Sicca syndrome/Sjögren's disease associated with cancer immunotherapy: a narrative review on clinical presentation, biomarkers, and management.

INTRODUCTION: Almost one-quarter of immune checkpoint inhibitor (ICI) recipients experience sicca syndrome, while Sjögren's disease (SjD) is estimated at 0.3-2.5%, possibly underreported. AREAS COVERED: This narrative review (Medline/Embase until January/31/2024) addresses the pathophysiology, incidence, demographic/clinical features, biomarkers, labial salivary gland biopsy (LSGB), fulfillment of the idiopathic SjD (iSjD) classificatory criteria, differential diagnosis, and management of sicca syndrome/SjD associated with ICIs. EXPERT OPINION: SjD associated with ICIs is underdiagnosed, since studies that performed the mandatory SjD investigation identified that 40-60% of patients with sicca syndrome associated with ICIs meet the iSjD classificatory criteria. LSGB played a fundamental role in recognizing these cases, as most of them had negative anti-Ro/SS-A antibody. Despite the finding of focal lymphocytic sialoadenitis in LSGB samples mimicking iSjD, immunohistochemical analysis provided novel evidence of a distinct pattern for sicca syndrome/SjD associated with ICIs compared to iSjD. The former has scarcity of B lymphocytes, which are a hallmark of iSjD. Additionally, patients with sicca syndrome/SjD associated with ICIs have demographical/clinical/serological and treatment response dissimilarities compared to iSjD. Dryness symptoms are more acute in the former than in iSjD, with predominance of xerostomia over xerophthalmia, and partial/complete response to glucocorticoids. Dryness symptoms in ICI-treated patients warrant prompt SjD investigation.

Sjögren's Syndrome Associated With Thrombotic Thrombocytopenic Purpura: A Case-Based Review.

OBJECTIVE: To review all published cases of the rare association between thrombotic thrombocytopenic purpura (TTP) and Sjögren's syndrome (SS). The authors report an additional case of this unique association. METHODS: Systematic review of the literature and a case report. The database were articles published in PubMed/MEDLINE, Web of Science, LILACS, and SciELO, registered from 1966 to August 2020. The DESH terms were "Sjögren's syndrome" and "thrombotic thrombocytopenic purpura," without language limitation. RESULTS: Most patients were female (88%), and the age varied from 30 to 75 years old. Concerning the sequence of disease appearance, SS followed by TTP was seen in seven articles, TTP and SS in three, and simultaneous appearance of both diseases in three studies. Primary SS was observed in 16 patients, and secondary SS was detected in two cases: dermatomyositis and rheumatoid arthritis. Anemia was the most common TTP manifestation, followed by thrombocytopenia, fever, consciousness alteration, renal impairment, and schistocytes' appearance on a blood smear. Treatment involved plasmapheresis, plasma exchange, rituximab, glucocorticoid, and cyclophosphamide. A good outcome was noted in most studies; few patients died. CONCLUSIONS: TTP is a rare manifestation associated with SS. After the TTP diagnosis, plasmapheresis and/or plasma exchange should be immediately implemented.

Puntaje de tinción ocular en pacientes con diagnóstico de síndrome de Sjögren en una institución de salud en Medellín, Colombia / Ocular staining score in patients diagnosed with Sjögren syndrome in a health institution in Medellín, Colombia

