RESUMEN
OBJECTIVE: Tissue-resident memory cells (Trm) are a subset of T cells residing persistently and long-term within specific tissues that contribute to persistent inflammation and tissue damage. We characterised the phenotype and function of Trm and the role of CD103 in primary Sjogren's syndrome (pSS). METHODS: In both pSS and non-pSS sicca syndrome patients, we examined Trm frequency, cytokine production in salivary glands (SG) and peripheral blood (PB). We also analysed Trm-related gene expression in SG biopsies through bulk and single-cell RNA sequencing (scRNAseq). Additionally, we investigated Trm properties in an immunisation-induced animal model of pSS (experimental SS, ESS) mouse model and assessed the effects of Trm inhibition via intraglandular anti-CD103 monoclonal antibody administration. RESULTS: Transcriptomic pSS SG showed an upregulation of genes associated with tissue recruitment and long-term survival of Trm cells, confirmed by a higher frequency of CD8+CD103+CD69+ cells in pSS SG, compared with non-specific sialadenitis (nSS). In SG, CD8+ CD103+ Trm contributed to the secretion of granzyme-B and interferon-γ, CD8+ Trm cells were localised within inflammatory infiltrates, where PD1+CD8+ T cells were also increased compared with nSS and MALT lymphoma. scRNAseq of PB and pSS SG T cells confirmed expression of CD69, ITGAE, GZMB, GZMK and HLA-DRB1 among CD3+CD8+ SG T cells. In the SG of ESS, CD8+CD69+CD103+ Trm producing Granzyme B progressively expanded. However, intraglandular blockade of CD103 in ESS reduced Trm, reduced glandular damage and improved salivary flow. CONCLUSIONS: CD103+CD8+Trm cells are expanded in the SG of pSS and ESS, participate in tissue inflammation and can be therapeutically targeted.
RESUMEN
In the past 20 years, earlier diagnosis and more intensive management have considerably improved the prognosis of rheumatoid arthritis (RA), with milder disease course achieved in particular in seropositive patients. In contrast, seronegative RA has remained largely neglected, and continues to be surrounded by uncertainties regarding its correct diagnosis, clinical phenotype, optimal treatment strategies and relevant outcomes.The purpose of this review is to summarise new insights about the pathogenic, clinical and prognostic peculiarities of seronegative RA that emerged during 2022, and that make this disease subset at least partially different from its seropositive counterpart.
Asunto(s)
Artritis Reumatoide , Factor Reumatoide , Humanos , Artritis Reumatoide/diagnóstico , Artritis Reumatoide/tratamiento farmacológico , Pronóstico , Progresión de la EnfermedadRESUMEN
Gut microbiota dysbiosis serves as a potential trigger that may contribute to metabolic and immune dysregulation that underlies the development of autoimmune diseases. Fecal microbiota transplantation (FMT) is restoration of disturbed microbiota by transplanting foreign gut microbiota from healthy individuals into the gastrointestinal tract of diseased individuals. In this issue of the Journal of Autoimmunity, Huang et al. conducted a 12-week, single-arm pilot clinical trial of oral FMT capsules in patients with active SLE. No serious adverse events (AEs) or deaths were observed and the rate of the primary endpoint (SLE Responder Index-4) was 42.12%. Alternations in bacteria, metabolites and immune parameters were linked to FMT treatment and clinical response in SLE patients. This is the first FMT trial in SLE patients and provides supportive evidence that FMT appears to be a safe, feasible and potentially effective treatment modality in SLE. We await future investigations conducting larger, randomized FMT clinical trials with a longer follow-up to confirm the long-term safety, effectiveness, and potential benefits of FMT-based intervention in SLE and to further demonstrate the underlying microbiological mechanisms.
