The hypothesis that oxidative stress favours flogistic and immune processes inducing autoimmune rheumatic diseases (ARDs) and their complications is still under discussion. In this review we take into consideration both the aetiopathological role of the diet in such diseases and the possible efficacy of dietary supports as adjuvants for the usual specific therapies. Moreover, we shall examine the hypothetical pathophysiological role of oxidative stress on ARDs and their complications, the methods for its evaluation and the possibility of intervening on oxidative pathways by means of nutritional modulation. It is possible that in the future we will be able to control connective pathology by associating an immuno-modulating therapy (‘re-educating’) with naturalproducts having an anti-oxidant activity to current immunosuppressive treatment (which has potentially toxic effects).
2003 Elsevier B.V. All rights reserved.Role of the diet and dietary supports in autoimmune rheumatic disease In 1880, Sir Jonathan Hutchinson suggested some healthy-life rules in the treatment of systemic lupus erythematosus (SLE). They included selected aliments and dietary support with cod-liver oil w1x. More than 100 years later, the role of the diet and the dietary supports is still under discussion. The complexity of the pathology and the number *Corresponding author. Tel.: q39-10-555-3985; fax: q39- 10-555-6850. E-mail address: samir.sukkar@hsanmartino.liguria.it (S.G. Sukkar). of concurrent factors often frustrate the efforts made in attributing symptomatic remission to a specific therapeutic support.

 We are dealing, in fact, with pathologies marked by time-variant clinicalpatterns, showing periods of spontaneous remission and influenced by many environmental factors able to sustain the illness’ activity or favour its flares. In a recent review—‘Diets, dietary supplements and nutritionaltherapies in rheumatic disease’— Henderson and Panush w2x critically examined approximately 200 publications on the subject and they did not find conclusive data about the role of diet in autoimmune rheumatic diseases (ARDs). In that review the authors highlight some considerations about the possible protective role of v-3 fatty acids in rheumatoid arthritis and that antioxidant vitamin A, E and C concentrations are decreased in RA and SLE w2–4x. 2. What role does oxidative stress have on autoimmune rheumatic disease? The reactive oxygen species (ROS) (superoxyde, hydrogen peroxide, hydroxilic radicals and nitric oxide) are physiologic activators of transcription factors for pro-inflammatory cytokines as: (1) Activator protein-1 (AP-1) that is a transcription factor of the gene for collagenases, TNFa, IL8, IL9, IL3 e IFNg, adhesion molecules related to the formation of atherosclerotic plaques and genes for the cell-division cycle; (2) Nuclear factor-kB (NF-kB) that activates the promoters of the genes for IL1, IL6, IL8 and TNF-a cytokines together with the genes for the inducible form of nitric oxide (i-NO), e-selectine and VCAM-1 adhesion molecules, class I and II HLA antigenes, IL2-receptors and severalacutephase proteins w5x. From this background we may suggest some ideas about the role of oxidative stress in ARD, and therefore some lines for clinical investigation. 

(a) The majority of the previously mentioned cytochines increase during the flares of ARD, as well as the i-NO; similarly, the endothelium, macrophages and antigen presenting cells show an increased expression of e-selectine and VCAM-1 during disease activity, or the class I and II HLA antigens are highly expressed on the activated lymphocytes. Therefore, we must suppose that the oxidative stress may trigger inflammatory activity and therefore it may induce a flare of the disease. (b) The activation of monocytes, endothelial and poly-morpho-nucleated cells, as it appears during infections, surgicalinterventions and traumatisms, induces an exalted release of ROS. As we discussed, the biologic effect is the exalted production of pro-inflammatory cytokines, the expression of adhesion molecules and the exalted production of i-NO, which sustains the immune reactions leading to inflammation and organ damage. From these points we may suggest how traumatic or flogistic events trigger andyor maintain the flares of ARD. (c) We suppose that the exalted production of ROS has a centralrole in the pathogenesis of two major complications: early atherosclerosis, with consequent cardiovascular pathology, and osteoporosis. 3. Survival curves for systemic lupus erythematosus In SLE, biological and clinical advances give us a better understanding of the disease, leading to a more effective clinical control. 