RESUMEN Introducción: El síndrome de Sjögren es una enfermedad autoinmune asociada a múltiples factores, tanto genéticos como ambientales, que afecta principalmente a las glándulas salivales y lagrimales con infiltración celular de estas, lo cual causa síntomas secos. Con frecuencia se describe la queratoconjuntivitis sicca y sus complicaciones. Sus criterios clasificatorios han cambiado a lo largo de los años por la diversidad de los órganos implicados y los espectros clínicos de la enfermedad. Hoy se cuenta con parámetros clínicos y paraclínicos para su identificación; uno de estos, el puntaje de tinción ocular ocular staining score (OSS, por sus siglas en inglés), estandarizado a partir de la cohorte SICCA. Objetivo: Describir los hallazgos en la evaluación ocular, el resultado de las pruebas que hacen parte del OSS y las características clínicas de los criterios clasificatorios en pacientes con síndrome de Sjögren en el servicio de consulta externa de reumatología de un hospital universitario en el noroccidente colombiano. Método: Se condujo un estudio observacional, descriptivo y de corte transversal. Se describieron las características de los criterios clasificatorios del síndrome de Sjögren, incluyendo el puntaje de tinción ocular durante un año. Se realizaron las pruebas clínicas y tinciones oculares estandarizadas, evaluando características de la superficie ocular, producción lagrimal y tinciones con verde lisamina y fluoresceína sobre la conjuntiva y la córnea. Según los hallazgos se asignó una puntuación a cada parámetro para evaluar positividad, de acuerdo con el estándar clasificatorio. Las variables cualitativas se expresaron por medio de frecuencias absolutas y relativas y las cuantitativas como mediana y rango intercuartílico (P25-P75), según la distribución de los datos. Se empleó el paquete estadístico Epidat, versión 4.2. Resultados: Se incluyeron 28 pacientes. Los síntomas de ojo seco estuvieron presentes en el 89,2% de ellos; un 96,4% tuvo hallazgos positivos en el examen ocular y el 78,5% alcanzó un puntaje a favor de los criterios clasificatorios en la evaluación del OSS. La mediana del OSS fue 6,14; los anticuerpos anti-Ro fueron positivos en un 57,1%. Conclusión: La evaluación ocular por medio de pruebas objetivas es un método sencillo y reproducible en los pacientes con síndrome de Sjögren. Los índices más afectados fueron aquellos de disminución en la producción lagrimal. Las tinciones oculares no tuvieron una relación directa con la positivad de anticuerpos ni del factor reumatoide.

ABSTRACT Introduction: Sjögren's syndrome is an autoimmune disease associated with multiple genetic and environmental factors. It mainly affects the salivary and lacrimal glands with cellular infiltration leading to dry eye symptoms, with keratoconjunctivitis sicca and its complications often being described. Its classification criteria have changed over the years, due to the diversity in the organs involved and clinical spectrum of the disease. Today, there are clinical and para-clinical parameters for its identification. One of these is the ocular staining score (OSS), standardised from the SICCA cohort. Objective: To describe the findings in the ocular evaluation, the results of the tests of the OSS, and the clinical characteristics of the classification criteria in patients with Sjögren syndrome in the outpatient service of Rheumatology Outpatient Department a university hospital in north-western Colombia. Methods: An observational, descriptive, cross-sectional study was conducted. The characteristics of the Sjögren syndrome classification criteria were described, including the OSS score for one year. Clinical tests and standardised ocular stains were performed, evaluating characteristics of the ocular surface, tearproduction, and lissamine green and fluorescein stains on the conjunctiva and cornea, assigning, according to the findings, a score to each parameter in order to assess positivity according to the classification standard. The qualitative variables were expressed by means of absolute and relative frequencies, and the quantitative ones as the median and interquartile range (P25-P75), according to the distribution of the data. Epidat statistical package, version 4.2, was used. Results: A total of 28 patients were included. Dry eye symptoms were present in 89.2%, 96.4% had positive findings in the eye examination, and 78.5% had a score on the OSS according to the classification criteria. The median OSS was 6.14, and anti-Ro antibodies were positive in 57.1%. Conclusion: Eye evaluation by objective tests is a simple and reproducible method in patients with Sjögren's syndrome. The most affected indices were those of a decrease in tearproduction. The ocular stains did not have a direct relationship with the positivity of antibodies, nor rheumatoid factor.

