Safety and efficacy of subcutaneous ianalumab (VAY736) in patients with primary Sjögren's syndrome: a randomised, double-blind, placebo-controlled, phase 2b dose-finding trial.

BACKGROUND: Sjögren's syndrome is an autoimmune disease characterised by dry eyes and mouth, systemic features, and reduced quality of life. There are no disease-modifying treatments. A new biologic, ianalumab (VAY736), with two modes of suppressing B cells, has previously shown preliminary efficacy. This dose-finding trial aimed to assess the safety and efficacy of different subcutaneous doses of ianalumab in patients with moderate to severe primary Sjögren's syndrome. METHODS: VAY736A2201 was a randomised, parallel, double-blind, placebo-controlled, phase 2b dose-finding study done in 56 centres in 19 countries. Patients aged 18-75 years with primary Sjögren's syndrome with moderate to severe disease activity (European Alliance of Associations for Rheumatology [EULAR] Sjögren's Syndrome Disease Activity Index [ESSDAI] score ≥6) and symptom severity (EULAR Sjögren's Syndrome Patient Reported Index score ≥5) were eligible. Participants were randomly assigned (1:1:1:1) to receive subcutaneous placebo or ianalumab (5 mg, 50 mg, or 300 mg) every 4 weeks for 24 weeks using a secure, online randomisation system. Randomisation was stratified by the ESSDAI score at baseline (≥10 or <10). Study personnel and patients were masked to treatment assignment. The primary outcome was the change in ESSDAI score from baseline to 24 weeks in all randomly assigned patients. Dose-related change in disease activity (ESSDAI) from baseline at week 24 was assessed by multiple comparison procedure with modelling analysis. Safety was measured in all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT02962895. FINDINGS: Between June 27, 2017, and Dec 06, 2018, 293 patients were screened, 190 of whom were randomly assigned (placebo n=49, ianalumab 5 mg n=47, ianalumab 50 mg n=47, ianalumab 300 mg n=47). Statistically significant dose-responses were seen for overall disease activity (ESSDAI score) in four of the five dose-response models tested (p<0·025 in four models, p=0·060 in one model). The ESSDAI score decreased from baseline in all ianalumab groups, with the maximal ESSDAI score change from baseline observed in the ianalumab 300 mg group: placebo-adjusted least-squares mean change from baseline -1·92 points (95% CI -4·15 to 0·32; p=0·092). There were four serious adverse events in three patients considered treatment-related (pneumonia [n=1] and gastroenteritis [n=1] in the placebo group; appendicitis plus tubo-ovarian abscess in the same patient in the ianalumab 50 mg group). INTERPRETATION: The study met its primary objective, showing a dose-related decrease in disease activity as measured by ESSDAI at week 24. Overall, ianalumab was well tolerated and safe, with no increase in infections. To our knowledge, this is the first large, randomised, controlled trial in primary Sjögren's syndrome that met its primary endpoint, and its results mean there is potential for more studies of this mechanism in the future. FUNDING: Novartis.

Predicting lymphoma in Sjögren's syndrome and the pathogenetic role of parotid microenvironment through precise parotid swelling recording.

OBJECTIVE: Parotid swelling (PSW) is a major predictor of non-Hodgkin's lymphoma (NHL) in primary SS (pSS). However, since detailed information on the time of onset and duration of PSW is scarce, this was investigated to verify whether it may lead to further improved prediction. NHL localization was concomitantly studied to evaluate the role of the parotid gland microenvironment in pSS-related lymphomagenesis. METHODS: A multicentre study was conducted among patients with pSS who developed B cell NHL during follow-up and matched controls that did not develop NHL. The study focused on the history of salivary gland and lachrymal gland swelling, evaluated in detail at different times and for different durations, and on the localization of NHL at onset. RESULTS: PSW was significantly more frequent among the cases: at the time of first referred pSS symptoms before diagnosis, at diagnosis and from pSS diagnosis to NHL. The duration of PSW was evaluated starting from pSS diagnosis, and the NHL risk increased from PSW of 2-12 months to >12 months. NHL was prevalently localized in the parotid glands of the cases. CONCLUSION: A more precise clinical recording of PSW can improve lymphoma prediction in pSS. PSW as a very early symptom is a predictor, and a longer duration of PSW is associated with a higher risk of NHL. Since lymphoma usually localizes in the parotid glands, and not in the other salivary or lachrymal glands, the parotid microenvironment appears to be involved in the whole history of pSS and related lymphomagenesis.

