Hematological involvement in sarcoidosis: from cytopenias to lymphoma.

INTRODUCTION: We present an updated overview of the hematological involvementassociated with sarcoidosis, including a management approach forcytopenias and revisiting the association with hematologicalmalignancies. AREAS COVERED: Theetiology of cytopenias in sarcoidosis can be attributed to two majoretiopathogenic mechanisms: infiltration of hematopoietic organs suchas the spleen and bone marrow, and autoimmune-mediated cytopenias.With respect to the association with hematological malignancies, itrequires careful evaluation of patients from a chronologicalperspective. Patients must be classified into one of three pathogenicscenarios, including preexisting hematological malignancies,synchronous development of malignancy and sarcoidosis due to commonpredisposing factors, or sarcoidosis as a predisposing factor formalignancies. EXPERT OPINION: The association between sarcoidosis and hematologic involvement isbest understood as a pathogenic continuum, with cytopenias andhematologic neoplasms intertwined due to various etiopathogenicmechanisms. These mechanisms include sarcoid infiltration ofhematopoietic organs, common predisposing immunogenetics for thedevelopment of autoimmune cytopenias and malignancies, and anincreased risk of neoplasm development in patients with autoimmunecytopenias. Collaboration among the main specialties involved in theclinical management of these patients is crucial for an earlymonitoring and management.

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.

Mortality risk factors in primary Sjögren syndrome: a real-world, retrospective, cohort study.

Background: What baseline predictors would be involved in mortality in people with primary Sjögren syndrome (SjS) remains uncertain. This study aimed to investigate the baseline characteristics collected at the time of diagnosis of SjS associated with mortality and to identify mortality risk factors for all-cause death and deaths related to systemic SjS activity measured by the ESSDAI score. Methods: In this international, real-world, retrospective, cohort study, we retrospectively collected data from 27 countries on mortality and causes of death from the Big Data Sjögren Registry. Inclusion criteria consisted of fulfilling 2002/2016 SjS classification criteria, and exclusion criteria included chronic HCV/HIV infections and associated systemic autoimmune diseases. A statistical approach based on a directed acyclic graph was used, with all-cause and Sjögren-related mortality as primary endpoints. The key determinants that defined the disease phenotype at diagnosis (glandular, systemic, and immunological) were analysed as independent variables. Findings: Between January 1st, 2014 and December 31, 2023, data from 11,372 patients with primary SjS (93.5% women, 78.4% classified as White, mean age at diagnosis of 51.1 years) included in the Registry were analysed. 876 (7.7%) deaths were recorded after a mean follow-up of 8.6 years (SD 7.12). Univariate analysis of prognostic factors for all-cause death identified eight Sjögren-related variables (ocular and oral tests, salivary biopsy, ESSDAI, ANA, anti-Ro, anti-La, and cryoglobulins). The multivariate CPH model adjusted for these variables and the epidemiological features showed that DAS-ESSDAI (high vs no high: HR = 1.68; 95% CI, 1.27-2.22) and cryoglobulins (positive vs negative: HR = 1.72; 95% CI, 1.22-2.42) were independent predictors of all-cause death. Of the 640 deaths with available information detailing the specific cause of death, 14% were due to systemic SjS. Univariate analysis of prognostic factors for Sjögren-cause death identified five Sjögren-related variables (oral tests, clinESSDAI, DAS-ESSDAI, ANA, and cryoglobulins). The multivariate competing risks CPH model adjusted for these variables and the epidemiological features showed that oral tests (abnormal vs normal results: HR = 1.38; 95% CI, 1.01-1.87), DAS-ESSDAI (high vs no high: HR = 1.55; 95% CI, 1.22-1.96) and cryoglobulins (positive vs negative: HR = 1.52; 95% CI, 1.16-2) were independent predictors of SjS-related death. Interpretation: The key mortality risk factors at the time of SjS diagnosis were positive cryoglobulins and a high systemic activity scored using the ESSDAI, conferring a 2-times increased risk of all-cause and SjS-related death. ESSDAI measurement and cryoglobulin testing should be considered mandatory when an individual is diagnosed with SjS. Funding: Novartis.