Ecografía de la glándula salival mayor en pacientes con síndrome seco: descripción de una cohorte colombiana, reporte preliminar / Major salivary gland ultrasound in patients with dry syndrome: Description of a Colombian cohort, and a preliminary report

RESUMEN Introducción: El síndrome de Sjögren (SS) es una enfermedad autoinmune que afecta a las glándulas exocrinas condicionando síndrome seco. Los criterios diagnósticos se basan en pruebas serológicas, oftalmológicas, histopatológicas y flujo salival. Se ha propuesto el uso de la ecografía glandular salival como prueba diagnóstica. Escasos estudios se han realizado en Latinoamérica. Objetivo: Describir las alteraciones ecográficas en las glándulas salivales en una población colombiana que asiste al servicio de reumatología con síntomas secos. Materiales y métodos: Estudio de corte transversal; análisis preliminar de 50 pacientes que asisten por consulta externa (agosto de 2019 a enero de 2020). Evaluación sociodemográfica y clínica a través de cuestionario estructurado, pruebas paraclínicas y oftalmológicas, biopsia de glándula salival menor y valoración ecográfica de las glándulas salivales mayores (puntuación 0-6 basada en De Vita). Análisis univariado y bivariado (Chi-cuadrado y prueba de Fischer). Resultados: El 94% de la población eran mujeres y el 38% tenían SS. El promedio de edad fue de 55,9 ± 9,6 arios. La proporción de pacientes con ecografía positiva para el SS y diagnóstico por criterios del SS es mayor respecto a los pacientes con ecografía negativa (p< 0,0001). Los pacientes con ecografía positiva presentaron mayor proporción de anti-La (p = 0,002), ANA (p = 0,008), anti-Ro (p< 0,0001), linfopenia (p = 0,007), xerostomía objetiva (p = 0,019) y subjetiva (p = 0,041). Conclusiones: La ecografía podría considerarse una herramienta útil en el diagnóstico del SS, dado que los pacientes que presentan alteraciones ecográficas glandulares tienen una mayor proporción de perfil inmunológico positivo (anti-Ro, ANA, anti-La) y su positividad se encuentra asociada al SS por criterios. Se requieren nuevos estudios para evaluar las características operativas de la prueba.

ABSTRACT Introduction: Sjögren's syndrome (SS) is an autoimmune disease affecting the exocrine glands causing dry syndrome. The diagnostic criteria are based on serological, ophthalmological, histopathological, and salivary flow tests. The use of salivary gland ultrasound has been proposed as a diagnostic test. Few studies have been carried out in Latin America. Objective: To describe the ultrasound patterns in the salivary glands in the Colombian population seen in the Rheumatology Department due to dry symptoms. Materials and methods: Cross-sectional study; a preliminary analysis was performed on 50 patients attending the Outpatient Clinic (August-January 2020). A sociodemographic and clinical evaluation was made using a questionnaire. Paraclinical and ophthalmological tests, minor salivary gland biopsy, and ultrasound assessment of the major salivary glands (De Vita score 0-6) were the main items to evaluate. Univariate and bivariate analyses (Chi-squared, Fischer test) were performed. Results: Most (94%) of the population were women, and 38% had SS. The mean age was 55.9±9.6 years old. The proportion of patients with positive ultrasound for SS and a diagnosis using SS criteria was higher compared to patients with negative ultrasound (p<.0001). Patients with positive ultrasound had a higher proportion of anti-La (p=.002), ANAS (p=.008), anti-Ro (p<.0001), lymphopenia (p=.007), and objective and subjective xerostomia (p=.019 and p=.041, respectively). Conclusions: Ultrasound assessment could be considered a useful tool in the diagnosis of SS, since more patients presenting with glandular ultrasound abnormalities have a higher positive immunological profile (anti-Ro, ANAS, anti-La) and their positivity is associated with SS criteria. New studies are required to evaluate the operational characteristics of the test.

