Search

Objectives Killer cell lectin-like receptor G 1 (KLRG1), a transmembrane receptor with inhibitory capacity expressed in human immune cells, emerged as a novel susceptibility gene for systemic lupus erythematosus (SLE). The aim of this study was to investigate the expression of KLRG1 in SLE patients compared to healthy controls (HC) on both NK and T cells and to evaluate its possible involvement in SLE pathogenesis. Methods Eighteen SLE patients and twelve healthy controls were enrolled. Peripheral blood mononuclear cells (PBMCs) from these patients were phenotypically characterized by immunofluorescence and flow cytometry. The effect of the hydroxychloroquine (HCQ) in vitro on KLRG1 expression and its signaling mediated functions in NK cells were analyzed. Results KLRG1 expression was significantly reduced on the analyzed immune cell populations in SLE patients compared to HC, especially on total NK cells. Moreover, expression of KLRG1 on total NK cells inversely correlated with the SLEDAI-2K. A direct association between KLRG1 expression on NK cells and patients’ treatment with HCQ was observed. In vitro treatment with HCQ increased KLRG1 expression on NK cells. In HC, KLRG1+ NK cells showed reduced degranulation and IFNγ production, while in SLE patient, this inhibition occurred only for the IFNγ production. Conclusion With this study we revealed a reduced expression and an impaired function of KLRG1 on NK cells in SLE patients. These results suggest a possible role of KLRG1 in the pathogenesis of SLE and as a novel biomarker of this disease.

Objectives To evaluate humoral and cell-mediated response after three doses of BNT162b2 SARS-CoV-2 vaccine in patients with systemic lupus erythematosus (SLE) treated with Belimumab (BLM). Methods SLE patients were vaccinated with three doses of BNT162b2-mRNA vaccine (two-dose primary vaccination, third booster dose after 6 months). The humoral immune response was assessed one and 6 months after the second dose (T1, T2), and 6 months after the booster dose (T3). Serological assay was performed (The Liaison® SARS-CoV-2 TrimericS IgG chemiluminescent). Spike-specific T-cell response was monitored 6 months after the second vaccine dose and the percentage of cytokines producing T cells was assessed by flow cytometry. Results Twelve patients [12F; median age 46 years (IQR 8.25); median disease duration 156 months (IQR 188)] were enrolled. At T1, all patients showed seroconversion (median anti-Spike IgG levels 1610 BAU/mL, IQR 1390). At T2––day of the third dose––a significant reduction of median anti-Spike IgG antibodies levels was observed [214 BAU/mL (IQR 94); p = 0.0009]. Anti-Spike IgG were significantly increased at T3, reaching a median value of 1440 BAU/mL (IQR 1316; p = 0.005). Despite declining humoral immunity, almost 60% of patients mounted a virus-specific CD4 + T-cell response 6 months after primary vaccination. Conclusions BLM does not impair humoral response to primary BNT162b2 SARS-CoV-2 vaccination. During the follow-up, a decline in antibody levels is evident and the third dose is crucial to increase the specific immune response. Finally, we observed a recall T-cell response to the Spike antigen 6 months after the first vaccination cycle.

Scientific literature demonstrated the impairment in cognitive/executive functions and pragmatic language in SLE patients, potentially involving also asymptomatic subjects. The present study focuses on the assessment in an SLE cohort of emotional intelligence, which is an ability regulated by the network of the executive functions, cognitive abilities involved in the initiation, planning, organization, and regulation of achievement-oriented behaviors: with emotional. Thus, emotional intelligence, defined as the ability to reason with emotions, was evaluated in a SLE cohort diagnosed according to the 1997 American College of Rheumatology criteria. As control healthy subjects were enrolled. The Mayer–Salovey–Caruso Emotional Intelligence Test (MSCEIT), a skill-scale that measures the ability to perform tasks and solve emotional problems, was administered to patients and controls. Second, a group of SLE patients underwent the Visual Thinking Strategies (VTS) method in order to assess the potential impact of art in cognitive skills like critical thinking, problem solving, and emotional intelligence quotient. The protocol also included the evaluation of the improvement of some skills using a validated VTS skill grid. Self-reported scales for anxiety and depression were performed to rule out the influence of mood disorders on emotional intelligence. The present study demonstrated similar quotient scores of emotional intelligence in SLE patients and healthy controls. Furthermore, VTS method could help in improving this cognitive ability in patients, by implementing critical thinking and problem solving, promoting empathy, and improving tolerance to ambiguity and relational capacity.

Davide Mohammad Reza Beigi, Greta Pellegrino, Marius Cadar, Ilaria Bisconti, Francesca Romana Di Ciommo, Katia Stefanantoni, Fabrizio Conti, Valeria Riccieri Dipartimento di Scienze Cliniche Internistiche, Anestesiologiche e Cardiovascolari, Sapienza University of Rome, Rome, ItalyCorrespondence: Davide Mohammad Reza Beigi, Dipartimento di Scienze Cliniche Internistiche, Anestesiologiche e Cardiovascolari, Sapienza University of Rome, Rome, Italy, Tel +393496300710, Email davidemrb@gmail.comObjective: This work aims to evaluate the prevalence of anxiety and COVID-19-related fear in systemic sclerosis (SSc) patients during the second and third waves of the SARS-CoV-2 pandemic in Italy and their possible associated factors.Methods: A cohort study was carried out on 114 SSc patients referred to our Scleroderma Clinic, matched for sex and age. Twenty-eight of them had missed scheduled examinations during the October 2020–March 2021 period and 86 has attended regular outpatient visits during the same period. Both groups were administered (by telephone for cases and in-person for controls) the Generalized Anxiety Disorder Scale-7 (GAD-7) questionnaire and the validated on SSc patients COVID-19 Fears Questionnaire for Chronic Medical Conditions (COVID-19 Fears). Concurrent factors related to higher scores were investigated in patients who did not have an outpatient follow-up.Results: The missing group had significantly more patients scoring ≥ 8 on the GAD-7 questionnaire [22 (78.6%) vs 16 (18.6%), p < 0.0001] and significantly higher scores on the COVID-19 Fears questionnaire (median [quartiles] 31.5 [26.25;37.25] vs 20 [13.75;28], p < 0.0001) than the attending group. Multivariate analysis performed on the missing patients group showed a significant association of the lack of work and ongoing therapy for anxiety/depression with GAD-7 (p = 0.0275 and p = 0.0188) and COVID-19 Fears score (p = 0.0016 and p = 0.0099).Conclusion: Anxiety disorder and COVID-19-related fear were greater in SSc patients who missed regular follow-ups and are associated with a lack of work activity. These findings aim to identify a subgroup deserving attention regarding risk factors for missed periodic controls.Keywords: systemic sclerosis, anxiety, COVID-19 fear

