Publications by authors named "Savino Sciascia"

175 Publications

Antiphospholipid antibodies and cerebrovascular thrombosis in the pediatric population: Few answers to many questions.

Lupus 2021 Jun 4:9612033211021488. Epub 2021 Jun 4.

Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon.

Most of the knowledge in pediatric antiphospholipid syndrome (APS) is derived from studies performed on the adult population. As in adults, antiphospholipid antibodies (aPL) can contribute to thrombosis, especially cerebrovascular thrombosis, in neonates and children. Since aPL have the potential to cross the placental barrier, and since the pediatric population is prone to infections, re-testing for their positivity is essential to specify their role in cerebrovascular thrombosis.In this review, we aimed at assessing the prevalence of aPL, criteria or non-criteria, in neonatal and childhood ischemic stroke and sinovenous thrombosis trying to find an association between aPL and cerebrovascular thrombosis in the neonatal and pediatric population. Also, we looked into the effect of aPL and anticoagulants/antiplatelets on the long term neurological outcomes of affected neonates or children. The questions regarding the prevalence of aPL among pediatric patients with cerebrovascular thrombosis, the relationship between the titers of aPL and incidence and recurrence of cerebrovascular events, the predictability of the long term neurological outcomes, and the most optimal anticoagulation plan are still to be answered. However, it is crucial for clinicians to screen neonates and children with cerebrovascular thrombosis for aPL and confirm their presence if positive.
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http://dx.doi.org/10.1177/09612033211021488DOI Listing
June 2021

Health Disparities in Rheumatic Diseases: Understanding Global Challenges in Africa, Europe, Latin America, and Asia and Proposing Strategies for Improvement.

Rheum Dis Clin North Am 2021 Feb;47(1):119-132

Shanghai Institute of Rheumatology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Rheumatic diseases reach across continents with some similarities as well as unique challenges. The intersection between genetic factors, environmental exposures and socioeconomic factors, as well as challenges, with delays in access to subspecialty care and medications, manifest in different ways. By understanding both the challenges and successes in different countries, while also recognizing the significant diversity both within and across continents, unified strategies to improve rheumatic disease outcomes and decrease disparities among the most vulnerable groups can be developed and disseminated.
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http://dx.doi.org/10.1016/j.rdc.2020.09.009DOI Listing
February 2021

16th International congress on antiphospholipid antibodies task force report on clinical manifestations of antiphospholipid syndrome.

Lupus 2021 Jul 27;30(8):1314-1326. Epub 2021 May 27.

Barbara Volcker Center for Women and Rheumatic Diseases, Hospital for Special Surgery, Weill Cornell Medicine, New York, NY, USA.

The objectives of the 16th International Congress on Antiphospholipid Antibodies (aPL) Task Force on Clinical Manifestations of Antiphospholipid Syndrome (APS) were to critically analyze: a) the definition of "APS"; b) the current knowledge on non-traditional manifestations associated with aPL; and c) the risk stratification strategies in aPL-positive patients. The quality of evidence was assessed by the GRADE system. The task force concluded that: a) APS does not have a uniform definition given the heterogeneity of the clinical presentations and different aPL profiles; b) current literature supports the role for aPL testing in cases of thrombocytopenia and recurrent cardiac events but are limited by vast heterogeneity, providing an overall low-to-very low level of evidence; and c) risk stratification strategies in aPL-positive patients, such as aPL-Score and Global APS Score, can be useful in clinical practice. International multicenter studies are still highly needed to improve the quality of available evidence and consequently the strength of future recommendations.
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http://dx.doi.org/10.1177/09612033211020361DOI Listing
July 2021

A new challenge for lupus nephritis management: Induction therapy without immunosuppressive maintenance regimen.

Autoimmun Rev 2021 Jul 7;20(7):102844. Epub 2021 May 7.

CMID-Nephrology and Dialysis Unit (ERK-net Member), Center of Research of Immunopathology and Rare Diseases - Coordinating Center of the Network for Rare Diseases of Piedmont and Aosta Valley, Department of Clinical and Biological Sciences, University of Turin and S. Giovanni Bosco Hub Hospital, Turin, Italy.

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http://dx.doi.org/10.1016/j.autrev.2021.102844DOI Listing
July 2021

Antiphospholipid Syndrome Alliance for Clinical Trials and International Networking (APS ACTION): 10-Year Update.

Curr Rheumatol Rep 2021 May 1;23(6):45. Epub 2021 May 1.

Haemostasis Research Unit, Department of Haematology, University College London, London, UK.

Purpose Of Review: APS ACTION is an international research network created to design and conduct large-scale, multicenter research in persistently antiphospholipid antibody (aPL)-positive patients. Given the expanding research activities of the network in the last decade since its creation, the purpose of this article is to review the scientific contributions of APS ACTION as well as future directions.

Recent Findings: APS ACTION has achieved increased international collaboration with internal and external investigators for outcome, interventional, and mechanistic antiphospholipid syndrome (APS) studies. This has been linked to substantial progress in Core laboratory work, which has demonstrated that laboratories can achieve good agreement in performance of aPL assays by use of the same reagents, analyzer type, and protocols. APS ACTION will continue to identify gaps in the existing aPL/APS literature, design mechanistic studies to elucidate underlying mechanisms, and conduct prospective, large-scale clinical studies, all for the ultimate goal of early diagnosis and improved management of aPL-positive patients.
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http://dx.doi.org/10.1007/s11926-021-01008-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8088198PMC
May 2021

A Prospective Study on Long-Term Clinical Outcomes of Patients With Lupus Nephritis Treated With an Intensified B-Cell Depletion Protocol Without Maintenance Therapy.

Kidney Int Rep 2021 Apr 3;6(4):1081-1087. Epub 2021 Feb 3.

CMID-Nephrology and Dialysis Unit (ERK-net Member), Center of Research of Immunopathology and Rare Diseases, Coordinating Center of the Network for Rare Diseases of Piedmont and Aosta Valley, Department of Clinical and Biological Sciences, University of Turin and S. Giovanni Bosco Hub Hospital, Turin, Italy.

Background: We aimed to investigate the safety and efficacy of an intensified B-cell depletion induction therapy (IBCDT) without immunosuppressive maintenance regimen compared with standard of care in biopsy-proven lupus nephritis (LN).

