Publications by authors named "Fulvia Ceccarelli"

139 Publications

The role of musculoskeletal ultrasound in predicting the response to JAK inhibitors: results from a monocentric cohort.

Clin Exp Rheumatol 2021 Jun 26. Epub 2021 Jun 26.

Arthritis Center, Reumatologia, Dipartimento di Scienze Cliniche Internistiche, Anestesiologiche e Cardiovascolari, Sapienza Università di Roma, Italy.

Objectives: In this longitudinal study, we assessed the role of musculoskeletal ultrasound (US) in predicting the efficacy of JAK inhibitors (JAKi) in rheumatoid arthritis (RA) patients.

Methods: We enrolled RA patients starting baricitinib or tofacitinib. All patients were evaluated at baseline and after 4, 12, 24, 48 weeks. Disease activity was calculated by Disease Activity Score 28 (DAS28CRP); US examination in 22 joints (I-V MCPs and PIPs, wrists) aimed at evaluating inflammatory features (synovial effusion and hypertrophy, power Doppler-PD), scored through a semi-quantitative scale (0-3). The total US (0-198) and PD (0-66) scores were calculated. We scanned bilateral flexor (I-V fingers of hands) and extensor compartments (1-6) tendons: tenosynovitis was scored as absent/present (0/1), resulting in a total score ranging from 0 to 22.

Results: We studied 102 patients (M/F 15/87; median age 59.2 years, IQR 17.75; median disease duration 144 months, IQR 126), 61 treated with baricitinib and 41 with tofacitinib. At baseline, the median total US score was 18 (IQR 19) and the median PD score 2 (4). We observed a significant reduction in both total and PD US scores at all time-points (p<0.0001). At baseline, 75.4% of patients showed tenosynovitis involving at least one tendon, with a median score of 2 (IQR 3.5) significantly decreasing after 24 weeks (p=0.02). At multivariate analysis, PD and tenosynovitis score significantly correlated with changes in DAS28CRP.

Conclusions: The present study confirmed the early efficacy of JAKi in RA patients by using US evaluation. Furthermore, we found that power Doppler and tenosynovitis scores could play a predictive role in response to treatment.
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June 2021

Application of Ultrasound in the Assessment of Oligoarticular Psoriatic Arthritis Subset: Results from Patients Treated with Apremilast.

Isr Med Assoc J 2021 Jul;23(7):412-415

Department of Clinical, Internal, Anesthetic and Cardiovascular Science-Rheumatology Unit, Sapienza University of Rome, Rome, Italy.

Background: Psoriatic arthritis (PsA) is an inflammatory rheumatic disease characterized by different phenotypes in terms of joint involvement. The so-called oligoarticular pattern involves fewer than five active joints at a different time points. The evaluation of disease activity in this subset of patients is an unmet need due to the lack of specific indices able to capture modifications over time.

Objectives: To evaluate the ability of musculoskeletal ultrasound to monitor the response to apremilast treatment in oligoarticular PsA patients.

Methods: We evaluated 24 oligoarticular patients (19 women, 5 men; median age 56 years, interquartile range (IQR) 19; median disease duration 5 years, IQR 5.75). All patients were assessed at baseline (T0), and after 6 (T1), 12 (T2), and 24 (T3) weeks. Clinical assessment included evaluation of 66 swollen joints and patient global health assessment. All the patients underwent ultrasound assessment of the clinically involved joints. Synovial effusion/hypertrophy and power Doppler were scored with a semi-quantitative scale (0-3). The total inflammatory score was the sum of the scores.

Results: We found a reduction in the ultrasound inflammatory score at all time points, with a significant improvement at 6 and 12 weeks of treatment compared with baseline: T0 median 8.5 (IQR 5.0); T1 3.5 (3.0); T2 2.0 (3.5); P  = 0.01. We observed a significant reduction of patient global health assessment after 24 weeks (T0 median 50 (32.5); T3 40 (57.5); P = 0.01).

Conclusions: Musculoskeletal ultrasound could be useful in the assessment of treatment response in PsA patients with oligoarticular subset.
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July 2021

Systemic Lupus Erythematosus before and after COVID-19 Lockdown: How the Perception of Disease Changes through the Lenses of Narrative Medicine.

Healthcare (Basel) 2021 Jun 12;9(6). Epub 2021 Jun 12.

Lupus Clinic, Reumatologia, Dipartimento di Scienze Cliniche, Internistiche, Anestesiologiche e Cardiovascolari, Sapienza Università di Roma, 00161 Roma, Italy.

Background: The COVID-19 pandemic contributes to the burden of living with different diseases, including Systemic Lupus Erythematosus (SLE). We described, from a narrative point of view, the experiences and perspectives of Italian SLE adults during the COVID-19 emergency, by distinguishing the illness experience before and after the lockdown.

Methods: Fifteen patients were invited to participate. Illness narratives were collected between 22 and 29 March 2020 using a written modality to capture patients' perspectives before and after the COVID-19 lockdown. We performed a two-fold analysis of collected data by distinguishing three narrative types and a qualitative analysis of content to identify the relevant themes and sub-themes reported.

Results: Eight narratives included in the final analysis (mean length 436.9 words) have been written by eight females (mean age 43.3 ± 9.9 years, mean disease duration 13.1 ± 7.4 years). Six patients provided a quest narrative, one a chaos and the remaining one a restitution narrative. By text content analysis, we identified specific themes, temporally distinct before and after the lockdown. Before COVID-19, all the patients referred to a good control of disease, however the unexpected arrival of the COVID-19 emergency broke a balance, and patients perceived the loss of health status control, with anxiety and stress.

Conclusions: We provided unique insight into the experiences of people with SLE at the time of COVID-19, underlining the perspective of patients in relation to the pandemic.
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http://dx.doi.org/10.3390/healthcare9060726DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8231514PMC
June 2021

SARS-CoV-2 vaccination efficacy and B-cell depletion therapy in systemic lupus erythematosus: Description of a case.

