Arthritis and Other Chronic Inflammatory Diseases

J. Clip. Biochem. Nutr., 20, 1-26, 1996

Review

Diet and Nutrition in Rheumatoid Arthritis and Other Chronic Inflammatory Diseases

Ann L. PARKE,1 Dennis V. PARKE ,2,* and Francis Avery JONES2

1 Division of Rheumatology, Department of Medicine, University of Connecticut School of Medicine, Farmington, CT, U.S.A. 2School of Biological Sciences, University of Surrey, Guildford, Surrey, GU2 5XH, U.K.

(Received October 25, 1995)

Summary A greater understanding of the etiology of rheumatoid and other inflammatory diseases, their association with reactive oxygen species (ROS), and the role of environmental chemicals as antigens , has opened the way to new approaches in disease prevention and treatment by dietary modulation. Normal protection against the inflammatory effects of ROS (antioxidant defense) and environmental chemicals (detoxication) requires constant dietary replenishment to provide the redox buffer, glutathione (GSH), the antioxidant vitamins, E, C, and A, and other essential components such as selenium for the GSH peroxidase enzymes. Fasting and some environmental chemicals (haloalkanes) induce the ROS-generating enzyme cytochrome P4502E, as also does inorganic iron; and the various dietary lipids provide prostanoids of different inflammatory potentials. Adequate calories (NADPH) are essential for maintaining the two defense systems, but caloric excess may lead to changes in membrane composition, electron leakage, ROS generation , and exacerbation of the inflammatory condition.

Key Words. rheumatoid arthritis, inflammatory disease , food, antioxidants, reactive oxygen

Rheumatoid arthritis (RA) and chronic inflammatory disease have long been associated with food and nutrition, both in disease causation and in treatment [1, 2]; and because of the known relationships between polyunsaturated fatty acids

* To whom correspondence should be addressed .

1 2 AL. PARKE, D.V. PARKE, and F.A, JONES

(PUFAs), prostanoids, cytokines, and inflammation [3, 4] there appeared to be some scientific rationale for this. Lay advocates of dietary treatment considered that "rheumatic diseases are caused by chemical poisoning from the additives put into our food" [5, 6], and prescribed a diet low in red meat, saturated fat, alcohol, food additives, and preservatives, but rich in seafood, vegetables , and rice-the Dong diet. However, in 1981, an Arthritis Foundation pamphlet advised RA patients that "no food has anything to do with causing arthritis and no food is effective in treating or curing it" [7] ; and later a 10-week scientific study of 25 RA subjects fed the popular Dong diet found only limited benefit among a small sub- group of patients [8]. Obviously, with so many dietary variants studied simultane- ously in the treatment of a multifactorial disease, one would expect an equivocal, largely negative response; and against a previous background of lay enthusiasm it would be wrong to summarily dismiss a possible association of RA with diet on the strength of a single study of some 25 patients. The difficulties in conducting such studies were further considered by Ziff, who advocated that the choice of diet for future investigations "should be based on a concept that links intermediary metabolism with immunity and chronic inflammation" [9]. Recent advances in our understanding of the molecular pathology of RA and autoimmunity [10-12] and of the role of oxygen radicals (reactive oxygen species, ROS) in the manifestation of inflammatory disease [13, 14], together with recent views on the role of nutrition in biological defense against ROS and toxic chemicals [15, 16], have brought into sharp focus the possible role of nutrition in the prevention and treatment of inflammatory disease. Hence, the objective of this paper is to review these recent developments, and to identify any association of food and nutrition with intermediary metabolism and chronic inflammation that might lead to the prevention and/or exacerbation of RA and other chronic inflammatory disease states.

MOLECULAR PATHOLOGY OF CHRONIC INFLAMMATORY DISEASE

The various manifestations of chronic inflammatory disease, e.g., RA, systemic lupus erythematosus (SLE), and inflammatory bowel disease (IBD), all involve ROS-mediated tissue damage [11, 13, 14]. It is uncertain whether ROS are the cause or effect, or both [17], but oxidative stress resulting in tissue injury is due to excess ROS production and/or defective biological antioxidant/detoxication defense systems. Oxygen radicals are produced by various mechanisms including: (i) the simple interaction of water, molecular 02, and inorganic iron; (ii) activation of leucocytes by cytokines; (iii) induction of cytochrome P4502E; (iv) prostanoid biosynthesis in the cyclooxygenase and lipoxygenase pathways [18]; (v) futile cycling of microsomal cytochromes P450 (CYP); (vi) redox cycling of quinone drug metabolites; (vii) xanthine oxidase functioning as an oxygenase; and (viii) electron leakage from mitochondrial and microsomal membranes; and although the first two mechanisms are probably the major ones involved in chronic

J. Clin. Biochem. Nutr. DIET AND NUTRITION IN RHEUMATOID ARTHRITIS 3 inflammatory disease, the other sources of ROS are also likely to contribute [11].

Iron This plays a major role in the pathology of RA and chronic inflammatory disease [11], since iron mobilized from ferritin or microsomal iron protein [19] effects the following: (i) the formation of highly toxic hydroxyl radicals (' OH) from the superoxide anion (O2-.) and peroxide; (ii) the production of ROS directly from 02 and water; (iii) membrane lipid peroxidation [16]; and (iv) chemotaxis for neutrophils (PMN) [20], which then generate ROS, thus perpetuating inflammatory tissue damage [21] (Fig. 1). RA patients with chronic anemia have high plasma ferritin levels, and low plasma B12 and folate levels [22], as would be expected from a high turnover of erythrocytes, hemoglobin, and other heme proteins resulting from lipid peroxidation. Further evidence of the critical role of iron in RA is that oral administration of iron produces a flare of rheumatoid synovitis [21], infusion of iron dextran promotes synovitis in previously inflamed joints [23], and the ferritin content of synovial fluid of RA patients is some 10- fold greater than that of healthy controls or osteoarthritic patients [24] . From the observations, Blake has proposed that in RA, inflamed joints result from iron- mediated generation of ROS, arising from intermittent intra-articular microhem- orrhage and hypoxic reperfusion injury [21]. Excessive absorption of dietary iron is normally prevented by its binding to gastrointestinal mucus [25] , but absorption of aluminum increases iron-mediated lipid peroxidation [26] possibly by displacing iron from natural silicic acid complexes in the body [27]. Silicic acid, present in cereals, is considered to be an essential nutrient for some species and protects against aluminum toxicity; deficiency may result in changes in col- lagenous connective tissue, and in osteomalacia, anemia, and dementia [27] .