Asunto(s)
Lupus Eritematoso Sistémico , Microbiota , Disbiosis/terapia , Trasplante de Microbiota Fecal/efectos adversos , Heces/microbiología , Humanos , Lupus Eritematoso Sistémico/etiología , Lupus Eritematoso Sistémico/terapia , Resultado del TratamientoRESUMEN
The aim of this study is to explore the role of labial minor salivary gland (LMSG) focus score (FS) in stratifying Sjögren's Syndrome (SS) patients, lymphoma development prediction and to facilitate early lymphoma diagnosis. Ιn an integrated cohort of 1997 patients, 618 patients with FS ≥ 1 and at least one-year elapsing time interval from SS diagnosis to lymphoma diagnosis or last follow up were identified. Clinical, laboratory and serological features were recorded. A data driven logistic regression model was applied to identify independent lymphoma associated risk factors. Furthermore, a FS threshold maximizing the difference of time interval from SS until lymphoma diagnosis between high and low FS lymphoma subgroups was investigated, to develop a follow up strategy for early lymphoma diagnosis. Of the 618 patients, 560 were non-lymphoma SS patients while the other 58 had SS and lymphoma. FS, cryoglobulinemia and salivary gland enlargement (SGE) were proven to be independent lymphoma associated risk factors. Lymphoma patients with FS ≥ 4 had a statistically significant shorter time interval from SS to lymphoma diagnosis, compared to those with FS < 4 (4 vs 9 years, respectively, p = 0,008). SS patients with FS ≥ 4 had more frequently B cell originated manifestations and lymphoma, while in patients with FS < 4, autoimmune thyroiditis was more prevalent. In the latter group SGE was the only lymphoma independent risk factor. A second LMSG biopsy is patients with a FS ≥ 4, 4 years after SS diagnosis and in those with FS < 4 and a history of SGE, at 9-years, may contribute to an early lymphoma diagnosis. Based on our results we conclude that LMSG FS, evaluated at the time of SS diagnosis, is an independent lymphoma associated risk factor and may serve as a predictive biomarker for the early diagnosis of SS-associated lymphomas.
Asunto(s)
Crioglobulinemia/epidemiología , Linfoma de Células B de la Zona Marginal/diagnóstico , Glándulas Salivales Menores/patología , Síndrome de Sjögren/complicaciones , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Biopsia , Crioglobulinemia/sangre , Crioglobulinemia/diagnóstico , Crioglobulinemia/inmunología , Detección Precoz del Cáncer/métodos , Femenino , Estudios de Seguimiento , Humanos , Linfoma de Células B de la Zona Marginal/sangre , Linfoma de Células B de la Zona Marginal/inmunología , Masculino , Persona de Mediana Edad , Medición de Riesgo/métodos , Factores de Riesgo , Glándulas Salivales Menores/inmunología , Síndrome de Sjögren/sangre , Síndrome de Sjögren/inmunología , Síndrome de Sjögren/patología , Factores de Tiempo , Adulto JovenRESUMEN
OBJECTIVES: To characterize the phenotypic presentation at diagnosis of childhood-onset primary SS. METHODS: The Big Data Sjögren Project Consortium is an international, multicentre registry using worldwide data-sharing cooperative merging of pre-existing clinical SS databases from the five continents. For this study, we selected those patients in whom the disease was diagnosed below the age of 19 years according to the fulfilment of the 2002/2016 classification criteria. RESULTS: Among the 12 083 patients included in the Sjögren Big Data Registry, 158 (1.3%) patients had a childhood-onset diagnosis (136 girls, mean age of 14.2 years): 126 (80%) reported dry mouth, 111 (70%) dry eyes, 52 (33%) parotid enlargement, 118/122 (97%) positive minor salivary gland biopsy and 60/64 (94%) abnormal salivary US study, 140/155 (90%) positive ANA, 138/156 (89%) anti-Ro/La antibodies and 86/142 (68%) positive RF. The systemic EULAR Sjögren's syndrome disease activity index (ESSDAI) domains containing the highest frequencies of active patients included the glandular (47%), articular (26%) and lymphadenopathy (25%) domains. Patients with childhood-onset primary SS showed the highest mean ESSDAI score and the highest frequencies of systemic disease in 5 (constitutional, lymphadenopathy, glandular, cutaneous and haematological) of the 12 ESSDAI domains, and the lowest frequencies in 4 (articular, pulmonary, peripheral nerve and CNS) in comparison with patients with adult-onset disease. CONCLUSIONS: Childhood-onset primary SS involves around 1% of patients with primary SS, with a clinical phenotype dominated by sicca features, parotid enlargement and systemic disease. Age at diagnosis plays a key role in modulating the phenotypic expression of the disease.