Methods: Thirty patients were administered an IBCDT (4 weekly rituximab [RTX] 375 mg/m and 2 more doses after 1 and 2 months; 2 infusions of 10 mg/kg cyclophosphamide [CYC], 3 methylprednisolone pulses), followed by oral prednisone (tapered to 5 mg/d by the third month). No immunosuppressive maintenance therapy was given. Thirty patients matched for LN class and age were selected as controls: 20 received 3 methylprednisolone pulses days followed by oral prednisone and mycophenolate mofetil (MMF) 2 to 3 g/d, whereas 10 were given the Euro Lupus CYC. MMF (1-2 g/daily) or azathioprine (AZA, 1-2 mg/kg/day) were given for > 3 years as a maintenance therapy.

Results: At 12 months, complete renal remission was observed in 93% of patients on IBCDT, in 62.7% on MMF, and in 75% on CYC ( = 0.03); the dose of oral prednisone was lower in the IBCDT group (mean ± SD 2.9 ± 5.0 mg/dl) than MMF (10.5 ± 8.0 mg/d,  < 0.01) or CYC group (7.5 ± 9.0 mg/d,  < 0.01). Mean follow-up after treatment was 44.5 months (interquartile range [IQR] 36-120 months), 48.6 months (IQR 36-120 months), and 45.3 (IQR 36-120 months) for IBCDT, MMF, and CYC, respectively. At their last follow-up visit, we observed no significant differences in proteinuria and serum creatinine, nor in the frequency of new flares among the 3 groups.

Conclusion: In biopsy-proven LN, the IBCDT without further immunosuppressive maintenance therapy was shown to be as effective as conventional regimen of MMF or CYC followed by >3-year maintenance either MMF or AZA regimen. Moreover, the use of IBCDT was associated with a marked reduction of glucocorticoid cumulative dose.
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http://dx.doi.org/10.1016/j.ekir.2021.01.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8071649PMC
April 2021

The role of antirheumatics in patients with COVID-19.

Lancet Rheumatol 2021 Jun 30;3(6):e447-e459. Epub 2021 Mar 30.

Danish Hospital for Rheumatic Diseases, University of Southern Denmark, Sønderborg, Danmark.

The COVID-19 pandemic has resulted in more than 2 million deaths globally. Two interconnected stages of disease are generally recognised; an initial viral stage and a subsequent immune response phase with the clinical characteristics of hyperinflammation associated with acute respiratory distress syndrome. Therefore, many immune modulators and immunosuppressive drugs, which are widely used in rheumatological practice, have been proposed as treatments for patients with moderate or severe COVID-19. In this Review, we provide an overview of what is currently known about the efficacy and safety of antirheumatic therapies for the treatment of patients with COVID-19. Dexamethasone has been shown to reduce COVID-19 related mortality, interleukin-6 inhibitors to reduce risk of cardiovascular or respiratory organ support, and baricitinib to reduce time to recovery in hospitalised patients requiring oxygen support. Further studies are needed to identify whether there is any role for glucocorticoids in patients with less severe COVID-19. Although evidence on the use of other antirheumatic drugs has suggested some benefits, results from adequately powered clinical trials are urgently needed. The heterogeneity in dosing and the absence of uniform inclusion criteria and defined stage of disease studied in many clinical trials have affected the conclusions and comparability of trial results. However, after the success of dexamethasone in proving the anti-inflammatory hypothesis, the next 12 months will undoubtedly bring further clarity about the clinical utility and optimal dose and timing of other anti-rheumatic drugs in the management of COVID-19.
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http://dx.doi.org/10.1016/S2665-9913(21)00062-XDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8009617PMC
June 2021

Improving the clinical accuracy in patients with antiphospholipid antibodies using anti-phosphatidylserine/prothrombin and anti-beta2 glycoprotein I domain and particle-based multi-analyte technology.

Thromb Res 2021 06 22;202:100-103. Epub 2021 Mar 22.

Center of Research of Immunopathology and Rare Diseases- Coordinating Center of Piemonte and Valle d'Aosta Network for Rare Diseases, S. Giovanni Bosco Hospital, Department of Clinical and Biological Sciences, University of Turin, Italy; Nephrology and Dialysis, Department of Clinical and Biological Sciences, S. Giovanni Bosco Hospital, University of Turin, Italy.

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http://dx.doi.org/10.1016/j.thromres.2021.03.019DOI Listing
June 2021

Utilizing type I interferon expression in the identification of antiphospholipid syndrome subsets.

Expert Rev Clin Immunol 2021 Apr 30;17(4):395-406. Epub 2021 Mar 30.

Center of Research of Immunopathology and Rare Diseases - Nephrology and Dialysis Coordinating Center of Piemonte and Aosta Valley Network for Rare Diseases, S. Giovanni Bosco Hospital, Department of Clinical and Biological Sciences, University of Turin, Turin Italy.

Introduction: Antiphospholipid Syndrome (APS) is a systemic autoimmune disease with a complex multifactorial pathogenesis, combining genetic background, traditional cardiovascular risk factors, disease-specific features such as the presence of antiphospholipid antibodies (aPL), and an imbalance of various immune system functions. Recent data support the role of interferons (IFNs), especially type IIFN (IFN-I), in the onset and development of APS clinical manifestations, including thrombotic events and obstetric complications.

Areas Covered: In this review, the authors aimed to discuss the growing body of evidence on the relevance of IFN-I pathways in APS, both from a basic mechanistic perspective, focusing on its possible use in disease/patients stratification. The IFN-I signature has shown promising, although preliminary, results in segregating aPL-positive subjects by aPL profile, association with other autoimmune conditions, such as lupus, age at onset, and current treatment, among others.

Expert Opinion: To date, the scarce available data as well as methodological and technical heterogeneity among studies limit the comparability of the results, thus requiring further validation to translate these findings to routine clinical practice. Therefore, further research is required in pursuit of more nuanced patient profiling and the development of new immunomodulatory therapeutic strategies for APS beyond anti-coagulant and antiplatelet agents.
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http://dx.doi.org/10.1080/1744666X.2021.1901581DOI Listing
April 2021

Antiphospholipid syndrome: the need for new international classification criteria.

Expert Rev Clin Immunol 2021 Apr 17;17(4):385-394. Epub 2021 Mar 17.

Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon.