Lupus 2021 Jul 1:9612033211027940. Epub 2021 Jul 1.

Lupus Clinic, Reumatologia, Dipartimento di Scienze Cliniche Internistiche, Anestesiologiche e Cardiovascolari, Sapienza Università di Roma, Roma, Italy.

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http://dx.doi.org/10.1177/09612033211027940DOI Listing
July 2021

Five-years drug survival of mycophenolate mofetil therapy in patients with systemic lupus erythematosus: Comparison between renal and non-renal involvement.

Joint Bone Spine 2021 Jun 24;88(6):105246. Epub 2021 Jun 24.

Lupus Clinic, Reumatologia, Dipartimento di Scienze Cliniche Internistiche, Anestesiologiche e Cardiovascolari, Sapienza Università di Roma, Viale del Policlinico 155, 00161 Roma, Italy.

Objective: The EULAR recommendations underline the use of MMF for Lupus Nephritis (LN) but also for the treatment of moderate/severe non-renal manifestations (NLN). This study aims at evaluating the 5-years drug retention rate (DRR) of MMF in a SLE cohort in a real-life scenario. Secondly, we investigated the MMF influence to control chronic damage progression.

Methods: We performed a longitudinal study including all the SLE patients starting MMF in our Lupus Clinic (from 2008 to 2020). The DRR was estimated using the Kaplan-Meier method.

Results: We evaluated 162 SLE patients (M/F 22/140). The most frequent indications for prescribing MMF were LN (101 patients, 62.3%) and musculoskeletal manifestations (39, 24.1%) followed by NPSLE (10, 6.2%) and other manifestations (12, 7.4%). We registered a median treatment duration of 30 months (IQR 55). At 60 months follow-up we observed a DRR of 61.1% for LN patients, which was similar to that registered for patients without renal involvement (60.5%). The DRR was higher in the subgroup of patients with joint involvement (75.4%, P non-significant). During the overall observation period, 92 patients (59.2%) discontinued MMF. The main cause of withdrawal was the achievement of remission, observed in 20 patients (21.7%). Moreover, MMF resulted able to control chronic damage progression, as demonstrated by the lack of significant increase in the median SDI values (baseline: 0.6, IQR 1; last: 0.93, IQR 1).

Conclusions: Our finding suggested that MMF is a safe and effective drug for SLE manifestations other than LN, especially for joint involvement. Moreover, it was able to control the chronic damage progression.
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http://dx.doi.org/10.1016/j.jbspin.2021.105246DOI Listing
June 2021

"Non-criteria antiphospholipid antibodies": bridging the gap between seropositive and seronegative Antiphospholipid Syndrome.

Rheumatology (Oxford) 2021 May 10. Epub 2021 May 10.

Reumatologia, Dipartimento di Scienze Cliniche Internistiche, Anestesiologiche e Cardiovascolari, Sapienza Università Roma, Rome, Italy.

Objective: We aimed to analyze the prevalence of non-criteria anti-phospholipid (aPL) antibodies and their role in the diagnosis, treatment and prognosis in a cohort of patients with clinical features consistent with a diagnosis of antiphospholipid syndrome (APS), but persistently negative for criteria aPL-anti-cardiolipin antibodies (aCL), anti-β2-glycoprotein I antibodies (aβ2-GPI), and lupus anticoagulant (LA) - named seronegative APS (SN-APS).

Methods: Sera from SN-APS patients were tested for aCL by TLC-immunostaining, anti-vimentin/cardiolipin (aVim/CL) and anti-phosphatidylserine/prothrombin (anti-PS/PT) by ELISA. Control groups of our study were APS patients and healthy controls.

Results: We enrolled 114 consecutive SN-APS patients, 69 (60.5%) resulted positive for at least one non-criteria test in two occasions 12 weeks apart. Among the persistently positive patients to these tests, 97% resulted positive for aCL by TLC-immunostaining, 52.3% for aVim/CL and 17.4% for aPS/PT. SN-APS patients with double positivity (aCL by TLC-immunostaining and aVim/CL) showed a likelihood positive ratio of 8 to present mixed thrombotic and obstetrical features. Among SN-APS patients tested positive, after the therapeutic changes, 3 cases of recurrent thrombosis were observed [median follow-up 41 months (IQR 39.5)]. Twenty pregnancies were recorded in 17 SN-APS patients after the detection of unconventional aPL and 12 of them (60%) experienced a good outcome under conventional treatment for APS.

Conclusions: This is the largest monocentric study demonstrating that aCL tested by TLC-immunostaining and aVim/CL can detect aPL positivity in SN-APS. It may encourage clinicians to monitoring and providing adequate targeted therapy, which improve SN-APS prognosis.
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http://dx.doi.org/10.1093/rheumatology/keab414DOI Listing
May 2021

mRNA expression analysis confirms CD44 splicing impairment in systemic lupus erythematosus patients.

Lupus 2021 Jun 1;30(7):1086-1093. Epub 2021 Apr 1.

Department of Biomedicine & Prevention, Genetics Section, University of Rome "Tor Vergata", Rome, Italy.

Background: Systemic Lupus Erythematosus (SLE) is a complex chronic autoimmune disease characterized by several immunological alterations. T cells have a peculiar role in SLE pathogenesis, moving from the bloodstream to the peripheral tissues, causing organ damage. This process is possible for their increased adherence and migration capacity mediated by adhesion molecules, such as CD44. Ten different variant isoforms of this molecule have been described, and two of them, CD44v3 and CD44v6 have been found to be increased on SLE T cells compared to healthy controls, being proposed as biomarkers of disease and disease activity. The process of alternative splicing of transcripts is not fully understood. We investigated the mRNA expression of and and also analyzed possible splicing regulators (ESRP1 molecule and rs9666607 polymorphism) in a cohort of SLE patients compared to healthy controls.

