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Use of Olive Oil in Patients with Rheumatoid Arthritis
Chapter 114
Use of Olive Oil in Patients with Rheumatoid Arthritis Décio Sabbatini Barbosa1, Andréa Colado Simão1 and Isaias Dichi2 1
Department of Pathology, Clinical Analysis and Toxicology-University of Londrina Paraná, Brazil Department of Internal Medicine, University of Londrina, Paraná, Brazil
2
114.1 Introduction Rheumatoid arthritis (RA) is a systemic inflammatory disorder that mainly affects the diarthrodial joint. It is the most common form of inflammatory arthritis, and has a substantial societal effect in terms of cost, disability, and lost productivity. This disease affects about 1% of the population, in a female/male ratio of 2.5/1, and can occur at any age, but it is most common among those aged 40–70 years, its incidence increasing with age (Lee and Weinblatt, 2001). RA is characterized in the early stages by persistent inflammation of the synovial lining of the joints, which can lead to the destruction of bone and cartilage and result in joint deformity. The range of presentations of rheumatoid arthritis is broad, but disease onset is insidious in most cases, and diagnosis can be delayed for several months before it can be ascertained. The predominant symptoms are pain, morning stiffness, and swelling of peripheral joints. The clinical course of the disorder is extremely variable, ranging from mild, self-limiting arthritis to rapidly progressive multisystem inflammation with profound morbidity and mortality. The systemic disturbances are most commonly fatigue, stiffness, anemia, weight loss, and extra-articular features such as rheumatoid nodules (Lee and Weinblatt, 2001). Two main characteristics of the condition are the presence of rheumatoid factor (RF) measured in blood and typical RA erosions seen on radiological examination of hands and feet. RF is used both in diagnosis and prognosis, but lacks sensitivity because it is found in only 70–80% of RA cases. It is also seen in approximately 5% of normal populations.
114.2 Etiology The etiology of RA, a chronic inflammatory disease, remains largely unknown, although microbiological, immune, genetic, hormonal, and dietary factors have been implicated in its pathogenesis (Linos et al., 1991). The cause of RA remains Olives and Olive Oil in Health and Disease Prevention. ISBN: 978-0-12-374420-3
uncertain, but genetic factors are known to be involved and the locus has been identified. It has been suggested that genetic susceptibility explains 40% of the risk of developing RA (Silman et al., 1993). The suggested causes of RA include: viral infections, immunization, hormonal factors (prolactin production during lactation), smoking, previous blood transfusion, obesity, stress and physical trauma (Symmons and Harrison, 2000). RA is characterized by infiltration of T lymphocytes, macrophages and plasma cells into the synovium, and the initiation of a chronic inflammatory state that involves overproduction of pro-inflammatory cytokines and a deregulated T-helper-1-type response. Products of free radical oxidation have been identified in synovial fluid, thus lending further support to the theory that RA itself may be, in part, mediated by free radical activity (Pattison et al., 2004). Increased lipid peroxidation and depletion of ascorbate is a result of oxidation during its antioxidant activity and antioxidant micronutrients may have an important role in preventing tissue damage caused by free radicals (Halliwell et al., 1998).
114.3 Pathophysiology of inflammation Inflammation is the body’s reaction to invasion by an infectious agent, antigen or physical damage. Antigen exposure triggers the immune response, resulting in a cascade of cellular activity and an inflammatory response in the end organ. In RA, the inflammatory response continues in articular tissue, as though in response to a persistent stimulus, leading in time to irreversible damage to tendons and joints. Although a greater understanding of efferent mechanisms of inflammation and tissue destruction in RA has evolved over the past 10 years, there is still little understanding as to why inflammation persists in RA (Pattison et al., 2004).
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Section | II Immunology and Inflammation
An inflamed synovium is central to the pathophysiology of RA. It is histologically striking, showing pronounced angiogenesis, cellular hyperplasia, influx of inflammatory leukocytes, and changes in the expression of cell-surface adhesion molecules, proteinases, proteinase inhibitors and many pro-inflammatory cytokines (Lee and Weinblatt, 2001). Following initiation of the immune response, activated macrophages, monocytes and granulocytes generate free oxygen radicals (Halliwell et al., 1998). The rapidly proliferating cells of the immune system are uniquely prone to oxidative damage by free radicals and pro-inflammatory prostaglandin E2 (PGE2), leukotriene B4 (LTB4), and cytokines, in particular TNF- and IL-1. The increased production of cytokines and the subsequent increase in reactive oxygen and nitrogen species are recognized hallmarks of inflammation. This process is regulated by a negative feedback mechanism and is closely followed by the secretion of anti-inflammatory cytokines to reduce the accumulation of reactive species. The cellular antioxidant defense system is also activated to limit the development of chronic inflammation (Bulló et al., 2007). The binding of pro-inflammatory cytokines to their receptors triggers the mitogen-activated protein kinase (MAPK) pathway that ultimately results in the activation of two redox-sensitive transcription factors: nuclear factor kappa B (NFB) and the c-Jun part of activating protein-1 (AP-1). These transcription factors activate the expression of a wide variety of genes including cytokines, chemokines, adhesion molecules and inducible effector enzymes such as iNOS and cyclooxygenase-2 (COX-2) (Bulló et al., 2007). The main features of rheumatoid arthritis are shown in Table 114.1.
114.4 Olive oil and inflammation Since the 1970s, a number of epidemiological studies have suggested that certain dietary fatty acids affect the immune response in both animals and humans, and more recently that they have anti-inflammatory effects. Olive oil (OO) exerts its beneficial effect modulating immune function, particularly the inflammatory process associated with the immune system, as seems to be the case in RA (Wale et al., 2004). Olive oil is mainly composed of oleic acid (18:1 n-9), a monounsaturated fatty acid (MUFA) that is converted to 8,9,11 eicosatrienoic acid (20:3 n-9; ETA) under restriction of n-6 fatty acids. ETA is converted to LTA3, which is a potent inhibitor of LTB4 synthesis (Figure 114.1). Therefore, oleic acid and its metabolite ETA may exert inflammatory effects through a mechanism similar to that of fish oil, which contains EPA. Because ETA is substantially
OLEIC ACID
Restriction of n-6 fatty acids
ETA
5-lipoxygenase LTA synthase
less unsaturated than EPA, it may have greater chemical stability, which would be an advantage for use as a dietary constituent or supplement (James et al., 1993). Virgin olive oil is a rich source of MUFA and retains all the lipophilic components of the olive fruit, especially the phenolic compounds with strong anti-oxidant and anti-inflammatory properties. The administration of OO with a high phenolic content has been shown to protect against inflammation. In addition, phenolic compounds derived from extra virgin oil were recently shown to decrease the production of inflammatory mediators in human whole-blood cultures and to inhibit endothelial adhesion molecule expression in vitro (Bulló et al., 2007). It has been attributed to extra virgin olive oil (EVOO) preventive properties with regard to chronic diseases, particularly those with an inflammatory etiology such as heart disease, cancer and RA (Wahle et al., 2004; Pacheco et al., 2007). The beneficial effects can be explained not only to the high monounsaturated content of OO, but also to the antioxidant property of its minor elements with high activity. The phenolic compounds are both lipophilic and hydrophilic. The lipophilics include tocopherols, while the hydrophilics include flavonoids, phenolic alcohols and acids, secoiridoids (oleuropein and ligstroside) and lignans (Tripoli et al., 2005). Oleuropein is the main polyphenol found in OO (Tripoli et al., 2005).
