Abatacept in individuals at high risk of rheumatoid arthritis (APIPPRA): a randomised, double-blind, multicentre, parallel, placebo-controlled, phase 2b clinical trial.

BACKGROUND: Individuals with serum antibodies to citrullinated protein antigens (ACPA), rheumatoid factor, and symptoms, such as inflammatory joint pain, are at high risk of developing rheumatoid arthritis. In the arthritis prevention in the pre-clinical phase of rheumatoid arthritis with abatacept (APIPPRA) trial, we aimed to evaluate the feasibility, efficacy, and acceptability of treating high risk individuals with the T-cell co-stimulation modulator abatacept. METHODS: The APIPPRA study was a randomised, double-blind, multicentre, parallel, placebo-controlled, phase 2b clinical trial done in 28 hospital-based early arthritis clinics in the UK and three in the Netherlands. Participants (aged ≥18 years) at risk of rheumatoid arthritis positive for ACPA and rheumatoid factor with inflammatory joint pain were recruited. Exclusion criteria included previous episodes of clinical synovitis and previous use of corticosteroids or disease-modifying antirheumatic drugs. Participants were randomly assigned (1:1) using a computer-generated permuted block randomisation (block sizes of 2 and 4) stratified by sex, smoking, and country, to 125 mg abatacept subcutaneous injections weekly or placebo for 12 months, and then followed up for 12 months. Masking was achieved by providing four kits (identical in appearance and packaging) with pre-filled syringes with coded labels of abatacept or placebo every 3 months. The primary endpoint was the time to development of clinical synovitis in three or more joints or rheumatoid arthritis according to American College of Rheumatology and European Alliance of Associations for Rheumatology 2010 criteria, whichever was met first. Synovitis was confirmed by ultrasonography. Follow-up was completed on Jan 13, 2021. All participants meeting the intention-to-treat principle were included in the analysis. This trial was registered with EudraCT (2013-003413-18). FINDINGS: Between Dec 22, 2014, and Jan 14, 2019, 280 individuals were evaluated for eligibility and, of 213 participants, 110 were randomly assigned to abatacept and 103 to placebo. During the treatment period, seven (6%) of 110 participants in the abatacept group and 30 (29%) of 103 participants in the placebo group met the primary endpoint. At 24 months, 27 (25%) of 110 participants in the abatacept group had progressed to rheumatoid arthritis, compared with 38 (37%) of 103 in the placebo group. The estimated proportion of participants remaining arthritis-free at 12 months was 92·8% (SE 2·6) in the abatacept group and 69·2% (4·7) in the placebo group. Kaplan-Meier arthritis-free survival plots over 24 months favoured abatacept (log-rank test p=0·044). The difference in restricted mean survival time between groups was 53 days (95% CI 28-78; p<0·0001) at 12 months and 99 days (95% CI 38-161; p=0·0016) at 24 months in favour of abatacept. During treatment, abatacept was associated with improvements in pain scores, functional wellbeing, and quality-of-life measurements, as well as low scores of subclinical synovitis by ultrasonography, compared with placebo. However, the effects were not sustained at 24 months. Seven serious adverse events occurred in the abatacept group and 11 in the placebo group, including one death in each group deemed unrelated to treatment. INTERPRETATION: Therapeutic intervention during the at-risk phase of rheumatoid arthritis is feasible, with acceptable safety profiles. T-cell co-stimulation modulation with abatacept for 12 months reduces progression to rheumatoid arthritis, with evidence of sustained efficacy beyond the treatment period, and with no new safety signals. FUNDING: Bristol Myers Squibb.

British Society for Rheumatology guideline on management of adult and juvenile onset Sjögren disease.

Sjögren disease (SD) is a chronic, autoimmune disease of unknown aetiology with significant impact on quality of life. Although dryness (sicca) of the eyes and mouth are the classically described features, dryness of other mucosal surfaces and systemic manifestations are common. The key management aim should be to empower the individual to manage their condition-conserving, replacing and stimulating secretions; and preventing damage and suppressing systemic disease activity. This guideline builds on and widens the recommendations developed for the first guideline published in 2017. We have included advice on the management of children and adolescents where appropriate to provide a comprehensive guideline for UK-based rheumatology teams.

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.

A randomized, double-blind, placebo-controlled, parallel group study on the effects of a cathepsin S inhibitor in primary Sjögren's syndrome.

