B-Cell Activation Biomarkers in Salivary Glands Are Related to Lymphomagenesis in Primary Sjögren's Disease: A Pilot Monocentric Exploratory Study.

Primary Sjögren's disease is primarily driven by B-cell activation and is associated with a high risk of developing non-Hodgkin's lymphoma (NHL). Over the last few decades, microRNA-155 (miR-155) has arisen as a key regulator of B-cells. Nevertheless, its role in primary Sjögren's disease remains elusive. Thus, the purpose of this study was (i) to explore miR-155, B-cell activating factor (BAFF)-receptor (BAFF-R), and Interleukin 6 receptor (IL-6R) expression in the labial salivary glands (LSG) of patients with primary Sjögren's disease, aiming to identify potential B-cell activation biomarkers related to NHL development. Twenty-four patients with primary Sjögren's disease, and with available tissue blocks from a LSG biopsy performed at diagnosis, were enrolled. Among them, five patients developed B-cell NHL during follow-up (7.3 ± 3.1 years). A comparison group of 20 individuals with sicca disease was included. Clinical and laboratory parameters were recorded and the LSG biopsies were evaluated to assess local inflammation in terms of miR-155/BAFF-R and IL-6R expression. Stratifying the primary Sjögren's disease cohort according to lymphomagenesis, miR-155 was upregulated in primary Sjögren's disease patients who experienced NHL, more so than those who did not experience NHL. Moreover, miR-155 expression correlated with the focus score (FS), as well as BAFF-R and IL-6R expression, which were increased in primary Sjögren's disease patients and in turn related to neoplastic evolution. In conclusion, epigenetic modulation may play a crucial role in the aberrant activation of B-cells in primary Sjögren's disease, profoundly impacting the risk of NHL development.

Prevalence of dyslipidemia and hypercholesterolemia awareness: results from the Lookup 7+ online project.

BACKGROUND: Cardiovascular disease still represents the leading cause of death worldwide. Management of risk factors remains crucial; despite this, hypercholesterolemia, which is one of the most important modifiable cardiovascular risk factor, is still high prevalent in general population. The aim of this study is to determine the prevalence of dyslipidemia and hypercholesterolemia awareness in a very large population. METHODS: More than 65 000 users completed the online, self-administered survey. It was structured like a 'journey' where each stage corresponded to a cardiovascular risk factor: blood pressure, body mass index, cholesterol, diet, physical exercise, smoke and blood sugar. At the end, the user received a final evaluation of his health status. RESULTS: The mean age was 52.5 years (SD 13.9, range 18-98), with 35 402 (53.7%) men. About 56% of all participants believed to have normal cholesterol values, when only 40% of them really showed values <200 mg/dl. Only about 30% of all participants self-predicted to have abnormal cholesterol values whereas we found high cholesterol levels in about 60% of people. CONCLUSIONS: Dyslipidemia is very prevalent and half of the people with high cholesterol is not aware of having high values.

Durable renal response and safety with add-on belimumab in patients with lupus nephritis in real-life setting (BeRLiSS-LN). Results from a large, nationwide, multicentric cohort.

BACKGROUND: Belimumab was recently approved for treatment of lupus glomerulonephritis (LN). AIM: To evaluate renal response and its predictors in LN patients receiving belimumab in real-life. PATIENTS AND METHODS: We considered all patients fulfilling the SLEDAI-2K renal items and/or having estimated glomerular filtration rate (eGFR)≤60 ml/min/1.73 m2, with positive anti-dsDNA and/or low C3/C4 enrolled in the multicentre Italian lupus cohort BeRLiSS (BElimumab in Real LIfe Setting Study), treated with monthly IV Belimumab 10 mg/kg over standard treatment. Primary efficacy renal response (PERR), defined as proteinuria ≤0.7 g/24 h, eGFR≥60 ml/min/1.73 m2 without rescue therapy, was considered as primary outcome. Complete renal response (CRR; proteinuria <0.5 g/24 h, eGFR≥90 ml/min/1.73 m2) was considered as secondary outcome. Prevalence and predictors of PERR were evaluated at 6, 12, 24 months by multivariate logistic regression. RESULTS: Among the 466 SLE patients of BeRLiSS, 91 fulfilled the inclusion criteria, 79 females, median age 41.0 (33.0-47.0) years, median follow-up 22.0 (12.0-36.0) months. Sixty-four (70.3%) achieved PERR, of whom 38.4% reached CRR. Among patients achieving PERR at 6 months, 86.7% maintained response throughout the follow-up. At multivariable analysis, hypertension (OR [95%CI]: 0.28 [0.09-0.89], p = 0.032), high baseline serum creatinine (0.97 [0.95-0.99], p = 0.01) and high baseline proteinuria (0.37, [0.19-0.74], p = 0.005) negatively predicted PERR. Positive predictors of PERR at 12 and 24 months were baseline anti-Sm positivity (OR [95%CI]: 6.2 [1.21-31.7], p = 0.029; 19.8 [2.01-186.7], p = 0.009, respectively) and having achieved PERR at 6 months (14.4 [3.28-63.6]; 11.7 [2.7-48.7], p = 0.001 for both). CONCLUSIONS: Add-on therapy with belimumab led to durable renal response in patients with LN in a real-life setting.

