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SJOGREN SYNDROME: PATIENTS STRATIFICATION AND DAMAGE ACCRUAL (ID 816)
IS017 - BIOMARKERS IN SJOGREN’S SYNDROME AS TOOLS FOR MOLECULAR STRATIFICATION (ID 817)
Abstract
Abstract Body
Primary Sjögren's syndrome (pSS) is a chronic, systemic autoimmune disease with diverse clinical picture and outcome. The disease affects primarily middle-aged females and involves the exocrine glands, leading to dry mouth and eyes. When the disease extends beyond the exocrine glands (systemic form), certain extraglandular manifestations involving liver, kidney, lungs, peripheral nervous system and the skin may occur. Primary SS is at the crossroad between autoimmunity and lymphoproliferation, since approximately 5% of patients develop NHL associated lymphomas. As with every chronic disease with complex aetiopathogenesis and clinical heterogeneity, pSS has certain unmet needs that have to be addressed: a) classification and stratification of patients; b) understanding the distinct pathogenetic mechanisms and clinical phenotypes; c) defining and interpreting the real needs of patients regarding the contemporary diagnostic and therapeutic approaches; d) physician and patients' training regarding the wide spectrum of the disease; e) creating common policies across European countries to evaluate and manage SS patients. To achieve these goals, an intense effort has been undertaken over the past few years by the HarmonicSS consortium with a primary aim to harmonize and integrate the largest European cohorts of pSS patients. In parallel, several laboratories are trying to define molecular biomarkers, serving as tools for molecular stratification of patient. Both clinical phenotyping of patients, through the harmonization processing and molecular stratification of patients are mostly important to define therapeutic strategies and, eventually develop approaches towards Precision Medicine.Primary Sjögren's syndrome (pSS) is a chronic, systemic autoimmune disease with diverse clinical picture and outcome. The disease affects primarily middle-aged females and involves the exocrine glands, leading to dry mouth and eyes. When the disease extends beyond the exocrine glands (systemic form), certain extraglandular manifestations involving liver, kidney, lungs, peripheral nervous system and the skin may occur. Primary SS is at the crossroad between autoimmunity and lymphoproliferation, since approximately 5% of patients develop NHL associated lymphomas. As with every chronic disease with complex aetiopathogenesis and clinical heterogeneity, pSS has certain unmet needs that have to be addressed: a) classification and stratification of patients; b) understanding the distinct pathogenetic mechanisms and clinical phenotypes; c) defining and interpreting the real needs of patients regarding the contemporary diagnostic and therapeutic approaches; d) physician and patients' training regarding the wide spectrum of the disease; e) creating common policies across European countries to evaluate and manage SS patients. To achieve these goals, an intense effort has been undertaken over the past few years by the HarmonicSS consortium with a primary aim to harmonize and integrate the largest European cohorts of pSS patients. In parallel, several laboratories are trying to define molecular biomarkers, serving as tools for molecular stratification of patient. Both clinical phenotyping of patients, through the harmonization processing and molecular stratification of patients are mostly important to define therapeutic strategies and, eventually develop approaches towards Precision Medicine.
O051 - LINKAGE OF ANTI-RO AND ANTI-LA SEROPOSITIVITY IN ADULTS WITH CARDIAC ARRHYTHMIAS: INSIGHTS FROM A LARGE CROSS-SECTIONAL STUDY (ID 54)
Abstract
Background and Aims
Anti-Ro/SSA(anti-Ro) and anti-La/SSB(anti-La) are autoantibodies from the IgG class, targeted against intracellular ribonucleoproteins. These antibodies are prevalent in several autoimmune diseases but are also relatively frequent in healthy adults. The arrhythmogenic effect of anti-Ro antibodies on the premature conductive system is well established, with substantial evidence demonstrating increased risk for congenital atrioventricular(AV)-block in neonates of seropositive mothers. Traditionally, adult cardiomyocytes were considered invulnerable to these effects, however recent reports begin to challenge this paradigm. Despite their wide distribution and their arrhythmogenic potential, to date there are no large-population studies conducted in seropositive healthy adults.Therefore, in the present study we aimed to perform the first large population-based study investigating the association between anti-Ro/La seropositivity to cardiac rhythm and conduction disturbances in healthy adults.
