Immunoglobulin G4-Related Disease: What an Allergist Should Know.

Immunoglobulin G4-related disease (IgG4-RD) is a fibroinflammatory disorder that begins in 1 or more organs as inflammatory tumors that progress toward fibrosis. It is often accompanied by elevated serum IgG4. IgG4-RD was first described in 2003 as a new concept encompassing a number of immunoallergic diseases that had previously been considered unrelated. IgG4-RD mainly affects middleaged and older men. It consists of upregulation and expansion of CD4+ cytotoxic T lymphocytes, oligoclonal plasmablasts, and other inflammatory cells that infiltrate affected tissues and induce inflammation, organ dysfunction, and fibrosis. Symptoms depend on the location, severity, and extent of the disease. Virtually any organ can be affected, including the pancreas, salivary glands, lacrimal glands, thyroid gland, retro-orbital tissue, lymph nodes, retroperitoneum, mediastinum, lung, kidney, aorta, serosal surfaces, and meninges. Patients with widespread disease may present general symptoms. At least 30%-40% of patients are atopic or display atopic traits such as eosinophilia and elevated serum IgE levels. Additional laboratory features include increased serum IgG4 concentrations, increased blood IgG4-plasmablasts, hypergammaglobulinemia, and hypocomplementemia. Diagnosis of IgG4-RD is based on a clinicopathological correlation. Lymphoplasmacytic infiltrate with abundant IgG4-positive plasma cells, storiform-type fibrosis, obliterative phlebitis, and tissue eosinophilia are the pathological hallmarks. Therapy for IgG4-RD is based primarily on corticosteroids but may include additional immunomodulatory drugs and monoclonal antibodies such as rituximab. In individuals with allergic features, IgG4-RD should be suspected when a history of unexplained swelling is observed in 1 or more organs, particularly if they respond to corticosteroids and the patients are men in the sixth decade of life and beyond.

Immunoglobulin G4–Related Disease: What an Allergist Should Know

Immunoglobulin G4–related disease (IgG4-RD) is a fibroinflammatory disorder that begins in 1 or more organs as inflammatory tumors that progress toward fibrosis. It is often accompanied by elevated serum IgG4. IgG4-RD was first described in 2003 as a new concept encompassing a number of immunoallergic diseases that had previously been considered unrelated. IgG4-RD mainly affects middleaged and older men. It consists of upregulation and expansion of CD4+ cytotoxic T lymphocytes, oligoclonal plasmablasts, and other inflammatory cells that infiltrate affected tissues and induce inflammation, organ dysfunction, and fibrosis. Symptoms depend on the location, severity, and extent of the disease. Virtually any organ can be affected, including the pancreas, salivary glands, lacrimal glands, thyroid gland, retro-orbital tissue, lymph nodes, retroperitoneum, mediastinum, lung, kidney, aorta, serosal surfaces, and meninges. Patients with widespread disease may present general symptoms. At least 30%-40% of patients are atopic or display atopic traits such as eosinophilia and elevated serum IgE levels. Additional laboratory features include increased serum IgG4 concentrations, increased blood IgG4-plasmablasts, hypergammaglobulinemia, and hypocomplementemia. Diagnosis of IgG4-RD is based on a clinicopathological correlation. Lymphoplasmacytic infiltrate with abundant IgG4-positive plasma cells, storiform-type fibrosis, obliterative phlebitis, and tissue eosinophilia are the pathological hallmarks. Therapy for IgG4-RD is based primarily on corticosteroids but may include additional immunomodulatory drugs and monoclonal antibodies such as rituximab. In individuals with allergic features, IgG4-RD should be suspected when a history of unexplained swelling is observed in 1 or more organs, particularly if they respond to corticosteroids and the patients are men in the sixth decade of life and beyond (AU)

A Dramatic Case of Odynophagia.

We report the case of a 77-year-old male with a history of aortic stenosis and interstitial lung disease, who debuted 3 years ago with an outbreak of necrotic and very painful canker sores. The severity of the lesions and their refractory response to treatment led to several hospital admissions and multiple consultations to different specialists (ENT, rheumatology, dermatology, ophthalmology, cardiology, and internal medicine). During this time, the patient received central parenteral nutrition with an episode of catheter-related septicemia, and he came to require psychiatric assistance for autolytic ideation. Numerous diagnostic tests were performed with inconclusive results, including biopsy of the lesion (histological study, immunohistochemistry for CD68 + , CD4 + , CD8 + , CD20 + , MCT +, and cytomegalovirus, PAS, Grocott-Gomori and Zielh-Neelsen staining, and in situ hybridization for Epstein Barr virus). Numerous treatments were unsuccessfully tested until thalidomide was administered, thus completely remitting lesions but leaving retractable scarring sequelae. Since then, the patient has had two recurrences, coinciding with the reduction of thalidomide dosages, which were controlled by increasing the dose of the immunomodulator. Recurrent necrotizing major aphthous stomatitis (Sutton's disease) is a clinical variant of recurrent aphthous stomatitis that may have a dramatic course. Unfortunately, the lack of etiopathogenetic uniformity precludes any specific treatment. In severe cases, immunomodulators, including thalidomide, may represent a valid therapeutic option.