The emergence of biologics with different modes of action (MoAs) and therapeutic targets has changed treatment patterns in patients with inflammatory rheumatic diseases. While tumour necrosis factor inhibitors (TNFis) are often utilized as the first biologic disease-modifying antirheumatic drug, some patients may not respond adequately (primary failure), fail to sustain response over time (secondary failure), or experience intolerable adverse events. Whether these patients would benefit more from cycling to a different TNFi or switching to a biologic with a different MoA is still unclear. We discuss here treatment outcomes of TNFi cycling versus MoA switching after treatment failure with a first TNFi in patients with inflammatory rheumatic diseases, focusing specifically on rheumatoid arthritis, psoriatic arthritis, axial spondyloarthritis, and juvenile idiopathic arthritis. Treatment guidelines for these patients are ambiguous and, at times, contradictory in their recommendations. However, this is due to a lack of high-quality head-to-head data to definitively support cycling between TNFis after failure to a first-line TNFi over switching to a different MoA.

Background The rate of antiphospholipid antibody (aPL) negativization in antiphospholipid syndrome (APS) patients is uncertain, but it is estimated to be as high as 8%. Currently, a consensus definition of aPL negativization is lacking, as well as international recommendations on how to approach treatment in patients with a persistent aPL-negative seroconversion. Aim The aim of the Delphi survey was to evaluate the clinical approach and level of consensus among experts from the APS Study Group of the Italian Society for Rheumatology (SIR-APS) in different clinical scenarios. Methods Experts of SIR-APS were contacted using a survey methodology. Results A structured survey was circulated among 30 experts. Up to 90% of the interviewed experts agreed on defining aPL negativization as the presence of two negative determinations, 1 year apart (90%). Almost full consensus exists among experts in some clinical settings, including: (1) the role of aPL negativization in the management of a thrombotic event determined by concomitant presence of cardiovascular risk factors, both modifiable and not modifiable (90%); (2) approach to young patients with triple aPL positivity who experienced pulmonary arterial thrombotic events and tested negative for aPL detection after 5 years of vitamin K antagonist (VKA) treatment (90%); (3) the use of “extra criteria” aPL antibody testing before pondering VKA suspension (93%). Conclusion A substantial agreement exists among experts on how to define aPL negativization. VKA suspension should be embraced with extreme caution, particularly in case of previous thrombotic events and/or triple aPL positivity. Nevertheless, VKA cessation might be considered when risk factors are carefully monitored/treated and the presence of “extra criteria” aPL is ruled out.

Objective Several studies show that age at onset has an impact on the clinical-serological presentation, comorbidities and disease course of patients with systemic lupus erythematosus (SLE). We evaluated whether, in patients with recent onset SLE, the age at onset correlates with clinical-serological manifestations and with comorbidities. Methods We analysed 171 patients with a SLE diagnosis obtained within 12 months of diagnosis enrolled in the Early Lupus project. Based on the age of onset of the first disease symptom, they were stratified into 2 groups: early onset (18–45 years) and late onset (>45 years). The analysis was replicated by stratifying patients based on age at diagnosis (fulfillment of ACR classification criteria). Each comparison was made at baseline and at 36 months of follow-up. Results Baseline: patients with late onset displayed comorbidities (hypertension, dyslipidaemia and osteoporosis) more frequently than early onset group. 11.4% of late onset patients had a malignancy in medical history, not recorded in the early onset cohort. The two groups differed neither in organ involvement (domain BILAG) nor in disease activity (ECLAM). Patients with early onset showed a disease with signs of higher serologic activity (higher frequency of anti-dsDNA positivity and lower mean C3 and C4 levels) and had malar rash more frequently than the late onset group (36.2% vs. 18.2%, p=0.042). Similar results were obtained by stratifying patients by age of diagnosis (18-45 years and >45 years), except for the higher frequency of discoid rash in the group with age at diagnosis >45 years (18% vs. 6.6%, p=0.045). 36 months: the 2 groups of patients independently of the stratification applied did not differ in the accumulation of damage, but showed a different pattern of 8 organ involvement. Musculoskeletal involvement was more frequent both in the late onset group (18.6% vs. 7.3%, p=0.043) and in the group with age at diagnosis >45 years (20.4% vs. 5.9%, p=0.009) compared to their counterparts, while renal involvement was more frequent in the group with age at diagnosis 18–45 years (21.4% vs. 6.1%, p=0.03).A sub analysis at 36 months on patients without hypertension and osteoporosis at enrollment showed that patients with older age at onset had a higher frequency of these comorbidities, compared to their counterparts. Conclusion In our cohort, younger disease SLE onset seems to correlate with a more active immunological profile, while late onset with a higher incidence of comorbidities.

Background Biologics have demonstrated efficacy in PsA in randomized clinical trials. More evidence is needed on their effectiveness under real clinical practice conditions. The aim of the present work is to provide real-world evidence of the effectiveness of biologics for PsA in the daily clinical practice. Methods CHRONOS was a multicenter, non-interventional, cohort study conducted in 20 Italian hospital rheumatology clinics. Results 399 patients were eligible (56.9% females, mean (SD) age: 52.4 (11.6) years). The mean (SD) duration of PsA and psoriasis was 7.2 (6.9) and 15.3 (12.2) years, respectively. The mean (SD) duration of the biologic treatment under analysis was 18.6 (6.5) months. The most frequently prescribed biologic was secukinumab (40.4%), followed by adalimumab (17.8%) and etanercept (16.5%). The proportion of overall responders according to EULAR DAS28 criteria was 71.8% (95% CI: 66.7–76.8%) out of 308 patients at 6 months and 68.0% (95% CI: 62.7–73.3%) out of 297 patients at 1 year. Overall, ACR20/50/70 responses at 6 months were 41.2% (80/194), 29.4% (57/194), 17.1% (34/199) and at 1-year were 34.9% (66/189), 26.7% (51/191), 18.4% (36/196), respectively. Secondary outcome measures improved rapidly already at 6 months: mean (SD) PASI, available for 87 patients, decreased from 3.2 (5.1) to 0.6 (1.3), the proportion of patients with dactylitis from 23.6% (35/148) to 3.5% (5/142) and those with enthesitis from 33.3% (49/147) to 9.0% (12/133). Conclusions The CHRONOS study provides real-world evidence of the effectiveness of biologics in PsA in the Italian rheumatological practice, confirming the efficacy reported in RCTs across various outcome measures.