Table 114.1 Key features of rheumatoid arthritis. l l
l
l
l
l
l
Rheumatoid arthritis (RA) is a systemic inflammatory disorder that mainly affects the joints It is the most common form of inflammatory arthritis and can lead to destruction of bone and cartilage resulting in profound morbidity and mortality The predominant symptoms are pain, morning stiffness, and swelling of peripheral joints, but systemic disturbances can also occur Two main characteristics of the condition are the presence of RF and typical RA erosions seen on radiological examination of hands and feet The etiology of RA remains largely unknown, although immune, and genetic factors are likely the most implicated in its pathogenesis RA is characterized by infiltration of T lymphocytes, macrophages and plasma cells into the synovium, and the initiation of a chronic inflammatory state that involves overproduction of pro-inflammatory cytokines, reactive oxygen and nitrogen species, and a deregulated T-helper1-type response The binding of pro-inflammatory cytokines to their receptors triggers the mitogen-activated protein kinase pathway that ultimately results in the activation of nuclear factor kappa B
LTA3
inhibit
LTA hydrolase
Figure 114.1 Anti-inflammatory action of oleic acid. ETA – 8,9,11 eicosatrienoic acid; LT – leukotriene.
LTB4
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Chapter | 114 Use of Olive Oil in Patients with Rheumatoid Arthritis
Lipid radicals are produced during reactions involved in the metabolism of arachidonic acid, during the synthesis of the eicosanoids by the action of the lipoxygenase (LOX) and COX. The reactive oxygen species (ROS) and reactive nitrogen species involved in RA include superoxide anions, hydrogen peroxide, hydroxyl and peroxynitrite radicals, and nitric oxide. The first three of these are produced by xanthine oxidase and are also generated by activated macrophages and neutrophils as a result of respiratory chain activity known as the oxidative burst. This is primarily due to NADPH oxidase activity leading to the formation of hypochlorous acid (HOCl) as a bactericidal agent. Hydrogen peroxide is formed partly by superoxide dismutase (SOD), by the reaction between superoxide radicals and protons. Hydrogen peroxide is metabolized by catalase and peroxidase enzymes, chiefly glutathione peroxidase (Darlington and Stone, 2001). Indeed, the evidence that oxidative damage occurs in RA is very strong. Thus, antioxidant micronutrients may have an important role in preventing tissue damage caused by ROS (Pattison et al., 2004). The biological activity of phenolic compounds of OO is not limited to their antioxidant ability, but extends to their interaction with important enzymic systems. In particular, it has been found that olive oil phenols inhibit platelet aggregation, reduce pro-inflammatory molecule formation such as thromboxane B2 (TBX2) and LTB4, and inhibit the use of oxygen in human neutrophils (Tripoli et al., 2005) (Figure 114.2). Olive oil is a non-oxidative dietary component, and the attenuation of the inflammatory process it elicits could explain the beneficial effects on disease risk since oxidative and inflammatory stresses appear to be underlying factors in the etiology of inflammatory diseases in humans. The antioxidant effects of olive oil are probably due to a combination of its high oleic acid content (low oxidation potential compared with linoleic acid) and its content of a variety of plant antioxidants, particularly oleuropein, hydroxytyrosol, and tyrosol (Walde et al., 2004).
114.5 Are there differences between olive oil and extra virgin olive oil use in the inflammatory process? The concentration of phenolic compounds in OO is the result of a complex interaction of various factors and is also affected by the extraction process (Visioli and Galli, 1998; Tripoli et al., 2005). It is necessary to point out that refined oils do not have a significant content of polyphenols. Extra virgin olive oil (EVOO) is obtained from the first physical cold pressure of the olive paste and is rich in phenolic compounds. Virgin olive oil, obtained through percolation (first extraction), has a higher content in phenols, 0-diphenols, hydroxytyrosol and tyrosol aglycones, and tochopherols than oils obtained through centrifugation (second extraction) (Visioli and Galli, 1998). The effect of a virgin olive oil-enriched diet in acute and chronic inflammation models in rats was analyzed and determined the effect of supplementing this oil with a higher content of its polyphenolic fraction (MartinezDomínguez et al., 2001). This study demonstrated that virgin olive oil with a high content of polyphenolic compounds, similar to those of extra virgin olive oil, shows protective effects in both models of inflammation (Martinez-Domínguez et al., 2001). Another study compared the effects of two diets enriched in olive oils, having the same fatty acid composition but with EVOO and without (refined olive oil, ROO) minor compounds, on postprandial levels of triacylglycerol and on the accumulation of soluble intercellular adhesion molecule (sICAM-1) and soluble vascular cell adhesion molecule (sVCAM-1) in healthy and dyslipidemic humans (Pacheco et al., 2007). The results of this study indicated that the consumption of EVOO may help in reducing postprandial levels of adhesion molecules, which suggests a protective postprandial antiinflammatory effect in healthy and hypertriacylglycerolemic subjects (Pacheco et al., 2007). It was also investigated
Bone Venule Synovial fibroblasts TNF-Alfa IL-6: IL-8: PGE2
ROS*
, OH, HOCL, ONOO−) (O− 2 *TXB /LTB* 2 4
T cells and macrophages
IL-1Beta
Neutrophils Synovial membrane Cartilage
Figure 114.2 Synovial inflammatory process in the knee joint. Asterisks indicate the most plausible mechanisms of olive oil action. ROS – reactive oxygen species; TXB2 – thromboxane B2; LTB4 – leukotriene B4; IL – interleukin; PGE2 – prostaglandin E2.
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whether a bolus ingestion of phenol-rich extra virgin olive oil affects the postprandial lipid profile, as well as selected surrogate markers of cardiovascular risk, of healthy volunteers. Moreover, the effects of EVOO with those of OO were compared (Bogani et al., 2007). A significant decrease in inflammatory markers, namely TXB2 and LTB4, 2 and 6 h after EVOO (but not OO) consumption and a concomitant increase of serum antioxidant capacity were recorded. The authors of this study concluded that these data reinforce the notion that the Mediterranean diet reduces the incidence of coronary heart disease (an inflammatory disease) partially due to the protective role of its phenolic components, including those of EVOO (Bogani et al., 2007). Although OO contains a relatively low concentration of -tocopherol, it is known to be highly resistant to oxidative degradation. This is due, in part, to the relatively low content of polyunsaturated fatty acids and also to the high concentration of polyphenolic antioxidants, particularly in EVOO. The antioxidant activity of OO phenolic compounds, and in particular of oleuropein and its byproduct hydroxytyrosol, has been studied in many experimental models (Wahle et al., 2004; Tripoli et al., 2005). The antioxidant activity of oleuropein and hydroxytyrosol has also been demonstrated in cellular models and animals (Tripoli et al., 2005). Some studies with human volunteers do not show the same attenuating effects of MUFA/OO on immune function and could reflect the high content of these components in the animals’ diets (Wahle et al., 2004). However, according to the discussion above, it is reasonable to imagine a possible mechanism of the use of extra virgin olive oil (with the characteristic high concentration of MUFA and the presence of minor components) in inflammatory diseases: it has inhibitory action on COX and LOX; reduces pro-inflammatory molecule formation such as TXB2 and LTB4, reducing the adhesion molecules and free radicals formation (Tripoli et al., 2005). Maybe future large trials and other studies can confirm this assumption.
114.6 Can olive oil predict the risk of rheumatoid arthritis? Olive oil, as well as fish consumption, was shown to be an important predictor of risk of RA in a case-control study in Greece (Linos et al., 1991). The Greek diet is based mainly on fruit and vegetables, either raw or cooked with olive oil, and contains less meat and more fish and pulses than the Western diet, food items that may influence risk of RA. Some years later, the same group (Linos et al., 1999) performed a case-control study in Greece, where the 145 patients and 188 controls were paired by sex, age, and health care facility. Persons in the lowest category of OO consumption had a 2.5 times higher risk of developing RA than did persons in the highest category of consumption. The excess daily OO consumption was 43 g day1 approximately.
