Diffuse Gastrointestinal Motor Compromise in Patients with Scleroderma: Utility of Minimally Invasive Techniques.

BACKGROUND: Scleroderma is a systemic inflammatory disorder that can compromise the gastrointestinal tract in up to 90% of patients. AIM: The purpose of this work is to characterize esophageal, gastric, and intestinal compromise in patients with scleroderma by means of minimally invasive methods and its association with symptoms and severity of their rheumatological condition. METHODS: Patients with systemic sclerosis were recruited according to the criteria of the American College of Rheumatology. The study of digestive involvement was carried out on four consecutive days: esophageal manometry was performed on the first day, intestinal manometry on the second day, surface electrogastrography on the third, and hydrogen breath test on the fourth. The Mann-Whitney test was used for quantitative variables and the chi-squared test for categorical variables (p < 0.05). RESULTS: A total of 30 patients were included, with an average age of 52.7 years and 93% women. Average disease evolution duration was 6.5 years, 70% with limited variety. Rodnan averaged 12 points, being higher in the diffuse variety. The main symptom was heartburn, followed by abdominal distension, with no differences between subtypes except for diffuse nausea; 80% had intestinal manometric compromise, 76% esophageal manometric compromise, and 30% electrogastrographic compromise. Bacterial overgrowth was evidenced in two-thirds (66%) of the patients, and 23% of the patients had simultaneous esophageal, gastric, and intestinal involvement, which correlated with greater skin involvement but not with gastrointestinal symptoms. CONCLUSIONS: Gastrointestinal involvement in patients with scleroderma is frequent and is observed regardless of the symptoms and clinical characteristics of the latter, except for skin involvement.

TNF-α Affects Signature Cytokines of Th1 and Th17 T Cell Subsets through Differential Actions on TNFR1 and TNFR2.

Tumor necrosis factor (TNF)-α is a pleiotropic cytokine implicated in the etiology of several autoimmune diseases, including rheumatoid arthritis (RA). TNF-α regulates diverse effector functions through the activation of TNF-α receptor (TNFR)1 and TNFR2. Although the detrimental role of this cytokine has been addressed in distinct disease settings, the effects of TNF-α on cytokine production by isolated CD4+ T helper type 1 (Th1) and Th17 cells, two T cell subpopulations that contribute to the pathogenesis of RA, have not been completely elucidated. Here, we show that TNF-α promotes a reduction and expansion in the frequency of both T cell subsets producing IFN-γ and IL-17, respectively. Selective blockade of TNFR1 or TNFR2 on Th1 and Th17 cells revealed that TNFR2 mediates the decrease in IFN-γ production, while signaling through both receptors augments IL-17 production. We also demonstrate that Th1, but not Th17 cells from RA patients present lower levels of TNFR1 compared to healthy controls, whereas TNFR2 expression on both T cell types is similar between patients and controls. Since TNF-α receptors levels in RA patients are not significantly changed by the therapeutic blockade of TNF-α, we propose that targeting TNFR2 may represent an alternative strategy to normalize the levels of key cytokines that contribute to RA pathogenesis.

Isolation of HLA-DR-naturally presented peptides identifies T-cell epitopes for rheumatoid arthritis.

OBJECTIVE: Rheumatoid arthritis (RA) immunopathogenesis revolves around the presentation of poorly characterised self-peptides by human leucocyte antigen (HLA)-class II molecules on the surface of antigen-presenting cells to autoreactive CD4 +T cells. Here, we analysed the HLA-DR-associated peptidome of synovial tissue (ST) and of dendritic cells (DCs) pulsed with synovial fluid (SF) or ST, to identify potential T-cell epitopes for RA. METHODS: HLA-DR/peptide complexes were isolated from RA ST samples (n=3) and monocyte-derived DCs, generated from healthy donors carrying RA-associated shared epitope positive HLA-DR molecules and pulsed with RA SF (n=7) or ST (n=2). Peptide sequencing was performed by high-resolution mass spectrometry. The immunostimulatory capacity of selected peptides was evaluated on peripheral blood mononuclear cells from patients with RA (n=29) and healthy subjects (n=12) by flow cytometry. RESULTS: We identified between 103 and 888 HLA-DR-naturally presented peptides per sample. We selected 37 native and six citrullinated (cit)-peptides for stimulation assays. Six of these peptides increased the expression of CD40L on CD4 +T cells patients with RA, and specifically triggered IFN-γ expression on RA CD4 +T cells compared with healthy subjects. Finally, the frequency of IFN-γ-producing CD4 +T cells specific for a myeloperoxidase-derived peptide showed a positive correlation with disease activity. CONCLUSIONS: We significantly expanded the peptide repertoire presented by HLA-DR molecules in a physiologically relevant context, identifying six new epitopes recognised by CD4 +T cells from patients with RA. This information is important for a better understanding of the disease immunopathology, as well as for designing tolerising antigen-specific immunotherapies.

