Publications by authors named "Maddalena Larosa"

27 Publications

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Evaluation of the severe preeclampsia classification criterion for antiphospholipid syndrome in a study of 40 patients.

Arthritis Res Ther 2021 05 4;23(1):134. Epub 2021 May 4.

AP-HP, Cochin Hospital, Internal Medicine Department, Centre de référence maladies auto-immunes et systémiques rares d'Ile de France, Paris, France.

Background: The criteria for antiphospholipid syndrome (APS) include severe preeclampsia and/or placental insufficiency leading to preterm delivery before 34 weeks of gestation, but this APS manifestation has been rarely studied. Thus, we report a series of severe preeclampsia occurred in patients with APS.

Methods: We retrospectively analysed data of women with APS (Sydney criteria) who experienced severe preeclampsia with delivery before 34 weeks' gestation between 2000 and 2017 at five French internal medicine departments and one Italian rheumatology unit.

Results: The 40 women had a mean age of 30.5 ± 4.6 years at their first episode of preeclampsia; 21 were nulligravid (52.5%), 12 (30%) had already been diagnosed with APS, and 21 (52.5%) had a triple-positive antiphospholipid (aPL) antibody test. Preeclampsia occurred at a median gestational age of 25.5 weeks (IQR 23-29). It was associated with HELLP in 18 cases (45%), eclampsia in 6 (15%), placental abruption in 3 (7.5%), catastrophic APS in 3 (7.5%), and foetal and neonatal death in 11 and 15 cases. Overall, 14 (35%) children survived, born at a median gestational age of 31 weeks. Among other APS criteria, 16 women (40%) experienced at least one thrombosis, 17 (42.5%) an intrauterine foetal death, and 19 (47.5%) at least one episode of HELLP during follow-up (median 5 years, IQR = 2-8). None had three or more consecutive miscarriages. Notably, 12 women (30%) had systemic lupus erythematosus.

Conclusions: Severe preeclampsia led to high mortality in the offspring. Almost half of these women experienced other APS features, but not three consecutive miscarriages.
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http://dx.doi.org/10.1186/s13075-021-02518-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8094564PMC
May 2021

SLE-DAS in the First Trimester of Gestation Predicts Maternal Lupus Flares Later in Pregnancy.

Front Pharmacol 2021 16;12:660123. Epub 2021 Apr 16.

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

Systemic Lupus Erythematosus (SLE) mainly occurs during childbearing age. Remission or low disease activity state (LDAS) before conception are recommended by experts to achieve a favourable lupus pregnancy outcome but little is known on the best way to evaluate remission or activity status during pregnancy. We tested SLE-disease activity score (SLE-DAS) in the first trimester as predictor of maternal flares and obstetrical complications in 2nd and 3rd trimester in a cohort of SLE pregnant women. Inclusion criteria were: 1) women ≥ 18 years; 2) affected with SLE (SLICC 2012); 3) enrolled in two referral centers (Italy and France) 4) with an ongoing singleton pregnancy at 12 weeks (only one pregnancy per patient). Disease activity was assessed at first trimester of pregnancy, using SLE-pregnancy disease activity index (SLEPDAI) and retrospectively applying SLE-DAS. Maternal lupus flares at 2nd and 3rd trimester were defined by the SELENA-SLEDAI Flare Index (SFI). Adverse pregnancy outcome (APO) included: fetal and neonatal death, placental insufficiency with premature delivery <37 weeks, and small for gestational age (SGA) (≤3rd percentile). We included 158 pregnant patients affected with SLE. At first trimester the median SLEPDAI (IQR) was 2 (0-4) and the median SLE-DAS (IQR) 1.32 (0.37-2.08). At least one flare occurred in 25 (15.8%) women during the 2nd and 3rd trimester. APO occurred in 19 (12.0%) patients. A significant correlation between SLE-DAS and SLEPDAI was found in this cohort (Spearman's = 0.97, Figure 1). At multivariate analysis, both SLE-DAS and SLEPDAI predicted maternal flares (adjOR = 1.2; 95% CI = 1.0-1.3, = 0.02; adjOR 1.3, 95% CI = 1.1-1.6 per unit increase, = 0.01, respectively). SLE-DAS and SLEPDAI were associated with APO at univariate analysis ( = 0.02). SLE-DAS was highly correlated with SLEPDAI and its use in the first trimester predicted maternal flares in the 2nd and 3rd trimester, making SLE-DAS a reliable instrument to measure SLE activity during pregnancy.
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http://dx.doi.org/10.3389/fphar.2021.660123DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8085518PMC
April 2021

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

Long-term Outcome of Children Born to Women with Autoimmune Rheumatic Diseases: A Multicentre, Nationwide Study on 299 Randomly Selected Individuals.