: As soon as the association of lupus anticoagulant (LAC) and anticardiolipin antibodies (aCL) with thrombosis and miscarriages was described in the 1980s, the definition of the antiphospholipid syndrome (APS) became a need. Early descriptions of the disease by members of the Graham Hughes team included broad categories and unexplained laboratory inclusions. Over time, new clinical and experimental data refined the criteria, especially the obstetric manifestations, as well as the laboratory criteria.: The authors performed a review of the literature using the PubMed database, and the following keywords were used: 'antiphospholipid antibody', 'antiphospholipid syndrome', and 'criteria of antiphospholipid'. The history of antiphospholipid criteria, clinical and experimental advancements, and other expert opinions were included in this paper.: It has been 14 years since an international congress on antiphospholipid antibodies has generated new classification based on the recent extensive research performed in the field. Currently, there is a need to update the international APS classification taking into consideration the inclusion of new clinical criteria such as aPL-related nephropathy as well as new standardized antibody specificities (e.g., anti-phosphatidylserine/prothrombin antibodies) with the adoption of a standardized scoring system that can stratify APS patients.
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http://dx.doi.org/10.1080/1744666X.2021.1900733DOI Listing
April 2021

Community Garden Initiatives Addressing Health and Well-Being Outcomes: A Systematic Review of Infodemiology Aspects, Outcomes, and Target Populations.

Int J Environ Res Public Health 2021 02 17;18(4). Epub 2021 Feb 17.

UNESCO Chair in Sustainable Development and Territory Management, University of Turin, 10100 Turin, Italy.

Previous research has suggested that activities such as community gardens could offer a wide range of health benefits. The aim of the article is to systematically review the available literature to analyse the magnitude of the phenomenon, the geographical distribution, and the main characteristics in terms of health outcomes and target populations. The search addresses the question whether the activity in community gardens improves health and well-being outcomes of individuals. From the total amount of 7226, 84 selected articles showed that:(1) up to 50% are published by U.S. universities or institutions; (2) up to 44% of the studies considered "community gardens" as the main activity of the research focus; (3) one-third of the studies included adults; (4) almost 25% of the studies used "general health" as the main outcome when investigating the benefits of community gardens; (5) the percentage of studies that achieved their outcomes was heterogeneous among the different health dimensions. In conclusion, while a certain degree of heterogeneity in the used definition and outcome still exist, community gardens may be a viable strategy for well-being promotion in terms of psychological, social, and physical health and may be considered as an innovative urban strategy to promote urban public health.
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http://dx.doi.org/10.3390/ijerph18041943DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7922762PMC
February 2021

An agent-to-agent real life comparison study of tocilizumab versus abatacept in giant cell arteritis.

Clin Exp Rheumatol 2021 Mar-Apr;39 Suppl 129(2):125-128. Epub 2021 Feb 23.

CMID-Nephrology and Dialysis Unit (ERK-net Member) Center of Research of Nephrology, Rheumatology, and Rare Diseases, Interregional Coordinating Centre of the Network of Rare Diseases, G. Bosco Hospital and University of Turin, Italy.

Objectives: The present study aimed at evaluating the efficacy of abatacept (ABA) compared to tocilizumab (TCZ), assumed as a gold standard biologic treatment in the management of patients with giant cell arteritis (GCA).

Methods: Thirty-three biospy-proven GCA consecutive patients were prospectively collected. Odd patients (from 1 to 33) were assigned to TCZ, given either intravenously (IV 8 mg/kg/month), #8 cases, or subcutaneously (SC 162 mg/week) #9, based on patient's preference. ABA was administered subcutaneously at the dose of 125 mg/week in 16 even patients (from 2 to 32). Biological therapies were prescribed in addition to oral prednisone.

Results: A single biologic agent was administered in 28 patients out of 33 (85%) (8 TCZ IV, 9 TCZ SC and 16 ABA). Five patients (15%) needed a therapeutic switch (one patient from TCZ to ABA, and 4 patients from ABA to TCZ). Among the TCZ IV group, all patients experienced a response (57% complete response and 43% partial response). Among the TCZ SC group, 7 experienced a clinical response (complete in 67% and partial in 16%). Among the ABA group, 10 patients (62%) achieved either complete (5 patients) or partial (5) response, respectively. After 12 months of therapy, 100% of patients in TCZ groups, both IV and SC, and 7 (43%) of ABA group were receiving doses of oral prednisone not exceeding 7.5 mg/day as maintenance.

Conclusions: Both TCZ and ABA can be proposed as an effective therapeutic option in GCA with relevant inflammatory symptoms. ABA can be considered in the patient with absolute or relative or contraindications to TCZ.
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May 2021

Incidence of a First Thrombo-Embolic Event in Patients With Systemic Lupus Erythematosus and Anti-phosphatidylserine/prothrombin Antibodies: A Prospective Study.

Front Med (Lausanne) 2021 1;8:621590. Epub 2021 Feb 1.

Department of Clinical and Biological Sciences, Center of Research of Immunopathology and Rare Diseases - Coordinating Center of Piemonte and Valle d'Aosta Network for Rare Diseases, Division of Nephrology and Dialysis, S. Giovanni Bosco Hospital, Turin, Italy.

This study aimed to prospectively investigate the incidence of first thromboembolic events (TEs) in a cohort of systemic lupus erythematosus (SLE) patients. The patients were positive for anti-phosphatidylserine/prothrombin (aPS/PT) antibodies and tested negative for anticardiolipin (aCL) and anti-β2-glycoprotein I (aβ2GPI) antibodies [regardless of their Lupus Anticoagulant (LA) status]. Inclusion criteria included: (a) SLE with no previous TEs; (b) no concomitant anti-thrombotic therapy; (c) isolated confirmed positive test for aPS/PT. From the total of 52 SLE patients (42, 80.8% women), 18 patients (34.6%) were found to be positive for aPS/PT (IgG/IgM). During a mean follow-up (3.9 ± 1.1 years), 3 TEs occurred (1.3%/year). The overall cumulative incidence of TEs was 5.8% after 2 years, and up to 16.7% when focusing on aPS/PT positive patients. All the TEs events (two cerebrovascular events and one thrombotic kidney microangiopathy) occurred in the aPS/PT positive group. When focusing on IgG aPS/PT, we found that patients who tested positive were at a significantly higher risk for TEs (crude HR 19.6, 95%; CI 1.1 to 357.6; < 0.05) compared to patients with negative aPS/PT. This study observed a rate of TEs of 1.3%/year, in aPS/PT positive only patients. Our prospective data suggest that aPS/PT might confer an increased risk for the development of TEs in SLE patients.
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http://dx.doi.org/10.3389/fmed.2021.621590DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7882486PMC
February 2021

Clinical manifestations in patients with antiphospholipid antibodies: Beyond thrombosis and pregnancy loss.