Immunosuppressive Mechanisms of Regulatory B Cells.

Regulatory B cells (Bregs) is a term that encompasses all B cells that act to suppress immune responses. Bregs contribute to the maintenance of tolerance, limiting ongoing immune responses and reestablishing immune homeostasis. The important role of Bregs in restraining the pathology associated with exacerbated inflammatory responses in autoimmunity and graft rejection has been consistently demonstrated, while more recent studies have suggested a role for this population in other immune-related conditions, such as infections, allergy, cancer, and chronic metabolic diseases. Initial studies identified IL-10 as the hallmark of Breg function; nevertheless, the past decade has seen the discovery of other molecules utilized by human and murine B cells to regulate immune responses. This new arsenal includes other anti-inflammatory cytokines such IL-35 and TGF-ß, as well as cell surface proteins like CD1d and PD-L1. In this review, we examine the main suppressive mechanisms employed by these novel Breg populations. We also discuss recent evidence that helps to unravel previously unknown aspects of the phenotype, development, activation, and function of IL-10-producing Bregs, incorporating an overview on those questions that remain obscure.

Cortisol levels in chronic fatigue syndrome and atypical depression measured using hair and saliva specimens.

BACKGROUND: Several diagnostic criteria for major depressive disorder (MDE) overlap with those of Chronic Fatigue Syndrome (CFS). Furthermore, atypical MDE (A-MDE), a subtype of MDE characterised by profound fatigue and which has frequently been linked with CFS, exhibits similar low cortisol levels to CFS. However, this result has been only found in specimens designed for measuring acute cortisol levels. In this study, we measure cortisol levels in subjects with CFS and in subjects with A-MDE, without psychiatric comorbidity, using both hair and saliva specimens, to gain a measure of both short and long-term cortisol levels in these two conditions. METHODS: Hair cortisol concentration, representing the cortisol concentration of the previous three months, and salivary cortisol, measured at six time-points across one day and including the cortisol awakening response (CAR), post-awakening delta cortisol and the total daily output, were assessed in an age and gender matched group of 34 controls, 15 subjects with A-MDE and 17 with CFS. RESULTS: CFS (mean 92.2 nmol/l.h, s.d. 33.2 nmol/l.h) and A-MDE (mean 89.1 nmol/l.h, s.d. 22.6 nmol/l.h) subjects both showed lower cortisol total daily output in saliva (AUCg) in comparison to healthy controls (mean 125.5 nmol/l.h, s.d. 40.6 nmol/l.h). However, hair cortisol concentration was not lower than that of controls in either patient group. CFS and A-MDE did not differ from one another on any cortisol measures. CFS subjects reported fewer daily hassles and less severe psychic anxiety symptoms in comparison to A-MDE subjects (all p < 0.05). However, they did not differ in the severity of somatic anxiety symptoms. There was also no difference in the presence of overlapping symptoms such as fatigability and concentration/memory problems between A-MDE and CFS subjects. CONCLUSION: Low levels of cortisol found using short-term measures of daily output may be transient, since cortisol levels were normal when a long-term measure (hair) was studied. This might be explained by a potential cortisol rhythm alteration. Although these disorders have their distinctive depressive and somatic features, they may from part of a wider group of Somatic Symptom Disorders (SSD), given the findings of the same pattern of cortisol secretion in both disorders and increased frequency of overlapping clinical features.

Regulation of Tolerogenic Features on Dexamethasone-Modulated MPLA-Activated Dendritic Cells by MYC.