Clin Rev Allergy Immunol 2021 Mar 16. Epub 2021 Mar 16.

Department of Medicine, Rheumatology Unit, University of Perugia, Piazzale Gambuli 1, 06132, Perugia, Italy.

The concern about the offspring's health is one of the reasons for a reduced family size of women with rheumatic diseases (RD). Increased risk of autoimmune diseases (AD) and neurodevelopmental disorders (ND) has been reported in children born to patients with RD. Within a nationwide survey about reproductive issues of women with RD, we aimed at exploring the long-term outcome of their children. By surveying 398 patients who received their diagnosis of RD during childbearing age (before the age of 45), information about the offspring were obtained from 230 women who declared to have had children. A total of 148 (64.3%) patients were affected by connective tissue diseases (CTD) and 82 (35.7%) by chronic arthritis. Data on 299 children (156 males, 52.1%; mean age at the time of interview 17.1 ± 9.7 years) were collected. Twelve children (4.0%), who were born to patients with CTD in 75% of the cases, were affected by AD (8 cases of celiac disease). Eleven children had a certified diagnosis of ND (3.6%; 6 cases of learning disabilities); 9 of them were born to mothers with CTD (5 after maternal diagnosis). No association was found between ND and prenatal exposure to either maternal autoantibodies or anti-rheumatic drugs. Absolute numbers of offspring affected by AD and ND were low in a multicentre cohort of Italian women with RD. This information can be helpful for the counselling about reproductive issues, as the health outcomes of the offspring might not be an issue which discourage women with RD from having children.
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http://dx.doi.org/10.1007/s12016-021-08857-2DOI Listing
March 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

Are remission and low disease activity state ideal targets for pregnancy planning in Systemic Lupus Erythematosus? A multicentre study.

Rheumatology (Oxford) 2021 Feb 16. Epub 2021 Feb 16.

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

Objectives: To determine whether disease remission or low disease activity state at the beginning of pregnancy in SLE patients is associated with better pregnancy outcome.

Methods: pregnancies in SLE patients prospectively monitored by pregnancy clinics at four rheumatology centres were enrolled. Patient demographics and clinical information were collected at baseline (pregnancy visit before 8 weeks of gestation) including whether patients were in remission according to DORIS criteria and and/or Lupus Low Disease Activity State (LLDAS). Univariate and multivariate analysis were performed to determine predictors of disease flare and adverse pregnancy outcomes (APOs) including preeclampsia, preterm delivery, small for gestational age infant, intrauterine growth restriction and intrauterine fetal death.

Results: 347 pregnancies were observed in 281 SLE patients. Excluding early pregnancy losses, 212 pregnancies (69.7%) occurred in patients who were in remission at baseline, 33 (10.9%) in patients in LLDAS, and the remainder in active patients. 73 flares (24%) were observed during pregnancy or puerperium, and 105 (34.5%) APOs occurred. Multivariate analysis revealed that patients in disease remission or taking hydroxychloroquine were less likely to have disease flare, while a history of lupus nephritis increased the risk. The risk of APOs was increased in patients with shorter disease duration, while being on hydroxychloroquine resulted a protective variable. An almost significant association between complete remission and a decreased risk of APOs was observed.

Conclusions: Prenatal planning with a firm treat-to-target goal of disease remission is an important strategy to reduce the risk of disease flares and severe obstetrical complications in SLE pregnancies.
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http://dx.doi.org/10.1093/rheumatology/keab155DOI Listing
February 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

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

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

An observational multicentre study on the efficacy and safety of assisted reproductive technologies in women with rheumatic diseases.

Rheumatol Adv Pract 2019 22;3(1):rkz005. Epub 2019 Feb 22.

Rheumathology and Clinical Immunology, ASST Spedali Civili and University of Brescia, Brescia.