Asunto(s)
Índice de Severidad de la Enfermedad , Síndrome de Sjögren/patología , Adolescente , Edad de Inicio , Femenino , Humanos , Masculino , Glándula Parótida/patología , Fenotipo , Sistema de Registros , Síndrome de Sjögren/diagnósticoRESUMEN
Genetic variants of the three-prime repair exonuclease 1 (TREX1) -an exonuclease involved in DNA repair and degradation- have been previously found to increase susceptibility to Aicardi Goutieres syndrome, familial chilblain lupus and systemic lupus erythematosus. We aimed to explore whether TREX1 common variants could influence the risk of primary Sjogren's syndrome (SS) and SS-related lymphoma. Three single nucleotide polymorphisms (SNPs) of the TREX1 gene (rs11797, rs3135941 and rs3135945) were evaluated in 229 SS, 89 SS-lymphoma (70 SS-MALT and 19 SS non-MALT) and 240 healthy controls by PCR-based assays. In available 52 peripheral blood and 26 minor salivary gland tissues from our SS cohort, mRNA expression of type I interferon (IFN) related genes and TREX1 was determined by real-time PCR. Significantly decreased prevalence of rs11797 A minor allele was detected in SS patients complicated by non-MALT lymphoma compared to controls (ΟR [95% CI]: 0.4 [0.2-0.9], p-value: 0.02). SS patients carrying the rs11797 AA genotype had increased type I IFN related gene mRNA expression in minor salivary gland tissues. These data support genetically related dampened type I IFN production as an additional mechanism for SS-related lymphomagenesis.
Asunto(s)
Exodesoxirribonucleasas/genética , Linfoma/genética , Fosfoproteínas/genética , Síndrome de Sjögren/genética , Anciano , Estudios de Casos y Controles , Exodesoxirribonucleasas/metabolismo , Femenino , Frecuencia de los Genes , Genotipo , Humanos , Interferón Tipo I/fisiología , Linfoma de Células B de la Zona Marginal/genética , Masculino , Persona de Mediana Edad , Fosfoproteínas/metabolismo , Polimorfismo de Nucleótido Simple , ARN Mensajero/metabolismo , Glándulas Salivales/metabolismo , Síndrome de Sjögren/complicaciones , Síndrome de Sjögren/diagnóstico , Síndrome de Sjögren/enzimologíaRESUMEN
OBJECTIVES: Thymic stromal lymphopoietin (TSLP) has been implicated in primary Sjögren's syndrome (pSS) and related B-cell lymphoproliferation and lymphoma (NHL) by studies on salivary pathologic tissues and serum. The purpose of this work was to validate serum TSLP as biomarker of pSS and related lymphoproliferation by the study of two additional independent cohorts. METHODS: Serum TSLP was measured by ELISA in the original published Cohort-1 from Udine, Italy, including 91 patients. Two additional cohorts were then studied for validation: Cohort-2, including 4 sub-cohorts comprising 125 patients from the Universities of Roma, L'Aquila, Pisa and Perugia, belonging to the Italian SS Study Group (GRISS), and Cohort-3, including 59 patients from the University of Athens, Greece. Overall, 159 control subjects were enrolled. Active pSS-NHL, as well as pre-lymphomatous conditions, i.e. persistent salivary gland swelling and mixed cryoglobulinaemia, were investigated in detail. In addition, serum samples from pSS-NHL in complete remission were analysed (n=27). RESULTS: TSLP serum levels were confirmed to be significantly higher in pSS compared to controls in both Cohort-2 and Cohort-3, in particular in patients with lymphoproliferation. Serum TSLP was much higher in pSS pre-lymphomatous conditions. Finally, active NHL showed the highest TSLP serum levels, while in NHL in remission TSLP resulted undetectable or significantly lower than in benign pSS. CONCLUSIONS: By the study of independent cohorts, it was again demonstrated that serum TSLP levels are increased in pSS, above all in more advanced B-cell lymphoproliferation and NHL. Serum TSLP can therefore represent a novel biomarker for pSS-related lymphoproliferation.
