Documento de recomendaciones sobre el tratamiento con inmunodepresores de la uveítis no anterior, no infecciosa, no neoplásica / Recommendations statement on the immunosuppressive treatment of non-infectious, non-neoplastic, non-anterior uveítis

OBJETIVO: Desarrollar recomendaciones basadas en la mejor evidencia disponible y experiencia sobre el uso de inmunomoduladores en pacientes con uveítis, las uveítis intermedias (UI), posteriores (UP) y panuveítis (PanU) no infecciosas, no neoplásicas. MÉTODOS: Se seleccionó un grupo multidisciplinar de 5 expertos, que definió el alcance, usuarios y apartados del documento. Posteriormente, se realizó una revisión sistemática de la literatura sobre la eficacia y seguridad de los inmunomoduladores en pacientes con UI, UP y PanU no infecciosa, no neoplásica. Se generaron 34 recomendaciones en base a la evidencia encontrada en la revisión sistemática y a la experiencia de los expertos. Mediante la metodología Delphi, el grado de acuerdo con las recomendaciones se extendió a 25 expertos más que votaron según una escala de 1 (total desacuerdo) a 10 (total acuerdo). El acuerdo se definió como una puntuación ≥ 7 en al menos el 70% de los participantes. El nivel de evidencia y grado de recomendación se clasificaron según el modelo del Center for Evidence Based Medicine de Oxford. RESULTADOS: Se aceptaron las 34 recomendaciones generadas tras 2 rondas Delphi (se modificaron 3 recomendaciones). Se incluyen recomendaciones específicas para pacientes con UI, UP y PanU no infecciosa, no neoplásica, así como para distintas líneas de tratamiento. CONCLUSIONES: En los pacientes con UI, UP y PanU no infecciosas, no neoplásicas, estas recomendaciones pueden ayudar en la toma de decisiones terapéuticas, dada la ausencia de estudios con potencia estadística suficiente, u otros algoritmos universalmente aceptados sobre los que apoyar dichas decisiones

OBJECTIVE: To generate recommendations on the use of immunomodulators in patients with non-infectious, non-neoplastic intermediate uveitis (IU), posterior uveitis (PU) and panuveitis (PanU) based on best evidence and experience. METHODS: A multidisciplinary panel of 5 experts was established, who defined the scope, users, and sections of the document. A systematic literature review (SLR) was performed to assess the efficacy and safety of immunomodulatory drugs in patients with non-infectious, non-neoplastic, non-anterior uveitis. The results of the SLR were presented and discussed during an expert meeting in which 34 recommendations were generated. The level of agreement with the recommendations was also tested in 25 additional experts following a Delphi process. Recommendations were voted from 1 (total disagreement) to 10 (total agreement). We defined agreement if at least 70% of the experts voted ≥ 7. The level of evidence and grade or recommendation were assessed using the Oxford Centre for Evidence-based Medicine Levels of Evidence. RESULTS: The SLR included 33 articles. The 34 recommendations were accepted after 2 Delphi rounds (3 of them were modified after the first round). They include specific recommendations on patients with non-infectious, non-neoplastic, PU and PanU, as well as different treatment guidelines. CONCLUSIONS: In patients with non-infectious, non-neoplastic, non-anterior uveitis these recommendations might help treatment decision making, due to the lack of robust evidence or other globally accepted algorithms

Recommendations statement on the immunosuppressive treatment of non-infectious, non-neoplastic, non-anterior uveitis. / Documento de recomendaciones sobre el tratamiento con inmunodepresores de la uveítis no anterior, no infecciosa, no neoplásica.