Nuts and bolts of salivary gland pathology in primary Sjögren's syndrome.

Primary Sjögren's syndrome (pSS) is a chronic, systemic, inflammatory autoimmune disease characterised by lymphocyte proliferation and progressive damage to exocrine glands. Salivary gland histopathology based on salivary gland biopsy is relevant for the diagnosis of pSS and therefore broadly applied in clinical practice. Tissue can be obtained from labial salivary glands (LSG) biopsy or from major salivary glands (MSG) biopsy, namely the parotid; in this latter scenario, the procedure can be either an open surgical biopsy or a US guided core needle biopsy.In this review we will: i) present the histopathological findings that may be encountered by pathologists on biopsies from pSS patients; ii) discuss the advantages and disadvantages of the surgical and/or imaging guided procedures to obtain tissues from LSG or MSG; iii) describe the histopathological features of lymphoma of MSG in pSS patients.

Secretagogue effect of PDE4 inhibitor apremilast on human salivary gland organoids obtained from primary Sjögren's syndrome patients.

OBJECTIVES: The aim of the study was to culture vital salivary gland organoids obtained through labial or parotid biopsy of primary Sjögren's syndrome (pSS) patients in order to evaluate their morphological and functional features in basal condition and after stimulation with Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) activator forskolin and phosphodiesterase 4 (PDE4) inhibitor apremilast, their in vitro regenerative capacity and the immune-histological resemblance with original tissue. METHODS: Salivary gland tissues from five pSS patients were processed to obtain vital organoids; swelling assay and cell proliferation tests were performed after forskolin and apremilast application. Immunochemistry evaluation on original salivary gland tissue and corresponding organoids was performed, and secretomics analysis was conducted to assess their functional status. REULTS: After application of forskolin and apremilast, we observed organoid swelling after 30 minutes, compatible with a positive functional status and enhancement of saliva production. In 3 cases, apremilast induced organoid proliferation. All cases were positive for cytokeratin 14 (CK14) and most for cytokeratin 5 (CK5). All the cases were positive for amylase; its secretion, and thus functional status of organoids, was confirmed by its high concentration in the culture medium. A focal ductal differentiation was found in some cases, highlighted by epithelial membrane antigen (EMA) positivity. The more differentiated EMA positive areas were negative for the staminal marker CK14, showing a sort of "complementary staining". CONCLUSIONS: Our data highlighted that differentiated cells and vital functional organoids that recapitulate the development of original salivary glands can be obtained from pSS epithelium. For the first time, the direct stimulating effect of PDE4 inhibitor apremilast on pSS human salivary gland organoids is reported, opening new perspectives on targeting oral dryness with drugs that combine secretagogue and immunomodulatory effects.

Clinical and histological features of patients with primary Sjögren's syndrome and autoimmune thyroiditis: a national multicentre cross-sectional study.