Nailfold capillaroscopy findings in patients with coronavirus disease 2019: Broadening the spectrum of COVID-19 microvascular involvement.

OBJECTIVE: Increasing evidence points to endothelial dysfunction as a key pathophysiological factor in coronavirus disease-2019 (COVID-19). No specific methods have been identified to predict, detect and quantify the microvascular alterations during COVID-19. Our aim was to assess microvasculature through nailfold videocapillaroscopy (NVC) in COVID-19 patients. METHODS: We performed NVC in patients with a confirmed diagnosis of COVID-19 pneumonia. Elementary alterations were reported for each finger according to a semi-quantitative score. Capillary density, number of enlarged and giant capillaries, number of micro-hemorrhages and micro-thrombosis (NEMO score) were registered. RESULTS: We enrolled 82 patients (mean age 58.8 ± 13.2 years, male 68.3%) of whom 28 during the hospitalization and 54 after recovery and hospital discharge. At NVC examination we found abnormalities classifiable as non-specific pattern in 53 patients (64.6%). Common abnormalities were pericapillary edema (80.5%), enlarged capillaries (61.0%), sludge flow (53.7%), meandering capillaries and reduced capillary density (50.0%). No pictures suggestive of scleroderma pattern have been observed. Acute COVID-19 patients, compared to recovered patients, showed a higher prevalence of hemosiderin deposits as a result of micro-hemorrhages (P = .027) and micro-thrombosis (P < .016), sludge flow (P = .001), and pericapillary edema (P < .001), while recovered patients showed a higher prevalence of enlarged capillaries (P < .001), loss of capillaries (P = .002), meandering capillaries (P < .001), and empty dermal papillae (P = .006). CONCLUSION: COVID-19 patients present microvascular abnormalities at NVC. Currently ill and recovered subjects are characterized by a different distribution of elementary capillaroscopic alterations, resembling acute and post-acute microvascular damage. Further studies are needed to assess the clinical relevance of NVC in COVID-19.

Tocilizumab therapy in rheumatoid arthritis with interstitial lung disease: a multicentre retrospective study.

BACKGROUND: Interstitial lung disease (ILD) is the most severe extra-articular manifestation of rheumatoid arthritis (RA). Although it is responsible of 10-20% of all RA mortality, no controlled studies are available for the treatment of RA-ILD and its therapeutic approach is still debated. AIMS: To analyse the evolution of ILD in a population of RA patients treated with tocilizumab (TCZ). METHODS: In this national multicentre study, we retrospectively collected patients with RA-ILD treated with at least one dose of TCZ. For each patient, disease activity and serological data were evaluated. Moreover, we analysed the evolution of high-resolution computed tomography (HRCT) and pulmonary function tests, including forced vital capacity (FVC) and diffusing capacity of the lung for carbon monoxide (DLCO). RESULTS: Twenty-eight RA-ILD patients were identified (females/males 18/10, mean age 61.6 years), with a mean follow up for TCZ therapy of 30 months. At the end of follow up, FVC remained stable in 14 (56%) patients, improved in 5 (20%) and worsened in 6 (24%). DLCO remained stable in 14 (56%) patients, improved in 5 (20%) and worsened in 6 (24%), even though in 3 patients DLCO and FVC showed an opposite trend. HRCT remained stable in the majority (25) of cases, worsened in two patients with a usual interstitial pneumonia pattern and improved in only one case with a non-specific interstitial pneumonia pattern. CONCLUSIONS: The management of RA-ILD patients remains a critical unmet need. TCZ demonstrated a good safety profile in patients with RA-ILD and a potential effect on the stabilisation of lung involvement.

