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.

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.

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.

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.

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.

Late infection of an embolized renal graft presented as buttock cellulitis.

Graft intolerance syndrome (GIS) is a common complication developed in failed kidney allografts left in situ when the patients returned to hemodialysis. GIS usually develops within the first 6 months after immunosuppression has been withdrawn. When medical treatment has failed, transplantectomy is the conventional therapy. Nevertheless, in recent years, transvascular ethanol embolization has been reported as an effective, safe, and less invasive technique than transplantectomy for the management of patients with GIS. Although infrequent, the most severe complication is infection of the graft or surrounding tissues, which usually appears in the first weeks after the procedure. We present the first case of late infection of an embolized renal graft, more than 2 years after embolization.

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.

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.

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)

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.

The influence of risk factors on the severity of anti-tuberculosis drug-induced hepatotoxicity.

BACKGROUND: Hepatotoxicity is one of the most serious adverse effects of anti-tuberculosis drugs (ATD). Although many risk factors have been associated with ATD-induced hepatotoxicity, their influence on hepatitis severity has not been studied systematically. OBJECTIVES: To evaluate whether the presence of hepatotoxicity risk factors (advanced age, chronic liver disease, abuse of alcohol or other drugs or malnutrition) influences the severity of ATD-induced hepatotoxicity. DESIGN: A prospective cohort study of 471 active tuberculosis patients treated with isoniazid, rifampicin and pyrazinamide and followed in a tuberculosis clinic between January 1998 and July 2002. Incidence of hepatotoxicity and its severity according to the presence or absence of ATD-induced hepatitis risk factors was evaluated. RESULTS: The incidence of ATD-induced hepatotoxicity (serum transaminase > 3 x the upper limit of normal [ULN]) was 18.2% (42/231 patients) in the risk factor group and 5.8% (14/240 patients) in the non-risk factor group (OR 3.5; 95% CI 1.9-6.7; P < 0.001). Severe hepatotoxicity (transaminase > 10 x ULN) occurred in 6.9% (16/231) of the risk factor group and in 0.4% (1/240) (OR 17.7; 95% CI 2.3-135; P < 0.001) of the group without risk factors. CONCLUSIONS: ATD-induced hepatitis is significantly more frequent and more severe in patients with hepatotoxicity risk factors.

Thalidomide for the treatment of acquired immunodeficiency syndrome-associated refractory oral ulcers.

A case of severe, oral, not otherwise specified ulcers in a human immunodeficiency virus-infected patient is described. The lesions did not respond to acyclovir, prednisone, pentoxifylline, or foscarnet sodium therapy. Dramatic clinical improvement and progressive ulcer healing were observed after starting oral thalidomide therapy. Clinicians should be aware of the usefulness of thalidomide for the treatment of acquired immunodeficiency syndrome-associated not otherwise specified ulcerations.

Immunohistochemical detection of parathyroid hormone-related protein in a cutaneous squamous cell carcinoma causing humoral hypercalcemia of malignancy.

Humoral hypercalcemia of malignancy is a cancer-related hypercalcemia caused by production of humoral factors by malignant cells in patients without bone metastases. Squamous cell carcinomas are the tumors most frequently associated with humoral hypercalcemia of malignancy, and parathyroid hormone-related protein is the main humoral factor implicated. In spite of the fact that normal keratinocytes produce parathyroid hormone-related protein, it is highly unusual for patients with squamous cell carcinomas of the skin to present with humoral hypercalcemia of malignancy. We present a well-documented case of cutaneous squamous cell carcinoma complicated by hypercalcemia in a patient with high levels of plasma parathyroid hormone-related protein and immunohistochemical evidence of high parathyroid hormone-related protein production by the tumoral cells.

[The incidence of gastric carcinoma after gastrectomy for peptic ulcer in the Vigo region. A case-control study]. / Frecuencia del carcinoma gástrico postgastrectomía para úlcera péptica en la comarca de Vigo. Estudio caso-control.

After reviewing 10,000 upper gastrointestinal endoscopies performed at the endoscopy unit of the city of Vigo over a 38 month period, we have found 485 partial gastric resections for peptic ulcer, 357 gastric carcinomas were found, of which 26 occurred after partial gastric resection for peptic ulcer. Therefore the incidence of gastric cancer in this area was 22-23/100,000. The frequency of gastric cancer after partial resective surgery was lower than expected during the first 20 years after surgery. However, thereafter a significant increase of gastric cancer occurred in those patients in which a Billroth-II but not Billroth-I procedure was used.

[Histiocytic necrotizing lymphadenitis or Kikuchi's disease. CT radiologic features]. / Linfadenitis necrotizante histiocitaria o enfermedad de Kikuchi. Apariencia radiológica mediante TC.

Histiocytic necrotizing lymphadenitis, Kikuchi Fujimoto's disease (KFD) is characterised by fever and lymphadenopathy, usually large cervical, unilateral lymph nodes. Such clinical presentation demands a work-up to exclude serious medical conditions like malignancy and infections. Foci of necrosis with lymphocytic Histiocytic predominance in association with scarce polymorphonuclear cells on lymph node examination, confirm the diagnosis of KFD. Many different patterns of computed tomographic (CT) appearance of KFD have been reported. We describe the CT scan finding in two patients with this disease. All our cases showed, after two and three weeks of evolution respectively, enlarged lymph nodes with hypodense centres and peripheral ring enhancement. These radiological alterations correlated with the central lymph node necrosis found in the anatomopathological studies. In conclusion, KFD should be considered in patients with fever, cervical lymph node enlargement and CT scan showing hypointense centres and peripheral ring enhancement.

[Cryptococcosis of the central nervous system and infection by HIV. Clinical-evolutive characteristics in 13 cases]. / Criptococosis del sistema nervioso central e infección por VIH. Características clínico-evolutivas de 13 casos.

Cryptococcosis is the fourth cause of infection of the Central Nervous System in patients with infection by HIV. Despite this fact, the series published in our country are referred to a limited number of cases. We describe the most relevant characteristics of 13 patients with meningitis by Cryptococcus neoformans. We used as inclusion criteria a positive culture of the Cephalorhachidian Fluid (CRF). We observed a significant reduction in the levels of CD4 lymphocytes in all patients, the absence of meningitic syndrome in more than 50% cases (8/13) and a normal CRF cytobiochemistry in three patients. The thoracic radiography was normal in all cases but two, although the cryptococcus was cultured in a transbronchial biopsia of a patient with normal thoracic radiography. The Computerized Axial Tomography showed frequent alterations (5/13). Eight patients were treated with amphotericin B (0.5 mg/kg/d) and five with fluconazol (400 mg/day). Despite following a maintenance therapy with fluconazol (200 mg/d), we had two cases of recurrence in the group previously treated with fluconazol. The level of leukocytes in the CRF was the only prognosis factor (p < 0.05). Five patients died during their first hospitalization due to causes related to the infection by cryptococcus. New therapeutical guidelines are needed in order to improve the prognosis of these patients.