Inadequate Calcium, Folic Acid, Vitamin E, Zinc, and Selenium Intake in Rheumatoid Arthritis Patients:

Results of a Dietary Survey

Jonathan Stone, Alan Doube, Denise Dudson, and Janelle Wallace

Objectives: To determine the adequacy of calcium, folic acid, vitamin E, zinc, and selenium intake in patients with rheumatoid arthritis (RA). Methods: We conducted an observational study on 48 patients (13 men, 35 women; mean age, 64.5 years) with RA attending a specialty clinic in New Zealand comparing their dietary intake as measured by a 5-day dietary survey with recommended dietary intake (RDI) guidelines. Information on disease activity, functional ability, and drug therapy also was obtained. Results: The percentage of patients who achieved the RDI was 23% for calcium, 46% for folic acid, 29% for vitamin E, 10% for zinc, and only 6% for selenium. Patients on methotrexate had a significantly reduced intake of folic acid as a percentage of RDI (P < .05) compared with those on other therapies. In contrast, dietary intake of iron and protein was largely adequate and unrelated to anemia. Conclusions: Patients with RA should receive dietary education or supplemen- tation to bring their intake of calcium, folic acid, vitamin E, zinc, and selenium up to the RDI. Semin Arthritis Rheum 27:180-185. Copyright © 1997 by W.B. Saunders Com- pany

INDEX WORDS: Rheumatoid arthritis; calcium; folic acid; selenium; zinc; vitamin E.

M UCH TIME and energy has been devoted to the study of the effects of dietary manipula-

tion on rheumatoid arthritis (RA). However, little work describes common dietary deficiencies that occur in populations of patients with RA.

Previous authors have studied nutritional status in RA, suggesting a prevalence of malnutrition of 26% (1) and 53% (2). Plasma deficiencies of folic acid (1,3), vitamin D (4), zinc (1,5), and selenium (6) have been recorded in RA populations. How- ever, these studies have invariably concentrated on anthropometric measurements and laboratory inves-

From the Department of Rheumatolog~; Waikato Hospital, Hamilton, New Zealand.

Jonathan Stone, MRCP: Registrar; Alan Doube, FRACP: ConsultantRheumatologist; Denise Dudson, NZRN: Rheumatol- ogy Nurse Educator; Janelle Wallace, NZRD: Clinical Nutrition Manager.

Supported by The Health Waikato Charitable Trust. Address reprint requests to Alan Doube, FRACP, Department

of Rheumatology, Waikato Hospital, Pembroke St, Private Bag 3200, Hamilton, New Zealand.

Copyright © 1997 by W.B. Saunders Company 0049-0172/97/2703-000755.00/0

tigations. Simple measurement of dietary intake alone is insufficient to assess overall nutritional status, but basic data on this subject that can be practically communicated to patients with RA are lacking. Our objective was to determine the dietary status of a local cohort of RA patients, to relate this to current New Zealand guidelines for recom- mended daily intake (RDI) (7), and to provide dietary advice for these patients.

PATIENTS AND METHODS

Forty-eight patients with RA replied to a postal questionnaire sent to 100 RA patients attending a rheumatology clinic. All patients satisfied four or more of the American College of Rhenmatology criteria for the diagnosis of RA. Patients were selected from a register established in 1989 to prospectively record data regarding disease activity and functional status if they attended the clinic at least once in the 12 months before the dietary survey. The most recently recorded data were used for analysis. The following information was obtained: age, gender, weight, height, disease duration in years, duration of early morning stiffness (EMS) in minutes, patient-assessed visual analog scores (VAS) for EMS and pain, number of clinic visits in 12 months, information on function using the modified Health Assessment Questionnaire (HAQ), Ritchie index, hemoglobin (Hb), platelet count, and erythrocyte sedimentation rate (ESR).