Section | II Immunology and Inflammation
Consumption of OO was inversely and independently associated with risk of RA in this population.
114.7 Studies using olive oil as placebo in rheumatoid arthritis patients Many patients look for complementary and alternative medicine options in coping with this debilitating disease and an estimated 60–90% of persons with RA use them (Rao et al., 1999). Olive oil certainly is one of these options. In the beginning of the 1980s, clinical studies which evaluated RA patients used OO as placebo. Olive oil was regularly used as control supplementation in experiments with fish oil (n-3 polyunsaturated fatty acids). At that time, MUFAs were typically regarded as being neutral fatty acids without interfering in the inflammatory process of RA (Firestein, 2003).
114.7.1 Studies Using n-3 Fatty Acids in Rheumatoid Arthritis Patients and Olive Oil as Placebo Darlington and Ramsey (1987) reported significant decreases in pain intensity, duration of morning stiffness, time taken to walk 18 m, and fibrinogen levels, and improved trends in erythrocyte sedimentation rate, C3, and right grip strength after 12 weeks of OO ingestion. Cleland et al. (1988) investigated clinical and biochemical effects of dietary fish oil supplements in RA and used OO as placebo. They demonstrated that 18 g day1 of OO reduced morning stiffness and pain score. They suggested that these findings could account for the lack of statistical significance between the groups. Kremer et al. (1990) performed a prospective, randomized, double-blind, parallel study with 49 patients with active arthritis during 24 weeks. Three groups were studied: two groups received different doses of fish oil dietary supplements, and one group received olive oil supplements as placebo. Patients who received fish oil demonstrated improvement on several clinical manifestations of RA. However, the improvements from baseline in the patients ingesting fish oil were usually not statistically significant compared with the patients taking olive supplements. Although the large and small doses of fish oil n-3 fatty acids produced better overall results, the OO group was the only one to show improvements in the patients’ global assessment. It should be noted that the clinical outcomes in the OO group may have been biased toward more favorable results because of the withdrawal of 11 of the original 23 patients in this study group. Macrophage IL-1 production decreased by 38.5% in the OO group. The authors concluded that dietary supplementation with OO is associated with certain changes in immune function. Olive oil
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Chapter | 114 Use of Olive Oil in Patients with Rheumatoid Arthritis
itself could have beneficial effects in RA patients due to cell membrane changes in lymphocytes resulting in altered immune function through a variety of mechanisms. Sköldstam et al. (1992) performed a controlled, randomized, double-blind study to assess the effect of n-3 fatty acids in patients with RA. Forty-three patients were allocated in two groups: 22 patients received fish oil (1 g) whereas 21 received a mixture of oils (corn, olive and peppermint) during 6 months. The group of patients which took fish oil showed a decrease in arthritis activity with significant reduction in non-steroidal anti-inflammatory drugs after 3 and 6 months. The control group patients (mixture oils) presented an increase in arthritis activity after 6 months. The groups did not show any improvement in joint pain, duration of morning stiffness, functional capacity, or in biochemical markers of inflammation. Geusens et al. (1994) found significant decreases in Ritchie’s articular index of pain and the number of painful
joints after 12 months of olive oil (6 g) and also after combined use of fish oil and olive oil. Therefore, although OO has classically been used as a placebo in studies investigating the effects of other oils, mainly fish oil, in patients with RA, without a definite purpose of being part of the therapeutic arsenal of RA, several studies above demonstrated its beneficial effects.
114.7.2 Studies Using n-3 Fatty Acids in Rheumatoid Arthritis Patients and Olive Oil as Adjuvant Therapy Berbert et al. (2005) evaluated whether supplementation with OO during 6 months could improve clinical and laboratory parameters of disease activity in patients with RA who were using fish oil supplements (Tables 114.2 and 114.3). Forty-three patients were assigned to one of three groups.
Table 114.2 Clinical indicators of disease activity in patients with rheumatoid arthritis receiving placebo (G1), n-3 fatty acids (G2) or n-3 fatty acids and oleic acid (G3). Baseline
12 weeks
24 weeks
Morning stiffness (minutes)
G1 G2 G3
38 42 44 68 60 65
46 47a 21 49 20 39
51 50a,b 5 8 11 26
Joint pain intensity
G1 G2 G3*
1.77 0.93 2.31 0.86 2.18 0.73
1.77 1.17a,b 1.46 0.66 1.00 0.71
1.85 1.21a,b 1.23 0.83 0.53 0.80
Time of onset of fatigue (min)
G1 G2 G3
19.5 3.5 20.9 12.1 23.4 14.1
19.3 3.5 17.1 10.2 21.7 13.0
21.4 5.2a,b 16.3 10.3 19.1 10.6
Ritchie articular index
G1 G2 G3
6.9 5.4 15.8 9.9 15.9 12.6
5.5 7.5 7.6 6.7 5.8 8.2
5.2 4.4a,b 3.6 2.4 1.2 2.3
Grip strength (right hand)
G1 G2 G3
62 37 54 35 63 58
60 29a,b 91 62 101 69
68 31a,b 105 78 114 84
Grip strength (left hand)
G1 G2 G3
74 43 57 35 67 52
68 35a,b 78 62 94 62
70 28a,b 108 75 110 82
Patient global assessment
G1 G2 G3
1.25 0.75 1.54 0.88 1.82 0.53
1.42 0.67a 1.62 0.87c 1.12 0.60
1.31 0.95a 1.23 0.60 0.88 0.70
Classification of functional status
G1 G2 G3*
1.85 0.80 2.54 0.78 2.65 1.22
2.00 1.08 2.23 1.01 2.53 1.28
2.00 0.91 2.15 1.07 2.00 1.28
Percentage change from baseline: a G1 versus G3 (p 0.05) b G1 versus G2 (p 0.05) c G2 versus G3 (p 0.05) * -within-group changes (p 0.05).
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Table 114.3 Health Assessment Questionnaire in patients with rheumatoid arthritis receiving placebo (G1), n-3 fatty acids (G2) or n-3 fatty acids and oleic acid (G3). Baseline
12 weeks
24 weeks
Dressing, including tying shoelaces
G1 G2 G3
0.15 0.56 1.46 1.27 1.24 1.30
0.15 0.38 0.69 1.32 0.77 1.15
0.23 0.60 0.77 1.17 0.53 1.18
Get in and out of bed
G1 G2 G3
0.15 0.38 0.54 1.13 0.77 0.90
0.23 0.60 0.39 0.96 0.53 1.01
0.46 0.88 0.39 0.87 0.65 1.17
Lift a cup or glass to your mouth
G1 G2 G3
0.0 0.0 0.46 0.66 0.53 0.87
0.08 0.28 0.31 0.48 0.18 0.73
0.00 0.0 0.15 0.56 0.24 0.07
Walk on flat ground
G1 G2 G3
0.39 0.77 0.62 1.04 1.18 1.13
0.39 0.77 0.54 0.78 0.88 1.17
0.54 1.05 0.54 0.78 0.77 1.20
Wash and dry your entire body
G1 G2 G3
0.08 0.28 0.77 1.30 0.82 1.02
0.23 0.60 0.54 0.97 0.41 0.87
0.31 0.75 0.39 0.77 0.29 0.85
Bend down to pick up clothing from the floor
G1 G2 G3
0.69 1.03 1.85 1.21 1.65 1.32
1.0 1.08b 1.15 1.41 1.35 1.41
1.31 1.38a,b 1.23 1.36 1.06 1.48
Turn faucets on and off
G1 G2 G3
0.92 1.04 1.23 1.10 1.59 1.06
1.08 1.04a 0.85 0.80 1.00 1.17
1.23 1.09a 0.92 0.86 0.77 1.09
Get in and out of a car
G1 G2 G3
0.46 0.66 1.46 1.27 1.53 1.23
0.31 0.63 0.69 1.18 1.18 1.33
0.69 1.03a,b 0.69 1.11 0.94 1.39
Percentage change from baseline: a G1 versus G3 (p 0.05) b G1 versus G2 (p 0.05).