The Physician Global Assessment International Standardisation COnsensus in Systemic Lupus Erythematosus (PISCOS) study aimed to obtain an evidence-based and expert-based consensus standardisation of the Physician Global Assessment (PGA) scoring of disease activity in systemic lupus erythematosus (SLE). An international panel of 79 SLE experts participated in a three-round Delphi consensus process, in which 41 statements related to the PGA in SLE were rated, using a 0 (strongly disagree) to 10 (strongly agree) numerical rating scale. Statements with agreement of 75% or greater were selected and further validated by the expert panel. Consensus was reached on 27 statements, grouped in 14 recommendations, for the use of the PGA in SLE, design of the PGA scale, practical considerations for PGA scoring, and the relationship between PGA values and levels of disease activity. Among these recommendations, the expert panel agreed that the PGA should consist of a 0–3 visual analogue scale for measuring disease activity in patients with SLE in the preceding month. The PGA is intended to rate the overall disease activity, taking into account the severity of active manifestations and clinical laboratory results, but excluding organ damage, serology, and subjective findings unrelated to disease activity. The PGA scale ranges from “no disease activity” (0) to the “most severe disease activity” (3) and incorporates the values 1 and 2 as inner markers to categorise disease activity as mild (≥0·5 to 1), moderate (>1 and ≤2) and severe (>2 to 3). Only experienced physicians can rate the PGA, and it should be preferably scored by the same rater at each visit. The PISCOS results will allow for increased homogeneity and reliability of PGA ratings in routine clinical practice, definitions of remission and low disease activity, and future SLE trials.

Objectives To investigate the expression of citrullinated and carbamylated proteins in extracellular microvesicles (EMVs) from RA patients. Methods We enrolled 24 RA naïve for biological therapy and 20 healthy donors (HD), matched for age and sex. For each patient, laboratory and clinical data were recorded and clinical indexes were measured (Clinical Disease Activity Index, Simplified Disease Activity Index, DAS28). EMVs in RA patients and HD were purified from plasma and measured by nanoparticle tracking analysis (NanoSight). Further, EMVs were incubated with anti-citrullinated/carbamylated proteins antibodies and processed by flow cytometry and western blot to evaluate the expression of citrullinated/carbamylated antigens. Results NanoSight revealed a significant increase of EMVs in RA compared with HD. Moreover, cytofluorimetric analysis showed a significative higher expression of citrullinated antigens on EMVs’ surface in RA than donors, while no substantial difference was found in the expression of carbamylated antigens. These data were confirmed by western blot which identified vimentin, glycolytic enzyme alpha-enolase 1 and collagen type II as the main citrullinated and carbamylated proteins carried by EMVs. Finally, a relevant correlation between the expression of citrullinated antigens and disease activity was found. Conclusions The results of this study suggest an involvement of EMVs in the pathogenesis of RA by inducing autoimmunity.

In the present study, we applied cluster analysis (CA) in SLE patients with joint involvement to identify which disease subset most commonly develops erosive damage.We collected clinical and laboratory data of SLE patients with a clinical history of joint involvement (arthritis/arthralgia). Ultrasonographic assessment was performed at level of MCPs and PIPs joints, to identify erosive arthritis, defined as the presence of erosions in at least one joint. Moreover, we detected RF, ACPA anti-CarP, and Dkk1 serum levels. We applied an unsupervised hierarchical CA to identify the aggregation of patients into different subgroups sharing common characteristics in terms of clinical and laboratory phenotypes.CA included 112 SLE patients (M/F 6/106; median age 45 years, IQR 17; median disease duration 96 months, IQR 165). Arthritis was observed in 82 patients (73.2%) and inflammatory arthralgia in 30 (26.8%). US-detected erosive arthritis was observed in 29 patients (25.9%). CA on clinical and laboratory features allowed the identification of four main clusters: in particular erosive arthritis was located in a cluster including renal and neuropsychiatric involvement, serositis, positivity for ACPA, anti-Carp, anti-Sm, anti-RNP, detectable levels of Dkk1.The application of CA made it possible to better characterise SLE phenotype including erosive arthritis. In particular, feature-driven CA leads to the identification of a more aggressive disease, due to a common pathogenic mechanism.

To compare real-world persistence, effectiveness and tolerability of ustekinumab versus TNF inhibitors (TNFi) in psoriatic arthritis (PsA).One-year data from Italian subjects enrolled in the PsABio study (PsA patients receiving 1st- to 3rd-line treatment with ustekinumab or TNFi) were evaluated. Treatment persistence was analysed using Kaplan-Meier curves; hazard ratios (HR) of stopping treatment, and the corresponding 95% confidence intervals (CI), were computed through Cox regression models. Proportions of patients reaching clinical effectiveness endpoints were analysed using logistic regression, including propensity score (PS) adjustment for imbalanced baseline covariates, and non-response imputation if treatment was stopped/switched.Among 222 participants with follow-up data (effectiveness set), 101 received ustekinumab and 121 TNFi. In the ustekinumab group, 74.3% continued treatment up to 12±3 months compared to 63.6% in the TNFi group. Ustekinumab showed better persistence than TNFi, overall and in specific subgroups (females, monotherapy without methotrexate, BMI25 or30 kg/m2, patients receiving ustekinumab as 2nd-line treatment instead of a second TNFi). Overall, the PS-adjusted HR of treatment discontinuation was 0.46 (95% CI: 0.26-0.82) for ustekinumab vs. TNFi. cDAPSA LDA/remission was achieved in 43.5% of ustekinumab and 43.6% of TNFi-treated patients, while MDA was achieved in 24.2% and 28.0% of patients, respectively. After PS adjustment, odds ratios of clinical effectiveness did not differ significantly. Both treatments showed an acceptable safety profile.This prospective, real-life study found a better persistence of ustekinumab than TNFi in PsA patients. At 1 year, both treatments showed similar effectiveness.