Really does temperature reduction and norepinephrine have similar effects on the energy metabolism in rat brown adipose tissue?

CONTEXT: Heat generation by brown adipose tissue (BAT) in response to temperature reduction seems to be entirely related to sympathetic nervous stimulation. OBJECTIVE: To analyse if temperature reduction and norepinephrine may differently affect the expression of proteins related to energy metabolism in BAT. MATERIALS AND METHODS: Isolated rats BAT was incubated with/without norepinephrine (10-6 mol/L, 24 h at 32 °C and 37 °C). RESULTS: In BAT, 32 °C increased the protein expression levels of carnitine palmitoyltransferase-I and -II, mitochondrial uncoupling protein-1 (UCP-1) and the expression and activity of lactate dehydrogenase. Mitochondrial F1-ATP synthase α-chain expression was decreased at 32 °C compared to 37 °C. Norepinephrine and at 32 °C exposure, UCP-1 expression was increased but cytochrome-c oxidase and F1-ATP synthase α-chain expression was reduced with respect to 37 °C. DISCUSSION: Sympathetic stimulation seems not to be the only factor associated with heat generation. CONCLUSIONS: Temperature reduction by itself exerts some different effects on the expression of proteins related to the energy metabolism than norepinephrine.

Características clínicas al diagnóstico de una cohorte prospectiva de pacientes con lupus eritematoso sistémico atendidos en servicios de Medicina Interna españoles: estudio RELES / Clinical characteristics during diagnosis of a prospective cohort of patients with systemic lupus erythematosus treated in Spanish Departments of Internal Medicine: the RELES study

Introducción. Los registros de pacientes son herramientas útiles para evaluar enfermedades poco frecuentes. Nuestro objetivo es presentar el «Registro español de pacientes con lupus eritematoso sistémico» (RELES). Pacientes y métodos. RELES se inició en 2008, como un registro multicéntrico de cohortes, observacional, prospectivo, incluyendo a pacientes desde el momento del diagnóstico, cuyo objetivo es analizar la incidencia y complicaciones no inflamatorias del lupus eritematoso sistémico (LES). Participan los servicios de Medicina Interna de 38 hospitales españoles. Resultados. Se incluyó a 298 pacientes con una edad media de 40,8±15,7 años, de los que el 88,9% eran mujeres y el 85,6% de raza caucásica. En la primera visita, predominaron las manifestaciones articulares (74,5%). Ciento setenta y siete pacientes (59,4%) mostraban positividad para anti-DNA nativo, siendo superior en estos la frecuencia de nefritis lúpica (26,7% vs. 14%, p=0,009; riesgo relativo [RR] 1,33), de anemia hemolítica (13,6% vs. 4,1%, p= 0,07; RR 1,46) y linfopenia (55,4% vs. 43,8%, p=0,05; RR 1,21). La mediana del Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI 2K) fue de 9,64 puntos (rango intercuartílico 4-13). Los tratados con antipalúdicos antes del diagnóstico de LES tenían una mediana de SLEDAI en la primera visita de 5, frente a 8 en los que no los tomaban (p=0,02). Conclusiones. RELES constituye la primera cohorte de pacientes con LES recogidos desde el momento del diagnóstico en España. La presencia de anti-DNA se ha relacionado con manifestaciones graves como nefritis y anemia hemolítica. El tratamiento con antipalúdicos antes del diagnóstico se asoció con una enfermedad menos activa al comienzo (AU)