Asunto(s)
Síndrome de Sjögren , Biomarcadores , Citocinas , Grecia , Humanos , Italia , Síndrome de Sjögren/diagnóstico , Linfopoyetina del Estroma TímicoRESUMEN
OBJECTIVES: To evaluate the systemic phenotype associated with the presence of isolated anti-La/SSB antibodies in a large international registry of patients with primary Sjögren's syndrome (pSS) fulfilling the 2002 classification criteria. METHODS: The Big Data Sjögren Project Consortium is an international, multicentre registry created in 2014. Baseline clinical information from leading centres on clinical research in SS of the 5 continents was collected. Combination patterns of anti-Ro/SSA-La/SSB antibodies at the time of diagnosis defined the following four immunological phenotypes: double positive (combined Ro/SSA and La/SSB,) isolated anti-Ro/SSA, isolated anti-La/SSB, and immunonegative. RESULTS: The cohort included 12,084 patients (11,293 females, mean 52.4 years) with recorded ESSDAI scores available. Among them, 279 (2.3%) had isolated anti-La/SSB antibodies. The mean total ESSDAI score at diagnosis of patients with pSS carrying isolated anti-La/SSB was 6.0, and 80.4% of patients had systemic activity (global ESSDAI score ≥1) at diagnosis. The domains with the highest frequency of active patients were the biological (42.8%), glandular (36.8%) and articular (31.2%) domains. Patients with isolated anti-La/SSB showed a higher frequency of active patients in all ESSDAI domains but two (articular and peripheral nerve) in comparison with immune-negative patients, and even a higher absolute frequency in six clinical ESSDAI domains in comparison with patients with isolated anti-Ro/SSA. In addition, patients with isolated anti-La/SSB showed a higher frequency of active patients in two ESSDAI domains (pulmonary and glandular) with respect to the most active immunological subset (double-positive antibodies). Meanwhile, systemic activity detected in patients with isolated anti-La/SSB was overwhelmingly low. Even in ESSDAI domains where patients with isolated anti-La/SSB had the highest frequencies of systemic activity (lymphadenopathy and muscular), the percentage of patients with moderate or high activity was lower in comparison with the combined Ro/SSA and La/SSB group. CONCLUSIONS: Patients carrying isolated La/SSB antibodies represent a very small subset of patients with a systemic SS phenotype characterised by a significant frequency of active patients in most clinical ESSDAI domains but with a relative low frequency of the highest severe organ-specific involvements. Primary SS still remains the best clinical diagnosis for this subset of patients.
Asunto(s)
Síndrome de Sjögren , Estudios de Cohortes , Femenino , Humanos , Fenotipo , Sistema de Registros , Síndrome de Sjögren/diagnósticoRESUMEN
Introduction: Primary Sjögren's syndrome (pSS) is an autoimmune systemic disease characterized by a complex and not yet completely elucidated etiopathogenesis, where autoimmune manifestations coexist with different degree of lymphoproliferation, resulting in multiple possible scenarios extremely heterogeneous from patient to patient. Although considerable progress has been made in the identifications of potential novel therapeutic targets in recent years, the biological complexity of pSS, combined to such heterogeneous clinical manifestations, makes the treatment of pSS, even today, a great challenge. Areas covered: A therapy specifically approved for pSS is still lacking. In recent years, several novel promising agents are being tested in pSS. Based on a deep revision of drugs evaluated for pSS therapy, it is striking that several clinical trials, some of them testing very promising agents, failed. Expert opinion: a renewal of clinical trial design, including the definition of novel inclusion criteria and outcome measures, together with the development of a stratification model of pSS patients and the advance in the definition of pathogenetic mechanisms underlying peculiar pSS subsets, represent preliminary and crucial steps to overcome the current therapeutic impasse in pSS.