Methods
This a cross-sectional study based on the electronic-health-records of HMO in Israel. All subjects that were tested positive for anti-Ro/anti-La antibodies between the years 2002-2019 were included and were matched by age, gender, and place of residence, with controls. Sensitivity analyses was performed using propensity score matching.
Results
17,231 anti-Ro/La seropositive subjects and 84,368 controls were enrolled. Anti-Ro seropositive patients had higher rates of conduction disturbances (3% vs. 1.7%,p<0.001) and rhythm disturbances (10.5% vs. 7%,p<0.001). Patients which were positive for anti-La alone did not demonstrate a significant association with arrythmias. Multivariate logistic-regression-analysis had demonstrated an increased risk for cardiac conduction disturbances (OR=1.43,95%CI 1.25-1.64,p<0.001), as well as for cardiac arrhythmias (OR=1.47,95%CI 1.37-1.57,p<0.001) among anti-RO seropositive patients.
Conclusions
Anti-Ro seropositivity is positively associated with cardiac rhythm and conduction disturbances in healthy adults.
O052 - MALADAPTIVE AUTOPHAGY IN THE PATHOGENESIS OF AUTOIMMUNE EPITHELITIS IN SJӦGREN’S SYNDROME (ID 378)
Abstract
Background and Aims
Salivary gland epithelial cells (SGECs) are key cellular drivers in the pathogenesis of primary Sjӧgren’s Syndrome (pSS); however, the mechanisms sustaining SGECs activation in pSS remain undetermined. The aim of this study is to determine the role of autophagy in the survival and activation of SGECs in pSS.
Methods
Primary SGECs isolated from minor salivary glands (SG) of patients with pSS or sicca syndrome were evaluated by flow-cytometry, immunoblotting, and immunofluorescence to assess autophagy (autophagic-flux, LC3IIB, p62, LC3B+/LAMP1+ staining), apoptosis (annexin V/PI, Caspase-3) and activation (ICAM, VCAM). Focus score and germinal centers presence was assessed in SG from the same patients to correlate with histological severity. Human salivary gland (HSG) cells were stimulated in vitro with PBMCs and serum from pSS patients in the presence or absence of autophagy inhibitors to determine changes in autophagy and epithelial cell activation.
Results
SGECs from pSS patients (n=24) exhibited increased autophagy (autophagic-flux p=0.001; LC3IIB p=0.02; p62 p=0.064; LC3IIB/LAMP1+ staining), increased expression of anti-apoptotic molecules (Bcl2 p=0.006), and reduced apoptosis (Annexin-V/PI p=0.002, Caspase-3 p=0.057) compared to sicca (n=16). Autophagy correlated with histologic disease severity. In vitro experiments on HSG cells stimulated with serum and PBMCs from pSS patients confirmed activation of autophagy and expression of adhesion molecules, which was reverted upon pharmacologic inhibition of autophagy.
Conclusions
In pSS SGECs, inflammation induces autophagy and pro-survival mechanisms, which promote SGEC activation and mirror histological severity. These findings indicate that autophagy is a central contributor to the pathogenesis of pSS and a new therapeutic target.
O053 - GLUTEN-FREE DIET IN NON-CELIAC AUOIMMUNE DISEASES (ID 89)
Abstract
Background and Aims
Background: A discrepancy exists between the worldwide increased wheat consumption and its popularity and between the scientific observations on the side effects of gluten, the major protein in wheat. Autoimmune disease (AD) incidence increases in parallel. Recently, gluten has been associated with autoimmune properties and even as a contributor to neurodegenerative conditions. In addition, celiac disease is associated with numerous ADs.
Methods
Methods: PubMed/MEDLINE, Web of Sciences, LILACS and Scielo, 1960-2021, were searched, using the keywords of various ADs and gluten-free diet (GFD). We selected non-celiac ADs, where GFD was studied.
Results
Results: 83 articles in which GFD was used to treat 29 ADs were found. These diseases spanned rheumatic, skin, muscle, connective tissue, intestinal, hepatic and biliary, pancreatic, thyroidal, adrenal, hematological, cardiac, kidney, ocular, gynecological, and cerebral as well. Age ranged from 9 months to 69 years. ADs duration between 0 to 20 ± 13 years. Duration of GFD varied between 1 month to 9 years. Interestingly, improvement of ADs after GFD was observed in 66 out of the 83 studies (79.5%), in 15.7% no changes were seen, in 3.6% worsening was seen and in 2.4% this data was not available. Symptomatic improvement was noticed in 911/1408 patients.