OBJECTIVES: Primary Sjögren's syndrome (pSS) is frequently associated with autoimmune thyroiditis (AT). The aim of this study was to evaluate the prevalence of AT in a national cohort of pSS and to describe the clinical and histological phenotype of patients with pSS and associated AT. METHODS: In this multicentre cross-sectional study, data from 2546 pSS were collected and the presence of AT was reported. In a subgroup, the histology of minor salivary glands was evaluated. Differences between pSS with and without AT were evaluated. RESULTS: A concomitant pSS and AT was detected in 19.6% of cases. Patients with pSS and AT displayed a lower prevalence of lymphoma, male sex and disease-modifying anti-rheumatic drugs (DMARDs) use and a higher prevalence of fibromyalgia, coeliac disease and hypergammaglobulinaemia. Multivariable analysis confirmed a higher prevalence of fibromyalgia and coeliac disease and lower use of DMARDs. In a subgroup of patients (n=232), a significantly higher focus score and number of foci was detected in pSS without AT (n=169) as compared to pSS with AT (n=54). CONCLUSIONS: This is the largest study evaluating the coexistence of pSS and AT. We confirm a high association between pSS and AT and describe the presence of a different phenotype characterized by a higher rate of celiac disease and fibromyalgia. Although not significant, the lower prevalence of both lymphoma and intake of DMARDs, along with a significantly lower focus score and number of foci, possibly suggest a more favourable outcome in concomitant pSS and AT which further deserve future investigations.

Interstitial lung disease in microscopic polyangiitis and granulomatosis with polyangiitis: demographic, clinical, serological and radiological features of an Italian cohort from the Italian Society for Rheumatology.

OBJECTIVES: Interstitial lung disease (ILD) has been described as a possible pulmonary involvement in antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitides (AAV), mainly granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA). Aim of this cross-sectional Italian national study was to describe demographic, clinical and serological profile of ILD related to MPA and GPA and investigate possible correlations between radiologic patterns of ILD and vasculitis features. METHODS: We enrolled 95 consecutive patients with AAV-ILD, 56 affected by MPA (58.9%) and 39 by GPA (41.1%). RESULTS: NSIP was the most frequently detected ILD pattern, observed in c-ANCA patients in 60.9% of cases, followed by UIP pattern mainly observed in p-ANCA patients (47.7%, p=0.03). ILD represented the first clinical manifestation, preceding vasculitis diagnosis in 22.1% of cases and, globally, ILD was already detectable at AAV diagnosis in 66.3% of patients. The diagnosis of ILD preceded that of AAV in 85.7% of p-ANCA positive-patients, while only one patient with c-ANCA developed ILD before AAV (p= 0.039). Multivariate analysis confirmed the correlation of UIP pattern with p-ANCA-positivity and a diagnosis of ILD before AAV, also when adjusted for age and sex. CONCLUSIONS: Our study confirms that UIP is a frequent pattern of lung disease in AAVILD patients. Our results also suggest that ILD can represent an early complication of AAV but also occur in the course of the disease, suggesting the need of a careful evaluation by both pulmonologist and rheumatologist to achieve an early diagnosis. Further prospective studies are needed to define ILD prevalence and evolution in AAV patients.

Exposure to air pollution as an environmental determinant of how Sjögren's disease is expressed at diagnosis.

OBJECTIVES: To analyse how the potential exposure to air pollutants can influence the key components at the time of diagnosis of Sjögren's phenotype (epidemiological profile, sicca symptoms, and systemic disease). METHODS: For the present study, the following variables were selected for harmonization and refinement: age, sex, country, fulfilment of 2002/2016 criteria items, dry eyes, dry mouth, and overall ESSDAI score. Air pollution indexes per country were defined according to the OECD (1990-2021), including emission data of nitrogen and sulphur oxides (NO/SO), particulate matter (PM2.5 and 1.0), carbon monoxide (CO) and volatile organic compounds (VOC) calculated per unit of GDP, Kg per 1000 USD. RESULTS: The results of the chi-square tests of independence for each air pollutant with the frequency of dry eyes at diagnosis showed that, except for one, all variables exhibited p-values <0.0001. The most pronounced disparities emerged in the dry eye prevalence among individuals inhabiting countries with the highest NO/SO exposure, a surge of 4.61 percentage points compared to other countries, followed by CO (3.59 points), non-methane (3.32 points), PM2.5 (3.30 points), and PM1.0 (1.60 points) exposures. Concerning dry mouth, individuals residing in countries with worse NO/SO exposures exhibited a heightened frequency of dry mouth by 2.05 percentage points (p<0.0001), followed by non-methane exposure (1.21 percentage points increase, p=0.007). Individuals inhabiting countries with the worst NO/SO, CO, and PM2.5 pollution levels had a higher mean global ESSDAI score than those in lower-risk nations (all p-values <0.0001). When systemic disease was stratified according to DAS into low, moderate, and high systemic activity levels, a heightened proportion of individuals manifesting moderate/severe systemic activity was observed in countries with worse exposures to NO/SO, CO, and PM2.5 pollutant levels. CONCLUSIONS: For the first time, we suggest that pollution levels could influence how SjD appears at diagnosis in a large international cohort of patients. The most notable relationships were found between symptoms (dryness and general body symptoms) and NO/SO, CO, and PM2.5 levels.

