Objectives To evaluate efficacy and safety of abatacept in adults with active primary Sjogren’s syndrome (pSS) in a phase III, randomised, double-blind, placebo-controlled trial. Methods Eligible patients (moderate-to-severe pSS [2016 ACR/European League Against Rheumatism (EULAR) criteria], EULAR Sjogren’s Syndrome Disease Activity Index [ESSDAI] ≥5, anti-SS-related antigen A/anti-Ro antibody positive) received weekly subcutaneous abatacept 125 mg or placebo for 169 days followed by an open-label extension to day 365. Primary endpoint was mean change from baseline in ESSDAI at day 169. Key secondary endpoints were mean change from baseline in EULAR Sjogren’s Syndrome Patient Reported Index (ESSPRI) and stimulated whole salivary flow (SWSF) at day 169. Other secondary clinical endpoints included glandular functions and patient-reported outcomes. Selected biomarkers and immune cell phenotypes were examined. Safety was monitored. Results Of 187 patients randomised, 168 completed double-blind period and 165 continued into open-label period. Mean (SD) baseline ESSDAI and ESSPRI total scores were 9.4 (4.3) and 6.5 (2.0), respectively. Statistical significance was not reached for primary (ESSDAI −3.2 abatacept vs −3.7 placebo, p=0.442) or key secondary endpoints (ESSPRI, p=0.337; SWSF, p=0.584). No clinical benefit of abatacept over placebo at day 169 was seen with other clinical and PRO endpoints. Relative to baseline, abatacept was associated with significant differences vs placebo in some disease-relevant biomarkers (including IgG, IgA, IgM-rheumatoid factor) and pathogenic cell subpopulations (post hoc analyses). No new safety signals were identified. Conclusions Abatacept treatment did not result in significant clinical efficacy compared with placebo in patients with moderate-to-severe pSS, despite evidence of biological activity.

https://ard.bmj.com/content/annrheumdis/80/3/339.full.pdf

Efficacy and safety of abatacept in active primary Sjögren's syndrome: Results of a phase III, randomised, placebo-controlled trial

Chloroquine (CQ) and hydroxychloroquine (HCQ) are derivatives of the heterocyclic aromatic compound quinoline. These economical compounds have been used as antimalarial agents for many years. Currently, they are used as monotherapy or in conjunction with other therapies for the treatment of autoimmune diseases such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), Sjogren's syndrome (SS) and antiphospholipid antibody syndrome (APS). Based on its effects on the modulation of the autophagy process, various clinical studies suggest that CQ and HCQ could be used in combination with other chemotherapeutics for the treatment of various types of cancer. Furthermore, the antiviral effects showed against Zika, Chikungunya, and HIV are due to the annulation of endosomal/lysosomal acidification. Recently, CQ and HCQ were approved for the U.S. Food and Drug Administration (FDA) for the treatment of infected patients with the coronavirus SARSCoV- 2, causing the disease originated in December 2019, namely COVID-2019. Several mechanisms have been proposed to explain the pharmacological effects of these drugs: 1) disruption of lysosomal and endosomal pH, 2) inhibition of protein secretion/expression, 3) inhibition of antigen presentation, 4) decrease of proinflammatory cytokines, 5) inhibition of autophagy, 6) induction of apoptosis and 7) inhibition of ion channels activation. Thus, evidence has shown that these structures are leading molecules that can be modified or combined with other therapeutic agents. In this review, we will discuss the most recent findings in the mechanisms of action of CQ and HCQ in the immune system, and the use of these antimalarial drugs on diseases.

The Role of Chloroquine and Hydroxychloroquine in Immune Regulation and Diseases.

Sjogren's syndrome (SS) is a systemic autoimmune disease that primarily affects the exocrine glands, resulting in dryness of the eyes and mouth due to lymphocytic infiltration of the salivary and lacrimal glands along with arthritis, kidney, liver, and lung involvement, chronic fatigue, musculoskeletal pain, vasculitis, and so on. Considerable advance has been made for the classification and treatment of primary SS in the past few years. This article reviews the recent classification criteria for primary SS and briefly discusses the conventional and novel therapies of the disease.

Advances in the diagnosis and treatment of Sjogren's syndrome.

