Vitamin E and neurological function: lessons from patients with abetalipoproteinaemia

For many years the role of vitamin E (α-tocopherol) in human nutrition was uncertain, but it is now recognised that this fat soluble vitamin is necessary for normal neurological structure and function. The evidence came initially from patients with abetalipoproteinaemia, then from patients with other chronic and severe fat malabsorptive states, from patients with an isolated deficiency of vitamin E without generalised fat malabsorption, and from comparative neuropathological studies in vitamin E deficient man, monkey and rat. Severe and chronic vitamin E deficiency in the different patient groups resulted in a characteristic neurological disorder which progressed to crippling and blindness. Early and appropriate supplementation with vitamin E can prevent the development of all the neurological signs and symptoms, and treatment of patients with established lesions invariably halts and in some cases can reverse the neuropathy. These clinical and pathological findings raise a number of basic questions regarding the function of vitamin E in neural tissues which are currently being addressed in an animal model.     

Vitamin E and heart disease: basic science to clinical intervention trials

A review is presented of studies on the effects of vitamin E on heart disease, studies encompassing basic science, animal studies, epidemiological and observational studies, and four intervention trials. The in vitro, cellular, and animal studies, which are impressive both in quantity and quality, leave no doubt that vitamin E, the most important fat-soluble antioxidant, protects animals against a variety of types of oxidative stress. The hypothesis that links vitamin E to the prevention of cardiovascular disease (CVD) postulates that the oxidation of unsaturated lipids in the low-density lipoprotein (LDL) particle initiates a complex sequence of events that leads to the development of atherosclerotic plaque. This hypothesis is supported by numerous studies in vitro, in animals, and in humans. There is some evidence that the ex vivo oxidizability of a subject's LDL is predictive of future heart events. This background in basic science and observational studies, coupled with the safety of vitamin E, led to the initiation of clinical intervention trials. The three trials that have been reported in detail are, on balance, supportive of the proposal that supplemental vitamin E can reduce the risk for heart disease, and the fourth trial, which has just been reported, showed small, but not statistically significant, benefits. Subgroup analyses of cohorts from the older three trials, as well as evidence from smaller trials, indicate that vitamin E provides protection against a number of medical conditions, including some that are indicative of atherosclerosis (such as intermittent claudication). Vitamin E supplementation also produces an improvement in the immune system and protection against diseases other than cardiovascular disease (such as prostate cancer). Vitamin E at the supplemental levels being used in the current trials, 100 to 800 IU/d, is safe, and there is little likelihood that increased risk will be found for those taking supplements. About one half of American cardiologists take supplemental vitamin E, about the same number as take aspirin. In fact, one study suggests that aspirin plus vitamin E is more effective than aspirin alone. There are a substantial number of trials involving vitamin E that are in progress. However, it is possible, or even likely, that each condition for which vitamin E provides benefit will have a unique dose-effect curve. Furthermore, different antioxidants appear to act synergistically, so supplementation with vitamin E might be more effective if combined with other micronutrients. It will be extremely difficult to do trials that adequately probe the dose-effect curve for vitamin E for each condition that it might affect, or to do studies of all the possible combinations of other micronutrients that might act with vitamin E to improve its effectiveness. Therefore, the scientific community must recognize that there never will be a time when the science is "complete." At some point, the weight of the scientific evidence must be judged adequate; although some may regard it as early to that judgement now, clearly we are very close. In view of the very low risk of reasonable supplementation with vitamin E, and the difficulty in obtaining more than about 30 IU/day from a balanced diet, some supplementation appears prudent now.     

Role of antioxidant systems in induced nutritional pancreatic atrophy in chicken

One-day-old chicks were reared using diets differing in their vitamin E and/or selenium content. The purpose of this research was to detect any possible imbalance in the antioxidant defense system, which could be related to development of nutritional pancreatic atrophy. Mitochondrial membranes from animals deficient in both nutrients, or just vitamin E, submitted to peroxidizability ‘in vitro’ had the production of TBARS greatly enhanced. Measurements of the 2-GSH/GSSG ratio suggested that selenium and vitamin E, the latter in higher magnitude, were responsible for maintenance of the reducing capacity of the cell. Enzymatic defense systems against oxidative stress were also studied. The results indicated that the total antioxidant enzymatic activity of pancreatic cells was not sufficient to scavenge all the ROS generated in the nutritionally deficient animals. The present study suggests that nutritional deficiency of selenium and/or vitamin E generates one imbalance between pro-oxidant and antioxidant systems in chicken pancreas, leading to oxidative stress and pancreatic atrophy.     

