Authors:
Prof. Monika Reuß-Borst (Rheumatology Practice, Bad Bocklet), Adjunct Prof. Gernot Keyßer (University Hospital Halle - Saale), Prof. Andreas Michalsen, Dr. Olaf Schultz (Rheumatology Clinic, Baden-Baden), Dr. Inna Frohne (University Hospital Düsseldorf), Dr. Mandy Gläß (Vogelsang-Gommern Rheumatology Clinic), Assistant Prof. Alexander Pfeil (University Hospital Jena), Associate Prof. Dr. Oliver Sander (University Hospital Düsseldorf), Prof. Olga Seifert (Commission for Complementary Medicine and Nutrition)
Patients and physicians know from personal experience that diet can influence disease activity and the frequency of flare-ups in inflammatory rheumatic diseases [1, 2]. In recent years, therefore, the importance of an appropriate diet has become a focus of scientific interest. There is evidence, for example, of the influence of diet or individual macro- and micronutrients on a variety of pathomechanisms of rheumatoid arthritis (RA) and other inflammatory rheumatic diseases in experimental models. The main areas of focus are: 1) pro-inflammatory, anti-inflammatory, or antioxidant effects of individual nutrients or entire dietary patterns, 2) effects on the gut microbiota and the gut-associated immune system, 3) effects of diet on major comorbidities of rheumatic diseases (diabetes mellitus, cardiovascular diseases), 4) weight normalization in cases of significant obesity.
However, the number of clinical controlled and randomized trials on dietary modification in rheumatic diseases remains limited, which is attributable, among other things, to difficulties in study design and funding. Consequently, most recommendations are based on observational studies in which specific dietary patterns were examined under uncontrolled conditions. This chapter presents the current state of the evidence, focusing not on individual food components but on the currently known effects of specific dietary patterns, such as the Mediterranean diet (see also the Commission’s separate chapter on this topic). Overall, the clinical evidence for rheumatic diseases is significantly weaker compared to that for cardiovascular and metabolic diseases and, with few exceptions, pertains only to RA.
In the 1990s, Kjelsen-Kragh’s research group in Oslo conducted extensive clinical and experimental studies on the benefits of fasting periods and/or vegetarian diets. In a subsequent randomized controlled trial, therapeutic benefits were demonstrated from an initial fasting regimen, followed by a plant-based and gluten-free diet, and subsequently (as a follow-up) a lacto-vegetarian diet over the 13-month study period [3].
In another randomized study, clinical improvement was observed with a vegan and gluten-free diet compared to a non-vegan diet [4], although the active treatment arm had a high dropout rate.
Sköldstam et al. published the first randomized study on the Mediterranean diet in RA. After 6 and 12 weeks of following a Mediterranean diet, the DAS28 improved by at least 0.6 points in 15 out of 26 patients in the intervention group and in 6 out of 23 patients in the control group; however, there was no difference between the groups regarding an improvement of at least 1.2 points (EULAR Response) [5]. In a larger controlled but non-randomized study on the implementation of a Mediterranean diet among patients with rheumatoid arthritis in a socially disadvantaged population, it was shown that regular educational and cooking classes are necessary to achieve even a minimal behavioral change sufficient to produce improvements in patient-centered outcomes such as HAQ or morning stiffness over a 6-month observation period [6] (See also the chapter on the Mediterranean diet).
A recently published randomized crossover study (ADIRA Trial) investigated the effects of a wholesome diet emphasizing vegetables, fruits, fish, reduced meat consumption, and probiotics as dietary supplements. Of 50 participants, 47 were included in the analysis. Only in the unadjusted analysis was a benefit for the intervention observed in the DAS28 score after 10 weeks. However, the study appears to be “underpowered” and the observation phase too short [7]. New concepts for comprehensive anti-rheumatic diets are being evaluated in clinical trials [8].
A 2009 Cochrane analysis by the Scandinavian working group led by Hagen identified 14 RCTs (randomized controlled trials) and one controlled study involving a total of 837 patients. The authors concluded: “The effects of dietary manipulation, including vegetarian, Mediterranean, elemental and elimination diets, on rheumatoid arthritis are still uncertain due to the included studies being small, single trials with moderate to high risk of bias.” [9].
A recent systematic review of RCTs on RA identified 27 publications on dietary interventions and their effects on disease activity, as measured by the DAS28. Three studies were highlighted (Mediterranean diet, vegan diet, anti-inflammatory diet). Potential positive effects of certain high-dose spices, such as ginger, cinnamon, and saffron, were emphasized. The authors concluded that while there are only a few meaningful studies, it is suspected that some interventions—such as antioxidants like the polyphenol quercetin or probiotics containing Lactobacillus casei—may have positive effects on RA disease activity, as measured by the DAS28 [10].
Another recent review identified 70 studies on the topics of diet, fasting, and dietary supplements. The authors found a possible beneficial effect of vitamin D supplementation and salt restriction on specific RA outcomes. Fasting was classified as effective in the short to medium term. While clinical improvement associated with the Mediterranean diet was described as moderately supported by evidence, the results for vegetarian and elimination diets were not considered consistent, and an individually variable response is suspected [11].
In a recent systematic review of 20 RCTs involving 717 RA patients, omega-3 fatty acid supplementation was assessed as beneficial for clinical outcome parameters [12]. A much more comprehensive body of data exists in cardiology. Here, large-scale studies have not confirmed the benefits of omega-3 fatty acid supplementation. Efficacy has been demonstrated only for a specific eicosapentaenoic acid ester [13]. A recommendation for omega-3 fatty acid supplementation cannot be made for RA.