OBJECTIVES: Primary SS (pSS) is a chronic autoimmune disorder characterized by mucosal dryness and systemic symptoms. We tested the effects of inhibition of cathepsin S using the potent and selective inhibitor RO5459072 on disease activity and symptoms of pSS. METHODS: This was a randomized, double-blind, placebo-controlled, parallel-group, Phase IIA study to investigate the effects of RO5459072 (100 mg twice daily; 200 mg per day). Seventy-five patients with pSS were randomized 1:1 to receive either RO5459072 or placebo for 12 weeks. The primary outcome was the proportion of patients with a ≥3 point reduction from baseline in EULAR SS Disease Activity Index (ESSDAI) score. We also investigated the effects of RO5459072 on quality of life, exocrine gland function, biomarkers related to SS, and safety and tolerability. RESULTS: The proportion of patients showing an improvement in ESSDAI score was not significantly different between the RO5459072 and placebo arms. No clinically meaningful treatment effects were observed in favour of RO5459072 for all secondary outcomes. Analysis of soluble biomarkers indicated target engagement between RO5459072 and cathepsin S. There were modest decreases in the number of circulating B cells and T cells in the RO5459072 group, although these did not reach significance. RO5459072 was safe and well-tolerated. CONCLUSIONS: There was no clinically relevant improvement in ESSDAI score (primary endpoint), and no apparent benefit in favour of RO5459072 in any of the secondary clinical endpoints. Further work is needed in order to understand the mechanisms of MHC-II-mediated immune stimulation in pSS. TRIAL REGISTRATION: ClinicalTrials.gov; NCT02701985.

Using Autoantibodies to Diagnose Systemic Autoimmune Diseases Triggered by Immune Checkpoint Inhibitors: A Clinical Perspective.

Immunotherapies, such as immune checkpoint inhibitors (ICIs), have significantly advanced the treatment of cancer and other conditions. However, these therapies can also cause immune-related adverse events (irAEs), which are unintended side effects due to their effects on the immune system of the treated patient. These effects can be classified as organ-specific or systemic, with the latter being of particular interest due to their potential overlap with systemic autoimmune diseases (SADs). Autoantibodies, which are proteins produced by the immune system that react with self components, are often used to diagnose and classify SAD. However, the diagnostic value of autoantibodies in the context of systemic irAEs (sirAEs) triggered by ICIs is not well understood. This review aims to evaluate the diagnostic value of conventional autoantibodies in the identification and classification of sirAEs. A comprehensive search of the literature was conducted using the PubMed database, with a focus on articles published in the past 10 years. The results of the review suggest that, although autoantibodies can be useful in the diagnosis and classification of some SAD triggered by ICIs, there is a clear predominance of seronegative irAEs. The lack of traditional autoantibodies may suggest a unique mechanism for sirAEs and increases the already complex diagnostic approach of these manifestations, requiring evaluation by multidisciplinary teams with extensive experience in immunomediated diseases. Further research is needed to fully understand the diagnostic value of autoantibodies in this context and to determine the optimal approach for their detection and interpretation.

The impact of concomitant Sjögren's disease on rheumatoid arthritis disease activity: a systematic review and meta-analysis.

OBJECTIVES: Rheumatoid arthritis (RA) and Sjögren's syndrome (SS) frequently co-exist but the consequence for RA disease activity of having concomitant SS (RA/SS) is not well established. We conducted a systematic review and meta-analysis to investigate the impact of SS on disease outcomes in individuals with RA. METHODS: We searched Web of Science (Core Collection, FSTA, Medline), PubMed and Cochrane databases, without language restriction. Studies reporting RA disease activity scores, joint counts, visual analogue scales (VAS), disability and joint damage, and comparing RA and RA/SS were selected. Outcomes reported in at least 3 studies in which the diagnosis of SS fulfilled classification criteria underwent meta-analysis, using a random effects model where heterogeneity was detected. RESULTS: The literature search identified 2991 articles and abstracts; 23 underwent full-text review and 16 were included. The studies included a total of 29722 patients (8614 with RA/SS and 21108 with RA). Using studies eligible for meta-analysis (744 patients with RA/SS and 4450 with RA), we found higher DAS-28 ESR scores (mean difference 0.50, 95% CI -0.008-1.006; p=0.05), higher swollen joint count scores (mean difference 1.05, 95% CI 0.42-1.67; p=0.001), and greater functional disability as measured by HAQ (mean difference 0.19, 95% CI 0.05-0.34; p=0.009) in RA/SS compared to RA alone. Other outcome measures (tender joint count, fatigue VAS) showed a numerical trend towards higher scores in RA/SS but were not statistically significant. CONCLUSIONS: RA/SS patients appear to have higher disease activity and more functional disability than patients with RA alone. The aetiology and clinical implications of this are unclear and warrant further investigation.