The first group (G1) received soy oil (placebo), the second group (G2) received fish oil n-3 fatty acids (3 g day1), and the third group (G3) received fish oil n-3 fatty acids (3 g day) and 6.8 g day1 of oleic acid (9.6 mL of OO). There was a statistically significant improvement in G2 and G3 in relation to G1 with respect to joint pain intensity, right and left handgrip strength, duration of morning stiffness, onset of fatigue, Ritchie’s articular index for pain joints, ability to bend down to pick up clothing from the floor, and getting in and out of a car. G3, but not G2, in relation to G1 showed additional improvements with respect to duration of morning stiffness, patient global assessment after, ability to turn faucets on and off, and rheumatoid factor. In addition, G3 showed a significant improvement in patient global assessment in relation to G2. The rheumatoid factor decrease in G3 has a huge clinical significance because patients who have high titers tend to have a more aggressive, destructive course. The authors concluded that ingestion of fish oil n-3 fatty acids relieved several clinical parameters used in the
present study. However, patients showed a more precocious and accentuated improvement when fish oil supplements were used in combination with OO. Table 114.4 resumes the trials in which olive oil was used in patients with RA.
114.8 Future perspectives As discussed above there is some limitation in the studies which used OO in patients with rheumatoid arthritis. First of all, OO was designed as placebo in almost all studies which verified the action of n-3 fatty acids to decrease inflammatory activity in RA. Although the results obtained through these studies are indirect, comparison of fish and olive oils with similar results in Kremer et al.’s (1990) work make a possible role of olive oil in RA patients very likely. Furthermore, a synergistic effect of OO on fish oil supplementation was clearly demonstrated in Berbert et al.’s
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Chapter | 114 Use of Olive Oil in Patients with Rheumatoid Arthritis
Table 114.4 Trials in which olive oil was used in patients with rheumatoid arthritis. Authors
n
Darlington and Ramsey (1987)
Cleland et al. (1988)
60
Design
Dose of n-3 fatty acids or oleic acid
Time of treatment
Clinical improvement with Olive oil
Laboratorial improvement with Olive oil
fish oil X olive oil
18 g
12 weeks
Yes
Yes
fish oil X olive oil
18 g d1
12 weeks
Yes
No
18 g
18 g d1
Kremer et al. (1990)
49
fish oil X olive oil
45 or 90 mg kg1 d1 X 6.8 g d1 (9.6 ml d1)
24 weeks
Yes
Yes
Sköldstam et al. (1992)
43
Fish oil X Olive maize peppermint oils
10 g d1
6 months
No
No
10 g d1
Geusens et al. (1994)
90
fish oil X olive oil
3 g d1 6 g d1
12 months
No
No
Berbert et al. (2005)
43
fish oil X fish oil olive oil X soy oil
3 g d1
6 months
Yes
Yes
3 g d1 6.8 g d1
n – number of patients; d – day.
(2005) study. A future study designed to have four groups of RA patients being evaluated concomitantly constituted by a first group receiving OO, a second receiving n-3 fatty acids, the third receiving both oils, and the fourth receiving placebo, certainly would help to identify more accurately the action of OO in RA. Another issue of concern when studying oils in RA patients is to choose the ideal placebo. There is no such ideal placebo oil in inflammatory disease studies. The ideal placebo oil should have the n-6/n-3 fatty acid ratio of 4:1 or less, similar to the ratio to reach a healthy diet (Crawford et al., 2000). Soy oil has a ratio near 8 (54 n-6 : 7 n-3), and corn, sunflower, and safflower oils have even higher ratios than soy oil (Alexander, 1998), and therefore could have a pro-inflammatory influence. On the other hand, oils rich in both n-3 and n-9, like canola oil, could have an antiinflammatory effect, and should not be used as placebo in inflammatory studies as well. However, it has been verified that soy oil may amplify the stress response in severe stress, but not in moderate stress (Furukawa et al., 2002).
The data obtained in our studies with patients with ulcerative colitis (Dichi et al., 2000; Barbosa et al., 2003) and RA (Berbert et al., 2005) in mild or moderate inflammatory activity using soy oil as placebo seem to confirm that this concern is related basically to severe stress conditions. In summary, more studies specifically designed to study the effects of OO alone or in combination with fish oil in RA patients are warranted to help to decrease the doses of the classical anti-inflammatory drugs and to proportionate a better quality of life to patients with this important disability disease.
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Berbert, A.A., Kondo, C.R.M., Almendra, C.L., Matsuo, T., Dichi, I., 2005. Supplementation of fish oil and olive oil in patients with rheumatoid arthritis. Nutrition 21, 131–136. Bogani, P., Galli, C., Villa, M., Visioli, F., 2007. Postprandial anti-inflammatory and antioxidant effects of extra virgin olive oil. Atherosclerosis 190, 181–186. Bulló, M., Casas-Agustench, P., Amigo-Correig, P., Aranceta, J., SalasSalvadó, J., 2007. Inflammation, obesity and comorbidities: the role of diet. Public Health Nutr 10 (10A), 1164–1172. Cleland, L.G., French, J.K., Betts, W.H. et al., 1988. Clinical and biochemical effects of dietary fish oil supplements in rheumatoid arthritis. J. Rheum. 15, 1471–1475. Crawford, M., Galli, C., Visioli, F., Renaud, S., Simopoulos, A.P., Spector, A.A., 2000. Role of plant-derived omega-3 fatty acids in human nutrition. Ann. Nutr. Metab. 44, 263–265. Darlington, L.G., Ramsey, N.W., 1987. Olive oil for rheumatoid arthritis? Br. J. Rheumatol. 26 (Suppl), 215. Darlington, L.G., Stone, T.W., 2001. Antioxidants and fatty acids in the amelioration of rheumatoid arthritis and related disorders. Br. J. Nut. 85, 251–269. Dichi, I., Frenhane, P., Dichi, J.B., Correa, C.R., Angeleli, A.Y.O., Bicudo, M.H., Rodrigues, M.A.M., Victoria, C.R., Burini, R.C., 2000. Comparison of -3 fatty acids and sulfasalazine in ulcerative colitis. Nutrition 16, 87–90. Firestein, G.S., 2003. Evolving concepts of rheumatoid arthritis. Nature 423, 356. Furukawa, K., Yamamori, H., Takagi, K., Suzuki, R., Nakagima, N., Tashiro, T., 2002. Influences of soybean oil emulsion on stress response and cell-mediated immune function in moderately or severely stressed patients. Nutrition 18, 235–240. Geusens, P., Wouters, C., Nijs, J. et al., 1994. Long-term effects of omega-3 fatty acid supplementation in active rheumatoid arthritis. A 12-month, double-blind, controlled study. Arth. Rheum. 37 (6), 824–829. Halliwell, B., Hoult, J.R., Blake, D.R., 1998. Oxidants, inflammation and anti-inflammatory drugs. FASEB J. 2, 2867–2873. James, M.J., Gibson, R.A., Neumann, M.A., Cleland, L.S., 1993. Effects of dietary supplementation with n-9 eicosatrienoic acid on leukotriene B4 synthesis in rats: a novel approach to inhibition of eicosanoid synthesis. J. Exp. Med. 178, 2261–2265.
