Mediterranean Diet and Risk of Rheumatoid Arthritis

A Population-Based Case-Control Study

Kari Johansson; Johan Askling; Lars Alfredsson; Daniela Di Giuseppe; on behalf of the EIRA study group

Arthritis Res Ther. 2018;20(175)

Abstract and Introduction

Abstract

Background: The Mediterranean diet has been associated with lower mortality and lower risk of cardiovascular diseases and cancer. Although its components have been analysed in several studies, only one study has specifically investigated the association between Mediterranean diet and risk of rheumatoid arthritis (RA), and reported no association.

Methods: Data on 1721 patients with incident RA (cases) and 3667 controls, matched on age, gender and residential area, from the Swedish epidemiological investigation of RA (EIRA), a population-based case-control study, were analysed using conditional logistic regression. The Mediterranean diet score, ranging from 0 to 9, was calculated from a 124-item food frequency questionnaire.

Results: In the EIRA study (median age of participants 53 years), 24.1% of the patients and 28.2% of the controls had high adherence to the Mediterranean diet (a score between 6 and 9). After adjustments for body mass index, educational level, physical activity, use of dietary supplements, energy intake, and smoking, high adherence reduced the odds of developing RA by 21% (OR 0.79; 95% CI 0.65–0.96) as compared to low adherence (a score between 0 and 2). The OR was even lower among men (OR 0.49; 95% CI 0.33–0.73), but no significant association was found among women (OR 0.94; 95% CI 0.74–1.18). An association between high diet score and low risk of RA was observed in rheumatoid factor (RF)-positive (OR 0.69; 95% CI 0.54–0.88), but not RF-negative RA (OR 0.96; 95% CI 0.68–1.34), and in RA characterised by presence of antibodies to citrullinated peptides (ACPA), but not in ACPA-negative RA.

Conclusions: In this large population-based case-control study, the Mediterranean diet score was inversely associated with risk of RA. However, an association was only found among men and only in seropositive RA.

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Arthritis Res Ther. 2018;20(175) © 2018 BioMed Central, Ltd.
Copyright to this article is held by the author(s), licensee BioMed Central Ltd. This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the article's original citation.

Abstract and Introduction
Background
Methods
Results
Discussion
Conclusion
References