Immunofibroblasts are pivotal drivers of tertiary lymphoid structure formation and local pathology.

Resident fibroblasts at sites of infection, chronic inflammation, or cancer undergo phenotypic and functional changes to support leukocyte migration and, in some cases, aggregation into tertiary lymphoid structures (TLS). The molecular programming that shapes these changes and the functional requirements of this population in TLS development are unclear. Here, we demonstrate that external triggers at mucosal sites are able to induce the progressive differentiation of a population of podoplanin (pdpn)-positive stromal cells into a network of immunofibroblasts that are able to support the earliest phases of TLS establishment. This program of events, that precedes lymphocyte infiltration in the tissue, is mediated by paracrine and autocrine signals mainly regulated by IL13. This initial fibroblast network is expanded and stabilized, once lymphocytes are recruited, by the local production of the cytokines IL22 and lymphotoxin. Interfering with this regulated program of events or depleting the immunofibroblasts in vivo results in abrogation of local pathology, demonstrating the functional role of immunofibroblasts in supporting TLS maintenance in the tissue and suggesting novel therapeutic targets in TLS-associated diseases.

Health-related quality of life and costs in Sjögren's syndrome.

Health-related quality of life (HRQoL) has an increasing role in medical decision-making. This review of the literature aims to provide an overview on HRQoL, costs, and work disability in SS, a disease characterized by focal lymphocytic infiltration of exocrine glands with no therapeutics of proven immunomodulatory potential. HRQoL is markedly reduced in SS in multiple studies across many countries when compared with HRQoL in healthy controls. The reduction in HRQoL is similar to that observed in other chronic diseases such as RA, SLE, FM and, interestingly, non-SS sicca syndrome. Impaired HRQoL in SS has been found to be associated with fatigue, pain/articular involvement, ocular and oral involvement, pruritus, sexual dysfunction, impaired sleep, pulmonary manifestations, psychological dysfunction and impaired physical function. Until now, no therapeutic has been shown to improve HRQoL in an adequately powered double-blind, placebo-controlled randomized controlled trial. Although primary SS does not, in general, impair life expectancy and is often inappropriately considered a benign 'nuisanvce' disease for those patients without systemic manifestations, the associated costs and work disability are striking. This, together with the significant reduction in HRQoL, strongly argues for the development of new therapeutic approaches to manage this neglected disease.

A phase 2 randomized, double-blind, placebo-controlled, proof-of-concept study of oral seletalisib in primary Sjögren's syndrome.

OBJECTIVES: This phase 2 proof-of-concept study (NCT02610543) assessed efficacy, safety and effects on salivary gland inflammation of seletalisib, a potent and selective PI3Kδ inhibitor, in patients with moderate-to-severe primary Sjögren's syndrome (PSS). METHODS: Adults with PSS were randomized 1:1 to seletalisib 45 mg/day or placebo, in addition to current PSS therapy. Primary end points were safety and tolerability and change from baseline in EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI) score at week 12. Secondary end points included change from baseline at week 12 in EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI) score and histological features in salivary gland biopsies. RESULTS: Twenty-seven patients were randomized (seletalisib n = 13, placebo n = 14); 20 completed the study. Enrolment challenges led to early study termination with loss of statistical power (36% vs 80% planned). Nonetheless, a trend for improvement in ESSDAI and ESSPRI [difference vs placebo: -2.59 (95% CI: -7.30, 2.11; P=0.266) and -1.55 (95% CI: -3.39, 0.28), respectively] was observed at week 12. No significant changes were seen in saliva and tear flow. Serious adverse events (AEs) were reported in 3/13 of patients receiving seletalisib vs 1/14 for placebo and 5/13 vs 1/14 discontinued due to AEs, respectively. Serum IgM and IgG concentrations decreased in the seletalisib group vs placebo. Seletalisib demonstrated efficacy in reducing size and organisation of salivary gland inflammatory foci and in target engagement, thus reducing PI3K-mTOR signalling compared with placebo. CONCLUSION: Despite enrolment challenges, seletalisib demonstrated a trend towards clinical improvement in patients with PSS. Histological analyses demonstrated encouraging effects of seletalisib on salivary gland inflammation and organisation. TRIAL REGISTRATION: https://clinicaltrials.gov, NCT02610543.

