The Role of TNF-α in Alzheimer's Disease: A Narrative Review.

This review analyzes the role of TNF-α and its increase in biological fluids in mild cognitive impairment, and Alzheimer's disease (AD). The potential inhibition of TNF-α with pharmacological strategies paves the way for preventing AD and improving cognitive function in people at risk for dementia. We conducted a narrative review to characterize the evidence in relation to the involvement of TNF-α in AD and its possible therapeutic inhibition. Several studies report that patients with RA and systemic inflammatory diseases treated with TNF-α blocking agents reduce the probability of emerging dementia compared with the general population. Animal model studies also showed interesting results and are discussed. An increasing amount of basic scientific data and clinical studies underscore the importance of inflammatory processes and subsequent glial activation in the pathogenesis of AD. TNF-α targeted therapy is a biologically plausible approach for cognition preservation and further trials are necessary to investigate the potential benefits of therapy in populations at risk of developing AD.

Antiphospholipid antibodies and anticoagulant therapy: capillaroscopic findings.

BACKGROUND: Antiphospholipid syndrome (APS) is a systemic autoimmune disease characterized by specific vascular and obstetric manifestations and by antiphospholipid antibodies (aPL) positivity. Microvascular damage in the course of APS and "aPL carrier" patients without symptoms is poorly investigated. OBJECTIVES: This study aims to compare nailfold videocapillaroscopy (NVC) microvascular parameters in APS patients and non-symptomatic "aPL carriers" and to investigate their possible correlations with different aPL subtypes. METHODS: NVC was performed during standard evaluations in 18 APS patients (mean age 50 ± 13.8 years), 24 "aPL carriers" without symptoms (mean age 46.4 ± 16.4 years), and 18 control patients (CTR) (mean age 74 ± 12.5 years) taking oral anticoagulants for non-immunological indications (i.e., cardiovascular accidents). All patients were investigated for the presence of dilated capillaries, giant capillaries, microhemorrhages, capillary loss, and further non-specific/specific abnormalities (i.e., branched "bushy" capillaries, sign of neoangiogenesis) by NVC. Every alteration was also classified according to a semi-quantitative score. Lupus anticoagulant, anticardiolipin antibodies, and antibeta2 glycoprotein I antibodies were tested in each patient. RESULTS: APS patients showed at NVC increased frequency of microhemorrhages (p = 0.039)-particularly a "comb-like" pattern (parallel hemorrhages) (p = 0.002)-than "aPL carriers". Of note, there were no significant differences concerning the isolated number of microhemorrhages between APS and the CTR group (p = 0.314), but "comb-like" hemorrhages were significantly more frequent in the APS group (p = 0.034). Not any significant correlation was found between the aPL subtypes and NVC parameters. CONCLUSIONS: APS patients showed significantly a greater number of non-specific NVC abnormalities than "aPL carriers", particularly the "comb-like" NVC pattern. Oral anticoagulants may represent a confounding factor for isolated microhemorrhages. Not any correlation was found between aPL subtypes and NVC parameters. Further investigations are needed to better characterize the microvascular endothelium damage induced by aPL.

Endothelial dysfunction in rheumatic autoimmune diseases.

Rheumatic autoimmune diseases have been associated with accelerated atherosclerosis and various types of vasculopathies. Atherosclerosis is an inflammatory condition which starts as a "response to injury" favoring endothelial dysfunction which is associated with increased expression of adhesion molecules, pro-inflammatory cytokines, pro-thrombotic factors, oxidative stress upregulation and abnormal vascular tone modulation. Endothelial dysfunction in rheumatic autoimmune diseases involves innate immune responses, including macrophages and dendritic cells expression of scavenger and toll-like receptors for modified or native LDL as well as neutrophil and complement activation, and dysregulation of adaptive immune responses, including proliferation of autoreactive T-helper-1 lymphocytes and defective function of dendritic and regulatory T cells. Specific differences for endothelial function among different disorders include: a) increased amounts of pro-atherogenic hormones, decreased amounts of anti-atherogenic hormones and increased insulin resistance in rheumatoid arthritis; b) autoantibodies production in systemic lupus erythematosus and antiphospholipid syndrome; c) smooth muscle cells proliferation, destruction of internal elastic lamina, fibrosis and coagulation and fibrinolytic system dysfunction in systemic sclerosis. Several self-antigens (i.e. high density lipoproteins, heat shock proteins, ß2-glycoprotein1) and self-molecules modified by oxidative events (i.e. low density lipoproteins and oxidized hemoglobin) have been identified as targets of autoimmune responses. Endothelial dysfunction leads to accelerated atherosclerosis in rheumatoid arthritis, systemic lupus erythematosus and spondyloarthropaties whereas obliterative vasculopathy is associated with systemic sclerosis. In this paper, we will briefly review the most relevant information upon endothelial dysfunction and inflammatory mechanisms in atherosclerosis and we will summarize the similarities and differences in vascular disease patterns underlying different rheumatic autoimmune diseases.