Influence of exposure to climate-related hazards in the phenotypic expression of primary Sjögren's syndrome.

OBJECTIVES: To analyse how the key components at the time of diagnosis of the Sjögren's phenotype (epidemiological profile, sicca symptoms, and systemic disease) can be influenced by the potential exposure to climate-related natural hazards. METHODS: For the present study, the following variables were selected for harmonisation and refinement: age, sex, country, fulfilment of 2002/2016 criteria items, dry eyes, dry mouth, and overall ESSDAI score. Climate-related hazards per country were defined according to the OECD and included seven climate-related hazard types: extreme temperature, extreme precipitation, drought, wildfire, wind threats, river flooding, and coastal flooding. Climatic variables were defined as dichotomous variables according to whether each country is ranked among the ten countries with the most significant exposure. RESULTS: After applying data-cleaning techniques and excluding people from countries not included in the OECD climate rankings, the database study analysed 16,042 patients from 23 countries. The disease was diagnosed between 1 and 3 years earlier in people living in countries included among the top 10 worst exposed to extreme precipitation, wildfire, wind threats, river flooding, and coastal flooding. A lower frequency of dry eyes was observed in people living in countries exposed to wind threats, river flooding, and coastal flooding, with a level of statistical association being classified as strong (p<0.0001 for the three variables). The frequency of dry mouth was significantly lower in people living in countries exposed to river flooding (p<0.0001) and coastal flooding (p<0.0001). People living in countries included in the worse climate scenarios for extreme temperature (p<0.0001) and river flooding (p<0.0001) showed a higher mean ESSDAI score in comparison with people living in no-risk countries. In contrast, those living in countries exposed to worse climate scenarios for wind threats (p<0.0001) and coastal flooding (p<0.0001) showed a lower mean ESSDAI score in comparison with people living in no-risk countries. CONCLUSIONS: Local exposure to extreme climate-related hazards plays a role in modulating the presentation of Sjögren across countries concerning the age at which the disease is diagnosed, the frequency of dryness, and the degree of systemic activity.

Bosentan Does Not Affect Renal Resistive Index in Scleroderma/Systemic Sclerosis Patients.