Table 1. Baseline characteristics of patients with RA (cases, n = 1721) and controls ( n = 3667) in the EIRA study, overall and by categories of the Mediterranean diet score as defined according to Trichopoulou et al. [17]
Med score	RA cases					Controls
Med score	Overall	0–2	3	4–5	6–9	Overall	0–2	3	4–5	6–9
Number	1721	351	327	629	414	3667	574	636	1424	1033
Female, n (%)	1251 (72.7)	228 (65.0)	242 (74.0)	458 (72.8)	323 (78.0)	2647 (72.2)	411 (71.6)	441 (69.3)	1026 (72.1)	769 (74.4)
Age, mean (std)	53.4 (13.5)	53.1 (14.5)	52.2 (14.3)	53.1 (13.6)	55.2 (11.4)	53.3 (13.3)	51.1 (14.8)	53.2 (13.6)	53.5 (13.0)	54.5 (12.6)
Current smoking, n (%)	409 (23.8)	125 (35.6)	92 (28.1)	132 (20.0)	60 (14.5)	543 (14.8)	122 (21.3)	116 (18.2)	210 (14.8)	95 (9.2)
Sedentary physical activity, n (%)	317 (18.4)	78 (22.2)	79 (24.2)	109 (17.3)	51 (12.3)	458 (12.5)	110 (19.2)	94 (14.8)	161 (11.3)	93 (9.0)
Education > 12 years, n (%)	955 (55.5)	150 (42.7)	176 (53.8)	345 (54.9)	284 (68.6)	2161 (58.9)	279 (48.6)	336 (52.8)	859 (60.3)	687 (66.5)
BMI, mean (std)	25.7 (4.6)	25.5 (4.9)	25.6 (4.3)	26.1 (4.7)	25.3 (4.5)	25.4 (5.0)	25.6 (4.8)	25.6 (4.2)	25.5 (4.2)	25.1 (6.4)
Use of supplements, n (%)	858 (50.1)	153 (44.1)	146 (44.8)	316 (50.3)	243 (58.8)	1616 (44.4)	214 (37.7)	260 (41.1)	624 (44.1)	518 (50.5)
Total energy intake, mean kcal/day (std)	1924 (735)	1848 (721)	1829 (730)	1949 (824)	2025 (574)	1897 (719)	1770 (763)	1776 (684)	1892 (743)	2048 (652)
Vegetables, servings/day (std)	3.07 (2.00)	1.60 (0.99)	2.41 (1.57)	3.26 (1.80)	4.53 (2.12)	3.22 (2.24)	1.78 (1.17)	2.25 (1.59)	3.22 (2.16)	4.61 (2.31)
Legumes, servings/day (std)	0.22 (0.26)	0.10 (0.14)	0.14 (0.15)	0.23 (0.24)	0.38 (0.33)	0.24 (0.31)	0.09 (0.09)	0.13 (0.16)	0.23 (0.27)	0.41 (0.41)
Fruit and nuts, servings/day (std)	1.57 (1.39)	0.76 (0.70)	1.11 (1.16)	1.61 (1.23)	2.53 (1.62)	1.67 (1.42)	0.82 (0.77)	1.15 (1.06)	1.69 (1.43)	2.42 (1.49)
Cereals, servings/day (std)	2.78 (1.90)	2.04 (1.76)	2.63 (1.88)	2.90 (1.91)	3.36 (1.79)	2.72 (1.83)	2.01 (1.71)	2.48 (1.86)	2.73 (1.82)	3.23 (1.73)
Fish, servings/day (std)	0.48 (0.44)	0.28 (0.16)	0.36 (0.23)	0.51 (0.61)	0.68 (0.33)	0.49 (0.38)	0.28 (0.20)	0.36 (0.23)	0.47 (0.39)	0.69 (0.40)
Meat, servings/day (std)	1.28 (0.73)	1.24 (0.72)	1.28 (0.66)	1.31 (0.75)	1.25 (0.75)	1.28 (0.83)	1.28 (0.72)	1.25 (0.74)	1.33 (0.96)	1.25 (0.74)
Dairy products, servings/day (std)	3.30 (2.49)	4.63 (2.35)	3.57 (2.48)	3.15 (2.48)	2.20 (2.03)	3.03 (2.41)	4.32 (2.39)	3.58 (2.62)	2.90 (2.31)	2.16 (1.98)
Alcohol, g/day (std)	7.06 (7.95)	5.15 (7.94)	6.98 (8.28)	7.28 (7.97)	8.38 (7.37)	8.48 (8.70)	6.20 (9.28)	7.95 (9.27)	8.54 (8.60)	9.94 (7.85)
Monoansaturated to saturated fat ratio (std)	0.78 (0.14)	0.69 (0.09)	0.74 (0.12)	0.80 (0.14)	0.86 (0.15)	0.79 (0.15)	0.70 (0.10)	0.74 (0.13)	0.80 (0.14)	0.87 (0.15)

RA rheumatoid arthritis, Med score Mediterranean diet score, std standard deviation, BMI body mass index

Table 2. Odds ratios of rheumatoid arthritis by categories of the Mediterranean diet score among participants of the EIRA study ( n = 1721 patients with RA (cases) and n = 3667 controls)
	Mediterranean-diet score
	0–2	3	4–5	6–9
Overall
Number	351/574	327/636	629/1424	414/1033
OR crude	Ref	0.87 (0.71–1.05)	0.74 (0.62–0.87)	0.66 (0.55–0.79)
OR adjusted	Ref	0.93 (0.76–1.14)	0.83 (0.69–0.99)	0.79 (0.65–0.96)
Female
Number	228/411	242/441	458/1026	323/769
OR crude	Ref	1.01 (0.80–1.28)	0.81 (0.66–0.99)	0.77 (0.62–0.95)
OR adjusted	Ref	1.09 (0.85–1.39)	0.92 (0.75–1.14)	0.94 (0.74–1.18)
OR adjusted 2	Ref	1.07 (0.84–1.37)	0.91 (0.73–1.12)	0.94 (0.74–1.18)
Male
Number	123/167	84/195	171/398	91/264
OR crude	Ref	0.61 (0.43–0.87)	0.59 (0.43–0.80)	0.45 (0.32–0.64)
OR adjusted	Ref	0.65 (0.45–0.95)	0.62 (0.45–0.87)	0.49 (0.33–0.73)
RF positive
Numbe	238/327	232/356	401/841	248/627
OR crude	Ref	0.90 (0.70–1.14)	0.66 (0.54–0.81)	0.55 (0.44–0.69)
OR adjusted	Ref	0.97 (0.75–1.25)	0.76 (0.61–0.95)	0.69 (0.54–0.88)
RF negative
Number	113/184	90/205	226/422	163/307
OR crude	Ref	0.77 (0.55–1.08)	0.91 (0.68–1.21)	0.89 (0.66–1.21)
OR adjusted	Ref	0.80 (0.56–1.14)	0.93 (0.68–1.27)	0.96 (0.68–1.34)
ACPA positive
Number	247/343	240/387	424/863	264/646
OR crude	Ref	0.87 (0.69–1.10)	0.68 (0.56–0.83)	0.58 (0.47–0.72)
OR adjusted	Ref	0.95 (0.74–1.21)	0.78 (0.63–0.97)	0.72 (0.57–0.92)
ACPA negative
Number	103/170	84/176	203/403	149/279
OR crude	Ref	0.84 (0.58–1.20)	0.88 (0.65–1.19)	0.91 (0.66–1.26)
OR adjusted	Ref	0.89 (0.61–1.30)	0.93 (0.67–1.29)	1.00 (0.70–1.42)