The use of biosimilars is constantly growing, prompting healthcare payers to encourage the switch to these drugs which are less expensive than the reference bio-originator. While switching from a bio-originator to a biosimilar is supported by increasing evidence, data on the switch between different biosimilars of the same reference product are scant. Our study aimed to evaluate the effectiveness of the non-medical switch both between adalimumab (ADA) bio-originator and SB5 biosimilar and between two different ADA biosimilars in patients with inflammatory chronic arthritis.We observed adult patients with a diagnosis of rheumatoid arthritis (RA), psoriatic arthritis (PsA), and axial spondyloarthritis (axSpA) treated with ADA bio-originator or ABP501 ADA biosimilar (Amgevita) who switched to SB5 ADA biosimilar (Imraldi) for administrative/economic reasons. Patients were followed up for 4 months.One hundred and ten patients [33 RA, 40 PsA, 37 axSpA; F:M= 49:61; median age 56 years (25th-75th percentile 48-66)] switched from ADA bio-originator to SB5. After 4 months (T4), we observed a significant reduction of patients in remission/low disease activity (baseline 92.7% vs. T4 80.9%; p=0.009), with a risk of moderate-high disease activity significantly higher after the switch [RR 2.6 (95% IC 1.2 to 5.7), p=0.01]. However, no differences were found in DAS28-CRP, DAPSA, ASDAS-CRP, and BASDAI, while patients with RA and PsA experienced a worsening in the patient global assessment-VAS (p=0.04 and p=0.02, respectively), and in patients with PsA a worsening in HAQ was also observed (p=0.03). Forty patients switched from ABP501 biosimilar to SB5 [12 with RA, 25 with PsA, and 3 with axSpA; F:M=24:16; median age 56 years (25th-75th percentile 44-66)]. After 4 months, no differences in DAS28-CRP and DAPSA nor in the percentage of patients in remission/low disease activity were found compared to baseline. Likewise, no differences were found in patient-reported outcomes (PROs).Our results provide a reassuring profile of effectiveness when switching from ADA originator to one of its biosimilars and between two different biosimilars. However, the worse outcome in PROs in patients initially treated with the bio-originator addresses the attention to a possible nocebo response, which should encourage comprehensive communication with patients.

Background Several data have demonstrated the occurrence of erosive arthritis in Systemic Lupus Erythematosus (SLE) patients. However, a few studies have focused on the pathogenic mechanisms involved in this feature. The implication of oral pathogens has been proved in Rheumatoid Arthritis: in particular, Porphyromonas gingivalis ( Pg), by inducing citrullination, could trigger autoimmune response. Here, we evaluated amount of Pg on the tongue in a cohort of SLE patients with arthritis, focusing on the association with the erosive phenotype. Methods SLE patients with arthritis were enrolled. DAS28 was applied to assess activity. Erosive damage was evaluated by ultrasound at level of MCP (metacarpophalangeal) and PIP (proximal interphalangeals) joints. All subjects underwent a tongue cytologic swab in order to quantify the amount of Pg (real-time PCR). The bacterium expression was obtained from the ratio between the patient’s DNA amount and that obtained from healthy subjects. Results 33 patients were enrolled (M/F 3/30; median age 47 years, IQR 17; median disease duration 216 months, IQR 180): 12 of them (36.4%) showed erosive damage, significantly associated with ACPA positivity ( p = 0.03) and higher values of DAS28 ( p = 0.01). A mean ratio of 19.7 ± 31.1 was found for Pg amount. Therefore, we used Pg mean values as threshold, identifying two groups of patients, namely, high Pg and low Pg. Erosive damage was significantly more frequent in high Pg patients in comparison with low Pg (60.0% vs 26.0%, p = 0.001). Furthermore, high Pg patients showed higher prevalence of skin manifestations, serositis, and neurological involvement ( p = 0.005, p = 0.03, p = 0.0001, respectively). Conclusion The possible contribution of oral microbiota in SLE erosive arthritis was here evaluated for the first time, finding a significant association between erosive damage and higher expression of Pg at tongue level.

Objectives Many axial spondylarthritis (axSpA) patients receive a conventional synthetic DMARD (csDMARD) in combination with a TNF inhibitor (TNFi). However, the value of this co-therapy remains unclear. The objectives were to describe the characteristics of axSpA patients initiating a first TNFi as monotherapy compared with co-therapy with csDMARD, to compare one-year TNFi retention and remission rates, and to explore the impact of peripheral arthritis. Methods Data was collected from 13 European registries. One-year outcomes included TNFi retention and hazard ratios (HR) for discontinuation with 95% CIs. Logistic regression was performed with adjusted odds ratios (OR) of achieving remission (Ankylosing Spondylitis Disease Activity Score (ASDAS)-CRP Results Amongst 24 171 axSpA patients, 32% received csDMARD co-therapy (range across countries: 13.5% to 71.2%). The co-therapy group had more baseline peripheral arthritis and higher CRP than the monotherapy group. One-year TNFi-retention rates (95% CI): 79% (78, 79%) for TNFi monotherapy vs 82% (81, 83%) with co-therapy (P Conclusion This large European study of axial SpA patients showed similar one-year treatment outcomes for TNFi monotherapy and csDMARD co-therapy, although considerable heterogeneity across countries limited the identification of certain subgroups (e.g. peripheral arthritis) that may benefit from co-therapy.

ObjectiveA subanalysis of the multicentre Early Lupus inception cohort was performed to investigate the real-world Glucocorticoids (GCs) Use in newly diagnosed systemic lupus erythematosus (SLE) Patients (GULP).MethodsPatients starting prednisone (PDN) ≥5 mg/day and concomitant hydroxychloroquine or immunosuppressant within 12 months of SLE classification were enrolled. Core set variables were recorded at baseline and every 6 months, including changes in PDN dose, European Consensus Lupus Activity Measurement (ECLAM) and Systemic Lupus International Collaborating Clinics damage index. Regression models analysed predictors of tapering PDNResultsThe GULP study included 127 patients with SLE; 73 (57.5%) tapered and maintained PDN ConclusionTapering PDN

Objective We aimed to analyse 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, three 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 monitor and provide adequate targeted therapy, which improve SN-APS prognosis.

