Publications by authors named "Margherita Zen"

59 Publications

Immunosuppressive therapy withdrawal after remission achievement in patients with lupus nephritis.

Rheumatology (Oxford) 2021 Apr 28. Epub 2021 Apr 28.

Rheumatology Unit, Department of Medicine, University of Padova, Padua, Italy.

Aim: Whether immunosuppressive therapy (IS) may be safely withdrawn in lupus nephritis (LN) is still unclear. We assessed rate and predictors of flare after IS withdrawal in patients with LN in remission.

Methods: Patients with biopsy-proven LN treated with IS between 1980 and 2020 were considered. Remission was defined as normal serum creatinine, proteinuria <0.5 g/24h, inactive urine sediment, and no extra-renal SLE activity on stable immunosuppressive and/or antimalarial therapy and/or prednisone ≤5mg/day. IS discontinuation was defined as the complete withdrawal of immunosuppressants, flares according to SLEDAI Flare Index. Predictors of flare were analyzed by multivariate logistic regression analysis.

Results: Among 513 SLE patients included in our database, 270 had LN. Of them, 238 underwent renal biopsy and were treated with ISs. Eighty-three patients (34.8%) discontinued IS, 46 ± 30 months after remission achievement. During a mean±SD follow-up of 116.5 ± 78 months, 19 patients (22.8%) developed a flare (8/19 renal) and were re-treated; 14/19 (73.7%) re-achieved remission after restarting therapy. Patients treated with IS therapy for at least three years after remission achievement had the lowest risk of relapse (OR 0.284, 95% CI 0.093-0.867, p= 0.023). At multivariate analysis, antimalarial maintenance therapy (OR 0.194, 95%CI 0.038-0.978, p= 0.047), age at IS discontinuation (OR 0.93, 95%CI 0.868-0.997, p= 0.040), remission duration >3 years before IS discontinuation (OR 0.231, 95%CI 0.058-0.920, p= 0.038) were protective against disease flares.

Conclusions: Withdrawal of IS is feasible in LN patients in remission for at least 3 years and on antimalarial therapy. Patients who experience flares can re-achieve remission with an appropriate treatment.
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http://dx.doi.org/10.1093/rheumatology/keab373DOI Listing
April 2021

Baseline characteristics of systemic lupus erythematosus patients included in the Lupus Italian Registry of the Italian Society for Rheumatology.

Lupus 2021 Jul 22;30(8):1233-1243. Epub 2021 Apr 22.

Rheumatology Unit, University of Padova, Padova, Italy.

Objective: To report baseline data of SLE patients enrolled in the Lupus Italian Registry (LIRE).

Methods: Patients affected by SLE aged ≥ 16 years were consecutively recruited in a multicenter prospective study comparing two cohorts: patients starting biologic immunosuppressants (BC) and patients starting non-biologic immunosuppresants (NBC).

Results: 308 patients were enrolled, 179 in NBC and 129 in BC. Mean age at disease onset and at diagnosis was significantly higher in NBC (p = 0.023, p = 0.045, respectively). Disease duration was longer in BC (p = 0.022). Patients in BC presented arthritis more frequently (p = 0.024), those in NBC nephropathy (p = 0.03). Quality of life was worse in BC (p = 0.031). Anti-dsDNA, low C3, were significantly more frequent in BC (p < 0.001, p = 0.009, respectively). Mycophenolate, methotrexate and azathioprine were the drugs more frequently prescribed in NBC, Belimumab and Rituximab in BC.

Conclusion: The predominant organ involvement was different in the two cohorts: kidney involvement predominated in NBC, joint involvement in BC. Despite the younger age at disease onset, patients of the BC had a longer disease duration and more frequently had taken a cumulative prednisone dosage greater than 10 g. Even the pattern of clinical manifestations inducing to prescribe biological rather than conventional immunosuppressants was quite different.Keywords: Autoantibody(ies), autoimmune disease, belimumab, cohort studies, glucocorticoids, immunosuppressants, rituximab, systemic lupus erythematosus.
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http://dx.doi.org/10.1177/09612033211012470DOI Listing
July 2021

Belimumab: a step forward in the treatment of systemic lupus erythematosus.

Expert Opin Biol Ther 2021 May 12;21(5):563-573. Epub 2021 Mar 12.

Division of Rheumatology, University of Padova, Padova, Italy.

: Systemic Lupus Erythematosus (SLE) is a chronic B cell-mediated autoimmune disease which can potentially involve several organs and systems. The development of SLE is associated with a complexity of genetic, hormonal and environmental factors leading to immune deregulation and production of autoantibodies. Therefore, novel therapies have focused on B cells as key effectors of SLE pathogenesis. Belimumab is a fully humanized monoclonal antibody that antagonizes B-lymphocyte stimulator (BLyS); it is the first and the only biological drug approved for SLE in over 50 years.: In this review we discuss the pharmacological properties of belimumab, new recommendations for its use in clinical practice and its evidence of efficacy and safety based on clinical trial and real-life data.: Efficacy and safety of belimumab in clinical practice have been well established. To date, it is known that early introduction of belimumab in SLE can maximize the efficacy of the drug. A number of questions are still open, such as the timing of belimumab discontinuation and its possible association with other biological drugs, which need to be assessed in future studies.
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http://dx.doi.org/10.1080/14712598.2021.1895744DOI Listing
May 2021

Comment on: Prevalence, outcome and management of patients with SLE and secondary antiphospholipid antibody syndrome after aPL seroconversion: reply.