Objectives: The aim was to determine whether assisted reproductive technologies (ARTs) confer additional risk in rheumatic patients (in terms of disease flare and fetal-maternal complications) and whether, if performed, their efficacy is affected by maternal disease.

Methods: Sixty infertile rheumatic women undergoing 111 ART cycles were included. Clinical pregnancy rate, live birth rate, maternal disease flares and maternal-fetal complications were recorded.

Results: One hundred and eleven ART cycles in 60 women were analysed. We reported 46 pregnancies (41.4%), 3 (3.1%) cases of ovarian hyperstimulation syndrome and no cases of thrombosis during stimulation, pregnancy and puerperium. One or more maternal complication was reported in 13 (30.2%) pregnancies, and fetal complications occurred in 11 fetuses (21.1%). The live birth rate was 98%, but we reported three (6%) perinatal deaths in the first days of life. During puerperium, we recorded one (2.5%) post-partum haemorrhage and one (2.5%) articular flare.

Conclusion: The safety and efficacy of the ARTs, demonstrated in the general population, seems to be confirmed also in rheumatic patients. No evidence was found to advise against their application, and the choice of therapy should be made depending on the patient's risk profile, irrespective of whether the pregnancy is natural or artificial induced.
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http://dx.doi.org/10.1093/rap/rkz005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6649948PMC
February 2019

Clinical outcomes and predictors of maternal and fetal complications in pregnancies of patients with systemic lupus erythematosus.

Expert Rev Clin Immunol 2019 06 19;15(6):617-627. Epub 2019 Apr 19.

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

Introduction: Systemic Lupus Erythematosus (SLE) mostly affects women during their childbearing years. Fertility is preserved in SLE patients, but pregnancy is often characterized by a high number of maternal and fetal complications. Adverse pregnancy outcomes (APO) have been widely studied over the last decades and several investigators have focused on the potential clinical and serological predictors of maternal and fetal complications. Areas covered: In this review, we analyzed maternal and fetal complications in SLE patients and predictors of APO. Active disease in the 6 months before conception, lupus nephritis, anti-phospholipid (aPL), anti-SSA/Ro and/or anti-SSB/La antibodies have been identified as the most consistent predictors of maternal and fetal complications to date. However, molecular mechanisms and underlying immunological pathways involved in APO still remain elusive. Expert opinion: Difficulties in assessing prevalence and predictors of APO in SLE patients are due to lack of uniformity in the definitions and methods used in the different studies. In addition, some maternal and fetal complications are difficult to diagnose and to differentiate from each other. Preconception counseling is paramount to prevent APO, and it should consider four main factors: disease activity/lupus nephritis, safety of drugs, aPL, anti-SSA/Ro, and/or anti-SSB/La antibodies.
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http://dx.doi.org/10.1080/1744666X.2019.1601557DOI Listing
June 2019

Idiopathic inflammatory myopathies: state of the art on clinical practice guidelines [corrected].

RMD Open 2018 26;4(Suppl 1):e000784. Epub 2019 Feb 26.

Research Laboratory and Academic Division of Clinical Rheumatology, Department of Internal Medicine, IRCCS Polyclinic Hospital San Martino, University of Genoa, Genoa, Italy.

Idiopathic inflammatory myopathies (IIMs) encompass a heterogeneous group of rare autoimmune diseases characterised by muscle weakness and inflammation, but in antisynthetase syndrome arthritis and interstitial lung disease are more frequent and often inaugurate the disease. Clinical practice guidelines (CPGs) have been proposed for IIMs, but they are sparse and heterogeneous. This work aimed at identifying: i) current available CPGs for IIMs, ii) patients ' and clinicians' unmet needs not covered by CPGs. It has been performed in the framework of the European Reference Network on rare and complex connective tissue and musculoskeletal diseases (ReCONNET), a network of centre of expertise and patients funded by the European Union's Health Programme. Fourteen original CPGs were identified, notably recommending that: i) extra-muscular involvements should be assessed; ii) corticosteroids and methotrexate or azathioprine are first-line therapies of IIMs. ii) IVIG is a treatment of resistant-DM that may be also used in other resistant-IIMs; iii) physical therapy and sun protection (in DM patients) are part of the treatment; v) tumour screening for patients with DM include imaging of chest, abdomen, pelvis and breast (in woman) along with colonoscopy (in patients over 50 years); vi) disease activity and damages should be monitor using standardised and validated tools. Yet, only half of these CPGs were evidence-based. Crucial unmet needs were identified both by patients and clinicians. In particular, there was a lack of large multidisciplinary working group and of patients ' preferences. The following fields were not or inappropriately targeted: diagnosis; management of extra-muscular involvements other than skin; co-morbidities and severe manifestations.
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http://dx.doi.org/10.1136/rmdopen-2018-000784DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6397434PMC
February 2019

Pulmonary arterial hypertension in connective tissue disorders: Pathophysiology and treatment.

