Increased incidence of Graves' disease during the SARS-CoV2 pandemic.

INTRODUCTION: COVID-19 has a wide spectrum of clinical severity and there is evidence that SARS-Cov2 affects several organs and systems. Among the organs affected since the beginning of the pandemic, the relationship between SARS-CoV-2 infection and thyroid involvement has been demonstrated. Novel and highly effective messenger RNA and DNA-based vaccines have been rapidly developed to decrease SARS-CoV-2 morbidity and mortality. Early after mass vaccinations, cases of thyroid dysfunction mainly including episodes of subacute thyroiditis, began to be reported like adverse effects. The objective of this study is to determine the impact of the pandemic, both due to SARS-CoV2 infections and vaccinations, on the incidence of Graves' disease (GD). METHODS: Cross-sectional, observational study comparing incidence of GD in adult population (over 18 years) before (2017-2019) and after (2020-2021) Covid-19 pandemic. Only patients with new cases of GD, no relapsed diseases, were included. SARS-CoV-2 diagnosis was based on nucleic acid amplification tests on nasopharyngeal swabs or measurement of class M and class G antibodies to SARS-CoV-2 by highly specific assays. Data on incidence and vaccination related to SARS-CoV-2 infection were obtained from the public records from Castilla y León autonomous regional government. RESULTS: A total of 180 subjects were diagnosed and treated for GD during the study period. We observed a notable increase in expected GD cases in 2021 compared to 2017-19. The number of GD cases was higher in the second (Q2) quarter. Among 2021 GD cases, 42/66 patients (63.6%) had been vaccinated in the 90 days before symptom onset, but none of them in the first quarter of the year. A total of 97.7% were women with a mean age of 48.9 (SD 15.6) years. On average they were diagnosed 19.9 (SD 17.6) days after receiving the vaccine. A total of 7/42 (16.67%) had another previously diagnosed autoimmune disease and 11/42 (26.19%) were smokers. DISCUSSION: Our results show a notable increase in the incidence of GD during the year 2021, specially in women with a history of smoking. Hyper activation of the immune system induced by SARS-CoV2 and by the recently released SARS-COV-2 vaccines has been highlighted in recent months. To assess whether this observed increase in the incidence of GD is sustained in the coming years or has simply been a precipitous trigger for individuals who were already predisposed to develop the disease, future studies will be needed.

Unexpected relevant role of gene mosaicism in patients with primary immunodeficiency diseases.

BACKGROUND: Postzygotic de novo mutations lead to the phenomenon of gene mosaicism. The 3 main types are called somatic, gonadal, and gonosomal mosaicism, which differ in terms of the body distribution of postzygotic mutations. Mosaicism has been reported occasionally in patients with primary immunodeficiency diseases (PIDs) since the early 1990s, but its real involvement has not been systematically addressed. OBJECTIVE: We sought to investigate the incidence of gene mosaicism in patients with PIDs. METHODS: The amplicon-based deep sequencing method was used in the 3 parts of the study that establish (1) the allele frequency of germline variants (n = 100), (2) the incidence of parental gonosomal mosaicism in families with PIDs with de novo mutations (n = 92), and (3) the incidence of mosaicism in families with PIDs with moderate-to-high suspicion of gene mosaicism (n = 36). Additional investigations evaluated body distribution of postzygotic mutations, their stability over time, and their characteristics. RESULTS: The range of allele frequency (44.1% to 55.6%) was established for germline variants. Those with minor allele frequencies of less than 44.1% were assumed to be postzygotic. Mosaicism was detected in 30 (23.4%) of 128 families with PIDs, with a variable minor allele frequency (0.8% to 40.5%). Parental gonosomal mosaicism was detected in 6 (6.5%) of 92 families with de novo mutations, and a high incidence of mosaicism (63.9%) was detected among families with moderate-to-high suspicion of gene mosaicism. In most analyzed cases mosaicism was found to be both uniformly distributed and stable over time. CONCLUSION: This study represents the largest performed to date to investigate mosaicism in patients with PIDs, revealing that it affects approximately 25% of enrolled families. Our results might have serious consequences regarding treatment and genetic counseling and reinforce the use of next-generation sequencing-based methods in the routine analyses of PIDs.