Rheumatology (Oxford) 2021 03;60(3):e115-e117

Division of Rheumatology, Department of Medicine DIMED, University of Padua, Padova, Italy.

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http://dx.doi.org/10.1093/rheumatology/keaa800DOI Listing
March 2021

Prevalence, outcome and management of patients with SLE and secondary antiphospholipid antibody syndrome after aPL seroconversion.

Rheumatology (Oxford) 2021 03;60(3):1313-1320

Division of Rheumatology, Department of Medicine DIMED, University of Padua, Padova, Italy.

Objective: The withdrawal of oral anticoagulation (OAC) in patients with SLE and secondary aPL syndrome (SAPS) who become seronegative has not been clearly investigated to date. Our aim was to evaluate the prevalence of aPL seroconversion and the prognosis of SLE patients with SAPS who withdrew OAC after aPL negativization.

Methods: We retrospectively analysed data of all SLE patients (ACR criteria) with SAPS (Sydney criteria) prospectively followed-up in our clinic. aPL seroconversion was defined as negativization of lupus anticoagulant, aCL, and anti-β2glycoprotein-1 antibodies on two or more consecutive measurements, at least 12 weeks apart. OAC discontinuation was defined as the definitive withdrawal of all anticoagulants.

Results: Fifty-five out of 513 (10.7%) SLE patients had vascular SAPS. Sixteen patients (29.1%) became aPL seronegative during follow-up. Immunosuppressive therapy predicted aPL negativization (odds ratio 5.211, 95%CI 1.341, 20.243), whereas APS diagnosis prior to that of SLE (odds ratio 0.078, 95%CI 0.008, 0.799) and triple-positive profile (odds ratio 0.264, 95%CI 0.115, 0.609) were negative predictors of aPL negativization. OAC was discontinued in 13/55 patients (23.6%), after a median follow-up of 45 months (range 1-276) from aPL seroconversion. SLE-related modifiable risk factors for thrombosis were observed in 10/13 patients (77%) at the time of the thrombotic event. No thrombotic recurrences were observed during a mean follow-up time of 44 (19) months from OAC discontinuation.

Conclusions: Our results suggest that OAC can be safely discontinued in SLE patients who became persistently seronegative for aPL, at least when aPL-related thrombotic events occurred in presence of other thrombotic risk factors.
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http://dx.doi.org/10.1093/rheumatology/keaa463DOI Listing
March 2021

Physician's global assessment is often useful in SLE, but not always: the case of clinical remission.

Ann Rheum Dis 2020 May 20. Epub 2020 May 20.

Department of Medicine DIMED, Division of Rheumatology, University of Padua, Padova, Italy

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http://dx.doi.org/10.1136/annrheumdis-2020-217611DOI Listing
May 2020

Remission in systemic lupus erythematosus: testing different definitions in a large multicentre cohort.

Ann Rheum Dis 2020 07 22;79(7):943-950. Epub 2020 Apr 22.

Department of Medicine, Division of Rheumatology, University of Padua, Padova, Italy

Objectives: Remission in systemic lupus erythematosus (SLE) is defined through a combination of 'clinical SLE Disease Activity Index (cSLEDAI)=0', 'physician's global assessment (PGA) <0.5' and 'prednisone (PDN) ≤5 mg/day'. We investigated the performance of these items, alone or in combination, in defining remission and in predicting SLICC/ACR Damage Index.

Methods: We tested seven potential definitions of remission in SLE patients followed-up for ≥5 years: PDN ≤5 mg/day; PGA <0.5; cSLEDAI=0; PGA <0.5 plus PDN ≤5 mg/day; cSLEDAI=0 plus PGA <0.5; cSLEDAI=0 plus PDN ≤5 mg/day; cSLEDAI=0 plus PDN ≤5 mg/day plus PGA <0.5. The effect of these definitions on damage was evaluated by Poisson regression analysis; the best performance was identified as the lowest Akaike and Bayesian information criterion (AIC and BIC). Positive and negative predictive values in identifying no damage increase were calculated.

Results: We included 646 patients (mean±SD disease duration 9.2±6.9 years). At multivariate analysis, ≥2 consecutive year remission according to all definitions protected against damage (OR, 95% CI: PGA <0.5 0.631, 0.444 to 0.896; cSLEDAI=0 0.531, 0.371 to 0.759; PGA <0.5 plus PDN ≤5 mg/day 0.554, 0.381 to 0.805; cSLEDAI=0 plus PGA <0.5 0.574, 0.400 to 0.826; cSLEDAI=0 plus PDN ≤5 mg/day 0.543, 0.376 to 0.785; cSLEDAI=0 plus PDN ≤5 mg/day plus PGA <0.5 0.532, 0.363 to 0.781, p<0.01 for all), except PDN ≤5 mg/day, which required four consecutive years (OR 0.534, 95% CI 0.325 to 0.877, p=0.013). Positive and negative predictive values were similar; however, cSLEDAI=0 showed the best performance (AIC 1082.90, BIC 1109.72, p<0.0001). Adding PGA <0.5 and/or PDN ≤5 mg/day to cSLEDAI=0 decreased remission duration (-1.8 and -1.5 year/patient, respectively) without increasing cSLEDAI=0 performance in predicting damage accrual.