EULAR recommendations for the management of Sjögren's syndrome with topical and systemic therapies.

The therapeutic management of Sjögren syndrome (SjS) has not changed substantially in recent decades: treatment decisions remain challenging in clinical practice, without a specific therapeutic target beyond the relief of symptoms as the most important goal. In view of this scenario, the European League Against Rheumatism (EULAR) promoted and supported an international collaborative study (EULAR SS Task Force) aimed at developing the first EULAR evidence and consensus-based recommendations for the management of patients with SjS with topical and systemic medications. The aim was to develop a rational therapeutic approach to SjS patients useful for healthcare professionals, physicians undergoing specialist training, medical students, the pharmaceutical industry and drug regulatory organisations following the 2014 EULAR standardised operating procedures. The Task Force (TF) included specialists in rheumatology, internal medicine, oral health, ophthalmology, gynaecology, dermatology and epidemiology, statisticians, general practitioners, nurses and patient representatives from 30 countries of the 5 continents. Evidence was collected from studies including primary SjS patients fulfilling the 2002/2016 criteria; when no evidence was available, evidence from studies including associated SjS or patients fulfilling previous sets of criteria was considered and extrapolated. The TF endorsed the presentation of general principles for the management of patients with SjS as three overarching, general consensus-based recommendations and 12 specific recommendations that form a logical sequence, starting with the management of the central triplet of symptoms (dryness, fatigue and pain) followed by the management of systemic disease. The recommendations address the use of topical oral (saliva substitutes) and ocular (artificial tear drops, topical non-steroidal anti-inflammatory drugs, topical corticosteroids, topical CyA, serum tear drops) therapies, oral muscarinic agonists (pilocarpine, cevimeline), hydroxychloroquine, oral glucocorticoids, synthetic immunosuppressive agents (cyclophosphamide, azathioprine, methotrexate, leflunomide and mycophenolate), and biological therapies (rituximab, abatacept and belimumab). For each recommendation, levels of evidence (mostly modest) and TF agreement (mostly very high) are provided. The 2019 EULAR recommendations are based on the evidence collected in the last 16 years in the management of primary 2002 SjS patients and on discussions between a large and broadly international TF. The recommendations synthesise current thinking on SjS treatment in a set of overarching principles and recommendations. We hope that the current recommendations will be broadly applied in clinical practice and/or serve as a template for national societies to develop local recommendations.

Equal rights in autoimmunity: is Sjögren's syndrome ever 'secondary'?

Sjögren's syndrome (SjS) accompanied by other systemic autoimmune rheumatic connective tissue diseases has historically been termed 'secondary' in contrast to 'primary' SjS as a standalone entity. However, it is a matter of a long-standing debate whether the prefixes 'primary' and 'secondary', including a temporal component, are obsolete in the terminology of SjS. We review the history and the pathophysiological, chronological, genetic, histological and clinical data underlying the concept of 'secondary' SjS. There are important unintended consequences of the nomenclature; notably 'secondary' SjS has been much less researched and is often excluded from clinical trials. We argue for further research, a change in terminology and more stringent classification. Further we highlight possible opportunities for trials in SjS and other systemic autoimmune diseases that might contribute to an advance in care for all patients with SjS.

CXCL13 as biomarker for histological involvement in Sjögren's syndrome.

OBJECTIVES: SS is an autoimmune condition characterized by systemic B-cell activation, autoantibody production and ectopic germinal centres' formation within the salivary gland (SG). The extent of SG infiltrate has been proposed as a biomarker of disease severity. Plasma levels of CXCL13 correlate with germinal centres' activity in animal models and disease severity in SS, suggesting its potential use as a surrogate serum marker to monitor local B-cell activation. The aim of this study was to evaluate the potential role of CXCL13 as a biomarker of SG pathology in two independent SS cohorts. METHODS: 109 patients with SS were recruited at Sapienza University of Rome (Italy) (n = 60), or at Queen Elizabeth Hospital in Birmingham and Barts Health NHS Trust in London (n = 49). Both sera and matched minor SG biopsy were available. Sicca (n = 57) and healthy subjects' (n = 19) sera were used as control. RESULTS: CXCL13 serum level was higher in SS patients compared with controls. Correlations between its serum levels and a series of histomorphological parameters, including size of the aggregates and the presence germinal centres', were observed. CONCLUSION: Our data foster the use of CXCL13 to monitor the extent of local pathology in SS and its validation in longitudinal clinical studies.