Determination of lymphotoxin-alpha levels in patients with psoriatic arthritis undergoing etanercept treatment.

Tumor necrosis factor (TNF)-α plays a central role in psoriatic arthritis (PsA). A subgroup of patients with PsA do not respond to anti-TNF-α antibodies but respond to TNF receptor p75-Fc IgG fusion protein (etanercept), which also neutralizes lymphotoxin (LT)-α. It has been suggested that LT-α might be involved in the development of the disease. We determined LT-α serum levels in 15 PsA patients before (T0) and after 3, 6, 9, and 12 months of etanercept therapy (T3, T6, T9, and T12, respectively) and correlated them with their response to treatment. Bath Ankylosing Spondylitis Disease Activity Index, Psoriasis Area Severity Index, Disease Activity Score (DAS28), erythrocyte sedimentation rate (ESR), and C reactive protein (CRP) levels were assessed at the same time points. All patients showed a clinical response at T6, which persisted up to T12; ESR and CRP mean levels significantly decreased at T3 and remained within the normal range up to T12. LT-α levels significantly increased from T3 to T6 and returned to baseline levels at T12. Therefore, the LT-α serum levels do not seem to correlate with clinical and laboratory parameters of the response to etanercept in PsA patients. Further studies are required to better define the role of LT-α and LT-α blockade by etanercept in PsA patients.

Update upon efficacy and safety of TNF-α inhibitors.

The ongoing progresses in the knowledge of the pathogenic mechanisms of various immune-mediated and inflammatory diseases as well as the availability of innovative biotechnological approaches have led to the development of new drugs that add to conventional treatments. Among these, tumor necrosis factor (TNF)-α inhibitors, that is, infliximab, adalimumab, etanercept, golimumab and certolizumab pegol, are now available for clinical use. This editorial discusses the recent indications of TNF-α inhibitors, the pretreatment considerations, the reported adverse events and, finally, the recommendations for its use in pregnancy.

Emerging biological drugs: a new therapeutic approach for Systemic Lupus Erythematosus. An update upon efficacy and adverse events.

B-cells abnormalities leading to autoantibody production play a central role in Systemic Lupus Erythematosus (SLE) pathogenesis. B-cell targeted therapies, including anti-B lymphocyte stimulator (BLyS) and anti-CD20 monoclonal antibodies, are at forefront of new SLE treatments. Biologic agents targeting specific pathways (i.e. T-B lymphocyte interaction, cytokines and complement) have been also proposed as new tools for SLE treatment. In this review we will focus on biological drugs whose potential efficacy has been evaluated in open-label and randomized clinical trials.

The role of Th17 lymphocytes in the autoimmune and chronic inflammatory diseases.

The emerging role of interleukin-17 as a hallmark proinflammatory cytokine of the adaptive immune system produced by a new T helper cell subset termed "Th17" has received considerable attention. In this review we will focus on recent information regarding IL-17 and its relevance in autoimmune and chronic inflammatory diseases.

Anti-tumor necrosis factor-α treatment with infliximab for disseminated granuloma annulare.

