Fish oil in knee osteoarthritis: a randomised clinical trial of low dose versus high dose.

OBJECTIVES: To determine whether high-dose fish oil is superior to low-dose supplementation for symptomatic and structural outcomes in knee osteoarthritis (OA). METHODS: A randomised, double-blind, multicentre trial enrolled 202 patients with knee OA and regular knee pain. They were randomised 1:1 to high-dose fish oil (4.5 g omega-3 fatty acids) 15 mL/day or (2) low-dose fish oil (blend of fish oil and sunola oil; ratio of 1:9, 0.45 g omega-3 fatty acids) 15 mL/day. The primary endpoints were Western Ontario and McMaster Universities Arthritis Index (WOMAC) pain score at 3, 6, 12 and 24 months, and change in cartilage volume at 24 months. Secondary outcomes included WOMAC function, quality of life, analgesic and non-steroidal anti-inflammatory drug use and bone marrow lesion score. RESULTS: Although there was improvement in both groups, the low-dose fish oil group had greater improvement in WOMAC pain and function scores at 2 years compared with the high-dose group, whereas between-group differences at 1 year did not reach statistical significance. There was no difference between the two groups in cartilage volume loss at 2 years. For other secondary endpoints, there was no difference between the two groups at 2 years. CONCLUSIONS: In people with symptomatic knee OA, there was no additional benefit of a high-dose fish oil compared with low-dose fish oil. The combination comparator oil appeared to have better efficacy in reducing pain at 2 years, suggesting that this requires further investigation. TRIAL REGISTRATION NUMBER: Australian New Zealand Clinical Trials Registry (ACTRN 12607000415404).

Plasma n-3 fatty acids and clinical outcomes in recent-onset rheumatoid arthritis.

A randomised controlled trial (RCT) of high-dose v. low-dose fish oil in recent-onset rheumatoid arthritis (RA) demonstrated that the group allocated to high-dose fish oil had increased remission and decreased failure of disease-modifying anti-rheumatic drug (DMARD) therapy. This study examines the relationships between plasma phospholipid levels of the n-3 fatty acids in fish oil, EPA and DHA, and remission and DMARD use in recent-onset RA. EPA and DHA were measured in blood samples from both groups of the RCT. The data were analysed as a single cohort, and Cox proportional hazards models were used to examine relationships between plasma phospholipid (PL) EPA and DHA and various outcome measures. When analysed as a single cohort, plasma PL EPA was related to time to remission, with a one unit increase in EPA (1% total fatty acids) associated with a 12% increase in the probability of remission at any time during the study period (hazard ratio (HR)=1.12; 95% CI 1.02, 1.23; P=0.02). Adjustment for smoking, anti-cyclic citrullinated peptide antibodies and 'shared epitope' HLA-DR allele status did not change the HR. Plasma PL EPA, adjusted for the same variables, was negatively related to time to DMARD failure (HR=0.85; 95% CI 0.72, 0.99; P=0.047). The HR for DHA and time to remission or DMARD failure were similar in magnitude to those for EPA, but not statistically significant. Biomarkers of n-3 status, such as plasma PL EPA, have the potential to predict clinical outcomes relevant to standard drug treatment of RA patients.

The role and utility of measuring red blood cell methotrexate polyglutamate concentrations in inflammatory arthropathies--a systematic review.

PURPOSE: Evidence regarding the relationship between red blood cell methotrexate polyglutamate concentration and response to treatment and adverse drug reactions in patients using methotrexate for inflammatory arthropathies is complex and in some respects appears conflicting. Accordingly, we undertook a systematic analysis of available evidence to determine the clinical utility of dosing methotrexate to a target red blood cell methotrexate polyglutamate concentration. METHODS: A systematic literature review was conducted to identify all studies that had reported an association between red blood cell methotrexate polyglutamate concentration and disease activity or adverse drug reactions in users of methotrexate for the treatment of rheumatoid arthritis, juvenile idiopathic arthritis or psoriatic arthritis. RESULTS: No randomised controlled trials were identified. Thirteen studies (ten in patients with rheumatoid arthritis and three in patients with juvenile idiopathic arthritis) were identified. All studies evaluated an association between red blood cell methotrexate polyglutamate concentration and response to treatment, and eight evaluated an association with toxicity. Eight studies identified lower disease activity with at least one higher red blood cell methotrexate polyglutamate concentration, although there was at least moderate potential for bias in all of these studies. Relatively large increases in concentration appeared to be required to produce a meaningful reduction in disease activity. Only one study identified an association between red blood cell methotrexate polyglutamate concentration and methotrexate-induced side effects, although studies were likely underpowered to detect this type of association. CONCLUSIONS: The manner in which data were presented in the included studies had many limitations that hampered its conclusive assessment, but red blood cell methotrexate polyglutamate concentrations appear to be a potentially useful guide to treatment in patients with inflammatory arthropathies, but the specific polyglutamate that should be monitored and how monitoring could be integrated into treat-to-target approaches should be clarified before it can be routinely implemented.