Diagnóstico diferencial dentro del espectro del síndrome de Sjögren / Differential diagnosis within the spectrum of Sjögren's syndrome

RESUMEN El síndrome de Sjögren es una enfermedad autoinmune sistémica caracterizada clínicamente por ojo y boca secos, acompañados de manifestaciones extraglandulares como edema de glándulas submandibulares y parotidomegalia. La prevalencia varía en diferentes estudios epidemiológicos del 5 al 30%, dependiendo de la población estudiada. La xeroftalmia es más común en mujeres y su frecuencia incrementa con la edad. Cuando evaluamos un paciente con síndrome de Sjögren, debemos tener en cuenta diagnósticos diferenciales que pueden simular esta patología, como causas locales, sistémicas que incluyen metabólicas, infecciosas, medicamentosas, infiltrativas y malignas. Es necesario el estudio de otras causas para decidir si la terapia dirigida puede ser benéfica y evitar riesgos de eventos adversos en pacientes con síndrome sicca no autoinmune. Se realizó una revisión narrativa sobre los diagnósticos diferenciales en el espectro de paciente con síndrome seco a través de búsqueda de la literatura en las bases de datos PubMed y Google Scholar.

ABSTRACT Sjögren's syndrome is a systemic autoimmune disease clinically characterised by dry eye and mouth accompanied by extra-glandular manifestations such as oedema of the sub-mandibular glands and parotidomegaly. The prevalence of dry eye varies from 5% to 30% in different epidemiological studies, depending on the studied population. Xerophthalmia is more common in women and its frequency increases with age. When evaluating a patient with Sjogrens syndrome, differential diagnoses with disease that can simulate this pathology must be taken into account, such as local, systemic causes that include metabolic, infectious, medicinal, infiltrative, and malignancy. The study of other causes is necessary to decide whether targeted therapy can be beneficial and avoid risks of adverse events in patients with non-autoimmune sicca syndrome. A narrative review was conducted on the differential diagnoses in the spectrum of patients with 'dry syndrome' using a literature search in the PubMed and Google Scholar databases.

Questions as regards the recognition of elderly-onset primary Sjögren's syndrome: Where we are and where we would rather be / Preguntas sobre el reconocimiento del síndrome de Sjögren primario con inicio en la edad avanzada: ¿dónde estamos y dónde preferiríamos estar?

ABSTRACT Several epidemiological studies have suggested that the prevalence of the onset of primary Sjögren's Syndrome in the elderly (EOpSS) is significantly higher (between five to eight times) than in other age groups. However, when a literature review was performed, the number of patients with EOpSS was much lower than epidemiologically expected. An evaluation was performed on Sjögren (sicca) syndrome, including immunological markers, labial salivary glands biopsy, and some extra-glandular manifestations. These could be confounding factors in the elderly patients, much more so than in other age groups, and lead to a misdiagnosis of EOpSS. This article presents a review of the most common difficulties that may be present in the recognition of EOpSS, and highlights the lack of elderly patient-centred studies as the most important unmet need.

RESUMEN Varios estudios epidemiológicos han sugerido que la prevalencia del síndrome de Sjögren primario (SSp) en la población de edad avanzada (Elderly-Onset primary Sjögren's Syndrome [EOpSS], según la clasificación inglés) es considerablemente mayor (entre 5 y 8 veces) que en grupos de edad diferente. Sin embargo, una revisión sistemática de la literatura mostró que el número de pacientes con EOpSS era mucho menor de lo que se esperaba epidemiológicamente. La evaluación del síndrome de sicca, los marcadores inmunológicos, la biopsia de las glándulas salivales labiales y algunas manifestaciones extraglandulares podrían convertirse en factores de confusión en pacientes de edad avanzada mucho más frecuentemente que en personas de otros grupos de edad, lo que favorecería un diagnóstico erróneo del EOpSS. En este artículo se revisan las principales dificultades que pueden afectar al reconocimiento del EOpSS, destacando la falta de estudios centrados en el paciente anciano como la necesidad insatisfecha más importante.

Effectiveness and safety of abatacept for the treatment of patients with primary Sjögren's syndrome.