Methods: This study involved 18 SLE patients and 18 healthy controls. Total RNA and DNA were extracted by peripheral blood mononuclear cells. The expression study was conducted by quantitative RT-polymerase chain reaction, using SYBR Green protocol. Genotyping of rs9666607 SNP was performed by direct sequencing.

Results: mRNA expression was higher in SLE patients compared to healthy controls (p = 0.028). mRNA ratio in healthy controls was strongly unbalanced towards isoform v3 compared to SLE patients (p = 0.002) and decreased progressively from healthy controls to the SLE patients in remission and those with active disease (p = 0.015). The expression levels of and mRNA correlated with the disease duration (p = 0.038, Pearson r = 0.493 and p = 0.038, Pearson r = 0.495, respectively). Splicing regulator expression positively correlated with CD44v6 expression in healthy controls (p = 0.02, Pearson r = 0.532) but not in SLE patients. The variant A allele of rs9666607 of was associated with higher level of global mRNA (p = 0.04) but not with the variant isoforms.

Conclusions: In SLE patients, the increase in CD44v6 protein correlates with a higher transcript level of this isoform, confirming an impairment of splicing in the disease, whose regulatory mechanisms require further investigation.
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http://dx.doi.org/10.1177/09612033211004725DOI Listing
June 2021

Comment on: Real-world single centre use of JAK inhibitors across the rheumatoid arthritis pathway.

Rheumatology (Oxford) 2021 Mar 2. Epub 2021 Mar 2.

Arthritis Center, Reumatologia, Dipartimento di Scienze Cliniche Internistiche, Anestesiologiche e Cardiovascolari-Sapienza University of Rome, Roma, Italy.

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http://dx.doi.org/10.1093/rheumatology/keab195DOI Listing
March 2021

Comprehensive disease control in systemic lupus erythematosus.

Semin Arthritis Rheum 2021 04 19;51(2):404-408. Epub 2021 Feb 19.

Lupus Clinic, Reumatologia, Dipartimento di Scienze Cliniche Internistiche, Anestesiologiche e Cardiovascolari, Sapienza Università di Roma, Viale del Policlinico 155, 00161 Rome, Italy.

Objectives: We evaluated a monocentric SLE cohort in order to assess the frequency of Lupus comprehensive disease control (LupusCDC), a condition defined by the achievement of remission and the absence of damage progression.

Methods: Our longitudinal analysis included SLE patients with 5-years follow-up and at least one visit per year. Disease activity was assessed by SLE Disease Activity Index 2000 (SLEDAI-2K) and three different remission levels were evaluated (Complete Remission, CR; Clinical remission off-corticosteroids; clinical remission on-corticosteroids). Chronic damage was assessed according to SLICC Damage Index (SDI). LupusCDC was defined as remission achievement for at least one year plus absence of chronic damage progression in the previous one year. A machine learning based analysis was carried out, applying and comparing Nonlinear Support Vector Machines (SVM) models and Decision Trees (DT), whereas features ranking was performed with the ReliefF algorithm.

Results: We evaluated 172 patients [M/F 16/156, median age 49 years (IQR 16.7), median disease duration 180 months (IQR 156)]. SDI values (baseline mean±SD 0.7 ± 1.1) significantly increased during the follow-up period. In all time-points analyzed, LupusCDC including CR was the most frequently detected. The failure to reach this condition was significantly associated with renal involvement and with the intake of immunosuppressant drugs and glucocorticoid (GC). Ten patients (5.8%) have maintained LupusCDC during the whole 5-year follow-up: these patients had never presented renal involvement and showed lower prevalence of anti-phospholipid antibodies (p = 0.0001). Finally, the prevalence of GC intake was significantly lower (p = 0.0001). The application of machine learning models showed that the available features were able to provide significant information to build predictive models with an AUC score of 0.703 ± 0.02 for DT and 0.713 ± 0.02 for SVM.

Conclusions: Our data on a monocentric cohort suggest that the LupusCDC can efficaciously merge into one outcome SLE-related disease activity and chronic damage in order to perform an all-around evaluation of SLE patients.
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http://dx.doi.org/10.1016/j.semarthrit.2021.02.005DOI Listing
April 2021

SARS-CoV-2 vaccine hesitancy among patients with rheumatic and musculoskeletal diseases: a message for rheumatologists.

Ann Rheum Dis 2021 07 23;80(7):953-954. Epub 2021 Feb 23.

Dipartimento di Scienze Cliniche, Internistiche, Anestesiologiche e Cardiovascolari- Reumatologia, Sapienza Università di Roma, Rome, Lazio, Italy.

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http://dx.doi.org/10.1136/annrheumdis-2021-220059DOI Listing
July 2021

Breastfeeding in women affected by systemic lupus erythematosus: Rate, duration and associated factors.

Lupus 2021 May 20;30(6):913-920. Epub 2021 Feb 20.

Lupus Clinic, Dipartimento di Scienze Cliniche Internistiche, Anestesiologiche e Cardiovascolari, Sapienza University of Rome, Rome, Italy.

Objective: Breastfeeding is a crucial moment for both mothers and child, providing a beneficial effect on child survival, nutrition, development and on maternal health. Despite the prevalent involvement of childbearing women in systemic lupus erythematosus (SLE), breastfeeding is still a neglected topic. The objective of this study was to evaluate breastfeeding frequency, duration and associated factors in SLE women.

Methods: We consecutively enrolled SLE pregnant women reporting demographic, clinical, serological, gynaecological and obstetric data. Breastfeeding experience was evaluated by using a specific questionnaire. Disease activity was assessed before and during pregnancy as well as during postpartum.

