Omega-3 Polyunsaturated Fatty Acids and the Treatment of Rheumatoid Arthritis: A Meta-analysis

doi:10.1016/j.arcmed.2012.06.011

Archives of Medical Research

Volume 43, Issue 5, July 2012, Pages 356-362

https://doi.org/10.1016/j.arcmed.2012.06.011 Get rights and content

Background and Aims

We undertook this study to assess the effects of omega-3 polyunsaturated fatty acids (PUFAs) (administered at ≥2.7 g/day) for a minimum duration of 3 months on clinical outcomes in patients with rheumatoid arthritis (RA).

Methods

The authors surveyed randomized controlled trials (RCTs) that examined the effects of omega-3 PUFAs on clinical outcomes in RA patients using Medline and the Cochrane Controlled Trials Register and by performing manual searches. Meta-analysis of RCTs was performed using fixed and random effects models. Outcomes are presented as standardized mean differences (SMD).

Results

Ten RCTs involving 183 RA patients and 187 placebo-treated RA controls were included in this meta-analysis. The analysis showed that omega-3 PUFAs clearly reduced nonsteroidal anti-inflammatory drug (NSAID) consumption (SMD −0.518, 95% CI −0.915 to −0.121, p = 0.011) without between-study heterogeneity (I² = 0%). Tender joint count (SMD −0.214, 95% CI−0.489–0.062, p = 0.128), swollen joint count (SMD −0.170, 95% CI−0.454–0.114, p = 0.241), morning stiffness (SMD −0.224, 95% CI−0.955–0.212, p = 0.221), and physical function (SMD 0.264, 95% CI−0.232–0.724, p = 0.314) showed a trend to improve more in patients treated with omega-3 PUFAs than in placebo-treated controls, but they did not reach statistical significance.

Conclusions

This meta-analysis suggests that the use of omega-3 PUFAs at dosages >2.7 g/day for >3 months reduces NSAID consumption by RA patients. Further studies are needed to explore the clinical and NSAID-sparing effects of omega-3 PUFAs in RA.

Introduction

Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by chronic inflammation of synovial joints and leads to disability and loss of quality of life. RA inflammation results in joint pain, tenderness, and swelling (1). These symptoms are to some extent due to the local productions of pro-inflammatory eicosanoids such as prostaglandin E₂ (PGE₂) and leukotriene B₄ (LTB₄) (2). PGE₂ and LTB₄ are products of arachidonic acid (AA) and other omega-6 polyunsaturated fatty acids (PUFAs) may be converted to AA. AA is the main omega-6 PUFA that can be metabolized into PGE₂ and LTB₄ by cyclooxygenase (COX) or lipoxygenase (LOX). PGE₂ results in swelling and hyperalgesia. Nonsteroidal anti-inflammatory drugs (NSAIDs) are used to decrease pain and inflammation in RA patients (3). These agents exert their analgesic effects by inhibiting COX. LTB₄ is formed from AA by 5-lipoxygenase and is a chemoattractant and activator of neutrophils; thus, they are an essential contributor to inflammatory arthritis (4). Because decreased AA production causes reductions in PGE₂ and LTB₄, AA concentration is an important factor in the synthesis of both PGE₂ and LTB₄.

Dietary omega-3 PUFAs, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) originate from fish oils but algae are the primary source of these PUFAs (5). A reduction of AA intake by meat or sausage also resulted in a higher benefit of omega-3 PUFAs; therefore, the evaluation of AA concentrations in human tissues, especially membranes, is important. Fish oil is a rich source of long-chain omega-3 PUFAs, containing 18% EPA and 12% DHA derived from marine fish (5). EPA and DHA inhibit activation of the nuclear factor κB (NF-κB) and release of interleukin-1 beta (IL-1β) and tumor necrosis factor α (TNF- α) 6, 7.