OBJECTIVE: To generate recommendations on the use of immunomodulators in patients with non-infectious, non-neoplastic intermediate uveitis (IU), posterior uveitis (PU) and panuveitis (PanU) based on best evidence and experience. METHODS: A multidisciplinary panel of 5 experts was established, who defined the scope, users, and sections of the document. A systematic literature review (SLR) was performed to assess the efficacy and safety of immunomodulatory drugs in patients with non-infectious, non-neoplastic, non-anterior uveitis. The results of the SLR were presented and discussed during an expert meeting in which 34 recommendations were generated. The level of agreement with the recommendations was also tested in 25 additional experts following a Delphi process. Recommendations were voted from 1 (total disagreement) to 10 (total agreement). We defined agreement if at least 70% of the experts voted ≥7. The level of evidence and grade or recommendation were assessed using the Oxford Centre for Evidence-based Medicine Levels of Evidence. RESULTS: The SLR included 33 articles. The 34 recommendations were accepted after 2 Delphi rounds (3 of them were modified after the first round). They include specific recommendations on patients with non-infectious, non-neoplastic, PU and PanU, as well as different treatment guidelines. CONCLUSIONS: In patients with non-infectious, non-neoplastic, non-anterior uveitis these recommendations might help treatment decision making, due to the lack of robust evidence or other globally accepted algorithms.

Duodenal mucosa FOXP3 expression in different etiologies of lymphocytic duodenosis.

BACKGROUND/AIMS: In celiac disease there is an increase of lymphocytes expressing FOXP3 in the intestinal mucosa associated with varying degrees of villous atrophy. Our aim was to evaluate FOXP3 expression in duodenal mucosa with lymphocytic enteritis according to aetiology and correlation with lymphocytes T-γδ. METHODS: We compared three adult patient groups suffering lymphocytic enteritis: celiacs following a gluten-free diet (n=12), first-degree relatives of celiac patients with genetic risks (n=14) and patients with functional dyspepsia (n=14), along with a control group not suffering from duodenal enteritis (n=16). The population of duodenal lymphocytes was analysed by immunohistochemistry assays for CD3+ characterisation and FOXP3 expression. Quantification of lymphocytes T-γδ in duodenal mucosa was performed by flow cytometry in fresh tissue samples. RESULTS: Presence of lymphocytes T-γδ was significantly higher in the group of celiac individuals compared to the group of relatives of these individuals (37.44 vs 5,52: p<0.0001) and the group with functional dyspepsia (37.44 vs 11.76: p=0.008). FOXP3 expression was also significantly higher in the celiac group than in the groups of relatives (18.85 vs 6.31; p=0.001) and functional dyspepsia patients (18.85 vs 7.61; p=0.023). The proportion of lymphocytes T-γδ and FOXP3- expressing lymphocytes was similar in the control group to that in the relatives or functional dyspepsia groups. CONCLUSIONS: Lymphocytic enteritis associated to celiac disease shows an increase of FOXP3 expression and lymphocytes T-γδ that is not detected in other etiologies of enteritis.

Documento de recomendaciones de tratamiento de la uveítis anterior no infecciosa / Treatment recommendations for non-infectious anterior uveitis

Fundamento y objetivo Desarrollar recomendaciones basadas en la mejor evidencia disponible y experiencia sobre el uso de inmunodepresores en pacientes con uveítis anterior (UA) no infecciosa no neoplásica. Material y métodos: Se seleccionó un grupo multidisciplinar de 5 expertos, que en la primera reunión de grupo nominal, acordó el alcance, usuarios y apartados del documento. Posteriormente, se realizó una revisión sistemática de la literatura sobre la eficacia y seguridad de los inmunodepresores en pacientes con UA no infecciosa no neoplásica. En la segunda reunión de grupo nominal, se generaron 33 recomendaciones en base a la evidencia encontrada en la revisión sistemática y a la experiencia de los expertos. Mediante la metodología Delphi, el grado de acuerdo con las recomendaciones se extendió a 25 expertos más que votaron según una escala de uno (total desacuerdo) a 10 (total acuerdo). El acuerdo se definió como una puntuación ≥7 en al menos el 70% de los participantes. El nivel de evidencia y grado de recomendación se clasificaron según el modelo del Center for Evidence Based Medicine de Oxford. Resultados: Se aceptaron las 33 recomendaciones generadas. Se incluyen recomendaciones específicas para pacientes con UA no infecciosa no neoplásica, así como para distintas líneas de tratamiento. Conclusiones: En los pacientes con UA no infecciosa no neoplásica, estas recomendaciones sobre el uso de inmunodepresores pueden servir como guía que ayude en la toma de decisiones terapéuticas, dada la ausencia de estudios con potencia estadística suficiente, u otros algoritmos universalmente aceptados sobre los que apoyar dichas decisiones (AU)