Introduction. Patient registries are useful tools for assessing rare diseases. Our objective is to present the Spanish registry of patients with systemic lupus erythematosus (Registro español de pacientes con lupus eritematoso sistémico, RELES). Patients and methods. RELES was started in 2008 as an observational, prospective, multicentre cohort registry that included patients from the time they were diagnosed. The registry's objective is to analyse the incidence and noninflammatory complications of systemic lupus erythematosus (SLE). The departments of internal medicine of 38 Spanish hospitals participate in this registry. Results. A total of 298 patients with a mean age of 40.8±15.7 years were included, 88.9% of whom were women and 85.6% of whom were white. In the first visit, there was a predominance of joint manifestations (74.5%). One hundred and seventy-seven patients (59.4%) were positive for anti-native DNA. In these patients, there was a higher rate of lupus nephritis (26.7% vs. 14%, p=.009; relative risk [RR], 1.33), haemolytic anaemia (13.6% vs. 4.1%, p=.07; RR, 1.46) and lymphopenia (55.4% vs. 43.8%, p=.05; RR, 1.21). The median Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI 2K) score was 9.64 points (interquartile range, 4-13). The patients treated with antimalarial drugs before the diagnosis of SLE had a median SLEDAI score in the first visit of 5, compared with 8 for those who were not treated with these drugs (p=.02). Conclusions. RELES constitutes the first Spanish patient cohort with SLE recorded from the time of the diagnosis. The presence of anti-DNA has been related to severe manifestations such as nephritis and haemolytic anaemia. Treatment with antimalarial drugs before the diagnosis was associated with less active disease at the initial presentation (AU)

Factors Influencing Serum Concentrations of Immunoglobulin D in the Adult Population: An Observational Study in Spain.

Immunoglobulin D (IgD) is the least studied of immunoglobulin classes. This study sought to investigate the potential relationship between demographic, metabolic, lifestyle and immunological factors, and serum IgD concentrations in a general adult population. We measured serum IgD concentrations by means of a commercial turbidimetric assay in 413 individuals (median age, 55 years; 45% males), randomly selected from the adult population of a Spanish municipality. Serum IgD concentrations displayed considerable variation in the population, ranging from undetectable (<6.7 mg/l) to 878 mg/l. Serum IgD concentrations were undetectable in 78 cases (18.9%) and >100 mg/l in 39 cases (9.4%). Median IgD was 21.9 mg/l. Serum IgD concentrations were negatively associated with age and positively associated with smoking, after adjustment for potential confounders. Overweight individuals showed lower concentrations of IgD than did normal-weight individuals. Atopy (positivity of skin tests to aeroallergens) was not significantly associated with IgD concentrations, although non-symptomatic atopics showed higher IgD concentrations. No consistent association was observed between serum IgD concentrations and gender, metabolic syndrome, or alcohol consumption. No significant association was found between baseline IgD concentrations and development of either allergic or immune disease after a median 11.4 years of follow-up. In conclusion, serum IgD concentrations in adults show a wide variation in the population and may be influenced by common factors, particularly age and smoking habit. These factors should be taken into account when defining reference ranges for serum IgD concentrations.

Clinical characteristics during diagnosis of a prospective cohort of patients with systemic lupus erythematosus treated in Spanish Departments of Internal Medicine: The RELES study. / Características clínicas al diagnóstico de una cohorte prospectiva de pacientes con lupus eritematoso sistémico atendidos en servicios de Medicina Interna españoles: estudio RELES.

INTRODUCTION: Patient registries are useful tools for assessing rare diseases. Our objective is to present the Spanish registry of patients with systemic lupus erythematosus (Registro español de pacientes con lupus eritematoso sistémico, RELES). PATIENTS AND METHODS: RELES was started in 2008 as an observational, prospective, multicentre cohort registry that included patients from the time they were diagnosed. The registry's objective is to analyse the incidence and noninflammatory complications of systemic lupus erythematosus (SLE). The departments of internal medicine of 38 Spanish hospitals participate in this registry. RESULTS: A total of 298 patients with a mean age of 40.8±15.7 years were included, 88.9% of whom were women and 85.6% of whom were white. In the first visit, there was a predominance of joint manifestations (74.5%). One hundred and seventy-seven patients (59.4%) were positive for anti-native DNA. In these patients, there was a higher rate of lupus nephritis (26.7% vs. 14%, p=.009; relative risk [RR], 1.33), haemolytic anaemia (13.6% vs. 4.1%, p=.07; RR, 1.46) and lymphopenia (55.4% vs. 43.8%, p=.05; RR, 1.21). The median Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI 2K) score was 9.64 points (interquartile range, 4-13). The patients treated with antimalarial drugs before the diagnosis of SLE had a median SLEDAI score in the first visit of 5, compared with 8 for those who were not treated with these drugs (p=.02). CONCLUSIONS: RELES constitutes the first Spanish patient cohort with SLE recorded from the time of the diagnosis. The presence of anti-DNA has been related to severe manifestations such as nephritis and haemolytic anaemia. Treatment with antimalarial drugs before the diagnosis was associated with less active disease at the initial presentation.