Synovial features of patients with rheumatoid arthritis and psoriatic arthritis in clinical and ultrasound remission differ under anti-TNF therapy: a clue to interpret different chances of relapse after clinical remission?

OBJECTIVE: To define the synovial characteristics of patients with rheumatoid arthritis (RA) and psoriatic arthritis (PsA) in clinical and ultrasound remission achieved by combination therapy with methotrexate (MTX) and tumour necrosis factor (TNF) blockers. METHODS: Patients with RA in remission (n=25) (disease activity score (DAS)<1.6 for at least 6 months), patients with RA in low disease activity (LDA) (n=10) (1.6

Serum Albumin Levels: A Biomarker to Be Repurposed in Different Disease Settings in Clinical Practice.

Serum albumin (ALB), one of the most important proteins in human physiology, has the main functions of maintaining plasma oncotic pressure and plasma volume, transporting hormones, vitamins, oligominerals and drugs, and exerting a powerful antioxidant-anti-inflammatory role. Its prognostic value in liver and malabsorption syndromes is well known. In this narrative review, an analysis of the most important studies evaluating the prognostic significance of low serum ALB levels in hospitalized patients was performed. Specifically, the risk in emergency medicine, cardiovascular diseases, Coronavirus Disease 19 (COVID-19) infection, nephrology, oncology, and autoimmune rheumatic diseases has been examined to fully explore its clinical value. ALB is a negative acute-phase reactant and the reduction in its serum levels represents a threatening parameter for long-term survival in several clinical settings, and a strong biomarker for a poor prognosis in most diseases. Therefore, clinicians should consider serum ALB as a valuable tool to assess the efficacy of specific therapies, both in hospitalized patients and in chronic follow-up.

Polymorphisms of the IgH enhancer HS1.2 and risk of systemic lupus erythematosus.

OBJECTIVE: To determine whether the allelic frequency variation of the HS1.2 enhancer of the immunoglobulin heavy chain (IgH) 3' regulatory region (3'RR-1) locus represents a risk factor for systemic lupus erythematosus (SLE) and to identify a possible functional difference in the two most frequent alleles (*1 and *2) in binding nuclear factor- κB (NF-κB) and Sp1. METHODS: The frequency of the enhancer HS1.2 alleles was determined in two cohorts of patients with SLE (n=293) and in 1185 controls. Electrophoretic mobility shift assays (EMSA) were carried out with B cell nuclear extracts with different probes of HS1.2 alleles *1 and *2 to map the consensus binding sites of the nuclear factors. A confirmatory cohort of 121 patients with SLE was also included. RESULTS: The frequency of allele *2 of the HS1.2 enhancer was significantly increased in patients with SLE compared with controls (OR 1.60, 95% CI 1.33 to 1.92, p<0.001). EMSA experiments showed the presence of the Sp1 binding site in both alleles whereas only allele *2 carried the consensus for the NF-κB factor. The presence versus absence of allele *2 in patients with SLE correlated with a higher concentration of IgM levels and with the expression of B cell activating factor receptor (BAFF-R). CONCLUSIONS: The increased frequency of allele *2 in patients with SLE identifies a new genetic risk factor for SLE. A possible biological effect of the polymorphism could be the difference observed in the localisation of an NF-κB binding site which is specific for allele *2 and absent in allele *1. These observations suggest a functional effect of the HS1.2 enhancer in this disease.

Peripheral blood CD4posCD25posFoxP3pos cells and inflammatory cytokines as biomarkers of response in rheumatoid arthritis patients treated with CTLA4-Ig.