180 Seminars in Arthritis and Rheumatism, Vol 27, No 3 (December), 1997: pp 180-185

RESULTS OF A DIETARY SURVEY IN RA PATIENTS 181

Each patient was given written instructions on how to complete a 5-day prospective dietary record of food and fluid intake. Food amounts and frequencies were recorded by the patient. Whenever the constituents of the recorded food were not obvious to the dietitian, recipes were obtained fiom the patient to allow appropriate analysis. Ambiguous or unusual records were reviewed by personal contact with the patient by an experienced dietitian. Vitamin tablets, added salt and pepper, and other dietary supplements were not included. Record analysis was accomplished using computer software specifically designed for foods in New Zealand to give a breakdown of dietary constituents (8).

New Zealand adopts RDI values proposed by Australia, which are broadly age and gender related where necessary. These are very similar to the recommended dietary allowances (RDA) adopted in the United States. Overall, the Australian RDI zend to be slightly higher than the American RDA; for example: calcium, RDI, 1,200 mg versus RDA, 800 mg; zinc, 15 mg RDI versus 12 mg RDA for men, (women unchanged); selenium, RDI 85 gg versus RDA 70 Bg for men; RDI 70 gg versus 55 ~tg RDA for women. The recommended intakes for folic acid and vitamin E are identical.

Data Analysis

Intake of dietary constituents were expressed simply as a percentage of RDI and were adjusted where stated for age, gender, and weight. "Patients at risk" are advised to obtain 100% RDI. However, a cutoff point of 75% of the RDI was used to break down the results further, assuming this intake level is probably sufficient to maintain a healthy person but not one with chronic disease. Mean values and standard deviations also were calculated for each constituent. For further statistical analysis, X 2 test, analysis of variance, and correlation matrices were used.

RESULTS

Table 1 shows the overall characteristics of the population studied. Seventy-three percent were women with an average age of 65 years. Average body mass index (BMI) was 25.9. This is similar to the general population for which RDI guidelines are intended, and slightly higher than the ideal range (20 to 25).

The breakdown of dietary constituents is shown in Table 2. The figures are expressed as the percentage of the population whose intake reached 75% and 100% of the RDI, respectively. Mean values are shown, although the wide standard deviations indicate these values may not be the best reflection of dietary inadequacies. For example, mean folic acid intake was above the RDI, but 42% of the population still failed to reach 75% of the RDI. The diet of our population of patients with RA

Table 1: General Clinical Features of the Population Studied

Age (yr); mean (range) 84.5 (33-80)

Sex (F:M) 35:13

BMI; mean (range) 25.9 (18-42)

Disease durat ion f rom onset

(yr); m e a n (range) 12.9 (1-55)

No. of cl inic visits in 12

months; mean (range) 2.1 (1-7)

Durat ion of EMS (minutes);

mean (range) 37 (0-240)

VAS of EMS (0 = none,

10 = most severe); mean

(range) 3.87 (0-10)

VAS of pain (0 = none,

10 = most severe); mean

(range) 4.6 (0-10)

HAQ score (0-3); mean (range) 0.97 (0-3)

Ritchie score (0-72), mean (range) 3.9 (0-23)

Hemog lob in (g/L); mean (range) 129.5 (95-164)

ESR (ram/h); mean (range) 31.5 (1-159)

Number taking metho-

t rexate 28

Number taking SAARD

other than methot rexate 14

Abbreviations: BMI, body mass index; EMS, early morning stiffness; VAS, visual analog scale; HAQ, Health Assessment Questionnaire; SAARD, slow-acting antirheumatic drugs; ESR, erythrocyte sedimentation rate.

contained satisfactory levels of protein, iron, thia- mine, niacin, vitamin B6, vitamin B12, and vitamin C. There were borderline deficiencies of vitamin A, phosphorus, and riboflavin. Magnesium intake was defcient, with only 27% achieving the RDI. Intake of calcium also was poor, with only 23% of patients attaining the RDI. Folic acid intake was marginally better, with 46% attaining 100% of the RDI. Fifty-eight percent of patients achieved 75% of the RDI for folic acid. Of these patients, 90% were taking methotrexate, a statistically significant result in this population (P < .05). Intake values of vitamin E, zinc, and selenium were significantly low at 29%, 10%, and 6% of the RDI, respectively. Sodium intake was high, even excluding added table salt, with 50% of patients consuming more than 100 mmol/day and 27% consuming more than 125 mmol/day (RDI, 40 to t00 mmol/day).