Síndrome de Sjögren / Sjögren syndrome

En 1933, el oftalmólogo sueco Hendrik Sjögren fue el primero en plantear que detrás de la sequedad que presentaban varios de sus pacientes podía existir una enfermedad sistémica relacionada con una respuesta inmune anormal. Desde entonces, se utilizó el término síndrome de Sjögren (Sjögren's syndrome, SjS), aunque se consideró como un trastorno menor e infrecuente respecto a otras enfermedades autoinmunitarias sistémicas (EAS) y, consecuentemente, con escaso interés tanto en la investigación clínica como en la evaluación de tratamientos específicos. La irrupción de las nuevas tecnologías a finales del siglo xx impulsó rápidamente el desarrollo de proyectos internacionales de gran impacto y difusión que han cambiado por completo este escenario, y en los últimos 20 años se ha avanzado de forma significativa en conocer los principales determinantes epidemiológicos y los mecanismos patogénicos, aumentar la precisión diagnóstica, y diseñar estrategias terapéuticas específicas e individualizadas. Hoy en día, el SjS es una de las EAS más frecuentes, su afectación es indudablemente sistémica y va más allá de la sequedad, y la identificación de los principales factores pronóstico permite un seguimiento personalizado y, por tanto, un diagnóstico precoz de las principales complicaciones que permite la instauración de intervenciones terapéuticas tempranas que eviten lesiones graves e irreversibles. (AU)

In 1933, the Swedish ophthalmologist Hendrik Sjögren was the first to suggest that behind the dryness that several of his patients presented, there could be a systemic disease related to an abnormal immune response. Since then, the term Sjögren's syndrome (SjS) has been used and it has been considered a minor and infrequent disorder compared to other systemic autoimmune diseases (SAD) and, consequently, with little progress both in clinical and therapeutic research. The emergence of new technologies at the end of the 20th century rapidly promoted the development of international projects of great impact and diffusion, which have completely changed this scenario, and in the last 20 years significant progress has been made in understanding the main epidemiological determinants and pathogenic mechanisms to increase the diagnostic accuracy and to design specific and individualized therapeutic strategies. Currently, SjS should be considered one of the most frequent SADs with an undoubtedly systemic phenotype beyond dryness, in which the identification of prognostic factors can allow personalized follow-up and, therefore, early therapeutic interventions that avoid severe, irreversible outcomes. (AU)

[Sjögren syndrome]. / Síndrome de Sjögren.

In 1933, the Swedish ophthalmologist Hendrik Sjögren was the first to suggest that behind the dryness that several of his patients presented, there could be a systemic disease related to an abnormal immune response. Since then, the term Sjögren's syndrome (SjS) has been used and it has been considered a minor and infrequent disorder compared to other systemic autoimmune diseases (SAD) and, consequently, with little progress both in clinical and therapeutic research. The emergence of new technologies at the end of the 20th century rapidly promoted the development of international projects of great impact and diffusion, which have completely changed this scenario, and in the last 20 years significant progress has been made in understanding the main epidemiological determinants and pathogenic mechanisms to increase the diagnostic accuracy and to design specific and individualized therapeutic strategies. Currently, SjS should be considered one of the most frequent SADs with an undoubtedly systemic phenotype beyond dryness, in which the identification of prognostic factors can allow personalized follow-up and, therefore, early therapeutic interventions that avoid severe, irreversible outcomes.

Characterisation of the coexistence between sarcoidosis and Sjögren's syndrome. Analysis of 43 patients.