BACKGROUND: Prognostic biomarkers of treatment response to distinct biologic disease-modifying anti-rheumatic drugs (b-DMARDs) are still lacking within the management of rheumatoid arthritis (RA). METHODS: Thirty-four b-DMARDs naive RA patients, divided by disease duration into early (cohort 1) and long standing (cohort 2), received CTLA4-Ig. At study entry, and every 3 months for 1 year, each patient underwent peripheral blood (PB)-derived CD4pos cell subpopulation assessment by flow cytometry, STAT3 and STAT5 expression by RT-PCR and IL-6, IL-12p70, TGFß, and IL-10 serum levels by ELISA. The DAS and CDAI remission was assessed at 6 and 12 months. RESULTS: DAS- and CDAI-defined remission within 12 months was achieved by 16 (47.1%) and 8 (23.5%) RA patients, respectively. Considering the whole RA cohort, CTLA4-Ig induced a significant decrease of IL-6 serum levels from baseline to 6 and 12 months, as well as of PB CD4posCD25posFoxP3pos cells at 6 and 12 months, and of CD4posIL17pos cells after 12 months. PB CD4pos cells of RA patients showed higher STAT3 and STAT5 expression than healthy controls, which remained unchanged within 12 months of treatment. At study entry, RA patients achieving DAS remission had significantly lower IL-6 serum levels than RA patients not achieving this outcome. In particular, having baseline IL-6 serum levels ≤ 8.4 pg/ml, significantly identified naïve to b-DMARDs RA patients more likely to achieve DAS-remission under CTLA4-Ig at 6 months (66.7%) compared to RA patients with baseline IL-6 serum levels > 8.4 pg/ml [15.4%, OR (95%Cis) 11.00 (1.75-55.82)]. Moreover, having CD4posCD25posFoxP3pos cells rate ≥ 6.0% significantly identifies naïve to b-DMARDs early RA patients more likely to achieve DAS remission at 6 months (83.3%) compared to RA patients with baseline CD4posCD25posFoxP3pos cells < 6.0% [16.7%, OR (95% Cis) 25.00 (1.00-336.81)]. CONCLUSIONS: Baseline IL-6 serum levels and peripheral blood-derived CD4pos subpopulations are putative novel prognostic biomarkers of CTLA4-Ig response in RA patients.

B-cell subsets in the joint compartments of seropositive and seronegative rheumatoid arthritis (RA) and No-RA arthritides express memory markers and ZAP70 and characterize the aggregate pattern irrespectively of the autoantibody status.

The aim of the present study was to determine whether different subsets of B cells characterize synovial fluid (SF) or synovial tissue (ST) of seropositive or seronegative rheumatoid arthritis (RA) with respect to the peripheral blood (PB). PB, SF and ST of 14 autoantibody (AB)-positive (rheumatoid factor [RF]-IgM, RF-IgA, anti-citrullinated peptide [CCP]), 13 negative RA and 13 no-RA chronic arthritides were examined for B-cell subsets (Bm1-Bm5 and IgD-CD27 classifications), zeta-associated protein kinase-70 (ZAP70) expression on B cells and cytokine levels (interleukin [IL]-1ß, tumor necrosis factor [TNF]-α, IL-6, IL-8 and monocyte chemotactic protein [MCP]-1). Synovial tissues were classified as aggregate and diffuse patterns. No differences were found in B-cell percentages or in subsets in PB and SF between AB(+) and AB(-) RA and no-RA. In both AB(+) and AB(-) RA (and no-RA), the percentage of CD19(+)/ZAP70(+) was higher in SF than in PB (AB(+): P = 0.03; AB(-): P = 0.01; no-RA: P = 0.01). Moreover, SF of both AB(+) and AB(-) RA (and no-RA) patients was characterized by a higher percentage of IgD-CD27(+) and IgD-CD27(-) B cells and lower percentage of IgD(+)CD27(-) (P < 0.05) B cells compared to PB. In SF, ZAP70 positivity is more represented in B cell CD27(+)/IgD(-)/CD38(-). The aggregate synovitis pattern was characterized by higher percentages of Bm5 cells in SF compared with the diffuse pattern (P = 0.05). These data suggest that no difference exists between AB(+) and AB(-) in B-cell subset compartmentalization. CD27(+)/IgD(-)/ZAP70(+) memory B cells accumulate preferentially in the joints of RA, suggesting a dynamic maturation of the B cells in this compartment.

Haemophilus parasuis (Glaesserella parasuis) as a Potential Driver of Molecular Mimicry and Inflammation in Rheumatoid Arthritis.