Section | II Immunology and Inflammation
Kremer, J.M., Lawrence, D.A., Jubiz, W. et al., 1990. Dietary fish oil and olive oil supplementation in patients with rheumatoid arthritis. Arthritis Rheum. 33 (6), 810–819. Lee, D.M., Weinblatt, M.E., 2001. Rheumatoid arthritis. Lancet 358, 903–911. Linos, A., Kaklamani, V.G., Kaklamania, E., Koumantaki, Y., Giziaki, E., Papazoglou, S., Mantzoro, C.S., 1999. Dietary factors in relation to rheumatoid arthritis: a role for olive oil and cooked vegetables? Am. J. Clin. Nutr. 70, 1077–1082. Linos, A., Kaklamania, E., Kontomerkos, A. et al., 1991. The effect of olive oil and fish consumption on rheumatoid arthritis: a case control study. Scand. J. Rheumatol. 20, 419–426. Martinez-Domínguez, E., de la Puerta, R., Ruiz-Gutiérrez, V., 2001. Protective effects upon experimental inflammation models of a polyphenolsupplemented virgin olive oil diet. Inflamm. Res. 50, 102–106. Pacheco, Y.M., Bermúdez, B., López, S., Abia, R., Villar, J., Muriana, J.G., 2007. Minor compounds of olive oil have postprandial antiinflammatory effects. Br. J. Nutr. 98, 260–263. Pattison, D.J., Symmons, D.P.M., Young, A., 2004. Does diet have a role in the aetiology of rheumatoid arthritis? Proc. Nutr. Soc. 63, 137–143. Rao, J., Mihaliak, K., Kroenke, K., Bradley, J., Tierney, W., Weinberger, M., 1999. Use of complementary therapies for arthritis among patients of rheumatologists. Ann. Intern. Med. 131, 409–416. Silman, A.J., MacGregor, A.J., Thomson, W. et al., 1993. Twin concordance rates for rheumatoid arthritis: results from a nationwide study. Br. J. Rheum. 32, 903–907. Sköldstam, L., Börjesson, O., Kjällman, A. et al., 1992. Effects of six months of fish oil supplementation in stable rheumatoid arthritis. A double-blind, controlled study. Scand. J. Rheum. 21, 178–185. Symmons, D., Harrison, B., 2000. Early inflammatory polyarthritis: results from the Norfolk Arthritis Register with a review of the literature. I. Risk factors for the development of inflammatory polyarthritis and rheumatoid arthritis. Rheumatology 39, 835–843. Tripoli, E., Giammanco, M., Tabacchi, G., Di Majo, D., Giammanco, S., La Guardia, M., 2005. The phenolic compounds of olive oil: structure, biological activity and beneficial effects on human health. Nutr. Res. Rev. 18, 98–112. Visioli, F., Galli, C., 1998. Olive oil phenols and their potential effects on human health. J. Agric. Food Chem. 46, 4292–4296. Wahle, K.W., Caruso, D., Ochoa, J.J., Quiles, J.L., 2004. Olive oil and modulation of cell signaling in disease prevention. Lipids 39 (12), 1223–1231.
Use of Olive Oil in Patients with Rheumatoid Arthritis Décio Sabbatini Barbosa1, Andréa Colado Simão1 and Isaias Dichi2 1
Department of Pathology, Clinical Analysis and Toxicology-University of Londrina Paraná, Brazil Department of Internal Medicine, University of Londrina, Paraná, Brazil
2
114.1 Introduction Rheumatoid arthritis (RA) is a systemic inflammatory disorder that mainly affects the diarthrodial joint. It is the most common form of inflammatory arthritis, and has a substantial societal effect in terms of cost, disability, and lost productivity. This disease affects about 1% of the population, in a female/male ratio of 2.5/1, and can occur at any age, but it is most common among those aged 40–70 years, its incidence increasing with age (Lee and Weinblatt, 2001). RA is characterized in the early stages by persistent inflammation of the synovial lining of the joints, which can lead to the destruction of bone and cartilage and result in joint deformity. The range of presentations of rheumatoid arthritis is broad, but disease onset is insidious in most cases, and diagnosis can be delayed for several months before it can be ascertained. The predominant symptoms are pain, morning stiffness, and swelling of peripheral joints. The clinical course of the disorder is extremely variable, ranging from mild, self-limiting arthritis to rapidly progressive multisystem inflammation with profound morbidity and mortality. The systemic disturbances are most commonly fatigue, stiffness, anemia, weight loss, and extra-articular features such as rheumatoid nodules (Lee and Weinblatt, 2001). Two main characteristics of the condition are the presence of rheumatoid factor (RF) measured in blood and typical RA erosions seen on radiological examination of hands and feet. RF is used both in diagnosis and prognosis, but lacks sensitivity because it is found in only 70–80% of RA cases. It is also seen in approximately 5% of normal populations.
114.2 Etiology The etiology of RA, a chronic inflammatory disease, remains largely unknown, although microbiological, immune, genetic, hormonal, and dietary factors have been implicated in its pathogenesis (Linos et al., 1991). The cause of RA remains Olives and Olive Oil in Health and Disease Prevention. ISBN: 978-0-12-374420-3
uncertain, but genetic factors are known to be involved and the locus has been identified. It has been suggested that genetic susceptibility explains 40% of the risk of developing RA (Silman et al., 1993). The suggested causes of RA include: viral infections, immunization, hormonal factors (prolactin production during lactation), smoking, previous blood transfusion, obesity, stress and physical trauma (Symmons and Harrison, 2000). RA is characterized by infiltration of T lymphocytes, macrophages and plasma cells into the synovium, and the initiation of a chronic inflammatory state that involves overproduction of pro-inflammatory cytokines and a deregulated T-helper-1-type response. Products of free radical oxidation have been identified in synovial fluid, thus lending further support to the theory that RA itself may be, in part, mediated by free radical activity (Pattison et al., 2004). Increased lipid peroxidation and depletion of ascorbate is a result of oxidation during its antioxidant activity and antioxidant micronutrients may have an important role in preventing tissue damage caused by free radicals (Halliwell et al., 1998).
114.3 Pathophysiology of inflammation Inflammation is the body’s reaction to invasion by an infectious agent, antigen or physical damage. Antigen exposure triggers the immune response, resulting in a cascade of cellular activity and an inflammatory response in the end organ. In RA, the inflammatory response continues in articular tissue, as though in response to a persistent stimulus, leading in time to irreversible damage to tendons and joints. Although a greater understanding of efferent mechanisms of inflammation and tissue destruction in RA has evolved over the past 10 years, there is still little understanding as to why inflammation persists in RA (Pattison et al., 2004).
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An inflamed synovium is central to the pathophysiology of RA. It is histologically striking, showing pronounced angiogenesis, cellular hyperplasia, influx of inflammatory leukocytes, and changes in the expression of cell-surface adhesion molecules, proteinases, proteinase inhibitors and many pro-inflammatory cytokines (Lee and Weinblatt, 2001). Following initiation of the immune response, activated macrophages, monocytes and granulocytes generate free oxygen radicals (Halliwell et al., 1998). The rapidly proliferating cells of the immune system are uniquely prone to oxidative damage by free radicals and pro-inflammatory prostaglandin E2 (PGE2), leukotriene B4 (LTB4), and cytokines, in particular TNF- and IL-1. The increased production of cytokines and the subsequent increase in reactive oxygen and nitrogen species are recognized hallmarks of inflammation. This process is regulated by a negative feedback mechanism and is closely followed by the secretion of anti-inflammatory cytokines to reduce the accumulation of reactive species. The cellular antioxidant defense system is also activated to limit the development of chronic inflammation (Bulló et al., 2007). The binding of pro-inflammatory cytokines to their receptors triggers the mitogen-activated protein kinase (MAPK) pathway that ultimately results in the activation of two redox-sensitive transcription factors: nuclear factor kappa B (NFB) and the c-Jun part of activating protein-1 (AP-1). These transcription factors activate the expression of a wide variety of genes including cytokines, chemokines, adhesion molecules and inducible effector enzymes such as iNOS and cyclooxygenase-2 (COX-2) (Bulló et al., 2007). The main features of rheumatoid arthritis are shown in Table 114.1.