Background and objective: To develop recommendations on the use of immunodepressors in patients with non-infectious, non-neoplastic anterior uveitis (AU) based on best evidence and experience. Material and methods: A multidisciplinary panel of five experts was established, who, in the first nominal group meeting defined the scope, users, and chapters of the document. A systematic literature review was performed to assess the efficacy and safety of immunosuppressors in patients with non-infectious, non-neoplastic AU. All the above was discussed in a second nominal group meeting and 33 recommendations were generated. Through the Delphi methodology, the degree of agreement with the recommendations was tested also by 25 more experts. Recommendations were voted on from one (total disagreement) to 10 (total agreement). We defined agreement if at least 70% voted ≥7. The level of evidence and degree of recommendation was assessed using the Oxford Centre for Evidence-based Medicine's Levels of Evidence. Results: The 33 recommendations were accepted. They include specific recommendations on patients with non-infectious, non-neoplastic AU, as well as different treatment lines. Conclusions: In patients with non-infectious, non-neoplastic AU, these recommendations on the use of immunosuppressors might be a guide in order to help in the treatment decision making, due to the lack of robust evidence or other globally accepted algorithms (AU)

Treatment recommendations for non-infectious anterior uveitis. / Documento de recomendaciones de tratamiento de la uveítis anterior no infecciosa.

BACKGROUND AND OBJECTIVE: To develop recommendations on the use of immunodepressors in patients with non-infectious, non-neoplastic anterior uveitis (AU) based on best evidence and experience. MATERIAL AND METHODS: A multidisciplinary panel of five experts was established, who, in the first nominal group meeting defined the scope, users, and chapters of the document. A systematic literature review was performed to assess the efficacy and safety of immunosuppressors in patients with non-infectious, non-neoplastic AU. All the above was discussed in a second nominal group meeting and 33 recommendations were generated. Through the Delphi methodology, the degree of agreement with the recommendations was tested also by 25 more experts. Recommendations were voted on from one (total disagreement) to 10 (total agreement). We defined agreement if at least 70% voted ≥7. The level of evidence and degree of recommendation was assessed using the Oxford Centre for Evidence-based Medicine's Levels of Evidence. RESULTS: The 33 recommendations were accepted. They include specific recommendations on patients with non-infectious, non-neoplastic AU, as well as different treatment lines. CONCLUSIONS: In patients with non-infectious, non-neoplastic AU, these recommendations on the use of immunosuppressors might be a guide in order to help in the treatment decision making, due to the lack of robust evidence or other globally accepted algorithms.

Tratamiento con fármacos anti-TNF: utilidad de la monitorización de niveles de fármaco y anticuerpos antifármaco en la práctica clínica / Anti-tumor necrosis factor drug therapy: The usefulness of monitoring drug levels and anti-drug antibodies in clinical practice

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Differences in gluten metabolism among healthy volunteers, coeliac disease patients and first-degree relatives.

Coeliac disease (CD) is an immune-mediated enteropathy resulting from exposure to gluten in genetically predisposed individuals. Gluten proteins are partially digested by human proteases generating immunogenic peptides that cause inflammation in patients carrying HLA-DQ2 and DQ8 genes. Although intestinal dysbiosis has been associated with patients with CD, bacterial metabolism of gluten has not been studied in depth thus far. The aim of this study was to analyse the metabolic activity of intestinal bacteria associated with gluten intake in healthy individuals, CD patients and first-degree relatives of CD patients. Faecal samples belonging to twenty-two untreated CD patients, twenty treated CD patients, sixteen healthy volunteers on normal diet, eleven healthy volunteers on gluten-free diet (GFD), seventy-one relatives of CD patients on normal diet and sixty-nine relatives on GFD were tested for several proteolytic activities, cultivable bacteria involved in gluten metabolism, SCFA and the amount of gluten in faeces. We detected faecal peptidasic activity against the gluten-derived peptide 33-mer. CD patients showed differences in faecal glutenasic activity (FGA), faecal tryptic activity (FTA), SCFA and faecal gluten content with respect to healthy volunteers. Alterations in specific bacterial groups metabolising gluten such as Clostridium or Lactobacillus were reported in CD patients. Relatives showed similar parameters to CD patients (SCFA) and healthy volunteers (FTA and FGA). Our data support the fact that commensal microbial activity is an important factor in the metabolism of gluten proteins and that this activity is altered in CD patients.