INTRODUCTION: If properly evaluated, chronic kidney disease can be found in up to 50% of patients with systemic sclerosis (SSc). The renal resistive index (RRI) is a marker of intrarenal vascular resistance and can predict SSc-associated vasculopathy. This study aimed to determine the impact of bosentan, a nonselective endothelin-1 receptor antagonist, on RRI and kidney function in SSc patients with recurrent digital ulcers. METHODS: Twenty-one patients (age 57 ± 9 years, 19 females) were recruited in a 16-week prospective open-label uncontrolled study. Standardized procedures were used to measure general clinical and laboratory characteristics, systolic, diastolic, and mean arterial pressure (MAP), pulse pressure (PP), diastolic to systolic blood pressure (D/S) ratio, and urinary endothelin-1 levels. The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation was used to calculate kidney function as an estimated glomerular filtration rate (eGFR). RRI was measured by Doppler ultrasound as the average of three samplings of intrarenal blood flow in different kidney regions of both kidneys. Patients with secondary causes of kidney disease or kidney diseases associated with albuminuria were excluded. RESULTS: Bosentan treatment for 16 weeks did not change RRI (0.731 ± 0.049-0.730 ± 0.054, p = 0.925), but increased urine endothelin-1 to creatinine ratio (0.27 ± 0.15-0.49 ± 0.57 pg/mg, p = 0.032) and reduced MAP (123 ± 10-101 ± 11 mm Hg, p < 0.001), PP (76 ± 11-68 ± 10 mm Hg, p = 0.003), D/S ratio (0.563 ± 0.044-0.538 ± 0.031, p = 0.006), and eGFR (92 ± 20-84 ± 24 mL/min/1.73 m2, p = 0.003). DISCUSSION/CONCLUSION: In conclusion, in patients with SSc complicated by digital ulcers and normal to mildly diminished kidney function, bosentan had no effect on intrarenal hemodynamics, but reduced blood pressure levels and kidney function.

High T-cell response rate after COVID-19 vaccination in belimumab and rituximab recipients.

OBJECTIVE: To evaluate B-cell- and T-cell-mediated immune response to SARS-CoV-2 mRNA vaccination in patients with complex or rare systemic autoimmune diseases previously been treated with or under continuous treatment with B-cell-targeted therapies including rituximab (RTX) and belimumab (BEL). MATERIALS AND METHODS: Twenty-eight consecutive patients receiving RTX (n = 11) or BEL (n = 17) treatment and 13 age-/sex-matched controls (non-rheumatic healthcare personnel) were recruited. None of the patients had detectable anti-SARS-CoV-2 antibodies caused by prior exposure to the virus. All the patients and controls received mRNA vaccines and were tested three to four weeks after completion of vaccination. In all the RTX patients, vaccination was started within 5 months from the last infusion, and B-cell depletion was confirmed in all but one of them. Total anti-SARS-CoV-2 RBD antibodies were analyzed using a diagnostic assay, while T-cell response was evaluated using the interferon-gamma release assay (IGRA). Further, SARS-CoV-2 pseudoviruses were employed to verify the strain-specific neutralizing capacity of the antibodies. RESULTS: Detectable anti-SARS-CoV-2 antibodies were documented in 1 out of the 11 RTX patients and 16 of the 17 BEL patients. The median concentration in the RTX and BEL patients was significantly lower than that in the controls (39.6 AU/ml vs. 1133 AU/ml, p = 0.002). The result of IGRA was positive in 8 of the 11 (72.7%) RTX patients and 16 of the 17 (94.1%) BEL patients, and interferon release in both the RTX and BEL patients was comparable to that in the control participants. CONCLUSION: B-cell-targeted therapies do not preclude SARS-CoV-2 vaccination, since virus-specific cellular immunity can be induced even in the absence of circulating B cells. An important finding was that lupus patients treated with BEL developed immune responses to SARS-CoV-2; this indicates retention of the immunogenicity of the COVID-19 vaccine.

Towards the identification of novel autoantibodies in Sjögren's syndrome.

Primary Sjögren's syndrome may be difficult to diagnose when antibodies against Ro/SSA are lacking, and can be grouped in at least four clusters indicating different pathophysiological pathways. Novel biomarkers, in particular autoantibodies, would be helpful in diagnosing Sjögren's syndrome and in further identification and characterisation of the clusters.In this review, we describe new technologies that may be utilised in the rapid identification of novel autoantibodies, and an example of how well characterised patients, here from the HarmonicSS cohort, are a prerequisite in the discovery of clinically meaningful biomarkers. This translational approach hold promise to optimise the diagnosis and treatment of individual pSS patient subsets.

