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Food can have pro-inflammatory and anti-inflammatory effects. Pro-inflammatory effects can result from irritants and immunoreactive substances. These factors tend to have their effects, within the gut, which can be avoided by specific dietary exclusion. With regard to anti-inflammatory effects of diet away from the gut, altering the balance of dietary polyunsaturated fatty acids (PUFA) in favour of n-3 PUFA provides the best documented examples of effective dietary intervention. PUFA are essential macronutrients. There are two non-interchangeable classes of dietary PUFA, n-6 and n- 3. These fatty acids are metabolized to mediators that regulate cardiovascular homeostasis and inflammation. n-6 rich diets tend to be pro-inflammatory. Diets rich in n-3 PUFA, by comparison, are anti-inflammatory. The difference is explained by the action of n-3 PUFA as competitive inhibitors of enzymes that metabolize n-6 fats and by the lesser biological activities of some n-3 mediators, compared with their n-6 counterparts. Dietary enrichment of n-3 PUFA has been used with benefit in the treatment of inflammatory diseases of joints, kidney, gut and skin. Long-term studies in rheumatoid arthritis show that this approach, in conjunction with pharmacotherapy, can be sustained in the long term (>5 years). A potential collateral benefit of this approach is reduced risk for adverse cardiovascular events. Long chain n-3 PUFA found in fish and fish oil appear to be more potent as anti-inflammatory agents than shorter chain n-3 PUFA found in some vegetable oils. The latter can be useful as part of a broader dietary prescription and may have preventive effects. [ABSTRACT FROM AUTHOR]

The article focuses on double-blind Randomised Controlled Trial (RCT) with low dose fish oil (FO) in rheumatoid arthritis (RA) in treat-to-target therapy. Topics discussed include effect of fish oil on disease-modifying anti-rheumatic drug (DMARD); reduced DMARD failure in the high dose FO group; and doses given according to an algorithm based on disease activity.

Objective : We undertook a comprehensive cross-sectional analysis of a multicentred Australian cohort of systemic sclerosis (SSc) patients to evaluate the associations of anti-Ro52/TRIM21 with SSc pulmonary involvement. Method : The study included 596 patients from the Australian Scleroderma Cohort Study database whose anti-Ro52/TRIM21 status was known. Anti-Ro52/TRIM21 was measured via line immunoassay. Data on demographic variables, autoantibody profiles, presence of interstitial lung disease (ILD), presence of pulmonary arterial hypertension (PAH), oxygen saturation, Six-Minute Walk Test distance, Borg dyspnoea score, and lung function tests were extracted. SPSS software was used to examine associations using univariate and multivariate analyses. Results : Anti-Ro52/TRIM21 was present in 34.4% of SSc patients. In the cross-sectional analysis, anti-Ro52/TRIM21 was independently associated with PAH [odds ratio 1.75, 95% confidence interval (CI) 1.05-2.90], but not ILD or other surrogate measures of pulmonary involvement such as average patient oxygen saturation. The antibody, however, was also associated with a higher forced vital capacity/diffusing capacity of the lung for carbon monoxide ratio. Prospectively, anti-Ro52/TRIM21 was also associated with an increased risk of death in patients with SSc (hazard ratio 1.62, 95% CI 1.11-2.35), independent of confounding factors. The primary cause of death appeared to be related to PAH and/or ILD, and anti-Ro52/TRIM21 was associated with PAH-related complications. Conclusion : Anti-Ro52/TRIM21 was independently associated with PAH and mortality in SSc patients. Future longitudinal studies are recommended to investigate the timing and pathogenic mechanisms of this autoantibody in PAH.