Table 3 gives the mean percentage contribution

182 STONE ET AL

Table 2: Average Daily Dietary Intake Expressed as a Percentage of Those Who Reached 75% and 100% of the Recommended Daily intake (RDI)

Percentage Percentage achieving achieving Mean intake

75% of RDI 100% of RDI (SD) RDI [71

Kilocalories (kcal) N/A N/A Carbohydrate (g) N/A N/A Fat (g) N/A N/A Protein (g) 98 85 Vitamins

Vitamin A (pg retinol equiva- lents) 77 52

Thiamine (mg) 94 75 Riboflavin (mg) 73 46 Niacin (mg) 100 96 Vitamin B6 (mg) 96 83 Vitamin B12 (IJg) 94 88 Vitamin C (rag) 100 96

Vitamin E (mg) 65 29

Folic Acid (pg) 58 46 Minerals

Sodium (mmol) t 100 100 Potassium (mmol) 98 77 Calcium (mg) 38 23 Iron (mg) 90 84 Phosphorus (mg) 83 60 Magnesium (mg) 60 27

Zinc (rag) 44 10 Copper (rag) 8 4 Selenium (pg) 13 6

1,605 (493) N/A 208 (60) N/A

58 (22) N/A 68 (23.4) 45 (F), 55 (M)

960 (752) 750 1.7 (1.4) 0.7-1.1" 1.5 (0.7) 1-1.7"

26.8 (9.8) 11-19" 1.4 (0.53) 0.8-1.9"

5 (7.8) 2.O 81.2(42) 30 (F), 40 (M)

(F: 84.7, M: 71.5) 7.2 (3.0) 7 (F), 10 (M)

(F: 7.0, M: 7.6) 2O5 (79) 200

111 (40) 40-100 68 (20.7) 50-140

641 (290) 800 10 (3.5) 7-16"

1,129 (454) 1,000 241 (91) 270 (F), 320 (M)

(F: 235, M: 260) 9 (3.2) 12 1 (0.5) 2.5

36 (21.9) 70 (F), 85 (M)

NOTE. Mean values and RDI values are shown (n = 48). *Age and sex related. tSodium: 50% consumed >100 mmol/day. 27% consumed >125 mmol/day. Abbreviations: N/A, not applicable; SD, standard deviation.

to total dietary intake of carbohydrate, fat, protein, and alcohol and compares this with a survey of 181 normal subjects between the ages of 50 and 54 years in New Zealand (9). Our patients with RA relied less on fat (32%) and alcohol (1%) when compared with these historical control values, suggesting that dairy produce, fatty foods, and alcohol are being avoided.

Statistical analysis with correlation mata'ices showed that calcium, folic acid, protein, and iron intake were not related to functional disability or disease activity. There was no statistical relation- ship between iron intake and anemia. Calcium and

folic acid intake were significantly related to BMI (P < .01), and calcium intake was inversely related to age (P < .01).

DISCUSSION

RA is associated with several obstacles to a healthy diet not faced by a healthy person, and general nutritional status is often impaired (1,2). Disability, fatigue, and pain can interfere with the purchase, preparation, and consumption of food. Temporomandibular pain can impair mastication. Antiinflammatory and antirheumatic medications commonly lead to nausea, dyspepsia, and altered

RESULTS OF A DIETARY SURVEY IN RA PATIENTS

Table 3: Present and Previous Studies in RA and Normal New Zealand Populations

183

Kremer and Paulin Present Bigaouette Kowshari Eising et al RDI series* (13)* et al (12)* (11)* (9)1 (7}

Population RA RA RA RA Normal Normal Year 1997 1996 1983 1963 1987 1990 Cour~try NZ USA USA USA NZ NZ No. of subjects 48 41 24 42 181 N/A Mean Age (yr) 65 57 56 46 50-54 N/A Sex 35F, 13M 24F, 17M 7F, 17M ND 82F, 99M N/A Calcium (mg) 641 731 (F) 676 761 655 (F) 800