Wolcott-Rallison syndrome

Familial hypocholesterolemia, namely abetalipoproteinemia, hypobetalipoproteinemia and chylomicron retention disease (CRD), are rare genetic diseases that cause malnutrition, failure to thrive, growth failure and vitamin E deficiency, as well as other complications. Recently, the gene implicated in CRD was identified. The diagnosis is often delayed because symptoms are nonspecific. Treatment and follow-up remain poorly defined. The aim of this paper is to provide guidelines for the diagnosis, treatment and follow-up of children with CRD based on a literature overview and two pediatric centers 'experience. The diagnosis is based on a history of chronic diarrhea with fat malabsorption and abnormal lipid profile. Upper endoscopy and histology reveal fat-laden enterocytes whereas vitamin E deficiency is invariably present. Creatine kinase (CK) is usually elevated and hepatic steatosis is common. Genotyping identifies the Sar1b gene mutation. Treatment should be aimed at preventing potential complications. Vomiting, diarrhea and abdominal distension improve on a low-long chain fat diet. Failure to thrive is one of the most common initial clinical findings. Neurological and ophthalmologic complications in CRD are less severe than in other types of familial hypocholesterolemia. However, the vitamin E deficiency status plays a pivotal role in preventing neurological complications. Essential fatty acid (EFA) deficiency is especially severe early in life. Recently, increased CK levels and cardiomyopathy have been described in addition to muscular manifestations. Poor mineralization and delayed bone maturation do occur. A moderate degree of macrovesicular steatosis is common, but no cases of steatohepatitis cirrhosis. Besides a low-long chain fat diet made up uniquely of polyunsaturated fatty acids, treatment includes fat-soluble vitamin supplements and large amounts of vitamin E. Despite fat malabsorption and the absence of postprandial chylomicrons, the oral route can prevent neurological complications even though serum levels of vitamin E remain chronically low. Dietary counseling is needed not only to monitor fat intake and improve symptoms, but also to maintain sufficient caloric and EFA intake. Despite a better understanding of the pathogenesis of CRD, the diagnosis and management of the disease remain a challenge for clinicians. The clinical guidelines proposed will helpfully lead to an earlier diagnosis and the prevention of complications.     

Genetic connections between neurological disorders and cholesterol metabolism

Cholesterol is an essential component of both the peripheral and central nervous systems of mammals. Over the last decade, evidence has accumulated that disturbances in cholesterol metabolism are associated with the development of various neurological conditions. In addition to genetically defined defects in cholesterol synthesis, which will be covered in another review in this Thematic Series, defects in cholesterol metabolism (cerebrotendinous xanthomatosis) and intracellular transport (Niemann Pick Syndrome) lead to neurological disease. A subform of hereditary spastic paresis (type SPG5) and Huntington''s disease are neurological diseases with mutations in genes that are of importance for cholesterol metabolism. Neurodegeneration is generally associated with disturbances in cholesterol metabolism, and presence of the E4 isoform of the cholesterol transporter apolipoprotein E as well as hypercholesterolemia are important risk factors for development of Alzheimer''s disease. In the present review, we discuss the links between genetic disturbances in cholesterol metabolism and the above neurological disorders.     

Pancreas disease in Atlantic salmon (Salmo salar) and vitamin E supplementation

A study was instigated to investigate the histopathological and clinical pathological lesions associated with a naturally occurring pancreas disease (PD) outbreak in farmed Atlantic salmon. An attempt was made to reduce the severity of PD and associated lesions by altering the antioxidative and peroxidative substrates in the diets. The results do not support the hypothesis that PD leads to a vitamin E deficiency which induces a myopathy. PD was not associated with a reduction in tissue vitamin E concentrations. Despite high tissue vitamin E concentrations, pancreatic lesions and cardiac and skeletal myopathy occurred amiost simultaneously. Severe myopathy appeared to be associated with high mortality. Dietary vitamin E concentrations > 500 mg/kg did not increase plasma and muscle vitamin E concentrations, which appear to be saturated. Liver concentrations were also high. However, differing concentrations of dietary vitamin E and fat were associated with differing mortality rates.     

