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Background. Belimumab (BEL) and Anifrolumab (ANI) are currently the only biologic drugs authorized for the treatment of Systemic Lupus Erythematosus (SLE). The aim of the study is to analyze the factors associated with the therapeutic choice between BEL and ANI in a monocentric cohort of patients affected by SLE.   Materials and Methods. We conducted a prospective observational study on consecutively enrolled patients affected by SLE and treated with BEL or ANI starting from June 2022, the date when the compassionate use of ANI began. Clinical, clinimetric, serological, and therapeutic data (prednisone, previous and concomitant therapy) were collected. Univariate analysis was performed using the chi-square or Fisher’s test for categorical variables and the Mann-Whitney or Student’s t test for continuous variables; for multivariate analysis, logistic regression models were created selecting variables with p<0.05.   Results. The study included 22 patients treated with ANI (21 women, 95.5%) and 39 with BEL (35 women, 89.7%). The demographic, clinical, and therapeutic characteristics of the two groups at baseline are reported in the table, together with the results of the univariate analysis. In multivariate analysis, the use of ANI was preferentially associated with a chronic-active disease course (OR 17.8; 95% CI 3.5-91.7; p<0.001) and with active cutaneous manifestations (OR 9.9; 95% CI 1.5-66.5; p<0.017). In particular, the sub-analysis of cutaneous involvement showed an association between the preferential use of ANI compared with BEL in patients with subacute lupus (OR 12.7; 95% CI 2.0-79.4; p<0.006) and alopecia with lupus hair (OR 6.2; 95% CI 1.7-22.0; p<0.005). The use of BEL was significantly associated with a relapsing-remitting disease course (OR 10.7; 95% CI 2.3-50.1; p=0.002) and with the presence of active arthritis (OR 5.3; 95% CI 1.2-23.0; p<0.002). In particular, the sub-analysis of articular involvement showed a preferential association between the use of BEL and the subtype of non-deforming and non-erosive arthritis (OR 6.5; 95% CI 1.8-23.8; p<0.004). Although univariate analysis showed more active serology, with anti-DNA positivity (p=0.015) and complement consumption (p=0.061), in patients treated with BEL, these differences were not significant in multivariate analysis. No significant differences emerged between the two groups in terms of corticosteroid dose and concomitant use of hydroxychloroquine (HCQ). However, a greater number of patients treated with ANI were taking methotrexate, in relation to the predominant cutaneous involvement.   Conclusions. The choice of biologic drug in patients with active SLE currently appears to be mainly guided by the clinical phenotype, in line with evidence from registration trials. Real-life studies and the development of predictive biomarkers of response to specific biologic drugs will allow for better personalization of therapy within the framework of precision medicine.

Background. We have seen clear evidence that belimumab is both effective and safe in treating systemic lupus erythematosus (SLE), showing good results across different disease domains. However, when it comes to hematologic manifestations, especially thrombocytopenia, the evidence remains limited.   Aim. To assess the efficacy of belimumab in hematologic manifestations, in particular thrombocytopenia, in a nationwide cohort of patients with SLE.   Methods. This study was based on a multicenter national cohort, involving 14 leading SLE referral centers across Italy. In particular, we enrolled 443 patients (n= 443) who met one of the following classification criteria for SLE: the ACR 1997 revised criteria, the SLICC 2012 criteria, or the EULAR/ACR 2019 criteria. In addition, all participants needed to be on either intravenous (10 mg/kg monthly) or subcutaneous treatment (200 mg weekly) with belimumab and have active disease at the time of enrollment. A positive serology was required, along with either joint or skin involvement. Among them we identified 44 patients with thrombocytopenia, defined as a platelet count <150,000/mm³ (Table 1). The efficacy of belimumab was assessed by evaluating the improvement in mean platelet count and the proportion of patients achieving platelet count normalization. The average daily dose of corticosteroids was also calculated at baseline and every 6 months. Univariate analyses were performed using paired t-tests and ANOVA for repeated measures, with SPSS version 29.   Results. Among patients with thrombocytopenia at baseline, platelet values increased significantly from a mean ± SD baseline value of 110.2±38.1×109/l to 176.6 ± 88.7 ×109/L at 48 months (p=0.004) (Graph 1) and the rate of thrombocytopenic patients decreased to 45% at 48 months. Glucocorticoids users decreased numerically, but not significantly, from a baseline value of 93.2% to 80% at 48 months (Graph 2); specularly, the percentage of low-dose PDN users, defined as a daily dose of prednisone <5 mg, increased from baseline (36.4%) to month 48 (90%); statistical significance was found also at month 6 (68.3%, p=0.001) and month 12 (81.6%, p=0.033). Mean GC dose (expressed as PDN equivalents) declined significantly from a mean ± SD baseline value of 10.8 ± 9.6 mg/d to 4.4 ± 5.5 mg/d at 48 months. During follow up, platelet values did not differ significantly between patients on IS in addition to belimumab compared to those on belimumab alone (p=0.66). Moreover, IS use did not significantly influence platelet value changes during follow up (respectively, p=0.65 and p=0.53) (Graphs 3 and Graph 4).   Conclusion. Add-on therapy with belimumab led to clinical improvement in a significant proportion of patients with thrombocytopenia in a real-life setting. Therapy with belimumab was associated with a glucocorticoid-sparing effect. This effect does not appear to depend on the co-administration of a conventional immunosuppressant.