Risk factors for intracranial lesions and mortality in older patients with mild traumatic brain injuries.

PRIMARY OBJECTIVE: To identify risk factors for intracerebral lesion (ICL) in older adults with mild traumatic brain injury (MTBI) and evaluate the influence of comorbidities on outcomes. RESEARCH DESIGN: Prospective cohort study. METHODS AND PROCEDURES: Information was gathered on clinical history/examination, cranial computed tomography, admission Glasgow Coma Scale (GCS) score, analytical and coagulation findings, and mortality at 1 week post-discharge. Bivariate and multivariate logistic regression analyses were performed, calculating odds ratios for ICL with 95% confidence interval. P < 0.05 was considered significant. MAIN OUTCOMES AND RESULTS: Data were analyzed on 504 patients with mean±SD age of 79.37 ± 8.06 years. Multivariate analysis showed that traffic accident, GCS score of 14/15, transient consciousness loss, nausea, and receipt of antiplatelets were predictors of ICL, while SRRI and/or benzodiazepine intake was a protective factor. A score was assigned to patients by rounding OR values, and a score ≥1 indicated moderate/high risk of ICL. CONCLUSIONS: MTBI management should be distinct in over-60 year-olds, who may not present typical symptoms, with frequent comorbidities. Knowledge of risk factors for post-MTBI ICL, associated with higher mortality, is important to support clinical decision-making. Further research is warranted to verify our novel finding that benzodiazepines and/or SSRI inhibitors may act as neuroprotectors.

Early renal graft function deterioration in recipients with preformed anti-MICA antibodies: partial contribution of complement-dependent cytotoxicity.

BACKGROUND: We previously reported that preformed anti-MHC class I-related chain A (MICA) antibodies increase the risk for renal graft rejection and enhance the deleterious effect of PRA(+) status early after transplantation. METHODS: We studied 727 kidney recipients. Days to reach optimal serum creatinine level, estimated glomerular filtration rate (eGFR) at Month 3 and chronic kidney disease (CKD) stages were recorded. Anti-MICA specificities and C1q binding were tested by solid-phase assay. Complement-dependent cytotoxicity (CDC) and flow cytometry (FC) cross-matches with HeLa and PMA/CD28-T-blasts were performed. RESULTS: PRA(+)MICA(+) recipients exhibited longer time to reach optimal serum creatinine level after transplantation (P = 0.005) and had the lowest eGFR at Month 3 (P = 0.006). PRA(+)MICA(+) status independently increased the risk for CKDT stage 5 at Month 3 [hazard ratio (HR) 4.92, P = 0.030]. Pre-transplant anti-MICA antibodies were polyspecific and showed stronger reactions when coexisting with anti-HLA antibodies (mean standard fluorescent intensity 112 157 ± 44 426 in HLA(+)MICA(+) sera versus 49 680 ± 33 116 in HLA(-)MICA(+) sera, P = 0.0006). Anti-AYVE supereplet reactivity was significantly higher in HLA(+)MICA(+) versus HLA(-)MICA(+) patients (P < 0.001) and significantly superior than anti-CMGWS supereplet within HLA(+)MICA(+) patients (P = 0.001). Three of 13 anti-MICA(+) pre-transplant sera were positive for the C1q binding assay; one of them (serum 3) exclusively recognized AYVE supereplet with a strong reactivity against MICA*027 antigen (same as MICA*008). Anti-MICA antibodies in anti-HLA-absorbed serum 3 bound native MICA molecules in MICA*008(+) HeLa and PMA/CD28-T-blasts and mediated cell death by activating complement. CONCLUSION: Preformed anti-MICA antibodies may occasionally be cytotoxic by fixing and activating complement. This way they might contribute to worse early kidney graft function.