The potential of tolerogenic dendritic cells (tolDCs) to shape immune responses and restore tolerance has turn them into a promising therapeutic tool for cellular therapies directed toward immune regulation in autoimmunity. Although the cellular mechanisms by which these cells can exert their regulatory function are well-known, the mechanisms driving their differentiation and function are still poorly known, and the variety of stimuli and protocols applied to differentiate DCs toward a tolerogenic phenotype makes it even more complex to underpin the molecular features involved in their function. Through transcriptional profiling analysis of monocyte-derived tolDCs modulated with dexamethasone (Dex) and activated with monophosphoryl lipid A (MPLA), known as DM-DCs, we were able to identify MYC as one of the transcriptional regulators of several genes differentially expressed on DM-DCs compared to MPLA-matured DCs (M-DCs) and untreated/immature DCs (DCs) as revealed by Ingenuity Pathway Analysis (IPA) upstream regulators evaluation. Additionally, MYC was also amidst the most upregulated genes in DM-DCs, finding that was confirmed at a transcriptional as well as at a protein level. Blockade of transactivation of MYC target genes led to the downregulation of tolerance-related markers IDO1 and JAG1. MYC blockade also led to downregulation of PLZF and STAT3, transcription factors associated with immune regulation and inhibition of DC maturation, further supporting a role of MYC as an upstream regulator contributing to the regulatory phenotype of DM-DCs. On the other hand, we had previously shown that fatty acid oxidation, oxidative metabolism and zinc homeostasis are amongst the main biological functions represented in DM-DCs, and here we show that DM-DCs exhibit higher intracellular expression of ROS and Zinc compared to mature M-DCs and DCs. Taken together, these findings suggest that the regulatory profile of DM-DCs is partly shaped by the effect of the transcriptional regulation of tolerance-inducing genes by MYC and the modulation of oxidative metabolic processes and signaling mediators such as Zinc and ROS.

Humanized Mouse Models of Rheumatoid Arthritis for Studies on Immunopathogenesis and Preclinical Testing of Cell-Based Therapies.

Rodent models of rheumatoid arthritis (RA) have been used over decades to study the immunopathogenesis of the disease and to explore intervention strategies. Nevertheless, mouse models of RA reach their limit when it comes to testing of new therapeutic approaches such as cell-based therapies. Differences between the human and the murine immune system make it difficult to draw reliable conclusions about the success of immunotherapies. To overcome this issue, humanized mouse models have been established that mimic components of the human immune system in mice. Two main strategies have been pursued for humanization: the introduction of human transgenes such as human leukocyte antigen molecules or specific T cell receptors, and the generation of mouse/human chimera by transferring human cells or tissues into immunodeficient mice. Recently, both approaches have been combined to achieve more sophisticated humanized models of autoimmune diseases. This review discusses limitations of conventional mouse models of RA-like disease and provides a closer look into studies in humanized mice exploring their usefulness and necessity as preclinical models for testing of cell-based therapies in autoimmune diseases such as RA.

TIM-1 defines a human regulatory B cell population that is altered in frequency and function in systemic sclerosis patients.

BACKGROUND: Systemic sclerosis (SSc) is a systemic autoimmune disease characterized by excessive production of extracellular matrix by fibroblasts on skin and internal organs. Although Th2 cells have been involved in fibroblast stimulation, hyperactivated B cells may also play an important role. Regulatory B cells (Bregs) are cells capable of inhibiting inflammatory responses and controlling autoimmune diseases. Although many Breg populations have in common the ability to produce high amounts of IL-10, a unique surface marker defining most human Bregs is lacking. It has been described in mice that T cell Ig and mucin domain protein 1 (TIM-1) is an inclusive marker for Bregs, and that TIM-1+ B cells are able to prevent the development of autoimmunity. The aim of this work was to evaluate TIM-1 as a marker for human IL-10+ Bregs, and to determine whether TIM-1+ B cells are defective in SSc patients. METHODS: SSc patients (n = 39) and 53 healthy subjects were recruited. TIM-1 and IL-10 expression was assessed in resting or activated peripheral blood CD19+ B cells by flow cytometry. The regulatory function of TIM-1+ or activated B cells from SSc patients and healthy subjects was assessed in autologous and allogenic co-cultures with CD4+ T cells, where T cell proliferation and IFN-γ, IL-17, TNF-α and IL-4 production by T cells was measured by flow cytometry. RESULTS: TIM-1 and IL-10 were preferentially expressed in transitional B cells, but were upregulated in naïve and memory B cells upon stimulation. The frequency of transitional TIM-1+ IL-10+ B cells was significantly decreased in SSc patients compared to healthy controls. In addition, activated B cells from SSc patients induced stronger allogenic Th1 and Th2 responses than activated B cells from healthy controls. Finally, TIM-1+ B cells, including transitional and non-transitional cells, exhibited a higher CD4+ T cell suppressive ability than TIM-1- B cells in healthy controls, but not in SSc patients. CONCLUSIONS: TIM-1 is a unique marker for the identification of a human IL-10+ Breg subpopulation which is partially superimposed with transitional B cells. Alterations in TIM-1+ B cells could contribute to the development of autoimmune diseases such as SSc.

