Specialised pro-resolving mediators of inflammation in inflammatory arthritis.

INTRODUCTION: Specialised pro-resolving mediators (SPM) are derived from n-3 long chain polyunsaturated fatty acids (n-3FA). They promote resolution of inflammation and may contribute to the beneficial effects of n-3FA in patients with arthritis. This study compared SPM in knee effusions and plasma of patients with arthritis taking n-3FA, and plasma of healthy volunteers taking n-3FA. METHODS: Thirty six patients taking n-3FA undergoing arthrocentesis for an inflammatory knee effusion and 36 healthy volunteers who had taken n-3FA (2.4g/day) for 4 weeks were studied. SPM in synovial fluid and plasma were measured by liquid chromatography-tandem mass spectrometry included 18-hydroxyeicosapentaenoic acid (18-HEPE), the precursor of the E-series SPM (RvE1, RvE2, RvE3, 18R-RvE3), and 17-hydroxydocosahexaenoic acid (17-HDHA), the precursor of the D-series SPM (RvD1, 17R-RvD1, RvD2). Other SPM included protectin D1 (PD1), 10S,17S-dihydroxydocosahexaenoic acid (10,17S-DHDHA), maresin-1 (MaR-1) and 14-hydroxydocosahexaenoic acid (14-HDHA) derived from docosahexaenoic acid (DHA). RESULTS: E- and D-series SPM and the precursors 18-HEPE and 17-HDHA were present in synovial fluid and plasma of the patients with inflammatory arthritis. Plasma SPM were negatively related to erythrocyte sedimentation rate in arthritis patients (P<0.01) and synovial fluid RvE2 was negatively associated with pain score (P=0.02). Conversion from 18-HEPE and 17-HDHA to E- and D-series SPM was greater in synovial fluid (P<0.01). Most plasma SPM in arthritis patients were elevated (P<0.05) compared with healthy volunteers, and conversion to E- and D-series SPM was greater (P<0.01). CONCLUSIONS: SPM are present in chronic knee effusions and although the levels are lower than in plasma, the association between synovial fluid RvE2 and reduced pain scores suggests that synthesis of SPM at the site of inflammation is a relevant mechanism by which n-3FA alleviate the symptoms of arthritis.

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.

Synovial fluid and plasma n3 long chain polyunsaturated fatty acids in patients with inflammatory arthritis.

Relationships between n-3 long chain polyunsaturated fatty acids (LC-PUFA) in plasma and synovial fluid (SF) were examined in 36 patients with knee effusion within the context of a variety of rheumatic diagnoses and various stated fish oil (FO) intakes (from 0 to 30mL of standard FO daily) of variable duration. In a sub-group of patients, correlations between PUFA in SF mononuclear cells (MNC) and cell-free supernatants of SF and between SF MNC and peripheral blood (PB) MNC were examined. Correlations were also sought between clinical data (stated FO intake, pain score) and n-3 LC-PUFA. Correlations between plasma n-3 LC-PUFA and SF n-3 LC-PUFA were very strong (r(2)>0.9, p<0.001). The LC-PUFA profiles of SF supernatants differed from those of MNC. PUFA profiles in PB MNC and SF MNC were similar, except for a higher proportion of DHA in the latter. Positive correlations were observed between stated intakes of FO and EPA in plasma and SF (for both r=0.37, p=0.02) and DHA in plasma (r=0.37, p=0.02) and SF (r=0.36, p=0.03). n-3 LC-PUFA in plasma and SF correlated inversely with pain score (plasma r(2)=0.16, p<0.02; SF r(2) 0.32, p=0.001). In conclusion, plasma n-3 LC-PUFA is a strong indicator of SF n-3 LC-PUFA status across a broad range of rheumatic diagnoses and FO intakes. Higher n-3 LC-PUFA in plasma and SF were associated with lesser pain experience.

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.

Pitfalls in the use of randomised controlled trials for fish oil studies with cardiac patients.