Pretransplant identification of acute rejection risk following kidney transplantation.

Lack of an accepted definition for 'high immunological risk' hampers individualization of immunosuppressive therapy after kidney transplantation. For recipient-related risk factors for acute rejection, the most compelling evidence points to younger age and African American ethnicity. Recipient gender, body mass, previous transplantation, and concomitant infection or disease do not appear to be influential. Deceased donation now has only a minor effect on rejection risk, but older donor age remains a significant predictor. Conventional immunological markers (human leukocyte antigen [HLA] mismatching, pretransplant anti-HLA alloantibodies, and panel reactive antibodies) are being reassessed in light of growing understanding about the role of donor-specific antibodies (DSA). At the time of transplant, delayed graft function is one of the most clear-cut risk factors for acute rejection. Extended cold ischemia time (≥ 24 h) may also play a contributory role. While it is not yet possible to establish conclusively the relative contribution of different risk factors for acute rejection after kidney transplantation, the available data point to variables that should be taken into account at the time of transplant. Together, these offer a realistic basis for planning an appropriate immunosuppression regimen in individual patients.

[Health-related quality of life in Latin American adolescents]. / Calidad de vida relacionada con la salud de adolescentes latinoamericanos.

OBJECTIVE: The objective of the present study was to find out if there are differences in terms of sex, age, or country of origin for the components of health-related quality of life (HRQL) in samples of adolescents from three cities-in Argentina, Brazil, and Chile, respectively-using data collected through an internationally recognized and validated survey questionnaire, KIDSCREEN-52. METHODS: The KIDSCREEN-52 questionnaire was administered to 1 357 adolescents between 12 and 17 years of age (48.6% of them male) in selected samples in the three countries. Univariate analysis of variation (ANCOVA) was used. Not only sex and age differences, but also differences for each component of HRQL, were found between the three country groups. RESULTS: The data showed significant differences between the three countries for each of the specific components of HRQL. Males scored significantly higher than females in the following components: Physical Well-being (P < 0.001), Psychological Well-being (P = 0.019), Moods and Emotions (P < 0.001), Self-perception (P = 0.001), Autonomy (P < 0.001), and Parent Relations and Home Life (P = 0.008). Furthermore, the average scores for Physical Well-being (P = 0.001), Psychological Well-being (P = 0.001), Self-Perception (P = 0.038), Autonomy (P = 0.001), Parent Relations and Home Life (P = 0.001), School Environment (P = 0.001), and Financial Resources (P = 0.022) showed a significantly declining trend with each advancing year, while average scores for the component Social Acceptance (Bullying) increased significantly with age (P < 0.001). CONCLUSIONS: The evidence suggests that interventions in disease prevention and health promotion should be developed for specific target groups, using appropriate actions depending on the sex and age of the adolescents.

Comparison of the long-term outcomes of kidney transplantation: USA versus Spain.

BACKGROUND: The long-term outcomes of kidney transplantation are suboptimal because many patients lose their allografts or experience premature death. Cross-country comparisons of long-term outcomes of kidney transplantation may provide insight into factors contributing to premature graft failure and death. We evaluated the rates of late graft failure and death among US and Spanish kidney recipients. METHODS: This is a cohort study of US (n = 9609) and Spanish (n = 3808) patients who received a deceased donor kidney transplant in 1990, 1994, 1998 or 2002 and had a functioning allograft 1 year after transplantation with follow-up through September 2006. Ten-year overall and death-censored graft survival and 10-year overall recipient survival and death with graft function (DWGF) were estimated with multivariate Cox models. RESULTS: Among recipients alive with graft function 1 year after transplant, the 10-year graft survival was 71.3% for Spanish and 53.4% for US recipients (P < 0.001). The 10-year, death-censored graft survival was 75.6 and 76.0% for Spanish and US recipients, respectively (P = 0.73). The 10-year recipient survival was 86.2% for Spanish and 67.4% for US recipients (P < 0.001). In recipients with diabetes as the cause of ESRD, the adjusted DWGF rates at 10 years were 23.9 and 53.8 per 1000 person-years for Spanish and US recipients, respectively (P < 0.001). Among recipients whose cause of ESRD was not diabetes mellitus, the adjusted 10-year DWGF rates were 11.0 and 25.4 per 1000 person-years for Spanish and US recipients, respectively. CONCLUSIONS: US kidney transplant recipients had more than twice the long-term hazard of DWGF compared with Spanish kidney transplant recipients and similar levels of death-censored graft function. Pre-transplant medical care, comorbidities, such as cardiovascular disease, and their management in each country's health system are possible explanations for the differences between the two countries.