Mediterranean diet and risk of Sjögren's syndrome.

OBJECTIVES: Non-genetic risk factors for Sjögren's syndrome (SS) are poorly understood. Adherence to a Mediterranean diet has been associated with reduction in other autoimmune diseases. We examined the association of Mediterranean diet with SS. METHODS: New patients attending a single centre warranting investigation for primary SS (pSS) were recruited into the Optimising Assessment in Sjögren's Syndrome cohort established in Birmingham, UK (2014-2018). Participants were classified into pSS and non-SS sicca, considered as cases and non-cases, respectively, and asked to complete an optional food frequency questionnaire on their diet before onset of symptoms. A semi-quantitative Mediterranean diet score (MDS) was calculated (possible range=0 to 18). Using multivariate logistic regression, corrected for energy intake, body-mass index, sex, age, symptom duration, and smoking status, we examined the association of MDS with SS. RESULTS: Dietary data were available for 133/243 (55%) eligible patients (n=82 pSS and n=51 sicca). In the adjusted model, a higher total MDS (mean ± SD, 9.41±2.31 points) was associated with lower odds of pSS (OR 0.81, 95% CI 0.66-0.99; p=0.038) per one unit of MDS. Among MDS components, the strongest association was seen with fish with OR 0.44 (95% CI 0.24-0.83; p=0.01) in the comparison between <1 portion/week and 1 to 2.5 portions/week. Higher galactose, vitamin A-retinol-equivalents and vitamin C showed associations with lower odds of pSS in multivariate analysis, where the association of vitamin C was attenuated when adjusted for MDS. CONCLUSIONS: When adjusted for potential confounders, adherence to the Mediterranean diet was associated with lower likelihood of having pSS.

A Training Tool to support the management and diagnosis of Sjögren's syndrome.

OBJECTIVES: The objective of this work is to present a Training Tool designed to support healthcare professionals involved in the diagnosis and management of Sjögren's syndrome. METHODS: The Training Tool aims to fulfil the gap of targeted education by providing a structured protocol of training including state of the art guidelines and practices. For the development of the Training Tool, latest relevant technologies have been used to assure efficiency and usability. Core functionalities include training by a series of multimedia courses, testing during the learning process, and profiling for monitoring the progress. An iterative requirement analysis process was established involving a large number of clinical experts, with the objective to identify user's training needs. RESULTS: Comprehensive usability evaluation was performed by applying, an Unmoderated Remote Usability Test resulting to 97.2% Success Rate; and the well-established System Usability Scale, reaching a score of 90.4 which classifies the Training Tool as "A" graded-excellent. CONCLUSIONS: The Training Tool offers open-online training of healthcare professionals involved in the diagnosis and management of Sjögren's syndrome, using a well-designed training protocol in highly usable manner. To our knowledge, this is the first such tool for Sjögren's syndrome.

Phosphatidylinositol 3-kinase delta pathway: a novel therapeutic target for Sjögren's syndrome.

BACKGROUND: The phosphatidylinositol 3-kinase delta isoform (PI3Kδ) belongs to an intracellular lipid kinase family that regulate lymphocyte metabolism, survival, proliferation, apoptosis and migration and has been successfully targeted in B-cell malignancies. Primary Sjögren's syndrome (pSS) is a chronic immune-mediated inflammatory disease characterised by exocrine gland lymphocytic infiltration and B-cell hyperactivation which results in systemic manifestations, autoantibody production and loss of glandular function. Given the central role of B cells in pSS pathogenesis, we investigated PI3Kδ pathway activation in pSS and the functional consequences of blocking PI3Kδ in a murine model of focal sialoadenitis that mimics some features of pSS. METHODS AND RESULTS: Target validation assays showed significant expression of phosphorylated ribosomal protein S6 (pS6), a downstream mediator of the phosphatidylinositol 3-kinase delta (PI3Kδ) pathway, within pSS salivary glands. pS6 distribution was found to co-localise with T/B cell markers within pSS aggregates and the CD138+ plasma cells infiltrating the glands. In vivo blockade of PI3Kδ activity with seletalisib, a PI3Kδ-selective inhibitor, in a murine model of focal sialoadenitis decreased accumulation of lymphocytes and plasma cells within the glands of treated mice in the prophylactic and therapeutic regimes. Additionally, production of lymphoid chemokines and cytokines associated with ectopic lymphoneogenesis and, remarkably, saliva flow and autoantibody production, were significantly affected by treatment with seletalisib. CONCLUSION: These data demonstrate activation of PI3Kδ pathway within the glands of patients with pSS and its contribution to disease pathogenesis in a model of disease, supporting the exploration of the therapeutic potential of PI3Kδ pathway inhibition in this condition.