Fish oil in recent onset rheumatoid arthritis: a randomised, double-blind controlled trial within algorithm-based drug use.

BACKGROUND: The effects of fish oil (FO) in rheumatoid arthritis (RA) have not been examined in the context of contemporary treatment of early RA. This study examined the effects of high versus low dose FO in early RA employing a 'treat-to-target' protocol of combination disease-modifying anti-rheumatic drugs (DMARDs). METHODS: Patients with RA <12 months' duration and who were DMARD-naïve were enrolled and randomised 2:1 to FO at a high dose or low dose (for masking). These groups, designated FO and control, were given 5.5 or 0.4 g/day, respectively, of the omega-3 fats, eicosapentaenoic acid + docosahexaenoic acid. All patients received methotrexate (MTX), sulphasalazine and hydroxychloroquine, and DMARD doses were adjusted according to an algorithm taking disease activity and toxicity into account. DAS28-erythrocyte sedimentation rate, modified Health Assessment Questionnaire (mHAQ) and remission were assessed three monthly. The primary outcome measure was failure of triple DMARD therapy. RESULTS: In the FO group, failure of triple DMARD therapy was lower (HR=0.28 (95% CI 0.12 to 0.63; p=0.002) unadjusted and 0.24 (95% CI 0.10 to 0.54; p=0.0006) following adjustment for smoking history, shared epitope and baseline anti-cyclic citrullinated peptide. The rate of first American College of Rheumatology (ACR) remission was significantly greater in the FO compared with the control group (HRs=2.17 (95% CI 1.07 to 4.42; p=0.03) unadjusted and 2.09 (95% CI 1.02 to 4.30; p=0.04) adjusted). There were no differences between groups in MTX dose, DAS28 or mHAQ scores, or adverse events. CONCLUSIONS: FO was associated with benefits additional to those achieved by combination 'treat-to-target' DMARDs with similar MTX use. These included reduced triple DMARD failure and a higher rate of ACR remission.

Fish oil supplementation increases the cyclooxygenase inhibitory activity of paracetamol in rheumatoid arthritis patients.

OBJECTIVE: To examine interactions between fish oil and paracetamol for inhibition of prostaglandin synthesis in patients with rheumatoid arthritis (RA). METHODS: Patients from an early RA clinic who were treated with a standardized combination DMARD regimen were enrolled. They were advised to consume an anti-inflammatory dose of fish oil containing the n-3 fatty acid, eicosapentaenoic acid (EPA), or a comparator oil. High EPA and Low EPA groups were defined by blood EPA levels >3.5% or <2%, respectively, of plasma phospholipid fatty acids. Participants provided a blood sample before, and 1h after ingestion of 1g paracetamol. The blood was incubated in different ways to allow measurement of COX-2 generated prostaglandin E(2) (PGE(2)) and COX-1 generated thromboxane A(2) (TXA(2)). RESULTS: Paracetamol suppressed the eicosanoid measures of COX-1 and COX-2 activities and the suppression was greater in the High EPA group. The results indicate that the combination of fish oil and paracetamol suppresses PGE(2) synthesis by an amount equivalent to that from maximum therapeutic doses of NSAIDs. CONCLUSION: Paracetamol is recommended for first-line use ahead of NSAIDs for symptom relief in RA or OA. Combining paracetamol with fish oil will enhance suppression of nociceptive PGE(2) synthesis and thereby may provide additive symptomatic benefits.

Dietary omega-3 fats for treatment of inflammatory joint disease: efficacy and utility.