Conclusions
Conclusion: Based on the results, gluten withdrawal was efficient in about 80% of the screened ADs. It might represent a new nutritional therapeutic strategy for autoimmunity. Gluten-induced adverse effects, dysbiosis, leaky gut, cross-linked antibodies, and sequence homology might be some of the pathophysiological mechanisms for the beneficial effect of gluten restriction.
O054 - NEUROLOGICAL ADVERSE EVENTS OF IMMUNE CHECKPOINT INHIBITORS: DIVERSITY OF CLINICAL PRESENTATIONS AND OUTCOMES (ID 423)
Abstract
Background and Aims
Neurological immune-related adverse events (n-irAEs) are an emerging group of disorders related to immune checkpoint inhibitors (ICIs) use. We aimed to describe the clinical presentations and to assess long-term outcomes of n-irAEs.
Methods
Patients with a final n-irAEs diagnosis were retrospectively identified from two reference centres. Classical paraneoplastic neurological syndromes (PNS) were defined according to published 2004 PNS definitions. Neurological disability was measured using the modified Rankin Scale (mRS). A Markov model was used to estimate the probability of transitioning across three states of disease (severe disability, mRS=3-5; favourable outcome, mRS<3; death, mRS=6).
Results
We included 147 patients (59% males; mean age at onset 63.4 years). The most frequent clinical phenotypes were myositis (n=52), diffuse encephalitis (n=23), polyradiculoneuropathy (n=22), limbic encephalitis (n=15), other focal central nervous system involvements (n=15), myasthenia gravis (MG, n=8), subacute sensory ganglionopathy (n=8), cranial neuropathies (n=8), and isolated meningitis (n=8); these overlapped in 15 cases (10.2%). Although most patients improved over time (Fig.1), 48 patients (33%) were dead at last visit (median follow-up 12 months, range 0.5-50; competitive risks of favourable outcome and death are shown in Fig.2). Myositis and classical PNS were associated with higher (HR 5.03, p<0.01) and lower (HR 0.19, p<0.01) probability of favourable outcome, respectively. Cancer progression was more frequent among patients dead at last visit compared with those who survived (66.7% vs. 19.7%, p<0.01).
Conclusions
These findings highlight the clinical heterogeneity of n-irAEs. Outcomes varied depending on both the initial clinical presentation and the occurrence of cancer progression.
O055 - CANNABINOIDS FOR PSORIATIC ARTHRITIS – FROM PAIN TO SALVAGE THERAPY (ID 260)
Abstract
Background and Aims
The anti-inflammatory and immunomodulatory role of cannabinoids has not been firmly established due to the difficulty in accurately determining the proper composition of the basic cannabinoids in different clinical conditions.
Methods
We hereby present a case of a female patient in her late 30s with psoriatic arthritis. She was treated with various biological agents. Over the course of her disease the symptoms became severe, and she suffered from painful arthritis not only in her ankles and knees, but also in her hand joints.
Results
Multiple drug regimens were used, starting from TNF-alpha inhibitors, etanercept, adalimumab and to be followed by secukinumab (IL-17 inhibitor) with no effects. Ustekinumab was initiated together with methotrexate with no improvement. Finally, JAK-kinase inhibitors, starting with tofacitinib, which was later changed to upadacitinib. Only following the addition of upadacitinib, a partial clinical improvement had been achieved. However, the patients continued to suffer from disturbing and limiting pain. Therefore, the use of cannabis was suggested at this stage in order to alleviate the aggravating pain. Surprisingly, the addition of cannabinoids induced a complete skin and joint remission.
Conclusions
In our discussion, we highlight the use of cannabinoids in rheumatic conditions and underline their anti-inflammatory and immunomodulatory role. Moreover, a review of available medical literature is presented.
O056 - PROGNOSIS OF IMMUNE CHECKPOINT INHIBITORS-INDUCED MYOCARDITIS: A CASE SERIES (ID 764)
Abstract
Background and Aims
Immune checkpoint inhibitors (ICI) have transformed cancer treatment in the last decade. Alongside this therapeutic improvement, a new variety of side effects has emerged, called immune related adverse events (irAEs), potentially affecting any organ. Among these irAEs, myocarditis is rare but life-threatening.