Will the 'Good Fairies' Please Prove to us that Vitamin E Lessens Human Degenerative Disease?

Recent research about the role of free radical derivatives of oxygen and nitrogen in biological systems has highlighted the possibility that antioxidants, such as vitamin E, that prevent these processes in vitro may be capable of carrying out a similar function in living organisms in vivo. There is increasing evidence that free radical reactions are involved in the early stages, or sometimes later on, in the development of human diseases, and it is therefore of particular interest to inquire whether vitamin E and other antioxidants, which are found in the human diets, may be capable of lowering the incidence of these diseases. Put simply, the proposition is that by improving human diets by increasing the quantity in them of antioxidants, it might be possible to reduce the incidence of a number of degenerative diseases. Of particular significance to these considerations is the likely role of the primary fat-soluble dietary antioxidant vitamin E in the prevention of degenerative diseases such as arteriosclerosis, which is frequently the cause of consequent heart attacks or stroke, and prevention of certain forms of cancer, as well as several other diseases. Substantial evidence for this proposition now exists, and this review is an attempt to give a brief account of the present position. Two kinds of evidence exist; on the one hand there is very substantial basic science evidence which indicates an involvement of free radical events, and a preventive role for vitamin E, in the development of human disease processes. On the other hand, there is also a large body of human epidemiological evidence which suggests that incidence of these diseases is lowered in populations having a high level of antioxidants, such as vitamin E, in their diet, or who have taken steps to enhance their level of intake of the vitamin by taking dietary supplements. There is also some evidence which suggests that intervention with dietary supplements of vitamin E can result in a lowered risk of disease, in particular of cardiovascular disease, which is a major killer disease among the developed nations of the world. The intense interest in this subject recently has as its objective the possibility that, by making some simple alterations to dietary lifestyle, or by enhancing the intake of vitamin E by fortification of foods, or by dietary supplements, it may be possible to reduce substantially the risk of a large amount of common, highly disabling human disease. By this simple means, therefore it may be possible to improve substantially the quality of human life, in particular for people of advancing years.     

Will the 'Good Fairies' Please Prove to us that Vitamin E Lessens Human Degenerative Disease?

Recent research about the role of free radical derivatives of oxygen and nitrogen in biological systems has highlighted the possibility that antioxidants, such as vitamin E, that prevent these processes in vitro may be capable of carrying out a similar function in living organisms in vivo. There is increasing evidence that free radical reactions are involved in the early stages, or sometimes later on, in the development of human diseases, and it is therefore of particular interest to inquire whether vitamin E and other antioxidants, which are found in the human diets, may be capable of lowering the incidence of these diseases. Put simply, the proposition is that by improving human diets by increasing the quantity in them of antioxidants, it might be possible to reduce the incidence of a number of degenerative diseases. Of particular significance to these considerations is the likely role of the primary fat-soluble dietary antioxidant vitamin E in the prevention of degenerative diseases such as arteriosclerosis, which is frequently the cause of consequent heart attacks or stroke, and prevention of certain forms of cancer, as well as several other diseases. Substantial evidence for this proposition now exists, and this review is an attempt to give a brief account of the present position. Two kinds of evidence exist; on the one hand there is very substantial basic science evidence which indicates an involvement of free radical events, and a preventive role for vitamin E, in the development of human disease processes. On the other hand, there is also a large body of human epidemiological evidence which suggests that incidence of these diseases is lowered in populations having a high level of antioxidants, such as vitamin E, in their diet, or who have taken steps to enhance their level of intake of the vitamin by taking dietary supplements. There is also some evidence which suggests that intervention with dietary supplements of vitamin E can result in a lowered risk of disease, in particular of cardiovascular disease, which is a major killer disease among the developed nations of the world. The intense interest in this subject recently has as its objective the possibility that, by making some simple alterations to dietary lifestyle, or by enhancing the intake of vitamin E by fortification of foods, or by dietary supplements, it may be possible to reduce substantially the risk of a large amount of common, highly disabling human disease. By this simple means, therefore it may be possible to improve substantially the quality of human life, in particular for people of advancing years.     