Granuloma annulare (GA) is a chronic inflammatory disease of unknown etiology characterized by the development of plaques preferentially localized to the distal extremities. Spontaneous remission and relapses are quite common and the course of GA is not easy to predict. Moreover, most therapeutic regimens have been used anecdotally and with variable success. We report the case of a 62-year-old White female patient affected by disseminated GA unsuccessfully treated with psoralen plus UVA photochemotherapy, prednisone, and cyclosporine (ciclosporin) who responded to the anti-tumor necrosis factor-α monoclonal antibody infliximab administered intravenously at a dosage of 5 mg/kg at weeks 0, 2, and 6 and thereafter at monthly intervals for 10 additional months. Most of the GA lesions improved within 8 weeks and then slowly resolved within 10 months of treatment. We suggest that infliximab may be proposed as an additional therapeutic option in the treatment of recalcitrant forms of disseminated GA.

Traditional and non traditional risk factors in accelerated atherosclerosis in systemic lupus erythematosus: role of vascular endothelial growth factor (VEGATS Study).

OBJECTIVE: To evaluate the role of vascular endothelial growth factor (VEGF) in accelerated atherosclerosis in patients with Systemic Lupus Erythematosus (SLE). METHODS: We have enrolled 80 SLE female patients and 80 age-matched healthy control females who underwent a structured interview, physical examination, routine laboratory tests, VEGF plasma level determination and B-mode ultrasonography of carotid arteries to determine carotid intima media thickness (IMT). Framingham risk factors for cardiovascular events were also calculated and VEGF plasma levels were correlated with traditional and nontraditional cardiovascular risk factors. RESULTS: SLE was significantly associated with higher mean IMT values (0.74+/-0.15 mm versus 0.59+/-0.12 mm in controls, p<0.001) and higher mean plasma VEGF levels (307.9+/-292.2 pg/mL versus 120.7+/-118.4 pg/mL in controls, p<0.001) independently from age, smoking habits, and Framingham risk factors. A significant correlation was also found between IMT and VEGF values (r=0.25; p<0.001). CONCLUSION: We show that SLE patients have increased mean IMT and VEGF values as compared with healthy age-matched controls and that IMT and VEGF values are independently and directly associated with SLE disease.

Serum vascular endothelial growth factor in allergic rhinitis and systemic lupus erythematosus.

Allergic rhinitis (AR) is characterized by an inflammatory reaction sustained by Th2 polarization, whereas systemic lupus erythematosus (SLE) is a typical autoimmune disorder. Vascular endothelial growth factor (VEGF) is a critical mediator of inflammation. The aim of this study was to compare serum VEGF levels in three groups of subjects: 40 normal subjects, 40 allergic patients, evaluated before and after specific immunotherapy, and 40 patients with inactive SLE. Patients who were allergic before immunotherapy had the lowest VEGF serum levels, which significantly increased after treatment; SLE patients had the highest VEGF serum levels. This comparative study provides evidence that serum VEGF levels depend on the type of immune response: they are high in autoimmune disease and low in Th2-polarized allergic reaction. The relevance of this phenomenon is further apparent, as it is also observed in patients with inactive disease.

Serum adiponectin levels in patients with pollen-induced allergic rhinitis.

BACKGROUND: Several studies have outlined a possible relationship between an increased body mass index and respiratory allergic diseases, such as asthma and rhinitis. OBJECTIVE: The aim of the study was to evaluate the serum adiponectin levels in a cohort of patients with pollen-induced allergic rhinitis, enrolled outside the pollen season, and in a group of healthy controls. METHODS: The study included 41 patients with moderate-severe persistent allergic rhinitis due to a pollen allergy and 34 normal subjects. All subjects were prospectively and consecutively evaluated. A skin prick test and blood sampling for assessing serum adiponectin levels were performed in all subjects. RESULTS: The comparison between allergic patients and normal subjects, globally considered without gender distinction, showed slightly higher values in the allergic population. After analysing genders separately, allergic patients show significantly higher levels than normal males (p = 0.0134), whereas the comparison between allergic and normal females was not significant (p = 0.1419). In addition, in normal males adiponectin serum levels are significantly related with age (p = 0.0123). CONCLUSION: This preliminary study provides the first evidence of significantly higher adiponectin serum levels in male patients with pollen-induced allergic rhinitis as compared to normal male subjects.

Body mass index in Th1 and Th2 diseases.

Several studies have outlined a relationship between increased body mass index (BMI) and respiratory allergic diseases. This study provides evidence of a significant different BMI between Th2-mediated disorders and Th1-mediated ones.

Autoimmune intrahepatic cholangiopathy associated with antiphospholipid antibody syndrome.