Lupus 2021 May 16;30(6):884-892. Epub 2021 Feb 16.

Center of Research of Immunopathology and Rare Diseases - Coordinating Center of Piemonte and Aosta Valley Network for Rare Diseases, S. Giovanni Bosco Hospital, Department of Clinical and Biological Sciences, University of Turin, Turin, Italy.

The clinical spectrum of the antiphospholipid syndrome (APS) encompasses additional manifestations other than thrombosis and pregnancy morbidity, which may potentially affect every organ and system. The pathophysiology of APS indeed cannot be explained exclusively by a prothrombotic state and the "extra-criteria" manifestations of the syndrome should be attributed to other mechanisms, such as inflammation, complement and platelet activation. In this case-series, we report patients with uncommon clinical APS presentations, to highlight relevant peculiarities of the syndrome, potentially paving the way for a further update of clinical as well as laboratory manifestations of this complex immunological condition.
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http://dx.doi.org/10.1177/0961203321995248DOI Listing
May 2021

A 3-Year Observational Study of Patients with Progressive Systemic Sclerosis Treated with an Intensified B Lymphocyte Depletion Protocol: Clinical and Immunological Response.

J Clin Med 2021 Jan 14;10(2). Epub 2021 Jan 14.

Center of Research of Rheumatology, Nephrology and Rare Diseases, Coordinating Center of the Interregional Network of Rare Diseases of Piedmont and Aosta Valley, SCDU CMID-Nephrology and Dialysis G. Bosco Hospital and University of Turin, 10154 Turin, Italy.

Background: B-cells have been suggested to play a role in the pathogenesis of systemic sclerosis (SSc), representing, therefore, a potential therapeutic target.

Objectives: We aimed at investigating the 36-month outcomes of 20 SSc patients who underwent an intensified B-depletion therapy (IBCDT) scheme, including both Rituximab (RTX) and cyclophosphamide (CYC).

Methods: Data from 20 severe patients (18 females and 2 males, mean age 66.7 ± 11.0 years) with diffuse SSc (anti-topoisomerase I antibody in 95%) patients with multiorgan involvement including interstitial lung disease (ILD) treated with an IBCDT were prospectively collected. IBCDT comprehended: RTX 375 mg/m administered for four weekly doses (on days 1, 8, 15, and 22), followed by two additional doses after 30 and 60 days, in addition to two administrations of 10 mg/kg of intravenous CYC plus three methylprednisolone pulses (15 mg/kg) and subsequently followed by oral prednisone rapidly tapered to low minimum dosage of 5 mg daily. In addition, 10 patients with more severe functional respiratory impairment at baseline were also treated with RTX 500 mg every 4 months during the first year and two times a year during the second and the third year.

Results: After 36 months of follow-up, we recorded significant amelioration in N-terminal-pro-brain natriuretic peptide (NT-proBNP) levels (mean 385.4 ± 517 pg/mL at baseline to 279 ± 543 after 36 months). In addition, a significant radiological improvement of ILD in 20% of patients (4/20) and a radiological stabilization with no sign of progression of interstitial involvement in 13/20 (65%) were documented. A total of 3 out of 20 (15%) patients experienced a worsening of the ILD. No patient showed further decrease in functional respiratory parameters, including forced vital capacity, forced expiratory volume in one second, and mean values of diffusing capacity for carbon monoxide Moreover, no patient showed any change in the ejection fraction and pulmonary artery pressure when comparing values at baseline and after 24 and 36 months of observation. No severe infection, renal flare, RTX-related side effects were observed. No patient died.

Conclusions: Our findings support that the IBCDT was well tolerated and might be a promising therapeutic option for the management of SSc, especially in those subjects with multiorgan involvement that includes ILD.
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http://dx.doi.org/10.3390/jcm10020292DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7830314PMC
January 2021

Antiphospholipid Antibodies in Inflammatory and Autoimmune Rheumatic and Musculoskeletal Diseases Beyond Lupus: A Systematic Review of the Available Evidence.

Rheumatol Ther 2021 Mar 9;8(1):81-94. Epub 2021 Jan 9.

Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon.

Background: The diagnosis of antiphospholipid syndrome (APS) requires the presence of thrombosis and/or recurrent miscarriages along with one or more anti-phospholipid antibodies (aPL). The role of aPL has been largely investigated in systemic lupus erythematosus (SLE) with minimal data on other autoimmune rheumatic diseases. In this review, we aim to assess the prevalence of aPL in patients with inflammatory and autoimmune rheumatic and musculoskeletal diseases (RMDs) other than SLE, and their association with thrombosis.

Results: A total of 20 studies, including 3242 patients, measured aPL in different inflammatory and autoimmune RMDs. The overall median percentage of aPL-positive patients was 14.05% (from 0 to 57.5%). For systemic sclerosis (SSc) patients, the median positivity was 14.05% for aPL, with IgG aCL being detected in up to 35.48% of all SSc aPL-positive patients. Only six studies (30%) performed an antibody confirmation test after 12 weeks, with the median prevalence being 10.88% (from 0 to 29.79%). Only six studies also assessed the number of double or triple aPL-positive patients. A total of eight (40%) studies including 1071 patients investigated the association between aPL and thrombotic events, namely five for SSc, one for SS, one for ANCA associated vasculitides (AAV), and one for RA. A median of 18.75% (7.69-71.43%) of aPL-positive patients experienced an arterial event in comparison to a median of 13.66% (7.69-31.25%) who underwent venous thrombotic event. Taking into consideration only the studies that performed a confirmation test, a median value of 34.36% (12.9-71.43%) of aPL-positive patients underwent an arterial event and a median value of 16.32% (9.68-25%) of aPL-positive patients underwent a venous event.

Conclusions: Anti-phospholipid antibodies can be detected in up to a third of patients with inflammatory and autoimmune RMDs, especially in SSc. However, there was a large heterogeneity among the retrieved studies. Available data supporting a general screening for aPL in all inflammatory and autoimmune RMDs are still insufficient. Screening for aPL in selected scenarios (e.g., pregnancy planning) could be considered.
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http://dx.doi.org/10.1007/s40744-020-00273-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7991011PMC
March 2021

The effect of hydroxychloroquine on platelet activation in model experiments.

J Thromb Thrombolysis 2021 Jan 2. Epub 2021 Jan 2.

Fifth Department of Medicine (Nephrology/Endocrinology/Rheumatology), University Medical Centre Mannheim, Medical Faculty Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167, Mannheim, Germany.