Therefore, it has been possible to observe a bimodal survival curve where deaths directly related to disease only account for approximately 30%, while cardiovascular accidents for early atherosclerosis and infections are the major cause of mortality w6x. 4. Oxidative stress and autoimmune rheumatic disease are concurrent causes of early atherosclerosis Oxidative stress favours a sequence of proatherogenetic events: the production of pro-inflammatory cytochines, macrophagic activation, cellular proliferation of the cellularis mucosae, endothelial activation, the synthesis of ox-LDL and the production of the i-NO w7x, and, finally, the ossifying activity of the cells of the muscolaris mucosae. The same events are found in ARDs, particularly in the SLE. This disease is characterized by vascular inflammation, endothelial and macrophagic activation, ox-LDL-synthesis, production anti-ox-LDL antibodies, as well as dyslipohaemia, hypertension, lymphocyte hyperactivation and organ damage. It is possible that SLE rapidly leads to the formation of atherogenetic lesions and, consequently, to the cardiovascular diseases partially by means of elevated oxidative stress observed in this disease. 5. Early atherosclerosis and ensuing vascular damage are serious complications of SLE A recent study w8x examined the ‘risk factors for cardiovascular disease in systemic lupus erythematosus’. Eight relevant risk factors are reported, six of them are related to vascular damage following early atherosclerosis, while lupus anticoagulants and homocystein levels represent independent vascular damage risk factors.

 Higher cumulative cortisone is not reported in this study as an independent vascular risk factor, but it is a risk factor for early atherosclerosis because it is related to a marked aggressiveness of the illness. Experiments on animalmodels confirm this interpretation, as they showed that steroid’s anti-atherosclerotic effect could be in turn related to its anti-inflammatory w9x and—given the autoimmune pathogenic hypothesis about atherosclerosis— immunosuppressive activity. 6. Association between atherosclerosis and osteoporosis, the role of oxidative stress In women affected by SLE with associated cardiovascular damages, a greater incidence of osteoporosis has been observed w8x. The association between atherosclerosis and osteoporosis is not confined to this disease, as it has also been found in post-menopausalwomen w10x. The proinflammatory cytokines, which have been reported to play a pivotal role in atherogenesis, likewise favour osteoporosis, as shown by a study on postmenopausalwomen w11x. In addition, oxidative stress plays a primary role in the pathogenesis of both diseases. Indeed, in vitro tests with mice cell lines showed that the ROS enhance the activity of osteoclasts w12x and calcifying vascular cells, while inhibiting osteoblastic cells w13x. 7. Which clinical and therapeutic measures are capable of reducing oxidative stress’ effect of the disease? 

From the above-mentioned data it could be suggested that the oxidative stress favours flogistic and immune processes sustaining ARD and their complications (like early atherosclerosis and osteoporosis). On the other hand, ARD and its complications start, increase and maintain oxidative processes, giving thereby rise to a vicious circle (oxidative stress—disease activity and expression of some complications—oxidative stress). These elements loop into a steady and self-sustained worsening of the clinical symptoms. The persistent production of large amounts of ROS may induce changes in signaltransduction and gene expression determining a chronic oxidative stress condition w14x. Therefore, the specific treatment of the disease (corticosteroids, anti-inflammatory, immunomodulatory and immunosuppressive drugs) can indirectly reduce oxidative stress and, partially, directly inhibit some oxidative processes. Treating oxidative stress by means of nutritionalmodulation could represent an optional complementary tool that could be developed in the near future in order to reduce treatment with standard drugs. 8. How to evaluate oxidative stress in the ‘at risk’ population? As far as oxidative stress plays an important role in favouring inflammation and vice versa, it is mandatory to evaluate oxidative stress in the population at risk even if the practical role of this evaluation is still a debatable matter.

 Anyway, as reported by Halliwell, some apparently healthy human beings show higher rates of lipid peroxidation than others, therefore as we do not administer antihypertensive drugs to patients in clinical trials without checking blood pressure, so why should we give anti-oxidants without checking that they have decreased oxidant status? w15x. But which measurements can we perform? According to Ref. w16x, we can evaluate the level of oxidative stress by means of checking some categories of by-products of the oxidization process or by the evaluation of dietary intake. Catabolites of lipidic peroxidation (i.e. thiobarbiturics acid reactant substances) w17x. Catabolites of protein oxidation (i.e. oxidized LDLs) w18x. Catabolites of DNA oxidation (timidine glicole and 8-HO-29-desoxiguanosine) w19x. Detection of the derivatives of reactive oxygen metabolites (D-Rom test) w20x. Evaluation of anti-oxidant dietary intake (i.e. Mediterranean Adequacy Index) w21x. 9. Will dietary derived substances capable of reducing oxidative stress play a therapeutic role in autoimmune rheumatic diseases? If we suggest a direct pathogenetic role for oxidative stress in ARD, we may suppose that therapeutic and dietary choices capable of maintaining oxidative stress could be of clinical benefit. 