114.4 Olive oil and inflammation Since the 1970s, a number of epidemiological studies have suggested that certain dietary fatty acids affect the immune response in both animals and humans, and more recently that they have anti-inflammatory effects. Olive oil (OO) exerts its beneficial effect modulating immune function, particularly the inflammatory process associated with the immune system, as seems to be the case in RA (Wale et al., 2004). Olive oil is mainly composed of oleic acid (18:1 n-9), a monounsaturated fatty acid (MUFA) that is converted to 8,9,11 eicosatrienoic acid (20:3 n-9; ETA) under restriction of n-6 fatty acids. ETA is converted to LTA3, which is a potent inhibitor of LTB4 synthesis (Figure 114.1). Therefore, oleic acid and its metabolite ETA may exert inflammatory effects through a mechanism similar to that of fish oil, which contains EPA. Because ETA is substantially
OLEIC ACID
Restriction of n-6 fatty acids
ETA
5-lipoxygenase LTA synthase
less unsaturated than EPA, it may have greater chemical stability, which would be an advantage for use as a dietary constituent or supplement (James et al., 1993). Virgin olive oil is a rich source of MUFA and retains all the lipophilic components of the olive fruit, especially the phenolic compounds with strong anti-oxidant and anti-inflammatory properties. The administration of OO with a high phenolic content has been shown to protect against inflammation. In addition, phenolic compounds derived from extra virgin oil were recently shown to decrease the production of inflammatory mediators in human whole-blood cultures and to inhibit endothelial adhesion molecule expression in vitro (Bulló et al., 2007). It has been attributed to extra virgin olive oil (EVOO) preventive properties with regard to chronic diseases, particularly those with an inflammatory etiology such as heart disease, cancer and RA (Wahle et al., 2004; Pacheco et al., 2007). The beneficial effects can be explained not only to the high monounsaturated content of OO, but also to the antioxidant property of its minor elements with high activity. The phenolic compounds are both lipophilic and hydrophilic. The lipophilics include tocopherols, while the hydrophilics include flavonoids, phenolic alcohols and acids, secoiridoids (oleuropein and ligstroside) and lignans (Tripoli et al., 2005). Oleuropein is the main polyphenol found in OO (Tripoli et al., 2005).
Table 114.1 Key features of rheumatoid arthritis. l l
l
l
l
l
l
Rheumatoid arthritis (RA) is a systemic inflammatory disorder that mainly affects the joints It is the most common form of inflammatory arthritis and can lead to destruction of bone and cartilage resulting in profound morbidity and mortality The predominant symptoms are pain, morning stiffness, and swelling of peripheral joints, but systemic disturbances can also occur Two main characteristics of the condition are the presence of RF and typical RA erosions seen on radiological examination of hands and feet The etiology of RA remains largely unknown, although immune, and genetic factors are likely the most implicated in its pathogenesis RA is characterized by infiltration of T lymphocytes, macrophages and plasma cells into the synovium, and the initiation of a chronic inflammatory state that involves overproduction of pro-inflammatory cytokines, reactive oxygen and nitrogen species, and a deregulated T-helper1-type response The binding of pro-inflammatory cytokines to their receptors triggers the mitogen-activated protein kinase pathway that ultimately results in the activation of nuclear factor kappa B
LTA3
inhibit
LTA hydrolase
Figure 114.1 Anti-inflammatory action of oleic acid. ETA – 8,9,11 eicosatrienoic acid; LT – leukotriene.
LTB4
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Chapter | 114 Use of Olive Oil in Patients with Rheumatoid Arthritis
Lipid radicals are produced during reactions involved in the metabolism of arachidonic acid, during the synthesis of the eicosanoids by the action of the lipoxygenase (LOX) and COX. The reactive oxygen species (ROS) and reactive nitrogen species involved in RA include superoxide anions, hydrogen peroxide, hydroxyl and peroxynitrite radicals, and nitric oxide. The first three of these are produced by xanthine oxidase and are also generated by activated macrophages and neutrophils as a result of respiratory chain activity known as the oxidative burst. This is primarily due to NADPH oxidase activity leading to the formation of hypochlorous acid (HOCl) as a bactericidal agent. Hydrogen peroxide is formed partly by superoxide dismutase (SOD), by the reaction between superoxide radicals and protons. Hydrogen peroxide is metabolized by catalase and peroxidase enzymes, chiefly glutathione peroxidase (Darlington and Stone, 2001). Indeed, the evidence that oxidative damage occurs in RA is very strong. Thus, antioxidant micronutrients may have an important role in preventing tissue damage caused by ROS (Pattison et al., 2004). The biological activity of phenolic compounds of OO is not limited to their antioxidant ability, but extends to their interaction with important enzymic systems. In particular, it has been found that olive oil phenols inhibit platelet aggregation, reduce pro-inflammatory molecule formation such as thromboxane B2 (TBX2) and LTB4, and inhibit the use of oxygen in human neutrophils (Tripoli et al., 2005) (Figure 114.2). Olive oil is a non-oxidative dietary component, and the attenuation of the inflammatory process it elicits could explain the beneficial effects on disease risk since oxidative and inflammatory stresses appear to be underlying factors in the etiology of inflammatory diseases in humans. The antioxidant effects of olive oil are probably due to a combination of its high oleic acid content (low oxidation potential compared with linoleic acid) and its content of a variety of plant antioxidants, particularly oleuropein, hydroxytyrosol, and tyrosol (Walde et al., 2004).
114.5 Are there differences between olive oil and extra virgin olive oil use in the inflammatory process? The concentration of phenolic compounds in OO is the result of a complex interaction of various factors and is also affected by the extraction process (Visioli and Galli, 1998; Tripoli et al., 2005). It is necessary to point out that refined oils do not have a significant content of polyphenols. Extra virgin olive oil (EVOO) is obtained from the first physical cold pressure of the olive paste and is rich in phenolic compounds. Virgin olive oil, obtained through percolation (first extraction), has a higher content in phenols, 0-diphenols, hydroxytyrosol and tyrosol aglycones, and tochopherols than oils obtained through centrifugation (second extraction) (Visioli and Galli, 1998). The effect of a virgin olive oil-enriched diet in acute and chronic inflammation models in rats was analyzed and determined the effect of supplementing this oil with a higher content of its polyphenolic fraction (MartinezDomínguez et al., 2001). This study demonstrated that virgin olive oil with a high content of polyphenolic compounds, similar to those of extra virgin olive oil, shows protective effects in both models of inflammation (Martinez-Domínguez et al., 2001). Another study compared the effects of two diets enriched in olive oils, having the same fatty acid composition but with EVOO and without (refined olive oil, ROO) minor compounds, on postprandial levels of triacylglycerol and on the accumulation of soluble intercellular adhesion molecule (sICAM-1) and soluble vascular cell adhesion molecule (sVCAM-1) in healthy and dyslipidemic humans (Pacheco et al., 2007). The results of this study indicated that the consumption of EVOO may help in reducing postprandial levels of adhesion molecules, which suggests a protective postprandial antiinflammatory effect in healthy and hypertriacylglycerolemic subjects (Pacheco et al., 2007). It was also investigated
Bone Venule Synovial fibroblasts TNF-Alfa IL-6: IL-8: PGE2
ROS*
, OH, HOCL, ONOO−) (O− 2 *TXB /LTB* 2 4
T cells and macrophages
IL-1Beta
Neutrophils Synovial membrane Cartilage
Figure 114.2 Synovial inflammatory process in the knee joint. Asterisks indicate the most plausible mechanisms of olive oil action. ROS – reactive oxygen species; TXB2 – thromboxane B2; LTB4 – leukotriene B4; IL – interleukin; PGE2 – prostaglandin E2.