Asunto(s)
Antirreumáticos/uso terapéutico , Diseño de Fármacos , Inmunosupresores/uso terapéutico , Síndrome de Sjögren/tratamiento farmacológico , Abatacept/uso terapéutico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Ensayos Clínicos como Asunto , Femenino , Humanos , Hidroxicloroquina/uso terapéutico , Masculino , Persona de Mediana Edad , Rituximab/uso terapéutico , Síndrome de Sjögren/epidemiología , Síndrome de Sjögren/inmunologíaRESUMEN
Primary Sjögren's syndrome (pSS) is an autoimmune connective tissue disease characterised by an enhanced lymphoproliferative status, with a greater risk of hesitating in malignant lymphoma. The pathological hallmark of pSS is the mucosa-associated lymphoid tissue (MALT) arising in chronically inflamed tissues, mainly in salivary glands (SG), where inflammation, autoimmunity and lymphoproliferation coexist. In the microenvironment of MALT, the B lymphocyte activating factor (BAFF or BLys) is one of the main actors contributing to B cell survival and hyperactivity in pSS. Due to such a lymphoproliferative background, targeting directly and/or indirectly B lymphocytes has become a cornerstone of developing therapeutic strategies for pSS. The simultaneous and direct targeting of the BAFF axis and of B cells represents a promising new treatment approach for pSS and other immune-mediated diseases, but only investigational at present. Immunobiological evidences support a sequential scheme of administration with belimumab preceding rituximab, aiming to firstly target the microenvironmental BAFF to improve the success of the subsequent depleting treatment in the MALT pathologic tissue with rituximab. In a real pSS case, the sequential therapy with belimumab alone followed by rituximab alone successfully led to a long-term clinical remission of lymphoma and cryoglobulinaemic vasculitis, together with the persistent normalization of B cell hyperactivity and the disappearance of persistent SG swelling and cryoglobulinaemia, which are strong predictors of lymphoma in pSS. Hopefully, further trials will assess if improvement in B-cell targeting will lead to the decrease in SG lymphoid infiltrate as well as to a possible reduction of lymphoma development in pSS.
Asunto(s)
Factor Activador de Células B , Síndrome de Sjögren , Linfocitos B , Humanos , Rituximab , Glándulas Salivales , Síndrome de Sjögren/inmunología , Síndrome de Sjögren/metabolismoRESUMEN
OBJECTIVES: To investigate the expression of thymic stromal lymphopoietin (TSLP) in primary Sjögren's syndrome (pSS), stratified according to the lymphoproliferative status, from a fully benign (fbSS) stage to myoepithelial sialadenitis (MESA) and to B-cell non-Hodgkin's lymphoma (NHL). METHODS: After initial serum studies in large numbers of pSS patients and in controls, TSLP was investigated also in pathologic salivary glands (SG) biopsies from 38 stratified pSS patients (13 fbSS; 13 MESA; 12 NHL) and from 13 controls with non-autoimmune sicca syndrome (nSS) by RT-PCR, immunohistochemistry and immunofluorescence. RESULTS: Significantly higher TSLP serum levels were shown in pSS than controls, increasing from fbSS to MESA and to NHL. In SG biopsies, TSLP-positive B lymphocytes increased with increasing lymphoproliferation, maximally in NHL, consistent with the detection of inducible TSLP long isoform (lfTSLP) mRNA only in MESA and NHL. By contrast, the constitutive TSLP short isoform (sfTSLP) mRNA showed no difference among subgroups. The TSLP expression by glandular epithelium declined with the progression from fbSS to MESA and to NHL. CONCLUSIONS: TSLP progressively increases from benign to malignant B-cell lymphoproliferation in pSS. The salivary epithelium expresses TSLP but, with the progression of lymphoproliferation, the B-cells may represent the major source of TSLP, in its long inducible isoform. A possible pathogenetic role of TSLP is herein hypothesised in pSS for the first time. Further analyses on TSLP, also as a biomarker of pSS and related lymphoproliferation, are worthwhile.
Asunto(s)
Citocinas/metabolismo , Linfoma de Células B , Sialadenitis , Síndrome de Sjögren , Humanos , Linfoma de Células B/inmunología , Linfoma de Células B/metabolismo , Síndrome de Sjögren/inmunología , Síndrome de Sjögren/metabolismo , Linfopoyetina del Estroma TímicoRESUMEN
OBJECTIVES: In primary Sjögren's syndrome (pSS) dryness of eye and mouth is the cardinal referred symptom. Assessing the rate of activity and damage in the salivary glands of pSS patients is essential to improve disease management. Up to now, a differentiation of activity and damage ultrasonographic (US) lesions is an open issue. The aim of this preliminary study was to identify US lesions which better correlate with loss of function of salivary glands in pSS. METHODS: Salivary glands ultrasonography of consecutive patients with established pSS, fulfilling AECG and ACR/EULAR criteria was performed. The association between sialometry and Visual Analogue Scale (VAS) oral dryness and SGUS lesions was assessed trough univariate and multivariate analysis. RESULTS: In 75 established pSS patients, mean disease duration 12.4±7.2 years, the hyperechoic bands of parotid gland (PG) and submandibular gland (SMG) were significantly associated with sialometry (p<0.001) and VAS oral dryness (PG p=0.002, SMG p<0.001). The global glandular involvement (scored according to De Vita et al., 1992) was associated with sialometry (PG p=0.025, SMG p<0.001) and with VAS oral sicca (PG p=0.015, SMG p<0.001). The multivariate analysis selected the hyperechoic bands of PG and SMG as the variables independently associated with sialometry and the hyperechoic bands and the homogeneity in the SMG as associated with VAS oral dryness. CONCLUSIONS: These results indicate that salivary impairment in pSS, as objectively evaluated by sialometry, could be mainly associated with damage (i.e., hyperechoic bands) in established pSS. Additional follow-up studies and improved scoring tools are needed.
