Dietary fish oil and olive oil supplementation in patients with rheumatoid arthritis. Clinical and immunologic effects.

Forty-nine patients with active rheumatoid arthritis completed a 24-week, prospective, double-blind, randomized study of dietary supplementation with 2 different dosages of fish oil and 1 dosage of olive oil. Clinical evaluations were performed at baseline and every 6 weeks thereafter, and immunologic variables were measured at baseline and after 24 weeks of study. The 3 groups of patients were matched for age, sex, disease severity, and use of disease-modifying antirheumatic drugs (DMARDs). Subjects continued receiving DMARDs and other background medications without change during the study. Twenty patients consumed daily dietary supplements of n3 fatty acids containing 27 mg/kg eicosapentaenoic acid (EPA) and 18 mg/kg docosahexaenoic acid (DHA) (low dose), 17 patients ingested 54 mg/kg EPA and 36 mg/kg DHA (high dose), and 12 patients ingested olive oil capsules containing 6.8 gm of oleic acid. Significant improvements from baseline in the number of tender joints were noted in the low-dose group at week 24 (P = 0.05) and in the high-dose group at week 18 (P = 0.04) and 24 (P = 0.02). Significant decreases from baseline in the number of swollen joints were noted in the low-dose group at weeks 12 (P = 0.003), 18 (P = 0.002), and 24 (P = 0.001) and in the high-dose group at weeks 12 (P = 0.0001), 18 (P = 0.008), and 24 (P = 0.02). A total of 5 of 45 clinical measures were significantly changed from baseline in the olive oil group, 8 of 45 in the low-dose fish oil group, and 21 of 45 in the high-dose fish oil group during the study (P = 0.0002). Neutrophil leukotriene B4 production decreased by 19% from baseline in the low-dose fish oil group (P = 0.0003) and 20% in the high-dose group (P = 0.03), while macrophage interleukin-1 production decreased by 38.5% in the olive oil group (P not significant), 40.6% in the low-dose group (P = 0.06), and 54.7% in the high-dose group (P = 0.0005). Tritiated thymidine incorporation in peripheral blood mononuclear cells after stimulation with concanavalin A increased significantly in all 3 groups after 24 weeks, compared with baseline values. We conclude that the clinical benefits of dietary supplementation with omega-3 fatty acids are more commonly observed in patients consuming higher dosages of fish oil for time intervals that are longer than those previously studied. Dietary supplementation with olive oil is also associated with certain changes in immune function, which require further investigation.

In vivo effects of 1,25-dihydroxyvitamin D3 and minerals on synthesis of leukotriene B4 and 5-hydroxyeicosatetraenoic acid by rat peritoneal neutrophils.

We investigated the in vivo effects of 1,25-dihydroxyvitamin D3, and serum calcium and inorganic phosphorus concentrations on productions of leukotriene B4 and 5-hydroxyeicosatetraenoic acid by glycogen stimulated peritoneal neutrophils of the rat. Neutrophils were incubated with ionophore A23187 for 5 min and the incubation medium was subjected to a reverse-phase high performance liquid chromatography for quantitation. Productions of these lipoxygenase metabolites by neutrophils from vitamin D depleted rats were decreased compared to the vitamin D sufficient levels. This difference was not observed when arachidonic acid was added to the incubation medium. When serum calcium concentrations of rats were altered by dietary calcium levels but 1,25-dihydroxyvitamin D3 was administered to those rats, the difference in serum calcium concentration did not show any effect on the production of leukotriene B4. In contrast, neutrophils from 1,25-dihydroxyvitamin D3 sufficient but phosphorus deficient rats still demonstrated decreased leukotriene B4 production. This reduction was corrected by exogenous arachidonic acid. The data suggest that 1,25-dihydroxyvitamin D3 or cellular calcium translocation mediated by the hormone, and serum inorganic phosphorus independent of 1,25-dihydroxyvitamin D3 affect arachidonic acid release, thus productions of leukotriene B4 and 5-hydroxyeicosatetraenoic acid.

Fish-oil fatty acid supplementation in active rheumatoid arthritis. A double-blinded, controlled, crossover study.

STUDY OBJECTIVE: to determine the efficacy of fish-oil dietary supplements in active rheumatoid arthritis and their effect on neutrophil leukotriene levels. DESIGN: nonrandomized, double-blinded, placebo-controlled, crossover trial with 14-week treatment periods and 4-week washout periods. SETTING: academic medical center, referral-based rheumatology clinic. PATIENTS: forty volunteers with active, definite, or classical rheumatoid arthritis. Five patients dropped out, and two were removed for noncompliance. INTERVENTIONS: treatment with nonsteroidal anti-inflammatory drugs, slow-acting antirheumatic drugs, and prednisone was continued. Twenty-one patients began with a daily dosage of 2.7 g of eicosapaentanic acid and 1.8 g of docosahexenoic acid given in 15 MAX-EPA capsules (R.P. Scherer, Clearwater, Florida), and 19 began with identical-appearing placebos. The background diet was unchanged. MEASUREMENTS AND MAIN RESULTS: the following results favored fish oil placebo after 14 weeks: mean time to onset of fatigue improved by 156 minutes (95% confidence interval, 1.2 to 311.0 minutes), and number of tender joints decreased by 3.5 (95% Cl, -6.0 to -1.0). Other clinical measures favored fish oil as well but did reach statistical significance. Neutrophil leukotriene B4 production was correlated with the decrease in number of tender joints (Spearman rank correlation r=0.53; p less than 0.05). There were no statistically significant differences in hemoglobin level, sedimentation rate, or presence of rheumatoid factor or in patient-reported adverse effects. An effect from the fish oil persisted beyond the 4-week washout period. CONCLUSIONS: fish-oil ingestion results in subjective alleviation of active rheumatoid arthritis and reduction in neutrophil leukotriene B4 production. Further studies are needed to elucidate mechanisms of action and optimal dose and duration of fish-oil supplementation.