740 (M) 793 (M) Folate (IJg) 206 154 (F) 115 ND 188 (F) 200

205 (M) 259 (M)

Vitamin E (mg) 7.2 18.6 (F) 3.2 ND ND 7 (F) 16.1 (M) 10 (M)

Zinc (mg) 9.3 5.0 (F) 9.0 ND 8 (F) 12 7.1 (M) 3 (M)

Selenium (pg) 36.3 ND ND ND ND 70 (F) 85 (M)

~Mean values for the groups studied. tMedian values. Abbreviations: RA, rheumatoid arthritis; USA, United States of America; NZ, New Zealand; F, female; M, male; ND, no data available; N/A, not applicable.

taste. Many patients seek palliation of their symp- toms by omitting dairy products, meat, or calories from their diet. Vegetarian, vegan, elimination, and fasting diets are just some of the numerous diets that have been advocated for RA. These have been extensively studied without the emergence of firm conclusions, and further long-term double-blind studies are needed (10). Economic factors also influence diet.

RDI values are derived from balance studies and epidemiological observations in healthy people and are only applicable to group needs. The final value usually incorporates an additional margin of safety for variations in absorption and metabolism. Thus, the RDI for many nutrients usually exceeds indi- vidual requirements in a healthy person. Patients with RA, however, may require increased intake of several nutrients to maintain a steady state. For example, protein requirements may rise in response to increased basal metabolic rate or there may be an increased antioxidant requirement to combat chronic inflammatory disease. Despite these flaws, RDI guidelines are the best available approximation to what constitutes a balanced diet.

We excluded vitamin and dietary supplements

from our study, although we are aware that many patients take a wide range of supplemental prod- ucts, and some may be purposefully prescribed, such as folic acid to reduce methotrexate-induced nausea. However, our primary purpose was to define dietary intake, and inclusion of supplements would have confounded our results.

Dietary intake of calcium, folic acid, vitamin E, zinc, and selenium were all significantly deficient in this study and are discussed later. In addition, sodium intake was excessive. This correlates to some extent with the results of a study on the dietary habits of healthy patients in New Zealand (9).

Table 3 compares the intakes of the nutrients found to be significantly deficient in this study with these two studies and with three others on dietary intake in RA (11-13).

Calcium

The role of prolonged inadequate calcium intake on the acceleration of osteoporosis is well known. Patients with RA are vulnerable to steroid-induced and disease-association osteoporosis. Previous stud- ies have identified mean daily calcium intake in R ~

184 STONE ET AL

Table 4: Mean Percentage Contribution (Standard Deviation) of Nutrients to Total

Energy Intake in Present Study and in a Survey of 181 Healthy 50- to 54-Year-Old Individuals in

New Zealand

Paulin Paulin Present et al (9) et al (9) Study (Men) (Women)

Population RA Normal Normal

Protein % 17 (3.1) 15 16

Fat% 31 (5.1) 38 39

Carbohydrate % 50 (6.7) 42 43

Alcohol % 1 (2.2) 5 2

Analysis of fats

Polyunsaturated 5 (5.2) 5 4

Monounsaturated 11 (2.7) 15 16

Saturated 16 (6.3) 18 18

Data from Paulin et al (9). Abbreviation: RA, rheumatoid arthritis.

populations ranging from 671 mg (12) to 761 mg (11), comparable to our own result of 641 nag. The RDI of calcium remains under debate with some authors suggesting values of 1,200 nag for perimeno- pausal women aged 35 to 50 years and 1,500 mg for postmenopausal women (14). Prospective fol- low-up studies are needed to determine whether adequate calcium intake may be more important in preventing osteoporosis in patients with RA than in the general population.

The high salt intake in our population may exacerbate calcium deficiency at the proximal tubule, where sodium and calcium absorption are linked. Although not specifically studied, many disabled people rely heavily on prepackaged food and meals, much of which is high in sodium.

