinical manifestations, patients with a high-risk profile (group3) showed significant differences from those presenting low-titres aPL (group 4) regarding the number of venous events (p=0.04), recurrence of any thrombotic event (p=0.01), of arterial events (5 vs 0, p=0.02), the occurrence of TIA (p=0.04), DVT (p=0.02) and, when analysing extracriteria manifestations, of peripheral artery disease (p=0.04).ConclusionsTGA seems a valuable approach to stratify aPL+ patients according to their risk profile. The differences among different populations of autoantibodies specificities could be considered a translational validation of the increased thrombotic risk of patients with triple or tetra aPL-positivity.

3beta-hydroxysteroid dehydrogenase type II deficiency (HSD3B2 deficiency), a rare form of congenital adrenal hyperplasia (CAH), is characterized by varying degrees of salt loss and incomplete masculinization in males and mild virilization or normal external genitalia in females. We report the case of a patient (46XY) showing salt loss and incomplete masculinization, markedly elevated levels of 17OHP (17 hydroxyprogesterone), ACTH (Adreno Cortico Tropic Hormone), testosterone and delta4androstenedione (delta4A), low levels of cortisol and absence of bone skeletal alterations that frequently characterize POR (Cytochrome P450 oxidoreductase) deficiency. Mutation analysis by Sanger sequencing of the HSD3B2 gene showed that the patient presented with a compound heterozygote for two novel variants c.370A>G p.Ser124Gly and c.308-6 G>A. The two HSD3B2 gene variants were also present in the patient’s older brother showing only incomplete masculinization. The in silico analysis revealed a probable damaging effect of c.370A>G p.Ser124Gly: residue p.Ser124 is highly conserved among species and seems to be located in the catalytic site of the enzyme, playing a pivotal role in NAD(H) binding to its substrate. Intronic c.308-6G>A variant is predicted to be likely pathogenic; the substitution seems to cause a change in the splice acceptor site located 6bp downstream of the variant. The two siblings seem to be affected by 3β-HSD2 deficiency; nevertheless, the two novel variants are likely to cause variable expressivity of the disease.

ObjectivesWhen treating Behçet’s disease (BD), anti-tumor necrosis factor (TNF)-α agents have become a second-line therapy when conventional immunosuppressive drugs have failed. However, in the case of failure of treatment with anti-TNFα drugs, further options are limited. Based on previous reports of the efficacy of vedolizumab (VDZ) in inflammatory bowel diseases, we decided to administer VDZ to treat a patient with intestinal BD.MethodsWe present the case of a 49-year-old female patient with BD. Her clinical manifestations included erythema nodosum, oro-genital ulcers, positive Pathergy test, positive HLA-B51, and biopsy-proven intestinal BD. The patient was unsuccessfully treated with conventional immunosuppressive and several biological agents.ResultsTreatment with VDZ was started intravenously at a dose of 300 mg at 0, 2, and 6 weeks and then every 4 weeks.After the second dose of VDZ, the patient reported a marked improvement of intestinal BD and a concomitant amelioration of arthralgia, erythema nodosum lesions and aphthosis. Clinical remission was achieved at 6 months after starting VDZ.ConclusionVDZ might represent a valid option to treat patients with BD who are non-responsive to standard treatments or anti-TNFα agents, particularly, those cases with intestinal involvement.

Background: The gold standard for diagnosis of lupus nephritis (LN) is still represented by renal biopsy, and serological prognostic biomarkers are still lacking. Dickkopf homolog-3 (DKK3) has been suggested as a marker of tissue fibrosis in different conditions; however, its role in autoimmune diseases needs to be elucidated. Here, we investigated the prognostic role of DKK3 in systemic lupus erythematosus (SLE) patients with and without LN, assessing its changes in relation to kidney function, flares, and interstitial fibrosis. Methods: Overall, 132 SLE patients (57 with LN) were included and prospectively followed up for at least 36 months. DKK3 was measured in serum at baseline. Biopsies were evaluated for glomerular involvement, interstitial fibrosis, and tubular atrophy. Results: Patients with biopsy-proven LN had significantly higher levels of DKK3 than those without (median [min–max]: 215 ng/mL [81–341] vs. 21.1 ng/mL [1–69], p < 0.01). DKK3 levels were associated with prevalent chronic kidney diseases (OR: 4.31 [C.I. 2.01–6.61] per DKK3 doubling, p < 0.01), higher chronicity index at biopsy (1.75 [1.51–2.77] per DKK3 doubling, p < 0.01), and flares rate (OR: 1.45 [C.I. 1.1–5.71] per DKK3 doubling, p < 0.044). Conclusions: While kidney biopsy still represents the gold standard for diagnostic and prognostic assessment in LN, DKK3 could represent an additional prognostic tool to monitor SLE patients and guide therapeutic choices.

To support the management of rheumatoid arthritis (RA) patients treated with tofacitinib, we designed the TuTOR (tailoring tofacitinib oral therapy in rheumatoid arthritis) mobile app. The impact of the app on medical adherence was evaluated using a crossover design alternating a paper-diary and the TuTOR App. Twenty patients with RA (mean age at inclusion, 59 ± 13 years) were included in the study. A statistically significant decrease in DAS28 was observed since the first month of therapy (mean DAS28 at baseline, 3.9 ± 1 vs. 1° month 3.1 ± 1, p = 0.0016). Similarly, the numerical rating scale (NRS) of perceived activity of disease and subjective fatigue progressively decreased. No differences were reported in DAS28 or NRS between the TuTOR app and the paper-diary groups. A significant decrease was observed in HAQ during the follow-up (baseline 1.38 ± 1.11 vs. six months 0.83 ± 0.9; p = 0.01). When filling out the self-reporting questionnaires, most of the patients (82%) preferred the TuTOR App helping them to remember to take the pills. Furthermore, 82% of patients used the app regularly (vs. 53% for the paper diary). Three patients suspended tofacitinib due to gastrointestinal intolerance. Both digital and paper devices can help maximize adherence to therapy; however, the TuTOR app was preferred by the patients for its simplicity and immediacy.