There is high level evidence (meta-analysis of randomized, controlled trials) for symptomatic benefits from fish oil use in rheumatoid arthritis, and there is biologic plausibility for its clinical effects. Fish oil also has safety advantages in reducing cardiovascular risk via direct cardiovascular effects and via nonsteroidal anti-inflammatory drug-sparing. This is an important aspect of fish oil use, given the increased cardiovascular risk in rheumatoid arthritis. Perceived barriers to clinical use are readily addressed.

Response-driven combination therapy with conventional disease-modifying antirheumatic drugs can achieve high response rates in early rheumatoid arthritis with minimal glucocorticoid and nonsteroidal anti-inflammatory drug use.

OBJECTIVES: To assess the safety and efficacy of combination therapy in recent-onset rheumatoid arthritis (RA), with dose adjustments determined by response, in a clinic setting over 3 years. METHODS: Disease-modifying antirheumatic drug (DMARD)-naive patients with RA of median duration of 12 weeks (n = 61) attending an early arthritis clinic were treated with methotrexate, sulfasalazine, hydroxychloroquine, and fish oil. Dosage adjustments and additions of further DMARDs were contingent on response to therapy and tolerance. Outcome measures for efficacy were Disease Activity Score (DAS28), clinical remission, and modified Sharp radiographic score and for safety, adverse events, and DMARD withdrawal. RESULTS: At baseline, subjects had at least moderately active disease (mean +/- SD DAS28 was 5.3 +/- 1.1), impaired function as measured by the modified Health Assessment Questionnaire (mHAQ) (0.9 +/- 0.5), and 37% had bone erosions. By 3 months, 29% were in remission; this increased to 54% at 3 years. The greatest fall in DAS28 and improvement in mHAQ scores occurred in the first 12 months. Erosions were detected in 62% at 3 years. The mean dose of parenteral glucocorticoid was equivalent to 0.1 mg/d of prednisolone. After 3 years, 48% remained on triple therapy; fish oil was consumed by 75% of patients, and 21% used nonsteroidal anti-inflammatory drugs. Gastrointestinal intolerance was the most frequent unwanted event (leading to DMARD withdrawal in 17 patients). Sulfasalazine was most frequently withdrawn (30%). CONCLUSION: This implementation study demonstrates the feasibility, safety, and efficacy of combination therapy with inexpensive DMARDs, fish oil, and minimal glucocorticoid use, in routine clinical practice using predefined rules for dosage adjustment.

Reduction of cardiovascular risk factors with longterm fish oil treatment in early rheumatoid arthritis.

OBJECTIVE: Rheumatoid arthritis (RA) is associated with increased risk for cardiovascular (CV) events through multiple factors. Fish oil has been shown to reduce symptoms in RA and to reduce CV risk. We assessed the effect of an antiinflammatory dose of fish oil on CV risk factors within a program of combination chemotherapy for patients with early RA. METHODS: Patients who chose not to take fish oil (n = 13) were compared with patients who achieved a sustained elevation of eicosapentaenoic acid (EPA) in plasma phospholipid fatty acids (> 5% total fatty acids) while taking fish oil over a 3-year period (n = 18). We examined cellular content of arachidonic acid (AA), synthesis of thromboxane A2 and prostaglandin E2, use of nonsteroidal antiinflammatory drugs (NSAID), traditional CV lipid risk factors, and disease activity at 3 years. RESULTS: At 3 years, AA (as a proportion of AA plus long-chain n-3 fatty acids that can compete with AA for cyclooxygenase metabolism) was 30% lower in platelets and 40% lower in peripheral blood mononuclear cells in subjects taking fish oil. Serum thromboxane B2 was 35% lower and lipopolysaccharide-stimulated whole-blood prostaglandin E2 was 41% lower with fish oil ingestion compared to no fish oil. NSAID use was reduced by 75% from baseline with fish oil (p < 0.05) and by 37% without fish oil (NS). Favorable changes in fasting blood lipids were seen with, but not without fish oil. Remission at 3 years was more frequent with fish oil use (72%) compared to no fish oil (31%). CONCLUSION: Fish oil reduces cardiovascular risk in patients with RA through multiple mechanisms.

Fish oil: what the prescriber needs to know.