Folic Acid

Low serum folic acid levels in RA patients have been reported previously (1,3), and such patients may be particularly susceptible to methotrexate toxicity (15). Patients in this study on methotrexate had a significantly lower intake of dietary folic acid than those on other therapies, highlighting the need to consider supplementation in this group. Foods high in folic acid, such as green leafy vegetables, take time and effort to prepare, which can be a disincentive to people with disability. However, we did not find a statistical relationship between physi- cal function, disease activity, and folic acid intake.

Vitamin E

Vitamin E is a biological antioxidant that may play a role in controlling chronic inflammation of any cause. To our knowledge, there have been no placebo-controlled trials of vitamin E supplementa- tion in RA. A supplementation trial in RA with another antioxidant, vitamin C, failed to show an effect on clinical course (16) although a low combined serum antioxidant level (vitamin E, beta-carotene, and selenium) may be a risk factor for RA (17).

Z/nc

Low levels of zinc intake in this study are similar to those found previously (13, 16). Zinc is a component of 200 enzymes in the body and is essential for the maintenance of the immune sys- tem. Low serum concentrations of zinc in RA patients have been shown on numerous occasions (1, 5). This may be explained partly by hypoalbu- minemia, the use of corticosteroids and nonsteroi- dal antiinflammatory drugs (18), or may be a nonspecific feature of inflammation. Serum zinc has been inversely related to the ESR. Trials of zinc supplementation in RA have been disappointing, but supranormal doses were given (19-22). No data exist on supplementing a group of zinc-deficient patients with RA up to the RDI.

Selenium

To our knowledge, dietary intake of selenium, as opposed to serum estimation, has not previously been studied in RA. Selenium intake in our popula- tion was the lowest of any of the dietary constitu- ents measured. In large part this may be because of the low environmental availability of selenium in New Zealand, which was taken into account by the dietary analysis. However, countries in the Euro- pean Union are also experiencing a reduction in environmental selenium and in imported selenium- rich flour from the United States, which may be contributing to cardiovascular disease and subfertit- ity (23). Mean daily selenium intake in the United Kingdom has recently been estimated at 34 ~g (24), similar to the value of 36 lag found in this study. Selenium is necessary for the production of the antioxidant glutathione peroxidase enzymes, and there is considerable recent interest in the role these may play in the pathogenesis of arthritis. Kashin-

RESULTS OF A DIETARY SURVEY IN RA PATIENTS 185

Beck disease, an endemic arthritis producing epiphyseal and metaphyseal dysplasia, occurs in selenium-deficient regions in China and Russia. Low serum selenium has been found in several studies on RA patients, even in areas with a high environmental selenium, but there have been con- flicting reports of the antiarthritic effects of supple- mentation (25, 26). This may relate either to a decreased ability in RA patients to synthesize glutathione peroxidase de novo in polymorpho- nuclear lymphocytes (27) or may depend on the population studied. Peretz et al (26) proposed that patients with recent-onset RA may respond better to selenium supplementation.

SUMMARY

Calcium, folic acid, vitamin E, zinc, and sele- nium have significant putative roles in influencing the onset, course, and limitation of drug toxicity in RA. Even in the absence of large-scale double- blind placebo trials on supplementation, patients with RA should consume the RDI of these constitu- ents. Clinicians should be aware that RA patients likely are consuming inadequate amounts of these nutrients and that specific action such as oral supplementation to reach the RDI, patient educa- tion, or liaison with dietetic services may produce significant long-term benefits.

REFERENCES 1. Helliwell M, Coombes EJ, Moody B J, et al. Nutritional

status in patients with rheumatoid arthritis. Ann Rheum Dis 1984;43:386-90.

2. Rayan GM, McCormack ST, Hoelzer DJ, et al. Nutrition and the rheumatoid hand patient. J Okla State Med Assoc 1989;82:505-9.

3. Gough KR, McCarthy C, Read AE, et al. Folic acid deficiency in rheumatoid arthritis. Br Med J 1964; 1:212-7.

4. Maddison PJ, Bacon PA. Vitamin D deficiency, spontane- ous fractures and osteopenia in rheumatoid arthritis. Br Med J 1974;4:433-5.