Background: Haemophilus parasuis (Hps; now Glaesserella parasuis) is an infectious agent that causes severe arthritis in swines and shares sequence similarity with residues 261-273 of collagen type 2 (Coll261-273), a possible autoantigen in rheumatoid arthritis (RA). Objectives/methods: We tested the presence of Hps sequencing 16S ribosomal RNA in crevicular fluid, synovial fluids, and tissues in patients with arthritis (RA and other peripheral arthritides) and in healthy controls. Moreover, we examined the cross-recognition of Hps by Coll261-273-specific T cells in HLA-DRB1*04pos RA patients, by T-cell receptor (TCR) beta chain spectratyping and T-cell phenotyping. Results: Hps DNA was present in 57.4% of the tooth crevicular fluids of RA patients and in 31.6% of controls. Anti-Hps IgM and IgG titers were detectable and correlated with disease duration and the age of the patients. Peripheral blood mononuclear cells (PBMCs) were stimulated with Hps virulence-associated trimeric autotransporter peptide (VtaA10755-766), homologous to human Coll261-273 or co-cultured with live Hps. In both conditions, the expanded TCR repertoire overlapped with Coll261-273 and led to the production of IL-17. Discussion: We show that the DNA of an infectious agent (Hps), not previously described as pathogen in humans, is present in most patients with RA and that an Hps peptide is able to activate T cells specific for Coll261-273, likely inducing or maintaining a molecular mimicry mechanism. Conclusion: The cross-reactivity between VtaA10755-766 of a non-human infectious agent and human Coll261-273 suggests an involvement in the pathogenesis of RA. This mechanism appears emphasized in predisposed individuals, such as patients with shared epitope.

Retention rate of a second line with a biologic DMARD after failure of a first-line therapy with abatacept, tocilizumab, or rituximab: results from the Italian GISEA registry.

OBJECTIVES: EULAR recommendations do not suggest which biologic disease-modifying anti-rheumatic drug (bDMARD) should be preferred after failure of a first bDMARD in the treatment of rheumatoid arthritis (RA). In particular, few data are available regarding the effectiveness of a second-line bDMARD after failure of abatacept (ABA), tocilizumab (TCZ), and rituximab (RTX). The aim of this study was to analyze the retention rate of a second line with tumor necrosis factor inhibitors (TNFi) or other mechanisms of action (MoAs), after the failure of either RTX, TCZ, or ABA. METHODS: Two hundred and seventy-eight RA patients from the Italian GISEA registry were included in the study. RTX was the first bDMARD in 18% of patients, ABA in 45.7%, and TCZ in 36.3%, while the second bDMARD was a TNFi (group 1) in 129 patients and an agent with a different MoA (group 2) in 149. RESULTS: During a median follow-up of 22 months (IQR 68), 129 patients discontinued their treatment; patients of group 1 discontinued the treatment more frequently than patients of group 2 (p<0.001) with retention rates of 33.6±5.7% and 63.6±4.6% after 104 weeks for group 1 and group 2, respectively (p<0.001). At multivariate analysis, the mechanism of action was the only predictor for the maintenance in therapy. CONCLUSIONS: According to our data, ABA, RTX, and TCZ seem to maintain a good retention rate also when used as a second-line therapy, suggesting their use after the failure of a non-TNFi as first-line therapy. However, specifically designed studies are needed to evaluate the more appropriate therapeutic strategies in RA, according to the first-line drug, including new targeted synthetic DMARDs. Key Points • A large proportion of rheumatoid arthritis patients fail the first biologic DMARD. • Few data are available about the efficacy of biologic DMARD after the failure of a non-TNF inhibitor. • Abatacept, rituximab, or tocilizumab seem to maintain a good retention rate after the failure of a first-course therapy with a non-TNF inhibitor.

Systemic Bone Density at Disease Onset Is Associated With Joint Erosion Progression in Early Naive to Treatment Rheumatoid Arthritis: A Prospective 12-Month Follow-Up Open-Label Study.