Conclusions: cSLEDAI=0 is the most attainable definition of remission, while displaying the best performance in predicting damage progression in the short-to-mid-term follow-up.
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http://dx.doi.org/10.1136/annrheumdis-2020-217070DOI Listing
July 2020

Early Disease and Low Baseline Damage as Predictors of Response to Belimumab in Patients With Systemic Lupus Erythematosus in a Real-Life Setting.

Arthritis Rheumatol 2020 08 12;72(8):1314-1324. Epub 2020 Jun 12.

Università degli Studi di Genova, Genoa, Italy.

Objective: To investigate predictors of response, remission, low disease activity, damage, and drug discontinuation in patients with systemic lupus erythematosus (SLE) who were treated with belimumab.

Methods: In this retrospective study of a multicenter cohort of SLE patients who received intravenous belimumab, the proportion of patients who achieved remission, low disease activity, and treatment response according to the SLE Responder Index 4 (SRI-4) was determined, and the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI) was used to score disease damage yearly over the follow-up. Predictors of outcomes were analyzed by multivariate logistic regression with the results expressed as odds ratios (ORs) and 95% confidence intervals (95% CIs).

Results: The study included 466 patients with active SLE from 24 Italian centers, with a median follow-up period of 18 months (range 1-60 months). An SRI-4 response was achieved by 49.2%, 61.3%, 69.7%, 69.6%, and 66.7% of patients at 6, 12, 24, 36, and 48 months, respectively. Baseline predictors of response at 6 months included a score of ≥10 on the SLE Disease Activity Index 2000 (SLEDAI-2K) (OR 3.14 [95% CI 2.033-4.860]) and a disease duration of ≤2 years (OR 1.94 [95% CI 1.078-3.473). Baseline predictors of response at 12 months included a score of ≥10 on the SLEDAI-2K (OR 3.48 [95% CI 2.004-6.025]) and an SDI score of 0 (OR 1.74 [95% CI 1.036-2.923]). Baseline predictors of response at 24 months included a score of ≥10 on the SLEDAI-2K (OR 4.25 [95% CI 2.018-8.940]) and a disease duration of ≤2 years (OR 3.79 [95% CI 1.039-13.52]). Baseline predictors of response at 36 months included a score of ≥10 on the SLEDAI-2K (OR 14.59 [95% CI 3.54-59.79) and baseline status of current smoker (OR 0.19 [95% CI 0.039-0.69]). Patients who were in remission for ≥25% of the follow-up period (44.3%) or who had low disease activity for ≥50% of the follow-up period (66.1%) accrued significantly less damage (P = 0.046 and P = 0.007). A baseline SDI score of 0 was an independent predictor of achieving low disease activity in ≥50% of the follow-up period and remission in ≥25% of the follow-up period. Our findings suggest that the lower the baseline damage, the greater the probability of achieving remission over the course of ≥25% of the follow-up. Further, there was a negative association between the number of flares reported prior to belimumab initiation and the frequency of belimumab discontinuation due to inefficacy (P = 0.009).

Conclusion: In patients with active SLE and low damage at baseline, treatment with belimumab early in the disease may lead to favorable outcomes in a real-life setting.
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http://dx.doi.org/10.1002/art.41253DOI Listing
August 2020

Preclinical and early systemic lupus erythematosus.

Best Pract Res Clin Rheumatol 2019 08 12;33(4):101422. Epub 2019 Jul 12.

Division of Rheumatology, Department of Medicine, University of Padova, Italy. Electronic address:

The challenge of early diagnosis and treatment is a timely issue in the management of systemic lupus erythematosus (SLE), as autoimmunity starts earlier than its clinical manifestations. Hence, growing efforts for stratification of patients according to the individual risk of developing specific clinical manifestations and/or predicting a better response to a given treatment have led to the proposal of several biomarkers, which require validation for use in clinical practice. In this viewpoint, we aim at distinguishing and discussing the features and the approach to asymptomatic immunological abnormalities potentially heralding the development of SLE, defined as preclinical lupus, and clinical manifestations consistent with SLE not yet fulfilling classification criteria, defined as early lupus. In case of preclinical SLE, careful surveillance using available screening tools is paramount, while patients with early lupus deserve an appropriate and timely diagnosis and, consequently, a proper treatment including hydroxychloroquine as the anchor drug.
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http://dx.doi.org/10.1016/j.berh.2019.06.004DOI Listing
August 2019

Prevalence and predictors of flare after immunosuppressant discontinuation in patients with systemic lupus erythematosus in remission.

Rheumatology (Oxford) 2020 07;59(7):1591-1598

Rheumatology Unit, Department of Medicine, University of Padova, Padova, Italy.