The remarkable similarity in inflammatory response and pathology of periodontal disease and rheumatoid arthritis has been recognized for several decades. However, how these two disease may be interrelated has been less clear. During the pathogenesis of rheumatoid arthritis there is a preclinical immunological phase which precedes the clinical manifestation of rheumatoid arthritis. During this phase serum autoantibodies appear many years before the clinical signs and symptoms of rheumatoid arthritis become apparent. To date, the two best studied autoantibodies have been rheumatoid factor and anti-citrullinated protein antibodies (ACPA). Of these the production of ACPA has been considered very important due to their high predictive value in future manifestation of rheumatoid arthritis. Citrullination is a common post-translational modification of proteins based on the enzymatic conversion of arginine into citrulline. Extra-articular citrullination and production of ACPA, as a priming immunological experience, is well documented in many tissues including the inflamed gingival tissues associated with periodontal disease. More recently, carbamylation of proteins has also been implicated in the pathogenesis of rheumatoid arthritis in a manner similar to citrullination. Carbamylation is a post translational modification of proteins by an enzyme-independent modification of lysine residues against which autoantibodies are subsequently induced. In this article we hypothesise that, like citrullination, carbamylation of proteins and associated antibody production during the gingival inflammation associated with gingivitis and periodontitis may play a role in the pathogenesis of rheumatoid arthritis., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

A semiphysiologically based pharmacokinetic (semi-PBPK) population model was used to evaluate the influence of enterohepatic recycling and protein binding, as well as the effect of genetic variability in CYP1A2, CYP2C19, and ABCG2, on the large interindividual variability of teriflunomide (active metabolite) concentrations following leflunomide administration in rheumatoid arthritis (RA) patients. The model was developed with total and free teriflunomide concentrations determined in RA patients taking leflunomide, as well as mean teriflunomide concentrations following the administration of leflunomide or teriflunomide extracted from the literature. Once developed, the 15-compartment model was able to predict total and free teriflunomide concentrations and was used to screen demographic and genotypic covariates, of which only fat-free mass and liver function (ALT) improved prediction. This approach effectively evaluated the effects of multiple covariates on both total and free teriflunomide concentrations, which have only been explored previously through simplistic one-compartment models for total teriflunomide.

Objectives: To determine the prevalence and correlates of antiphospholipid antibodies (APLA) in systemic sclerosis (SSc)., Methods: Nine hundred and forty SSc patients were tested for APLA using an ELISA assay at recruitment. Clinical manifestations were defined as present, if ever present from SSc diagnosis. Logistic regression analysis was used to determine the associations of APLA., Results: One or more types of APLA were present in 226 (24.0%) patients. Anticardiolipin (ACA) IgG (ACA-IgG) antibodies were associated with right heart catheter-diagnosed pulmonary arterial hypertension (PAH), with higher titres corresponding with a higher likelihood of PAH (moderate titre (20-39 U/ml) ACA-IgG odds ratio [OR] 1.70, 95% CI: 1.01-2.93, p=0.047; high titre (>40 U/ml) ACA-IgG OR 4.60, 95% CI:1.02-20.8, p=0.047). Both ACA-IgM (OR 2.04, 95% CI: 1.4-3.0, p<0.0001) and ACA-IgG (OR 1.84, 95% CI: 1.2-2.8, p=0.005) were associated with interstitial lung disease (ILD). Increasing ACA-IgM and IgG titres were associated with increased likelihood of ILD. ACA-IgG was a marker of coexistent pulmonary hypertension and ILD (ILD-PH) (OR 2.10, 95% CI: 1.1-4.2, p=0.036). We also found an association between ACA-IgG and digital ulcers (OR 1.76, 95% CI: 1.16-2.67, p=0.008) and ACA-IgM and Raynaud's phenomenon (OR 2.39, 95% CI: 1.08-5.27, p=0.031). There was no association between APLA and SSc disease subtype, peak skin score, presence of other autoantibodies, mortality or other disease manifestations., Conclusions: The association of APLA with PAH, ILD, ILD-PH, Raynaud's phenomenon and digital ulcers suggests that endothelial abnormalities and small vessel thrombosis may be important in the pathogenesis of these disease features.

Eicosanoids derived from the n-6 fatty acid, arachidonic acid, and the cytokines interleukin-1beta and tumour necrosis factor-alpha are involved in the signs and symptoms of inflammatory joint disease, as well as the cartilage degradation seen in established rheumatoid arthritis (RA). Then n-3 fatty acids in fish and fish oil can inhibit production of both eicosanoid and cytokine inflammatory mediators and therefore, have the potential to modify RA pathology. Epidemiological studies suggest that fish intake may be preventive for RA and double-blind placebo-controlled studies demonstrate that dietary fish oil can alleviate the signs and symptoms of RA. The implementation of these findings will require among other things, a range of n-3 fat enriched foods, as well as physician awareness of the possibilities for dietary n-3 fat increases to be used as adjunctive therapy in RA.