Objectives: Osteoporosis and bone erosions are hallmarks of rheumatoid arthritis (RA) since disease onset is underpinned by the inflammatory burden. In this observational study, we aimed to dissect the putative RA-related parameters and bone-derived biomarkers associated with systemic and focal bone loss at disease onset and with their progression. Methods: One-hundred twenty-eight patients with early rheumatoid arthritis (ERA) were recruited at disease onset. At study entry, demographic, clinical, and immunological parameters were recorded. Each ERA patient underwent plain X-rays of the hands and feet at study entry and after 12 months to assess the presence of erosions. After enrollment, each patient was treated according to the recommendations for RA management and followed up based on a treat-to-target (T2T) strategy. At baseline, blood samples for soluble biomarkers were collected from each patient, and plasma levels of osteoprotegerin (OPG), receptor activator of nuclear factor κB ligand (RANKL), Dickkopf-1 (DKK1), and interleukin 6 (IL-6) were assessed by enzyme-linked immunosorbent assay (ELISA). Seventy-one ERA patients underwent bone mineral density (BMD) measurement at the left femoral neck and second to fourth lumbar spine vertebrae (L2-L4) by dual-energy X-ray absorptiometry (DXA). Results: Among the whole cohort, 34 (26.6%) ERA patients with bone erosions at study entry had a higher disease activity (p = 0.02) and IL-6 plasma levels (p = 0.03) than non-erosive ones. Moreover, at DXA, 33 (46.5%) ERA patients had osteopenia, and 16 (22.5%) had osteoporosis; patients with baseline bone erosions were more likely osteopenic/osteoporotic than non-erosive ones (p = 0.03), regardless of OPG, RANKL, and DKK1 plasma levels. Obese ERA patients were less likely osteopenic/osteoporotic than normal weight ones (p = 0.002), whereas anti-citrullinated protein antibodies (ACPA) positive ERA patients were more likely osteopenic/osteoporotic than ACPA negative ones (p = 0.034). At logistic regression analysis, baseline Disease Activity Score measured on 44 joints (DAS44) [OR: 2.46 (1.11-5.44)] and osteopenic/osteoporosis status [OR: 7.13 (1.27-39.94)] arose as independent factors of erosiveness. Baseline osteopenic/osteoporotic status and ACPA positivity were associated with bone damage progression during the follow-up. Conclusions: Bone erosions presence is associated with systemic bone loss since the earliest phases of RA, suggesting that the inflammatory burden and autoimmune biology, underpinning RA, represent crucial enhancers of bone remodeling either locally as at systemic level.

Inclusion of Synovial Tissue-Derived Characteristics in a Nomogram for the Prediction of Treatment Response in Treatment-Naive Rheumatoid Arthritis Patients.

OBJECTIVE: This study applied a synovitis score obtained during routine care from ultrasound (US)-guided biopsies of synovial tissue (ST) in patients with rheumatoid arthritis (RA) and patients with other inflammatory and noninflammatory joint diseases to identify pretreatment synovial biomarkers associated with disease characteristics, and to integrate the findings into a multiparameter nomogram for use in baseline prediction of diagnosis and treatment response in treatment-naive rheumatoid arthritis (RA) patients. METHODS: The study enrolled a total of 1,015 patients with various autoimmune diseases (545 patients with RA, 167 patients with psoriatic arthritis [PsA], 199 patients with undifferentiated peripheral inflammatory arthritis [UPIA], 18 patients with crystal-induced arthritis, 26 patients with connective tissue diseases, and 60 patients with osteoarthritis [OA] [as part of the SYNGem cohort]). All patients underwent a US-guided ST biopsy at baseline, and patients were then stratified according to disease phase. The KSS, along with disease characteristics and clinical outcomes, were incorporated into a nomogram for prediction of achievement of clinical remission in RA patients who were previously naive to treatment. In patients in whom a treat-to-target strategy was applied, remission was defined as change in the Disease Activity Score in 28 joints (DAS28) at 6 months after treatment initiation. RESULTS: The KSS significantly differed among RA patients, as well as PsA patients and UPIA patients, when compared to OA patients. In RA, the KSS directly correlated with the DAS28 and was related to autoantibody positivity in treatment-naive RA patients. Moreover, at baseline, treatment-naive RA patients achieving 6-month remission according to DAS28 had a lower KSS, shorter duration of symptoms (very early RA [VERA]), and lower disease activity than treatment-naive RA patients not achieving remission according to DAS28. Results of logistic regression analysis identified the following synergistic predictive factors of achievement of DAS28-based disease remission at 6 months: having a short disease duration (VERA), not having high disease activity, and having a KSS of <5 at baseline. A nomogram integrating these baseline clinical and histologic characteristics in treatment-naive RA patients yielded an up to 81.7% probability of achieving 6-month remission according to the DAS28. CONCLUSION: The KSS is a reliable tool for synovitis assessment on US-guided ST biopsy, contingent on the phase of the disease and the autoimmune profile of each patient. This tool could be integrated within a therapeutic response-predictive nomogram for the prediction of treatment response in RA patients who were previously naive to treatment.

Prevalence and Predictors of Persistence of COVID-19 Symptoms in Older Adults: A Single-Center Study.