OBJECTIVES: To characterise the key epidemiological, clinical, immunological, imaging, and pathological features of the coexistence between sarcoidosis and Sjögren's syndrome (SS). METHODS: All centres included in two large multicentre registries (the Sjögren Syndrome Big Data Consortium and the Sarco-GEAS-SEMI Registry) were contacted searching for potential cases of coexistence between SS and sarcoidosis seen in daily practice. Inclusion criteria were the fulfilment of the current classification criteria both for SS (2016 ACR/EULAR) and sarcoidosis (WASOG). The following features were considered for evaluating a coexisting immunopathological scenario between the two diseases: non-caseating granulomas (NCG), focal lymphocytic sialadenitis (FLS) and positive anti-Ro antibodies. RESULTS: We identified 43 patients who fulfilled the inclusion criteria (38 women, with a mean age of 53 years at diagnosis of SS and of 52 years at diagnosis of sarcoidosis). In 28 (65%) cases, sarcoidosis was diagnosed concomitantly with SS, or during the follow-up of patients with an already diagnosed SS, while in the remaining 15 (35%), SS was diagnosed during the follow-up of an already diagnosed sarcoidosis. Patients in whom sarcoidosis was diagnosed first showed a lower mean age (43.88 vs. 55.67 years, p=0.005) and were less frequently women (73% vs. 96%, p=0.04) in comparison with those in whom sarcoidosis was diagnosed concomitantly with SS, or during the follow-up of an already diagnosed SS. We identified the following immunopathological scenarios: a combination of NCG involving extrasalivary tissues and anti-Ro antibodies in 55% of patients, a coexistence of both pathological scenarios (extrasalivary NCG and FLS in MSGB) in 42% (with positive anti-Ro antibodies in two thirds of cases), and NCG involving salivary glands and anti-Ro antibodies in 3% of cases. CONCLUSIONS: We have characterised the largest reported series of patients who fulfilled the current classification criteria for both SS and sarcoidosis. This implies that sarcoidosis (and not just the presence of isolated NCG on salivary gland biopsy) may, like other systemic autoimmune diseases, coexist with SS, and that a sarcoidosis diagnosis does not preclude the development of SS in the future.

Safety and efficacy of SARS-CoV-2 vaccination in 1237 patients with primary Sjögren syndrome.

OBJECTIVES: To investigate the safety and efficacy of SARS-Cov-2 vaccination in patients with primary Sjögren syndrome (pSS) due to scarcity of data in this population. METHODS: By the first week of May 2021, all Big Data SS Consortium centres patients who had received at least one dose of any SARS-CoV-2 vaccine were included in the study. The in-charge physician asked patients about local and systemic reactogenicity to collect SARS-CoV-2 vaccination data. RESULTS: The vaccination data of 1237 patients were received. A total of 835 patients (67%) reported any adverse events (AEs), including local (53%) and systemic (50%) AEs. Subjective symptoms (63%) were the most common local AEs, followed by objective signs at the injection site (16%), and general symptoms were the most commonly reported systemic AEs (46%), followed by musculoskeletal (25%), gastrointestinal (9%), cardiopulmonary (3%), and neurological (2%). In addition, 141 (11%) patients reported a significant worsening/exacerbation of their pre-vaccination sicca symptoms and fifteen (1.2%) patients reported active involvement in the glandular (n=7), articular (n=7), cutaneous (n=6), pulmonary (n=2), and peripheral nervous system (n=1) domains due to post-vaccination SS flares. In terms of vaccination efficacy, breakthrough SARS-CoV-2 infection was confirmed after vaccination in three (0.24 %) patients, and positive anti-SARS-Cov-2 antibodies were detected in approximately 95% of vaccinated SS patients, according to data available. CONCLUSIONS: Our data suggest that patients with pSS develop adequate humoral response and no severe AEs after SARS-CoV-2 vaccination and therefore raise no concerns about the vaccine's efficacy or safety profile in this population.

Practical diagnostic tips for the Sjögren Clinic: pearls, myths and mistakes.

More than 90 years have passed since Hendrik Sjögren began to consider that behind the dryness that several of his patients presented, there could be a systemic disease potentially linked to abnormal immune responses. For many years, the disease was mostly considered a minor syndrome compared with other systemic autoimmune diseases such as systemic lupus erythematosus (SLE), systemic sclerosis (SSc) and vasculitis, and advances in its understanding were slow and little recognised. The irruption of new technologies at the end of the 20th century rapidly promoted the development of international projects with a wide impact and diffusion. In the last 20 years, a significant improvement has been achieved in epidemiological determinants, pathogenic mechanisms, diagnostic accuracy, and a standardised therapeutic approach for patients with Sjögren's syndrome (SS). These developments have provided the tools for an early diagnosis and personalised management for most patients. However, a significant number of early myths and ongoing controversies are still making the appropriate management of SS difficult in daily clinical practice. This review provides a selection of pearls, myths, and mistakes that may serve as practical diagnostic tips for the Sjögren Clinic in four specific scenarios: defining the appropriate epidemiological background, enabling the earliest diagnostic suspicion as possible, improving the systemic characterisation of the disease, and designing an optimal follow-up of patients.