Serum ex vivo lipoprotein oxidizability in patients with ischemic heart disease supplemented with vitamin E

The decreased oxidizability of plasma lipoproteins is related to the increased vitamin E intake and its association with a relatively lower incidence of coronary heart disease has been proposed. We investigated the effect of the in vivo vitamin E supplementation on the oxidizability of serum lipids in patients with ischemic heart disease and a moderate hypercholesterolemia. Thirty-two patients (16 males and 16 postmenopausal women) participated in this placebo-controlled, randomized trial. They were treated with 400 mg vitamin E/day for 6 weeks. The copper-induced serum lipid oxidizability ex vivo was assessed by measuring conjugated diene formation at 245 nm. We also measured vitamin E, malondialdehyde (MDA) and uric acid concentrations in the plasma. Because of observed significant differences in parameters of serum lipid oxidizability (lag time and maximal rate of oxidation), plasma alpha-tocopherol and MDA levels between male patients and postmenopausal women supplemented with vitamin E, the results were compared between both genders. Six weeks of vitamin E supplementation significantly increased plasma vitamin E levels (by 87 %) in male patients but in postmenopausal women only by 34 %. Concomitantly with increased plasma levels of vitamin E the decrease in plasma MDA levels was observed in male patients (decrease by 20 %; p=0.008), but in postmenopausal women the decrease did not attain statistical significance. Plasma uric acid levels were not apparently changed in placebo or vitamin E supplemented groups of patients. The changes in ex vivo serum lipid oxidizability after vitamin E, supplementation have shown a significantly prolonged lag time (by 11 %; p=0.048) and lowered rate of lipid oxidation (by 21 %; p=0.004) in male patients in comparison with postmenopausal women. Linear regression analysis revealed a significant correlation between plasma vitamin E levels and the lag time (r=0.77; p=0.03) and the maximal rate of serum lipid oxidation (r=-0.70; p=0.05) in male patients. However, in postmenopausal women the correlations were not significant. We conclude that 400 mg vitamin E/day supplementation in patients with ischemic heart disease and a moderate hypercholesterolemia influenced favorably ex vivo serum lipid oxidation of male patients when compared with postmenopausal women. The observed differences between both genders could be useful in the selection of the effective vitamin E doses in the prevention of coronary heart disease.     

Hepatic uptake and antihepatotoxic properties of vitamin E and liposomes in the mouse

Intravenous administration of soybean phosphatidylcholine liposomes containing different amounts of tocopherol acetate leads to a dose and time dependent increase of mouse liver tocopherol content, which was not observed when the preparation was given orally. When benzo[a]pyrene pretreated mice intoxicated with 400 mg/kg AAP were pretreated 2 h before with 1 g/kg phosphatidylcholine liposomes containing 4 mg/kg vitamin E acetate, these animals were protected against liver damage. Vitamin E alone or liposomes lacking vitamin E showed no protection. In an inflammatory liver disease model, i.e. fulminant hepatitis induced by intraperitoneal administration of 700 mg/kg galactosamine and 1 microgram/kg lipopolysaccharide phosphatidylcholine liposomes protected at a dose of 1 g/kg i.v. In this case, however, the protection was not due to the presence of vitamin E. These findings demonstrate the usefulness of phosphatidylcholine for liver protection and show that the protective spectrum is improved when they contain vitamin E. The data suggest that phosphatidylcholine is an excellent carrier for delivery of vitamin E to the liver.     

Adverse effects of vitamin E by induction of drug metabolism

Observational studies with healthy persons demonstrated an inverse association of vitamin E with the risk of coronary heart disease or cancer, the outcome of large-scale clinical trials conducted to prove a benefit of vitamin E in the recurrence and/or progression of such disease, however, was disappointing. Vitamin E did not provide benefits to patients with cardiovascular diseases, cancer, diabetes or hypertension. Even harmful events and worsening of pre-existing diseases were reported, which are hard to explain. Since vitamin E is metabolized along the same routes as xenobiotics and induces drug-metabolizing enzymes in rodents, it is hypothesized that a supplementation with high dosages of vitamin E may also lead to an induction of the drug-metabolizing system in patients that depend on drug therapy. Compromising essential therapy might therefore outweigh any benefit of vitamin E in patients. It is recommended to work out at which threshold the drug-metabolizing system can be induced in humans before new trials with high dosages of vitamin E are started.     

