Here, we report that a gluten-free vegan diet in patients with RA induced a decrease in total cholesterol, LDL, and the ratio LDL/HDL whereas TGs and HDL did not change significantly. In contrast, the balanced diet in the control group did not influence lipid values significantly. There is now a large body of evidence indicating that this change of lipid profile is favorable in relation to atherosclerosis and CVD, and this diet therefore is likely to be antiatherogenic also in RA. We also report that both BMI and weight decreased significantly in the vegan diet group, which was not the case in the control group. Cholesterol, LDL, and BMI also differed significantly between groups and not only within the vegan group.

These findings are compatible with previous results of vegetarian/vegan dietary regimens in non-RA subjects which have shown lower blood pressure, lower BMI, and lower incidence of CVD [27–29]. Furthermore, these individuals had lower total cholesterol and lower LDL [30, 31]. When matched for BMI, subjects on a vegetarian diet had a body fat percentage similar to that of omnivore subjects [32]. Further evidence for the importance of diets on lipoprotein profile is the low incidence of myocardial infarction in Greenland Eskimos, whose high-fat diet is rich in marine lipids [33, 34].

In the vegan group, neither the levels of cholesterol, LDL, and the ratio LDL/HDL nor the changes differed between responders and non-responders (in contrast to oxLDL) nor were there any correlations between these changes and inflammatory activity. Such independence of inflammatory activity is similar to that reported concerning changes of linoleic acid found during vegan and vegetarian diets [35]. This implies that the change in lipid profile was a consequence of the vegan diet and not a result of reduced inflammatory activity and that the change in lipids did not have any impact on disease activity in RA.

In contrast to LDL and cholesterol values, TGs did not change as a consequence of vegan diet. In systemic lupus erythematosus, we have reported that high TGs are characteristic of this rheumatic disease and that TGs are strongly associated with disease activity and inflammation) [36, 37]. The dyslipidemia in RA therefore may differ somewhat from the 'lupus pattern of dyslipidemia', in which there appears to be a clearer association with inflammation.

Another finding herein is that levels of circulating oxLDL decreased in the vegan group, which was not the case among controls. OxLDL stimulates endothelial and monocyte adhesiveness [38, 39] and is taken up by macrophages in the artery wall, which develop into foam cells [40]. OxLDL itself, or otherwise modified LDL, also has many pro-inflammatory and immune stimulatory properties, including activation of T cells [41] and monocytes/macrophages [39]. Therefore, it is possible that the reduction in oxLDL also could contribute to the decreased disease activity due to its anti-inflammatory properties, a possibility supported by the finding that the reduction of oxLDL was seen only in diet responders.

One important mechanism by which oxLDL promotes immune activation is through platelet-activating factor (PAF), PAF-like lipids, and lysophosphatidylcholine in oxLDL which have PC as one determining epitope [42–44]. Furthermore, oxLDL is taken up by macrophages through scavenger receptors, including CD36, which has PC as ligand [45]. Circulating oxLDL has been reported to be a risk marker for CVD and atherosclerosis [46], and decreased levels of oxLDL thus could contribute to a less atherogenic profile. Little is known about a possible role of oxLDL in promoting the chronic inflammation present in RA, but it is interesting to note that oxLDL is present in foam cells in synovia from patients with RA [47], indicating that oxLDL also could play a role in the pathogenesis of RA.

Antibodies against OxLDL (aOxLDLs) are raised in RA, but their clinical importance for CVD and atherosclerosis has been much discussed [48, 49]. Initially, aOxLDLs were reported to be pro-atherogenic, but subsequent studies suggest that at least at an early stage of disease they could in fact be anti-atherogenic [48, 50–52]. This latter possibility is supported by animal experiments from several groups in which immunization with oxLDL causes decreased atherosclerosis development. Varying results may also depend on the fact that LDL oxidation is difficult to standardize [15, 50].

Instead of aOxLDLs, we have focused on anti-PCs, and one major finding is that anti-PC levels of IgM and IgA subclasses were raised after a vegan diet. Low levels of anti-PC IgM were more common in the control group than among vegans. Anti-PC IgM was also significantly higher in the vegan group as compared with the control diet group, whereas there was only a trendwise increase in anti-PC IgA.

We recently reported that there is an inverse correlation between anti-PC IgM levels and atherosclerosis development in humans [17]. Further to this, low levels of anti-PC IgM predict an increased risk of CVD in a population-based study (Frostegård et al, unpublished observation). Furthermore, animal experiments indicate that administration of anti-PCs ameliorates atherosclerosis development [53]. These changes in anti-PC levels which were induced by a vegan diet thus are likely to be antiatherogenic, although the role of anti-PC IgA in this respect has been less studied. PC is known to be immunogenic and present on important human pathogens like S. pneumoniae [18], and apoptotic cells expose this antigen, which is normally cryptic [54].

Earlier, we reported a decrease in serum levels of IgG antibodies to gliadin and β-lactoglobulin in the group of patients who responded positively to the vegan diet but not in other patients [19]. This reduction was suggested to be explained by diminished immune response to exogenous food antigens. In contrast, anti-PC was thus raised after a vegan diet. The cause of this increased response is not clear. However, we recently reported that anti-PC IgM is much lower in a Swedish population than in individuals from New Guinea living a traditional life as horticulturalists [55]. Their food contains much less of dairy products, refined fat, and grain-derived food and much more of fish, vegetables, and roots. We found that, in this population, anti-PC IgM levels were associated with a polyunsaturated fatty acid (FA) dihomo-gama-linolic acid 20:3 n-6, and we hypothesized that exposure to easily oxidized FA (for example, in the gut immune system) could elicit more robust anti-PC IgM and IgA levels in contrast to saturated FAs, which are not oxidized. Further studies are needed to clarify whether such a mechanism could be of importance. Hypothetically, the gut flora could be changed and so too could exposure of PC, another possibility that deserves further studies. Whether gluten plays a role in the effects presented herein remains to be elucidated.

Our preliminary experiments indicate that polyclonal human anti-PCs of the IgM subclass can inhibit uptake of oxLDL in macrophages and also inhibit pro-inflammatory effects mediated by PAF-like lipids generated during LDL oxidation (Frostegård et al. unpublished observation). Some of these effects thus could be anti-inflammatory, at least in the context of chronic inflammation. In principle, anti-PCs could play a role also in chronic inflammation as protective antibodies in general as in RA and be developed into novel treatment modalities in addition to other protective antibodies discussed in RA [56].

The vegan group also showed significantly lower levels of CRP, a physiologic marker of subclinical inflammation, which has been shown to be associated with insulin resistance and CVD [57, 58]. Elevated levels of CRP have been suggested to reflect overproduction by expanded adipose tissue mass [57]. In line with our previous findings [19], both DAS28 and HAQ decreased in the vegan group whereas only DAS28 at 3 months decreased in the control diet group.

Some limitations in the present study should be considered. First, a small number of patients participated. Nonetheless, the size of our groups was sufficient to detect several differences between diet groups, but we could not exclude the possibility of even more differences if a larger number had been studied. Second, a long-term diet study always poses special questions concerning compliance. The fact that compliance was monitored both via regular contacts between the patients and staff of the project and via dietary intake records made us confident that compliance to diet was high among the patients in both the vegan and non-vegan groups. The change in anti-rheumatic medication was considered too limited to have any consequences for results.