Objectives: Patients with SLE are often exposed to prolonged immunosuppression since few data on flare recurrence in remitted patients who discontinued immunosuppressants are available. We aimed to assess the rate and predictors of flare after immunosuppressant withdrawal in SLE patients in remission.

Methods: SLE patients diagnosed between 1990 and 2018 (according to the ACR criteria), ever treated with immunosuppressants and currently in follow-up were considered. Immunosuppressant discontinuation was defined as complete withdrawal of any immunosuppressive drug. Reasons for discontinuation were remission, defined as clinical SLEDAI-2K = 0 on a stable immunosuppressive and/or antimalarial therapy and/or on prednisone ⩽5 mg/day, or poor adherence/intolerance. Flares were defined according to the SLEDAI Flare Index. Predictors of a subsequent flare were analysed by multivariate logistic regression.

Results: There were 319 eligible patients out of 456 (69.9%). Of the 319 patients, 139 (43.5%) discontinued immunosuppressants, 105 (75.5%) due to remission, 34 (24.5%) due to poor adherence/intolerance. The mean (s.d.) follow-up time after immunosuppressant withdrawal was 91 (71) months (range 6-372). Among the patients who discontinued immunosuppressants, 26/105 remitted (24.7%) and 23/34 unremitted patients (67.6%) experienced a flare (P < 0.001) after a median (range) follow-up of 57 (6-264) and 8 months (1-72), respectively (P = 0.009). In patients who discontinued immunosuppressants due to remission, maintenance therapy with antimalarials (OR 0.243, 95% CI 0.070, 0.842) and the duration of remission at immunosuppressant discontinuation (OR 0.870, 0.824-0.996) were independent protective factors against disease flare.

Conclusion: SLE flares are not uncommon after immunosuppressant discontinuation, even in remitted patients; however, antimalarial therapy and durable remission can significantly reduce the risk of flare.
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http://dx.doi.org/10.1093/rheumatology/kez422DOI Listing
July 2020

Response to: 'Performance of the systemic lupus erythematosus disease activity score (SLE-DAS) in a Latin American population' by Rodríguez-González .

Ann Rheum Dis 2020 12 7;79(12):e159. Epub 2019 Aug 7.

Rheumatology Department, Centro Hospitalar e Universitario de Coimbra, Coimbra, Portugal

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http://dx.doi.org/10.1136/annrheumdis-2019-216110DOI Listing
December 2020

Response to: 'SLE-DAS: ready for routine use' by Mathew .

Ann Rheum Dis 2020 09 14;79(9):e117. Epub 2019 Jun 14.

Rheumatology Department, Centro Hospitalar e Universitario de Coimbra, Coimbra, Portugal

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http://dx.doi.org/10.1136/annrheumdis-2019-215794DOI Listing
September 2020

Response to: 'Assessment of responsiveness of the musculoskeletal component of SLE-DAS in an independent cohort', by Hassan .

Ann Rheum Dis 2020 05 25;79(5):e52. Epub 2019 Apr 25.

Rheumatology Department, Centro Hospitalar e Universitario de Coimbra EPE, Coimbra, Portugal.

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http://dx.doi.org/10.1136/annrheumdis-2019-215430DOI Listing
May 2020

Undifferentiated connective tissue disease: state of the art on clinical practice guidelines.

RMD Open 2018 26;4(Suppl 1):e000786. Epub 2019 Feb 26.

Department of Rheumatology, Ghent University Hospital, Ghent, Belgium.

The term 'undifferentiated connective tissue disease' (UCTD) is generally used to describe clinical entities characterised by clinical and serological manifestations of systemic autoimmune diseases but not fulfilling the criteria for defined connective tissue diseases (CTDs). In this narrative review, we summarise the results of a systematic literature research, which was performed as part of the ERN ReCONNET project, aimed at evaluating existing clinical practice guidelines (CPGs) or recommendations. No specific CPG on UCTD were found, potential areas of intervention are absence of a consensus definition of UCTD, need for specific monitoring and therapeutic protocols, stratification of UCTD based on the risk of developing a defined CTD and preventive measure for the future development of a more severe condition. Patients feel uncertainty regarding the name of the disease and feel the need of a better education and understanding of these conditions and its possible changes over time.
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http://dx.doi.org/10.1136/rmdopen-2018-000786DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6397427PMC
February 2019

IL-12 and IL-23/Th17 axis in systemic lupus erythematosus.

Exp Biol Med (Maywood) 2019 01 21;244(1):42-51. Epub 2019 Jan 21.

1 Department of Medicine-DIMED, Division of Rheumatology, University of Padova, 35128 Padova, Italy.

Impact Statement: Our article is focused on emerging pathogenetic pathways in systemic lupus erythematosus (SLE). Notably, IL-12 and IL-23 have been described as emerging cytokines in SLE pathogenesis. We know that IL-23 stimulates Th17 cells to produce IL-17. We try to point out the importance of IL-23/Th17 axis in SLE and to focus on the interaction between this axis and IL-12. Ustekinumab, a fully human IgG1κ monoclonal antibody directed towards the p40 shared subunit of IL-12 and IL-23, has been recently investigated in SLE, suggesting a potential novel therapeutic strategy in SLE. To our knowledge, there are no reviews which simultaneously focus on IL-12 an IL-23/Th17 axis in SLE. Thus, we believe our work will be of interest to the readers.
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http://dx.doi.org/10.1177/1535370218824547DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6362534PMC
January 2019

Derivation and validation of the SLE Disease Activity Score (SLE-DAS): a new SLE continuous measure with high sensitivity for changes in disease activity.