Results: A total of 57 pregnancies in 43 SLE women were included in the present study. In almost all the pregnancies, mothers planned to breastfeed their child (96.5%) and forty-one (71.9%) actually did breastfeed. The median time of breastfeeding was 3 months (IQR 7). Non-breastfeeding women showed a more frequent caesarean section (p = 0.0001), IUGR occurrence (p = 0.004) and disease relapse (p = 0.0001) after pregnancy. When comparing patients according with breastfeeding duration (cut-off 6 months), we found a significant more frequent smoking (p = 0.02), caesarean section (p = 0.009), and joint involvement during postpartum (p = 0.0001) in women breastfeeding for less than or equal to 6 months, together with higher median BMI (p = 0.0001). Moreover, breastfeeding duration was positively associated with disease duration and hydroxychloroquine (HCQ) treatment during disease history, pregnancy and postpartum.

Conclusions: SLE women didn't show lower breastfeeding rate in comparison with general population but they presented higher prevalence of early discontinuation within three months. Early interruption was positively associated with smoking, BMI, joint involvement; meanwhile disease duration and HCQ treatment during postpartum were positively associated with a longer breastfeeding duration.
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http://dx.doi.org/10.1177/0961203321995263DOI Listing
May 2021

The Impact of Caffeine Intake on Patients with Systemic Lupus Erythematosus: Protect Yourself, Drink More Coffee!

Mediterr J Rheumatol 2020 Dec 28;31(4):374-375. Epub 2020 Dec 28.

Lupus Clinic, Dipartimento di Scienze Cliniche, Internistiche, Anestesiologiche e Cardiovascolari, Sapienza Università di Roma, Rome, Italy.

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http://dx.doi.org/10.31138/mjr.31.4.374DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7841092PMC
December 2020

ISG15 protects human Tregs from interferon alpha-induced contraction in a cell-intrinsic fashion.

Clin Transl Immunology 2020 23;9(12):e1221. Epub 2020 Dec 23.

Dipartimento di Scienze Cliniche Internistiche, Anestesiologiche e Cardiovascolari Sapienza Università di Roma Rome Italy.

Objectives: Type I interferons (IFNs) inhibit regulatory T-cell (Treg) expansion and activation, making them beneficial in antiviral responses, but detrimental in autoimmune diseases. Herein, we investigate the role of ISG15 in human Tregs in the context of refractoriness to type I IFN stimulation.

Methods: ISG15 expression and Treg dynamics were analysed and from patients with chronic hepatitis C, with lupus and ISG15 deficiency.

Results: ISG15 is expressed at high levels in human Tregs, renders them refractory to the IFN-STAT1 signal, and protects them from IFN-driven contraction. , Tregs from healthy controls upregulate ISG15 upon activation to higher levels than conventional CD4 T cells, and ISG15-silenced Tregs are more susceptible to IFNα-induced contraction. In human ISG15 deficiency, patient Tregs display an elevated IFN signature relative to Tregs from healthy control. , in patients with chronic hepatitis C, 2 days after starting pegIFN/ribavirin therapy, a stronger ISG15 inducibility correlates with a milder Treg depletion. , in systemic lupus erythematosus patients, higher levels of ISG15 are associated to reduced STAT1 phosphorylation in response to IFNα, and also to increased frequencies of Tregs, characterising active disease.

Conclusion: Our results reveal a Treg-intrinsic role of ISG15 in dictating their refractoriness to the IFN signal, thus preserving the Treg population under inflammatory conditions.
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http://dx.doi.org/10.1002/cti2.1221DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7758615PMC
December 2020

Effectiveness and safety of baricitinib in rheumatoid arthritis: a monocentric, longitudinal, real-life experience.

Clin Exp Rheumatol 2021 May-Jun;39(3):525-531. Epub 2020 Dec 18.

Reumatologia, Dipartimento di Scienze Cliniche, Internistiche, Anestesiologiche e Cardiovascolari, Sapienza Università di Roma, Italy.

Objectives: Baricitinib is a Janus-kinase (JAK) 1/2 inhibitor, approved for the treatment of moderate-to-severe rheumatoid arthritis (RA) patients with inadequate response to conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs). We report the first real-life experience with baricitinib in a monocentric cohort of unselected RA patients.

Methods: We enrolled consecutive RA patients starting baricitinib. At baseline and after 4, 12, 24 and 48 weeks we assessed the disease activity by composite indices (SDAI, CDAI and DAS28CRP) and ultrasonography, and we recorded any adverse events. The primary endpoint was the percentage of patients achieving SDAI remission at week 4.

Results: We enrolled 59 patients [(F:M = 50:9, median age 58.1 years (IQR 12.8), median disease duration 144 (IQR 150) months] treated with baricitinib in combination with a csDMARD (52.5%) or monotherapy (47.5%) for a median follow-up of 24 weeks (IQR 36). The 12-month drug retention rate was 74%. At weeks 4, 12, 24 and 48 we observed a significant reduction of DAS28, CDAI and SDAI, global health and pain (p<0.001 for all). After 4 weeks of treatment, 12% of patients achieved SDAI remission. Concomitant csDMARDs, previous biological DMARDs, gender, seropositivity and BMI did not affect the efficacy of baricitinib. Baricitinib allowed a significant reduction in prednisone dose after 12 and 24 weeks and a rapid and sustained ultrasound improvement. No serious adverse events, serious infections or cardiovascular events were recorded.

Conclusions: Our study confirms the efficacy and safety profile and rapid onset of the effect of baricitinib in RA patients in a real-life setting.
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May 2021

Altered expression of miR-142, miR-155, miR-499a and of their putative common target in systemic lupus erythematosus.

Epigenomics 2021 Jan 18;13(1):5-13. Epub 2020 Dec 18.

