It is widely known that particular foodstuffs can affect the metabolism and/or pharmacological effects of drugs, including drugs used in the treatment of rheumatoid arthritis (RA). However, information on such foodstuff–drug interactions is limited and whether patients are aware of them is unknown.
In our rheumatology clinic, using a questionnaire sheet, we surveyed how often patients with RA were informed about the potential interactions between foods and drugs. We found that such knowledge was very limited among RA patients (unpublished). Here we summarise the potential food–drug interactions, focusing on their implications in rheumatology as a reference for medical staff.
Methotrexate (MTX) and folic acid (FA)
Interaction between vitamin B complex folic acid (FA) and the antifolate agent MTX is well known to most rheumatologists. MTX blocks the enzyme dihydrofolate reductase (DHFR), which converts dihydrofolate (DHF) to tetrahydrofolate (THF), which is the reduced, active form of FA (Fig. 1). Thus, MTX induces cellular depletion of active folate. In addition, as a downstream product, 5-methyl-THF serves as a methyl donor by which homocysteine is converted to methionine. MTX indirectly increases plasma and urine levels of homocysteine, as demonstrated in MTX treatment, including in RA patients.
Although the antifolate activity or folate antagonism of MTX is the basis of its efficacy, it also causes side effects such as gastrointestinal intolerance or hematological abnormalities. Therefore, FA deficiency is a major risk factor for MTX toxicity. The involvement of FA metabolism in MTX toxicity is also supported by the reported association between the genotype of 5,10-methylene-tetrahydrofolate reductase (MTHFR; a key enzyme in FA metabolism that reduces 5,10-methylene-THF to 5-methyl-THF [Fig. 1]) and MTX-related side effects.[3, 4]
To prevent toxicity, guidelines set by the Japan College of Rheumatology in 2011 (http://www.ryumachi-jp.com/index.html) strongly recommended coadministration of FA (≤ 5 mg/week) with MTX in RA patients treated with ≥ 8 mg/week of MTX and/or those who are at high risk of adverse effects due to FA deficiency. The effect of FA supplementation in preventing MTX toxicities has been widely established, and FA supplements do not appear to significantly reduce the effectiveness of MTX.[2, 5, 6] FA abolishes the increased production of homocysteine.[2, 7] In case of serious adverse effects or MTX overdose, 5-formyl-tetrahydrofolic acid (folinic acid), rather than FA, can be used as an antidote. Folinic acid (also known as leucovorin) is a 5-formyl derivative of THF that could be readily converted to other FA derivatives without DHFR, the target enzyme of MTX. FA supplementation may also be considered in RA patients who are undergoing combination therapy of MTX with sulphasalazine (SSZ)[9-11] because SSZ has been reported to influence FA concentrations, mainly by interference with intestinal absorption of FA.[9, 10]
Dietary FA may modulate serum concentrations of FA as well as the efficacy of MTX. Specifically, a high-folate diet can increase the serum concentration of FA and abolish MTX activity, even though the bioavailability of FA will widely vary with different types of foods and cooking styles employed. Such interference may not occur often if the daily dietary intake of FA is within the normal range; it has been reported that the dietary intake of FA may not necessarily correlate with serum concentrations of FA, particularly in females. However, attention should be paid if the patient is taking high dosages of FA-fortifying supplements or has a special type of diet with extremely low levels of FA. In such cases, appropriate nutritional consultation should be sought.[12, 15, 16] Smoking is also reported to reduce serum concentrations of FA regardless of dietary intake of folate.[14, 17]
Representative examples of food regularly consumed in Japan with high FA content are shown in Table 1. In some countries, mandatory folate fortification of food has been implemented as a policy (to prevent neural tube defects), but not in Japan. However, in Japan, specific attention should be paid to the widespread use of aojiru (green leaf squeeze), that is, vegetable juice made from green leafy vegetables such as kale and young barley leaves. Asahina et al.  reported that aojiru use was higher among elderly people (≥ 65 years) and more importantly, among people undergoing long-term medical treatment. FA content in naturally derived aojiru varies, but commercial aojiru may contain ≥ 200 μg/portion (Table 1). It is likely that patients often drink more than one glass a day in addition to other FA-rich foods. Therefore, it is recommended that attending physicians ask if patients are taking aojiru when administering MTX and check the ingredients of aojiru (including FA). Consumption of green tea, black tea or oolong tea may affect serum levels of FA.[20, 21] However, the FA content per 100 g of the edible portions of such teas is not high except for gyokuro (Table 1).
|Red-tip leaf lettuce||Sani-retasu||Raw||120|
|Hen's eggs, yolk||Ran-oh||Raw||140|
|Peanuts||Oil-roasted and salted||98|
|Sea urchin, raw gonads||Nama-uni||Raw||360|
|Japanese anchovy||Katakuchi-iwashi (Tazukuri)||230|
|Green tea (Sencha)||Infusion||16|
|Green tea (Gyokuro)||Infusion||150|
|‘Aojiru’ green leaf squeeze (according to nutritional facts)||Sample #1||45–200|
Recently, Kinoshita et al.  reported an immunological role of dietary FA: mice fed an FA-deficient diet showed reduction of Foxp3+ regulatory T cells in the colon. The immune system in the intestine plays a key role in systemic innate immunity; therefore, dietary vitamins (including FA) may have potent modulatory functions in normal or pathological immune functions in humans. Furthermore, FA is a nutritional factor that supplies methyl units for DNA methylation; thus, dietary FA may be involved in epigenetic disease mechanisms in RA, as in the case of cancer.[23, 24]
Isoniazide (INH) and fish
As the use of MTX and biologic agents such as anti-tumour necrosis factor (TNF)-α antibody expands, preventing serious adverse events caused by such immunosuppressive drugs becomes very important. One of the most important adverse events that often occurs with such use is severe opportunistic infection. In this regard, pulmonary tuberculosis (TB) is common in immunosuppressed patients in Japan. Thus, providing prophylactic treatment against TB before prescribing biologic agents or MTX is crucial. To this end, oral administration of INH is the standard protocol in most rheumatology clinics and hospitals in Japan.