Ann Rheum Dis 2019 03 9;78(3):365-371. Epub 2019 Jan 9.

Rheumatology Department, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal

Objectives: To derive and validate a new disease activity measure for systemic lupus erythematosus (SLE), the SLE Disease Activity Score (SLE-DAS), with improved sensitivity to change as compared with SLE Disease Activity Index (SLEDAI), while maintaining high specificity and easiness of use.

Methods: We studied 520 patients with SLE from two tertiary care centres (derivation and validation cohorts). At each visit, disease activity was scored using the Physician Global Assessment (PGA) and SLEDAI 2000 (SLEDAI-2K). To construct the SLE-DAS, we applied multivariate linear regression analysis in the derivation cohort, with PGA as dependent variable. The formula was validated in a different cohort through the study of: (1) correlations between SLE-DAS, PGA and SLEDAI-2K; (2) performance of SLEDAI-2K and SLE-DAS in identifying a clinically meaningful change in disease activity (ΔPGA≥0.3); and (3) accuracy of SLEDAI-2K and SLE-DAS time-adjusted means in predicting damage accrual.

Results: The final SLE-DAS instrument included 17 items. SLE-DAS was highly correlated with PGA (r=0.875, p<0.0005) and SLEDAI-2K (r=0.943, p<0.0005) in the validation cohort. The optimal discriminative ΔSLE-DAS cut-off to detect a clinically meaningful change was 1.72. In the validation cohort, SLE-DAS showed a higher sensitivity than SLEDAI-2K (change ≥4) to detect a clinically meaningful improvement (89.5% vs 47.4%, p=0.008) or worsening (95.5% vs 59.1%, p=0.008), while maintaining similar specificities. SLE-DAS performed better in predicting damage accrual than SLEDAI-2K.

Conclusion: SLE-DAS has a good construct validity and has better performance than SLEDAI-2K in identifying clinically significant changes in disease activity and in predicting damage accrual.
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http://dx.doi.org/10.1136/annrheumdis-2018-214502DOI Listing
March 2019

New therapeutic strategies in systemic lupus erythematosus management.

Nat Rev Rheumatol 2019 01;15(1):30-48

Unit of Rheumatology, Department of Medicine, University of Padova, Padova, Italy.

The current treatment approach for systemic lupus erythematosus (SLE), as outlined in the recommendations by international medical associations including EULAR and the ACR, is mostly eminence-based rather than evidence-based. However, knowledge on SLE is growing quickly, and such new advances need to be translated into clinical practice. Questions remain regarding the choice and timing of drug administration and tapering until withdrawal, which both can affect the balance between the control of disease activity and damage to organs triggered by long-standing and/or disproportionate immunosuppression. Currently, the treating physicians of patients with SLE are required to weigh the present with the future situation of their patients in an optimized balance between therapeutic harm and benefit. In this Review, the available therapeutic strategies and main challenges in the approach to SLE treatment are discussed. Remission and low disease activity are desirable therapeutic goals. Although the drug armamentarium for SLE has not expanded much in the past few decades, there are nonetheless opportunities to make better choices and explore combination therapies; such opportunities offer the potential of a personalized medicine strategy.
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http://dx.doi.org/10.1038/s41584-018-0133-2DOI Listing
January 2019

Correction to: Effectiveness, Tolerability, and Safety of Belimumab in Patients with Refractory SLE: a Review of Observational Clinical-Practice-Based Studies.

Clin Rev Allergy Immunol 2018 10;55(2):237

Division of Rheumatology, University of Padova, Via Giustiniani, 2, 35128, Padova, Italy.

The following changes are made for this article: (1.) Maddalena Larosa's given name and surname were inadvertently interchanged. The authorgroup section is now corrected. (2.) The author(s)' decision to opt for Open Choice.
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http://dx.doi.org/10.1007/s12016-018-8704-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6182622PMC
October 2018

Underage victims and perpetrators of murder in Italy: 2007-2015.

J Forensic Leg Med 2018 Oct 14;59:39-44. Epub 2018 Aug 14.

Legal Medicine and Toxicology, Department of Legal and Work Medicine, Toxicology and Public Health, University Hospital of Padova, Via G. Falloppio n.50, Padova, 35121, Italy.