Department of Biomedicine & Prevention, Genetics Section, University of Rome Tor Vergata, Rome 00133, Italy.

To evaluate genetic and expression variability of three miRNAs potentially involved in systemic lupus erythematosus (SLE) and to identify any miRNA's target gene. Gene polymorphisms and expression levels of three miRNAs have been evaluated in a cohort of SLE patients and controls. miR-142 and miR-499a were significantly down-expressed in patients (p = 0.005 and p = 0.02, respectively). A trend for down-expression of miR-155 was also observed (p = 0.07). The lower expression of miR-142 was associated with the rs2632516 polymorphism variant allele (p = 0.002). Predictive analyses identified a target gene common to the three miRNAs, , whose higher expression was seen in patients compared with controls (p = 0.03). The three miRNAs and MDM2 might be involved in SLE.
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http://dx.doi.org/10.2217/epi-2020-0278DOI Listing
January 2021

Joint involvement influences quality of life in systemic lupus erythematosus patients.

Lupus 2021 Mar 15;30(3):478-483. Epub 2020 Dec 15.

Lupus Clinic, Reumatologia, Dipartimento di Scienze Cliniche Internistiche, Anestesiologiche e Cardiovascolari, Sapienza Università di Roma, Roma, Italy.

Introduction: Joint involvement represents the major determinant in quality of life (QoL)in Systemic Lupus Erhytematosus (SLE) patients. However, QoLhas been generally evaluated by non-specific questionnaires. We evaluated the relationship between SLE musculoskeletal manifestations and QoL, assessed by LupusQoL.

Methods: Patients with joint involvement (group A) were compared with those without this feature (group B). Disease activity was assessed by SLEDAI-2k in the whole population, while DAS28 and swollen to tender ratio were applied to assess joint activity. LupusQoL was administered to all the patients.

Results: Group A included 110 patients [M/F 8/102; median age 49 years (IQR 13), median disease duration 156 months (IQR 216)], group B 58 [M/F 11/47; median age 40 years (IQR 15), median disease duration 84 months (IQR 108)].We found significanlty lower values in all the LupusQoL domains except for one (burden to others) in group A in comparison with group B. A significant correlation between DAS28 values and all the LupusQoL domains in group A was found; only three domains correlated with SLEDAI-2k.

Conclusions: SLE-related joint involvement significantly influences disease-specific QoL. DAS28 better correlated with LupusQoL domains in comparison with SLEDAI-2k, confirming the need for specific musculoskeletal activity indices.
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http://dx.doi.org/10.1177/0961203320979039DOI Listing
March 2021

Belimumab is Able to Induce a Significant Improvement of Joint Activity Status in Patients Diagnosed with Systemic Lupus Erythematosus: Results From a 12-Month Longitudinal Study.

Isr Med Assoc J 2020 Jul;22(7):415-419

Lupus Clinic, Rheumatology, Department of Internal Medicine, Sapienza University of Rome, Rome, Italy.

Background: Belimumab was the first biological drug approved for the treatment of systemic lupus erythematosus (SLE) patients. Phase II/III randomized controlled trials and real-life studies identified patients with musculoskeletal involvement as best responders.

Objectives: To evaluate the effectiveness of belimumab in SLE-related joint involvement.

Methods: The cohort comprised SLE patients receiving belimumab for musculoskeletal indications. Belimumab was intravenously administrated according to protocols; all the patients were evaluated at baseline (T0) and after 3 (T1), 6 (T2), and 12 (T3) months. We assessed joint activity by disease activity score 28, simple disease activity index (SDAI), clinical disease activity index (CDAI), and swollen tender ratio. Each patient underwent musculoskeletal ultrasound of 34 joints to assess synovial effusion synovial hypertrophy, and power Doppler; by using a semi-quantitative scale (0-3) we obtained the total inflammatory score (0-216).

Results: We evaluated 20 patients (males/females 1/19, median age 45 years [interquartile range (IQR) 12], median disease duration 144 months [IQR 144]). CDAI and SDAI significantly decreased at T1 (P = 0.02 and P = 0.01 respectively) and this improvement was maintained at the following time-points (CDAI: T2 P = 0.008, T3 P = 0.004; SDAI: T2 P = 0.006, T3 P = 0.01). A significant reduction of median ultrasound score was identified at T1 (T0 20.5 [IQR 13.5] vs. T1 7.5 [IQR 4.7], P < 0.001), and maintained at T2 (7.0 [IQR 5], P < 0.0001), and T3 (7.0 [IQR 9.0], P < 0.0001).

Conclusions: Belimumab induces a sustained improvement of ultrasound-detected inflammatory status at the articular level.
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July 2020

IgM-Rheumatoid factor confers primary resistance to anti-PD-1 immunotherapies in NSCLC patients by reducing CD137T-cells.

EBioMedicine 2020 Dec 6;62:103098. Epub 2020 Nov 6.

Department of Experimental Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161 Rome, Italy. Electronic address:

Background: ICIs have strongly improved the outcome of NSCLC patients. However, primary and secondary resistance occur during treatment in most of the patients, with several of them developing fast progressions. Autoantibodies can be related with a dysfunctional immune system, although their association with immune-based anti-cancer therapies has never been investigated. Moreover, so far no reliable predictive factor is currently available to aid in treatment selection. CD137T-cells are largely known to be the anti-tumor activated effector cells, but they have never been associated with the response to immunotherapies.

Methods: Forty-two patients with metastatic NSCLC receiving anti-PD-1 ICIs at Sant'Andrea Hospital and Policlinico Umberto I, from June 2016 to September 2018 were enrolled. Circulating levels of IgM-Rheumatoid Factor were evaluated at baseline and correlated with patients clinical response following the anti-PD-1 treatment. IgM-RF interaction and effect on T-cells in vivo and in vitro were investigated.