Differences in faecal bacteria populations and faecal bacteria metabolism in healthy adults and celiac disease patients.

UNLABELLED: Differences in the intestinal microbiota between children and adults with celiac disease (CD) have been reported; however, differences between healthy adults and adults with CD have not been clearly demonstrated. The aim of this study was to evaluate the differences in the intestinal microbiota between adults with CD and healthy individuals. Microbial communities in faecal samples were evaluated by PCR-denaturing gradient gel electrophoresis (DGGE) and gas-liquid chromatography of short chain fatty acids (SCFAs). The study group included 10 untreated CD patients, 11 treated CD patients and 11 healthy adults (in normal gluten diet and in GFD). UPGMA clustered the dominant microbial communities of healthy individuals together and separated them from the dominant microbial communities of the untreated CD patients. Most of the dominant microbial communities of the treated CD patients clustered together with those of healthy adults. The treated CD patients showed a reduction in the diversity of Lactobacillus and Bifidobacterium species. The presence of Bifidobacterium bifidum was significantly higher in untreated CD patients than healthy adults. There was a significant difference between untreated CD patients and healthy adults, as well as between treated CD patients and healthy adults, regarding acetic acid, propionic acid, butyric acid, and total SCFAs. IN CONCLUSION: healthy adults have a different faecal microbiota from that of untreated CD patients. A portion of the treated CD patients displayed a restored "normal" microbiota. The treated CD patients significantly reduce the Lactobacillus and Bifidobacterium diversity. Healthy adults have a different faecal SCFAs content from that of CD patients.

[Gastrointestinal manifestations in patients with primary immunodeficiencies causing antibody deficiency]. / Manifestaciones gastrointestinales en pacientes con inmunodeficiencias primarias que cursan con déficit de anticuerpos.

INTRODUCTION: Primary immunodeficiencies can lead to gastrointestinal manifestations that are still not well defined. OBJECTIVE: To analyze gastrointestinal manifestations associated with primary immunodeficiencies. MATERIAL AND METHODS: We performed a retrospective study that included patients diagnosed with primary antibody deficiencies in a third-level hospital. The patients were divided into two groups: isolated IgA deficiency and common variable immunodeficiency syndrome (CVIS). The timing of presentation and type of gastrointestinal symptoms were analyzed. RESULTS: There were 57 patients: 20 with CVIS (35%) and 37 with isolated IgA deficiency (65%). Diagnosis was made in the pediatric age in 17 patients, of whom 13 had isolated IgA deficiency. In 84% of the patients, diagnosis of immunodeficiency was made before the development of gastrointestinal manifestations. Digestive symptoms were found in 74% of the patients, the most frequent being diarrhea. In 46% of the patients, digestive disease was confirmed, mainly through endoscopy. Celiac-like lesions, chronic atrophic gastritis, ulcerative colitis-like disease and Crohn's disease were more common in CVIS. In isolated IgA deficiency, Helicobacter pylori-positive chronic gastritis predominated. Mean age was significantly higher (36 vs. 24 years, p=0.02) and IgA titer significantly lower (17 vs. 34UI/ml; p=0.008) in patients with associated gastrointestinal disease. CONCLUSIONS: Gastrointestinal symptoms are frequent and lead to endoscopic diagnosis in half of patients with primary immunodeficiencies. Ulcerative colitis, and celiac- and Crohn's-like disease are atypical entities that occur in CVIS.

Age-related clinical, serological, and histopathological features of celiac disease.