Sarcoidosis / Sarcoidosis

La sarcoidosis es una enfermedad autoinmune y sistémica que se asocia al desarrollo de granulomas no caseificantes. Afecta especialmente a los ganglios linfáticos, los pulmones, la piel y los ojos. Es una enfermedad poco frecuente pero no rara, especialmente en el norte de Europa, EE. UU. y la India. La sarcoidosis afecta más a mujeres y se diagnostica entre los 30 y los 50 años. Etiopatogénicamente está muy vinculada a factores ambientales, especialmente exposiciones laborales. Clínicamente destaca por una gran variedad de fenotipos de presentación (diagnóstico casual, afectación de un único órgano o presentación sistémica). Su diagnóstico es complejo y requiere la integración de datos clínicos, analíticos, radiológicos e histológicos en unidades clínicas multidisciplinares. La evolución es muy heterogénea y variable, así como la indicación de tratamiento, basado en los glucocorticoides en primera línea, el uso de inmunodepresores como segunda línea terapéutica y los anticuerpos anti-TNF en casos graves y/o refractarios. (AU)

Sarcoidosis is a systemic autoimmune disease that is associated with the development of non-caseating granulomas. The disease especially affects the lymph nodes, lungs, skin and eyes. It is an infrequent but not rare disease, especially in northern Europe, the United States and India. Sarcoidosis affects more women and is diagnosed between the ages of 30 and 50. Etiopathogenically, it is closely linked to environmental factors, especially occupational exposures. Clinically, it stands out for a wide variety of presentation phenotypes (casual diagnosis, involvement of a single organ or systemic presentation). The diagnosis of sarcoidosis is complex and requires the integration of clinical, analytical, radiological, and histolopathogical data carried out by multidisciplinary clinical units. The evolution of the disease is variable, as is the indication for systemic treatment, based on the use of corticosteroids as first-line option, the use of immunosuppressants as second-line therapy, and anti-TNF agents in severe and/or refractory cases. (AU)

Immune-related adverse events of cancer immunotherapies targeting kinases.

Immunotherapies are designed to target a specific molecule of the immune system and emerged at the end of the last century as effective therapies the treatment of a widening spectrum of inflammatory diseases. Paradoxically, their use was quickly linked to the development of autoimmune disorders, whose treatment indications often include the very biological agent producing the adverse event. The scenario has changed dramatically in recent years due to the increasing use of immunotherapies in patients with solid cancers (mainly checkpoint inhibitors, but also tyrosine-kinase inhibitors and others). Cancer immunotherapies are broadly defined as therapies directly or indirectly targeting any component of the immune system involved in the immune response against cancer. These therapies include different molecules (monoclonal antibodies, small proteins, fusion proteins) that target specific proteins of cancer or immune cells. A key challenge that has emerged with the progressive broad implementation of these treatments in daily practice has been the collateral side effects on the immune system of treatment, which may lead to immune-related adverse events (irAEs). The cumulated number of cases of irAEs related to cancer immunotherapies has increased exponentially during this century. As the objective of cancer immunotherapy is to stimulate the immune system, these autoimmune and inflammatory irAEs were expected. The pharmacological targeting of kinases has led to a significant change in the therapeutic management of cancer. About one-third of all protein targets under research in the pharmaceutical industry are kinase inhibitors, overwhelmingly used in the treatment of malignancies. Very few studies have reviewed the broad scenario of irAEs related to kinase inhibitors, in contrast with the large number of studies published on irAEs caused by checkpoint inhibitors, with an often-fragmented view according to the specialty. The purpose of this review is to update current knowledge on the wide pharmacological and phenotypic scenario of irAEs associated with kinase inhibitors from a multidisciplinary perspective.

Sarcoidosis. / Sarcoidosis.

Sarcoidosis is a systemic autoimmune disease that is associated with the development of non-caseating granulomas. The disease especially affects the lymph nodes, lungs, skin and eyes. It is an infrequent but not rare disease, especially in northern Europe, the United States and India. Sarcoidosis affects more women and is diagnosed between the ages of 30 and 50. Etiopathogenically, it is closely linked to environmental factors, especially occupational exposures. Clinically, it stands out for a wide variety of presentation phenotypes (casual diagnosis, involvement of a single organ or systemic presentation). The diagnosis of sarcoidosis is complex and requires the integration of clinical, analytical, radiological, and histolopathogical data carried out by multidisciplinary clinical units. The evolution of the disease is variable, as is the indication for systemic treatment, based on the use of corticosteroids as first-line option, the use of immunosuppressants as second-line therapy, and anti-TNF agents in severe and/or refractory cases.