Fig. 1. Iron toxicity. •0H, Hydroxyl radical; OZ'-, superoxy anion; PMN , polymorphonuclear leucocytes.

Vol. 20, No. 1, 1996 4 AL. PARKE, D.V. PARKE, and F.A. JONES

Table 1. Some of the families of the cytochromes P450.

TCDD, 2,3,7,8-Tetrachlorodibenzo-p-dioxin; PAH, polycylic aromatic hydrocarbons; EETEs, epoxyeicosatetraenoic acids; HETEs, hydroxyeicosatetraenoic acids .

Cytochrome P4502E1 (CYP2E) In recent studies into the molecular pathology of ROS-mediated tissue damage, surgical trauma, and multiple system organ failure, we identified a role for CYP-mediated ROS production. CYP2E, a unique member of the GYP superfamily, is a potent generator of ROS, and is activated by fasting (acetone), ethanol, ether, certain halogenated anesthetics and solvents, and many other low molecular weight chemicals (Table 1). Exposure of experimental animals to fasting and ether/halothane anesthesia resulted in extensive lipid peroxidation in liver and kidney, with loss of other isoforms of GYP [28, 29]. Furthermore, in a hepatic ischemia-reperfusion model for hemorrhage and hypovolemic shock, the initial phase of xanthine oxidase-mediated ROS production was followed by PMN infiltration and a second greater burst of ROS production, mediated by PMN leucocytes [30], PMNs also infiltrated the lungs although reperfusion was limited to the liver, indicating that iron, cytokines or prostanoids produced by inflammation in one organ or tissue can mediate leucotaxis in another tissue [30].

Food as a cause of chronic inflammatory disease Sensitivity to particular foods has long been considered to be a possible cause of RA and other chronic inflammatory disease, but there is little evidence to support this. In only a small percentage (less than 5%) of patients with RA can this disease be attributed to "allergy" to food [2]. A few RA patients have immunological hypersensitivity to milk and dairy products [2], and in some rheumatoid patients, exclusion of dairy products from the diet has been associated with a clinical improvement in inflammatory synovitis [31]. Food antigens are

J. Clin. Biochem. Nutr. DIET AND NUTRITION IN RHEUMATOID ARTHRITIS 5 predominantly proteins, but lipids and food additives (sulphites, tartrazine, monosodium glutamate) may also precipitate food hypersensitivity [32] . The gastrointestinal barrier is permeable, and food proteins may cross this and circu- late as antigens or as immune complexes. All subjects may absorb food antigens from the gut and have intact dietary proteins in the circulating blood [33]; and many normal subjects have serum antibodies to bovine serum albumin, oval- bumin, lactoglobulin, and other dietary antigens [34] . Some infants fed cows' milk have circulating immune complexes that could lead to production of anti-idiotypic autoantibodies [33] . The consumption of alfalfa seed has been associated with SLE, and this has been shown to be due to the amino-acid L-canavanine [35]. Absorption of dietary antigens from the gut may be enhanced by changes in gastrointestinal permeability due to immaturity, immunodeficiency, allergy, or other diseases [33] due to pathological states associated with an increase in gastrointestinal permeability including coeliac disease, atopy, IBD, and due to the adverse effects of non-steroidal anti-inflammatory drugs. Changes in bowel permeability, because of IBD, may result in the absorption of food or microbial antigens, resulting in formation of circulating immune complexes. It has been suggested that it is also possible that leucocytes activated in the gut at a site of inflammation may migrate and lodge in joints, thus resulting in synovitis [36]. This increased exposure to foreign antigens may result in extra-intestinal pathology similar to that described in patients who developed the arthritis dermatitis syndrome secondary to bowel bypass operations performed in the 1970s [36]. Total fasting by RA patients results in rapid relief of pain and inflammation, a decrease in serum acute-phase proteins, decreased release of the PMN leukotriene B4 (LTB4), and decreased release of PMN lysozyme, but may be continued safely for only 1 week [37]. The mechanism is unknown but may involve removal of aggravating food antigens, changes in intermediary metabolism, especially lipid metabolism, and decreased basal metabolism resulting in lower tissue oxygen uptake and hence decreased ROS production [38]. The recent occurrence of two widespread, fatal, scleroderma-like, chronic inflammatory syndromes associated with the ingestion of specific foods , namely, the toxic oil syndrome associated with rapeseed oil and the eosinophilia-myalgia syndrome associated with the amino acid L-tryptophan, have revealed the poten- tially serious hazard of food inflammotoxins and could lead eventually to a better understanding of the molecular pathology involved in food-provoked inflammatory disease. The first of these two tragic occurrences, which closely paralleled each other, was the toxic oil syndrome (TOS) that developed in Spain in 1981 following the ingestion of fraudently marketed, illicitly recovered , denatured rapeseed oil [39-42] . Over 20,000 cases were recorded with symptoms of fever, rash, gastrointestinal pain, hepatomegaly, pulmonary and neurological distur- bances, arthralgia and myalgia; over 300 died and many had persistent scleroderma symptoms for a decade or so [39]. Rapeseed oil, long known to be atherogenic due to its content of erucic acid-a natural mono-unsaturated fatty acid , metabolized