Findings: IgM-RF in NSCLC patient sera strongly predicted the development of early progression to ICIs. Also, a significant reduction of progression-free survival rate in anti-PD-1 treated patients could be identified when patients were stratified based on IgM-RF positivity and titers. IgM-RF bound preferentially circulating naïve and central memory T-cells and a significant reduction of CD137 anti-tumor T effector cells was found in IgM-RF positive patients. In addition, a higher percentage of CD137T-cells in peripheral blood of NSCLC patients at baseline resulted as a strong independent prognostic factor for a better outcome in terms of PFS and OS after the anti-PD-1 treatment. Furthermore, T-cells exposed to IgM-RF showed a robust defect in their migratory ability in response to CCL19 chemokine.

Interpretation: In this study we showed that serum IgM-RF can be regarded as predictive factor for the development of early progression and prognostic factor of a reduced progression-free survival and overall-survival in anti-PD-1 treated NSCLC patients. The ability of IgM-RF to bind naïve and central memory T-cells and impair their migration could make account for the reduction of the tumor-reactive CD137 T-cells population that may cause a non-effectiveness of these T-cells targeting drugs.

Fundings: AIRC, MIUR and Sapienza University of Rome.
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http://dx.doi.org/10.1016/j.ebiom.2020.103098DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7658668PMC
December 2020

Increased eryptosis in patients with primary antiphospholipid syndrome (APS): a new actor in the pathogenesis of APS.

Clin Exp Rheumatol 2021 Jul-Aug;39(4):838-843. Epub 2020 Oct 29.

Department of Clinical Internal, Anesthetic and Cardiovascular Sciences, Sapienza University of Rome, Italy.

Objectives: Antiphospholipid syndrome (APS) is an autoimmune disease characterised by a hypercoagulable state and the presence of antiphospholipid antibodies (aPL). During the mechanism of red blood cells (RBCs) death, called eryptosis, RBCs can adhere to vascular wall participating in the development of a pro-thrombotic state. It is known that enhanced eryptosis contributes to several pathological conditions but the role of this process in APS has not been investigated yet. We analysed spontaneous eryptosis in a cohort of APS patients and aPL carriers (asymptomatic subjects with positive aPL tests). The effect on eryptosis of antibodies (Abs) purified from serum of APS patients and aPL carriers was also investigated.

Methods: In this study, 30 patients with primary APS (PAPS) and 17 aPL carriers were recruited. Twenty healthy donors (HD) and 13 patients affected by autoimmune haemolytic anaemia (AHIA) were also recruited. RBCs were incubated with PAPS and aPL carriers Abs, purified by ammonium sulfate precipitation. Levels of eryptosis were analysed by flow cytometry.

Results: In vitro Abs from APS patients induced eryptosis in RBCs isolated from HD after 4 h of culture. On the contrary, Abs from aPL carriers had no effect on the percentage of phosphatidylserine-exposing RBCs. Ex vivo, APS patients showed higher levels of spontaneous eryptosis compared to HD and aPL carriers.

Conclusions: In this study, we demonstrated a potential new aspect of APS pathogenesis based on the ability of Abs isolated from APS patients, not identified in aPL carriers, to stimulate eryptosis suggesting a possible contribution of this process in the clinical manifestations of APS.
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July 2021

Pregnancy outcome in systemic lupus erythematosus patients: a monocentric cohort analysis.

Rheumatology (Oxford) 2021 04;60(4):1747-1754

Lupus Clinic, Dipartimento di Scienze Cliniche Internistiche, Anestesiologiche e Cardiovascolari, Sapienza University of Rome, Rome, Italy.

Objective: SLE is an autoimmune disease, mainly affecting women of childbearing age, with possible impact on pregnancy. In this study, we evaluated pregnancy outcomes in all pregnant patients affected by SLE, followed in the context of a rheumatology/gynaecology multi-disciplinary team.

Methods: Since 2008, we evaluated 70 consecutive pregnancies occurring in 50 SLE patients referring to the Lupus Clinic of Sapienza University of Rome; as controls we evaluated 100 consecutive pregnancies in 100 women without autoimmune diseases.

Results: By comparing SLE patients and controls, we did not find differences in terms of pregnancy outcomes, except for the occurrence of small for gestational age, which was significantly higher in the SLE group (22.8% vs 11%, P =0.003). Small for gestational age was associated with the positivity for anti-dsDNA, anti-Sm and anti-RNP (P =0.009, P =0.02, P =0.002, respectively). A disease flare was reported in 28 pregnancies (40%) and in 31 puerperium periods (44.3%). Flare during pregnancy was associated with anti-SSA (P =0.02), while puerperium relapse with previous MMF treatment (P =0.01) and haematological flare during pregnancy (P =0.03).

Conclusion: The present study confirms how pre-gestational counselling and a multi-disciplinary approach could result in positive pregnancy outcomes for SLE patients. The high percentage of disease relapse justifies even more the need for multi-disciplinary management.
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http://dx.doi.org/10.1093/rheumatology/keaa470DOI Listing
April 2021

Genetic diversity of Staphylococcus aureus influences disease phenotype of systemic lupus erythematosus.

Rheumatology (Oxford) 2021 02;60(2):958-966

Lupus Clinic, Dipartimento di Scienze Cliniche, Internistiche, Anestesiologiche e Cardiovascolari, Sapienza Università di Roma, Rome, Italy.

Objective: We investigated the genetic diversity, molecular epidemiology and evolutionary dynamics of Staphylococcus aureus (SA) isolated from SLE patients by means of phylogenetic analysis.

Methods: Consecutive SLE patients (ACR 1997 criteria) were enrolled: clinical/laboratory data were collected and nasal swab for SA identification was performed. On the basis of the translation elongation factor (tuf) gene, a phylogenetic analysis was performed to investigate relationships and to assess significant clades. Selective pressure analysis was used to investigate the evolution of the SA tuf gene. The gene sequences from non-SLE individuals, downloaded from the GenBank database, were compared through phylogenetic analysis with the tuf gene from SLE patients.