Determinación de niveles de vitamina D en pacientes con fibromialgia: estudio de casos y controles / Vitamin D levels in patients with fibromyalgia: case control study

Introduction: fibromyalgia (FM) is characterized by diffuse chronic muscle pain, fatigue and disability, affecting quality of life. In recent years there are many reports that show a high prevalence of vitamin D deficiency in different populations. In patients with FM there are conflicting results about the associations with vitamin D deficiency. Method: Case control study matched controls by age and sex. A clinical interview, measurement of 25-OH vitamin D, calcium, phosphorus and intact PTH was measured. The definitions of the American Society of Endocrinology were used: Insufficient vitamin D levels of 21-29 ng/ml and deficiency when they are less than 20 ng/ml. Results: 39 female patients were included in each group. The average age was 46.33 years (SD 10.6) in patients with FM and 45.92 years (SD 11.9) in controls. VD average levels in women with FM was 26.13 ng/ml (SD 8.3) and the controls of 28.45 ng/ml (SD 8.7) p = 0.082. No group differences were found when using cutoffs of 30 ng/dl (OR 2.75 with p = 0.35 [95 percent CI 0.96 to 8.06]) or 20 ng/dl (OR 0,6 p = 0.38 [95 percent CI 0.15 to 2.18]). No VD patients with levels below 10 ng/dl were presented. Conclusions: We found no differences between groups in VD levels when considering the average levels of VD or using different cutoffs.

Treatment with Dexamethasone and Monophosphoryl Lipid A Removes Disease-Associated Transcriptional Signatures in Monocyte-Derived Dendritic Cells from Rheumatoid Arthritis Patients and Confers Tolerogenic Features.

Tolerogenic dendritic cells (TolDCs) are promising tools for therapy of autoimmune diseases, such as rheumatoid arthritis (RA). Here, we characterize monocyte-derived TolDCs from RA patients modulated with dexamethasone and activated with monophosphoryl lipid A (MPLA), referred to as MPLA-tDCs, in terms of gene expression, phenotype, cytokine profile, migratory properties, and T cell-stimulatory capacity in order to explore their suitability for cellular therapy. MPLA-tDCs derived from RA patients displayed an anti-inflammatory profile with reduced expression of co-stimulatory molecules and high IL-10/IL-12 ratio, but were capable of migrating toward the lymphoid chemokines CXCL12 and CCL19. These MPLA-tDCs induced hyporesponsiveness of autologous CD4+ T cells specific for synovial antigens in vitro. Global transcriptome analysis confirmed a unique transcriptional profile of MPLA-tDCs and revealed that RA-associated genes, which were upregulated in untreated DCs from RA patients, returned to expression levels of healthy donor-derived DCs after treatment with dexamethasone and MPLA. Thus, monocyte-derived DCs from RA patients have the capacity to develop tolerogenic features at transcriptional as well as at translational level, when modulated with dexamethasone and MPLA, overcoming disease-related effects. Furthermore, the ability of MPLA-tDCs to impair T cell responses to synovial antigens validates their potential as cellular treatment for RA.

Systemic Sclerosis Patients Present Alterations in the Expression of Molecules Involved in B-Cell Regulation.