Vol. 20, No. 1, 1996 6 AL. PARKS, D.V. PARKE, and FA. JONES with great difficulty and associated with atherosclerosis-was marketed as an industrial lubricant after denaturation by addition of aniline/pyridine and a brown dye to prevent human consumption. Illicit treatment to remove the aniline is thought to have resulted in the production of toxic acyl anilides [43] . Erucic acid is resistant to /3-oxidation and consequently is metabolized only by microsomal w-oxidation, resulting in induction of CYP4 and hepatic peroxisomal proliferation, which are associated with peroxide formation and hepatotoxicity (Table 1). As anilides of fatty acids are even more resistant to /l-oxidation, they would accumulate, and could manifest immunotoxicity. Although not normally antigenic, fatty acids can be made immunogenic by chemical modification , and antibodies to several common fatty acids have been prepared [44] . In 1989, the second such epidemic of chronic inflammatory disease, namely, eosinophilia- myalgia syndrome (EMS), associated with the ingestion of L-tryptophan , occurred in the U.S.A. [45, 46]. The average consumption of L-tryptophan was 1.5 g/day for 4 months, and > 1,500 cases and some 27 deaths have been reported. The subacute and chronic stages of EMS were marked by progressive neuromuscular, pulmonary, and skin manifestations that resembled the symptoms of TOS. Metabolites of tryptophan, notably quinolinic acid, have been implicated; but all clinical cases were related to the product of a single manufacturer, which was found to contain an impurity with the chemical structure of two tryptophan molecules joined by an ethylidine bridge [47].

Drug- and chemical-induced chronic inflammatory disease Drugs and chemicals have been indicated in the formation of neoantigens and the consequent increased immune response and chronic inflammation, and conversely, in the loss of immunological defense resulting in lethal infections, such as AIDS. In many chronic inflammatory conditions, circulating autoantibodies to liver and kidney endoplasmic reticulum, to "phospholipid," ribosomal phospho- protein, and CYP have been demonstrated [11, 48-50], indicating involvement of the cell endoplasmic reticulum, and probably the microsomal oxygenases (CYP), in the formation of neoantigens and consequent production of autoantibodies [11]. Many individual drugs, e.g., procainamide, hydralazine, and penicillamine, are known to give rise to SLE, hepatitis, and blood dyscrasias [11, 51]. This potential for causing autoimmune-mediated disease appears to be dependent on the metabolic activation of these drugs to reactive intermediates by liver microsomal CYP, leucocyte myeloperoxidase and other oxygenases, and subsequent binding to DNA and protein to form neoantigens [52]. The highest incidence of drug-induced lupus occurs with procainamide; and although > 50% of patients on procainamide therapy develop antinuclear antibodies, the incidence of clinical lupus is <30%. Procainamide is normally detoxicated by N-acetylation, and "slow acetylators" are more susceptible than "fast acetylators" to develop drug-induced lupus. The mechanism of this immunotoxicity involves N-hydroxylation to the corresponding hydroxylamine, which is subsequently oxidized non-enzymatically

J Clin. Biochem. Nutr. DIET AND NUTRITION IN RHEUMATOID ARTHRITIS 7

Table 2. Mutagenicity of some heterocyclic amines in food.

Data are from ref. [54]. to the nitroso analogue, which then binds covalently to proteins to form neoantigens [11]. Hence, genetic impairment of the normal drug detoxication pathway results in an alternative route of metabolism that activates the drug molecule and results in immunotoxicity. While both pathways of drug metabolism are catalyzed by liver enzymes, the oxidative metabolism of procainamide also takes place in the leucocytes, catalyzed by myeloperoxidase of activated PMNs or monocytes; the nitroso metabolite may also bind to myeloperoxidase itself [11, 53]. Other lupus- inducing drugs, such as hydralazine, sulphasalazine, and practolol, are similarly activated by N-hydroxylation of the corresponding aromatic amines [11]. It is also likely that some of the numerous heterocyclic amines that are produced in the cooking of food [54] and are activated to potent mutagens by N- hydroxylation catalyzed by hepatic CYP 1A2 [54] (Table 2) would bind covalently to proteins to form neoantigens; indeed, this might be one of the missing links between food and autoimmune disease, and certainly merits more detailed investi- gation. Scleroderma is also associated, in susceptible individuals, with exposure to certain environmental chemicals, such as trichloroethylene and vinyl chloride, and again may be the consequence of genetically-impaired detoxication, such as the impaired N-hydroxylation of dapsone and hydroxylation of S-mephenytoin, which correlate well with the occurrence of scleroderma [55] . Similarly, only certain individuals were susceptible to the immune-mediated hepatotoxicity of halothane [56] or tienilic acid [57], both of which are activated by CYP to radical or epoxide reactive intermediates that react with tissue proteins to form neoantigens. Penicillin, which probably causes more allergic reactions than any

Vol. 20, No. 1, 1996 8 AL. PARKE, D.V. PARKS, and FA. JONES other drug, is activated by the opening of the jS-lactam ring followed by covalent binding of the carbonyl group to protein lysine residues , creating neoantigens with penicilloyl groups as major antigenic determinants [58]; similarly, penicillamine can undergo N-oxidation to form reactive intermediates capable of forming drug- protein conjugates. Yet another mechanism of drug activation , resulting in the formation of antigenic protein conjugates, is that of deconjugation . Acyl ester glucuronides, e.g., benzoyl glucuronide, are metastable; and nucleophilic displacement of the glucuronide moiety by amino acid residues leads to the binding of the drug aglycone to the protein. Several non-steroidal anti-inflammatory carboxylic acid drugs, e.g., zomepirac and tolmetin, are considered to manifest their immunotoxicity by this mechanism [52, 59, 60]. Many industrial and environmental chemicals (e.g., PCBs and dioxins) that are metabolized and eliminated only with great difficulty have long biological half-lives (ca. 100 years), and may be sequestered into tissues for an animal's lifespan [61] . These chemicals are mostly planar , halogenated, lipid-soluble substances that are slowly metabolized by CYPI (activates carcinogens) . They interact with the Ah receptor, a cytosolic protein of the steroid receptor superfamily, found in liver, leucocytes, and other tissues [62]; and this results in the induction of CYPI biosynthesis, activation of protein kinase C, and initiation of ROS production and lipid peroxidation. The archetypal compound of these environmentally-persistent chemicals is TODD (2,3,7,8-tetrachlorodibenzo-p-dioxin), the ubiquitous combustion product of chlorinated chemicals . TODD induces oxidative stress [63] and causes marked immunotoxicity by induction of CYP- mediated arachidonate metabolism to reactive epoxy- and hydroxy-eicos- atetraenoic acids (EETEs and HETEs) [64], and also results in impaired cellular immunity by a direct action on peripheral lymphocytes [65] . Hence, these chemical pollutants can produce chronic inflammatory conditions by (i) direct oxidative stress, and/or indirectly by (ii) induction of the CYP of liver, leucocytes , and other tissues, with the subsequent activating oxygenation of arachidonic acid . Because of the lifetime persistence of such chemicals and their high potency , TCDD and similar environmental pollutants could result in chronic inflammatory disease states that would persist for many years if the antioxidant defense system were deficient. Hence, the most likely chemicals in food and the environment that could precipitate chronic inflammatory disease and immunotoxicity are (i) the food pyrolysis mutagens-as they have potential to form neoantigens and are numerous and ubiquitous in food [54], and (ii) the planar polyhalogenated hydrocarbons (TODD, PCBs)-which are also numerous and ubiquitous, are highly persistent, and can induce ROS production [63]. Although numerous drugs and chemicals with immunosuppressant actions are known, one topical example will serve to illustrate this other aspect of drug- induced inflammatory disease. Acquired immunodeficiency syndrome (AIDS) ,