Chest high-resolution computed tomography in primary Sjögren's syndrome: an up-to-date primer for rheumatologists.

Pulmonary manifestations, including airway involvement and interstitial lung disease, are the most frequent extra-glandular complications of primary Sjögren's syndrome (pSS). Chest high-resolution computed tomography (HRCT) is a cornerstone of pulmonary diagnostic imaging, aiming to detect, characterise, and quantify such conditions. In patients with pSS-related lung abnormalities, HRCT proved helpful in various clinical scenarios, including baseline and follow-up evaluation, assessment of superimposed infections, suspected progressive interstitial lung diseases, and acute exacerbation. This review aims to provide a primer for rheumatologists on chest HRCT, illustrating the up-to-date technique, imaging findings, and clinical indications in pSS and highlighting the importance of rheumatologist-radiologist constructive collaboration in the clinical management of such patients.

Usefulness of ultrasound guided core needle biopsy of the parotid gland for the diagnosis of primary Sjögren's syndrome.

OBJECTIVES: The diagnosis and classification of primary Sjögren's syndrome (pSS) relies on labial biopsy, whereas the role of open parotid biopsy is mainly reserved to evaluate the lymphoproliferative complications. Recently ultrasound-guided core needle biopsy (US-guided CNB) appeared as a novel and safe technique useful in lymphoma assessment, however, its potential role in the diagnosis of pSS has never been assessed.The main aim of this study was to evaluate the diagnostic value of US-guided CNB of the parotid glands in patients affected by pSS. METHODS: Patients affected by pSS who underwent US-guided CNB for a suspected glandular lymphoma were included. Adequacy of the samples and histopathological features related to pSS were analysed. RESULTS: US-guided CNB was performed on 29 parotid glands. The biopsied samples were adequate for diagnosis in 28/29 (96.5%) cases. Fifteen patients showed pathologic features of parotid lymphoma. Among the remaining patients, 9/13 presented focus score≥1; LELs were present in 8/13 patients, and GCs in 11/13. In 8 cases the histological features were coherent with MESA/LESA. Acinar atrophy, fibrosis and duct dilatation were also evaluated. CONCLUSIONS: This preliminary study suggests the possible usefulness of US-guided CNB for the diagnosis of pSS by enabling the collection of adequate salivary gland tissue to assess the FS, GCs, LELs, and other histopathologic features also useful in the management of pSS patients.

A real-world economic analysis of biologic therapies for psoriatic arthritis in Italy: results of the CHRONOS observational longitudinal study.

BACKGROUND: Psoriatic arthritis (PsA) is a chronic, immune-mediated, spondyloarthropathy characterised by musculoskeletal signs and symptoms with associated joint pain and tenderness. The average worldwide PsA prevalence is 133/100,000, while in the Italian population is 90-420/100,000. Traditionally, nonsteroidal anti-inflammatory drugs, glucocorticoid, and disease-modifying antirheumatic drugs have been used in the treatment of PsA. However, for those patients who are not adequately controlled with conventional therapies, the new biologics compounds represent a valid option. Biologic therapies have been shown to be more effective but also more expensive than conventional systemic treatments. Based on the CHRONOS study, the economic analyses presented in this paper aim to assess the annualised direct costs and the cost-per-responder of biologics in a real-world context assuming the Italian National Health System perspective. METHODS: The economic assessments were carried out on the overall cohort of patients, and on the tumour necrosis factor alpha inhibitors (TNFi) and the secukinumab subgroup, the most prescribed biologic therapies within the CHRONOS study. RESULTS: The annual economic impact of PsA in the overall group was €12,622, €11,725 in the secukinumab subgroup, and €12,791 in the TNFi subgroup. Biologics absorbed the main expenditure costs in the treatment of PsA accounting for about the 93% of total costs. At 6 months, secukinumab performed better in all the considered outcomes: cost-per-responder according to EULAR DAS28 and ACR50 response criteria were €12,661- €28,975, respectively, while they were €13,356 - €33,368 in the overall cohort and €13,138 - €35,166 in the TNFi subgroup. At 12 months secukinumab remained the subgroup with the lowest cost-per-responder ratio in EULAR DAS28 and ACR50 response criteria, while TNFi subgroup was the lowest one considered the ACR20. CONCLUSION: Despite some potential methodological limitations, our cost-per-response analysis provides physicians and payers additional insights which can complement the traditional risk-benefit profile assessment and drive treatment decisions.