Hydroxychloroquine (HCQ) is an antimalarial agent with pleiotropic effects and now represents a cornerstone in the management of patients with autoimmune conditions. While clinical series suggest anti-thrombotic properties, the way in which HCQ exerts this effect remains to be fully explained. Following a 24-h incubation of human umbilical vein endothelial cells (HUVEC) and human umbilical arterial endothelial cells (HUAEC) with HCQ (concentration 500, 1000 and 2000 ng/ml), these cells were then stimulated for an hour with tumor necrosis factor alpha (TNF-α) and were subsequently incubated in direct contact with thrombin-activated platelets. The expression of CD40L on platelets was measured by flow cytometry. The expression of CD40L on platelets significantly increased after direct incubation with 1000 ng/ml and 2000 ng/ml concentrations of HCQ. In contrast, after pre-incubation of HUAECs with 1000 ng/ml HCQ and following stimulation with platelets the expression of CD40L was significantly reduced also after stimulation with thrombin and TNF-α activated platelets. It was shown that the expression of CD40L on the platelets was not significantly reduced by different HCQ concentrations after contact with HCQ pre-incubated HUVECs. HCQ reduces the stimulatory effect of thrombin and TNF-α on platelet activation in the presence of endothelial cells. Our experiments suggest that HCQ pre-incubated HUAEC cells result in a reduced platelets activation measured by means of CD40L expression. Further, our results show that direct HCQ incubation of platelets (without the presence of EC) increased the expression of CD40L suggesting that the observed effect of HCQ on platelet activation may be EC mediated.
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http://dx.doi.org/10.1007/s11239-020-02325-yDOI Listing
January 2021

Validation of the Particle-Based Multi-Analyte Technology for Detection of Anti-PhosphatidylSerine/Prothrombin Antibodies.

Biomedicines 2020 Dec 17;8(12). Epub 2020 Dec 17.

Center of Research of Immunopathology and Rare Diseases-Coordinating Center of Piemonte and Valle d'Aosta Network for Rare Diseases, S. Giovanni Bosco Hospital, Department of Clinical and Biological Sciences, University of Turin, 10154 Turin, Italy.

Among "extra-criteria" antiphospholipid antibodies (aPL), anti-phosphatidylserine/prothrombin (aPS/PT) antibodies, are considered a part of risk assessment strategies when investigating patients suspected of having antiphospholipid syndrome (APS). aPL detection is currently performed by solid-phase assays to identify anti-cardiolipin (aCL), anti-β2glycoprotein I (aβ2GPI) and aPS/PT antibodies, but new techniques are emerging. Among these, particle-based multi-analyte technology (PMAT), which allows the full automation and simultaneous digital detection of autoantibodies and proteins, including IgG, IgA and IgM isotypes of aCL, aβ2GPI and aPS/PT. The aim of this study was to investigate the agreement of aPS/PT testing between enzyme-linked immunosorbent assay (ELISA) and the PMAT platform. A total of 94 patients were enrolled in the study, including 71 patients with confirmed APS and 23 "aPL carriers". aPS/PT IgG showed a moderate binomial agreement between ELISA and PMAT (k = 0.57, 95% CI 0.45-0.75), and aPS/PT IgM showed a moderate agreement (k = 0.60, 95% CI 0.45-0.75). Moreover, when considering the continuous agreement, both aPS/PT IgG and IgM showed a statistically significant correlation between ELISA and PMAT (Spearman's correlation = 0.69, < 0.001 and 0.72, < 0.001, respectively). This study demonstrates that PMAT technology is a reliable method for aPS/PT IgG and IgM testing when compared to the available commercial ELISA kit.
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http://dx.doi.org/10.3390/biomedicines8120622DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7766094PMC
December 2020

Genetic Factors in Antiphospholipid Syndrome: Preliminary Experience with Whole Exome Sequencing.

Int J Mol Sci 2020 Dec 15;21(24). Epub 2020 Dec 15.

Center of Research of Immunopathology and Rare Diseases-Coordinating Center of Piemonte and Aosta Valley Network for Rare Diseases, S. Giovanni Bosco Hospital, Department of Clinical and Biological Sciences, University of Turin, 10154 Turin, Italy.

As in many autoimmune diseases, the pathogenesis of the antiphospholipid syndrome (APS) is the result of a complex interplay between predisposing genes and triggering environmental factors, leading to a loss of self-tolerance and immune-mediated tissue damage. While the first genetic studies in APS focused primarily on the region, more recent data highlighted the role of other genes in APS susceptibility, including those involved in the immune response and in the hemostatic process. In order to join this intriguing debate, we analyzed the single-nucleotide polymorphisms (SNPs) derived from the whole exome sequencing (WES) of two siblings affected by APS and compared our findings with the available literature. We identified genes encoding proteins involved in the hemostatic process, the immune response, and the phospholipid metabolism (, , , , , , and ) of potential interest when debating the pathogenesis of the syndrome. The study of the selected SNPs in a larger cohort of APS patients and the integration of WES results with the network-based approaches will help decipher the genetic risk factors involved in the diverse clinical features of APS.
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http://dx.doi.org/10.3390/ijms21249551DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7765384PMC
December 2020

The Challenging Management of Cancer: An Immunonephrologist's Perspective.

Kidney Blood Press Res 2021 16;46(1):114-120. Epub 2020 Dec 16.

Nephrology and Dialysis Unit & CMID (Center of Research of Immunopathology and Rare Diseases), Coordinating Center of the Network for Rare Diseases of Piedmont and Aosta Valley, San Giovanni Bosco Hub Hospital of Turin, and Department of Clinical and Biological Sciences, University of Turin, Turin, Italy.

Introduction: Onconephrology is an emerging medical subspecialization that focuses on the numberless interrelations between cancer and kidney diseases. Tumor cells evade immune surveillance through activation of immune checkpoint pathways that suppress antitumor immune responses. By blocking checkpoints, new anticancer agents disrupt immune homeostasis but potentially induce immune-mediated diseases. Nephrologists and nephroimmunologists should be able to treat the nephrotoxic sequelae of cancer therapy and ensure continuation of the life-saving treatment.

Methods: Thirty-seven renal biopsies have been carried out over 42 months in oncologic patients, that is, 5.2% of the total native renal biopsies were carried out in the same period. The commonest diagnoses (>6 cases) were interstitial tubular nephritis, membranous glomerulopathy, IgA nephropathy, vasculitis, and focal and segmental glomerulosclerosis.