OBJECTIVES: Symptom persistence weeks after laboratory-confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) clearance is a relatively common long-term complication of Coronavirus disease 2019 (COVID-19). Little is known about this phenomenon in older adults. The present study aimed at determining the prevalence of persistent symptoms among older COVID-19 survivors and identifying symptom patterns. DESIGN: Cross-sectional study. SETTING AND PARTICIPANTS: We analyzed data collected in people 65 years and older (n = 165) who were hospitalized for COVID-19 and then admitted to the Day Hospital Post-COVID 19 of the Fondazione Policlinico Universitario "Agostino Gemelli" IRCCS (Rome, Italy) between April and December 2020. All patients tested negative for SARS-CoV-2 and met the World Health Organization criteria for quarantine discontinuation. MEASURES: Patients were offered multidisciplinary individualized assessments. The persistence of symptoms was evaluated on admission using a standardized questionnaire. RESULTS: The mean age was 73.1 ± 6.2 years (median 72, interquartile range 27), and 63 (38.4%) were women. The average time elapsed from hospital discharge was 76.8 ± 20.3 days (range 25-109 days). On admission, 137 (83%) patients reported at least 1 persistent symptom. Of these, more than one-third reported 1 or 2 symptoms and 46.3% had 3 or more symptoms. The rate of symptom persistence was not significantly different when patients were stratified according to median age. Compared with those with no persistent symptoms, patients with symptom persistence reported a greater number of symptoms during acute COVID-19 (5.3 ± 3.0 vs 3.3 ± 2.0; P < .001). The most common persistent symptoms were fatigue (53.1%), dyspnea (51.5%), joint pain (22.2%), and cough (16.7%). The likelihood of symptom persistence was higher in those who had experienced fatigue during acute COVID-19. CONCLUSIONS AND IMPLICATIONS: Persistent symptoms are frequently experienced by older adults who have been hospitalized for COVID-19. Follow-up programs should be implemented to monitor and care for long-term COVID-19-related health issues.

Predictive Factors for a New Positive Nasopharyngeal Swab Among Patients Recovered From COVID-19.

INTRODUCTION: As an emerging infectious disease, the clinical and virologic course of COVID-19 requires better investigation. The aim of this study is to identify the potential risk factors associated with persistent positive nasopharyngeal swab real-time reverse transcription‒polymerase chain reaction tests in a large sample of patients who recovered from COVID-19. METHODS: After the acute phase of SARS-CoV-2 epidemic infection, the Fondazione Policlinico A. Gemelli IRCSS of Rome established a post-acute care service for patients discharged from the hospital and recovered from COVID-19. Between April 21 and May 21, 2020, a total of 137 individuals who officially recovered from COVID-19 were enrolled in this study. All patients were tested for the SARS-CoV-2 virus with nucleic acid RT-PCR tests. Analysis was conducted in June 2020. RESULTS: Of the 131 patients who repeated the nasopharyngeal swab, 22 patients (16.7%) tested positive again. Some symptoms such as fatigue (51%), dyspnea (44%), and coughing (17%) were still present in a significant percentage of the patients, with no difference between patients with a negative test and those who tested positive. The likelihood of testing positive for SARS-CoV-2 infection was significantly higher among participants with persistent sore throat (prevalence ratio=6.50, 95% CI=1.38, 30.6) and symptoms of rhinitis (prevalence ratio=3.72, 95% CI=1.10, 12.5). CONCLUSIONS: This study is the first to provide a given rate of patients (16.7%) who test positive on RT-PCR test for SARS-CoV-2 nucleic acid after recovering from COVID-19. These findings suggest that a significant proportion of patients who have recovered from COVID-19 still could be potential carriers of the virus. In particular, if patients continue to have symptoms related to COVID-19, such as sore throat and rhinitis, it is reasonable to be cautious by avoiding close contact, wearing a face mask, and possibly repeating a nasopharyngeal swab.

COVID-19 and RA share an SPP1 myeloid pathway that drives PD-L1+ neutrophils and CD14+ monocytes.