There is a general belief among doctors, in part grounded in experience, that patients with arthritis need nonsteroidal anti-inflammatory drugs (NSAIDs). Implicit in this view is that these patients require the symptomatic relief provided by inhibiting synthesis of nociceptive prostaglandin E2, a downstream product of the enzyme cyclo-oxygenase (COX), which is inhibited by NSAIDs. However, the concept of 'safe' NSAIDs has collapsed following a multiplicity of observations establishing increased risk for cardiovascular events associated with NSAID use, especially but not uniquely with the new COX-2-selective NSAIDs. This mandates greater parsimony in the use of these agents. Fish oils contain a natural inhibitor of COX, reduce reliance on NSAIDs, and reduce cardiovascular risk through multiple mechanisms. Fish oil thus warrants consideration as a component of therapy for arthritis, especially rheumatoid arthritis, in which its symptomatic benefits are well established. A major barrier to the therapeutic use of fish oil in inflammatory diseases is ignorance of its mechanism, range of beneficial effects, safety profile, availability of suitable products, effective dose, latency of effects and instructions for administration. This review provides an evidence-based resource for doctors and patients who may choose to prescribe or take fish oil.

A biomarker of n-3 compliance in patients taking fish oil for rheumatoid arthritis.

Dietary fish oil supplements have been shown to have benefits in rheumatoid arthritis (RA), other inflammatory diseases, and in cardiovascular disease. As with any medical advice, variability will exist with regard to adherence and consequent biochemical or pharmacophysiologic effects. The aim was to explore the utility of plasma phospholipid EPA as a measure of n-3 PUFA intake and response to standardized therapeutic advice given in an outpatient or office practice setting, to increase dietary n-3 PUFA, including a fish oil supplement. Patients with early RA were given verbal and written advice to alter their dietary n-3 PUFA intake, including ingestion of 20 mL of bottled fish oil on juice daily. The advice included instructions to increase n-3 PUFA and to avoid foods rich in n-6 PUFA. Every 3 mon, blood samples were obtained for analysis of plasma phospholipid FA. Plasma phospholipid EPA was used as the primary index of n-3 PUFA intake. A diverse response was seen, with about one-third of patients achieving a substantial elevation of plasma phospholipid EPA over the 12-mon study period. A third had little change, with the remainder achieving intermediate levels. Data obtained longitudinally from individual patients indicated that substantial elevations of EPA (> 5% total plasma phospholipid FA) could be maintained for more than 3 yr. Plasma phospholipid EPA is a convenient measure of adherence to advice to take a dietary n-3 PUFA-rich fish oil supplement This measure may prove a useful adjunct to intention to treat analyses in determining the effect of dietary fish oil supplements on long-term outcomes in arthritis and other chronic inflammatory diseases. It may also provide a guide to the effectiveness of therapeutic and preventive messages designed to increase n-3 PUFA intake.

The role of fish oils in the treatment of rheumatoid arthritis.

Fish oils are a rich source of omega-3 long chain polyunsaturated fatty acids (n-3 LC PUFA). The specific fatty acids, eicosapentaenoic acid and docosahexaenoic acid, are homologues of the n-6 fatty acid, arachidonic acid (AA). This chemistry provides for antagonism by n-3 LC PUFA of AA metabolism to pro-inflammatory and pro-thrombotic n-6 eicosanoids, as well as production of less active n-3 eicosanoids. In addition, n-3 LC PUFA can suppress production of pro-inflammatory cytokines and cartilage degradative enzymes. In accordance with the biochemical effects, beneficial anti-inflammatory effects of dietary fish oils have been demonstrated in randomised, double-blind, placebo-controlled trials in rheumatoid arthritis (RA). Also, fish oils have protective clinical effects in occlusive cardiovascular disease, for which patients with RA are at increased risk. Implementation of the clinical use of anti-inflammatory fish oil doses has been poor. Since fish oils do not provide industry with the opportunities for substantial profit associated with patented prescription items, they have not received the marketing inputs that underpin the adoption of usual pharmacotherapies. Accordingly, many prescribers remain ignorant of their biochemistry, therapeutic effects, formulations, principles of application and complementary dietary modifications. Evidence is presented that increased uptake of this approach can be achieved using bulk fish oils. This approach has been used with good compliance in RA patients. In addition, an index of n-3 nutrition can be used to provide helpful feedback messages to patients and to monitor the attainment of target levels.Collectively, these issues highlight the challenges in advancing the use of fish oil amid the complexities of modern management of RA, with its emphasis on combination chemotherapy applied early.