Objectives Antiphospholipid syndrome (APS) is a prothrombotic condition defined by recurrent thrombosis, pregnancy complications and circulating antiphospholipid antibodies (aPL), including anti-β2-glycoprotein I (β2-GPI). In clinical practice it is possible to find patients with APS persistently negative for the aPL tests according to Sydney criteria (‘seronegative APS’, SN-APS). Recently, several autoimmune responses have been described as a consequence of post-translational modifications of their target autoantigens. This study was undertaken to test carbamylated-β2-GPI (Carb-β2-GPI) as a new autoantigen of APS. Methods β2-GPI was carbamylated by potassium cyanate and used to investigate its effect on monocyte-derived dendritic cell (moDC) phenotype and function. Sera from 114 SN-APS patients, 60 APS, 20 patients with RA, 20 non-APS thrombosis and 50 healthy donors were analysed for anti-Carb-β2-GPI by ELISA. Results Carb-β2-GPI is able to activate moDCs, inducing upregulation of CD80, CD86 and CD40, activation of extracellular signal-regulated kinase, p38 mitogen-activated protein kinase and nuclear factor-κB, and IL-12p70 release. Serological results showed that both 37/114 SN-APS (32.46%) and 23/60 APS (38.33%) patients resulted positive for anti-Carb-β2-GPI. Interestingly, SN-APS patients who tested positive for anti-Carb-β2-GPI showed a higher prevalence of thrombocytopenia (P = 0.04, likelihood positive ratio of 3.9). Conclusion Data obtained from both functional tests on moDCs and immunological approaches prompted identification of Carb-β2-GPI as a ‘new’ antigenic target in APS. In particular, anti-Carb-β2-GPI revealed a potential usefulness in identification of a significant proportion of SN-APS patients. Moreover, since patients who tested positive for anti-Carb-β2-GPI reported a high risk of thrombocytopenia, this test may be considered a suitable approach in the clinical evaluation of SN-APS.

Since the onset of the COVID-19 outbreak, concern has been raised about reliability of SARS-CoV-2 serological tests in people with serum positivity for rheumatoid factor (RF), due to its ability to interfere during tests carried out with immunoassay techniques, leading to false positive results. The aim of this study was to analyse, on sera from RF seropositive rheumatoid arthritis (RA) patients, the interference between RF IgM and anti-S1 RBD IgM.The study was conducted on consecutive patients affected by RF seropositive RA and, as control group, COVID-19 patients with SARS-CoV-2 pneumonia hospitalised at Sapienza University of Rome from April 2020 and April 2021. Serum samples from COVID-19 patients during their hospitalisation were collected, while RA subjects' samples were harvested prior to the onset of the COVID-19 pandemic. All samples were tested for RF IgM using nephelometry and ELIA, and for anti-S1 RBD IgM by ELISA.Forty RF seropositive RA and 42 COVID-19 patients were enrolled. In all RA patients, both nephelometric assay and ELIA showed RF IgM positivity, while only one patient of the control group tested positive for RF IgM by nephelometric assay and ELIA. IgM directed to S1 RBD were not detected in sera of RA patients, while all COVID-19 patients presented anti-S1 RBD IgM (median anti-S1 RBD IgM COVID-19 vs. RA: 368.5 IU/mL, IQR 654 IU/mL vs. 18.45 IU/mL, IQR 20 IU/mL; p0.0001).This study confirmed the lack of cross-reactivity between RF and anti-S1 RBD IgM, offering to clinicians a valuable tool for a better management of RA patients undergoing SARSCoV-2 serological tests.

Systemic lupus erythematosus (SLE)–related arthritis has been traditionally defined as non-erosive and is therefore considered a minor manifestation requiring a mild treatment. However, the concept of non-erosive arthritis in SLE has been challenged with the advent of sensitive imaging techniques, such as high-resolution ultrasound with power Doppler or magnetic resonance. The application of these new imaging tools has demonstrated that up to 40% of SLE patients with joint involvement can develop erosive damage. Thus, this more aggressive phenotype can be identified not only in patients overlapping with rheumatoid arthritis (RA). This issue has been considered for the first time in the classification criteria proposed by Systemic Lupus International Collaborating Clinics in 2012, in which the old definition of “non-erosive arthritis” was replaced with either synovitis or tenderness in two or more joints with morning stiffness, suggesting the possible presence of an erosive phenotype. Accordingly, the 2019 EULAR/ACR’s SLE recommendations advise treatment with immunosuppressant or biological drugs for patients with RA-like moderate arthritis. As a result, several studies have investigated the presence of biomarkers associated with SLE erosive damage. A relevant role seems to be played by the autoantibodies directed against post-translational modified proteins: above all, a significant association has been observed with antibodies directed against citrullinated and carbamylated proteins. Conversely, the rheumatoid factor was not associated with this more aggressive SLE-related arthritis. Nonetheless, some pro-inflammatory factors have been associated with erosive damage in SLE patients. These results suggest new pathogenic mechanisms underlining erosive arthritis, only partially shared with RA. Hence, in the present narrative review, we summarized available data about erosive arthritis in SLE patients, in the light of its impact on therapeutic decisions.

Objectives: Women of childbearing age may be affected by psoriatic arthritis (PsA) and ankylosing spondylitis (AS). The aim was to assess the impact of biological agents (bDMARDs) on the fertility of women with PsA and AS by evaluating the serum levels of anti-Müllerian hormone (AMH), follicle-stimulating hormone (FSH) and luteinising hormone (LH). Methods: Consecutive female patients (18-45 years) affected by PsA or AS starting a bDMARD were retrospectively evaluated at baseline (T0) and after 8 months (T8) of treatment. At both visits, demographic and clinical data were obtained. AMH, LH, and FSH serum levels were measured. A population of fertile women matched for age, body mass index and smoking habit was included as healthy controls (HCs). Results: Twenty-four patients with PsA, 20 with AS, and 44 HCs were included. The median (25th-75th percentile) levels of AMH in patients were 0.74 ng/ml (0.29-2) at baseline and 0.71 ng/ml (0.19-1.9) (p=n.s.) at T8. The median levels of AMH in HCs were 1.56 ng/ml (0.37-2.90), with no difference compared to patients. No correlation was found between the serum AMH levels and the indexes of disease activity for both PsA and AS. No differences were found in the serum levels of FSH and LH before and after treatment with bDMARDs. Conclusions: Our results support the use of bDMARDs in female patients with SpA. AMH levels were not influenced by bDMARDs nor by disease activity. AMH could be useful to assess the quantitative aspect of ovarian reserve in female SpA patients.