A biomarker for lymphoma development in Sjogren's syndrome: Salivary gland focus score.

The aim of this study is to explore the role of labial minor salivary gland (LMSG) focus score (FS) in stratifying Sjögren's Syndrome (SS) patients, lymphoma development prediction and to facilitate early lymphoma diagnosis. Ιn an integrated cohort of 1997 patients, 618 patients with FS ≥ 1 and at least one-year elapsing time interval from SS diagnosis to lymphoma diagnosis or last follow up were identified. Clinical, laboratory and serological features were recorded. A data driven logistic regression model was applied to identify independent lymphoma associated risk factors. Furthermore, a FS threshold maximizing the difference of time interval from SS until lymphoma diagnosis between high and low FS lymphoma subgroups was investigated, to develop a follow up strategy for early lymphoma diagnosis. Of the 618 patients, 560 were non-lymphoma SS patients while the other 58 had SS and lymphoma. FS, cryoglobulinemia and salivary gland enlargement (SGE) were proven to be independent lymphoma associated risk factors. Lymphoma patients with FS ≥ 4 had a statistically significant shorter time interval from SS to lymphoma diagnosis, compared to those with FS < 4 (4 vs 9 years, respectively, p = 0,008). SS patients with FS ≥ 4 had more frequently B cell originated manifestations and lymphoma, while in patients with FS < 4, autoimmune thyroiditis was more prevalent. In the latter group SGE was the only lymphoma independent risk factor. A second LMSG biopsy is patients with a FS ≥ 4, 4 years after SS diagnosis and in those with FS < 4 and a history of SGE, at 9-years, may contribute to an early lymphoma diagnosis. Based on our results we conclude that LMSG FS, evaluated at the time of SS diagnosis, is an independent lymphoma associated risk factor and may serve as a predictive biomarker for the early diagnosis of SS-associated lymphomas.

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.

Influenza vaccination in chronic inflammatory arthritis undergoing immunosuppressive treatments: temporal trend and factors of adherence.

OBJECTIVES: To verify the level of adherence to the influenza vaccination program in a population of patients suffering from RA, PsA or AS undergoing immunosuppressive treatment. METHODS: Administrative databases from the Regional Health Information System of Friuli Venezia Giulia (FVG), Italy, were used. Subjects were residents in FVG, suffered from chronic inflammatory arthritis and had at least one prescription for a DMARD in the 9 months before the start of the vaccination season (from 1 October to 31 December). The observation ranged from 2006 to 2018. Logistic regression was used to assess the association between vaccination and the patient's characteristics in the 2018-2019 influenza season. RESULTS: Overall, vaccination adherence decreased from the highest value of 35.7% (662/1853) in 2006 to the lowest value of 25.3% (926/3663) in 2014; in people ≥65 years of age it also decreased over time from 61.6% (577/936) in 2008 to 43.9% (701/1595) in the 2014. By logistic analysis on the 2018-2019 season, which included 4460 patients, older subjects were more likely to be vaccinated [people 65-74 years, odds ratio (OR) 4.58 (95% CI 3.72, 5.64); people 75-84 years, OR 6.47 (95% CI 5.04, 8.32); both vs <65] as were those with diabetes [OR 1.66 (95% CI 1.05, 2.64)]. Treatment with a biologic agent alone [OR 0.64 (95% CI 0.52, 0.80)] and RA diagnosis [OR 0.69 (95% CI 0.51, 0.93)] were associated with lower adherence. CONCLUSION: Influenza vaccination adherence is alarmingly low in a population at higher risk of infectious complications, in particular in elderly patients.