Renal transplantation using kidneys from hepatitis C-infected donors: A review of 30-years' experience.

Kidney transplantation is the optimal therapy for end-stage kidney disease but limited by the available number of organs. Using HCV+ donors, both in HCV+ and HCV- recipients, is a rational response to the organ shortage. We review the historic experience using HCV+ donors in HCV+ recipients and assess long-term results. We also discuss contemporary practices, including the transplantation of HCV-viremic kidneys into HCV- recipients with different approaches to posttransplant HCV therapy.

Risk factors for graft loss and mortality after renal transplantation according to recipient age: a prospective multicentre study.

BACKGROUND: To describe the causes of graft loss, patient death and survival figures in kidney transplant patients in Spain based on the recipient's age. METHODS: The results at 5 years of post-transplant cardiovascular disease (CVD) patients, taken from a database on CVD, were prospectively analysed, i.e. a total of 2600 transplanted patients during 2000-2002 in 14 Spanish renal transplant units, most of them receiving their organ from cadaver donors. Patients were grouped according to the recipient's age: Group A: <40 years, Group B: 40-60 years and Group C: >60 years. The most frequent immunosuppressive regimen included tacrolimus, mycophenolate mofetil and steroids. RESULTS: Patients were distributed as follows: 25.85% in Group A (>40 years), 50.9% in Group B (40-60 years) and 23.19% in Group C (>60). The 5-year survival for the different age groups was 97.4, 90.8 and 77.7%, respectively. Death-censored graft survival was 88, 84.2 and 79.1%, respectively, and non death-censored graft survival was 82.1, 80.3 and 64.7%, respectively. Across all age groups, CVD and infections were the most frequent cause of death. The main causes of graft loss were chronic allograft dysfunction in patients <40 years old and death with functioning graft in the two remaining groups. In the multivariate analysis for graft survival, only elevated creatinine levels and proteinuria >1 g at 6 months post-transplantation were statistically significant in the three age groups. The patient survival multivariate analysis did not achieve a statistically significant common factor in the three age groups. CONCLUSIONS: Five-year results show an excellent recipient survival and graft survival, especially in the youngest age group. Death with functioning graft is the leading cause of graft loss in patients >40 years. Early improvement of renal function and proteinuria together with strict control of cardiovascular risk factors are mandatory.

Acute graft pyelonephritis in renal transplant recipients: incidence, risk factors and long-term outcome.