J. Clin. Biochem. Nutr. DIET AND NUTRITION IN RHEUMATOID ARTHRITIS 9 though generally believed to result from HIV infection, is now often considered to be a disease resulting from several interacting factors, including a virus-induced cysteine/glutathione deficiency [66], and the cytotoxicity of vasodilatory drugs [67]. Volatile vasodilatory alkyl nitrites, used as recreational drugs [6S], are cytotoxic to lymphocytes [67], and are a possible cofactor in AIDS [69]; they form S-nitrosylglutathione, which further depletes the protective intracellular GSH and mediates ATP depletion, lipid peroxidation, and cell death [70].

Biological defense against ROS and environmental chemicals Recent advances in molecular biology have shown that biological survival has been dependent on the evolution of an antioxidant defense system to protect against ROS, namely, superoxide anion (02-'), hydroxyl radical ('0H), peroxide (022-), and singlet oxygen (102), all of which can promote oxidative stress, lipid peroxidation, cell death, and genetic damage in living systems [14] (Fig. 1). These studies have also indicated that some 300 million years of plant-animal warfare in the evolution of man has endowed us with a highly efficient chemical defense (detoxication) system to protect against the numerous toxic chemicals (phytoalex- ins) elaborated by plants to defend themselves from animals foraging for food [71, 72]. Most chemical toxicity is ultimately mediated by ROS, either by the formation of ROS or by the involvement of glutathione in conjugation reactions, thereby depleting the antioxidant defense system. The antioxidant defense and chemical defense systems are therefore interdependent, so that exposure to environmental chemicals puts an additional load on antioxidant defense, and may exacerbate conditions involving oxidative stress, such as RA and chronic inflammatory disease. The antioxidant defense system (Fig. 2) is a complex integrated array of enzymes, antioxidants, and radical scavengers, dependent largely on glutathione (GSH) and involving GSH reductase, GSH S-transferases, GSH peroxidases (GPX), phospholipid hydroperoxide GSH peroxidase (PHGPX) [73], superoxide dismutase (SOD), catalase, the tocopherols (vitamin E), ascorbic acid (vitamin C), retinoids (vitamin A), and bilirubin [15, 16]. The chemical defense system (Fig . 2) also comprises numerous enzymes including the CYP superfamily, which catalyzes numerous oxygenation and oxidation reactions (phase 1 reactions, e.g., C-, N- and S-oxygenations and oxidations, N- and 0-dealkylations , etc.), and the superfamilies of GSH S-transferases, glucuronyl transferases, and sulphotransfer- ases (phase 2 or conjugation reactions). Both the antioxidant and chemical defense systems are dependent on food and nutrition for efficacy, and 24-h fasting markedly increases the toxicity of many chemicals [74]. The major nutritional requirements for the efficient functioning of these biological defense systems are (i) energy (NADPH) to maintain GSH in its reduced form and to activate oxygen for CYP oxygenations, (ii) sulphur amino acids for GSH biosynthesis and GSH- and sulpho-conjugations, (iii) antioxidant vitamins, such as ascorbic acid, tocopherol , and retinoids, and (iv) lipotropes (choline) and unsaturated fatty acids for effective

Vol. 20, No. 1, 1996 10 AL. PARKE, D.V. PARKS, and F.A. JONES

Fig. 2. Mechanisms of antioxidant defense and chemical detoxication. PMN, Polymor- phonuclear leucocytes; CYP, cytochrome P450; GSH, reduced glutathione; PAPS, phosphoadenosine phosphosulphate; UDPGA, uridine diphosphate glucuronic acid; SOD, superoxide dismutase; GPX, glutathione peroxidase; vit. A, E and C, vitamins A, E, and C. membrane electron transport [15, 16] to minimize electron leakage and consequent increased ROS generation.

THE ROLE OF NUTRITION IN BIOLOGICAL DEFENSE

Carbohydrates and energy These are needed to provide ATP, NADH, and NADPH for muscular work, biosynthesis, and the needs of the antioxidant and detoxication defense systems. Deprivation of dietary carbohydrate, and fasting, accelerates fatty acid oxidations, raising the blood levels of acetone and other ketone bodies, leading to increased activity of CYP2E 1, a potent generator of ROS, which effect tissue lipid peroxidation [75, 76]. Recent studies into surgical trauma have revealed that overnight fasting and inhalation anesthesia enhance CYP2E 1 activity, increasing ROS production and tissue damage [28, 29]. In contrast, food restriction decreases the age-dependent increase in lipid peroxidation of microsomal and mitochondrial membranes, maintains normal membrane fluidity, and membrane cholesterol/ phospholipid ratios [77, 78], thereby preventing electron leakage and consequent ROS generation.

J. Clin. Biochem. Nutr. DIET AND NUTRITION IN RHEUMATOID ARTHRITIS 11

Hence, both fasting and ad libitum feeding, at least in rats, can result in increased ROS generation and lipid peroxidation. Moreover, excessive feeding leading to obesity may result in sequestration of increased amounts of ROS- generating environmental chemicals (TODD, PCBs). So, in RA and other inflammatory diseases it is desirable to avoid both excessive eating and dieting alike, so as to minimize ROS production.