Exp Biol Med (Maywood) 2019 02 22;244(2):120-131. Epub 2019 Jan 22.

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

Impact Statement: Our article focuses on the pathogenesis and treatment of CTD-PAH. In the latest ESC/ESR guidelines for PAH, the authors underline that although CTD-PAH should follow the same treatment protocol as idiopathic PAH, the therapeutic approach is more complex and difficult in the former. This review throws light on several peculiar aspects of CTD-PAH and the latest findings in the pathogenesis, namely, the role of inflammation in the maladaptive right ventricle remodeling in SSc-PAH where immunosuppressants are classically believed to be ineffective. Furthermore, we discuss the major critical points in the therapy of CTD-PAH which is one of the strengths of our article. To the best of our knowledge, there are no other reviews that exclusively focus on the pathogenesis and treatment of CTD-PAH patients, with an emphasis on the more critical issues. Thus, it is our contention that our work would be of interest to the readers.
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http://dx.doi.org/10.1177/1535370218824101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6405825PMC
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

"Disease knowledge index" and perspectives on reproductive issues: A nationwide study on 398 women with autoimmune rheumatic diseases.

Joint Bone Spine 2019 07 21;86(4):475-481. Epub 2018 Dec 21.

Rheumatology Unit, Department of Medicine, University of Perugia, Piazzale Gambuli, 1, 06132 Perugia, Italy.

Objective: The reproductive choices of women affected by rheumatic diseases (RD) can be influenced by several factors, including the quality of physician-patient communication. We conducted a survey on reproductive issues aiming at exploring the unmet needs of women with RD during childbearing age.

Methods: We administered 65 multiple-choice and 12 open-answer questions about pregnancy counselling, contraception, use of drugs during pregnancy and other women reproductive issues to 477 consecutive women with RD aged 18-55 years followed-up in 24 rheumatology centres in Italy. Analysis was restricted to 398 patients who received their diagnosis of RD before the age of 45. According to the RD diagnosis, patients were subdivided into 2 groups: connective tissue diseases (n = 249) and chronic arthritis (n = 149).

Results: At the time of interview, women in both groups had a mean age of 40 years. Nearly one third of patients in each group declared not to have received any counselling about either pregnancy desire nor contraception. A smaller family size than desired was reported by nearly 37% of patients, because of concerns related to maternal disease in one fourth of the cases. A "Disease Knowledge Index" (DKI) was created to investigate the degree of patients' information about the implications of their RD on reproductive issues. Having received counselling was associated with higher DKI values and with a positive impact on family planning.

Conclusion: Italian women of childbearing age affected by RD reported several unmet needs in their knowledge about reproductive issues. Strategies are needed to implement and facilitate physician-patient communication.
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http://dx.doi.org/10.1016/j.jbspin.2018.12.002DOI Listing
July 2019

Disease activity assessment of rheumatic diseases during pregnancy: a comprehensive review of indices used in clinical studies.

Autoimmun Rev 2019 Feb 18;18(2):164-176. Epub 2018 Dec 18.

Department of Medicina dei Sistemi, Rheumatology, Allergology and Clinical Immunology, University of Rome Tor Vergata, Rome, Italy.