Background. To evaluate the feasibility and safety of belimumab (BEL) dose spacing and withdrawal in patients with systemic lupus erythematosus (SLE) who were in long-standing remission on BEL.   Methods. Patients above 18 years of age with a diagnosis of SLE and persistent disease remission while on BEL were enrolled. Persistent remission was defined as >6 months on stable immunosuppressive therapy without experiencing a clinical flare of SLE (i.e. clinical SLE disease activity index [C-SLEDAI] less or equal to 2). All the patients started BEL spacing at enrolment. Patients were assessed by an experienced rheumatologist with physical examinations and laboratory tests every 12 weeks for 24 months for disease activity and damage accrual according to Systemic Lupus International Collaborative Clinics/American College of Rheumatology (SLICC/ACR) Damage Index. If the patient was in clinical remission (C-SLEDAI less or equal to 2 and absent [British Isles Lupus Assessment Group] BILAG A or B items), BEL was tapered as follows: - Step 1: BEL 200 mg subcutaneous (SC) every 10 days OR 10 mg/Kg intravenous (IV) every 6 weeks - Step 2: BEL 200 mg SC every 14 days OR 10 mg/Kg IV every 8 weeks - Step 3: BEL 200 mg SC every 21 days OR 10 mg/Kg IV every 12 weeks - Step 4: stop BEL Primary outcome: number of disease flares during follow-up. Secondary outcomes: progression of SLICC/ACR damage index, death.   Results. Twenty-two patients were enrolled (Table 1), 21 were females (95.5%), with a mean age of 48±10 years. Mean disease duration was 21±11 years. Seven patients (31.8%) had a history of lupus nephritis. At the start of BEL spacing, 6 patients were on glucocorticoid (GC) therapy at a mean dose of 4.4±1.7 mg/day Prednisone equivalents), and 15 were taking Hydroxychloroquine (HCQ). Patients were treated with BEL for an average of 6±3 years before enrolment. Patients were observed for a median of 21 (Q1–Q3: 16–24) months. Five patients were stopped BEL during follow-up. One patient on BEL SC every 14 days experienced a disease relapse (C-SLEDAI 4) and was started HCQ at 15 months. One patient who stopped BEL had a C-SLEDAI of 1 and low complement at baseline and during the follow-up. She developed anti-dsDNA positivity and was initiated Azathioprine at month 21. None of the patients had to return to the previous BEL step nor required an increase in GC dose. No major disease relapses, deaths nor increases in SLICC/ACR organ damage index were reported during the follow-up.   Conclusion. Progressive BEL dose spacing and withdrawal, paired with close monitoring for disease activity, can be a feasible and safe approach for SLE patients in long-standing remission on BEL.