From the epidemiological and criminological points of view, murders committed by minors, including both victims and perpetrators, differ from those observed in adults. Analysis of trends and characteristics of murders at national level could provide useful information to assess the phenomenon and address political and social choices aiming at preventing violence involving children and adolescents. This study focuses on the trends of murders in Italy during the period 2007-2015 and compares the data with those for other age groups. Data on murders regarding trends, gender, age and ethnic group from the Italian Institute of Statistics were analysed by chi-square with odds ratio and linear regression. Results show that, after standardization, murders involving minors as victims and perpetrators were less frequent with respect to data observed in all age groups. Trend analysis showed that murders involving minors remained stable in the period considered, but the stability of the rate of murders of minors was in contrast with reduced rates in other age groups. Among minors, males aged 14-17 are at higher risk of being the perpetrators and victims of homicide. The rate of perpetrators and victims among foreign-born minors was higher than that among the native-born. Further studies are needed to determine risk factors associated with these results and to propose preventive strategies through appropriate policies and interventions.
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http://dx.doi.org/10.1016/j.jflm.2018.08.002DOI Listing
October 2018

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

Ann Rheum Dis 2018 09 5;77(9):1318-1325. Epub 2018 May 5.

Division of Rheumatology, Department of Medicine, DIMED, University of Padua, Padua, Italy.

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.
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http://dx.doi.org/10.1136/annrheumdis-2017-212732DOI Listing
September 2018

Effectiveness, Tolerability, and Safety of Belimumab in Patients with Refractory SLE: a Review of Observational Clinical-Practice-Based Studies.

Clin Rev Allergy Immunol 2018 04;54(2):331-343

Division of Rheumatology, University of Padova, Via Giustiniani, 2, 35128, Padova, Italy.

To date, belimumab is the only biological drug approved for the treatment of patients with active refractory SLE. We compared and critically analyzed the results of 11 observational clinical-practice-based studies, conducted in SLE referral centers. Despite the differences in endpoints and follow-up duration, all studies remarked that belimumab provides additional benefits when used as an add-on to existing treatment, allowing a higher rate of patients to reach remission and to taper or discontinue corticosteroids. In the OBSErve studies, 2-9.6% of patients discontinued corticosteroids and 72-88.4% achieved a ≥ 20% improvement by physician's judgment at 6 months. In Hui-Yuen's study, 51% of patients attained response by simplified SRI at month 6. In Sthoeger's study, 72.3% of patients discontinued corticosteroids and 69.4% achieved clinical remission by PGA after a median follow-up of 2.3 years. In the multicentric Italian study, 77 and 68.7% of patients reached SRI-4 response at months 6 and 12, respectively. In all the studies, disease activity indices decreased over time. Retention rates at 6, 9, and 12 months were 82-94.1, 61.2-83.3, and 56.7-79.2%, respectively. The main limitations of these studies include the lack of a control group, the short period of observation (6-24 months) and the lack of precise restrictions regarding concomitant medication management. This notwithstanding, these experiences provide a more realistic picture of real-life effectiveness of the drug compared with the randomized controlled clinical trials, where stringent inclusion/exclusion criteria and changes in background therapy could limit the inference of data to the routine clinical care.
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http://dx.doi.org/10.1007/s12016-018-8675-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6132773PMC
April 2018

Response to: 'Remission or low disease activity as a target in systemic lupus erythematosus' by Ugarte-Gil .

Ann Rheum Dis 2019 01 17;78(1):e4. Epub 2018 Jan 17.

Rheumatology Unit, Department of Medicine, University of Padova, Padova, Italy.

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http://dx.doi.org/10.1136/annrheumdis-2017-212911DOI Listing
January 2019

Women victims of intentional homicide in Italy: New insights comparing Italian trends to German and U.S. trends, 2008-2014.

J Forensic Leg Med 2018 Jan 28;53:73-78. Epub 2017 Nov 28.

Division of Rheumatology, Department of Medicine, University of Padova, via Giustiniani n.2, Padova, 35128, Italy.

National statistics on female homicide could be a useful tool to evaluate the phenomenon and plan adequate strategies to prevent and reduce this crime. The aim of the study is to contribute to the analysis of intentional female homicides in Italy by comparing Italian trends to German and United States trends from 2008 to 2014. This is a population study based on data deriving primarily from national and European statistical institutes, from the U.S. Federal Bureau of Investigation's Uniform Crime Reporting and from the National Center for Health Statistics. Data were analyzed in relation to trends and age by Chi-square test, Student's t-test and linear regression. Results show that female homicides, unlike male homicides, remained stable in the three countries. Regression analysis showed a higher risk for female homicide in all age groups in the U.S. Middle-aged women result at higher risk, and the majority of murdered women are killed by people they know. These results confirm previous findings and suggest the need to focus also in Italy on preventive strategies to reduce those precipitating factors linked to violence and present in the course of a relationship or within the family.
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http://dx.doi.org/10.1016/j.jflm.2017.11.007DOI Listing
January 2018

Lupus low disease activity state is associated with a decrease in damage progression in Caucasian patients with SLE, but overlaps with remission.

Ann Rheum Dis 2018 Jan 26;77(1):104-110. Epub 2017 Sep 26.

Department of Medicine, University of Padova, Division of Rheumatology, Padova, Italy.

Objective: To evaluate the prevalence, duration and effect on damage accrual of the 'Lupus Low Disease Activity State' (LLDAS) in a monocentric cohort of patients with systemic lupus erythematosus (SLE).