BACKGROUND: Celiac disease (CD) is a common disorder in children and adults. However, limited data are available when comparing differences between both populations. AIMS: To prospectively evaluate and compare the clinical and histological features present at diagnosis in a cohort of celiac children and adults. METHODS: Consecutive new cases diagnosed between 2000 and 2006 were prospectively included (66 children and 54 adults). The clinical spectrum was categorized in two groups: (a) typical (malabsorption, chronic diarrhea, or failure to thrive) and (b) oligosymptomatic (abdominal pain, anemia, hypertransaminasemia, or screening in risk groups or in relatives). The histological results were divided into mild (i.e., Marsh I, II, and IIIA) and severe (i.e., Marsh IIIB, IIIC). In all cases, the human antitissue transglutaminase IgA antibodies (TTGA) were determined. RESULTS: Overall, a female/male ratio (2.6:1) was observed. This ratio was significantly higher in adults (5.7:1) than in children (1.6:1) (P= 0.009). Typical symptoms were present in 62.5% children versus 31% adults (P= 0.01). The average time to diagnosis after the appearance of symptoms was 7.6 months for children and 90 months for adults (P < 0.001). TTGA levels were higher in children and correlated with age (P < 0.001) and with the degree of villous atrophy (P < 0.001). Histological analysis revealed a marked atrophy in 86% children versus 52% adults (P < 0.001). The degree of villous atrophy was inversely correlated with age (P < 0.001). Classic symptoms were also associated with more severe villous atrophy. CONCLUSIONS: At initial diagnosis, CD shows age-related differences, which consist of more evident clinical and histological features in children. Furthermore, IgA TTGA levels correlate both with the degree of villous atrophy and with the patient's age.

[Clinical performance of antigen-specific interferon-gamma assay for the diagnosis of latent tuberculosis in risky hospital-based populations]. / Aplicación clínica de una prueba de producción de interferón gamma para el diagnóstico de tuberculosis latente en poblaciones hospitalarias de riesgo.

BACKGROUND AND OBJECTIVE: To evaluate the performance and the usefulness of an in vitro interferon gamma release assay in the diagnosis of latent tuberculosis infection in immunocompromised hospital-based population. PATIENTS AND METHOD: A cohort of 445 high-risk adults from a hospital located in an intermediate tuberculosis burden area were prospectively evaluated for latent tuberculosis by means of the whole blood in vitro QuantiFERON-TB Gold assay (QTF), measuring tuberculosis-specific interferon gamma release by memory-effector T lymphocytes. RESULTS: Overall the test displayed a positive result in 15.43% patients. Among the different risk groups, hemodialysis patients revealed the highest positive rates (30.23%). Indeterminate results (10.19% on the whole) were more often seen in neoplastic (18.03%) patients and in patients with autoimmune disease (17%). In 291 patients in whom QTF and Mantoux were simultaneously performed, concordance was moderate (kappa = 0.4520) with a 76.8% agreement when Mantoux was negative (179/233) but reaching only 50% (29/58) when Mantoux positive patients were selected. CONCLUSIONS: QFT test is suitable for routine latent tuberculosis diagnosis in hospital-based immunocompromised patients. At least in some of them, i.e. hemodialysis and patients with autoimmune suppression, QFT adds valuable information for therapeutical decision-making. In Mantoux positive patients, it is very useful for ruling-out false positives due to BCG-vaccination and/or non-tuberculous mycobacterial infection.

Aplicación clínica de una prueba de producción de interferón gamma para el diagnóstico de tuberculosis latente en poblaciones hospitalarias de riesgo / Clinical performance of antigen-specific interferon-gamma assay for the diagnosis of latent tuberculosis in risky hospital-based populations

FUNDAMENTO Y OBJETIVO: Evaluar la aplicabilidad en el medio hospitalario de una prueba de interferóngamma in vitro en respuesta a antígenos específicos, así como valorar su utilidad en el diagnóstico de tuberculosis latente en pacientes con alto riesgo de reactivación tuberculosa.PACIENTES Y MÉTODO: Estudio descriptivo y prospectivo realizado en una cohorte de pacientes hospitalariosformada por 445 adultos seleccionados por pertenecer a grupos de riesgo para el desarrollo de enfermedad tuberculosa activa, procedentes de una región con una incidencia intermedia de tuberculosis activa declarada en la población general. Se realizó una prueba deproducción de interferón gamma in vitro en sangre total tras estimulación específica de antígeno, denominada QuantiFERON-TB Gold assay (QTF), que valora la respuesta de los linfocitos T efectores de memoria, específicos de tuberculosis.RESULTADOS: La prueba fue positiva en el 15,43% de los casos. El mayor número de positivos (30,23%) se observó entre los pacientes en hemodiálisis. Los resultados indeterminados (un 10,19% en total) fueron más frecuentes en pacientes con enfermedades neoplásicas y autoinmunitarias (el 18,03 y el 17%, respectivamente). En 291 casos en que se realizó simultáneamente la intradermorreacción de Mantoux, la concordancia fue moderada (kappa = 0,4520), con un 76,8% de acuerdo en caso de Mantoux negativo (179/233), pero sólo del 50% (29/58) cuando el Mantoux fue positivo.CONCLUSIONES: La prueba QTF puede aplicarse habitualmente en el medio hospitalario para eldiagnóstico de tuberculosis latente en pacientes inmunodeprimidos. Al menos en algunos de éstos (pacientes en hemodiálisis, con enfermedades autoinmunitarias) aporta información adicionalmuy valiosa a la hora de tomar decisiones terapéuticas. En pacientes con Mantoux positivo es muy útil para descartar falsos positivos debidos a vacunación antituberculosa y/o infección por micobacterias atípicas