To explore the pathogenic association between periodontal disease and rheumatoid arthritis focusing on the role of Porphyromonas gingivalis.In the last decades our knowledge about the pathogenesis of rheumatoid arthritis substantially changed. Several evidences demonstrated that the initial production of autoantibodies is not localized in the joint, rather in other immunological-active sites. A central role seems to be played by periodontal disease, in particular because of the ability of P. gingivalis to induce citrullination, the posttranslational modification leading to the production of anticitrullinated protein/peptide antibodies, the most sensitive and specific rheumatoid arthritis biomarker.The pathogenic role of P. gingivalis has been demonstrated in mouse models in which arthritis was either triggered or worsened in infected animals. P. gingivalis showed its detrimental role not only by inducing citrullination but also by means of other key mechanisms including induction of NETosis, osteoclastogenesis, and Th17 proinflammatory response leading to bone damage and systemic inflammation.

BackgroundAdhesion molecule CD44 contributes to T cell migration into target organs. A higher expression of CD44v3 and v6 isoforms has been identified on T cells from systemic lupus erythematosus (SLE) patients. The aim of this study was to investigate the expression of CD44v3/v6 on T cells of SLE patients in order to evaluate their correlation with clinical features.MethodsSixteen healthy subjects (HSs) and 33 SLE female patients were enrolled. Fifteen patients were in remission (Systemic Lupus Erythematosus Disease Activity Index-2000 (SLEDAI-2K) = 0) and 18 patients had an active disease (SLEDAI-2K ≥ 4). Experiments were conducted by flow cytometry.ResultsExpression of CD44v3 on CD4+and CD8+T cells was higher in active patients compared to HSs ( p = 0.0097 and p = 0.0096). CD44v3 on CD8+T cells was also higher in active patients compared to patients in remission ( p = 0.038). CD44v6 was higher on CD4+and CD8+T cells from active patients compared to HSs ( p = 0.003 and p = 0.0036) and to patients in remission ( p = 0.01 and p = 0.02). In active patients the ratio CD44v3/v6 was unbalanced towards isoform v6 on both T cell populations. In a receiver operating characteristic curve analysis, CD44v6 on CD4+T cells was the most sensitive and specific one (specificity of 81.8%, sensitivity of 75%). Expression of CD44v6 on CD4+and CD8+T cells correlated with the SLEDAI-2K ( p = 0.03, r = 0.38 and p = 0.02, r = 0.39). CD44v6 and CD44v3 on CD8+T cells associated with nephritis and arthritis ( p = 0.047 and p = 0.023).ConclusionsCD44v3/v6 can be used as biomarkers of disease activity and phenotypes; isoform v6 on CD4+T cells can be useful as a diagnostic biomarker.

Specific indices are not available to evaluate systemic lupus erythematosus (SLE) joint involvement; indeed, the application of indices validated for rheumatoid arthritis has been suggested. We evaluated the usefulness of organ specific composite indices, i.e. the Disease Activity Score on 28 joints (DAS28), Simplified Disease Activity Index (SDAI), Clinical Disease Activity Index (CDAI), and the ratio of swollen to tender joints (STR), to assess SLE joint activity by analyzing the correlation between these indices and ultrasonography (US) inflammatory status. We evaluated SLE patients with arthralgia and/or arthritis: the above-mentioned indices were calculated and the SLE Disease Activity Index 2000 (SLEDAI-2k) was applied to assess global disease activity. US of I–V metacarpophalangeal, I–V proximal interphalangeal, wrist, and knee bilateral was performed. Synovial effusion/hypertrophy and power Doppler findings were scored according to a semi-quantitative scale (0–3) to obtain an inflammatory total score (0–216). One hundred and six patients (M/F 7/99, median age 49.5 years (IQR 17.0), median disease duration 8.5 years (IQR 17.0)) were enrolled. We identified a positive correlation between US score and DAS28-CRP ( r = 0.3, p = 0.007), STR ( r = 0.42, p = 0.0005), SDAI ( r = 0.33, p = 0.02), CDAI ( r = 0.29, p = 0.03); US score reflected different levels of clinimetric joint activity. In conclusion, we suggest the ability of composite indices in detecting SLE joint inflammation and their possible real-life use.

Objective: Despite the well-established efficacy of methotrexate (MTX) in rheumatoid arthritis (RA), monotherapy is not sufficient in almost half of patients. The aim of this registry-based study was to detect possible predictive factors for the early failure of MTX as a first-line treatment in early RA patients. Materials and Methods: Five-hundred and ninety RA patients beginning MTX as the first-line treatment were included. Persistence on therapy was re-evaluated after 12 months. Baseline features of disease were evaluated by means of univariate Cox regression, and parameters significantly associated to the outcome were included in multivariate model. Results: One hundred and forty-nine patients (25.3%) failed MTX during the 1st year, for inefficacy in 43.6% and adverse events in 37.5% of cases, respectively. At univariate analysis, patients who discontinued or failed treatment showed lower mean age, higher prevalence of anti-citrullinated peptide antibodies (ACPAs), and higher number of tender/swollen joints. The dose of MTX was correlated with the efficacy and the tolerance of the drug. In particular, patients treated with 7.5 mg of MTX weekly showed a higher rate of discontinuation for inefficacy than adverse events, and the contrary was detected for higher doses. On multivariate analysis, age, ACPA, and number of tender joints were directly associated with MTX discontinuation or failure. Conclusions: More than 25% of RA patients treated with MTX as a first-line therapy failed treatment at 12 months. ACPA positivity, age, and number of tender joints were associated with early withdrawal of MTX in RA patients, while the dose of MTX was correlated to the efficacy and safety of the drug.

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.

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 habitus (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.

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.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.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 (p0.0001). 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.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.

Proteinuria is one of the most typical manifestations of kidney involvement in Systemic Lupus Erythematosus (SLE). We report the case of a 23-year-old woman with a 6-year-long history of SLE presenting with proteinuria after a three-year remission on hydroxychloroquine. Kidney histological examination showed alterations inconsistent with lupus nephritis and suggestive of hydroxychloroquine toxicity or Fabry disease. The latter was confirmed by genetic assay.