Asunto(s)
Glándula Parótida/diagnóstico por imagen , Glándulas Salivales/diagnóstico por imagen , Síndrome de Sjögren , Ultrasonografía/métodos , Humanos , Síndrome de Sjögren/diagnóstico por imagen , Glándula Submandibular/diagnóstico por imagenRESUMEN
OBJECTIVES: To address the need for automatically assessing the quality of clinical data in terms of accuracy, relevance, conformity, and completeness, through the concise development and application of an automated method which is able to automatically detect problematic fields and match clinical terms under a specific domain. METHODS: The proposed methodology involves the automated construction of three diagnostic reports that summarise valuable information regarding the types and ranges of each term in the dataset, along with the detected outliers, inconsistencies, and missing values, followed by a set of clinically relevant terms based on a reference model which serves as a set of terms which describes the domain knowledge of a disease of interest. RESULTS: A case study was conducted using anonymised data from 250 patients who were diagnosed with primary Sjögren's syndrome (pSS), yielding reliable outcomes that were highlighted for clinical evaluation. Our method was able to successfully identify 28 features with detected outliers, and unknown data types, as well as, identify outliers, missing values, similar terms, and inconsistencies within the dataset. The data standardisation method was able to match 76 out of 85 (89.41%) pSS-related terms according to a standard pSS reference model which has been introduced by the clinicians. CONCLUSIONS: Our results confirm the clinical value of the data curation method towards the improvement of the dataset quality through the precise identification of outliers, missing values, inconsistencies, and similar terms, as well as, through the automated detection of pSS-related relevant terms towards data standardisation.
Asunto(s)
Curaduría de Datos , Síndrome de Sjögren , Exactitud de los Datos , HumanosRESUMEN
OBJECTIVES: To investigate if indicators of a heavier involvement of mucosa-associated lymphoid tissue (MALT) in primary Sjögren's syndrome (pSS), i.e. persistent salivary gland (SG) swelling and cryoglobulinaemia, might better evaluate the lymphoma risk compared to the ESSDAI. Therefore, the current concept of disease activity of pSS should be re-evaluated, based solely on ESSDAI. METHODS: A cohort of 255 pSS patients, including 30 pSS with B-cell lymphoma, was investigated. Three subgroups were distinguished, i.e. pSS developing lymphoma in the follow-up (n=12), pSS with lymphoma at cohort inclusion (n=18), and control pSS not developing lymphoma in the follow-up (n=225). SG swelling, cryoglobulinaemia and ESSDAI were evaluated at baseline, in the follow-up to one year before lymphoma diagnosis, and at lymphoma diagnosis. RESULTS: SG swelling and/or cryoglobulinaemia at baseline were significantly higher (p=0.0003) in pSS patients evolving into lymphoma if compared to pSS controls, while ESSDAI showed no significant difference. Both SG swelling and cryoglobulinaemia persisted and sometimes developed ex novo in the follow-up. SG swelling and cryoglobulinaemia were present in 24/30 (80%) cases the time of lymphoma diagnosis, and lymphoma itself was usually of MALT/marginal zone histotype (90%), leading to peculiar manifestation of lymphoma in pSS. CONCLUSIONS: The autoimmune and lymphoproliferative involvement of MALT is the biological substrate of pSS. If this involvement is heavier, as reflected by SG swelling and cryoglobulinaemia, disease activity may be considered higher, and the risk of lymphoma is increased. The current concept and evaluation of activity of pSS, based solely on the ESSDAI, needs revision.