Pregnancy requires a special management in women with inflammatory rheumatic diseases (RDs), with the aim of controlling maternal disease activity and avoiding fetal complications. Despite the heterogeneous course of RDs during pregnancy, their impact on pregnancy largely relates to the extent of active inflammation at the time of conception. Therefore, accurate evaluation of disease activity is crucial for the best management of pregnant patients. Nevertheless, there are limitations in using conventional measures of disease activity in pregnancy, as some items included in these instruments can be biased by symptoms or by physiological changes related to pregnancy and the pregnancy itself may influence laboratory parameters used to assess disease activity. This article aims to summarize the current literature about the available instruments to measure disease activity during pregnancy in RDs. Systemic lupus erythematosus is the only disease with instruments that have been modified to account for several adaptations which might interfere with the attribution of signs or symptoms to disease activity during pregnancy. No modified-pregnancy indices exist for women affected by other RDs, but standard indices have been applied to pregnant patients. The current body of knowledge shows that the physiologic changes that occur during pregnancy need to be either adapted from existing instruments or developed to improve the management of pregnant women with RDs. Standardized instruments to assess disease activity during pregnancy would be helpful not only for clinical practice but also for research purposes.
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http://dx.doi.org/10.1016/j.autrev.2018.08.008DOI Listing
February 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

Therapy of scleroderma renal crisis: State of the art.

Autoimmun Rev 2018 Sep 10;17(9):882-889. Epub 2018 Jul 10.

Division of Rheumatology, Department of Medicine (DIMED), University of Padova, Via Giustiniani 2, 35128 Padova, Italy. Electronic address:

Scleroderma renal crisis (SRC) is an uncommon but still life-threatening manifestation of systemic sclerosis (SSc). The incidence of SRC has decreased in the last few decades, probably due to a widespread use of vasodilators in SSc patients. It is well-recognized that exposure to different drugs can trigger SRC (corticosteroids, cyclosporine) or might prevent its occurrence (iloprost, calcium channel blockers). The prognosis of this life-threatening manifestation has not substantially improved since 1980s, when ACE-inhibitors were introduced in its treatment. ACE-inhibitors remain the mainstay in the therapy of SRC due to their efficacy in controlling malignant hypertension; indeed, the prognosis largely depends on the rapid improvement of the ongoing renal ischemia. Calcium-channel blockers and in third line diuretics and alpha-blockers should be used as additional therapy if blood pressure control remains suboptimal despite maximum tolerated doses of ACE-inhibitors. Given the growing evidence on the role of complement activation and endothelin-1 in the pathogenesis of SRC, recent case-series and case reports have suggested the use of C5-inhibitors and endothelin receptor antagonists in the therapy of SRC, mainly in the refractory cases. Plasma-exchange seems to give some benefits in patients with SRC and microangiopathy or intolerant to ACE-inhibitors. Renal transplantation is the last treatment option and its outcome is similar to that reported in other connective tissue disorders, with a 5-year patient survival rate of about 82%. In this review we summarize the current knowledge in the treatment of SRC.
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http://dx.doi.org/10.1016/j.autrev.2018.03.012DOI 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

Can we manage lupus nephritis without chronic corticosteroids administration?

Autoimmun Rev 2018 Jan 3;17(1):4-10. Epub 2017 Nov 3.

Division of Nephrology, Department of Medicine, University Health Network, Toronto, Canada.

The outcome of lupus nephritis (LN) has changed since the introduction of glucocorticoids (GCs), which dramatically reduced the mortality related to one of the most severe complications of systemic lupus erythematosus (SLE). Since the 1950's, other immunosuppressants, including biologic drugs (i.e. rituximab) have aided in maintaining remission, preserving kidney function, but not preventing treatment-related toxicity. GCs still remain the cornerstone in the treatment of SLE, including LN, and they are widely used in clinical practice. However, GC administration represents a double-edged sword. Indeed, from one side they allow a fast and effective control of disease activity by dampening inflammation; from the other side, they have many and severe side effects leading to organ damage. In this paper, we will discuss pros and cons of the chronic use of GCs, especially focusing on LN.
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http://dx.doi.org/10.1016/j.autrev.2017.11.002DOI 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

Effects of Belimumab on Flare Rate and Expected Damage Progression in Patients With Active Systemic Lupus Erythematosus.

Arthritis Care Res (Hoboken) 2017 01 18;69(1):115-123. Epub 2016 Nov 18.

University of Padova, Padova, Italy.

Objective: To investigate effectiveness and safety of belimumab in patients with active systemic lupus erythematosus (SLE) in a clinical practice setting.