Odds ratio (OR) crude was conditioned on age, gender and residential area. OR adjusted was adjusted for smoking, physical activity, education level, body mass index, energy intake and supplements use. OR adjusted 2 was additionally adjusted for parity, use of oral contraceptive, use of hormone replacement therapy and age at menarche
RA rheumatoid arthritis, ACPA antibodies to citrullinated peptides, Ref reference

Table 3. Odds ratios for rheumatoid arthritis (RA) by categories of the Mediterranean diet score among participant in the EIRA study who were current smokers and carrying at least one HLA-DRB1 shared epitope allele ( n = 266 patients with RA (cases) and n = 121 controls)
	Mediterranean diet score
	0–2	3	4–5	6–9
Overall
Number	83/23	61/29	79/48	43/21
OR crude	Ref	0.61 (0.31–1.18)	0.45 (0.25–0.83)	0.57 (0.27–1.18)
OR adj usted	Ref	0.61 (0.31–1.22)	0.53 (0.28–1.02)	0.63 (0.28–1.37)

Table S1. Baseline characteristics of female cases (n=1251) and controls (n=2647) participating to the EIRA study, by categories of the Mediterranean-diet score.
	RA cases				Controls
Med Score	0–2	3	4–5	6–9	0–2	3	4–5	6–9
N	228	242	458	323	411	441	1026	769
Vegetables, servings/day	1.75 (1.02)	2.60 (1.59)	3.44 (1.75)	4.80 (2.17)	1.92 (1.13)	2.45 (1.71)	3.40 (2.18)	4.96 (2.43)
Legumes, servings/day	0.09 (0.14)	0.13 (0.13)	0.24 (0.25)	0.40 (0.35)	0.09 (0.09)	0.13 (0.16)	0.23 (0.28)	0.43 (0.44)
Fruit and nuts, servings/day	0.85 (0.72)	1.18 (1.02)	1.73 (1.29)	2.72 (1.58)	0.93 (0.82)	1.30 (1.13)	1.82 (1.43)	2.63 (1.51)
Cereals, servings/day	2.04 (1.63)	2.47 (1.65)	2.75 (1.72)	3.12 (1.58)	2.02 (1.62)	2.40 (1.73)	2.61 (1.67)	3.09 (1.60)
Fish, servings/day	0.29 (0.17)	0.39 (0.23)	0.50 (0.31)	0.68 (0.31)	0.29 (0.21)	0.39 (0.24)	0.48 (0.32)	0.70 (0.41)
Meat, servings/day	1.20 (0.71)	1.24 (0.65)	1.25 (0.73)	1.23 (0.76)	1.24 (0.66)	1.21 (0.72)	1.26 (0.71)	1.19 (0.72)
Dairy products, servings/day	4.44 (2.19)	3.36 (2.39)	3.05 (2.40)	2.25 (2.10)	4.33 (2.35)	3.57 (2.56)	2.85 (2.29)	2.15 (1.96)
Alcohol, g/day	4.35 (7.08)	6.52 (8.26)	6.43 (7.32)	7.45 (6.53)	5.70 (9.37)	7.19 (8.92)	7.62 (7.86)	9.00 (7.02)
Monoansaturated to saturated fat ratio	0.69 (0.09)	0.74 (0.12)	0.79 (0.14)	0.86 (0.15)	0.68 (0.09)	0.74 (0.13)	0.79 (0.14)	0.87 (0.16)