We report the case of a 26-year-old woman who developed thrombophlebitis in her left leg in 2002, followed by fever, asthenia and headache in 2004. Antinuclear antibodies, antimitochondrial antibodies, anti-liver kidney microsome, anti-Smith, antiphospholipid (aPL) and antineutrophil cytoplasmic antibodies, as well as lupus- anticoagulant activity were positive. Systemic lupus erythematosus (SLE) with aPL syndrome was diagnosed and the patient was treated with azathioprine and heparin. Symptoms persisted and itching arose in the following months. The patient was admitted to our department in January 2005 for jaundice and skin rash. Elevated levels of acute phase proteins and cholestasis and liver necrosis indexes were present. Antinuclear antibodies, aPL and antimitochondrial antibodies (M5) antibodies were positive. Liver histology showed minimal focal hepatocyte necrosis, intrahepatic biliary stasis and intralobular inflammatory cell infiltrate. The absence of clinical signs that are characteristic of SLE as well as the failure to confirm antiSmith antibody positivity led us to rule out a diagnosis of SLE. On the basis of clinical, immunological and histological data, autoimmune intrahepatic cholangiopathy associated with primary aPL syndrome was diagnosed. The patient was treated with intravenous methylprednisolone followed by oral prednisone, warfarin and ursodeoxycholic acid. Liver necrosis and cholestasis indexes rapidly improved within 1 month and progressively reached the normal range. To our knowledge, this is the first description of a patient with an association of intrahepatic cholangiopathy and aPL, thus suggesting that autoimmune liver disease might associate with aPL syndrome.

Intima-media thickness: a marker of accelerated atherosclerosis in women with systemic lupus erythematosus.

Accelerated atherosclerosis is an emerging problem in patients with systemic lupus erythematosus (SLE). We planned an observational study to determine whether in patients with SLE carotid intima-media thickness (IMT) represents an early sign of accelerated atherosclerosis and to confirm that SLE adds to the traditional cardiovascular Framingham risk factors. Thirty females with SLE (age 18-65 years) underwent anamnestic, clinical, and laboratory evaluation and B-mode ultrasonography of carotid arteries, which provides a direct and noninvasive assessment of subclinical atherosclerosis. IMT measurements were performed on the right and left common carotid arteries 1.0 cm proximal to the carotid bulb and the mean IMT value was calculated with a dedicated software. The Framingham Point Score was also calculated for each subject. SLE patients showed a mean IMT value of 0.73 +/- 0.12 (SD) mm. This value is significantly (P < 0.05) higher than that reported for an age-matched healthy female control population (0.66 +/- 0.11 SD mm). A preliminary evaluation of the Framingham Point Score, estimating the 10-year risk for women to develop cardiovascular events, indicated an increased risk of early cardiovascular events in SLE patients. In our study we have shown that patients with SLE have an increased mean IMT value compared with a healthy females control. Moreover, the evaluation of the Framingham Point Score suggests that SLE is an additional risk factor for cardiovascular disease.

Maternal arrhythmias during pregnancy.

INTRODUCTION: An increased incidence of maternal cardiac arrhythmias is observed during pregnancy and they can range from clinically irrelevant isolated premature beats to debilitating supraventricular and ventricular tachycardias. DISCUSSION: Management of arrhythmias during pregnancy is similar to that in non-pregnant patients. However, the presence of the foetus and the risk of teratogenicity, the haemodynamic changes, the effect of therapy on labour, delivery and lactation must be evaluated. Antiarrhythmic drug selection depends on the specific arrhythmia being treated and the cardiac condition of the mother. Although no drug is completely safe, most are well tolerated and can be given with relatively low risk. Some antiarrhythmic agents, such as propranolol, metoprolol, digoxin and quinidine, have been extensively tested during pregnancy and have proved to be safe; they should therefore, whenever possible, be used as a first-line. For supraventricular tachycardia, intravenous adenosine may be used to terminate the arrhythmia if vagal manoeuvres fail. If possible, drug therapy should be avoided during the first trimester of pregnancy. When drug treatment fails or is not indicated because of the haemodynamic instability of the patient, direct current cardioversion can be used. CONCLUSION: Most patients with arrhythmias during pregnancy can be treated with an excellent result.