BACKGROUND: The influence of acute graft pyelonephritis (AGPN) on graft outcome in renal transplant recipients still remains controversial. METHODS: We retrospectively analysed 189 patients (113 males; mean age: 49.7 ± 13.1 years) undergoing renal transplantation at the University Hospital 12 de Octubre (Madrid, Spain) from January 2002 to December 2004, with a minimum follow-up of 36 months. Factors associated with AGPN were assessed by logistic regression analysis. Long-term graft function was compared according to the occurrence of this complication during follow-up. 'Decline in renal graft function' was defined as the increase in serum creatinine (SC) levels > 0.33 mg/dL between Month 3 and Year 1 after transplantation. RESULTS: Nineteen patients (10.0%) were diagnosed with 25 episodes of AGPN (incidence rate: 4.4 episodes per 100 patient-years). The presence of glomerulonephritis as the underlying disease [odds ratio (OR) 4.2; 95% confidence interval (95%CI): 1.3-14.1] and the previous occurrence of two to five (OR 9.4; 95%CI: 1.5-56.8) or more than five episodes of asymptomatic bacteriuria after transplantation (OR 19.8; 95%CI: 2.4-160.2) emerged as independent predictors for AGPN. A near-significant association was found for cytomegalovirus infection (OR 4.2; 95%CI: 0.9-18.4), whereas receiving a single-kidney transplant (vs. double-kidney) showed a protective effect (OR 0.2; 95%CI: 0.0-0.8). During the 36-month follow-up, levels of SC, creatinine clearance and 24-h proteinuria did not differ significantly between patients with or without AGPN, and this complication did not exert any effect on the risk for decline in renal graft function. CONCLUSIONS: AGPN does not impair long-term graft function in renal transplant recipients.

Critical role of interleukin (IL)-17 in inflammatory and immune disorders: An updated review of the evidence focusing in controversies.

Interleukin 17 (IL-17) is a proinflammatory cytokine that has been the focus of intensive research because of its crucial role in the pathogenesis of different diseases across many medical specialties. In this context, the present review in which a panel of 13 experts in immunology, dermatology, rheumatology, neurology, hematology, infectious diseases, hepatology, cardiology, ophthalmology and oncology have been involved, puts in common the mechanisms through which IL-17 is considered a molecular target for the development of novel biological therapies in these different fields. A comprehensive review of the literature and analysis of the most outstanding evidence have provided the basis for discussing the most relevant data related to IL-17A blocking agents for the treatment of different disorders, such as psoriasis, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, cardiovascular disorders, non alcoholic fatty liver disease, multiple sclerosis, inflammatory bowel disease, uveitis, hematological and solid cancer. Current controversies are presented giving an opening line for future research.

Artificial Stone Silicosis: Rapid Progression Following Exposure Cessation.

BACKGROUND: Silicosis is rapidly emerging in high-income countries in relation to the replacement of natural stone with artificial stone, especially in the manufacturing and installation of kitchen and bathroom countertops. Progression of this form of silicosis following the cessation of exposure is unknown. RESEARCH QUESTION: The objective of this study was to determine the radiologic progression and lung function in individuals with artificial stone silicosis. STUDY DESIGN AND METHODS: Between 2009 and 2018, a total of 106 patients were diagnosed with artificial stone silicosis in the Bay of Cádiz area (southern Spain), 14.15% by using biopsy results and the remainder according to chest radiography and high-resolution CT imaging. Follow-up consisted of respiratory function tests and radiographic studies. All patients stopped working in the stone industry following diagnosis. RESULTS: All patients were men; their mean ± SD age at diagnosis was 36.2 ± 7.0 years, and the mean duration of exposure was 12.0 ± 4.3 years. At diagnosis, 99 patients were considered to have simple silicosis (93.4%) and seven to have progressive massive fibrosis (PMF) (6.6%). After a mean follow-up of 4.01 ± 2.1 years, disease in 56% of patients had progressed two or more International Labour Office subcategories, and the number of patients with PMF had increased to 40 (37.7%). Regarding lung function, there was a decrease in FVC and FEV1, with an average decrease of 86.8 and 83.4 mL per year, respectively; in 25% of patients, the annual decrease was > 157 mL in FVC and > 133 mL in FEV1. Multivariable analysis showed that lower FVC at diagnosis and longer duration of exposure to silica were associated with progression to PMF. INTERPRETATION: Artificial stone silicosis rapidly progresses to PMF even following exposure cessation, and a significant percentage of patients experience a very rapid decrease in lung function.

[Chronic nephropathy in non-kidney transplantation: [prevention, early diagnosis and management]. / Nefropatía crónica en trasplante no renal: prevención, diagnóstico precoz y manejo.