Vitamin E: an overview of major research directions

During the last 90 years since the discovery of vitamin E, research has focused on different properties of this molecule, the focus often depending on the specific techniques and scientific knowledge present at each time. Originally discovered as a dietary factor essential for reproduction in rats, vitamin E has revealed in the meantime many more important molecular properties, such as the scavenging of reactive oxygen and nitrogen species with consequent prevention of oxidative damage associated with many diseases, or the modulation of signal transduction and gene expression in antioxidant and non-antioxidant manners. Research over the last 30 years has also resolved the biosynthesis and occurrence of vitamin E in plants, the proteins involved in the cellular uptake, tissue distribution and metabolism, and defined a congenital recessive neurological disease, ataxia with vitamin E deficiency (AVED), characterized by impaired enrichment of -tocopherol in plasma as a result of mutations in the liver -tocopherol transfer gene. This review is giving a brief introduction about vitamin E by following the major research directions since its discovery with a historical perspective.     

Low Levels of Vitamin D in Neuromyelitis Optica Spectrum Disorder: Association with Disease Disability

Patients with autoimmune disorders often have low levels of 25-hydroxyvitamin D [25(OH)D₃], which correlates with disability or disease activity. Vitamin D may play a role in neuromyelitis optica (NMO) or NMO spectrum disorder (NMOSD), as an important factor involved in immunological pathways. We investigated the relationship between vitamin D levels and disease related disability and clinical activity in patients with NMOSD. Blood samples from 51 patients with NMOSD who were positive for anti-aquaporin4-antibody (AQP4-ab) and 204 healthy controls were collected for 25(OH)D₃ measurement. Clinical parameters, including expanded disability status scale (EDSS) score, annualized relapse rate (ARR) and time of blood sampling relative to attack, were determined in patients with NMOSD. We found that 25(OH)D₃ levels were significantly lower in patients with NMOSD compared to healthy controls. There was no difference between 25(OH)D3 levels in blood samples taken at relapse or remission, and no association between 25(OH)D3 levels and ARR, but there was an inverse correlation between 25(OH)D3 levels and EDSS scores in patients with NMOSD. It remains to be determined whether low vitamin D levels predispose to NMO and/or modify disease severity, or are secondary to neurological disability. In either case the results could also be of relevance to other neurological diseases such as multiple sclerosis as well as NMO.     

Effects of exogenous vitamin E supplementation on the levels of oxidants and antioxidants in chronic obstructive pulmonary disease

Oxidative stress has been recognized as a central feature of smoke induced chronic obstructive pulmonary disease (COPD). Imbalance between oxidant and antioxidant enzymes is also an established fact in these patients. But studies in regard to stable COPD patients and effect of vitamin E supplementation are lacking. Thirty patients with COPD were included in the study. Their baseline clinical examination, spirometry, plasma malondialdehyde (MDA), alpha-tocopherol and red blood cell superoxide dismutase (SOD) levels were mea sured. Twenty healthy non-smokers who were matched for age and sex served as controls. All the above parameters were repeated after 12 weeks of supplementation with 400 IU of vitamin E daily. The mean malondialdehyde levels in the patients at baseline were higher than controls (5.91 +/- 1.23 nmol/ml vs 4.55 +/- 1.51 nmol/ml, P = 0 001), so also was plasma alpha-tocopherol levels (P < 0 001), while SOD levels were lower in the patients compared to controls (1692 +/- 259 units g/Hb vs 2451 +/- 131 units g/Hb, P < 0 001). Exogenous vitamin E (400 IU per day) supplementation did not bring about any significant change in plasma alpha-tocopherol and SOD levels. The Pearson s co-efficient of correlation between the levels of MDA, vitamin E, SOD; and spirometric measurements were not significant either on day 1 or after 12 weeks of vitamin E supplementation. The present study shows that initially the plasma lipid peroxide (MDA) levels are high and antioxidants (alpha-tocopherol and SOD) are low in patients with COPD. Exogenous supplementation with vitamin E does not have any significant effect on the spirometric measurements though it brings down the levels of MDA showing attenuation of further damage. However, inclusion of larger number of patients and supple mentation with vitamin E for longer periods may throw more light on free radical injury and protective effects of antioxidants.     