The activation threshold of B cells is tightly regulated by an array of inhibitory and activator receptors in such a way that disturbances in their expression can lead to the appearance of autoimmunity. The aim of this study was to evaluate the expression of activating and inhibitory molecules involved in the modulation of B cell functions in transitional, naive, and memory B-cell subpopulations from systemic sclerosis patients. To achieve this, blood samples were drawn from 31 systemic sclerosis patients and 53 healthy individuals. Surface expression of CD86, MHC II, CD19, CD21, CD40, CD22, Siglec 10, CD35, and FcγRIIB was determined by flow cytometry. IL-10 production was evaluated by intracellular flow cytometry from isolated B cells. Soluble IL-6 and IL-10 levels were measured by ELISA from supernatants of stimulated B cells. Systemic sclerosis patients exhibit an increased frequency of transitional and naive B cells related to memory B cells compared with healthy controls. Transitional and naive B cells from patients express higher levels of CD86 and FcγRIIB than healthy donors. Also, B cells from patients show high expression of CD19 and CD40, whereas memory cells from systemic sclerosis patients show reduced expression of CD35. CD19 and CD35 expression levels associate with different autoantibody profiles. IL-10(+) B cells and secreted levels of IL-10 were markedly reduced in patients. In conclusion, systemic sclerosis patients show alterations in the expression of molecules involved in B-cell regulation. These abnormalities may be determinant in the B-cell hyperactivation observed in systemic sclerosis.

Skewing dendritic cell differentiation towards a tolerogenic state for recovery of tolerance in rheumatoid arthritis.

To date, the available options to treat autoimmune diseases such as rheumatoid arthritis (RA) include traditional corticoids and biological drugs, which are not exempt of adverse effects. The development of cellular therapies based on dendritic cells with tolerogenic functions (TolDCs) has opened a new possibility to efficiently eradicate symptoms and control the immune response in the field of autoimmunity. TolDCs are an attractive tool for antigen-specific immunotherapy to restore self-tolerance in RA and other autoimmune disorders. A promising strategy is to inject autologous self-antigen-loaded TolDCs, which are able to delete or reprogram autoreactive T cells. Different protocols for the generation of stable human TolDCs have been established and the therapeutic effect of TolDCs has been investigated in multiple rodent models of arthritis. Pilot studies in humans confirmed that TolDC application is safe, encouraging clinical trials using self-antigen-loaded TolDCs in RA patients. Although an abundance of molecular regulators of DC functions has been discovered in the last decade, no master regulator of tolerogenicity has been identified yet. Further research is required to define biomarkers or key regulators of tolerogenicity that might facilitate the induction and monitoring of TolDCs.

Discontinuation of tumour necrosis factor inhibitors in patients with rheumatoid arthritis in low-disease activity: persistent benefits. Data from the Corrona registry.

BACKGROUND: There is increasing interest in discontinuing biological therapies for patients with rheumatoid arthritis (RA) achieving good clinical responses, provided patients maintain clinical benefit. METHODS: We assessed patients with RA from the Corrona registry who discontinued treatment with their first tumour necrosis factor inhibitor (TNFi) while in low-disease activity (LDA) or lower levels of disease activity. Patients were followed until they lost clinical benefit, defined as increased disease activity or change in RA medications. Duration of maintenance of clinical benefit was estimated using the Kaplan-Meier method. Cox proportional hazard models were assessed to identify factors related to maintenance of benefit. RESULTS: We identified 717 eligible patients with RA from 35,656 in the Corrona registry. At discontinuation, patients had a median RA duration of 8 years, mean clinical disease activity score of 4.3±0.11; 41.8% were using TNFi as monotherapy. 73.4% of patients maintained benefit for >12 months after discontinuing therapy and 42.2% did so through 24 months. Factors predictive of maintaining clinical benefit in multivariate analysis included lower disease activity, less pain and better functional status at the time of TNFi discontinuation. Among 301 patients initiating their first TNFi within the registry, faster responders (ie, those who achieved LDA in 4 months or less) did better than slower responders (HR 1.54 (95% CI 1.17 to 2.04)). RA disease duration did not affect maintenance of clinical benefit. CONCLUSIONS: Discontinuation of a first course of TNFi may be associated with persistent clinical benefit. Half of patients maintained response through 20 months. Several patient characteristics may help predict persistent benefit.