Gene Variation at Immunomodulatory and Cell Adhesion Molecules Loci Impacts Primary Sjögren's Syndrome.

Primary Sjögren's syndrome (pSS) is an autoimmune disease triggered by a combination of environmental and host genetic factors, which results in the focal lymphocytic infiltration of exocrine glands causing eye and mouth dryness. Glandular infiltrates include T and B cell subsets positive for CD5 and/or CD6, two surface scavenger receptors involved in the fine-tuning of intracellular signals mediated by the antigen-specific receptor complex of T (TCR) and B (BCR) cells. Moreover, the epithelial cells of inflamed glands overexpress CD166/ALCAM, a CD6 ligand involved in homo and heterotypic cell adhesion interactions. All this, together with the reported association of functionally relevant single nucleotide polymorphisms (SNPs) of CD5, CD6, and CD166/ALCAM with the risk or prognosis of some immune-mediated inflammatory disorders, led us to investigate similar associations in a local cohort of patients with pSS. The logistic regression analyses of individual SNPs showed the association of CD5 rs2241002T with anti-Ro/La positivity, CD6 rs17824933C with neutropenia, and CD6 rs11230563T with increased leukopenia and neutropenia but decreased peripheral nervous system EULAR Sjögren's syndrome disease activity index (ESSDAI). Further analyses showed the association of haplotypes from CD5 (rs2241002T-rs2229177C) with anemia and thrombocytopenia, CD6 (rs17824933G-rs11230563C-rs12360861G) with cutaneous ESSDAI, and CD166/ALCAM (rs6437585C-rs579565A-rs1044243C and rs6437585C-rs579565G-rs1044243T) with disease susceptibility and several analytical parameters (anti-nuclear antibodies, neurological ESSDAI, and hematologic cytopenias). These results support the relevance of gene variation at loci coding for cell surface receptors involved in the modulation of T and B lymphocyte activation (CD5, CD6) and epithelial-immune cell adhesion (CD166/ALCAM) in modulating the clinical and analytical outcomes in patients with pSS.

Characterization and outcomes of 414 patients with primary SS who developed haematological malignancies.

OBJECTIVE: To characterize 414 patients with primary SS who developed haematological malignancies and to analyse how the main SS- and lymphoma-related features can modify the presentation patterns and outcomes. METHODS: By January 2021, the Big Data Sjögren Project Consortium database included 11 966 patients fulfilling the 2002/2016 classification criteria. Haematological malignancies diagnosed according to the World Health Organization (WHO) classification were retrospectively identified. RESULTS: There were 414 patients (355 women, mean age 57 years) with haematological malignancies (in 43, malignancy preceded at least one year the SS diagnosis). A total of 376 (91%) patients had mature B-cell malignancy, nearly half had extranodal marginal zone lymphoma (MZL) of mucosa-associated lymphoid tissue (MALT lymphoma) (n = 197), followed by diffuse large B-cell lymphoma (DLBCL) (n = 67), nodal MZL lymphoma (n = 29), chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) (n = 19) and follicular lymphoma (FL) (n = 17). Rates of complete response, relapses and death were 80%, 34% and 13%, respectively, with a 5-year survival rate of 86.5% after a mean follow-up of 8 years. There were significant differences in age at diagnosis (younger in MALT, older in CLL/SLL), predominant clinical presentation (glandular enlargement in MALT lymphoma, peripheral lymphadenopathy in nodal MZL and FL, constitutional symptoms in DLBCL, incidental diagnosis in CLL/SLL), therapeutic response (higher in MALT lymphoma, lower in DLBCL) and survival (better in MALT, nodal MZL and FL, worse in DLBCL). CONCLUSION: In the largest reported study of haematological malignancies complicating primary SS, we confirm the overwhelming predominance of B-cell lymphomas, especially MALT, with the salivary glands being the primary site of involvement. This highly-specific histopathological scenario is linked with the overall good prognosis with a 5-year survival rate of nearly 90%.