Methods: Sixty-seven patients with active SLE, mean ± SD age 39.3 ± 10.2 years, from 2 Italian prospective cohorts were treated with belimumab (10 mg/kg on day 0, 14, 28, and then every 28 days) added to background therapy. The Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K), the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index, the Disease Activity Score in 28 joints (DAS28), 24-hour proteinuria, the Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) activity score, anti-double-stranded DNA (anti-dsDNA), C3 and C4 levels, and prednisone daily dose were recorded at baseline, month 3, 6, 9, 12, 18, and 24. Arthritis was subdivided into "classical" (CLP) and "rheumatoid-like"; skin manifestations into acute (ACLE), subacute (SCLE), and chronic. SLE flares, defined according to the SLEDAI Flare Index, were calculated before and after belimumab initiation. Adverse events were carefully evaluated during treatment. Statistics were performed by the SPSS package (version 21.0).

Results: Mean ± SD followup was 16.2 ± 9.5 months. Main refractory manifestations treated with belimumab were musculoskeletal (37.3%), mucocutaneous (22.4%), and renal (23.9%). SLEDAI-2K, prednisone daily dose, anti-dsDNA, DAS28, CLASI, and 24-hour proteinuria decreased during treatment. DAS28 score decreased in patients with polyarthritis (P < 0.001), particularly in those with CLP (P < 0.001), and CLASI decreased in patients with skin manifestation (P = 0.003), either ACLE (P = 0.051) or SCLE (P = 0.047). Flare rate was lower 1 and 2 years after belimumab initiation than in the periods before (P = 0.001). Belimumab was well-tolerated and no damage accrual was observed after initiation.

Conclusion: Belimumab was effective and safe in a clinical practice setting; it decreased the number of flares and hindered damage progression in patients with active SLE.
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http://dx.doi.org/10.1002/acr.22971DOI Listing
January 2017

Advances in the diagnosis and classification of systemic lupus erythematosus.

Expert Rev Clin Immunol 2016 Dec 8;12(12):1309-1320. Epub 2016 Jul 8.

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

Introduction: Systemic lupus erythematosus (SLE) is the prototype of systemic autoimmune diseases. Patients with SLE display a wide spectrum of clinical and serological findings that can mislead and delay the diagnosis. Diagnostic criteria have not been developed yet, whereas several sets of classification criteria are available; however, none of them has 100% sensitivity and 100% specificity, i.e. the hallmark of diagnostic criteria. Nevertheless, classification criteria are often misused as diagnostic criteria, which may affect earliness of diagnosis and lead to more misdiagnosed cases. Areas covered: In this review, we compare old and new classification criteria, discussing their application and pinpointing their limitations in the management of patients. Moreover, we will focus on current and novel biomarkers for SLE diagnosis, highlighting their predictive value and applicability in clinical practice. Expert commentary: SLE diagnosis still represents a challenge, remaining largely based on a clinical judgment. Besides SLE diagnosis, even its classification is still challenging to date. Indeed, although classification of SLE seems to be achieved more frequently with the 2012 SLICC criteria than with the previous 1997 ACR criteria, this last-updated 2012 set might be improved. Notably, diagnostic and classification criteria should be applied to any subject in the world, and consequently they should include immunological variables validated in different populations, which is still an unmet need.
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http://dx.doi.org/10.1080/1744666X.2016.1206470DOI Listing
December 2016

Cardiovascular risk factors, burden of disease and preventive strategies in patients with systemic lupus erythematosus: a literature review.

Expert Opin Drug Saf 2015 29;14(9):1373-85. Epub 2015 Jul 29.

a 1 University of Padova, Division of Rheumatology, Department of Medicine , Via Giustiniani 2, 35128 Padova, Italy +390 498 212 202, +393 388 072 644 ; +390 498 212 191 ;

Introduction: Risk of developing cardiovascular disease (CVD) is increased in systemic lupus erythematosus (SLE) compared with the general population. Traditional risk factors cannot account for the totality of CV events and adequate prevention may be challenging.

Areas Covered: This review summarizes traditional and emerging risk factors of CVD in SLE patients and goes over potential pathogenic mechanisms involved in CVD development. Role of commonly used drugs and preventive strategies exploitable in everyday clinical practice are also discussed.

Expert Opinion: SLE-related risk factors involve both disease- and treatment-related features, including disease activity, disease phenotype, corticosteroid misuse and alterations of innate and adaptive immunity. Primary prevention is mandatory in management of lupus patients through appropriate disease control, corticosteroid tapering, use of antimalarials and eventually vitamin D supplementation.
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http://dx.doi.org/10.1517/14740338.2015.1073259DOI Listing
May 2016