Randomised controlled trials (RCT) examining the effects of fish oil supplementation on cardiac outcomes have yielded varying results over time. Although RCT are placed at the top of the evidence hierarchy, this methodology arose in the framework of pharmaceutical development. RCT with pharmaceuticals differ in important ways from RCT involving fish oil interventions. In particular, in pharmaceutical RCT, the test agent is present only in the intervention group and not in the control group, whereas in fish oil RCT, n-3 fats are present in the diet and in the tissues of both groups. Also, early phase studies with pharmaceuticals determine pharmacokinetics and pharmacodynamics to design the dose of the RCT intervention so that it is in a predicted linear dose-response range. None of this happens in fish oil RCT, and there is evidence that both baseline n-3 intake and tissue levels may be sufficiently high in the dose-response range that it is not possible to demonstrate a clinical effect with a RCT. When these issues are considered, it is possible that the changing pattern of fish consumption and fish oil use over time, especially in cardiac patients, can explain the disparity where benefit was observed in the early fish oil trials but not in the more recent trials.

Prostaglandin D(2) in inflammatory arthritis and its relation with synovial fluid dendritic cells.

Prostaglandin (PG)D2 has been shown to be an active agent in the resolution of experimentally induced inflammation. This study was undertaken to determine the presence of PGD2 in chronic joint effusions and to explore the potential contributions of dendritic cells (DC) and monocytes to the intra-articular synthesis of PGD2. Synovial fluid (SF) was obtained from patients with inflammatory arthritis and knee effusions. PGD2 and PGE2 were detected in SF by ultrahigh-performance tandem mass spectrometry. Cellular fractions in SF were separated by density-gradient centrifugation and flow cytometry. The expression of hematopoietic prostaglandin D-synthase (hPGDS) and PGE-synthase (PGES) mRNA was determined by RT-PCR. Both PGD2 and PGE2 were detected in blood and SF, with PGD2 being more abundant than PGE2 in SF. mRNA for hPGDS was more abundant in SF mDCs than SF monocytes (P < 0.01) or PB monocytes (P < 0.001). SF mDC expressed significantly more hPGDS than PGES. Expressions of PGD2 and hPGDS were inversely associated with serum C-reactive protein (P < 0.01) and erythrocyte sedimentation rate (P < 0.01). The findings suggest that synovial DCs may be an important source of hPGDS and that systemic disease activity may be influenced by actions of PGD2 in RA and other arthropathies.

Fish oil administration in older adults: is there potential for adverse events? A systematic review of the literature.

BACKGROUND: Omega-3 (n-3) fatty acid supplementation is becoming increasingly popular. However given its antithrombotic properties the potential for severe adverse events (SAE) such as bleeding has safety implications, particularly in an older adult population. A systematic review of randomized control trials (RCT) was conducted to explore the potential for SAE and non-severe adverse events (non-SAE) associated with n-3 supplementation in older adults. METHODS: A comprehensive search strategy using Medline and a variety of other electronic sources was conducted. Studies investigating the oral administration of n-3 fish oil containing eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) or both against a placebo were sourced. The primary outcome of interest included reported SAE associated with n-3 supplementation. Chi-square analyses were conducted on the pooled aggregate of AEs. RESULTS: Of the 398 citations initially retrieved, a total of 10 studies involving 994 older adults aged ≥60 years were included in the review. Daily fish oil doses ranged from 0.03 g to 1.86 g EPA and/or DHA with study durations ranging from 6 to 52 weeks. No SAE were reported and there were no significant differences in the total AE rate between groups (n-3 intervention group: 53/540; 9.8%; placebo group: 28/454; 6.2%; p = 0.07). Non-SAE relating to gastrointestinal (GI) disturbances were the most commonly reported however there was no significant increase in the proportion of GI disturbances reported in participants randomized to the n-3 intervention (n-3 intervention group: 42/540 (7.8%); placebo group: 24/454 (5.3%); p = 0.18). CONCLUSIONS: The potential for AEs appear mild-moderate at worst and are unlikely to be of clinical significance. The use of n-3 fatty acids and the potential for SAE should however be further researched to investigate whether this evidence is consistent at higher doses and in other populations. These results also highlight that well-documented data outlining the potential for SAE following n-3 supplementation are limited nor adequately reported to draw definitive conclusions concerning the safety associated with n-3 supplementation. A more rigorous and systematic approach for monitoring and recording AE data in clinical settings that involve n-3 supplementation is required.

Efficacy and mechanisms of action of vitamin D in experimental polyarthritis.