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.

Post-COVID-19 syndrome in patients with primary Sjögren's syndrome after acute SARS-CoV-2 infection.

OBJECTIVES: To analyse the frequency and characteristics of post-COVID-19 syndrome in patients with primary Sjögren's syndrome (pSS) affected by acute SARS-CoV-2 infection. METHODS: By the first week of April 2021, all centres included in the Big Data Sjögren Consortium were contacted asking for patients included in the Registry diagnosed with SARSCoV-2 infection according to the ECDC guidelines. According to the NICE definitions, symptoms related to COVID-19 were classified as acute COVID-19 (signs and symptoms for up to 4 weeks), ongoing symptomatic COVID-19 (presence of signs and symptoms from 4 to 12 weeks) and post-COVID-19 syndrome (signs and symptoms that continue for > 12 weeks not explained by an alternative diagnosis after a protocolized study). RESULTS: We identified 132 patients who were followed a mean follow-up of 137.8 days (ranging from 5 days to 388 days) after being diagnosed with COVID-19. In the last visit, 75 (57%) patients remained symptomatic: 68 (52%) remained symptomatic for more than 4 weeks fulfilling the NICE definition for ongoing symptomatic post-COVID-19, and 38 (29%) remained symptomatic for more than 12 weeks fulfilling the definition of post-COVID-19 syndrome. More than 40% of pSS patients reported the persistence of four symptoms or more, including anxiety/depression (59%), arthralgias (56%), sleep disorder (44%), fatigue (40%), anosmia (34%) and myalgias (32%). Age-sex adjusted multivariate analysis identified raised LDH levels (OR 10.36), raised CRP levels (OR 7.33), use of hydroxychloroquine (OR 3.51) and antiviral agents (OR 3.38), hospital admission (OR 8.29), mean length of hospital admission (OR 1.1) and requirement of supplemental oxygen (OR 6.94) as factors associated with a higher risk of developing post-COVID-19 syndrome. A sensitivity analysis including hospital admission in the adjusted model confirmed raised CRP levels (OR 8.6, 95% CI 1.33-104.44) and use of hydroxychloroquine (OR 2.52, 95% CI 1.00-6.47) as the key independent factors associated with an enhanced risk of developing post-COVID-19 syndrome. CONCLUSIONS: This is the first study that analyses the frequency and characteristics of post-COVID-19 syndrome in patients affected by a systemic autoimmune disease. We found that 57% of patients with pSS affected by COVID-19 remain symptomatic after a mean follow-up of 5 months. The risk of developing post-COVID-19 syndrome in patients who required hospitalisation was 8-times higher than in non-hospitalised patients, with baseline raised CRP levels and the use of hydroxychloroquine being independent risk factors for post-COVID-19.

Practical guidelines for the early diagnosis of Sjögren's syndrome in primary healthcare.

Primary care physicians can play a crucial role by recognising Sjögren's syndrome (SS) in the early stages identifying those patients with the greatest probability of being diagnosed with SS. SS has a very specific epidemiological profile at presentation (female aged 30-50 years), which may aid an early diagnosis. Although the disease may be expressed in many guises, there are three predominant clinical presentations that should be considered as key clues to increased clinical suspicion (multiple symptoms of dryness, asthenia-polyalgia syndrome and systemic organ-specific manifestations). The physical examination may provide important clues to systemic involvement (parotid gland enlargement, skin lesions suggestive of purpura or annular erythema, respiratory crackles, arthritis, neurological sensory or motor deficits). Simple laboratory studies may be very useful in reinforcing the clinical suspicion of SS, and the triad of cytopenia, raised erythrocyte sedimentation rate and high serum gamma globulin levels is a very specific "biological" pattern suggesting SS. A solid clinical suspicion of SS requires both the patient reporting sicca symptoms and objective evidence that these symptoms are associated with dysfunction of the lachrymal and salivary glands. Ultrasonography of the parotid glands, a non-invasive method, may be a major advance in the diagnostic approach to SS in primary care. Primary care physicians must be considered essential members of the multidisciplinary team in charge of the follow-up of SS patients, due to their key role in the continuum of patient care and their cross-sectional knowledge of common diseases that frequently coexist in patients with SS.