Protein Apart from daily needs of dietary protein for growth, tissue repair, and renewal of epithelia and leucocytes, protein is also required for biosynthesis of antioxidant and detoxication enzymes, including the intracellular redox buffer glutathione. The amino acids, glycine, glutamine, and taurine are involved in conjugation of drugs and chemicals; the sulphur amino acids also provide sulphate (PAPS) for conjugation of phenols, so that patients on drug therapy require adequate dietary protein, particularly rich in sulphur amino acids, to detoxicate their medications. Methionine deficiency decreases liver GSH, and increases paracetamol hepatotoxicity in rodents [79]; methionine is also important for effective use of dietary selenium and hence for GSH peroxidase activity and detoxication of lipid peroxides [80]. High-protein diets enhance the metabolism and excretion of a variety of drugs, and parenteral administration of amino acids increased aminopyrine clearance in human volunteers by 20% [81].

Vitamins and minerals Vitamin C (ascorbic acid), a potent hydrophilic antioxidant and radical scavenger, together with the lipophilic vitamin E (tocopherols), coenzymes Q [82] and glutathione, comprises the intracellular, redox-coupled, antioxidant system protecting against ROS-mediated lipid peroxidation. Ascorbate is essential for CYP activity, the detoxication of drugs and toxic chemicals, cholesterol homeosta- sis, and bile acid synthesis [83]. It decreases the covalent binding of reactive intermediates, reduces toxic quinones, eliminates free radical metabolites, and blocks the formation of nitrosamines [83]; and ascorbate rather than glutathione protects against the toxicity of paracetamol by reducing the paracetamol phenoxyl radical [84]. Ascorbate deficiency decreases CYP-mediated drug oxidations and glucuronide conjugations, the latter being quantitatively the most important detoxifying reactions in mammals [85]. However, high-dose ascorbate should be prescribed with caution, as this vitamin exerts both antioxidant and pro-oxidant effects in vivo, dependent on the tissue concentration of iron, which metal catalyzes the formation of hydroxyl radical [14, 17]. The vitamins E (tocopherols) are all potent biological antioxidants, quench- ing singlet oxygen and terminating free-radical chain-reactions in membrane phospholipid [86]. They are the most important lipid-soluble, radical-scavenging antioxidants of biological membranes and plasma, being hydrogen-bonded to the unsaturated fatty acid moieties of phospholipids, thereby inhibiting membrane

Vol. 20, No. 1, 1996 12 AL. PARKS, D.V. PARKE, and F.A. JONES lipid peroxidation [87] and modulating prostanoid production to decrease thromboxane formation [88, 89]. Vitamin E also inhibits 5-lipoxygenase by binding to the enzyme, a mechanism independent of its antioxidant activity; thus its cellular levels may have profound effects on leukotriene formation [90] . Vitamin E deficiency in rats increases the aging, and consequent phagocytosis, of erythrocytes and in humans shortens the erythrocyte life-span [91], causing hemolytic anemia , characteristic of many diseases associated with chronic inflammation . The antioxidant activity of carotenoids is much less than that of vitamin E, but /l-carotene and a-tocopherol act synergistically, thereby greatly enhancing the radical-trap- ping activity of vitamin E [92]. Vitamin A and retinoids are essential for cellular growth and differentiation , and are protective against lipid peroxidation and chemical carcinogenesis. Retinoic acid inhibits the proliferation of carcinogen-induced human breast carcinoma cells [93], retinol decreases the mutagenicity of cooked-food mutagens , the aminoimidoazaarenes IQ, McIQ, and McIQx, by inhibiting their CYP 1A2- dependent activation [94] ; and /l-carotene and other carotenoids inhibit aflatoxin B1 mutagenesis [95] . Retinoids have been used successfully in treatment and prevention of many forms of malignancy in humans [96]. They are also concerned with inflammation and inhibit the PMN generation of ROS, but have little effect on the ROS generation in the xanthine-xanthine oxidase system [97] . Retinoids should therefore be therapeutically beneficial in chronic inflammatory conditions mediated by PMNs, such as inflammatory skin diseases. Vitamin A deficiency in humans is associated with decreased resistance to infection , and in experimental animals has many adverse effects on the immune system [98]. However , ingestion of large amounts of vitamin A (retinol) can be deleterious and has been associated with birth defects [15, 99]. Concerning other vitamins, riboflavin is an essential component of CYP reductase and flavoprotein oxidases, and hence is a necessary dietary factor for maintaining the efficacy of the chemical detoxication system. Thiamine deficiency increases drug metabolism and specifically enhances the activity of CYP2E 1, thereby increasing ROS production [100]; it should therefore be specifically avoided in patients with chronic inflammatory disease. Selenium is essential for the efficacy of the antioxidant defense system, and is a vital constituent of GSH peroxidase (GPX) and phospholipid hydroperoxide GSH peroxidase (PHGPX), enzymes protecting against ROS, lipid peroxidation, and oxidative membrane damage. Selenium deficiency, by decreasing GPX and PHGPX activities, results in increased thromboxane (TXB2) formation at the expense of prostacyclin (PGI2) production, possibly leading to increased vascular injury during thrombotic and inflammatory episodes [101]. Dietary selenium, as selenomethionine, protects against ethanol-induced lipid peroxidation, cirrhosis, cancer, and cardiovascular disease [99]; and the synthetic selenium organic compound Ebselen has anti-inflammatory activity consequent upon its inhibition of neutrophil adhesion to vascular endothelium in response to inflammatory

J. Clin. Biochem. Nutr. DIET AND NUTRITION IN RHEUMATOID ARTHRITIS 13 mediators [102]. Zinc appears to be necessary for maintenance of cellular membrane structure and function, and dietary deficiency of this metal in rats results in increased susceptibility to lipid peroxidation, decreased CYP, and decreased drug-metabolizing activity [103]. Iron is essential for the biosynthesis of heme and the cytochromes, but iron deficiency does not decrease CYP activity; excess iron, however, does enhance ROS formation, lipid peroxidation, and membrane damage, and when suitably complexed to enter the cell (Fe nitrilotriacetate), can result in oxidative stress, tissue necrosis, malignancy, and fatalities [15]. Excess iron is therefore to be avoided in chronic inflammatory disease states.