As previously mentioned, laboratory and clinical data sustaining this idea are the following: 1. patients with ARD showed a reduced antioxidant condition (reduction of vitamins A, C and E), which was supposed to play a pathogenic role for the disease w22,23x; 2. serum values of vitamins with anti-oxidant activity (alpha-tocopherol, carotene and rhetinol), measured in samples stored in a serum bank from blood donors who developed after 2–15 years RA or SLE, were lower than for the controls w22x; 3. high vitamin-E doses administered to RApatients were effective in reducing pain symptomatology w24,25x. Furthermore, a hypotheticalfield of intervention takes into account foods rich in anti-oxidants: in fact, in in vitro studies they have shown antiinflammatory effects linked to the down-regulation of NF-kB. Green tea has shown significant anti-inflammatory actions in cell culture systems in vivo experimentalinflammatory processes w26x. These biological effects of green tea are determined by tea polyphenols, known also as tea catechins, which may inhibit NF-kB activation. Epigallocatechin 3-gallate (EGCG), the main polyphenol of green tea, may inhibit TNF-a-induced degradation of IkB and activation of NF-kB in cancer and normal cells w27x. The impairment of NF-kB activity observed by treatment with EGCG seems to be a consequent to the decrease of IKK activity. Moreover, EGCG specifically inhibits IKK activity in cytosolic extracts of TNF-a-stimulated cells w28x.

 Sesquiterpene lactones derived by herbalpreparations from Asteraceae plants commonly used in alternative medicine for rheumatoid arthritis w29x specifically strong inhibit NF-kB pathway in in vitro models w30,31x. Sesquiterpene lactone parthenolide selectively inhibits activation of the NFkB pathway by targeting IKK w30x andyor preventing the degradation of IkB-a and IkB-b, without interfering with ROS formation, in in vitro experiments w31x. Capsiate and its dihydroderivatives (capsaicin (CPS) and nordihydrocapsiate (CPT)) that are the major capsaicinoids of sweet pepper inhibit NFkB activation in response to different agents including TNF-a. CPS itself does not affect the DNA-binding ability of NF-kB but it prevents IkB kinase activation and IkB-a degradation in a dose-dependent manner w32x. Curcumin, the most important component of turmeric —a spice component of curry—commonly adopted as an anti-inflammatory compound in eastern medicinalpractices, shows inhibition of NF-kB activation in a concentration-dependent manner in endothelial cells w33x. Resveratrol, an edible polyphenolic stilbene found in the skin of red grapes, which has antioxidant properties similar to vitamin E, has been reported as being capable of suppressing IL-1binduced activation of NF-kB in acute myeloid leukemia cells w34x. A fermented wheat germ extract with standardized benzoquinone content (FWGE ) has shown an improvement of clinical and laboratory parameters on mice subject to SLE w35x. Authors postulate that results may be related to a rebalancing of the lymphocytes subclasses Th1yTh2 (inhibition of IL4 and IL10 production). This product contains large amounts of chinolonics and flavonoids having an intense anti-oxidant activity.

 It is therefore likely that the immunomodulatory therapeutic effect can be ascribed to them w35x. Nevertheless, there are no experimental studies in vivo which demonstrate the therapeutic potential as an anti-inflammatory of all the previous substances in ARD. Clinical trials are in progress at our unit to verify the activity of FWGE in SLE patients. In conclusion, during ARDs a lack of antioxidant vitaminic factors has been reported. These vitamins, like diet derived substances of vegetal origin, could represent a complementary therapeutic option by reducing the dysregulation of ROS steady state, throughout various mechanisms, of which the inhibition of the NF-kB activation could be the most important. As far as clinical efficacy is concerned, the results of vitamin E treatment in RA and rheumatic polyarthritis are encouraging, while controlled clinical studies on vegetal antioxidant compounds are still lacking, as well as information about their pharmacokinetics and toxicity. Therefore, further trials are mandatory to verify, possibly in large multicentric studies, the efficacy of vitamins and efficacy and safety of naturalantiinflammatory substances as well as better understanding the mechanisms of their action and their role in the nutritional prevention of ARD.