Clinical parameters and biomarkers for anti-TNF treatment prognosis in rheumatoid arthritis patients.

Tumor necrosis factor (TNF) plays a pivotal role in the pathogenesis of rheumatoid arthritis (RA). This finding has led to the development of TNF blockers for RA treatment. However, response to these therapies is heterogeneous with success in only two thirds of patient. Some clinical aspects useful in the attempt to predict the response to TNF inhibitors is the promptness and the magnitude of the response at the first weeks and a low basal disease activity, while comorbidities, tobacco, glucocorticoids treatment, and high basal radiological score correlate with a poorer response. The role of TNF promoter polymorphisms in clinical response to anti-TNF therapies is controversial. A correlation between the presence of high baseline titers of rheumatoid factor (RF) and decreased response to anti-TNF treatment has been reported. Most studies show decreased RF titers during anti-TNF treatment mainly in patients who responded to treatment. There is no consensus about the usefulness of basal anti-citrullinated protein antibodies (ACPA) levels, and a decrease in ACPA titers as predictor of clinical response to anti-TNF therapy. Despite some promising markers identified to fulfill this role, currently the predictive value of single markers seems not strong enough to predict treatment response in an individual RA patient.

A short protocol using dexamethasone and monophosphoryl lipid A generates tolerogenic dendritic cells that display a potent migratory capacity to lymphoid chemokines.

BACKGROUND: Generation of tolerogenic dendritic cells (TolDCs) for therapy is challenging due to its implications for the design of protocols suitable for clinical applications, which means not only using safe products, but also working at defining specific biomarkers for TolDCs identification, developing shorter DCs differentiation methods and obtaining TolDCs with a stable phenotype. We describe here, a short-term protocol for TolDCs generation, which are characterized in terms of phenotypic markers, cytokines secretion profile, CD4+ T cell-stimulatory ability and migratory capacity. METHODS: TolDCs from healthy donors were generated by modulation with dexamethasone plus monophosphoryl lipid A (MPLA-tDCs). We performed an analysis of MPLA-tDCs in terms of yield, viability, morphology, phenotypic markers, cytokines secretion profile, stability, allogeneic and antigen-specific CD4+ T-cell stimulatory ability and migration capacity. RESULTS: After a 5-day culture, MPLA-tDCs displayed reduced expression of costimulatory and maturation molecules together to an anti-inflammatory cytokines secretion profile, being able to maintain these tolerogenic features even after the engagement of CD40 by its cognate ligand. In addition, MPLA-tDCs exhibited reduced capabilities to stimulate allogeneic and antigen-specific CD4+ T cell proliferation, and induced an anti-inflammatory cytokine secretion pattern. Among potential tolerogenic markers studied, only TLR-2 was highly expressed in MPLA-tDCs when compared to mature and immature DCs. Remarkable, like mature DCs, MPLA-tDCs displayed a high CCR7 and CXCR4 expression, both chemokine receptors involved in migration to secondary lymphoid organs, and even more, in an in vitro assay they exhibited a high migration response towards CCL19 and CXCL12. CONCLUSION: We describe a short-term protocol for TolDC generation, which confers them a stable phenotype and migratory capacity to lymphoid chemokines, essential features for TolDCs to be used as therapeutics for autoimmunity and prevention of graft rejection.

Evaluation of the efficacy of two mouthrinses formulated for the relief of xerostomia of diverse origin in adult subjects.