Methods: We studied 293 Caucasian patients with SLE during a 7-year follow-up period. Disease activity was assessed by SLE Disease Activity Index 2000 (SLEDAI-2K) and SELENA-SLEDAI physician global assessment (PGA), and damage by Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI). We considered the following definition of LLDAS: SLEDAI-2K ≤4 without major organ activity, no new disease activity, PGA (0-3)≤1, prednisone ≤7.5 mg/day and well-tolerated immunosuppressant dosages. The effect of LLDAS on SDI was evaluated by multivariate regression analysis. We also evaluated remission defined as clinical SLEDAI-2K=0 and prednisone ≤5 mg/day in patients treated with/without stable immunosuppressants and/or antimalarials.

Results: LLDAS lasting 1, 2, 3, 4 or ≥5 consecutive years was achieved by 33 (11.3%), 43 (14.7%), 39 (13.3%), 31 (10.6%) and 109 (37.2%) patients, respectively. Patients who spent at least two consecutive years in LLDAS had significantly less damage accrual compared with patients never in LLDAS (p=0.001), and they were significantly less likely to have an increase in SDI (OR 0.160, 95% CI 0.060 to 0.426, p<0.001). On average, 84% of patients in LLDAS also fulfilled the criteria for remission.

Conclusions: LLDAS was associated with a decrease in damage progression in Caucasian patients with SLE. The majority of patients in LLDAS were in remission, which can largely contribute to the protective effect of LLDAS on damage accrual.
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http://dx.doi.org/10.1136/annrheumdis-2017-211613DOI Listing
January 2018

Clinical predictors of response and discontinuation of belimumab in patients with systemic lupus erythematosus in real life setting. Results of a large, multicentric, nationwide study.

J Autoimmun 2018 01 19;86:1-8. Epub 2017 Sep 19.

Division of Rheumatology, Department of Medicine-DIMED, University of Padova, Padova, Italy. Electronic address:

Objective: To investigate efficacy, safety and survival of belimumab and to identify predictors of drug response and drug discontinuation in patients with active SLE in clinical practice.

Patients And Methods: Data of SLE patients, treated with belimumab, from 11 Italian prospective cohorts were analyzed. SLEDAI-2K, anti-dsDNA, C3, C4, prednisone daily dose, DAS-28, 24-h proteinuria, CLASIa (Cutaneous LE Disease Area and Severity Index Activity) were recorded at baseline and every 6 months. SLE Responder Index-4 (SRI-4) was calculated at 12 and 24 months. Demographic and clinical features and comorbidities were included in the univariate and multivariate analysis. Adverse events were recorded at each visit. Statistics was performed using the SPSS software.

Results: We studied 188 SLE patients, mean follow-up 17.5 ± 10.6 months. The most frequent manifestations, which required the use of belimumab, were polyarthritis (45.2%) and skin rashes (25.5%). SRI-4 was achieved by 77.0% and 68.7% of patients at 12 and 24-months. Independent predictors of 12-month response were SLEDAI-2K ≥ 10 (OR 40.46, p = 0.001) and polyarthritis (OR 12.64, p = 0.001) and of 24-month response were SLEDAI-2K ≥ 10 (OR 15.97, p = 0.008), polyarthritis (OR 32.36, p = 0.006), and prednisone ≥7.5 mg/day (OR 9.94, p = 0.026). We observed a low rate of severe adverse events. Fifty-eight patients (30.8%) discontinued belimumab after a mean follow-up of 10.4 ± 7.5 months. The drug survival was 86.9%, 76.9%, 69.4%, 67.1%, and 61.9% at 6, 12, 18, 24, and 30 months, respectively. No factors associated with drug discontinuation were found.

Conclusion: Belimumab is effective and safe when used in clinical practice setting.
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http://dx.doi.org/10.1016/j.jaut.2017.09.004DOI Listing
January 2018

The Management of Systemic Lupus Erythematosus (SLE) Patients in Remission.

Isr Med Assoc J 2017 Jul;19(7):454-458

Division of Rheumatology, Department of Medicine, DIMED, University of Padua, Italy.

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July 2017

Crimes against the elderly in Italy, 2007-2014.

J Forensic Leg Med 2017 Aug 27;50:20-27. Epub 2017 Jun 27.

Legal Medicine and Toxicology, Department of Legal and Work Medicine, Toxicology and Public Health, University Hospital of Padova, via G. Falloppio n.50, Padova 35121, Italy.

Crimes against the elderly have physical, psychological, and economic consequences. Approaches for mitigating them must be based on comprehensive knowledge of the phenomenon. This study analyses crimes against the elderly in Italy during the period 2007-2014 from an epidemiological viewpoint. Data on violent and non-violent crimes derived from the Italian Institute of Statistics were analysed in relation to trends, gender and age by linear regression, T-test, and calculation of the odds ratio with a 95% confidence interval. Results show that the elderly are at higher risk of being victimized in two types of crime, violent (residential robbery) and non-violent (pick-pocketing and purse-snatching) compared with other age groups during the period considered. A statistically significant increase in residential robbery and pick-pocketing was also observed. The rate of homicide against the elderly was stable during the study period, in contrast with reduced rates in other age groups. These results may be explained by risk factors increasing the profiles of elderly individuals as potential victims, such as frailty, cognitive impairment, and social isolation. Further studies analysing the characteristics of victims are required. Based on the results presented here, appropriate preventive strategies should be planned to reduce crimes against the elderly.
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http://dx.doi.org/10.1016/j.jflm.2017.06.005DOI Listing
August 2017

When to use belimumab in SLE.