Transplant from solid nonrenal organ has experienced an important increase in the last decades. It is due to the increasing improvement of the results obtained with the above mentioned transplants. Parallel, many nonrenal transplanted patients have developed a chronic renal failure that has determined, in some cases, the need of beginning the substitution of renal function by means of dialysis and/or transplant. The origin of the same one is multifactorial and the consequences derived from it are very important so much in morbimortality as of economic nature for the set of the system. The present review tries to help to the identification of risk factors of renal insufficiency in the nonrenal transplanted patient and to determine which might be the basic concepts of prevention, early diagnosis and of derivation to the nephrologist expert in transplants and renal dysfunction. Finally, we check the possibilities of managing of the immunosuppressive treatment and substitution of renal function by means of dialysis and/or simple or double transplant.

Hepatitis C and kidney transplant: The eradication time of the virus has arrived. / Hepatitis C y trasplante renal: el tiempo de la erradicación del virus ha llegado.

Hepatitis C virus (HCV) infection is a factor that reduces the survival of the patient and the graft in renal transplant (RT). The availability of directly acting antivirals agents (DAAs), very effective and with an excellent safety profile, it allows eradicate HCV from patients with kidney disease, and this is a revolutionary radical change in the natural evolution of this infection, until now without effective and safe treatment for the contraindication use of interferon in kidney transplant patients. The efficiency of some DAAs for all genotypes, even in patients with renal insufficiency constitutes a huge contribution to eradicate HCV in the RT population independently the genotype, severity of kidney failure, progression of liver disease and previous anti HCV therapy. All this is raising, although with controversies, the possibility of use kidneys from infected HCV+ donors for transplant in uninfected receptors and can be treated successfully in the early post-TR, thus increasing the total "pool" of kidneys for RT.

Antiphospholipid Syndrome and Renal Allograft Thrombosis.

Renal allograft thrombosis is the most frequent and devastating complication in the early postrenal transplantation period. Several risk factors to develop graft thrombosis depending on donors and recipients are well known. Antiphospholipid syndrome (APS) is well recognized as an important cause of kidney injury, with specific clinical and histological features that may lead to renal injury caused by thrombosis at any location within the renal vasculature. There are 3 forms of APS, primary (the most common form), associated to other systemic autoimmune diseases (SAD-APS), and catastrophic. Nevertheless, patients with SAD-APS and renal failure only represent 2% to 5% in hemodialysis or transplantation. The presence of pretransplant antiphospholipid antibodies increases risk of graft thrombosis. A new form of APS based on IgA anti-ß-2-glycoprotein-I (B2GPI) antibodies, representing up to 30% of patients in end-stage renal disease and renal transplantation, is the main independent risk factor for graft thrombosis and early graft loss after renal transplantation. In addition, B2GP1 bound to IgA aB2GP1 immunocomplexes have been described as a marker to predict thrombosis after renal transplantation in patients with antiphospholipid antibodies. Anticoagulation remains the main treatment to prevent renal allograft thrombosis, although new preventive strategies are coming. Future studies may help to identify better therapeutic targets.

The IgA Isotype of Anti-ß2 Glycoprotein I Antibodies Recognizes Epitopes in Domains 3, 4, and 5 That Are Located in a Lateral Zone of the Molecule (L-Shaped).