Abstract Objective The aim of this study was to characterize the safety and efficacy of filgotinib, lanraplenib and tirabrutinib in patients with active SS. Methods This multicentre, double-blind study randomized patients with active primary or secondary SS [EULAR SS disease activity index (ESSDAI) ≥5) to receive filgotinib 200 mg (Janus kinase-1 inhibitor), lanraplenib 30 mg (spleen tyrosine kinase inhibitor), tirabrutinib 40 mg (Bruton’s tyrosine kinase inhibitor), or placebo. The composite primary end point was the week-12 proportion of patients fulfilling protocol-specified improvement criteria (based on CRP and SS-related symptoms). The EULAR SS patient-reported index (ESSPRI) and the ESSDAI change from baseline (CFB) were secondary end points. Exploratory end points included disease-related biomarkers. Treatment-emergent adverse events (AEs) represented safety outcomes. Results The mean of the baseline ESSDAI was 10.1, and of ESSPRI was 6.2 in the 150 patients who were treated; 125 completed the 24-week placebo-controlled treatment period. At week 12, 43.3% of the filgotinib group achieved the primary end point (P = 0.17 vs placebo) vs 42.3% (P = 0.16), 34.7% (P = 0.33), and 26.7% of lanraplenib, tirabrutinib, and placebo groups, respectively. Neither secondary end point was met. Biomarker reductions included immunoglobulins classically associated with SS disease activity. Filgotinib ESSDAI CFB appeared more pronounced in subgroups with baseline ESSDAI ≥14 or without DMARDs/CSs. Most AEs were Grade 1 or 2. Conclusion Three drugs with disparate mechanisms were tested, but no significant differences vs placebo in primary or secondary end points were observed. These results may be considered hypothesis-generating, given the drug tolerability, subgroup analysis, and biomarker findings. Trial registration ClinicalTrials.gov, https://clinicaltrials.gov, NCT03100942.

Safety and efficacy of filgotinib, lanraplenib and tirabrutinib in Sjögren’s syndrome: a randomized, phase 2, double-blind, placebo-controlled study

Introduction: Primary Sjogren’s syndrome (pSS) is one of the most common systemic autoimmune diseases. At the moment, there is no cure for this disease and its etiopathology is complex. Interferons (IFNs) play an important role in the pathogenesis of this disease and are a potential treatment target. Areas covered: Here we discuss the role of IFNs in pSS pathogenesis, complications encountered upon studying IFN-induced gene expression, and comment on the current knowledge on easy clinical applicable ‘IFN signatures’. The current treatment options targeting IFNs in pSS are summarized and the perspective of potential new strategies discussed. Expert commentary: The authors provide their perspective on the role of IFNs in pSS and how this knowledge could be used to improve pSS diagnosis, provide new treatment targets, to monitor clinical trials and to stratify pSS patients in order to move toward precision medicine.

Interferon activation in primary Sjögren’s syndrome: recent insights and future perspective as novel treatment target

The use of hydroxychloroquine (HCQ) in Primary Sjogren’s Syndrome (pSS) has been assessed in different studies over the last years, with conflicting results regarding its efficacy in sicca syndrome and extraglandular manifestations (EGM). The goal of this study was to compare the incidence rate of EGM in pSS patients with and without HCQ therapy. We performed a multicenter retrospective study, including patients with pSS (European classification criteria) with at least 1 year of follow-up. Subjects with concomitant fibromyalgia, autoimmune hepatitis, primary biliary cirrhosis, and primary sclerosing cholangitis were excluded. Demographics and pSS characteristics were recorded. The EGM were defined by EULAR-SS disease activity index (ESSDAI). Patients were divided into two groups according to their use or not of HCQ therapy. We evaluated the use of HCQ and its relationship to EGM. HCQ therapy was defined as the continuous use of the drug for at least 3 months. A descriptive analysis of demographics and pSS characteristics was performed. We compared the incidence of EGM between groups defined by HCQ therapy using chi2 test or Fisher’s exact test. A total of 221 patients were included (97.3% women), mean age, 55.7 years (SD 14). Mean age at diagnosis, 48.8 years (SD 15); median disease duration, 60 months (IQR 35–84). One hundred and seventy patients (77%) received HCQ. About half of the patients had at least one EGM during the course of the disease, 20% of them developed an EGM before the onset of the sicca syndrome and 26% simultaneously with dryness symptom. Overall, EGM were less frequent in those on HCQ therapy (36.5% vs 63.5%, p < 0.001). Considering each EGM individually, the following manifestations were more frequent in the non-treated group: arthritis (p < 0.001), fatigue (p < 0.001), purpura (p = 0.01), Raynaud phenomenon (p = 0.003), and hypergammaglobulinemia (p = 0.006). Immunosuppressive treatment was indicated on 28 patients (12.7%), 13 of which were receiving also HCQ. The first reason for those treatments was the presence of arthritis in 12/28 patients (42.8%), and the drug used in all the cases was methotrexate. Only three patients required immunosuppressive therapy with cyclophosphamide, due to the presence of glomerulonephritis, vasculitis, and interstitial lung disease. None of the patients received biologic therapy. The lower incidence of EGM was observed in patients on HCQ therapy supports its efficacy in pSS. However, further large scale prospective studies are needed to confirm these findings.