Case Presentation: Three example cases, including focusing on key questions which could involve the nephrologists are reported in detail. They include a cancer-related Goodpasture Syndrome, the peculiar toxic effects of pemetrexed on tubular cells, and the intriguing relationship between bevacizumab and cryoglobulinemic glomerulonephritis.

Conclusion: As shown by these 3 example cases, nephrologists need to be open-minded with regard to kidney biopsy in order to get a timely diagnosis. Nephrologists also need to improve their knowledge of cancer biology and therapy in order to prevent kidney problems, manage therapy-related immune-mediated disorders, and improve patient life expectancy.
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http://dx.doi.org/10.1159/000511256DOI Listing
June 2021

Antiphospholipid Antibody Profile Stability Over Time: Prospective Results From the APS ACTION Clinical Database and Repository.

J Rheumatol 2020 Sep 1. Epub 2020 Sep 1.

The APS ACTION registry was created using REDCAP provided by the Clinical and Translational Science Center at Weill Cornell Medical College (CTSC grant UL1 TR000457). For this work, EG was supported by Clinical and Translational Science Center at Weill Cornell Medicine (UL1 TR002384). E. Gkrouzman, MD, MS, Hospital for Special Surgery, New York, New York, USA; E. Sevim, MD, Department of Medicine, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, New York, New York, USA; J. Finik, MPH, Department of Psychiatry and Behavioral Sciences, Memorial Sloan Kettering Cancer Center, New York, New York, USA; D. Andrade, MD, PhD, University of São Paulo, São Paulo, Brazil; V. Pengo, MD, University Hospital Padova, Padova, Italy; S. Sciascia, MD, PhD, Center of Research of Immunopathology and Rare Diseases, University of Turin, Turin, Italy; M.G. Tektonidou, MD, PhD, National and Kapodistrian University of Athens, Athens, Greece; A. Ugarte, MD, Hospital Universitario Cruces, Barakaldo, País Vasco, Spain; C.B. Chighizola, MD, PhD, Clinical Immunology & Rheumatology Unit, IRCCS Istituto Auxologico Italiano, Milan, Italy; H.M. Belmont, MD, Hospital for Joint Diseases, New York University, New York, New York, USA; C. Lopez-Pedrera, PhD, Rheumatology Service, IMIBIC/Reina Sofia Hospital, University of Cordoba, Cordoba, Spain; L. Ji, MD, Rheumatology and Immunology Department, Peking University First Hospital, Beijing, China; P. Fortin, MD, CHU de Québec-Université Laval, Québec City, Québec, Canada; M. Efthymiou, PhD, H. Cohen, MD, Haemostasis Research Unit, Department of Haematology, University College London, London, UK; G. Ramires de Jesus, MD, MSc, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, Brazil; D.W. Branch, MD, University of Utah and Intermountain Healthcare, Salt Lake City, Utah, USA; C. Nalli, MD, Rheumatology and Immunology Unit, ASST Spedali Civili of Brescia, Brescia, Italy; M. Petri, MD, MPH, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA; E. Rodriguez, MD, Hospital Universitario 12 de Octubre, Madrid, Spain; R. Cervera, MD, PhD, FRCP, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Catalonia, Spain; J.S. Knight, MD, PhD, Division of Rheumatology, University of Michigan, Ann Arbor, Michigan, USA; T. Atsumi, MD, PhD, Hokkaido University Hospital, Sapporo, Japan; R. Willis, MD, Antiphospholipid Standardization Laboratory, University of Texas Medical Branch, Galveston, Texas, USA; M.L. Bertolaccini, PhD, Academic Department of Vascular Surgery, King's College London British Heart Foundation Centre of Excellence, School of Cardiovascular Medicine & Sciences, London, UK; J. Rand, MD, Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, New York, USA; D. Erkan, MD, MPH, Barbara Volcker Center for Women and Rheumatic Diseases, Hospital for Special Surgery, Weill Cornell Medicine, New York, New York, USA. MP (Hopkins Lupus Cohort) is supported by a grant from the NIH RO1 AR069572. PF is recipient of a tier 1 Canada Research Chair on Systemic Autoimmune Rheumatic Diseases. MLB is supported by the King's British Heart Foundation Centre for Research Excellence Award RE/18/2/34213. The rest of the authors report no conflicts of interest. Address correspondence to Dr. E. Gkrouzman, 535 East 70th Street, New York, NY 10021, USA. Email: Accepted for publication August 18, 2020.

Objective: The APS ACTION Registry studies long-term outcomes in persistently antiphospholipid antibody (aPL)-positive patients. Our primary objective was to determine whether clinically meaningful aPL profiles at baseline remain stable over time. Our secondary objectives were to determine (1) whether baseline characteristics differ between patients with stable and unstable aPL profiles, and (2) predictors of unstable aPL profiles over time.

Methods: A clinically meaningful aPL profile was defined as positive lupus anticoagulant (LAC) test and/or anticardiolipin (aCL)/anti-β glycoprotein-I (anti-β-GPI) IgG/M ≥ 40 U. Stable aPL profile was defined as a clinically meaningful aPL profile in at least two-thirds of follow-up measurements. Generalized linear mixed models with logit link were used for primary objective analysis.

Results: Of 472 patients with clinically meaningful aPL profile at baseline (median follow-up 5.1 yrs), 366/472 (78%) patients had stable aPL profiles over time, 54 (11%) unstable, and 52 (11%) inconclusive. Time did not significantly affect odds of maintaining a clinically meaningful aPL profile at follow-up in univariate ( = 0.906) and multivariable analysis ( = 0.790). Baseline triple aPL positivity decreased (OR 0.25, 95% CI 0.10-0.64, = 0.004) and isolated LAC test positivity increased (OR 3.3, 95% CI 1.53-7.13, = 0.002) the odds of an unstable aPL profile over time.

Conclusion: Approximately 80% of our international cohort patients with clinically meaningful aPL profiles at baseline remain stable at a median follow-up of 5 years; triple aPL-positivity increase the odds of a stable aPL profile. These results will guide future validation studies of stored blood samples through APS ACTION Core Laboratories.
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http://dx.doi.org/10.3899/jrheum.200513DOI Listing
September 2020

Clinical exome sequencing is a powerful tool in the diagnostic flow of monogenic kidney diseases: an Italian experience.

J Nephrol 2020 Nov 23. Epub 2020 Nov 23.

Department of Medical Sciences, University of Turin, via Santena 19, 10126, Turin, Italy.