Vitamin C treatment reduces elevated C-reactive protein

Plasma C-reactive protein (CRP) is an inflammatory biomarker that predicts cardiovascular disease. Lowering elevated CRP with statins has reduced the incidence of cardiovascular disease. We investigated whether vitamin C or E could reduce CRP. Healthy nonsmokers (N=396) were randomized to three groups, 1000 mg/day vitamin C, 800 IU/day vitamin E, or placebo, for 2 months. Median baseline CRP was low, 0.85 mg/L. No treatment effect was seen when all participants were included. However, a significant interaction was found, indicating that treatment effect depends on baseline CRP concentration. Among participants with CRP indicative of elevated cardiovascular risk (> or =1.0 mg/L), vitamin C reduced the median CRP by 25.3% vs placebo (p=0.02) (median reduction in the vitamin C group, 0.25 mg/L, 16.7%). These effects are similar to those of statins. The vitamin E effect was not significant. In summary, treatment with vitamin C but not vitamin E significantly reduced CRP among individuals with CRP > or =1.0 mg/L. Among the obese, 75% had CRP > or =1.0 mg/L. Research is needed to determine whether reducing this inflammatory biomarker with vitamin C could reduce diseases associated with obesity. But research on clinical benefits of antioxidants should limit participants to persons with elevations in the target biomarkers.     

The effect of vitamins C and E on biomarkers of oxidative stress depends on baseline level

Oxidative stress is elevated in obesity, and may be a major mechanism for obesity-related diseases. Nonsmokers (n=396) were randomized to 1000 mg/day vitamin C, 800 IU/day vitamin E, or placebo, for 2 months. Treatment effect was examined in multiple regression analyses using an intention-to-treat approach. Vitamin C (P=0.001) and vitamin E (P=0.043) reduced plasma F2-isoprostanes. In the overall sample, changes from baseline were +6.8, -10.6, and -3.9% for placebo, vitamin C, and vitamin E groups, respectively. However, a significant interaction with baseline F2-isoprostane was found. When baseline F2-isoprostane was >50 microg/mL, vitamin C reduced F2-isoprostane by 22% (P=0.01). Vitamin E reduced it by 9.8% (P=0.46). Below that cut point, neither treatment produced further reductions. F2-isoprostane>50 microg/mL was strongly associated with obesity, and was present in 42% of the sample. Change in malondialdehyde concentration was minimal. These findings suggest a role for vitamin C in reducing lipid peroxidation. Future research on effects of vitamins C or E on plasma F2-isoprostane should limit participants to those with baseline levels >50 mug/mL. Further studies are needed to establish whether treatment with vitamins C or E in persons with concentrations above that cut point could slow the development of cardiovascular disease.     

Morphological and physiological retinal degeneration induced by intravenous delivery of vitamin A dimers in rabbits

The eye uses vitamin A as a cofactor to sense light and, during this process, some vitamin A molecules dimerize, forming vitamin A dimers. A striking chemical signature of retinas undergoing degeneration in major eye diseases such as age-related macular degeneration (AMD) and Stargardt disease is the accumulation of these dimers in the retinal pigment epithelium (RPE) and Bruch’s membrane (BM). However, it is not known whether dimers of vitamin A are secondary symptoms or primary insults that drive degeneration. Here, we present a chromatography-free method to prepare gram quantities of the vitamin A dimer, A2E, and show that intravenous administration of A2E to the rabbit results in retinal degeneration. A2E-damaged photoreceptors and RPE cells triggered inflammation, induced remolding of the choroidal vasculature and triggered a decline in the retina’s response to light. Data suggest that vitamin A dimers are not bystanders, but can be primary drivers of retinal degeneration. Thus, preventing dimer formation could be a preemptive strategy to address serious forms of blindness.KEY WORDS: Vitamin A, Neurodegeneration, Bisretinoids, A2E, RPE, Vitamin A dimer, Age-related macular degeneration, AMD, Stargardt     

Serum levels of vitamins A, C, and E, β-carotene, selenium, and zinc in patients with behçet’s disease

Behçet’s disease is a multisystemic disease characterized by activation and remission periods. The etiopathogenesis is not exactly known; a genetic defect in the immunoregulatory system induced by infectious agents, like viruses and bacteria, is thought to cause the disease. In this study, we examine the serum levels of vitamins A, C, and E, β-carotene, selenium, and zinc in Behçet’s disease patients and investigate the relationship between these serum levels and the activation of the disease. We conclude that adding vitamin E to the treatment of Behçet’s disease patients and its effects on the prognosis of the disease need to be further investigated by controlled studies.