The potential for INH to cause drug interactions through inactivation of the cytochrome CYP450 superfamily of enzymes, such as CYP2C9 and CYP3A4, is well accepted among physicians. Nevertheless, the interaction between INH and certain foodstuffs should also be highlighted[26, 27] (Fig. 2).
INH is an inhibitor of monoamine oxidase (MAO) and diamine oxidase (DAO). MAO and DAO contribute to the metabolism of histamine and tyramine, which are present in some types of fish and cheese. For example, tuna and mackerel contain histidine, and there are histamine-producing bacteria (HPB), such as Photobacterium phosphoreum and Raoultella planticola, in fish microflora that exert histidine decarboxylase (HDC) activity (which converts histidine into histamine). Other important biogenic amines that may be present in seafood include tyramine, tryptamine, putrescine and cadaverine, which are formed from tyrosine, tryptophan, ornithine and lysine, respectively, by a similar mechanism. Tyramine is also present in cheese (particularly aged cheese) and red wine, at different concentrations.[31-33]
These biogenic amines can be detoxified rapidly by amine oxidases in healthy individuals, whereas those with low MAO/DAO activity are at risk of food poisoning or intolerance when ingesting even low levels of histamine- or tyramine-containing food.[34, 35] Such toxification, which is often accompanied by the consumption of contaminated fish of the scombroid family (e.g. tuna, mackerel, herring, marlin, bonito and jacks) is known as scombrotoxic fish poisoning and is not rare as outbreaks have been recorded. Potentiation of the biological effects (e.g. hypertensive reaction) of dietary tyramine by MAO inhibitors are known as cheese reactions or the cheese effect, which may limit the use of such drugs.[37-39] In this context, patients receiving INH may be particularly at risk of such food poisoning. For example, Morinaga et al.  reported in 1997 that an 83-year-old woman who was receiving INH developed symptoms of histamine toxification, including headache, palpitations and skin eruptions with itching, while eating raw tuna. An outbreak of histamine toxification was reported from a TB ward only in patients receiving INH after consumption of ground saury (sanma in Japanese) paste.
A category of monoamine oxidase inhibitor (MAOI) diet has been proposed in which avoidance of aged cheese and soy products is recommended.[31, 42] However, according to improvements in the side effect profile of MAOIs, such caution may not be required. Nevertheless, considering the outbreaks of poisoning mentioned above, RA patients undergoing (or considering) INH treatments (or other immunosuppressive therapy) should be aware of the food–drug interactions caused by INH. It has been reported that, for example, pizzas from large-chain commercial outlets are safe for consumption with MAOIs, but patients should take care when ordering pizzas that may contain aged cheeses.
Calcineurin inhibitors and grapefruit
Calcineurin inhibitors such as tacrolimus and cyclosporine may be used for RA therapy or its comorbidities in Japan because their efficacy and safety have been shown to be promising. Tacrolimus is metabolized primarily by human liver CYP3A4, which is responsible for the metabolism of 50–60% of currently known drugs.[45, 46] Grapefruit is an inhibitor of the intestinal CYP3A4 system; therefore, tacrolimus could interact with grapefruit juice if taken concomitantly. That is, inhibition of the CYP450 system by grapefruit may result in unexpected elevation of the serum concentration of the ingested drug, including tacrolimus.
P-glycoprotein (Pgp) is a 170-kDa phosphorylated glycoprotein encoded by the human MDR1 gene. Pgp is known to regulate drug pharmacokinetics as an adenosine triphosphate (ATP)-driven efflux pump, and also has a broad range of substrates. There is significant overlapping of substrates between CYP3A4 and Pgp, and tacrolimus and cyclosporine are controlled by CYP3A4 and Pgp.
It has been suggested that the activity and expression of Pgp can be affected by groups of foodstuffs (e.g. herbal constituents such as curcumin, ginsenosides, piperine, green tea catechins), some natural components from grapefruit juice (e.g. bergamottin, quercetin) and ginger.[48, 49] Hence, the interaction between Pgp and these foodstuffs may result in altered absorption and bioavailability of drugs that are Pgp substrates. In this regard, elevation of trough blood concentrations of tacrolimus by grapefruit (or pomelo) juice has been reported in recipients of liver or kidney transplants.[50-52] Although the modulating effect on drug concentrations may differ among genotypes of CYP or MDR1,[47, 53] RA patients (particularly those with liver or kidney dysfunction) may be recommended to avoid concomitant ingestion of tacrolimus/cyclosporin and grapefruit or other citrus fruits.
Among other drugs frequently used in rheumatology clinics, 1,4-dihydropyridine calcium-channel blockers (CCBs) and hydroxymethyl glutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) may show potential interactions with grapefruit (reviewed in Kane and Lipsky). Modulation of the pharmacokinetics of statins by grapefruit may vary between different classes of these agents.[55, 56]
Food–drug interactions should be highlighted to healthcare professionals and patients not only in TB wards or psychiatry departments, but also in rheumatology clinics. We propose that nutritional consultation should be considered for RA patients to avoid food–drug interactions, as well as to reduce metabolic or nutritional risks that may play a part in the perpetuation of inflammation.[57, 58]