Background: A considerable minority of patients on waiting lists for kidney transplantation either have no diagnosis (and fall into the subset of undiagnosed cases) because kidney biopsy was not performed or histological findings were non-specific, or do not fall into any well-defined clinical category. Some of these patients might be affected by a previously unrecognised monogenic disease.

Methods: Through a multidisciplinary cooperative effort, we built an analytical pipeline to identify patients with chronic kidney disease (CKD) with a clinical suspicion of a monogenic condition or without a well-defined diagnosis. Following the stringent phenotypical and clinical characterization required by the flowchart, candidates meeting these criteria were further investigated by clinical exome sequencing followed by in silico analysis of 225 kidney-disease-related genes.

Results: By using an ad hoc web-based platform, we enrolled 160 patients from 13 different Nephrology and Genetics Units located across the Piedmont region over 15 months. A preliminary "remote" evaluation based on well-defined inclusion criteria allowed us to define eligibility for NGS analysis. Among the 138 recruited patients, 52 (37.7%) were children and 86 (62.3%) were adults. Up to 48% of them had a positive family history for kidney disease. Overall, applying this workflow led to the identification of genetic variants potentially explaining the phenotype in 78 (56.5%) cases.

Conclusions: These results underline the importance of clinical exome sequencing as a versatile and highly useful, non-invasive tool for genetic diagnosis of kidney diseases. Identifying patients who can benefit from targeted therapies, and improving the management of organ transplantation are further expected applications.
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http://dx.doi.org/10.1007/s40620-020-00898-8DOI Listing
November 2020

The global antiphospholipid syndrome score in women with systemic lupus erythematosus and adverse pregnancy outcomes.

Clin Exp Rheumatol 2020 Nov 12. Epub 2020 Nov 12.

Center of Research of Immunopathology and Rare Diseases - Coordinating Center of Piemonte and Valle d'Aosta Network for Rare Diseases, Department of Clinical and Biological Sciences, and SCDU Nephrology and Dialysis, S. Giovanni Bosco Hospital, Turin, Italy.

Objectives: To validate the global antiphospholipid syndrome score (GAPSS) in a cohort of women with systemic lupus erythematosus (SLE) and antiphospholipid antibodies (aPL).

Methods: This retrospective study included 143 women ever pregnant with SLE who presented in our outpatient clinic were included. Data on cardiovascular risk factors and aPL status were retrospectively collected and their individual GAPSS score was calculated.

Results: Significantly higher GAPSS values were found in women with any placental medicated complication (such as foetal death, placental abruption, prematurity, pre-eclampsia or intrauterine growth restriction (IUGR)) (GAPSS 8.2±3.0 vs. 3.5±3.0, p<0.001). Significantly higher GAPSS values were also found in those with recurrent miscarriages (RM) <10 weeks, foetal death, placental abruption, prematurity, pre-eclampsia or IUGR) (GAPSS 8.3±4.5 vs. 3.2±2.6, p<0.001). Patients with 3 or more consecutive early miscarriages (<10 weeks), foetal death, miscarriage <10 weeks' gestation, premature birth (<34 weeks), pre-eclampsia (<34 weeks), stillbirth, and placental infarction had significantly higher GAPSS values compared to those without previous pregnancy complications. The odds ratio of having any pregnancy morbidity when having a GAPSS value ≥8 was 20 compared to those with a GAPSS of ≤1 (p<0.001).

Conclusions: Women with a history of aPL-related pregnancy complications had higher GAPSS values in this retrospective cohort compared to women without pregnancy complications. This study is the first step to assess the clinical utility of the GAPSS score in pregnancy. A prospective validation is needed.
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November 2020

Cryoglobulinemic glomerulonephritis: clinical presentation and histological features, diagnostic pitfalls and controversies in the management. State of the art and the experience on a large monocentric cohort treated with B cell depletion therapy.

Minerva Med 2021 Apr 16;112(2):162-174. Epub 2020 Nov 16.

Unit of Nephrology and Dialysis (ERKnet Member), Department of Clinical and Biological Sciences, Center of Research of Immunopathology and Rare Diseases, Coordinating Center of the Network for Rare Diseases of Piedmont and Aosta Valley, San Giovanni Bosco Hospital, University of Turin, Turin, Italy -

Cryoglobulinemia is defined by the presence of immunoglobulins having the following characteristics: forming a gel when temperature is <37 °C, precipitate in a reversible manner in the serum, and redissolve after rewarming. The presence of both polyclonal IgG and monoclonal IgM (type II), or of polyclonal IgG and polyclonal IgM (type III) identifies the mixed cryoglobulinemia (MC). The identification of the Hepatitis C virus (HCV) infection in most of the cases previously defined as "essential" represented a cornerstone in the understanding the pathogenesis of this condition. The picture of MC comprehends heterogeneous clinical presentations: from arthralgias, mild palpable purpura, fatigue to severe vasculitis features with skin necrotic pattern, peripheral neuropathy and, less commonly, lungs, central nervous system, gastrointestinal tract, and heart involvement. The kidney represents the most common organ presentation, and the presence of glomerulonephritis is a key element when considering prognosis. We discuss the clinical presentation and histological features, diagnostic pitfalls, and controversies in the management of patients with cryoglobulinemic glomerulonephritis, with a special focus on reporting our experience in treating patients with B cell depletion therapy.
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http://dx.doi.org/10.23736/S0026-4806.20.07076-7DOI Listing
April 2021

Long-term effects of intensive B cell depletion therapy in severe cases of IgG4-related disease with renal involvement.

Immunol Res 2020 12 10;68(6):340-352. Epub 2020 Nov 10.

Nephrology and Dialysis Universitary Unit, and Center of Research of Immunopathology and Rare Diseases (CMID) San Giovanni Bosco Hospital, and Department of Clinical and Biological Sciences, University of Turin, Turin, Italy.