Fasting
In a study by Kjeldsen-Kragh [3] published as early as 1991, the beneficial effects of a 7- to 10-day fasting regimen were documented. However, these results were obtained before the era of modern drug therapy for RA. Similarly, the meta-analytic evidence presented from four studies on fasting in RA [14] also dates back to the pre-biologic era. Empirically, there is long-standing experience with the symptom-relieving and anti-inflammatory effects of fasting in specialized clinics. However, these data from registries and the aforementioned studies (with the exception of Kjeldsen-Kragh [3]) cover only short-term periods of 6 to 12 weeks. Data on the long-term effects of repeated fasting regimens are lacking, as are data on the influence of fasting on radiographic progression.
Ketogenic diet
The so-called ketogenic diet represents a fasting-mimicking therapeutic approach in which, similar to fasting, the body derives most of its energy from the metabolism of ketone bodies [15]. However, unlike during fasting, these are not produced by the breakdown of the body’s own fat, but rather through the intake of exogenous (ideally predominantly plant-based) fats. To achieve this, patients follow a diet that is very high in fat and extremely low in carbohydrates. The resulting ketone bodies (primarily β-hydroxybutyrate) are believed to have antioxidant and anti-inflammatory effects [16, 17]. Although this is an interesting (fasting-mimicking) therapeutic approach, unlike in other therapeutic areas such as type 2 diabetes mellitus [18], there have been no clinical studies on rheumatic diseases to date [19].
Microbiome
It is considered highly likely that the microbiome plays a role in the development of rheumatic diseases as well as numerous other autoimmune diseases. Distinct changes in the microbiota have been documented in “new-onset” RA [20].
The most important factor influencing the microbiome is diet. However, it is currently unclear exactly how dietary interventions can be used to specifically induce health-promoting changes in the microbiome. Further research in the coming years will be needed to address this. Initial clinical studies suggest that high-fiber and fermented foods can reduce inflammatory markers and exert immunomodulatory effects by modifying the microbiome [21, 22].
Based on animal models [23–28] and existing clinical studies, there is broad consensus on the following classifications of the macronutrients fat and carbohydrates:
Fats:
Arachidonic acid and its precursors have pro-inflammatory effects and should be reduced; the same applies to saturated fats and individual metabolites such as trimethylamine oxide (TMAO), a breakdown product of the phospholipid choline. These fats are found in meat and sausage, respectively; accordingly, a reduced intake of meat can be inferred to be beneficial.
Omega-3 fatty acids (O-3 FAs) of plant or marine origin have anti-inflammatory effects in experimental models. Replacing saturated fatty acids with oils, vegetables, nuts, algae, and fish containing O-3 FAs appears advisable as part of a health-oriented diet. There are no specific dosage recommendations, particularly since the absorption of omega-3 fatty acids varies greatly from person to person. Furthermore, their bioavailability can be increased, for example, by consuming a high-fat meal [29].
Carbohydrates:
Refined sugars have been shown to have adverse cardiovascular, adipogenic, and mildly pro-inflammatory effects [30]. However, specific study data on established rheumatic diseases are lacking. Experimental studies have described pro-inflammatory effects of gluten, even in the absence of celiac disease; however, consistent study data on the benefits of a gluten-free diet are lacking.
Few side effects are to be expected when following the dietary approaches discussed here. During fasting, care should be taken to ensure adequate fluid intake to prevent, for example, the onset of gout attacks. Fasting should not be undertaken during an acute flare-up of a rheumatic disease or in cases of poorly controlled rheumatic conditions, nor in cases of active gout or symptomatic gallstones. Fasting is contraindicated in cases of underweight and eating disorders. In some cases, fasting—as well as the ketogenic diet—may cause mild headaches and other discomfort in the first few days. A ketogenic diet is also contraindicated in type 1 diabetes and rare fat oxidation disorders. In general, dietary interventions such as prolonged fasting periods should only be undertaken under the supervision of trained personnel.
Based on the studies available to date, a wholesome diet rich in vegetables and fruits (high in fiber) and low in meat can be recommended for patients with inflammatory rheumatic diseases as a supportive measure that promotes self-efficacy. This applies in particular given the health-promoting effects of such a diet on frequently associated comorbidities (e.g., cardiovascular diseases), as demonstrated in studies.
The strongest evidence for this comes from the Mediterranean diet (see also the chapter on the Mediterranean Diet). It should be noted, however, that the classic Mediterranean diet (as studied in particular in trials such as PREDIMED) was always low in carbohydrates, particularly with regard to the proportion of refined sugar [20].
The Commission generally recommends providing patients with qualified and comprehensive information about a diet that inhibits inflammatory processes or, at the very least, does not further exacerbate them. To this end, resources should be enhanced in the coming years. The emphasis should always be on a supportive therapeutic approach—pharmacological therapy should be continued in all cases. Long-term studies would also be desirable, particularly regarding adherence, disease progression, and long-term prognosis under specific dietary regimens. Future research should also address the question of which phase of the disease course represents the optimal starting point for nutritional interventions and to what extent disease activity can actually be influenced by diet.
Routine microbiome analysis as the basis for individualized nutritional therapy cannot currently be recommended, as it does not yield any therapeutic recommendations beyond those currently in use. Furthermore, these tests are costly and are not covered by health insurance.
Fasting therapies—whether in the form of traditional therapeutic fasting lasting 5–10 days or modern fasting-mimicking diets—can be monitored by physicians experienced in the method and used on a trial basis as a supplement to nutritional therapy, provided there are no contraindications. Since there is now growing evidence of the beneficial effects of fasting on high blood pressure and type 2 diabetes, fasting may also be recommended in the presence of these comorbidities, particularly when patients are motivated to undertake such a measure.
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Last updated: April 18, 2023