Primary Sjögren's syndrome: Extraglandular manifestations and hydroxychloroquine therapy.

Background: In 2019 ACR and EULAR published in joint collaboration the new classification criteria for Systemic Lupus Erythematosus (SLE). Compared to the previous ones, these criteria have shown higher sensitivity and specificity in multiple cohorts. To our knowledge, its performance has not been evaluated in a cohort of patients with rheumatological diseases living in Argentina. Objectives: The aim of this study was to evaluate the sensitivity and specificity of the ACR/ EULAR 2019 criteria in a cohort of patients with connective tissue diseases residing in Argentina. Secondary objectives were to determine the Likelihood Ratio (LR) of these criteria and the correlation of their global score with activity and damage indexes of the disease. Methods: Multicentre, retrospective and analytical study. Patients ≥ 18 years old with diagnosis of SLE (ACR 1997/SLICC 2012) without other associated collagen diseases (case group), and patients with other non-SLE connective tissue diseases (control group) were included. Those with active infectious disease, oncohematological disease, drug-induced lupus and overlap syndrome were excluded. Sociodemographic data, characteristics of the disease and treatment were recorded. In addition, activity and damage indexes were recorded in the group with SLE. Three SLE experts, blinded to the diagnosis determined, for every individual if the patient had SLE or another rheumatological disease. An interrater agreement of 100% (including the 3 evaluators) was considered “defined SLE” and used as gold standard. In all cases, ACR 1997/SLICC 2012/ACR / EULAR 2019 criteria were applied and compared with the gold standard. Statistical analysis: Descriptive statistics was estimated. Sensitivity, specificity, positive and negative LR of the criteria were determined. The association between the final score of the ACR-EULAR 2019 criteria and the disease activity and damage indexes were estimated with Spearman correlation test. STATA 15.0 was used for data analysis. Results: A total of 365 patients from 7 centres in Argentina were included. A One hundred and eighty-three belonged to the SLE group: 92.3% women, mean age 39 years (SD 13.3), median disease duration 92 months (IQR 37-150). The most frequent manifestations of the disease were mucocutaneous (94%), musculoskeletal (82.5%) and haematological (69%). All patients presented ANA +, 88% hypocomplementemia, 69.4% Anti-DNA and 19.5% antiphospholipid antibodies. Median SLEDAI and SLICC were 2 (IQR 0-6) and 0 (IQR 0-1), respectively. In the control group, 182 patients were recruited: 84% women, mean age 53.6 years (SD 14.2) and median disease duration 82.5 months (IQR 38-151). The most frequent diseases were Rheumatoid Arthritis (46.1%), Scleroderma (18.1%) and Sjogren’s Syndrome (16.5%) and most common manifestations were musculoskeletal (81.9%), immunological (73.6%) and constitutional (25.3%). A total of 62.6% of patients presented ANA+, 8.6% hypocomplementemia, and 1.3% Antiphospholipid antibodies. Ninety-one percent of patients in the case group were classified as defined SLE and 3.8% in the control group. The ACR / EULAR 2019 Criteria showed a 99.4% sensitivity and an 89.1% specificity, with a LR+ of 9.1 and a LR- of 0.007. The sensitivity and specificity of SLICC 2012 criteria were 98.3% and 88%, respectively with a LR+ of 8.2 and a LR- of 0.02; and the ACR 1997 criteria showed a 93.96% sensitivity and 90.1% specificity, with LR + of 8.21 and LR - of 0.07. The correlations between the ACR/EULAR 2019 Criteria global score, and activity and damage indexes were 0.19 and -0.006, respectively. Conclusion: The new ACR / EULAR 2019 criteria have shown high sensitivity, a specificity comparable to its predecessors, and a higher ability to distinguish SLE from other diseases and to exclude it in non-SLE patients. No correlation was observed between the criteria scores and activity and damage indexes. References: [1]Aringer M, Costenbader K, Daikh D, et al 2019 EULAR/ACR classification criteria for SLE. Ann Rheum 2019; 78: 1151-1159. Disclosure of Interests: None declared

https://ard.bmj.com/content/annrheumdis/80/Suppl_1/635.1.full.pdf

Pos0763 performance of the new acr/eular 2019 classification criteria for systemic lupus erythematosus (sle) in a cohort of argentinian patients

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Primary Sjögren's syndrome: Extraglandular manifestations and hydroxychloroquine therapy.

Pos0763 performance of the new acr/eular 2019 classification criteria for systemic lupus erythematosus (sle) in a cohort of argentinian patients