Sjögren's syndrome is an autoimmune disease characterized by inflammation of the exocrine glands. The disease can be primary or secondary (if it is associated with another autoimmune disease). In Barring symptom management, there is no established treatment. To evaluate the effectiveness and safety of abatacept as a treatment of primary Sjögren's syndrome over the course of 24 months. Eleven patients with primary Sjögren's syndrome from the Rheumatology Department of Universidade Santo Amaro, Sao Paulo, Brazil were enrolled for a prospective observational study. Eligible participants were diagnosed according to the 2002 American-European consensus criteria and had a score greater than 3 on the EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI). Participants received intravenous abatacept for 24 months at a weight-adjusted dose of 500 mg for patients weighing < 60 kg and 750 mg for those weighing > 60 kg. The outcomes were ESSDAI activity index, non-stimulated salivary flow rate, ocular dryness (Schirmer test, tear film break-up time, and ocular staining score), SF-36 questionnaire, and Fatigue domain of the FACIT (Functional Assessment of Chronic Illness Therapy) index. There was a statistically significant reduction in ESSDAI index and improvement of salivary flow. One subscale of the SF-36 index-emotional role functioning-showed improvement. There was no change in ocular parameters or in the FACIT index. In this sample of 11 patients with primary Sjögren's syndrome, abatacept therapy improved xerostomia and systemic disease activity.Key Points• Abatacept is safe and effective for the treatment of primary Sjögren's syndrome.• Abatacept can improve salivary flow and ESSDAI index in this patient population.

Morphological alterations in minor salivary glands of HTLV1+ patients: A pilot study

BACKGROUND: Among the complex of HTLV­associated diseases, Sjögren's syndrome (SS) is one of the most controversial. This work aims to detect morphological and inflammatory alterations, including clues of the presence of HTLV­1, in minor salivary glands of patients with dryness symptoms. METHODS: We have assessed HTLV­1­seropositive patients (HTLV­1 group) and patients with SS (SS group). We used formalin­fixed, paraffin­embedded minor salivary gland tissue to evaluate the morphological aspects and, by means of immunohistochemistry, the presence of Tax protein, CD4, CD8 and CD20 cells. Additionally, viral particles and proviral load were analysed by PCR. RESULTS: The HTLV­1 group had the highest prevalence of non­specific chronic sialadenitis (85.71%; P = 0.017) and greater amount of T CD8+ cells. In the SS group, focal lymphocytic sialadenitis (80%; P = 0.017) prevailed, with a greater amount of B CD20+. Both immunohistochemistry and PCR identified the Tax protein and its gene in the salivary glands of both groups and in similar proportions. CONCLUSION: The results indicate that HTLV­1­seropositive patients have different patterns of morphological/inflammatory alterations, suggesting a likely difference in the process of immune activation

Morphological alterations in minor salivary glands of HTLV1+ patients: A pilot study.

BACKGROUND: Among the complex of HTLV-associated diseases, Sjögren's syndrome (SS) is one of the most controversial. This work aims to detect morphological and inflammatory alterations, including clues of the presence of HTLV-1, in minor salivary glands of patients with dryness symptoms. METHODS: We have assessed HTLV-1-seropositive patients (HTLV-1 group) and patients with SS (SS group). We used formalin-fixed, paraffin-embedded minor salivary gland tissue to evaluate the morphological aspects and, by means of immunohistochemistry, the presence of Tax protein, CD4, CD8 and CD20 cells. Additionally, viral particles and proviral load were analysed by PCR. RESULTS: The HTLV-1 group had the highest prevalence of non-specific chronic sialadenitis (85.71%; P = 0.017) and greater amount of T CD8+ cells. In the SS group, focal lymphocytic sialadenitis (80%; P = 0.017) prevailed, with a greater amount of B CD20+ . Both immunohistochemistry and PCR identified the Tax protein and its gene in the salivary glands of both groups and in similar proportions. CONCLUSION: The results indicate that HTLV-1-seropositive patients have different patterns of morphological/inflammatory alterations, suggesting a likely difference in the process of immune activation.