OBJECTIVE: To evaluate the efficacy of two new mouthrinses in the reduction of xerostomía-associated symptomatology. BACKGROUND: Xerostomia is a common chronic health condition that affects a great number of adults and significantly deteriorates quality of life, such that treatment is necessary. MATERIALS AND METHODS: Sixty-seven adult subjects of both sexes presenting xerostomia of diverse origin were selected. Mouthrinses were tested using a double-blind, randomized, cross-over clinical trial with an intervining wash out period. RESULTS: The 100% of subjects presented sensation of dry mouth, and 86% stated sensation of thick saliva. Burning tongue sensation, need to drink liquids to swallow and the sensation of swallowing difficulty were recorded in more than 50% of the patients. The most frequent pathologies in the sample were depression, arthritis, and arterial hypertension. Results of the clinical tests showed that mouthrinse 1 relieves sensation of dry mouth, need to drink liquids, and swallowing difficulty. In contrast, mouthrinse 2 relieves only latter two symptoms. Both rinses were more effective in relieving xerostomía-associated symptomatology in patients taking 3 or more medicines simultaneously. CONCLUSION: Both mouthrinses were effective in relieving various xerostomia symptoms, could be distributed at a low cost, thereby improving the quality of life of population affected.

Weak CD4+ T-cell responses to citrullinated vimentin in rheumatoid arthritis patients carrying HLA-DR9 alleles.

Citrullinated vimentin (cVIM) is one of the antigens specifically targeted by anti-citrullinated protein antibodies (ACPA) in rheumatoid arthritis (RA) patients. The association between ACPA and certain HLA-DRB1 alleles, those coding for the shared epitope (SE), suggests that this response could be T-cell mediated. HLA-DR9 alleles, which do not code for the SE, have recently been associated with ACPA (+) RA. The objective of this work was to study CD4+ T cell responses to cVIM in RA patients and healthy controls carrying HLA-DR9 alleles. Fourteen RA patients and ten healthy controls previously genotyped for HLA-DRB1 were studied for the presence of serum anti-cVIM antibodies by Western blot and ELISA. Peripheral blood mononuclear cells were stimulated with native vimentin and cVIM, and CD4+ T cells proliferation was assessed by flow cytometry. Citrulline-specific CD4+ T cells proliferation was found not only in RA patients but also in healthy controls. Although most patients carrying HLA-DR9 alleles present anti-cVIM antibodies, HLA-DR9 alleles were associated with weaker cVIM-driven CD4+ T-cell responses among RA patients. These results suggest that HLA-DR9 alleles could exert a protective effect on the recognition of cVIM epitopes by CD4+ T cells. In this context, other citrullinated proteins may break T and B cell tolerance, with cVIM only acting as a cross-reactive target for ACPA.

Guía clínica: lupus eritematoso sistémico (LES) / Systemic lupus erythematosus: a clinical guide

El Lupus Eritematoso Sistémico (LES) es una enfermedad inflamatoria, sistémica, crónica, de patogenia autoinmune. Sus manifestaciones varían desde afecciones leves a graves o fatales. En más común en mujeres y su prevalencia varía entre 40 a 200 casos/100.000 habitantes. El diagnóstico y reconocimiento precoz de sus manifestaciones sistémicas son críticos para una adecuada derivación, tratamiento y pronóstico de los pacientes. A petición del MINSAL, la Sociedad Chilena de Reumatología designó un grupo de trabajo para la elaboración de una guía clínica de LES. Objetivos: Definir niveles de atención, criterios de derivación según gravedad y elaborar recomendaciones para el diagnóstico, tratamiento y seguimiento de los principales compromisos del LES siguiendo la metodología de realización de guías clínicas. Metodología: Se siguieron las indicaciones para realización de guías clínicas basadas en criterios de evaluación (AGREE) y una combinación de criterios de medicina basada en la evidencia y consenso de expertos. La pesquisa bibliográfica se centró en la búsqueda de respuesta para 13 preguntas seleccionadas, respecto a: niveles de atención y criterios de derivación; abordaje general; principales compromisos graves del LES y situaciones especiales. Para cada pregunta se hizo una recomendación. La evidencia se estableció usando una escala tradicional. Además, se midió el grado de acuerdo (GdA) con las recomendaciones efectuadas, mediante una escala de 0 a 10 puntos, por los reumatólogos integrantes del grupo de trabajo y por cinco pares independientes. Resultados: Se desarrollaron 13 recomendaciones respecto a: 1) Rol del médico no especialista y criterios de derivación. 2) Rol del reumatólogo. 3) Sospecha y diagnóstico precoz del LES. 4) Pronóstico y gravedad. 5) Evaluación de actividad y daño en el LES. 6) Patología asociada al LES. 7) Fármacos utilizados en el LES y su toxicidad. 8) Bases diagnósticas de nefropatía lúpica. 9) Tratamiento de nefropatía lúpica...