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whether a bolus ingestion of phenol-rich extra virgin olive oil affects the postprandial lipid profile, as well as selected surrogate markers of cardiovascular risk, of healthy volunteers. Moreover, the effects of EVOO with those of OO were compared (Bogani et al., 2007). A significant decrease in inflammatory markers, namely TXB2 and LTB4, 2 and 6 h after EVOO (but not OO) consumption and a concomitant increase of serum antioxidant capacity were recorded. The authors of this study concluded that these data reinforce the notion that the Mediterranean diet reduces the incidence of coronary heart disease (an inflammatory disease) partially due to the protective role of its phenolic components, including those of EVOO (Bogani et al., 2007). Although OO contains a relatively low concentration of -tocopherol, it is known to be highly resistant to oxidative degradation. This is due, in part, to the relatively low content of polyunsaturated fatty acids and also to the high concentration of polyphenolic antioxidants, particularly in EVOO. The antioxidant activity of OO phenolic compounds, and in particular of oleuropein and its byproduct hydroxytyrosol, has been studied in many experimental models (Wahle et al., 2004; Tripoli et al., 2005). The antioxidant activity of oleuropein and hydroxytyrosol has also been demonstrated in cellular models and animals (Tripoli et al., 2005). Some studies with human volunteers do not show the same attenuating effects of MUFA/OO on immune function and could reflect the high content of these components in the animals’ diets (Wahle et al., 2004). However, according to the discussion above, it is reasonable to imagine a possible mechanism of the use of extra virgin olive oil (with the characteristic high concentration of MUFA and the presence of minor components) in inflammatory diseases: it has inhibitory action on COX and LOX; reduces pro-inflammatory molecule formation such as TXB2 and LTB4, reducing the adhesion molecules and free radicals formation (Tripoli et al., 2005). Maybe future large trials and other studies can confirm this assumption.
114.6 Can olive oil predict the risk of rheumatoid arthritis? Olive oil, as well as fish consumption, was shown to be an important predictor of risk of RA in a case-control study in Greece (Linos et al., 1991). The Greek diet is based mainly on fruit and vegetables, either raw or cooked with olive oil, and contains less meat and more fish and pulses than the Western diet, food items that may influence risk of RA. Some years later, the same group (Linos et al., 1999) performed a case-control study in Greece, where the 145 patients and 188 controls were paired by sex, age, and health care facility. Persons in the lowest category of OO consumption had a 2.5 times higher risk of developing RA than did persons in the highest category of consumption. The excess daily OO consumption was 43 g day1 approximately.
Section | II Immunology and Inflammation
Consumption of OO was inversely and independently associated with risk of RA in this population.
114.7 Studies using olive oil as placebo in rheumatoid arthritis patients Many patients look for complementary and alternative medicine options in coping with this debilitating disease and an estimated 60–90% of persons with RA use them (Rao et al., 1999). Olive oil certainly is one of these options. In the beginning of the 1980s, clinical studies which evaluated RA patients used OO as placebo. Olive oil was regularly used as control supplementation in experiments with fish oil (n-3 polyunsaturated fatty acids). At that time, MUFAs were typically regarded as being neutral fatty acids without interfering in the inflammatory process of RA (Firestein, 2003).
114.7.1 Studies Using n-3 Fatty Acids in Rheumatoid Arthritis Patients and Olive Oil as Placebo Darlington and Ramsey (1987) reported significant decreases in pain intensity, duration of morning stiffness, time taken to walk 18 m, and fibrinogen levels, and improved trends in erythrocyte sedimentation rate, C3, and right grip strength after 12 weeks of OO ingestion. Cleland et al. (1988) investigated clinical and biochemical effects of dietary fish oil supplements in RA and used OO as placebo. They demonstrated that 18 g day1 of OO reduced morning stiffness and pain score. They suggested that these findings could account for the lack of statistical significance between the groups. Kremer et al. (1990) performed a prospective, randomized, double-blind, parallel study with 49 patients with active arthritis during 24 weeks. Three groups were studied: two groups received different doses of fish oil dietary supplements, and one group received olive oil supplements as placebo. Patients who received fish oil demonstrated improvement on several clinical manifestations of RA. However, the improvements from baseline in the patients ingesting fish oil were usually not statistically significant compared with the patients taking olive supplements. Although the large and small doses of fish oil n-3 fatty acids produced better overall results, the OO group was the only one to show improvements in the patients’ global assessment. It should be noted that the clinical outcomes in the OO group may have been biased toward more favorable results because of the withdrawal of 11 of the original 23 patients in this study group. Macrophage IL-1 production decreased by 38.5% in the OO group. The authors concluded that dietary supplementation with OO is associated with certain changes in immune function. Olive oil
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Chapter | 114 Use of Olive Oil in Patients with Rheumatoid Arthritis
itself could have beneficial effects in RA patients due to cell membrane changes in lymphocytes resulting in altered immune function through a variety of mechanisms. Sköldstam et al. (1992) performed a controlled, randomized, double-blind study to assess the effect of n-3 fatty acids in patients with RA. Forty-three patients were allocated in two groups: 22 patients received fish oil (1 g) whereas 21 received a mixture of oils (corn, olive and peppermint) during 6 months. The group of patients which took fish oil showed a decrease in arthritis activity with significant reduction in non-steroidal anti-inflammatory drugs after 3 and 6 months. The control group patients (mixture oils) presented an increase in arthritis activity after 6 months. The groups did not show any improvement in joint pain, duration of morning stiffness, functional capacity, or in biochemical markers of inflammation. Geusens et al. (1994) found significant decreases in Ritchie’s articular index of pain and the number of painful
joints after 12 months of olive oil (6 g) and also after combined use of fish oil and olive oil. Therefore, although OO has classically been used as a placebo in studies investigating the effects of other oils, mainly fish oil, in patients with RA, without a definite purpose of being part of the therapeutic arsenal of RA, several studies above demonstrated its beneficial effects.
114.7.2 Studies Using n-3 Fatty Acids in Rheumatoid Arthritis Patients and Olive Oil as Adjuvant Therapy Berbert et al. (2005) evaluated whether supplementation with OO during 6 months could improve clinical and laboratory parameters of disease activity in patients with RA who were using fish oil supplements (Tables 114.2 and 114.3). Forty-three patients were assigned to one of three groups.