Lipids Evidence that diets high in fat and cholesterol are associated with a high incidence of degenerative disease, especially heart disease and cancer , is now being critically revised and more precisely addressed. The subject is far more complex than generally realized, and involves the structure and fluidity of cellular membranes, prostanoid production, ROS formation, and lipid peroxidation, and hence is of as much concern to RA and chronic inflammatory disease as it is to cancer and heart disease. The roles played by individual lipids, the differences between short-chain and long-chain saturated fatty acids and between the c~-3 and w-6 series of PUFAs, the intimately associated antioxidant vitamins E and A, the biosynthesis and functions of cholesterol, and the formation of the prostanoids and their effects on cytokine production show that lipid nutrition involves a most complex interplay of numerous biochemical and physiological functions . High-fat diets do appear to promote carcinogenesis and cardiovascular disease [104], probably by mechanisms involving ROS, and hence might similarly promote rheumatoid and chronic inflammatory diseases. In contrast, butterfat, which contains rapidly-metabolizable, short-chain saturated fatty acids and high levels of vitamin E-quite different from the long-chain saturated fatty acids of meat fat -decreases chemical carcinogenesis in rats [105] . Furthermore, while PUFAs are essential for cellular membranes and prostanoid formation , their dietary excess results in lipid peroxidation [106], and has been associated with increased risk of cancer and drug toxicity from co-oxygenation [107]. Even PUFAs are highly diverse with varying biological functions (Fig . 3). Fish oils, rich in c~-3 fatty acids (eicosapentaenoic acid: EPA , 020:5, n-3; and docosahexaenoic acid: DHA, 022:6, n-3) form a series of prostanoids , with less inflammatory leukotrienes, different from those formed from c~-6 fatty acids (arachidonic acid: 020:4, n-6; or linoleic acid: C18:2, n-6) found in corn oil and other cereal lipids. Prostanoids derived from arachidonic acid, particularly prostaglandin E2 (PGE2), result in the formation of edema, erythema, and hyper- algesia. Leukotriene LTB4 is highly chemotactic for leucocytes , and the thromboxane TXB2 is pro-inflammatory. Supplementation of diets with EPA decreases PGE2 (by 60%), LTB4 (by 50%), and TXB2 (by 75%) in rat inflammatory exudate

Val. 20, No. 1, 1996 14 AL. PARKE, D.V. PARKE, and F.A. JONES

Fig. 3. Metabolic pathways of dietary polyunsaturated fatty acids. PG, Prostaglandin; TX, thromboxane; LT, leukotriene,

[108]. Diets rich in fish-oil lipids (EPA and DHA) increase the EPA content of PMNs and monocytes> 7-fold, and are anti-inflammatory by inhibiting the 5- lipoxygenase pathway and the LTB4-mediated functions of PMNs [109] . High dietary intakes of EPA, DHA, oleic, and/or y-linoleic acid decrease the production of inflammatory mediators such as PGEZ, LTB4., and LTC4, and interleukin- 1, and improve the clinical conditions of patients with rheumatoid arthritis [110]. The synthesis and biological functions of cytokines are modified by c~-3 PUFAs, and this may contribute to preventing the development of RA [111]. Two other aspects of lipid metabolism that merit attention are those of (i) lipotropes and (ii) dietary fiber. The lipotropes, especially choline, methionine, folic acid, and cobalamin, are dietary factors necessary for the biosynthesis of phosphatidylcholine, phospholipids, and hence biological membranes. Phos- phatidylcholine is essential for mammalian life, has a critical role in the structure and function of eucaryotic membranes, is a major component of plasma very low density lipoproteins (VLDL), and is involved in the excretion of VLDL and lysophosphatidylcholine from liver [112]. Newberne and others have shown that cancer-promoting, high-fat diets are deficient in lipotropes, especially choline [113] and that rats fed a choline-free diet as the only treatment develop hepatocel- lular carcinoma [114]. The hepatocarcinogenicity of high-fat, low-lipotrope diets in rats can be prevented by indomethacin, an inhibitor of prostanoid synthesis [115]; and the lipid peroxidation and DNA damage associated with choline deficiency can be inhibited by a synthetic free-radical scavenger [116]. These studies indicate that (i) phosphatidylcholine deficiency allows electron leakage

J. Clin. Biochem. Nutr. DIET AND NUTRITION IN RHEUMATOID ARTHRITIS 15 from mitochondrial and endoplasmic reticula membranes, with consequent generation of ROS and lipid peroxidation, (ii) excess dietary saturated fatty acids enhance endogenous cholesterol biosynthesis and increase the membrane cholesterol/phospholipid ratio thereby exacerbating electron leakage, and (iii) a high intake of PUFAs results in increased prostanoid formation, co-oxygenation, and lipid peroxidation. Phosphatidylcholine is also an integral component of the liver CYP detoxication system, and reconstituted preparations of solubilized CYP enzymes require phosphatidylcholine as an essential component [15]. The most desirable situation in lipid nutrition is therefore to increase the intake of c~-3 PUFAs (EPA, DHA), short-chain saturated fatty acids (butterfat), and the fat-soluble antioxidant vitamins (tocopherol and retinol), and to decrease the intake of w-6 PUFAs and of the long-chain saturated fatty acids, which may be difficult to metabolize and give rise to high levels of cholesterol biosynthesis or ketone bodies. Dietary cholesterol intake would appear to be irrelevant to the blood cholesterol level, since the oxidative elimination of blood cholesterol by cholesterol 7a-hydroxylase, and the consequent production of cholic acid, is determined by the blood bilirubin and blood total cholesterol concentrations [117]. High intake of dietary fiber keeps the bile acids in the stool, preventing the negative feedback of cholic acid on plasma cholesterol 7a-hydroxylase, thereby lowering serum cholesterol and triglyceride concentrations, and decreasing blood pressure [118]. In contrast, the consequence of low-fiber diets is high bile acid recirculation, impaired cholesterol oxidation, hypercholesterolemia and hyper- lipidemia, high cholesterol/phospholipid ratio, loss of membrane fluidity, ROS production, and oxidative stress.