Sjögren's syndrome and sicca symptoms in patients with systemic sclerosis / Síndrome de Sjögren y síntomas de sicca en pacientes con esclerosis sistémica

Introduction: Several autoimmune diseases can be accompanied by dysfunction of the salivary glands, regardless of the presence or absence of association with Sjögren's syndrome (SS). A recent study by Maeshima and colleagues found salivary hyposecretion in 58.3% of patients with various connective tissue diseases, particularly systemic sclerosis (SSc). Objective: To determine the prevalence of SS and Sicca symptoms in patients with SSc. Assess whether the presence of SS in patients with SSc causes worsening of the disease. Methods: 69 SSc patients periodically monitored in the rheumatology clinic at NHU/UFMS composed the study. All patients were questioned about sicca symptoms and clinical features. We evaluated the RF levels, ANA, anti-Ro/La. Results and discussion: 69 SSc patients were enrolled in the study, with average age of 51.2 years, 98.3% females and 50% caucasian. Sicca symptoms were present in 48 patients (69.5%) with SSc; 43/69 patients (62.3%) with dry mouth and 46/69 patients (66.7%) with dry eye. Sicca symptoms were observed in patients with limited and diffuse form of the disease. The antinuclear antibody positivity was 95% and the rheumatoid factor (RF) was observed in 14 patients (23.3%). Anti-Ro (SSA) antibodies were detected in 11 patients (15.9%) and anti-La (SSB) in 6 patients (8.7%) in this study. Only 16 patients (23.2%) had true SS, according to the American-European Consensus Group on Classification Criteria for Sjögren's syndrome. The findings in the study corroborate data found in literature. Conclusion: This study confirms that Sicca symptoms are found in a large number of patients with SSc. Sjögren prevalence was observed in 23.2% of the SSc patients, including patients with limited and diffuse cutaneous subtype of disease. Key words: Sicca syndrome, Sjögren's syndrome, overlap, autoantibodies, systemic sclerosis

Introducción: Varias enfermedades autoinmunes pueden ir acompañadas de disfunción de las glándulas salivales, independientemente de la presencia o ausencia de asociación con el síndrome de Sjögren (SS). Un estudio reciente de Maeshima y sus colegas hallaron hiposecreción salival en el 58,3% de los pacientes con diversas enfermedades del tejido conectivo, particularmente la esclerosis sistémica (SSc). Objetivo: Determinar la prevalencia de los síntomas de SS y sicca en pacientes con SSc. Evaluar si la presencia de SS en pacientes con SSc provoca empeoramiento de la enfermedad. Métodos: 69 pacientes SSc periódicamente monitorizados en la clínica de reumatología en NHU/UFMS formaron parte del estudio. Todos los pacientes fueron interrogados acerca de síntomas sicca y características clínicas. Se evaluaron los niveles de FR, FAN, anti-Ro/La. Resultados y discusión: Se incluyeron 69 pacientes SSc en el estudio, con edad promedio de 51,2 años, 98,3% mujeres y 50% caucásicos. Los síntomas de Sicca estuvieron presentes en 48 pacientes (69,5%) con SSc; 43/69 pacientes (62,3%) con boca seca y 46/69 pacientes (66,7%) con ojo seco. Síntomas sicca se observaron en pacientes con forma limitada y difusa de la enfermedad. La positividad del anticuerpo antinuclear fue del 95% y el factor reumatoideo se observó en 14 pacientes (23,3%). Anticuerpos Anti-Ro (SSA) se detectaron en 11 pacientes (15,9%) y anti-La (SSB) en 6 pacientes (8,7%) en este estudio. Sólo 16 pacientes (23,2%) tenían verdaderas SS, según el Grupo de Consenso Americano-Europeo sobre los criterios de clasificación para el síndrome de Sjögren. Los hallazgos del estudio corroboran los datos encontrados en la literatura. Conclusión: Este estudio confirma que los síntomas sicca se encuentran en un gran número de pacientes con SSc. Se observó una prevalencia de Sjögren en el 23,2% de los pacientes con esclerodermia, incluyendo pacientes con subtipo cutáneo limitado y difuso