Vitamin D (vit D) status has been linked to the occurrence and severity of auto-immune and inflammatory diseases. This study evaluates the effects of vit D status on adoptive transfer of adjuvant-induced arthritis (ATA). Rats maintained on diets replete or deficient in vit D3 received arthritogenic thoracic duct cells and were monitored for severity of arthritis. CD45(+) cells obtained by collagenase digestion of hind-paw synovium-rich tissues (SRTs) were analysed to observe the effects of dietary vit D3 on the inflammatory process. Arthritis was more severe in vitamin D-deficient (vit-D(-)) rats compared with vitamin D-replete (vit-D(+)) rats. Resolution was delayed in vit-D(-) rats compared with vit-D(+) rats, or rats fed standard chow. During the acute phase of ATA, numbers of CD45(+) cells were significantly increased in the SRTs of vit-D(-) rats compared with vit-D(+) rats. This increase involved T-cells, polymorphonuclear leukocytes, macrophages, dendritic cells (DCs) and MHC II(hi) cells that resemble activated monocytes. A major difference between the dietary groups was that most DCs at the peak of inflammation in vit-D(-) rats were CD4(-), whereas in convalescent vit-D(+) rats most expressed CD4. Multiple categories of genes expressed by DCs differed between deficient and replete rats, with deficiency being associated with relative upregulation of certain pro-inflammatory genes and replete status being associated with upregulation of genes associated with resolution of inflammation. The findings indicate that ATA is more severe and prolonged in vit-D deficiency, that vit-D deficiency promotes accumulation of CD4(-) DCs in synovium during ATA and that a gene-expression profile is likely to contribute to the observed increased severity and duration of arthritis.

Effect of dietary fish oil on atrial fibrillation after cardiac surgery.

An open-label study reported that ingestion of a fish oil concentrate decreased the incidence of atrial fibrillation (AF) after coronary artery bypass grafting (CABG) surgery. However, a general cardiac surgery population involves valve and CABG surgeries. We undertook a double-blinded randomized controlled trial to examine the effectiveness of fish oil supplementation on the incidence of postsurgical AF after CABG and valve procedures. The primary end point was incidence of AF in the first 6 days after surgery. Two hundred patients were randomized to receive fish oil (providing 4.6 g/day of long-chain ω-3 fatty acids) or a control oil starting 3 weeks before surgery; 194 subjects completed the study, with 47 of 97 subjects in the control group and 36 of 97 subjects in the fish oil group developing AF (odds ratio 0.63, 95% confidence interval [CI] 0.35 to 1.11). There was a nonstatistically significant delay in time to onset of AF in the fish oil group (hazard ratio 0.66, 95% CI 0.43 to 1.01). There was a significant decrease in mean length of stay in the intensive care unit in the fish oil group (ratio of means 0.71, 95% CI 0.56 to 0.90). In conclusion, in a mixed cardiac surgery population, supplementation with dietary fish oil did not result in a significant decrease in the incidence of postsurgical AF. However, there was a significant decrease in time spent in the intensive care unit.

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.

Effect of dietary n-3 polyunsaturated fatty acids on the inducibility of ventricular tachycardia in patients with ischemic cardiomyopathy.

Increased consumption of fish and/or fish oil was associated with decreased risk of sudden cardiac death (SCD). The study aim was to evaluate the antiarrhythmic effect of dietary fish oil on the inducibility of ventricular tachycardia (VT) at high risk of SCD. Patients with coronary artery disease undergoing defibrillator implantation were recruited if sustained monomorphic VT could be induced by programmed extra stimuli at 2 cycle lengths. After the initial study, 12 patients consumed 3 g/d of encapsulated fish oil for approximately 6 weeks before a repeated electrophysiologic study. To control for fluctuations in the inducibility of VT, an additional 14 patients with no dietary manipulation were also studied. Aggressiveness of stimulation required to induce VT was ranked from least aggressive to most aggressive based on cycle length and number of extra stimuli, with noninducibility ranked highest. At the repeated electrophysiologic study, in the fish-oil group, 42% had no inducible VT, 42% required more aggressive stimulation to induce VT, 8% required identical stimulation, and 8% required less stimulation compared with 7%, 36%, 36%, and 21% in the control group, respectively. Overall, there was a change to noninducible or less inducible VT in the fish-oil group, but no change in the control group (p = 0.003 and p = 0.65, respectively; Wilcoxon's sign-rank test). In conclusion, dietary n-3 fatty acid supplementation decreased the inducibility of VT in patients at risk of SCD. These findings suggest that dietary fish oil can have an antiarrhythmic effect.