Alterations of glucocorticoid actions by other drugs and disease states.

Glucocorticoids are used in physiological and pharmacological amounts in the management of a variety of clinical conditions. Concomitant utilisation of other drugs or the presence of some diseases may affect the physiological action of the steroid in the tissues. Phenytoin, phenobarbitone, ephedrine and rifampicin accelerate the metabolism of glucocorticoids thereby decreasing their biological activity. A similar phenomenon occurs in patients with hyperthyroidism. In contrast, glucocorticoid action is enhanced in hypothyroid patients and in those with hepatic damage as the result of a defect in the clearance of the hormone from blood. In turn, glucocorticoids antagonise the effects of cholinesterase inhibitors and ganglion blocking agents. The above mentioned effects should be kept in mind whenever glucocorticoids are utilised in the diagnosis and management of endocrine or non-endocrine conditions.

Effect of indomethacin on the hypothalamic-pituitary-adrenal axis in man.

The effect of the cyclo-oxygenase inhibitor, indomethacin, on hypothalamic-pituitary-adrenal function was investigated in five normal males. Baseline 0800 and 1600 h plasma ACTH and cortisol, plasma ACTH and 11-deoxycortisol responses to metyrapone, and plasma cortisol responses to dexamethasone and exogenous ACTH were not affected by indomethacin. However, the area under the curve for plasma ACTH after iv injection of regular insulin (0.1 U/kg) was significantly decreased during indomethacin administration (control, 88.0 +/- 32.6 cm2, mean +/- sd; indomethacin, 47.6 +/- 23.1, P less than 0.01). Plasma cortisol levels were decreased only at 30 min. Our results support the hypothesis that prostaglandins or any of their precursors play a role in the hypothalamic control of ACTH secretion and indicate that evaluation of hypophyseal ACTH secretory capacity by means of insulin-induced hypoglycemia may yield abnormal results in patients receiving indomethacin.

Abnormalities in the regulation of growth hormone in chronic renal failure.

Carbohydrate intolerance is a common abnormality in patients with chronic renal failure. In this group of patients we investigated the interrelation among glucose, insulin, and growth hormone and confirmed the presence of carbohydrate intolerance and hyperinsulinemia. In addition we demonstrated alterations in growth hormone regulation, characterized by (1) the lack of suppression of growth hormone by orally induced hyperglycemia and paradoxical increase in serum levels of growth hormone after the administration of intravenous glucose or glucagon; (2) lack of release of growth hormone with induced hypoglycemia and an exaggerated response to levodopa administration. Furthermore, thyrotrophin-releasing hormone stimulated growth hormone release, a phenomenon not observed in the control population. Our studies show an impaired hypothalamic regulation of growth hormones secretion in patients with renal failure undergoing long-term hemodialysis.

Plasma 1,25-dihydroxyvitamin D levels in patients receiving anticonvulsant drugs.

Recent evidence has linked altered plasma vitamin D metabolite levels to the reported occurrence of hypocalcemia and other metabolic abnormalities in patients receiving anticonvulsant drugs. We have measured plasma levels of 25-hydroxyvitamin D (25-(OH)D) and 1,25-dihydroxyvitamin D (1,25-(OH)2D) in institutionalized patients on diphenylhydantoin (Dilantin) and/or phenobarbital therapy. Values were compared with those obtained in institutionalized patients receiving no drugs and with normal ambulatory subjects. Although plasma 25-(OH)D levels were lower in the patients on drugs, a deficiency of 1,25-(OH)2D, the tissue active metabolite of vitamin D, was not present. These results indicate that in patients taking anticonvulsant drugs, the serum calcium, phosphorus, alkaline phosphatase and parathyroid hormone (PTH) abnormalities are not caused by a defective formation of 1,25-(OH)2D.

Osteomalacia associated with anticonvulsant drug therapy in mentally retarded children.

A survey of 289 severely retarded inpatients at a school for retarded children in American Fork; Utah revealed 67 patients with osteomalacia as defined by hypocalcemia, hypophosphatemia, elevated serum alkaline phosphatase levels, and appropriate bone changes. Investigation of the variables which might influence bone mineralization revealed no differences in age, sex, physical activity, sunshine exposure, or dietary intake of vitamin D between the osteomalacia and nonosteomalacia groups. However, all of the patients with osteomalacia were receiving anticonvulsant medications, either phenobarbital, diphenylhydantoin, or both. Duration of anticonvulsant therapy was the most important contributing factor to the development of osteomalacia. Seventy-five percent of patients who had received anticonvulsants for more than ten years had osteomalacia. The single most costly medical problem at the school is the treatment of pathologic bone fractures due to demineralized bone.