Background. The aim of this study was to evaluate preliminary laboratory results of the BLAST trial. Belimumab was given for 40 weeks in 15 patients positive for antiphospholipid antibodies (aPL) showing refractory and/or non criteria APS manifestations.   Materials and Methods This is an open-label, single-centre trial. Laboratory endpoints were determined at baseline, 8, 20 and 40 weeks. Outcomes included routine tests, aPL, thrombin generation assay, lymphocytes immunophenotyping and BAFF determination.   Results. We observed a reduction of aPL levels following 40 weeks of treatment: 60% showed a reduction of aCL IgG levels, 53% showed a reduction of aB2GPI IgG levels , 47% showed a reduction of aB2GPI Domain I levels, 33% showed a reduction of aPS/PT IgG levels and 40% showed a reduction of aPS/PT IgM levels (Figure 1). When considering TGA profile, a normalization of the curves were observed following treatment: 40% of patients showed a normalization of TGA parameters at week 40, meaning a reduction of tLag and tPeak and an increase of Peak and AUC. Table 1 summarizes the delta of aPL levels and TGA parameters between week 40 and baseline. When analyzing aPL levels and TGA parameters, significant correlations were demonstrated showing a normalization of the thrombogram and reduction of aPL levels following treatment. This finding was confirmed for the following specificities: aPS/PT IgG [tLag (p=0.001/Pearson+0.4), tPeak (p=0.001/Pearson+0.4), Peak (p=0.001/Pearson-0.4) and AUC (p=0.002/Pearson-0.4)]; aCL IgG [tLag (p<0.001/Pearson+0.6), tPeak (p<0.001/Pearson+0.6), Peak (p<0.001/Pearson-0.5) and AUC (p=0.002/Pearson-0.4)]; aB2GPI IgG [tLag (p<0.001/Pearson+0.6), tPeak (p<0.001/Pearson+0.6), Peak (p=0.001/Pearson-0.4) and AUC (p=0.002/Pearson-0.4)]; aB2GPI Domain I [tLag (p<0.001/Pearson+0.5), tPeak (p<0.001/Pearson+0.5), Peak (p=0.001/Pearson-0.4) and AUC (p=0.002/Pearson-0.3)]. When considering the whole cohort, a statistically significant reduction of BAFF serum levels was observed after 8 weeks of treatment. CD20+ and CD19+ cells significantly decreased after 20 weeks. In the subgroup of patients showing a complete response after 40 weeks of treatment, a significant reduction of BAFF was observed at week 8, starting from higher levels of BAFF at baseline. In this case, CD20+ and CD19+ cells showed a statistically significant reduction after 40 weeks of treatment.   Conclusions. The use of Belimumab was associated with a change in the immunological/prothrombotic profile when evaluated by changes in the aPL levels at week 40 and the normalization of the thrombogram as shown in the TGA testing. These are preliminary laboratory results of the BLAST trial, to be confirmed after all 20 enrolled patients finish 2 years treatment.  

Active neutrophils participate in innate and adaptive immune responses through various mechanisms, one of the most important of which is the formation and release of neutrophil extracellular traps (NETs). The NETs are composed of network-like structures made of histone proteins, DNA and other released antibacterial proteins by activated neutrophils, and evidence suggests that in addition to the innate defense against infections, NETosis plays an important role in the pathogenesis of several other non-infectious pathological states, such as autoimmune diseases and even cancer. Therefore, targeting NET has become one of the important therapeutic approaches and has been considered by researchers. NET inhibitors or other molecules involved in the NET formation, such as the protein arginine deiminase 4 (PAD4) enzyme, an arginine-to-citrulline converter, participate in chromatin condensation and NET formation, is the basis of this therapeutic approach. The important point is whether complete inhibition of NETosis can be helpful because by inhibiting this mechanism, the activity of neutrophils is suppressed. In this review, the biology of NETosis and its role in the pathogenesis of some important diseases have been summarized, and the consequences of treatment based on inhibition of NET formation have been discussed.

To evaluate belimumabf's efficacy in refractory lupus nephritis (LN) patients and identify predictive serum biomarkers for treatment response. In this single-arm retrospective study, we assessed clinical responses in LN patients at baseline and six months after initiating belimumab. Serum cytokines (IL-2, IL-4, IL-6, IL-10, TNF-α, IFN-γ) were quantified using multiplex magnetic bead flow immunoassay before and after treatment. Fourteen patients with various subtypes of refractory LN participated in the study: seven with class III and V LN, three with type V alone, two with class III, and two with class IV+V and V LN. Post six months of belimumab therapy, all participants exhibited a reduction in the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI)-2K scores from their respective baseline values. Notably, most patients showed a decrease in the dosage of prednisone, levels of 24-hour urinary protein, immunoglobulins, erythrocyte sedimentation rate (ESR), and anti-double-stranded DNA antibody IgM, along with serum levels of IL-4, IL-6, IL-10, and IFN-γ. Meanwhile, levels of C3, C4, IL-2, and TNF-α were observed to increase. Of the participants, nine (64.29%) achieved a complete renal response, one (7.14%) showed a partial response, and four (28.57%) exhibited no response. Significantly, higher baseline serum IFN-γ levels were found in patients who did not achieve complete renal response (CR) compared to those who did (p = 0.009). Receiver operating characteristic (ROC) curve analysis demonstrated that baseline IFN-γ levels had an area under curve (AUC) of 0.96 (0.70-1.00), with a sensitivity of 0.89 and a specificity of 1.00 (p < 0.001). Belimumab shows potential efficacy in treating refractory LN. Baseline serum IFN-γ levels may predict response to belimumab therapy, potentially enabling more targeted treatment approaches for this challenging condition.