DIET IN RHEUMATOID ARTHRITIS AND OTHER INFLAMMATORY DISEASE

Since diet may be involved in the formation of neo antigens and the initiation of autoimmune disease, as well as in the extent and severity of the inflammatory response, dietary modulation may both decrease the likelihood of autoimmune phenomena and reduce the severity of any consequent inflammatory disease.

Dietary decrease in neoantigen formation Dietary mutagens, such as nitrosamines and the food pyrolysis heterocyclic amines, are as likely to form neoantigens by metabolic activation and covalent binding to tissue proteins as they are to initiate their known malignancy by covalent binding to DNA. High intakes of dietary ascorbic acid, and other antioxidants, will minimize the formation of nitrosamines, both in the food and in vivo, from food amines and dietary nitrate/nitrite. The possibility that food pyrolysis heterocyclic amines might result in the formation of neoantigens and thus initiate immune disease, certainly merits study. However, in any event, since the food pyrolysis amines are all known mutagens, their ingestion in food should be minimized by decreasing the consumption of meat and fish cooked at high

Vol. 20, No. 1, 1996 16 AL. PARKS, D.V. PARKS, and FA. JONES temperatures, by frying, roasting or grilling, and increasing the eating of boiled fish and meat, which are free from these mutagenic products . Diets rich in fish oil lipids like EPA and DHA have been shown to protect mice against the development of autoimmune glomerulonephritis and to inhibit the formation of certain autoantibodies, although the beneficial effects against experimental autoimmune disease are capricious [119]. It is therefore suggested that dietary supplements of marine lipids may prove beneficial in the treatment of SLE [119]. Dietary iron and iron supplements are a direct source of ROS production without requiring the formation of neoantigens or autoantigens . Iron, in its inorganic form, or as simple complexes such as iron nitrilotriacetate , is highly toxic and carcinogenic, by virtue of its ability to generate ROS. Intraperitoneal injection of iron nitrilotriacetate into rodents results in hepatic and renal necrosis and death [28]. Inorganic iron, either as the oxide or simple salts, is added to bread, cornflakes, and other staple foods, in ignorance and with good intention; and, even when attention is directed to the potential toxic hazard, it is considered that the iron is unlikely to be absorbed. Even so, inorganic iron would generate ROS in the gut, as in the tissues, and hence would lead to depletion of antioxidant nutrients, such as the tocopherols, with consequent toxicity, or could lead to direct damage of the gut mucosa [120]. RA and other chronic inflammatory disease are often associated with anemia probably due to the cytokine-driven uptake of iron by the reticulo-endothelial system [23], or to the ROS-mediated lysis of erythrocytes. Such patients possibly need folate for treatment of their anemia, but not inorganic iron, which would exacerbate the anemia and the RA . Even when iron is needed, as for example, after prolonged hemorrhage in a rheumatoid patient with uterine fibroids, it is best provided in a highly complexed organic form, such as hemoglobin or myoglobin of meat, liver, blood sausage, etc. that is readily absorbed and does not facilitate ROS generation. A dietary deficiency of zinc leads to impaired immunocompetency, and mice fed diets with low levels of zinc exhibited a delay in the onset of autoimmune anemia and lupus-like autoimmune syndrome [121]. While it is probably imprac- ticable, and of questionable safety, to prescribe diets deficient in zinc, the use of zinc supplements should be contra-indicated in paptients with autoimmune disease [121].

Dietary modulation of the inflammatory response The inflammatory response to chronic immune or autoimmune stimuli may be diminished, and the tissue-damaging effects of the ROS inhibited, by dietary modulation for (i) appropriate lipids, (ii) adequate antioxidants and radical scavengers, (iii) optimum intake of calories and restriction of cytochrome P4502E activity, and (iv) optimization of dietary mineral intake. Lipids. Dietary lipids modulate immune function by changing membrane phospholipids, with the consequent production of prostanoids and cytokines. The

J. Clin. Biochem. Nutr. DIET AND NUTRITION IN RHEUMATOID ARTHRITIS 17 2-series of prostanoids, derived from arachidonic acid (20:4, c~-6) are inflammatory and immunosuppresive, whereas the 3- and 5-series of prostanoids derived from fish-oil EPA (20:5, c~-3) are less inflammatory, and can antagonize the production of the 2-series prostanoids. Dietary supplementation with c-3 polyunsaturated fatty acids can lead to inhibition of three pathways for the synthesis of lipid mediators of inflammation, namely, 1) the cyclo-oxygenase pathway (NSAIDs are probably more effective here) 2) the 5-lipoxygenase pathway for the synthesis of leukotrienes 3) the platelet-activating factor (PAF) synthesis pathway [122]. Six controlled, blinded studies have shown that supplementation with w-3 PUFAs (fish oil) is associated with reproducible benefits in patients with rheumatoid arthritis [123, 124] . Improvements are not seen until after 12 weeks of continuous use, and increase with treatment up to 24 weeks. A cross-over format is not appropriate, in these studies, as there is prolonged suppression of IL-1 after stopping the fish oil intake. The suppression of PMN LTB4 (60%) occurs before clinical improvement is seen, indicating that suppression of monocyte IL-1, and other changes, may contribute more to the clinical benefit. Toxicity of the dietary supplementation is minimal, but uncertainty regarding dosage, and its precise role in the treatment regimen, needs to be resolved by further long-term clinical studies [123]. Evening primrose oil (EPO) is currently one of the most popular unorthodox treatments for rheumatoid arthritis and SjOgren's syndrome. This is based on its high content of y-linoleic acid (9%), which is metabolized into dihomo-y-linoleic acid, the precursor of the 1-series prostaglandins (Fig. 3). This series of prostaglandins is anti-inflammatory and competitively inhibitory of the pro-inflammatory prostanoids derived from arachidonic acid. Controlled studies of the effect of EPO on RA [125, 126] showed variable benefit, even at a high dosage (540 mg/day y- linoleic acid), and produced serum fatty acid changes (decreased EPA, increased arachidonate) associated with prostanoids that may be unfavorable to RA patients [125]. Antioxidants. Dietary vitamin C, vitamin E, and the retinoids provide an integrated antioxidant system protecting tissues from ROS-induced oxidative damage, which is characteristic of RA and other chronic inflammatory disease. A study of patients with systemic sclerosis showed that they had lower serum concentrations of ascorbate, cr-tocopherol, /l-carotene, and selenium than control subjects, and had significantly lower daily intakes of ascorbic acid, retinoids, tocopherol, folate, and cobalamin, with lower dietary intakes of fruit and vegetables [127]. Although nutritional support for patients with systemic sclerosis may not alter the progress of the disease, it may avert the progressive debilitation associated with the nutritional depletion. Decreased levels of ascorbate were found in the blood and joint fluids of RA patients, although there is no convincing evidence that ascorbic acid has any beneficial effect on patients with this condition [2]. Nevertheless, as tissue damage, and probably the chronicity of the disease, is