SARS-CoV-2 vaccines appear to be the most promising strategy for fighting the virus and protecting also those who might be at higher risk of severe COVID-19, such as patients with rheumatic and musculoskeletal diseases (RMDs). However, vaccine hesitancy might greatly impair the possibility to reach herd immunity and curtail the virus.1 2 As underlined by some studies performed before vaccine availability, a non-negligible proportion of subjects among the general population would have refused vaccination against COVID-19.3 4 During the first weeks of the ongoing vaccination campaign, we proposed an online survey to adult patients with RMDs residing in the Lazio region followed up at our tertiary referral centre in Rome, Italy. Healthy controls (HCs) were recruited using the ‘best friend’ system. Participants had to report on eight different domains with two possible answers: ‘yes’ or ‘no’ (table 1). View this table: Table 1 Multivariable models predicting willingness to receive COVID-19 vaccination and other SARS-CoV-2 and/or vaccine-related outcomes in patients with RMDs and healthy controls Only for the item ‘Willingness to receive COVID-19 vaccination’, answers were ‘yes’ or ‘no/don’t know’, with the possibility to give an explanation in case …

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 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.

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.

Objective To report baseline data of SLE patients enrolled in the Lupus Italian Registry (LIRE). Methods Patients affected by SLE aged ≥ 16 years were consecutively recruited in a multicenter prospective study comparing two cohorts: patients starting biologic immunosuppressants (BC) and patients starting non-biologic immunosuppresants (NBC). Results 308 patients were enrolled, 179 in NBC and 129 in BC. Mean age at disease onset and at diagnosis was significantly higher in NBC (p = 0.023, p = 0.045, respectively). Disease duration was longer in BC (p = 0.022). Patients in BC presented arthritis more frequently (p = 0.024), those in NBC nephropathy (p = 0.03). Quality of life was worse in BC (p = 0.031). Anti-dsDNA, low C3, were significantly more frequent in BC (p Conclusion The predominant organ involvement was different in the two cohorts: kidney involvement predominated in NBC, joint involvement in BC. Despite the younger age at disease onset, patients of the BC had a longer disease duration and more frequently had taken a cumulative prednisone dosage greater than 10 g. Even the pattern of clinical manifestations inducing to prescribe biological rather than conventional immunosuppressants was quite different. Keywords: Autoantibody(ies), autoimmune disease, belimumab, cohort studies, glucocorticoids, immunosuppressants, rituximab, systemic lupus erythematosus

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.

Objective: Salivary gland epithelial cells (SGECs) are key cellular drivers in the pathogenesis of primary Sjögren's syndrome (SS); however, the mechanisms sustaining SGEC activation in primary SS remain unclear. We undertook this study to determine the role of autophagy in the survival and activation of SGECs in primary SS. Methods: Primary SGECs isolated from the minor SGs of patients with primary SS or sicca syndrome were evaluated by flow cytometry, immunoblotting, and immunofluorescence to assess autophagy (autophagic flux, light chain 3 IIB [LC3-IIB], p62, LC3-IIB+/lysosome-associated membrane protein 1 [LAMP-1] staining), apoptosis (annexin V/propidium iodide [PI], caspase 3), and activation (intercellular adhesion molecule, vascular cell adhesion molecule). Focus score and germinal center presence were assessed in the SGs from the same patients to assess correlation with histologic severity. Human SG (HSG) cells were stimulated in vitro with peripheral blood mononuclear cells (PBMCs) and serum from primary SS patients in the presence or absence of autophagy inhibitors to determine changes in autophagy and epithelial cell activation. Results: SGECs from primary SS patients (n=24) exhibited increased autophagy (autophagic flux [P=0.001]; LC3-IIB [P=0.02]; p62 [P=0.064]; and as indicated by LC3-IIB/LAMP-1+ staining), increased expression of antiapoptotic molecules (Bcl-2 [P=0.006]), and reduced apoptosis (annexin V/PI [P=0.002]; caspase 3 [P=0.057]), compared to samples from patients with sicca syndrome (n=16). Autophagy correlated with histologic disease severity. In vitro experiments on HSG cells stimulated with serum and PBMCs from primary SS patients confirmed activation of autophagy and expression of adhesion molecules, which was reverted upon pharmacologic inhibition of autophagy. Conclusion: In primary SS SGECs, inflammation induces autophagy and prosurvival mechanisms, which promote SGEC activation and mirror histologic severity. These findings indicate that autophagy is a central contributor to the pathogenesis of primary SS and a new therapeutic target.

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 CD44 transcripts is not fully understood. We investigated the mRNA expression of CD44v3 and CD44v6 and also analyzed possible CD44 splicing regulators (ESRP1 molecule and rs9666607 CD44 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 CD44v6 mRNA expression was higher in SLE patients compared to healthy controls (p = 0.028). CD44v3/v6 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 CD44v3 and CD44v6 mRNA correlated with the disease duration (p = 0.038, Pearson r = 0.493 and p = 0.038, Pearson r = 0.495, respectively). Splicing regulator ESRP1 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 CD44 was associated with higher level of global CD44 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 CD44 splicing in the disease, whose regulatory mechanisms require further investigation.

Musculoskeletal conditions represent one-third to more than one-half of all non-communicable disease multimorbidities in the elderly, worsening their disability because of pain and limited physical function, often concurring with their mental decline. Musculoskeletal conditions significantly contribute to frailty and global disability, second only to mental health conditions. Furthermore, premature mortality, generally due to an increased risk of developing cardiovascular disease, has been documented in several rheumatic diseases, including osteoarthritis, gout, vasculitis, etc., which largely affect older people. In the elderly, rheumatic diseases cover a spectrum of conditions affecting all age groups, especially those are seen more often in the aging population. This non-systematic review focuses on the elderly and may hopefully contribute to raising awareness of these issues beyond the rheumatology community. We believe that this constitutes a critical step for prompt and proper diagnosis and referral of patients to ameliorate their overall long-term outcome.