Background: Antiphospholipid syndrome (APS) is characterized by thrombosis and/or pregnancy morbidity with presence of anti-phospholipid antibodies (aPL). The APS classification criteria only consider the aPL of IgG/IgM isotype, however testing of aPL of IgA isotype is recommended when APS is suspected and consensus aPL are negative. IgA anti-ßeta-2 glycoprotein-I (B2GP1) has been clearly related with occurrence of thrombotic events. Antibodies anti-B2GP1 of IgG/M isotypes recognize an epitope in Domain 1 (R39-G43), the epitopes that recognize IgA anti-B2GP1 antibodies are not well-identified. Aim: To determine the zones of B2GP1 recognized by antibodies of IgA isotype from patients with APS symptomatology and positive for IgA anti-B2GP1. Methods: IgA antibodies to Domain-1(D1) and Domain-4/5(D4/5) of B2GP1 (ELISA) and epitope mapping on oligopeptide arrays of B2GP1 were evaluated in sera from a group of 93 patients with at least one thrombotic and with isolated positivity for IgA anti-B2GP1 antibodies (negative for other aPL). Results: A total of 47 patients (50.5%) were positive for anti-D4/5 and 23(25%) were positive for anti-D1. When peptide arrays were analyzed, three zones of B2GP1 reactivity were identified for more than 50% of patients. The center of these zones corresponds to amino acids 140(D3), 204(D4), and 264(D5). The peptides recognized on D3 and D4 contain amino acid sequences sharing high homology with proteins of microorganism that were previously related with a possible APS infectious etiology. In the three-dimensional structure of B2GP1, the three peptides, as the R39-G43 epitope, are located on the right side of the molecule (L-shape). The left side (J-shape) does not bind the antibodies. Conclusions: Patients with thrombotic APS clinical-criteria, and isolated IgA anti-B2GP1 positivity appear to preferentially bind, not to the D1 or D4/5 domains of B2GP1, but rather to three sites in D3, D4, and D5. The sites on D3 and D4 were previously described as the target identified by human monoclonal antibodies derived from patients that were capable of inducing APS in animal models. The localization of these epitopes opens a new route to explore to increase understanding of the patholophysiology of the APS and to propose new alternatives and therapeutic targets.

[Refractory celiac disease]. / Enfermedad celíaca refractaria.

The main cause of lack of response to a gluten-free diet is continued, usually inadvertent, gluten intake. Diagnosis of refractory celiac disease is established on the basis of exclusion of other disorders, persistence of malabsorption and villous atrophy. Refractory celiac disease affects a heterogeneous group of patients, usually adults and, fortunately, is infrequent (<5% of the population). Detection of alterations in the intraepithelial lymphocyte population is essential for diagnosis. Some alterations in these lymphocytes, such as the absence of T cell surface receptor expression (CD3 and CD), indicate an aggressive form of the disease with the potential for malignant transformation (type II refractory celiac disease). Treatment is based on adequate nutritional support and on the use of corticosteroids and/or immunosuppressive agents (mainly azathioprine and infliximab). Because of the high risk of progression to intestinal T cell lymphoma, patients diagnosed with type 2 refractory disease require different -generally more aggressive- therapeutic strategies. At present, no treatment has been demonstrated to be effective in the long term, but two options that should be considered in type II disease are immunotherapy with anti-CD52 or similar agents, and autologous bone marrow transplantation. Trials with antibodies that block epithelial secretion of interleukin-15, a key molecule in the pathogenesis of the disease, are promising.

Gluten-degrading bacteria are present in the human small intestine of healthy volunteers and celiac patients.

Gluten is the only known environmental factor that triggers celiac disease. Several studies have described an imbalance between the intestinal microbiota of different individuals based on diagnoses. Moreover, recent studies have suggested that human bacteria may play an important role in gluten hydrolysis. However, there has been no research focusing on the small intestine. This study aimed to characterize the adult small intestine microbiota possibly implicated in gluten hydrolysis. Duodenal biopsies from different diagnosed individuals were cultured in a gluten-containing medium, and the grown microbiota was analyzed by culture dependent/independent methods. Results showed that gluten-degrading bacteria can be found in the human small intestine. Indeed, 114 bacterial strains belonging to 32 species were isolated; 85 strains were able to grow in a medium containing gluten as the sole nitrogen source, 31 strains showed extracellular proteolytic activity against gluten protein and 27 strains showed peptidolytic activity towards the 33 mer peptide, an immunogenic peptide for celiac disease patients. We found that there are no differences based on the diagnosis, but each individual has its own population of gluten-hydrolyzing bacteria. These bacteria or their gluten-degrading enzymes could help to improve the quality of life of celiac disease patients'.