First month prednisone dose predicts prednisone burden during the following 11†months: an observational study from the RELES cohort.

AIM: To study the influence of prednisone dose during the first month after systemic lupus erythematosus (SLE) diagnosis (prednisone-1) on glucocorticoid burden during the subsequent 11 months (prednisone-2-12). METHODS: 223 patients from the Registro Español de Lupus Eritematoso Sistémico inception cohort were studied. The cumulative dose of prednisone-1 and prednisone-2-12 were calculated and recoded into a four-level categorical variable: no prednisone, low dose (up to 7.5 mg/day), medium dose (up to 30 mg/day) and high dose (over 30 mg/day). The association between the cumulative prednisone-1 and prednisone-2-12 doses was tested. We analysed whether the four-level prednisone-1 categorical variable was an independent predictor of an average dose >7.5 mg/day of prednisone-2-12. Adjusting variables included age, immunosuppressives, antimalarials, methyl-prednisolone pulses, lupus nephritis and baseline SLE Disease Activity Index (SLEDAI). RESULTS: Within the first month, 113 patients (51%) did not receive any prednisone, 24 patients (11%) received average low doses, 46 patients (21%) received medium doses and 40 patients (18%) received high doses. There was a strong association between prednisone-1 and prednisone-2-12 dose categories (p<0.001). The cumulative prednisone-1 dose was directly associated with the cumulative prednisone-2-12 dose (p<0.001). Compared with patients on no prednisone, patients taking medium (adjusted OR 5.27, 95% CI 2.18 to 12.73) or high-dose prednisone-1 (adjusted OR 10.5, 95% CI 3.8 to 29.17) were more likely to receive prednisone-2-12 doses of >7.5 mg/day, while patients receiving low-dose prednisone-1 were not (adjusted OR 1.4, 95% CI 0. 0.38 to 5.2). If the analysis was restricted to the 158 patients with a baseline SLEDAI of ≥6, the model did not change. CONCLUSION: The dose of prednisone during the first month after the diagnosis of SLE is an independent predictor of prednisone burden during the following 11 months.

Influence of the IL17A locus in giant cell arteritis susceptibility.

OBJECTIVE: Different lines of evidence have highlighted the role of IL-17A in the inflammatory process occurring in giant cell arteritis (GCA). The aim of the present study was to assess whether the IL17A locus influences GCA susceptibility and its clinical subphenotypes. METHODS: We carried out a large meta-analysis including a total of 1266 biopsy-proven GCA patients and 3779 healthy controls from four European populations (Spain, Italy, Germany and Norway). Five IL17A polymorphisms (rs4711998, rs8193036, rs3819024, rs2275913 and rs7747909) were selected by tagging and genotyped using TaqMan assays. Allelic combination and dependency tests were also performed. RESULTS: In the pooled analysis, two of the five analysed polymorphisms showed evidence of association with GCA (rs2275913: PMH=1.85E-03, OR=1.17 (1.06-1.29); rs7747909: PMH=8.49E-03, OR=1.15 (1.04-1.27)). A clear trend of association was also found for the rs4711998 variant (PMH=0.059, OR=1.11 (1.00-1.23)). An independent effect of rs2275913 and rs4711998 was evident by conditional regression analysis. In addition, the haplotype harbouring the risk alleles better explained the observed association than the polymorphisms independently (likelihood p value <10(-05)). CONCLUSIONS: Polymorphisms within the IL17A locus show a novel association with GCA. This finding supports the relevant role of the Th17 cells in this vasculitis pathophysiology.

El método de Sherlock Holmes en la práctica clínica / The Sherlock Holmes method in clinical practice

En este artículo se exponen los elementos integrantes del método de Sherlock Holmes, que está fundamentado en una recogida inteligente de información mediante la observación minuciosa, una escucha atenta y un examen detallado. Los datos, así obtenidos, son analizados para elaborar la hipótesis principal y las alternativas, que se van perfilando durante el proceso deductivo hasta dar con la clave que llevará a la solución del problema. El método de trabajo de Holmes, aplicado a la práctica clínica, destaca la conveniencia de que los médicos razonen y busquen las causas de la enfermedad con los datos obtenidos a partir de la observación aguda, de una historia clínica detallada y de una exploración física cuidadosa (AU)

This article lists the integral elements of the Sherlock Holmes method, which is based on the intelligent collection of information through detailed observation, careful listening and thorough examination. The information thus obtained is analyzed to develop the main and alternative hypotheses, which are shaped during the deductive process until the key leading to the solution is revealed. The Holmes investigative method applied to clinical practice highlights the advisability of having physicians reason through and seek out the causes of the disease with the data obtained from acute observation, a detailed review of the medical history and careful physical examination (AU)

The Sherlock Holmes method in clinical practice.

