Introduction Systemic Lupus Erythematosus (SLE) is a rare chronic multisystemic inflammatory disease in the pediatric population: despite its prevalence, the burden of physical and psychological disability that can derive from its natural history can be relevant. Potentially every organ can be damaged by SLE and kidney involvement, known as Lupus Nephritis (LN), has a major role in quoad vitam prognosis. Pediatric form of SLE and LN is basically the same as in adults, however, the care of children and adolescents has key features related to growth and long-life expectancy of this population. Historically the lack of pediatric patients hampered the collection of data in this subset, forcing clinicians to use adult-derived evidence-based practice in children. Aim of the study Our study aims to collect and analyze clinical, histological, therapeutic and follow-up data derived from a 20-year experience in managing pediatric patients affected by SLE and LN, collected from a multicenter network of Italian Lupus Clinics, and to compare our results with those from the EUROlupus study. Patients and methods We conducted as a retrospective observational multicenter cohort study involving four Italian pediatric Lupus clinics. A total of 28 Italian patients affected by pediatric onset LN (pLN) were enrolled. All patients met the following inclusion criteria: a diagnosis of SLE according to ACR/SLICC criteria formulated during the last 20 years, age < 18 years at the time of SLE diagnosis, biopsy-proven LN, treatment according to EUROlupus protocol. The study was approved by the ethics committees of all participating hospitals. Patients were evaluated every 6 to 12 months as outpatients or during short hospitalization, with a shared protocol between pediatric Rheumatologists and Nephrologists. Data were reported and analyzed using descriptive and analytical statistics, using Fisher’s exact test, Friedman’s test, Shapiro-Wilk test and Log-rank test. Results The primary endpoint of our study was the evaluation of overall treatment failure, that affected 6/27 patients (22.2%). Secondly, we investigated how different variables (such as socio-demographic and clinical features), impacted on the primary endpoint: interestingly, we noticed that the absence of extrarenal manifestations at diagnosis of pLN is related to a higher probability of treatment failure. Afterward, we focused on the secondary endpoint, that is renal remission, defined according to urine protein (UPr) or hypertension (HTN) criteria. Respectively 19/25 (76%) and 23/25 (92%) patients were in renal remission at 1 year of FU, according to the previous criteria, as 21/26 (80.8%) and 22/26 (84.6%) were at the last FU visit available. Moreover, we investigated the possible relationship between the different variables and renal remission: the absence of extrarenal manifestation was linked to a less probable renal remission at 1 year (UPr criterion), as Gaslini patients were linked to a more probable renal remission at the last FU visit (UPr criterion). Furthermore, patients with elevated blood pressure at the end of FU period are linked to the absence of renal remission (UPr criterion) at the same visit. The efficacy or EUROlupus protocol was evaluated drawing response kinetics for plasma creatinine, 24H urine protein, plasma albumin, C3 and C4 levels and ECLAM score at each FU visit. For every variable analyzed over time we demonstrated statistically significant improvement from T0 baseline. Considering renal flare as the event, we draw a Kaplan-Meier analysis of the event-free survival estimates dividing patients according to sex, age, histological class and extrarenal manifestations at LN onset: no data reached statistical significance in the analysis. Finally, we recorded 6 severe renal flares in 5 patients and 3 severe infections in 3 patients during FU period. Moreover, we documented 1 case of cancer (cervical intraepithelial tumor treated with local surgical therapy and optimal outcome) and 1 case of kidney transplant, after the FU period. Conclusion The efficacy of EUROlupus protocol is high regarding the primary outcome, both when we consider patients with renal impairment and patients with nephrotic syndrome at the time of protocol administration. This data has been confirmed considering the rate or renal remission at 1 year and 5 years/last FU visit and is related to the great efficacy over time of EUROlupus protocol combined with immunosuppressive therapies. Later, we had slightly less renal flares than in the original study (17.9% vs 27%): this could be related to a global shorter observational period. Moreover, our study demonstrated optimal safety of EUROlupus protocol: indeed no patients had major problems during FU period. In conclusion, this study reproduced the good results in terms of efficacy and safety obtained in the original article (adult patients) among Italian pediatric patients affected by proliferative LN. Our study has two main strong points: it is indeed a database filled with Italian pediatric-onset SLE and notably, pediatric-onset LN; for this reason, its implementation is of particular interest for efficacy and safety studies regarding this disease in such a special subset of patients. Moreover, this database includes patients derived both from the first and second decade of the 21st century: during these years several changes occurred mainly in immunosuppressive therapies started after EUROlupus administration, hence the collected data are of great interest for further studies. The weak points are the small number of patients included until now and the high rate of drop off before 60 months of FU. This is mainly related to the pandemic situation at the time of Centers enrolling and the low rate of LN incidence among pediatric patients. Finally, patients reaching 16 to 18 years old (depending on Centers protocol) usually have moved from pediatric to adult care. For all these reasons, it is desirable in the future to increase the number of centers participating in this project.