Table 114.2 Clinical indicators of disease activity in patients with rheumatoid arthritis receiving placebo (G1), n-3 fatty acids (G2) or n-3 fatty acids and oleic acid (G3). Baseline
12 weeks
24 weeks
Morning stiffness (minutes)
G1 G2 G3
38 42 44 68 60 65
46 47a 21 49 20 39
51 50a,b 5 8 11 26
Joint pain intensity
G1 G2 G3*
1.77 0.93 2.31 0.86 2.18 0.73
1.77 1.17a,b 1.46 0.66 1.00 0.71
1.85 1.21a,b 1.23 0.83 0.53 0.80
Time of onset of fatigue (min)
G1 G2 G3
19.5 3.5 20.9 12.1 23.4 14.1
19.3 3.5 17.1 10.2 21.7 13.0
21.4 5.2a,b 16.3 10.3 19.1 10.6
Ritchie articular index
G1 G2 G3
6.9 5.4 15.8 9.9 15.9 12.6
5.5 7.5 7.6 6.7 5.8 8.2
5.2 4.4a,b 3.6 2.4 1.2 2.3
Grip strength (right hand)
G1 G2 G3
62 37 54 35 63 58
60 29a,b 91 62 101 69
68 31a,b 105 78 114 84
Grip strength (left hand)
G1 G2 G3
74 43 57 35 67 52
68 35a,b 78 62 94 62
70 28a,b 108 75 110 82
Patient global assessment
G1 G2 G3
1.25 0.75 1.54 0.88 1.82 0.53
1.42 0.67a 1.62 0.87c 1.12 0.60
1.31 0.95a 1.23 0.60 0.88 0.70
Classification of functional status
G1 G2 G3*
1.85 0.80 2.54 0.78 2.65 1.22
2.00 1.08 2.23 1.01 2.53 1.28
2.00 0.91 2.15 1.07 2.00 1.28
Percentage change from baseline: a G1 versus G3 (p 0.05) b G1 versus G2 (p 0.05) c G2 versus G3 (p 0.05) * -within-group changes (p 0.05).
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Table 114.3 Health Assessment Questionnaire in patients with rheumatoid arthritis receiving placebo (G1), n-3 fatty acids (G2) or n-3 fatty acids and oleic acid (G3). Baseline
12 weeks
24 weeks
Dressing, including tying shoelaces
G1 G2 G3
0.15 0.56 1.46 1.27 1.24 1.30
0.15 0.38 0.69 1.32 0.77 1.15
0.23 0.60 0.77 1.17 0.53 1.18
Get in and out of bed
G1 G2 G3
0.15 0.38 0.54 1.13 0.77 0.90
0.23 0.60 0.39 0.96 0.53 1.01
0.46 0.88 0.39 0.87 0.65 1.17
Lift a cup or glass to your mouth
G1 G2 G3
0.0 0.0 0.46 0.66 0.53 0.87
0.08 0.28 0.31 0.48 0.18 0.73
0.00 0.0 0.15 0.56 0.24 0.07
Walk on flat ground
G1 G2 G3
0.39 0.77 0.62 1.04 1.18 1.13
0.39 0.77 0.54 0.78 0.88 1.17
0.54 1.05 0.54 0.78 0.77 1.20
Wash and dry your entire body
G1 G2 G3
0.08 0.28 0.77 1.30 0.82 1.02
0.23 0.60 0.54 0.97 0.41 0.87
0.31 0.75 0.39 0.77 0.29 0.85
Bend down to pick up clothing from the floor
G1 G2 G3
0.69 1.03 1.85 1.21 1.65 1.32
1.0 1.08b 1.15 1.41 1.35 1.41
1.31 1.38a,b 1.23 1.36 1.06 1.48
Turn faucets on and off
G1 G2 G3
0.92 1.04 1.23 1.10 1.59 1.06
1.08 1.04a 0.85 0.80 1.00 1.17
1.23 1.09a 0.92 0.86 0.77 1.09
Get in and out of a car
G1 G2 G3
0.46 0.66 1.46 1.27 1.53 1.23
0.31 0.63 0.69 1.18 1.18 1.33
0.69 1.03a,b 0.69 1.11 0.94 1.39
Percentage change from baseline: a G1 versus G3 (p 0.05) b G1 versus G2 (p 0.05).
The first group (G1) received soy oil (placebo), the second group (G2) received fish oil n-3 fatty acids (3 g day1), and the third group (G3) received fish oil n-3 fatty acids (3 g day) and 6.8 g day1 of oleic acid (9.6 mL of OO). There was a statistically significant improvement in G2 and G3 in relation to G1 with respect to joint pain intensity, right and left handgrip strength, duration of morning stiffness, onset of fatigue, Ritchie’s articular index for pain joints, ability to bend down to pick up clothing from the floor, and getting in and out of a car. G3, but not G2, in relation to G1 showed additional improvements with respect to duration of morning stiffness, patient global assessment after, ability to turn faucets on and off, and rheumatoid factor. In addition, G3 showed a significant improvement in patient global assessment in relation to G2. The rheumatoid factor decrease in G3 has a huge clinical significance because patients who have high titers tend to have a more aggressive, destructive course. The authors concluded that ingestion of fish oil n-3 fatty acids relieved several clinical parameters used in the
present study. However, patients showed a more precocious and accentuated improvement when fish oil supplements were used in combination with OO. Table 114.4 resumes the trials in which olive oil was used in patients with RA.
114.8 Future perspectives As discussed above there is some limitation in the studies which used OO in patients with rheumatoid arthritis. First of all, OO was designed as placebo in almost all studies which verified the action of n-3 fatty acids to decrease inflammatory activity in RA. Although the results obtained through these studies are indirect, comparison of fish and olive oils with similar results in Kremer et al.’s (1990) work make a possible role of olive oil in RA patients very likely. Furthermore, a synergistic effect of OO on fish oil supplementation was clearly demonstrated in Berbert et al.’s
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Chapter | 114 Use of Olive Oil in Patients with Rheumatoid Arthritis
Table 114.4 Trials in which olive oil was used in patients with rheumatoid arthritis. Authors
n
Darlington and Ramsey (1987)
Cleland et al. (1988)
60
Design
Dose of n-3 fatty acids or oleic acid
Time of treatment
Clinical improvement with Olive oil
Laboratorial improvement with Olive oil
fish oil X olive oil
18 g
12 weeks
Yes
Yes
fish oil X olive oil
18 g d1
12 weeks
Yes
No
18 g
18 g d1
Kremer et al. (1990)
49
fish oil X olive oil
45 or 90 mg kg1 d1 X 6.8 g d1 (9.6 ml d1)
24 weeks
Yes
Yes
Sköldstam et al. (1992)
43
Fish oil X Olive maize peppermint oils
10 g d1
6 months
No
No
10 g d1
Geusens et al. (1994)
90
fish oil X olive oil
3 g d1 6 g d1
12 months
No
No
Berbert et al. (2005)
43
fish oil X fish oil olive oil X soy oil
3 g d1
6 months
Yes
Yes
3 g d1 6.8 g d1
n – number of patients; d – day.
(2005) study. A future study designed to have four groups of RA patients being evaluated concomitantly constituted by a first group receiving OO, a second receiving n-3 fatty acids, the third receiving both oils, and the fourth receiving placebo, certainly would help to identify more accurately the action of OO in RA. Another issue of concern when studying oils in RA patients is to choose the ideal placebo. There is no such ideal placebo oil in inflammatory disease studies. The ideal placebo oil should have the n-6/n-3 fatty acid ratio of 4:1 or less, similar to the ratio to reach a healthy diet (Crawford et al., 2000). Soy oil has a ratio near 8 (54 n-6 : 7 n-3), and corn, sunflower, and safflower oils have even higher ratios than soy oil (Alexander, 1998), and therefore could have a pro-inflammatory influence. On the other hand, oils rich in both n-3 and n-9, like canola oil, could have an antiinflammatory effect, and should not be used as placebo in inflammatory studies as well. However, it has been verified that soy oil may amplify the stress response in severe stress, but not in moderate stress (Furukawa et al., 2002).
The data obtained in our studies with patients with ulcerative colitis (Dichi et al., 2000; Barbosa et al., 2003) and RA (Berbert et al., 2005) in mild or moderate inflammatory activity using soy oil as placebo seem to confirm that this concern is related basically to severe stress conditions. In summary, more studies specifically designed to study the effects of OO alone or in combination with fish oil in RA patients are warranted to help to decrease the doses of the classical anti-inflammatory drugs and to proportionate a better quality of life to patients with this important disability disease.
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Section | II Immunology and Inflammation
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