BACKGROUND AND OBJECTIVE: To evaluate the performance and the usefulness of an in vitro interferon gamma release assay in the diagnosis of latent tuberculosis infection in immunocompromisedhospital-based population.PATIENTS AND METHOD: A cohort of 445 high-risk adults from a hospital located in an intermediatetuberculosis burden area were prospectively evaluated for latent tuberculosis by means of the whole blood in vitro QuantiFERON-TB Gold assay (QTF), measuring tuberculosis-specific interferon gamma release by memory-effector T lymphocytes.RESULTS: Overall the test displayed a positive result in 15.43% patients. Among the different risk groups, hemodialysis patients revealed the highest positive rates (30.23%). Indeterminate results (10.19% on the whole) were more often seen in neoplastic (18.03%) patients and in patients with autoimmune disease (17%). In 291 patients in whom QTF and Mantoux were simultaneously performed, concordance was moderate (kappa = 0.4520) with a 76.8% agreement when Mantoux was negative (179/233) but reaching only 50% (29/58) when Mantoux positive patients were selected.CONCLUSIONS: QFT test is suitable for routine latent tuberculosis diagnosis in hospital-based immunocompromised patients. At least in some of them, i.e. hemodialysis and patients with autoimmunesuppression, QFT adds valuable information for therapeutical decision-making. In Mantoux positive patients, it is very useful for ruling-out false positives due to BCG-vaccination and/or non-tuberculous mycobacterial infection

Human recombinant anti-transglutaminase antibody testing is useful in the diagnosis of silent coeliac disease in a selected group of at-risk patients.

BACKGROUND: Functional dyspepsia, unexplained chronic hypertransaminasaemia (CHT) and hepatitis C virus (HCV) are common gastrointestinal situations that have been related to coeliac disease. Antibodies to tissue transglutaminase (tTG) have been claimed recently to be highly effective as a screening method for coeliac disease. AIM: To assess the prevalence of coeliac disease by means of detection of antibodies against human tTG in the above-mentioned groups of patients. PATIENTS AND METHODS: A control group consisted of 165 normal blood donors. Patient groups comprised 90 CHT patients, 102 HCV patients and 92 functional dyspepsia patients. All patients were tested for anti-tTG (immunoglobulin A, IgA) antibodies. Anti-endomysium (IgA) antibodies (AEA) and antigliadin (IgA) antibodies (AGA) and antigliadin (immunoglobulin G, IgG) antibodies (AGG) were also tested. When anti-tTG or AEA was positive, a duodenal biopsy was recommended. RESULTS: One of 165 blood donors, three of 92 functional dyspepsia patients, four of 90 CHT patients and none of 102 HCV patients were positive for anti-tTG antibodies. In the anti-tTG-positive group, all but one were AEA-positive. There were no AEA- or AGA IgA-positives that revealed a negative anti-tTG test. Duodenal biopsy confirmed a diagnosis of coeliac disease in all the cases. Statistically significant differences were found between the controls and the functional dyspepsia group and between the controls and the CHT group, but not between the controls and the HCV group. CONCLUSIONS: Both CHT and functional dyspepsia may represent a true oligosymptomatic form of coeliac disease. In such conditions, the detection of anti-tTG antibodies is useful as a screening method. Coeliac disease is not an autoimmune manifestation of HCV, so screening for coeliac disease in HCV patients cannot be recommended.