Systemic lupus erythematosus (SLE) is an inflammatory, systemic and chronic disease of autoimmune pathogenesis. Manifestations vary from mild to serious or fatal conditions. It is most common among women and its prevalence varies between 40 to 200 cases/100.000 inhabitants. Early diagnosis as well as identification of systemic manifestations are critical for adequate referral, treatment and prognosis. At the request of Chile's health ministry, the Chilean Society of Rheumatology designated a work group to elaborate clinical guidelines for SLE. Objectives: Define levels of attention, criteria for referral according to seriousness, and elaborate recommendations for diagnosis, treatment and follow-up of the main disorders of SLE following the clinical guideline execution methodology. Methodology: Indications for the creation of clinical guidelines based on the AGREE evaluation criteria and a combination of medical criteria based on expert evidence and consensus were followed. Bibliographical investigation was centered on responding 13 selected questions with respect to: level of attention and referral criteria; general approach; main critical SLE compromises, and special situations. A recommendation was given for each question. Evidence was established using a traditional scale. Moreover, the degree of agreement was measured (GdA) with the recommendations carried out, by means of a scale from 0 to 10 by the rheumatologists who made up the work group and by five independent peers. Results: 13 recommendations were developed with respect to: 1) Role played by non-specialized physicians and referral criteria; 2) Role played by rheumatologist; 3) Suspicion and early diagnosis of SLE; 4) Prognosis and seriousness; 5) evaluation of SLE activity and damage; 6) Pathology associated to SLE; 7) Drugs used for SLE and their toxicity; 8) Diagnostic basis for lupus nephritis; 9) Treatment for lupus nephritis; 10) Neuropsychiatric manifestations of SLE; 11) SLE and...

Anti-TNF therapy in patients with rheumatoid arthritis decreases Th1 and Th17 cell populations and expands IFN-γ-producing NK cell and regulatory T cell subsets.

The aim of this work was to study the effect of anti-TNF treatment on CD4+ Th1, Th17 and regulatory T cells (Tregs), together with CD8+ T cells and NK cells from rheumatoid arthritis (RA) patients. For this purpose, 18 RA patients received adalimumab during 16weeks and their peripheral blood lymphocytes were assessed by flow cytometry at the beginning and at the end of the study. We found that the proportion of Th17 cells was directly correlated with Th1 cells, but inversely correlated with IFN-γ-producing NK cells. A decrease was observed in Th1, Th17 cells and IFN-γ-producing CD8+ T cells by anti-TNF therapy. Conversely, the proportion of Tregs increased, as did the percentage of IFN-γ-producing NK cells. We postulate that a rise in IFN-γ production due to recovery of NK cells' function, together with expanded Tregs, contribute to decrease the Th17 response in anti-TNF-treated RA patients.

The presence of anti-citrullinated protein antibodies (ACPA) does not affect the clinical response to adalimumab in a group of RA patients with the tumor necrosis factor (TNF) α-308 G/G promoter polymorphism.

The introduction of antitumor necrosis factor (TNF) agents has improved the outcome for many patients with rheumatoid arthritis (RA). To date, the only replicated genetic predictor of anti-TNF response is the -308 G > A single-nucleotide polymorphism in the TNF promoter region. The presence of the -308 TNF G/G genotype appears to be a marker of good response to anti-TNF treatment. Anti-citrullinated protein antibodies (ACPA) have been linked with erosive disease, and have been established as the single most reliable prognostic factor in clinical practice. To test the hypothesis that the ACPA status may affect the -308 G/G patients rate of response to TNF blockade, we prospectively investigated a group of 52 RA patients with the -308 G/G genotype who were ACPA (+) or ACPA (-). All patients were treated with adalimumab, and the clinical response was studied using the Disease Activity Score in 28 joints (DAS28) at 24 weeks of treatment. Over 85% of patients were DAS28 responders in both groups. No significant differences were found between patients from both groups, according to the DAS28 criteria of response at week 24 (p = 0.79). In conclusion, our findings suggest that the ACPA status does not affect the clinical response to anti-TNF therapy in -308 TNF G/G patients.