It has been suggested that the symptomatic benefit of a daily omega-3 PUFA intake of >2.7 g/day can be delayed and take 2–3 months, and a daily omega-3 PUFA intake of >2.7 g/day is required to achieve anti-inflammatory effects (8). The effects of omega-3 PUFAs have been studied in RA 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, but the effects of omega-3 PUFAs on clinical outcomes are controversial, which may be due to the small sample sizes and low statistical power of the studies conducted. Meta-analysis is a statistical procedure that involves combining the results of several studies to produce a single estimate of a major effect with enhanced precision 19, 20, 21. The major advantage of meta-analysis is that it increases sample size, which possibly reduces the likelihood that random error will produce false-positive or -negative associations (22). Thus, the aim of the present study was to investigate, using a meta-analysis approach, the effects of a daily omega-3 PUFA intake of >2.7 g/day for ≥3 months on clinical outcomes in patients with RA.

Section snippets

Identification of Eligible Studies and Data Extraction

We performed an exhaustive search for studies that examined the effects of omega-3 PUFAs on clinical outcomes in RA patients. Literature searches were carried out using MEDLINE and the Cochrane Controlled Trials Register to identify available articles (up to December 2011). The following key words and subject terms were used in the searches: omega-3, fish oil, polyunsaturated fatty acids, PUFAs, rheumatoid arthritis, and RA. In addition, all references in the studies were reviewed to identify

Studies Included in the Meta-analysis

Thirty three studies were identified by electronic or manual search and 14 were selected for full-text review based on title and abstract contents 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 29, 30, 31, 32. However, four of the 14 studies were excluded due to use of low omega-3 PUFA dosages 29, 30, 31 or short-term follow-up (32). Thus, ten studies met the inclusion criteria 9, 10, 11, 12, 13, 14, 15, 16, 17, 18. These ten studies involved a total of 183 patients and 187 controls. Relevant features

Discussion

In the present meta-analysis, we combined the clinical data of ten randomized controlled trials, which included 183 patients and 187 controls. Omega-3 PUFAs were not found to improve clinical outcome measures except for NSAID consumption. Meta-analysis revealed a tendency toward tender joint count, swollen joint count, morning stiffness, and physical function improvements in the omega-3 PUFAs group, but differences did not reach statistical significance. Nevertheless, NSAID requirements were

Acknowledgments

This study was supported by a grant from the Korea Healthcare Technology R&D Project, Ministry of Health and Welfare, Republic of Korea (A102065).

Conflict of interest statement: The authors have no financial or nonfinancial conflicts of interest to declare.

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Original ArticleClinicalOmega-3 Polyunsaturated Fatty Acids and the Treatment of Rheumatoid Arthritis: A Meta-analysis

Background and Aims

Methods

Results

Conclusions

Introduction

Section snippets

Identification of Eligible Studies and Data Extraction

Studies Included in the Meta-analysis

Discussion

Acknowledgments

Am J Clin Nutr

Pain

Nutrition

Control Clin Trials

Clin Ther

Control Clin Trials

Gastroenterology

J Nutr Biochem

J Clin Epidemiol

Semin Arthritis Rheum

Induction of macrophage migration inhibitory factor in ConA-stimulated rheumatoid arthritis synovial fibroblasts through the P38 map kinase-dependent signaling pathway

Korean J Intern Med

Pharmacological analysis of cyclooxygenase-1 in inflammation

Proc Natl Acad Sci USA

Pain management today—what have we learned?

Clin Rheumatol

Neutrophil-derived leukotriene B4 is required for inflammatory arthritis

J Exp Med

Fish oil: what the prescriber needs to know

Arthritis Res Ther

NF-kappa B inhibition by omega -3 fatty acids modulates LPS-stimulated macrophage TNF-alpha transcription

Am J Physiol Lung Cell Mol Physiol

Effects of n-3 fatty acids on serum interleukin-6, tumour necrosis factor-alpha and soluble tumour necrosis factor receptor p55 in active rheumatoid arthritis

J Int Med Res

Alpha-linolenic acid in the treatment of rheumatoid arthritis. A double-blind, placebo-controlled and randomized study: flaxseed vs. safflower seed

Rheumatol Int

Effects of fish oil supplementation on non-steroidal anti-inflammatory drug requirement in patients with mild rheumatoid arthritis—a double-blind placebo controlled study

Br J Rheumatol

The effects of dietary supplementation with n-3 polyunsaturated fatty acids in patients with rheumatoid arthritis: a randomized, double blind trial

Eur J Clin Invest

Original Article
Clinical
Omega-3 Polyunsaturated Fatty Acids and the Treatment of Rheumatoid Arthritis: A Meta-analysis