This article lists the integral elements of the Sherlock Holmes method, which is based on the intelligent collection of information through detailed observation, careful listening and thorough examination. The information thus obtained is analyzed to develop the main and alternative hypotheses, which are shaped during the deductive process until the key leading to the solution is revealed. The Holmes investigative method applied to clinical practice highlights the advisability of having physicians reason through and seek out the causes of the disease with the data obtained from acute observation, a detailed review of the medical history and careful physical examination.

Identification of the PTPN22 functional variant R620W as susceptibility genetic factor for giant cell arteritis.

OBJECTIVE: To analyse the role of the PTPN22 and CSK genes, previously associated with autoimmunity, in the predisposition and clinical phenotypes of giant cell arteritis (GCA). METHODS: Our study population was composed of 911 patients diagnosed with biopsy-proven GCA and 8136 unaffected controls from a Spanish discovery cohort and three additional independent replication cohorts from Germany, Norway and the UK. Two functional PTPN22 polymorphisms (rs2476601/R620W and rs33996649/R263Q) and two variants of the CSK gene (rs1378942 and rs34933034) were genotyped using predesigned TaqMan assays. RESULTS: The analysis of the discovery cohort provided evidence of association of PTPN22 rs2476601/R620W with GCA (PFDR=1.06E-04, OR=1.62, CI 95% 1.29 to 2.04). The association did not appear to follow a specific GCA subphenotype. No statistically significant differences between allele frequencies for the other PTPN22 and CSK genetic variants were evident either in the case/control or in stratified case analysis. To confirm the detected PTPN22 association, three replication cohorts were genotyped, and a consistent association between the PTPN22 rs2476601/R620W variant and GCA was evident in the overall meta-analysis (PMH=2.00E-06, OR=1.51, CI 95% 1.28 to 1.79). CONCLUSIONS: Our results suggest that the PTPN22 polymorphism rs2476601/R620W plays an important role in the genetic risk to GCA.

A case-control study suggests that the CCR6 locus is not involved in the susceptibility to giant cell arteritis.

OBJECTIVES: Polymorphisms of the CC chemokine receptor 6 (CCR6) gene have been recently reported to be associated with a number of autoimmune diseases. We aimed to investigate the possible influence of CCR6 rs3093024 gene variant in the susceptibility to and clinical expression of GCA. METHODS: The CCR6 polymorphism rs3093024 was genotyped in a total of 463 Spanish patients diagnosed with biopsy-proven GCA and 920 healthy controls using a TaqMan® allelic discrimination assay. PLINK software was used for the statistical analyses. RESULTS: No significant association between this CCR6 variant and GCA was observed (p=0.42, OR=0.94, CI95% 0.79-1.10). Similarly, when patients were stratified according to the specific clinical features of GCA such as polymyalgia rheumatica, visual ischaemic manifestations or irreversible occlusive disease, no statistical significant difference was detected either between the case subgroups and the control set or between GCA patients with and without the specific features of the disease. CONCLUSIONS: Our results suggest that the CCR6 rs3093024 polymorphism may not play a relevant role in the GCA pathophysiology.

Livedoid vasculopathy and recurrent thrombosis in a patient with lupus: seronegative antiphospholipid syndrome?

Livedoid vasculopathy is a rare condition which predominantly affects young women. It is characterized by intense painful purpuric maculae in the legs, ankles and feet, due to thrombosis of the small and medium-sized dermal vessels, in the absence of vasculitis. Livedoid vasculopathy has been frequently associated with hypercoagulable states and antiphospholipid syndrome. We describe a 34-year-old White woman suffering from systemic lupus erythematosus, livedo reticularis, haemolytic anaemia, severe thrombocytopenia and recurrent venous thrombosis who was admitted to the hospital for extremely painful purpuric lesions in her lower limbs. The clinical and histological findings were diagnostic of livedoid vasculopathy. Once the initial sub-therapeutic international normalized ratio levels were corrected, livedoid vasculopathy did not recur. Tests for antiphospholipid antibodies were repeatedly negative. This case, the first reported of livedoid vasculopathy in a patient with seronegative antiphospholipid syndrome and systemic lupus erythematosus, draws attention to livedoid vasculopathy, a thrombotic dermopathy that may be under-diagnosed in patients with antiphospholipid syndrome.