Table S2. Baseline characteristics of male cases (n=470) and controls (n=1020) participating to the EIRA study, by categories of the Mediterranean-diet score.
	RA cases				Controls
Med Score	0–2	3	4–5	6–9	0–2	3	4–5	6–9
N	123	85	171	91	163	195	398	264
Vegetables, servings/day	1.32 (0.87)	1.85 (1.36)	2.77 (1.86)	3.58 (1.63)	1.43 (1.19)	1.78 (1.14)	2.75 (2.03)	3.61 (1.53)
Legumes, servings/day	0.10 (0.13)	0.15 (0.20)	0.19 (0.22)	0.32 (0.25)	0.08 (0.08)	0.12 (0.16)	0.20 (0.25)	0.34 (0.30)
Fruit and nuts, servings/day	0.59 (0.63)	0.93 (1.49)	1.29 (0.96)	1.89 (1.61)	0.56 (0.54)	0.81 (0.80)	1.35 (1.36)	1.83 (1.23)
Cereals, servings/day	2.03 (1.99)	3.07 (2.37)	3.32 (2.30)	4.18 (2.20)	2.00 (1.92)	2.67 (2.13)	3.05 (2.13)	3.67 (2.00)
Fish, servings/day	0.25 (0.15)	0.29 (0.18)	0.53 (1.04)	0.69 (0.40)	0.23 (0.15)	0.31 (0.18)	0.46 (0.54)	0.67 (0.36)
Meat, servings/day	1.32 (0.75)	1.39 (0.70)	1.47 (0.80)	1.29 (0.71)	1.38 (0.85)	1.35 (0.79)	1.50 (1.39)	1.42 (0.77)
Dairy products, servings/day	4.98 (2.59)	4.17 (2.65)	3.42 (2.67)	2.01 (1.79)	4.28 (2.49)	3.60 (2.76)	3.04 (2.35)	2.16 (2.04)
Alcohol, g/day	6.60 (9.18)	8.26 (8.25)	9.61 (9.15)	11.67 (9.10)	7.49 (8.95)	9.66 (9.83)	10.93 (9.89)	12.71 (9.36)
Monoansaturated to saturated fat ratio	0.71 (0.09)	0.77 (0.12)	0.82 (0.13)	0.87 (0.15)	0.72 (0.11)	0.76 (0.12)	0.82 (0.13)	0.87 (0.12)

Table S3. Baseline characteristics of RA cases with (n=1119) or without (n=592) rheumatoid factor (RF) participating to the EIRA study, by categories of the Mediterranean-diet score.
	RF positive							RF negative
Med Score	0–2		3		4–5		6–9	0–2	3	4–5	6–9
N	238	232		401		248		113	90	226	163
Vegetables, servings/day	1.65 (0.97)	2.44 (1.61)		3.29 (1.84)		4.45 (2.06)		1.51 (1.03)	2.33 (1.49)	3.19 (1.73)	4.67 (2.23)
Legumes, servings/day	0.10 (0.15)	0.14 (0.14)		0.23 (0.24)		0.39 (0.30)		0.08 (0.10)	0.14 (0.19)	0.22 (0.25)	0.37 (0.37)
Fruit and nuts, servings/day	0.76 (0.70)	1.11 (1.00)		1.62 (1.19)		2.46 (1.49)		0.75 (0.72)	1.13 (1.53)	1.59 (1.29)	2.67 (1.79)
Cereals, servings/day	2.06 (1.75)	2.81 (1.93)		2.81 (1.90)		3.35 (1.75)		2.00 (1.77)	2.26 (1.66)	3.07 (1.92)	3.37 (1.87)
Fish, servings/day	0.27 (0.17)	0.37 (0.22)		0.50 (0.72)		0.67 (0.32)		0.28 (0.15)	0.35 (0.24)	0.52 (0.33)	0.71 (0.35)
Meat, servings/day	1.27 (0.75)	1.29 (0.70)		1.31 (0.80)		1.30 (0.78)		1.19 (0.65)	1.25 (0.60)	1.32 (0.66)	1.16 (0.70)
Dairy products, servings/day	4.57 (2.48)	3.70 (2.47)		3.07 (2.50)		2.05 (1.90)		4.74 (2.05)	3.23 (2.52)	3.29 (2.44)	2.42 (2.21)
Alcohol, g/day	4.60 (7.06)	6.45 (7.41)		7.27 (8.08)		7.65 (6.60)		6.25 (9.43)	8.15 (10.23)	7.32 (7.80)	9.25 (8.22)
Monoansaturated to saturated fat ratio	0.70 (0.09)	0.74 (0.12)		0.79 (0.13)		0.87 (0.15)		0.69 (0.09)	0.76 (0.13)	0.80 (0.14)	0.85 (0.16)