Results: We enrolled 118 patients [M/F 10/108; median (interquartile range (IQR)) age 45.5 (13.2) years; median (IQR) disease duration 120 (144) months]. Twenty-four patients (20.3%) were SA carriers (SA+), three of them MRSA. SA+ SLE showed significantly higher SLEDAI-2k values [SA+: median (IQR) 2 (3.75); SA-: 0 (2); P = 0.04]. The phylogenetic analysis, restricted to 21 non-MRSA SA+, revealed a statistically supported larger clade (A, n = 17) and a smaller one (B, n = 4). Patients located in clade A showed a significantly higher prevalence of joint involvement (88.2%) in comparison with clade B (50.0%, P < 0.0001) and SA- (62.7%, P < 0.0001). Haematological manifestations were significantly more frequent in clade A (64.7%) compared with B (50.0%, P = 0.004).

Conclusion: We suggest a possible role of SA nasal carriage status in SLE disease activity. Moreover, our findings support the hypothesis that bacterial genetic variants may be associated with specific disease features.
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http://dx.doi.org/10.1093/rheumatology/keaa519DOI Listing
February 2021

Up-regulation of autophagy by etanercept treatment results in TNF-induced apoptosis reduction in EA.hy926 endothelial cell line.

Clin Exp Rheumatol 2021 May-Jun;39(3):606-611. Epub 2020 Sep 3.

Department of Clinical Internal, Anesthetic and Cardiovascular Sciences, Sapienza University of Rome, Italy.

Objectives: Rheumatoid arthritis (RA) is an autoimmune systemic inflammatory disease associated with a high prevalence of atherosclerosis. Endothelial dysfunction has emerged as a potentially valuable prognostic tool in predicting the development of atherosclerosis. Tumour necrosis factor (TNF) is the main cytokine involved in RA pathogenesis, exerting a pro-atherogenic role. TNF-inhibitors are effective treatments in RA, also improving endothelial function. Regarding this, no experimental data are known about the involvement of etanercept. We investigated the contribution of TNF to endothelial dysfunction and the effect of in vitro treatment with etanercept, with a special focus on autophagy and apoptosis pathways.

Methods: Autophagy and apoptosis were evaluated by Western blot and flow cytometry in EA.hy926 endothelial cells treated with TNF alone or in combination with etanercept for 24h.

Results: Blocking autophagy, TNF was able to induce endothelial cell apoptosis. Co-treatment with etanercept reverted this effect, up-regulating the autophagy pathway.

Conclusions: Our results confirm the protective role of etanercept, by restoring autophagy on TNF-induced endothelial damage.
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May 2021

Systemic lupus erythematosus onset in patient receiving anti-PD1 treatment with pembrolizumab: a case report.

Rheumatology (Oxford) 2021 02;60(2):e39-e40

Lupus Clinic, Reumatologia, Dipartimento di Scienze Cliniche, Internistiche, Anestesiologiche e Cardiovascolari, Sapienza Università di Roma, Rome, Italy.

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http://dx.doi.org/10.1093/rheumatology/keaa389DOI Listing
February 2021

Caffeine intake influences disease activity and clinical phenotype in systemic lupus erythematosus patients.

Lupus 2020 Oct 23;29(11):1377-1384. Epub 2020 Jul 23.

Lupus Clinic, Department of Clinical, Internal, Anesthesiological and Cardiovascular Sciences, 9311Sapienza University of Rome, Rome, Italy.

Objective: Caffeine, one of the most widely consumed products in the world, seems to interact with multiple components of the immune system by acting as a non-specific phosphodiesterase inhibitor. In vitro dose-dependent treatment with caffeine down-regulates mRNA levels of key inflammation-related genes in peripheral blood mononuclear cells. So far, no robust data are available about the possible contribution of caffeine in systemic lupus erythematosus (SLE). The aim of this study was to evaluate the impact of caffeine consumption on SLE-related disease phenotype and activity, in terms of clinimetric assessment and cytokine serum levels.

Methods: We performed a cross-sectional study, enrolling consecutive patients and reporting their clinical and laboratory data. Disease activity was assessed by SLE Disease Activity Index 2000 (SLEDAI-2K). Caffeine intake was evaluated by a 7-day food frequency questionnaire, including all the main sources of caffeine. As previously reported, patients were divided into four groups according to the daily caffeine intake: <29.1 mg/day (group 1), 29.2-153.7 mg/day (group 2), 153.8-376.5 mg/day (group 3) and >376.6 mg/day (group 4). At the end of questionnaire filling, blood samples were collected from each patient to assess cytokine levels. These were assessed by using a panel by Bio-Plex assays to measure the levels of IL-6, IL-10, IL-17, IL-27, IFNγ, IFNα and BLyS.

Results: We enrolled 89 consecutive SLE patients. We observed a negative correlation between caffeine consumption and disease activity, measured with SLEDAI-2K. A significantly higher prevalence of lupus nephritis, neuropsychiatric involvement, haematological manifestations, hypocomplementaemia and anti-dsDNA positivity was observed in patients with a low intake of caffeine. Furthermore, patients with a low intake of caffeine were more frequently treated with glucocorticoids. Regarding cytokine analysis, a negative correlation between daily caffeine consumption and serum level of IFNγ was found ( = 0.03,  = -0.2); furthermore, patients with a high intake of caffeine showed lower serum levels of IFNα ( = 0.02), IL-17 ( = 0.01) and IL-6 ( = 0.003).