Salivary gland ultrasonography in primary Sjögren's syndrome: opportunities and challenges.

Salivary gland ultrasonography (SGUS) has an established role in detecting typical structural gland abnormalities in primary Sjögren's Syndrome (pSS). SGUS might be included in pSS classification and could be used as a prognostic and follow-up biomarker, but for this purpose additional efforts, new techniques and larger cohort studies are needed. HarmonicSS, an ongoing Horizon, EU-supported project in pSS, will apply artificial intelligence to SGUS in pSS. Many questions are still unresolved and challenging, but data collected up to now underscore the concept that SGUS will be an important tool for the study of pSS in the near future.

Ultrasound-guided core needle biopsy compared with open biopsy: a new diagnostic approach to salivary gland enlargement in Sjögren's syndrome?

OBJECTIVE: Persistent (≥2 months) major salivary gland enlargement in primary SS (pSS) patients is a well-known sign of possible involvement by B cell lymphoma. The study aimed to evaluate the diagnostic accuracy and safety of US-guided core needle biopsy (CNB) of major salivary glands compared with open surgical biopsy. METHODS: Prospective pSS patients (cases) with clinically persistent salivary gland enlargement underwent US-guided CNB and were compared with retrospective pSS patients (controls) submitted to open surgical biopsy. The features analysed were pre-biopsy clinical and laboratory findings, adequacy of the material for histology and diagnostic-rendered and biopsy-related complications (reported by the patient with a questionnaire and clinically verified). RESULTS: Thirteen cases underwent US-guided CNB: in nine, biopsy was performed on the parotid gland and in four it was performed on the submandibular gland. Sufficient material was obtained for pathological diagnosis in all samples. The final diagnoses were 5 (38.5%) B cell lymphoma, 1 (7.7%) lymphoepithelial sialadenitis, 4 (30.7%) other sialadenitis (granulomatous consistent with sarcoidosis, IgG4-related disease, chronic sclerosing, diffuse chronic) and 3/13 (23.1%) miscellaneous lesions. Thirteen controls underwent open surgical biopsy of the parotid. In one, inadequate material was obtained, while in 12 (92.3%) the pathologic diagnoses were 4 (33.3%) B cell lymphoma, 2 (16.7%) lymphoepithelial sialadenitis, 4 (33.3%) uncertain lymphoproliferative lesions and 2 (16.7%) miscellaneous lesions. Six cases (46.1%) reported six transient complications and 12/13 (92.3%) controls had 2 persistent and 14 transient complications. CONCLUSION: US-guided CNB represents a novel, clinically relevant and safe approach for the management of pSS patients with parotid or submandibular persistent enlargement.

Patient-reported experience and health-related quality of life in patients with primary Sjögren's syndrome in Europe.

OBJECTIVES: The study aims to provide novel findings on geographic variation in the management of primary Sjögren's syndrome (pSS) in Europe, an underdiagnosed, long-term autoimmune disease. METHODS: Starting from the lack of comparable information on patients' experience, quality and efficiency of care delivered to pSS patients in Europe, the approach is to collect and analyse patients reported data from an international survey. To assess and compare access and quality of care to pSS along their care-path we developed and validated a questionnaire administered to a large cohort of pSS patients in selected European countries. Regression models have been applied to survey data to compare quality and volumes of care across Europe. RESULTS: Both follow-up and number of visits with a specialist of the patient are influenced by the severity of the disease with differences among countries. The results show some extent of variations in access and treatments delivered to pSS patients and also their perceived quality of life and satisfaction for SS care in Europe. CONCLUSIONS: Findings contribute to support healthcare professionals' decision making and the organisation of care delivery by taking into consideration the patients' point of view and preferences.