We explored the potential link between chronic inflammatory arthritis and COVID-19 pathogenic and resolving macrophage pathways and their role in COVID-19 pathogenesis. We found that bronchoalveolar lavage fluid (BALF) macrophage clusters FCN1+ and FCN1+SPP1+ predominant in severe COVID-19 were transcriptionally related to synovial tissue macrophage (STM) clusters CD48hiS100A12+ and CD48+SPP1+ that drive rheumatoid arthritis (RA) synovitis. BALF macrophage cluster FABP4+ predominant in healthy lung was transcriptionally related to STM cluster TREM2+ that governs resolution of synovitis in RA remission. Plasma concentrations of SPP1 and S100A12 (key products of macrophage clusters shared with active RA) were high in severe COVID-19 and predicted the need for Intensive Care Unit transfer, and they remained high in the post-COVID-19 stage. High plasma levels of SPP1 were unique to severe COVID-19 when compared with other causes of severe pneumonia, and IHC localized SPP1+ macrophages in the alveoli of COVID-19 lung. Investigation into SPP1 mechanisms of action revealed that it drives proinflammatory activation of CD14+ monocytes and development of PD-L1+ neutrophils, both hallmarks of severe COVID-19. In summary, COVID-19 pneumonitis appears driven by similar pathogenic myeloid cell pathways as those in RA, and their mediators such as SPP1 might be an upstream activator of the aberrant innate response in severe COVID-19 and predictive of disease trajectory including post-COVID-19 pathology.

Diagnostic performance of anti-citrullinated peptide antibodies for the diagnosis of rheumatoid arthritis: the relevance of likelihood ratios.

BACKGROUND: The goal of our study was to evaluate the diagnostic performance of the anti-cyclic citrullinated peptide 2 (anti-CCP2) assay in patients with autoimmune and inflammatory disorders. METHODS: We tested the specificity and sensitivity of anti-CCP2 antibodies measured by ELISA in 787 patients with rheumatoid arthritis (RA), 1024 patients with other autoimmune/inflammatory rheumatic disease and 401 subjects without autoimmune rheumatic disease. The optimal cut-off value was defined as the value with the highest diagnostic accuracy (receiver operating characteristic curve analysis). Interval-specific likelihood ratios (LRs) were calculated for each range bounded by defined anti-CCP2 values. RESULTS: To distinguish between patients with RA and controls, the cut-off value with the highest diagnostic accuracy for anti-CCP2 was 2.8 U/mL. Comparing the optimal cut-off value for anti-CCP2 to that recommended by the manufacturer (5.0 U/mL), an increase in prevalence between the proportions of test-positive patients was found for RA, undifferentiated connective tissue disease and undifferentiated arthritis. Evaluating interval-specific LRs for the selected ranges bound by two anti-CCP2 values, in RA and diseased controls, the LRs were 0.40 for values <5.0 U/mL, 6.66 for 5.0-15.0 U/mL, 27.01 for 15.1-30.0 U/mL and 28.89 for >30.0 U/mL. CONCLUSIONS: The cut-off value of 2.8 U/mL for anti-CCP2 has the highest diagnostic accuracy. A value of anti-CCP2 >15 U/mL is associated with an increase in the likelihood of RA disease.

Rituximab Followed by Belimumab Controls Severe Lupus Nephritis and Bullous Pemphigoid in Systemic Lupus Erythematosus Refractory to Several Combination Therapies.

Systemic lupus erythematosus (SLE) and bullous pemphigoid (BP) are chronic autoimmune diseases in which B cells play an important pathogenic role in the different stages of the disease. B cell-targeted therapies have been suggested as a new rational approach for treating SLE. Rituximab (RTX), an anti-CD20 chimeric monoclonal antibody, failed to achieve primary endpoints in two clinical trials (EXPLORER and LUNAR) despite multiple observational and retrospective studies showing its beneficial effect on SLE. Moreover, RTX is recommended in cases of BP that is unresponsive to conventional treatments. Belimumab (BLM), a human immunoglobulin G1 λ monoclonal antibody that inhibits soluble B-lymphocyte stimulator (BlyS)/B-cell activating factor (BAFF), is the only biological treatment approved for standard therapy of refractory autoantibody-positive active SLE. Animal models and a few case reports have supported the efficacy of the combined use of RTX followed by BLM as maintenance therapy in severe lupus nephritis (LN), suggesting that their combined use may be more effective than their single use, without compromising safety. In this study, we describe the clinical case of a SLE patient with predominant renal involvement in overlap with BP, refractory to conventional therapy including RTX alone, achieving significant steroid sparing and clinical remission under sequential treatment of RTX-BLM. Moreover, we describe the first case of BP successfully treated with BLM. This case report may encourage further clinical research studies in B lymphocyte targeted combination therapy in patients affected by SLE with major organ involvement or with refractory disease, suggesting that RTX and BLM sequential therapy may be a valid option for the treatment of SLE manifestations, including conventional therapy and RTX-resistant LN.