Management of rheumatic complications of immune checkpoint inhibitor therapy - an oncological perspective.

Immune checkpoint inhibitors (CPIs) are an effective treatment for many cancers but cause diverse immune-related adverse events (IrAEs). Rheumatological IrAEs include arthralgia, arthritis, tenosynovitis, myositis, polymyalgia rheumatica and sicca syndrome. CPI use can unmask RA as well as causing flares of prior autoimmune or connective tissue disease. Oncologists categorize and grade IrAEs using the Common Terminology Criteria for Adverse Events and manage them according to international guidelines. However, rheumatological events are unfamiliar territory: oncologists need to work with rheumatologists to elicit and assess symptoms, signs, results of imaging and autoantibody testing and to determine the use of steroids and DMARDs. Myositis may overlap with myasthenic crisis and myocarditis and can be life-threatening. Treatment should be offered on balance of risk and benefit, including whether to continue CPI treatment and recognizing the uncertainty over whether glucocorticoids and DMARDs might compromise cancer control.

Sicca/Sjögren's syndrome triggered by PD-1/PD-L1 checkpoint inhibitors. Data from the International ImmunoCancer Registry (ICIR).

OBJECTIVES: To analyse the worldwide occurrence of sicca/Sjögren's (SS) syndrome associated with the use of immune checkpoint inhibitors (ICI) in patients with cancer. METHODS: The ImmunoCancer International Registry (ICIR) is a Big Data-Sharing multidisciplinary network composed by 40 specialists in Rheumatology, Internal Medicine, Immunology and Oncology from 18 countries focused on the clinical and basic research of the immune-related adverse events (irAEs) related to cancer immunotherapies. For this study, patients who were investigated for a clinical suspicion of SS after being exposed to ICI were included. RESULTS: We identified 26 patients (11 women and 15 men, with a mean age at diagnosis of 63.57 years). Underlying cancer included lung (n=12), renal (n=7), melanoma (n=4), and other (n=3) neoplasia. Cancer immunotherapies consisted of monotherapy (77%) and combined regimens (23%). In those patients receiving monotherapy, all patients were treated with PD-1/PD-L1 inhibitors (nivolumab in 9, pembrolizumab in 7 and durvalumab in 4); no cases associated with CTLA-4 inhibitors were identified. The main SS-related features consisted of dry mouth in 25 (96%) patients, dry eye in 17 (65%), abnormal ocular tests in 10/16 (62%) and abnormal oral diagnostic tests in 12/14 (86%) patients. Minor salivary gland biopsy was carried out in 15 patients: histopathological findings consisted of mild chronic sialadenitis in 8 (53%) patients and focal lymphocytic sialadenitis in the remaining 7 (47%); a focus score was measured in 5 of the 6 patients (mean of 1.8, range 1-4). Immunological markers included positive ANA in 13/25 (52%), anti-Ro/ SS-A in 5/25 (20%), RF in 2/22 (9%), anti-La/SS-B in 2/25 (8%), low C3/C4 levels in 1/17 (6%) and positive cryoglobulins in 1/10 (10%). Classification criteria for SS were fulfilled by 10 (62%) out of 16 patients in whom the two key classificatory features were carried out. Among the 26 patients, there were only 3 (11%) who presented exclusively with sicca syndrome without organ-specific autoimmune manifestations. Therapeutic management included measures directed to treat sicca symptoms and therapies against autoimmune-mediated manifestations (glucocorticoids in 42%, second/third-line therapies in 31%); therapeutic response for systemic features was observed in 8/11 (73%). No patient died due to autoimmune involvement. CONCLUSIONS: Patients with Sjögren's syndrome triggered by ICI display a very specific profile different from that reported in idiopathic primary SS, including more frequent occurrence in men, a higher mean age, a predominant immunonegative serological profile, and a notable development of organ-specific autoimmune involvement in spite of the poor immunological profile. The close association found between sicca/Sjögren's syndrome and primarily PD-1 blockade requires further specific investigation.