5. Balogh Z, E1-Ghobarey AF, Fell GS, et al. Plasma zinc and its relationship to clinical symptoms and drug U-eatment in rheumatoid arthritis. Ann Rheum Dis 1980;39:329-32.

6. Peretz A, Neve J, Vertongen E et al. Selenium status in relation to clinical variables and corticosteroid treatment in rheumatoid arthritis. J Rheumatol 1987; 14:1104-7.

7. Trnswell AS, Dreosti IE, English RM, et al. Recom- mended nutrient intakes. Australian papers. Sydney: Australian Professional Publishers, 1990.

8. The New Zealand Food Composition Database. Diet/One Nutrient calculation software version 4, OCNZ96 © Xyris software. New Zealand Institute of Crop and Food Research, Palmerston North, New Zealand, 1996.

9. Paulin JM, McNab IM, Simpson FO, et al. What do middle-aged New Zealanders eat? A dietary survey in 50-54 year olds in South Canterbury and North Otago. N Z Med J 1993;101:159-62.

10. DarIington LG, Ramsey NW. Review of dietary therapy for rheumatoid arthritis. Br J Rheumatol 1993;32:507-14.

1I. Eising L. Dietary intake in patients with amhfitis and other chronic diseases. B one Joint Surg 1963 ;45:62-9.

12. Kowsari B, Finnie SK, Carter RL, et al. Assessment of the diet of patients with rheumatoid arthritis and osteoarthritis, j Am Diet Assoc 1983;82:657-9.

13. Kremer JM, Bigaouette J. Nutrient intake of patients with rheumatoid arthritis is deficient in pyridoxine, zinc, copper and magnesium. J Rheumatol 1996;23:6.

14. Heaney RP, Recker RR, Saville PD. Menopausal changes in calcium balance performance. J Lab Clin Med 1978;92:953.

15. Morgan SL, Baggott JE, Vaugh WH, et al. The effect of folic acid supplementation on the toxicity of low-dose methotrex- ate in patients with rheumatoid arthritis. Arthritis Rheum 1990;33:9-18.

16. Hall MG, Darling RC, Taylor FHC. The vitamin C requirement in rheumatoid arthritis. Ann Intern Med 1939;13: 415.

17. Heli6vaara M, Knekt R Aho K, et al. Serum antioxidants and risk of arthritis. Ann Rheum Dis 1994;53:51-3.

18. Milanino R, Frigo A, Bambara LM, et al. Copper and zinc status in rheumatoid arthritis: Studies of plasma, erythro- cytes and urine and their relationship to disease markers and pharmacological treatment. C!in Exp Rheumatol 1993;1l: 271-8I.

19. Simkin PA. Oral zinc sulphate in rheumatoid arthritis. Lancet 1976;ii:539-42.

20. Job C, Menkes CJ, Delbarre E Zinc sulfate in the treatment of rheumatoid arthritis. Arthritis Rheum 1980;23: 1408-9.

21. Rasker JJ, Kardaun SH. Lack of beneficial effect of zinc sulfate in rheumatoid arthritis. Scand J Rheumatol 1982; 11:168.

22. Mattingly PC, Mowat AG. Zinc sulphate in rheumatoid arthritis. Ann Rheum Dis 1982;41:456-7.

23. Rayman MR Dietary Selenium: Time to act. BMJ 1997;314:387-8.

24. Barclay MNI, MacphersonA, Dixon J. Selenium content of a range of UK foods. J Food Comp Anal 1995;8:307-18.

25. Tarp U, Overvad K, Thorling EB, et al. Selenium treatment in rheumatoid arthritis. Scand J RheumatoI 1985;30: 1162-6.

26. Peretz A, Neve J, Duchateau J, et al. Adjuvant treatment of recent onset rheumatoid arthritis by selenium supplementa- tion: Preliminary observations. Br J Rheumatol 1992;31:281-2.

27. Tarp U, Stengaard-Pedersen K, Hansen JC, Thorling EB. Glutathione redox cycle enzymes and selenium in severe rheumatoid arthritis: Lack of antioxidative responsive to sele- nium supplementation in polymorphonuclear lymphocytes. Ann Rheum Dis 1992;51:1044-9.