Vol. 20, No. 1, 1996 18 AL. PARKS, D.V. PARKS, and FA. JONES attributable to the high level of ROS production, adequate dietary intakes of antioxidants must be advantageous to RA patients. Vitamin E has low toxicity; and a daily dose of 100-300 mg is considered harmless, except in vitamin K deficiency, when it can exacerbate the blood coagulation defect [128]. This dose is recommended for subjects at risk, such as post-surgery patients, patients undergoing radiotherapy, or individuals with ROS- mediated inflammatory disease. Retinoids scavenge ROS and also act directly on PMN leucocytes to prevent their generation of hydroxyl radicals. Hence, retinoid therapy would be appropriate in ROS-mediated diseases, including cutaneous lupus erythematosus and other dermatological disorders [97]. In addition to the natural dietary antioxidants, there may be an important role for synthetic antioxidants, such as BHT (butylated hydroxytoluene) and BHA (butylated hydroxyanisole), which have been added to fats and other foodstuffs for nearly half a century with nothing but beneficial effects [129]. Ebselen is a more recent synthetic antioxidant; it is a selenium-containing heterocycle that acts by reducing fatty acid hydroperoxides, but does not scavenge ROS [130]. It has GSH- peroxidase-like activity, inhibiting leucocyte 5-lipoxygenase and prostaglandin formation, and converts LTB4 to an inactive isomer [131], thus inhibiting inflammation and autoxidative tissue injury. This broad range of anti- inflammatory activity has recently stimulated the initiation of clinical trials of Ebselen in RA patients. Energy. As RA and chronic inflammatory disease respond well to fasting, optimization of calorie intake would appear to be critical. Deficiency of calories would result in lipid mobilization with acetone formation, induction of cytochrome P4502E 1, and consequent ROS production and tissue damage, culminating in PMN migration and activation. Excess dietary calories would lead to triglyceride and cholesterol synthesis, and the raising of the membrane cholesterol/phospholipid ratio, thus allowing some of the excess energy to be leaked from mitochondria and endoplasmic membranes to reduce molecular oxygen to superoxide and other ROS, which again could lead to PMN migration and activation. It is therefore essential to avoid the "binging" and dieting now so common, to eat breakfast, and to consume a regular diet with no excess calories (steady body weight), one rich in crude carbohydrates (whole cereals), low in triglycerides, but adequate in phospholipid and/or lipotropes (choline, folate, cobalamin). For similar reasons, namely, for minimizing P4502E1 induction, limiting rapidly available carbohydrate, and restricting triglyceride and cholesterol biosynthesis, the consumption of alcohol should be avoided [132]. Folic acid supplementation (1 mg/day) is valuable in promoting the physiological utilization of iron for hemesynthesis [22] ; and for RA patients on low-dose methotrexate treatment it is beneficial in avoiding the clinical manifestations of folate deficiency, and in decreasing any drug toxicity without affecting efficacy [133].

J. Cin. Biochem. Nutr. DIET AND NUTRITION IN RHEUMATOID ARTHRITIS 19

Minerals. The most important aspect of mineral nutrition for the RA patient is the desirability of decreasing the intake of iron; and, thus, the consumption of iron-rich food such as red meat, liver, and blood products should be kept to a minimum. Conversely, high intakes of silicic acid, which forms complexes with tissue inorganic iron and thus decreases its ability to generate ROS, initiate membrane lipid peroxidation, anddmobilize leucocytes, are highly desirable and may be achieved by the consumption of whole cereals and other crude carbohydrates. Zinc nutrition has long been associated with immune competence, and zinc- deficient diets impaired the development of autoimmune syndromes in mice but had little effect on autoimmune disease progression [121]. For these reasons, high zinc supplementation, often favored by diet therapists, should be avoided until the effects of zinc in human patients with RA and chronic inflammatory disease have been evaluated [121]. Dietary selenium is critical, since selenium is essential for activity of the antioxidant enzymes, i.e., GSH peroxidase and phospholipid hydroperoxide GSH peroxidase; and dietary deficiencies have been associated with increased thromboxane formation [101], and with Kashin-Beck and Keschin disease [134]. Dietary supplementation of 9 patients with severe RA with selenium as L-selenomethionine (250 1ug per day) restored the low levels of blood serum and erythrocyte Se and GSH-peroxidase to normal after 6 months of treatment, but had no effect on the low levels of PMN GSH-peroxidase [135]. This lack of antioxidative response of the PMN enzyme to selenium supplementation may have significance in the inflammation and joint destruction seen in patients with RA [135].

CONCLUSIONS

In conclusion, a mechanistic consideration of diet for those suffering from RA and other inflammatory diseases indicates that foods to be avoided are red meats and blood products (Fe), meat fat (Cs~-6PUFAs), and alcohol (CYP2E). Foods to be encouraged include vegetables and fruits (ascorbate, retinoids), whole cereals (tocopherols, fiber, silicic acid), dairy products (tocopherols, phospholipids, the S amino acids of casein), pulses (tocopherols, phospholipids, fiber), and fish (c-3 PUFAs, S amino acids). This is not incompatible with the diet recommended by Dong and Banks [5, 6], namely, a diet rich in seafood, vegetables, and rice, and low in red meat, saturated fat, and alcohol.

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