High erythrocyte levels of the n-6 polyunsaturated fatty acid linoleic acid are associated with lower risk of subsequent rheumatoid arthritis in a southern European nested case-control study.

OBJECTIVES: Findings relating to dietary intake of n-3 polyunsaturated fatty acids (PUFA) and risk of rheumatoid arthritis (RA) are mixed. Erythrocyte membrane PUFA is an accurate objective biomarker of PUFA status; however, there are little data on erythrocyte membrane PUFA and risk of RA. The objective was therefore to compare erythrocyte membrane PUFA between pre-RA individuals and matched controls from a population-based sample, and specifically to test the hypothesis that higher levels of longer chain n-3 PUFA are associated with lower risk of RA. METHODS: The European Prospective Investigation into Cancer and Nutrition (EPIC) is a large European prospective cohort study of apparently healthy populations. We undertook a nested case-control study by identifying RA cases with onset after enrolment (pre-RA) in four EPIC cohorts in Italy and Spain. Confirmed pre-RA cases were matched with controls by age, sex, centre, and date, time and fasting status at blood collection. Conditional logistic regression analysis was used to estimate associations of PUFA with the development of RA, adjusting for potential confounders including body mass index, waist circumference, education level, physical activity, smoking status and alcohol intake. RESULTS: The study analysed samples from 96 pre-RA subjects and 258 matched controls. In this analysis, the median time to diagnosis (defined as time between date of blood sample and date of diagnosis) was 6.71 years (range 0.8-15). A significant inverse association was observed with n-6 PUFA linoleic acid (LA) levels and pre-RA in the fully adjusted model (highest tertile: OR 0.29; 95% CI 0.12 to 0.75; P for trend 0.01). No association was observed with any individual n-3 PUFA, total n-3 PUFA or total n-3:n-6 ratio. CONCLUSIONS: Erythrocyte levels of the n-6 PUFA LA were inversely associated with risk of RA, whereas no associations were observed for other n-6 or n-3 PUFA. Further work is warranted to replicate these findings and to investigate if lower LA levels are a bystander or contributor to the process of RA development.

Effect of rituximab on a salivary gland ultrasound score in primary Sjögren's syndrome: results of the TRACTISS randomised double-blind multicentre substudy.

OBJECTIVES: To compare the effects of rituximab versus placebo on salivary gland ultrasound (SGUS) in primary Sjögren's syndrome (PSS) in a multicentre, multiobserver phase III trial substudy. METHODS: Subjects consenting to SGUS were randomised to rituximab or placebo given at weeks 0, 2, 24 and 26, and scanned at baseline and weeks 16 and 48. Sonographers completed a 0-11 total ultrasound score (TUS) comprising domains of echogenicity, homogeneity, glandular definition, glands involved and hypoechoic foci size. Baseline-adjusted TUS values were analysed over time, modelling change from baseline at each time point. For each TUS domain, we fitted a repeated-measures logistic regression model to model the odds of a response in the rituximab arm (≥1-point improvement) as a function of the baseline score, age category, disease duration and time point. RESULTS: 52 patients (n=26 rituximab and n=26 placebo) from nine centres completed baseline and one or more follow-up visits. Estimated between-group differences (rituximab-placebo) in baseline-adjusted TUS were -1.2 (95% CI -2.1 to -0.3; P=0.0099) and -1.2 (95% CI -2.0 to -0.5; P=0.0023) at weeks 16 and 48. Glandular definition improved in the rituximab arm with an OR of 6.8 (95% CI 1.1 to 43.0; P=0.043) at week 16 and 10.3 (95% CI 1.0 to 105.9; P=0.050) at week 48. CONCLUSIONS: We demonstrated statistically significant improvement in TUS after rituximab compared with placebo. This encourages further research into both B cell depletion therapies in PSS and SGUS as an imaging biomarker. TRIAL REGISTRATION NUMBER: 65360827, 2010-021430-64; Results.