Six months following the beginning of Covid-19 pandemic in China, data on the risk of SARS-CoV-2 infection among patients with autoimmune rheumatic diseases are now available. However, the rapid spread of the pandemic has not allowed proper design of prospective studies, thus evidence came mostly from case series and observational studies. The early enthusiasm on hydroxychloroquine (HCQ) anti-viral properties should not suggest that patients who are long-term treated with antimalarials, such as patients with systemic lupus erythematosus (SLE), are protected against SARS-CoV-2 infection. Indeed, a French report on 17 HCQ-treated SLE patients dampened the enthusiasm.1 A recent report from Covid-19 Global Rheumatology Alliance has described 80 SLE patients with Covid-19, mostly females under 65 years of age, 64% of whom were already taking HCQ before the infection: the rate of hospitalisation and the need for intensive care did not differ between patients who were and those who were not taking HCQ.2 A study group from Northern Italy – the Italian epicentre of the pandemic – reported an incidence of 2.5% of Covid-19 (higher compared to the general population of the same region) in 165 patients with SLE.3 Patients with SLE are possibly at risk of developing symptomatic or severe Covid-19, not only because of their disease or treatment but as a consequence of associated comorbidities known to worsen the outcome of SARS-COv-2 infection.4 5 What do we know so far? SLE patients should not withdraw their medication. Before drawing any other conclusion, large registry data are needed to clarify the incidence and the outcome of Covid-19 in patients with SLE. Learning Objectives Describe the current evidence for risk of SARS-CoV-2 infection among patients with autoimmune rheumatic diseases, notably SLE Explain why it is important to ensure robust evidence are available to clarify the outcome of Covid-19 in patients with SLE References Mathian A, Mahevas M, Rohmer J, et al. Clinical course of coronavirus disease 2019 (COVID-19) in a series of 17 patients with systemic lupus erythematosus under long-term treatment with hydroxychloroquine. Ann Rheum Dis 2020;79(6):837–39. Konig MF, Kim AH, Scheetz MH, et al. Baseline use of hydroxychloroquine in systemic lupus erythematosus does not preclude SARS-CoV-2 infection and severe COVID-19. Ann Rheum Dis 2020 doi: 10.1136/annrheumdis-2020-217690 [published Online First: 2020/05/10]. Bozzalla Cassione E, Zanframundo G, Biglia A, et al. COVID-19 infection in a northern-Italian cohort of systemic lupus erythematosus assessed by telemedicine. Ann Rheum Dis 2020 doi: 10.1136/annrheumdis-2020-217717 [published Online First: 2020/05/14]. Wallace B, Waher L, Correspondence regarding Research Letter to the Editor by Mathian A, et al. ‘Clinical course of coronavirus disease 2019 (COVID-19) in a series of 17 patients with systemic lupus under long-term treatment with hydroxychloroquine’. Ann Rheum Dis 2020. doi:10.1136/annrheumdis-2020-217794. Gianfrancesco M, Hyrich KL, Al-Adely S, et al. Characteristics associated with hospitalisation for COVID-19 in people with rheumatic disease: data from the COVID-19 Global Rheumatology Alliance physician-reported registry. Ann Rheum Dis 2020;79(7):859–66.

We thank Konstantinos Parperis for his correspondence to our letter ‘To consider or not antimalarials as a prophylactic intervention in the SARS-CoV-2 (Covid-19) pandemic’ speculating on prophylactic use of antimalarials for subjects at high risk of getting infected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).1 2 As the author highlights, at this time, it is preferable to be cautious when addressing this topic. These days, the scientific information is moving faster than usual, and new data are available every day; however, the scientific evidence collected to …

We thank Sergei Moiseev and colleagues for their comment in response to our letter ‘To consider or not antimalarials as a prophylactic intervention in the SARS-CoV-2 (Covid-19) pandemic’.1 2 Antimalarial drugs hydroxychloroquine (HCQ) and chloroquine have been largely used for treating patients with systemic lupus erythematosus and other autoimmune rheumatic diseases (ARDs) for decades, and they are safe and well tolerated in such patients.3 Conversely, there is still little evidence on their effectiveness in patients with Covid-19. As Moiseev and colleagues have pointed out, more data have been published after the submission of our letter; therefore, we welcome the opportunity to give an update. The results of five studies are now available: three open-label and two randomised controlled trials4–8 (table 1). All studies have small sample sizes and enrolled non-critically ill patients. Gautret et al extended their previous results confirming the fast reduction of viral load in 80 hospitalised Covid-19 patients treated …

ObjectivesRemission in systemic lupus erythematosus (SLE) is defined through a combination of ‘clinical SLE Disease Activity Index (cSLEDAI)=0’, ‘physician's global assessment (PGA) MethodsWe tested seven potential definitions of remission in SLE patients followed-up for ≥5 years: PDN ≤5 mg/day; PGA ResultsWe included 646 patients (mean±SD disease duration 9.2±6.9 years). At multivariate analysis, ≥2 consecutive year remission according to all definitions protected against damage (OR, 95% CI: PGA ConclusionscSLEDAI=0 is the most attainable definition of remission, while displaying the best performance in predicting damage progression in the short-to-mid-term follow-up.

Objective To investigate risk factors for damage development in a prospective inception cohort of early diagnosed SLE patients. Methods The Early Lupus Project recruited an inception cohort of patients within 12 months of SLE classification (1997 ACR criteria). At enrolment and every 6 months thereafter, the SLICC/ACR Damage Index was recorded. The contribution of baseline and time-varying covariates to the development of damage, defined as any SLICC/ACR Damage Index increase from 0 to ≥1, was assessed using univariate analysis. Forward-backward Cox regression models were fitted with covariates with P Results Overall, 230 patients with a mean (s.d.) age of 36.5 (14.4) years were eligible for this study; the mean number of visits per patient was 5.3 (2.7). There were 51 (22.2%) patients with SLICC/ACR Damage Index ≥1 after 12 months, 59 (25.6%) after 24 months and 67 (29.1%) after 36 months. Dyslipidaemia [P = 0.001; hazard ratio (HR) 2.9; 95% CI 1.5, 5.6], older age (P = 0.001; HR 3.0; 95% CI 1.6, 5.5), number of organs/systems involved (P = 0.002; HR 1.4; 95% CI 1.1, 1.8) and cardiorespiratory involvement (P = 0.041; HR 1.9; 95% CI 1.0, 3.7) were independently associated with an increased risk of developing damage. Risk profiles for damage development differed for glucocorticoid-related and -unrelated damage. HCQ use (P = 0.005; HR 0.4; 95% CI 0.2, 0.8) reduced the risk of glucocorticoid-unrelated damage. Conclusion We identified risk factors of damage development, but little effect of glucocorticoids, in this early SLE cohort. Addressing modifiable risk factors from the time of SLE diagnosis might improve patient outcomes.

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.