Il protocollo EUROlupus nel trattamento della nefrite lupica in età pediatrica: 20 anni di esperienza nei centri italiani di reumatologia e nefrologia

D'ALESSANDRO, MATTEO
2022-07-07

Abstract

Introduction Systemic Lupus Erythematosus (SLE) is a rare chronic multisystemic inflammatory disease in the pediatric population: despite its prevalence, the burden of physical and psychological disability that can derive from its natural history can be relevant. Potentially every organ can be damaged by SLE and kidney involvement, known as Lupus Nephritis (LN), has a major role in quoad vitam prognosis. Pediatric form of SLE and LN is basically the same as in adults, however, the care of children and adolescents has key features related to growth and long-life expectancy of this population. Historically the lack of pediatric patients hampered the collection of data in this subset, forcing clinicians to use adult-derived evidence-based practice in children. Aim of the study Our study aims to collect and analyze clinical, histological, therapeutic and follow-up data derived from a 20-year experience in managing pediatric patients affected by SLE and LN, collected from a multicenter network of Italian Lupus Clinics, and to compare our results with those from the EUROlupus study. Patients and methods We conducted as a retrospective observational multicenter cohort study involving four Italian pediatric Lupus clinics. A total of 28 Italian patients affected by pediatric onset LN (pLN) were enrolled. All patients met the following inclusion criteria: a diagnosis of SLE according to ACR/SLICC criteria formulated during the last 20 years, age < 18 years at the time of SLE diagnosis, biopsy-proven LN, treatment according to EUROlupus protocol. The study was approved by the ethics committees of all participating hospitals. Patients were evaluated every 6 to 12 months as outpatients or during short hospitalization, with a shared protocol between pediatric Rheumatologists and Nephrologists. Data were reported and analyzed using descriptive and analytical statistics, using Fisher’s exact test, Friedman’s test, Shapiro-Wilk test and Log-rank test. Results The primary endpoint of our study was the evaluation of overall treatment failure, that affected 6/27 patients (22.2%). Secondly, we investigated how different variables (such as socio-demographic and clinical features), impacted on the primary endpoint: interestingly, we noticed that the absence of extrarenal manifestations at diagnosis of pLN is related to a higher probability of treatment failure. Afterward, we focused on the secondary endpoint, that is renal remission, defined according to urine protein (UPr) or hypertension (HTN) criteria. Respectively 19/25 (76%) and 23/25 (92%) patients were in renal remission at 1 year of FU, according to the previous criteria, as 21/26 (80.8%) and 22/26 (84.6%) were at the last FU visit available. Moreover, we investigated the possible relationship between the different variables and renal remission: the absence of extrarenal manifestation was linked to a less probable renal remission at 1 year (UPr criterion), as Gaslini patients were linked to a more probable renal remission at the last FU visit (UPr criterion). Furthermore, patients with elevated blood pressure at the end of FU period are linked to the absence of renal remission (UPr criterion) at the same visit. The efficacy or EUROlupus protocol was evaluated drawing response kinetics for plasma creatinine, 24H urine protein, plasma albumin, C3 and C4 levels and ECLAM score at each FU visit. For every variable analyzed over time we demonstrated statistically significant improvement from T0 baseline. Considering renal flare as the event, we draw a Kaplan-Meier analysis of the event-free survival estimates dividing patients according to sex, age, histological class and extrarenal manifestations at LN onset: no data reached statistical significance in the analysis. Finally, we recorded 6 severe renal flares in 5 patients and 3 severe infections in 3 patients during FU period. Moreover, we documented 1 case of cancer (cervical intraepithelial tumor treated with local surgical therapy and optimal outcome) and 1 case of kidney transplant, after the FU period. Conclusion The efficacy of EUROlupus protocol is high regarding the primary outcome, both when we consider patients with renal impairment and patients with nephrotic syndrome at the time of protocol administration. This data has been confirmed considering the rate or renal remission at 1 year and 5 years/last FU visit and is related to the great efficacy over time of EUROlupus protocol combined with immunosuppressive therapies. Later, we had slightly less renal flares than in the original study (17.9% vs 27%): this could be related to a global shorter observational period. Moreover, our study demonstrated optimal safety of EUROlupus protocol: indeed no patients had major problems during FU period. In conclusion, this study reproduced the good results in terms of efficacy and safety obtained in the original article (adult patients) among Italian pediatric patients affected by proliferative LN. Our study has two main strong points: it is indeed a database filled with Italian pediatric-onset SLE and notably, pediatric-onset LN; for this reason, its implementation is of particular interest for efficacy and safety studies regarding this disease in such a special subset of patients. Moreover, this database includes patients derived both from the first and second decade of the 21st century: during these years several changes occurred mainly in immunosuppressive therapies started after EUROlupus administration, hence the collected data are of great interest for further studies. The weak points are the small number of patients included until now and the high rate of drop off before 60 months of FU. This is mainly related to the pandemic situation at the time of Centers enrolling and the low rate of LN incidence among pediatric patients. Finally, patients reaching 16 to 18 years old (depending on Centers protocol) usually have moved from pediatric to adult care. For all these reasons, it is desirable in the future to increase the number of centers participating in this project.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11567/1090631
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