Table S4. Baseline characteristics of RA cases with (n=1173) or without (n=538) anti-citrullinated protein (ACPA) participating to the EIRA study, by categories of the Mediterranean-diet score.
	ACPA positive							ACPA negative
Med Score	0–2		3		4–5		6–9	0–2	3	4–5	6–9
N	246	240		423		264		103	84	203	148
Vegetables, servings/day	1.57 (0.96)	2.41 (1.57)		3.26 (1.83)		4.46 (2.06)		1.68 (1.05)	2.41 (1.59)	3.25 (1.74)	4.65 (2.23)
Legumes, servings/day	0.10 (0.14)	0.14 (0.16)		0.24 (0.25)		0.38 (0.28)		0.09 (0.13)	0.13 (0.12)	0.21 (0.22)	0.37 (0.40)
Fruit and nuts, servings/day	0.72 (0.58)	1.03 (0.91)		1.63 (1.29)		2.50 (1.63)		0.86 (0.93)	1.36 (1.68)	1.58 (1.10)	2.59 (1.60)
Cereals, servings/day	2.04 (1.79)	2.60 (1.89)		2.81 (1.88)		3.37 (1.78)		2.07 (1.68)	2.71 (1.84)	3.11 (1.96)	3.34 (1.82)
Fish, servings/day	0.27 (0.17)	0.37 (0.22)		0.51 (0.71)		0.67 (0.32)		0.29 (0.15)	0.35 (0.25)	0.50 (0.29)	0.70 (0.36)
Meat, servings/day	1.28 (0.78)	1.30 (0.69)		1.26 (0.77)		1.27 (0.74)		1.17 (0.58)	1.21 (0.60)	1.41 (0.70)	1.21 (0.77)
Dairy products, servings/day	4.67 (2.51)	3.53 (2.47)		3.08 (2.47)		2.15 (1.91)		4.55 (1.91)	3.73 (2.54)	3.28 (2.50)	2.23 (2.23)
Alcohol, g/day	4.82 (7.11)	6.86 (8.44)		6.93 (7.60)		7.70 (6.19)		5.88 (9.66)	7.19 (7.91)	8.03 (8.69)	9.67 (9.00)
Monoansaturated to saturated fat ratio	0.70 (0.09)	0.74 (0.12)		0.79 (0.13)		0.87 (0.15)		0.69 (0.09)	0.74 (0.12)	0.80 (0.14)	0.86 (0.15)

Table S5. Odds ratios of rheumatoid arthritis by categories of the Mediterranean-diet score among participant of the EIRA study, stratified by smoking status (RA cases n=1594, Controls n=3367)
		Mediterranean-diet score
		0–2	3	4–5	6–9
Never smokers
	N	106/253	110/296	229/716	160/522
	OR adjusted	Ref	0.91 (0.66–1.26)	0.80 (0.61–1.06)	0.76 (0.56–1.03)
Current smokers
	N	125/122	92/116	132/210	60/95
	OR adjusted	Ref	0.76 (0.52–1.11)	0.63 (0.45–0.60)	0.62 (0.40–0.95)
Former smokers
	N	98/142	99/181	228/401	155/313
	OR adjusted	Ref	0.85 (0.59–1.23)	0.88 (0.64–1.21)	0.79 (0.56–1.10)

Table S6. Odds ratios of rheumatoid arthritis by categories of the Mediterranean-diet score among participant of the EIRA study, stratified by HLA-DRB1 shared epitope allele (SE)RA cases n=1426, Controls n=1559)
		Mediterranean-diet score
		0–2	3	4–5	6–9
With SE
	N	226/104	204/141	357/319	257/270
	OR adjusted	Ref	0.71 (0.51–0.99)	0.59 (0.44–0.79)	0.60 (0.44–0.82)
Without SE
	N	65/98	70/129	149/279	98/219
	OR adjusted	Ref	0.92 (0.59–1.44)	1.01 (0.68–1.50)	0.90 (0.59–1.39)