Asunto(s)
Crioglobulinemia/etiología , Técnicas de Apoyo para la Decisión , Tejido Linfoide/patología , Linfoma de Células B de la Zona Marginal/etiología , Neoplasias de las Glándulas Salivales/etiología , Glándulas Salivales/patología , Síndrome de Sjögren/complicaciones , Adulto , Anciano , Estudios de Casos y Controles , Proliferación Celular , Crioglobulinemia/inmunología , Crioglobulinemia/patología , Progresión de la Enfermedad , Femenino , Humanos , Tejido Linfoide/inmunología , Linfoma de Células B de la Zona Marginal/inmunología , Linfoma de Células B de la Zona Marginal/patología , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Pronóstico , Estudios Prospectivos , Medición de Riesgo , Factores de Riesgo , Neoplasias de las Glándulas Salivales/inmunología , Neoplasias de las Glándulas Salivales/patología , Glándulas Salivales/inmunología , Índice de Severidad de la Enfermedad , Síndrome de Sjögren/inmunología , Síndrome de Sjögren/patologíaRESUMEN
OBJECTIVES: Belimumab, a monoclonal anti-B lymphocyte Stimulator (BLyS) antibody, appeared effective in Sjögren's syndrome (SS) in the phase II open-label 52-week BELISS study. Herein, the follow-up after the end of the BELISS study and suspension of the drug was reported in order to further verify the efficacy of belimumab in SS. METHODS: 13 SS patients were followed after the end of the belimumab treatment. The patients were all female, aged 54±15 years; all the patients presented anti-SSA and/or anti-SSB positivity. Composite scores for SS disease activity were collected at month 6 and month 12 after the end of the trial. The changes of IgG, IgA, IgM immunoglobulin serum levels, and rheumatoid factor (RF) level were reported. BLyS serum levels were also analysed. Statistics for paired comparisons were used. RESULTS: ESSDAI score increased from 3.5±3.7 at week 52 (end of the trial) to 7.0±5.7 at month 12 after the end of the trial (p=0.003). RF level increased from 31.0 (8.0-224.6) IU/ml at week 52 to 69 (11-666) IU/ml at month 12 after the end of the trial (p=0.008). IgM level increased from 131.9±73.6 mg/dl at week 52 to 165±84.6 mg/dl at month 12 after the end of the trial (p=0.04). A significant increase of serum BLyS levels also increased from 1304 (667-3835) pg/ml at week 52 to 2882 (1353-6178) pg/ml twelve months after belimumab suspension (p=0,04). CONCLUSIONS: Targeting BLyS by belimumab appears effective in SS, with the inhibition of RF-positive B cell proliferation.
Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Factor Activador de Células B/antagonistas & inhibidores , Factor Reumatoide/sangre , Síndrome de Sjögren/tratamiento farmacológico , Adulto , Anciano , Femenino , Estudios de Seguimiento , Humanos , Inmunoglobulina M/sangre , Persona de Mediana Edad , Síndrome de Sjögren/inmunologíaRESUMEN
OBJECTIVE: To report the efficacy and safety of long-term treatment of SS with belimumab, targeting the B-cell-activating factor. METHODS: Patients with primary SS were included in the BELISS open-label phase II study, a 1-year open-label trial, if they were positive for anti-SSA or anti-SSB antibodies and had systemic complications or persistent salivary gland enlargement or early disease or biomarkers of B-cell activation. They received belimumab, 10 mg/kg i.v., at weeks 0, 2 and 4 and then every 4 weeks; if response was observed at week 28, or if the clinician and the patient agreed to continue the study in the absence of side effects, treatment was continued for 1 year. Efficacy and safety were analysed during the 1-year period of treatment. RESULTS: Among the 30 patients recruited, 28 were evaluated at week 28 as already reported. Nineteen terminated the 52-week study, 15 of them being responders and 4 non-responders at week 28. Thirteen of the 15 responders at week 28 also responded at week 52 (86.7%). The improvement in the EULAR Sjögren's Syndrome Disease Activity Index and EULAR Sjögren's Syndrome Patient Reported Index scores observed at week 28 showed a trend to further improvement at week 52, and the amelioration of peculiar EULAR Sjögren's Syndrome Disease Activity Index domains (glandular, lymphadenopathy, articular) appeared of particular relevance. The decrease in biomarkers of B-cell activation observed at week 28 persisted unchanged until week 52, with RF decreasing further. Salivary flow, Schirmer's test and the focus score of salivary biopsy did not change. Safety of treatment was good. CONCLUSION: Long-term treatment with belimumab may be beneficial in SS. Randomized, double-blind, controlled studies in larger populations are encouraged.
Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Antirreumáticos/uso terapéutico , Inmunosupresores/uso terapéutico , Síndrome de Sjögren/tratamiento farmacológico , Adulto , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/efectos adversos , Antirreumáticos/administración & dosificación , Antirreumáticos/efectos adversos , Esquema de Medicación , Femenino , Humanos , Inmunosupresores/administración & dosificación , Inmunosupresores/efectos adversos , Masculino , Persona de Mediana Edad , Psicometría , Calidad de Vida , Índice de Severidad de la Enfermedad , Resultado del TratamientoRESUMEN
Sjögren's disease is a clinically and pathophysiologically heterogeneous disease to which precision medicine, on the basis of clinical and biological heterogeneity, has been not always applicable. In patients with Sjögren's disease, the relationship between dysregulated biological pathways and symptoms such as fatigue and pain or clinical manifestations is often difficult to establish. This clinical and biological dissociation also poses challenges when defining appropriate clinical endpoints for clinical trials. In the last few years, however, research efforts have been focused on gaining a better understanding of the considerable heterogeneity of Sjögren's disease by developing stratification models aimed at clustering patients with this condition into homogenous subgroups characterised by distinctive molecular signatures, biomarkers, clinical features, and outcomes. In this Review, we discuss current evidence regarding clinical, laboratory, histological, and biomolecular stratification in Sjögren's disease and examine how available stratification data can guide precision medicine and inform the design of future clinical trials.
RESUMEN
Spondyloarthritis (SpA), rheumatoid arthritis (RA), and inflammatory bowel diseases (IBD) are chronic inflammatory autoimmune diseases that are associated with alterations in the composition of the intestinal microbiota (i.e., dysbiosis). For SpA and RA, a gut-joint-enthesis axis is hypothesized and recent data suggests that dysbiosis may contribute directly to initiating and perpetuating joint and spine inflammation. Biologic drugs targeting tumor necrosis factor (TNF) are effective in treating these diseases and have been shown to partially restore the disrupted microbiome. Hence, drugs that affect both the intestinal and joint components of these diseases, such as anti-TNF drugs, may act on the intestinal microbiome. However, despite the remarkable efficacy of anti-TNF-α treatments, non-responders are frequent, and predictors of patient outcomes have not been identified. In this narrative review, we summarize recent research on the downstream effects of anti-TNF drugs on the intestinal microbiota in SpA, RA, and IBD. We also discuss whether these changes could have a role as predictive biomarkers of anti-TNF response.
RESUMEN
Inflammatory rheumatic diseases are different pathologic conditions associated with a deregulated immune response, codified along a spectrum of disorders, with autoinflammatory and autoimmune diseases as two-end phenotypes of this continuum. Despite pathogenic differences, inflammatory rheumatic diseases are commonly managed with a limited number of immunosuppressive drugs, sometimes with partial evidence or transferring physicians' knowledge in different patients. In addition, several randomized clinical trials, enrolling these patients, did not meet the primary pre-established outcomes and these findings could be linked to the underlying molecular diversities along the spectrum of inflammatory rheumatic disorders. In fact, the resulting patient heterogeneity may be driven by differences in underlying molecular pathology also resulting in variable responses to immunosuppressive drugs. Thus, the identification of different clinical subsets may possibly overcome the major obstacles that limit the development more effective therapeutic strategies for these patients with inflammatory rheumatic diseases. This clinical heterogeneity could require a diverse therapeutic management to improve patient outcomes and increase the frequency of clinical remission. Therefore, the importance of better patient stratification and characterization is increasingly pointed out according to the precision medicine principles, also suggesting a new approach for disease treatment. In fact, based on a better proposed patient profiling, clinicians could more appropriately balance the therapeutic management. On these bases, we synthetized and discussed the available literature about the patient profiling in regard to therapy in the context of inflammatory rheumatic diseases, mainly focusing on randomized clinical trials. We provided an overview of the importance of a better stratification and characterization of the clinical heterogeneity of patients with inflammatory rheumatic diseases identifying this point as crucial in improving the management of these patients.