IgG4-related disease (IgG4-RD) is an immune-mediated disorder often showing elevated serum IgG4 concentrations, dense T and B lymphocyte infiltration, and IgG4-positive plasma cells and storiform fibrosis. We prospectively evaluated for 4 years 5 patients with histologically proven IgG4-RD of whom 3 had tubulointerstitial nephritis (TIN) and 2 had retroperitoneal fibrosis (RPF). They received an intensive B depletion therapy with rituximab. The estimated glomerular filtration rate of TIN patients after 1 year increased from 9 to 24 ml/min per 1.73 m2. IgG/IgG4 dropped from 3236/665 to 706/51 mg/dl, C3/C4 went up from 49/6 to 99/27 mg/dl, and the IgG4-RD responder index fell from 10 to 1. CD20 B cells decreased from 8.7 to 0.5%. A striking drop in interstitial plasma cell infiltrate as well as normalization of IgG4/IgG-positive plasma cells was observed at repeat biopsy. Both clinical and immunological improvement persisted over a 4-year follow-up. Treating these patients who were affected by aggressive IgG4-RD with renal involvement in an effort to induce a prolonged B cells depletion with IgG4 and cytokine production decrease resulted in a considerable rise in eGFR, with IgG4-RD RI normalization and a noteworthy improvement in clinical and histological features. Furthermore, the TIN subgroup was shown not to need for any maintenance therapy.
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http://dx.doi.org/10.1007/s12026-020-09163-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7674183PMC
December 2020

Endothelial dysfunction and cardiovascular risk in lupus nephritis: New roles for old players?

Eur J Clin Invest 2021 Feb 15;51(2):e13441. Epub 2020 Nov 15.

Department of Clinical and Biological Sciences, Center of Research of Immunopathology and Rare Diseases-Nephrology and Dialysis S. Giovanni Bosco Hospital, University of Turin, Turin, Italy.

In systemic lupus erythematosus (SLE) patients, most of the clinical manifestation share a vascular component triggered by endothelial dysfunction. Endothelial cells (ECs) activation occurs both on the arterial and venous side, and the high vascular density of kidneys accounts for the detrimental outcomes of SLE through lupus nephritis (LN). Kidney damage, in turn, exerts a negative feedback on the cardiovascular (CV) system aggravating risk factors for CV diseases such as hypertension, stroke and coronary syndrome among others. Despite the intensive investigation on SLE and LN, the role of endothelial dysfunction, as well as the underlying mechanisms, remains to be fully understood, with no specifically targeted pharmacological treatment. It is not known, in fact, if the activation pathway(s) in venous ECs are similar to the one in arterial ECs and doubts persist on the shared manifestation of microcirculation compared to macrocirculation. In this work, we aim to review the recent literature about the role of endothelial activation and dysfunction in the development of CV complications in SLE and LN patients. We, therefore, focus on arteriovenous similarities and differences and on specific pathways of great vessels compared to capillaries. Critically summarising the available data is of pivotal importance for both basic researchers and clinicians in order to develop and test new pharmacological approaches in the treatment of basic components of SLE and LN.
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http://dx.doi.org/10.1111/eci.13441DOI Listing
February 2021

EULAR recommendations for a core data set for pregnancy registries in rheumatology.

Ann Rheum Dis 2021 01 14;80(1):49-56. Epub 2020 Oct 14.

Epidemiology and Health Care Research, German Rheumatism Research Center Berlin, Berlin, Germany.

Background And Objective: There is an urgent need for robust data on the trajectories and outcomes of pregnancies in women with inflammatory rheumatic diseases (IRD). In particular when rare outcomes or rare diseases are to be investigated, collaborative approaches are required. However, joint data analyses are often limited by the heterogeneity of the different data sources.To facilitate future research collaboration, a European League Against Rheumatism (EULAR) Task Force defined a core data set with a minimum of items to be collected by pregnancy registries in rheumatology covering the period of pregnancy and the 28-day neonatal phase in women with any underlying IRD.

Methods: A stepwise process included a two-round Delphi survey and a face-to-face meeting to achieve consensus about relevant items.

Results: A total of 64 multidisciplinary stakeholders from 14 different countries participated in the two rounds of the Delphi process. During the following face-to-face meeting of the EULAR Task Force, consensus was reached on 51 main items covering 'maternal information', 'pregnancy' and 'treatment'. Generic instruments for assessment are recommended for every item. Furthermore, for the five most frequent IRDs rheumatoid arthritis, spondyloarthritis, juvenile idiopathic arthritis, systemic lupus erythematosus and other connective tissue diseases, disease-specific laboratory markers and disease activity measurements are proposed.

Conclusion: This is the first consensus-based core data set for prospective pregnancy registries in rheumatology. Its purpose is to stimulate and facilitate multinational collaborations that aim to increase the knowledge about pregnancy course and safety of treatment in women with IRDs during pregnancy.
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http://dx.doi.org/10.1136/annrheumdis-2020-218356DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7788063PMC
January 2021

Daratumumab Monotherapy in Severe Patients with AL Amyloidosis and Biopsy-Proven Renal Involvement: A Real Life Experience.

J Clin Med 2020 Oct 9;9(10). Epub 2020 Oct 9.

CMID-Nephrology and Dialysis Unit (ERK-net Member)-Center of Research of Nephrology, Rheumatology, and Rare Diseases, Interregional Coordinating Center of the Network of Rare Diseases, G. Bosco Hospital and University of Turin, 10152 Turin, Italy.

Objectives: This paper aims to describe the clinical experience with Daratumumab (DARA), a first-in-class anti-CD38 human monoclonal IgG1κ antibody monotherapy, in severe patients with AL and biopsy-proven renal involvement. Immunoglobulin light chain (AL) amyloidosis with multi-organ involvement is characterized by short survival. Novel powerful drugs are expanding the therapeutic options. Current treatment of AL amyloidosis, which has been adopted from multiple myeloma (MM), is based on chemotherapy targeting the underlying plasma cell clone. DARA is effective in treating MM. The clinical activity and toxicity profile of DARA as a single agent in the treatment of AL amyloidosis is currently under evaluation.

Patients And Methods: DARA was administered in a series of patients with severe AL amyloidosis and biopsy-proven renal involvement. Five patients(mean age 64.2 years) were treated. One patient was refractory and one intolerant to conventional bortezomib-based therapy, two were treated with DARA for relapsing disease, and one was treated front-line.

Results: Data showed that DARA monotherapy resulted in good clinical results, with the disappearance of M-proteins in four out of five patients and with serum free light chains (sFLC) ratio normalization in three out of four and a remarkable amelioration in the remaining patient. The four patients with still preserved renal function at baseline also showed serum creatinine stabilization or improvement and a decrease in proteinuria. These data were paralleled by the reduction of the N-terminal prohormone of brain natriuretic peptide (NT pro-BNP)values.

Conclusions: Our data show that monotherapy with DARA had significant clinical efficacy in pretreated/naïve patients with severe AL amyloidosis and biopsy-proven renal involvement.
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http://dx.doi.org/10.3390/jcm9103232DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7600836PMC
October 2020