Conclusions: In this report we demonstrated the impact of caffeine on SLE disease activity status, as confirmed by the inverse correlation between its intake and both SLEDAI-2K values and cytokine levels. Moreover, patients with a low caffeine consumption seem to have a more severe disease phenotype.
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http://dx.doi.org/10.1177/0961203320941920DOI Listing
October 2020

High Fat Diet, Metabolic Syndrome and Systemic Lupus Erythematosus: A Causal Loop.

Mediterr J Rheumatol 2020 Jun 15;31(2):172-173. Epub 2020 Jun 15.

Lupus Clinic, Dipartimento di Medicina Interna e Specialità Mediche, Sapienza University of Rome, Rome, Italy.

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http://dx.doi.org/10.31138/mjr.31.2.172DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7362113PMC
June 2020

An exploratory cross-sectional study of subclinical vascular damage in patients with polymyalgia rheumatica.

Sci Rep 2020 07 9;10(1):11407. Epub 2020 Jul 9.

Department of Clinical Internal, Anesthesiological and Cardiovascular Sciences, Rheumatology Unit, Sapienza University of Rome, viale del Policlinico 155, 00161, Rome, Italy.

The aim of the study was to investigate the presence of subclinical vascular damage in polymyalgia rheumatica (PMR). We enrolled PMR patients having major cardiovascular risk factors (MCVRF) and, as controls, patients with MCVRF. All underwent: color Doppler ultrasound to evaluate the common carotid intima-media thickness (IMT), the anterior-posterior abdominal aortic diameter (APAD), and the prevalence of carotid artery stenosis; the cardio-ankle vascular index (CAVI) to measure arterial stiffness together with the ankle-brachial index (ABI) to investigate the presence of lower-extremity peripheral arterial disease. Finally, we measured the serum levels of adipocytokines implicated in vascular dysfunction. As a result, 48 PMR and 56 MCVRF patients were included. An increase of IMT (1.07/0.8-1.2 vs 0.8/0.8-1.05; p = 0.0001), CAVI (8.7/7.8-9.3 vs 7.6/6.9-7.8; p < 0.0001) and APAD values (21.15/18.1-25.6 vs 18/16-22; p = 0.0013) was found in PMR patients with respect to controls. No differences were reported in the prevalence of carotid artery stenosis or ABI values between the two groups. A significant correlation between IMT and CAVI in PMR and MCVRF subjects (r = 0.845 and r = 0.556, respectively; p < 0.01) was found. Leptin levels (pg/mL; median/25th-75th percentile) were higher in PMR than in MCVRF subjects (145.1/67-398.6 vs 59.5/39.3-194.3; p = 0.04). Serum levels of adiponectin (ng/mL) were higher in PMR patients (15.9/10.65-24.1 vs 6.1/2.8-22.7; p = 0.01), while no difference in serum levels of resistin (ng/mL) was found between PMR and MCVRF subjects (0.37/0.16-0.66 vs 0.26/0.14-1.24). Our study shows an increased subclinical vascular damage in PMR patients compared to those with MCVRF, paving the way for further studies aimed at planning primary cardiovascular prevention in this population.
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http://dx.doi.org/10.1038/s41598-020-68215-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7347873PMC
July 2020

Evaluation of renal resistive index in different autoimmune diseases.

Clin Exp Rheumatol 2021 Jan-Feb;39(1):229-230. Epub 2020 Jun 4.

Lupus Clinic, Reumatologia, Dipartimento di Scienze Cliniche Internistiche, Anestesiologiche e Cardiovascolari, Sapienza University of Rome, Italy.

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February 2021

Treatment with Gonadotropin Releasing Hormone Agonists in Systemic Lupus Erythematosus Patients Receiving Cyclophosphamide: A Long-term Follow-up Study.

Isr Med Assoc J 2020 Jun;22(6):343-347

Lupus Clinic, Department of Clinical, Internal, Anesthetic and Cardiovascular Science-Rheumatology Unit, Sapienza University of Rome, Rome, Italy.

Background: Cyclophosphamide treatment has been associated with ovarian function impairment. Co-treatment with gonadotropin-releasing hormone-analogue (GnRH-a) seems to be able to prevent this complication. However, even though data are available on neoplastic patients, limited data have been published on systemic lupus erythematosus (SLE) women cohorts.

Objectives: To evaluate GnRH-a efficacy on ovarian function preservation in SLE women receiving cyclophosphamide treatment.

Methods: The authors performed a retrospective study including SLE women requiring cyclophosphamide treatment and compared those treated with and without GnRH-a (case and controls, respectively). All patients were evaluated before cyclophosphamide treatment and every 3 months in the following years. Ovarian function was evaluated using hormonal profiles.

Results: The study comprised 33 SLE cyclophosphamide-treated women: 18 co-treated with triptorelin and 15 controls. The mean follow-up was 8.1 ± 5.1 years (range 4-11). Premature ovarian failure (POF) prevalence was significantly lower in SLE women treated by cyclophosphamide plus triptorelin compared to controls (11.1% vs. 33.3%, P = 0.0002). The occurrence of POF was significantly associated with higher age at the time of cyclophosphamide treatment (P = 0.008). Only patients in the GnRH-a treated group had successful pregnancies.

Conclusions: The study provides information about the efficacy of co-treatment with GnRH-a in SLE women receiving cyclophosphamide, as demonstrated by the lower POF incidence compared to untreated subjects, based on long-term follow-up. These results reinforce the use of GnRH-a for fertility preservation in premenopausal SLE patients treated by cyclophosphamide.
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June 2020

Janus kinases inhibitors for treating patients with rhupus.

Joint Bone Spine 2020 12 10;87(6):673-674. Epub 2020 Jun 10.

Sapienza Università di Roma, Dipartimento di Scienze Cliniche, Internistiche, Anestesiologiche e Cardiovascolari, 00161 Roma, Italy.

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http://dx.doi.org/10.1016/j.jbspin.2020.05.010DOI Listing
December 2020