Effects of fish-oil supplementation on myocardial fatty acids in humans.

BACKGROUND: Increased fish or fish-oil consumption is associated with reduced risk of cardiac mortality, especially sudden death. This benefit putatively arises from the incorporation of the long-chain n-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) into cardiomyocyte phospholipids. OBJECTIVE: The study examined the kinetics of incorporation of n-3 fatty acids into human myocardial membrane phospholipids during supplementation with fish oil and alpha-linolenic acid-rich flaxseed oil. DESIGN: Patients with low self-reported fish intake (<1 fish meal/wk and no oil supplements) accepted for elective cardiac surgery involving cardiopulmonary bypass were randomly allocated to 1 of 6 groups: no supplement; fish oil (6 g EPA+DHA/d) for either 7, 14, or 21 d before surgery; flaxseed oil; or olive oil (both 10 mL/d for 21 d before surgery). Right atrial appendage tissue removed during surgery and blood collected at enrollment and before surgery were analyzed for phospholipid fatty acids. RESULTS: Surgery rescheduling resulted in a range of treatment times from 7 to 118 d. In the fish-oil-treated subjects, accumulation of EPA and DHA in the right atrium was curvilinear with time and reached a maximum at approximately 30 d of treatment and displaced mainly arachidonic acid. Flaxseed oil supplementation yielded a small increase in atrial EPA but not DHA, whereas olive oil did not significantly change atrial n-3 fatty acids. CONCLUSION: The results of the present study show that dietary n-3 fatty acids are rapidly incorporated into human myocardial phospholipids at the expense of arachidonic acid during high-dose fish-oil supplementation.

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.

A system for improving vitamin D nutrition in residential care.

OBJECTIVE: To assess the feasibility of administering an inexpensive preparation of vitamin D(3) 100 000 IU orally 3 monthly to aged-care residents. DESIGN: Prospective, controlled open-label implementation trial. SETTING: Residential aged care, November 2003 to May 2004 (primary study). PARTICIPANTS: 137 ambulant residents: 107 treated (mean age, 85 years; 79 were women), 30 untreated controls (mean age, 87 years; 22 were women). INTERVENTIONS: Lactose microencapsulated vitamin D(3) 100 000 IU orally at baseline, then 3 monthly (three or more doses); untreated subjects were observed contemporaneously. MAIN OUTCOME MEASURES: Serum levels of 25-hydroxyvitamin D [25(OH)D] at 6 months compared with baseline; acceptability of the program to residents and staff. RESULTS: At baseline, 95% of residents assessed (n = 137) had serum 25(OH)D levels below the desirable range of 60-160 nmol/L. At 6 months, all treated residents (n = 98) achieved desired levels, with the mean (+/- SD) 25(OH)D level increasing from 36.4 +/- 12.6 nmol/L (range, 12-75 nmol/L) at baseline to 124.0 +/- 27.9 nmol/L (range, 68-244 nmol/L). In no resident did 25(OH)D approach toxic levels. The mean serum 25(OH)D level remained low in the control group (n = 27): 42.8 +/- 18.3 nmol/L (range, 18-98 nmol/L). The difference between the mean 25(OH)D levels of treatment and control groups at 6 months was 81.2 nmol/L (95% CI, 69.7-92.0 nmol/L). The cost of the supplement was $4 per resident per annum. Substudies showed mean trough serum 25(OH)D levels in the desired range at 3 months (n = 31), but below the desired range at 6 months (n = 50). Subjects given 3-monthly doses for up to 2 years maintained serum 25(OH)D levels within the desired range, with no trend toward undesirable accumulation (n = 11). CONCLUSIONS: Vitamin D(3) 100 000 IU given orally 3 monthly is a practical, safe, effective and inexpensive way to meet the vitamin D(3) requirements of aged-care residents.

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.