Methods
We conducted a multicenter cross-sectional retrospective study in the aim to better characterize ICI-related myocarditis. Myocarditis diagnosis was based on guidelines of the European Society of Cardiology.
Results
Twenty-nine patients were identified, from 6 different referral centers. Most patients (55%) were treated using anti-programmed-death1, rather than ICI combination (35%) or anti-programmed- death-ligand1 (10%). Transthoracic echocardiography was pathologic in 52% of them, and cardiac magnetic resonance showed abnormal features in 14/24 patients (58%). Eleven patients (38%) were classified as CTCAE grade 4 or 5. Compared to other patients, they had more frequently pre-existing systemic auto-immune disease (45% vs 6%, p = 0.018), higher troponin level on admission (42-fold the upper limit vs 3,55-fold, p = 0.001), and exhibited anti-acetylcholine receptor autoantibodies (p = 0.001). Seven patients (24%) had myocarditis-related death, and 7 more patients died from cancer progression during follow-up. Twenty-eight patients received glucocorticoids, 10 underwent plasma exchanges, 8 received IVIg, and 5 other immunosuppressants. ICI re-challenge was performed in 6 patients, with only one myocarditis relapse.
Conclusions
The management of ICI-related myocarditis may be challenging and requires a multidisciplinary approach. Prognostic features are herein described and may help to allow ICI re- challenge for some patients with smoldering presentation, after an accurate evaluation of benefit-risk balance.
O057 - SJÖGREN SYNDROME OVERLAPPING WITH ANCA-ASSOCIATED VASCULITIS: FOUR ADDITIONAL CASES AND SYSTEMATIC LITERATURE REVIEW (ID 774)
Abstract
Background and Aims
Sjögren’s syndrome (SS) and ANCA-associated vasculitis (AAV) have distinct clinical presentation and evolution, with paucity of reports on overlap syndrome. We aimed to better characterize this entity.
Methods
We report four additional cases from our university hospital. We also performed a systematic literature review, according to PRISMA guidelines, in Medline, Embase, Web of science, Cochrane Library, and grey literature. Demographic, clinical, and paraclinical data on SS and AAV were analysed.
Results
A total of 3133 articles was identified in databases, with 2695 articles screened for eligibility. After exclusion, we had 30 articles on 40 patients to analyse, in addition to 4 patients from our local recruitment (44 patients overall). Patients were female in 81.8%, with median age at AAV onset of 63.5 years. All patients but one presented with SS before, or concomitantly to the diagnosis of AAV, with a median delay of 12 months between both diagnoses. AAV predominantly had renal involvement (35/44 patients, 79.5%), anti-MPO antibodies being the most frequent (35 patients), even in patients presenting with granulomatosis with polyangiitis. We observed significantly more Raynaud phenomenon and associated auto-immune diseases in the group of non-granulomatous AAV (10 patients versus 1, p=0.015 and 8 patients versus 0, p=0.013, respectively).
Conclusions
This is the largest descriptive study on the association between SS and AAV, providing information on this challenging diagnosis and interplay between these two diseases. Particular attention should be paid in the first months after diagnosis, given the specific complications and outcomes of each disease.
O058 - SLE AND INFECTIONS- AN UPDATE (ID 769)
Abstract
Background and Aims
Lupus patients are more prone to infections than the normal population and may be due to the dysfunction of their immune system. Infections may occur early in the diagnosis of SLE and/or peak after 5 years of disease. In addition, lupus patients will be more prone to severe infections if they are treated with very potent immunosuppressive drugs. Infections may be a trigger to the development or exacerbation of lupus
Methods
. Infections can mimic a flare of lupus, where the appropriate diagnosis and therapy can prevent morbidity and mortality. In addition, SLE and infections may be concurrent in 41% of cases. In these patients, an elevated CRP will indicate infection. Hospitalized lupus patients are more prone to develop infections that are hospital acquired, activation of latent pathogens, or opportunistic pathogens.
Results
Over the past four decades, infection rates have not declined and remain a major cause of death in SLE patients. In the past decade, hospital and ICU admissions are for sepsis more than pneumonia as in the past. There is no decline in the mortality rates due to infections.
Conclusions
There has been a significant improvement in the diagnosis of infections and a major increase of available antibiotics. However, one of the major causes of death remains severe infections in lupus patients. This finding indicates that possibly different unknown mechanisms do not participate in the fight against infections in this prototopic autoimmune disease.