Expert Rev Clin Immunol 2017 08 5;13(8):737-740. Epub 2017 May 5.

a Division of Rheumatology , University of Padova , Padova , Italy.

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http://dx.doi.org/10.1080/1744666X.2017.1324784DOI Listing
August 2017

The effect of different durations of remission on damage accrual: results from a prospective monocentric cohort of Caucasian patients.

Ann Rheum Dis 2017 Mar 24;76(3):562-565. Epub 2016 Nov 24.

Division of Rheumatology, Department of Medicine, University of Padova, Padova, Italy.

Aim: To identify the shortest duration of remission associated with improved outcomes in systemic lupus erythematosus (SLE).

Methods: We studied 293 Caucasian patients with SLE during 7-year follow-up. Disease activity was assessed by SLE Disease Activity Index 2000 and damage by Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI). We defined three remission levels: complete, clinical off-corticosteroids, clinical on-corticosteroids (prednisone 1-5 mg/day). The effect of different durations of remission (1, 2, 3, 4 and ≥5 consecutive years) on damage was evaluated by multivariate logistic regression analysis.

Results: Among patients achieving 1-year (27 patients), 2-year (47 patients), 3-year (45 patients), 4-year (26 patients) remission, damage was similar irrespective of the level of remission achieved, whereas, among patients achieving ≥5-year remission (113 patients), damage was higher in those in clinical remission on-corticosteroids (p<0.001).In multivariate analysis, ≥2 consecutive year remission was protective against damage (OR (95% CI)): 2 years 0.228 (0.061 to 0.850); 3 years 0.116 (0.031 to 0.436); 4 years 0.118 (0.027 to 0.519) and ≥5 years 0.044 (0.012 to 0.159). Predictors of damage were cumulative prednisone dose ≥180 mg/month (3.136 (1.276 to 7.707)), antiphospholipid antibody syndrome (5.517 (2.092 to 14.546)), vasculitis (3.107 (1.030 to 9.307)) and number of flare/year (8.769 (1.692 to 45.449)).

Conclusions: Two consecutive years is the shortest duration of remission associated with a decrease in damage progression in Caucasian patients with SLE.
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http://dx.doi.org/10.1136/annrheumdis-2016-210154DOI Listing
March 2017

Fetal outcome and recommendations of pregnancies in lupus nephritis in the 21st century. A prospective multicenter study.

J Autoimmun 2016 11 2;74:6-12. Epub 2016 Aug 2.

Department of Clinical and Experimental Medicine, Rheumatology Unit, University of Pisa, Italy.

The aim of this multicenter study was to assess the present risk of fetal complications and the inherent risk factors in pregnant women with lupus nephritis. Seventy-one pregnancies in 61women (59 Caucasians and 2 Asians) with lupus nephritis were prospectively followed between October 2006 and December 2013. All patients received a counselling visit within 3 months before the beginning of pregnancy and were followed by a multidisciplinary team. At baseline mild active nephritis was present in 15 cases (21.1%). Six pregnancies (8.4%) resulted in fetal loss. Arterial hypertension at baseline (P = 0.003), positivity for lupus anticoagulant (P = 0.001), anticardiolipin IgG antibodies (P = 0.007), antibeta2 IgG (P = 0.018) and the triple positivity for antiphospholipid antibodies (P = 0.004) predicted fetal loss. Twenty pregnancies (28.2%) ended pre-term and 12 newborns (16.4%) were small for gestational age. Among the characteristics at baseline, high SLE disease activity index (SLEDAI) score (P = 0.027), proteinuria (P = 0.045), history of renal flares (P = 0.004), arterial hypertension (P = 0.009) and active lupus nephritis (P = 0.000) increased the probability of preterm delivery. Odds for preterm delivery increased by 60% for each quarterly unit increase in SLEDAI and by 15% for each quarterly increase in proteinuria by 1 g per day. The probability of having a small for gestational age baby was reduced by 85% in women who received hydroxychloroquine therapy (P = 0.023). In this study, the rate of fetal loss was low and mainly associated with the presence of antiphospholipid antibodies. Preterm delivery remains a frequent complication of pregnancies in lupus. SLE and lupus nephritis activity are the main risk factors for premature birth. Arterial hypertension predicted both fetal loss and preterm delivery. Based on our results the key for a successful pregnancy in lupus nephritis is a multidisciplinary approach with close medical, obstetric and neonatal monitoring. This entails: a) a preconception evaluation to establish and inform women about pregnancy risks; b) planning pregnancy during inactive lupus nephritis, maintained inactive with the lowest possible dosage of allowed drugs; c) adequate treatment of known risk factors (arterial hypertension, antiphospholipid and antibodies); d) close monitoring during and after pregnancy to rapidly identify and treat SLE flares and obstetric complications.
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http://dx.doi.org/10.1016/j.jaut.2016.07.010DOI Listing
November 2016
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