A system has been established to assess the recruitment of 99mTc-hexamethylpropylene amine oxamine (99mTc-HMPAO)-labelled PBMC and [125I]iododeoxyuridine-labelled Con A stimulated lymphoblasts to allogeneic human synovial xenografts in the ears of SCID mice. Successful engraftment of osteoarthritic synovium was achieved in approximately 90% of cases and a connection between the human microvasculature of the xenograft and the circulation of the mouse was shown. Cells were delivered to the xenograft by a system of regional vascular perfusion, thus avoiding the major murine vascular beds. The accumulation of 99mTc-HMPAO-labelled PBMC in mouse ears was monitored in real time. Direct injection of xenograft-bearing ears with recombinant human TNF-alpha, 7 h prior to perfusion, increased the accumulation of both PBMC and lymphoblasts in cytokine-injected ears compared to contralateral control-injected ears. Autoradiography revealed the presence of [125I]iododeoxyuridine-labelled lymphoblasts associated with human microvasculature within the xenograft. However, the increased accumulation of lymphoblasts in cytokine-injected ears occurred in the tissues surrounding the xenograft, where lymphoblasts were associated more often with murine than human vessels. Although the system described offers advantages over similar models, the propensity for mouse endothelium to interact with human leucocytes is likely to be a generic disadvantage for models of human leucocyte recruitment to xenografts in immunodeficient mice.

Objective: To examine expression of adhesion molecules within human synovial xenografts in vivo after injection of human cytokines or peripheral blood mononuclear cells (PBMC)., Methods: Rheumatoid synovium was transplanted into subcutaneous pouches in the ears of severe combined immunodeficient (SCID) mice. Tumor necrosis factor-alpha (TNF-alpha), interleukin 1beta (IL-1beta), or PBMC were injected into the xenografts. The grafts were assessed by immunohistochemistry and quantitative video image analysis., Results: TNF-alpha, IL-1beta, and concanavalin A activated PBMC increased the expression of vascular cellular adhesion molecule 1 and intercellular adhesion molecule 1 significantly on vessels and nonvascular synovial cells compared with injection of medium only. Vascular expression of E-selectin, but not of MHC Class II, was also increased. These stimuli also induced the migration of murine leukocytes into the xenografts., Conclusion: Rheumatoid synovial xenografts in SCID mice respond by upregulation of adhesion molecule expression when challenged in vivo with proinflammatory cytokines or activated PBMC.

This work was undertaken to examine whether human synovium could be engrafted into subcutaneous pouches in the ears of severe combined immunodeficient (SCID) mice. Synovium was transplanted into surgically constructed ear pouches. The grafts were examined by histological and immunohistochemical methods after varying periods after engraftment, or after percutaneous injection of TNF-alpha. Normal, osteo-arthritic and rheumatoid synovium was engrafted successfully in subcutaneous ear pouches. The general morphology and cellular compositions of xenografts were retained including human endothelial cells. In rheumatoid xenografts, macrophages, fibroblasts and lymphocytes persisted for at least 4 weeks. Vascular expression of intercellular adhesion molecule-1 (ICAM-1) was maintained but expression of vascular adhesion molecule-1 (VCAM-1), E-selectin and MHC class II diminished with time. Percutaneous injection of TNF-alpha induced up-regulation of VCAM-1. Human synovium can be engrafted into subcutaneous ear pouches in SCID mice. The xenografts are accessible and respond to injection of a pro-inflammatory cytokine.

Objective: To devise and use a method for assessing the effect of dynamic exercise on synovial blood flow in knees with effusions., Methods: The clearance rate of intraarticular 99mTc-DTPA (diethylene triamine pentaacetic acid) was continuously monitored by a gamma camera during periods of rest or flexion. The rate of 99mTc-DTPA disappearance during a fixed period of exercise which was interposed between 2 rest periods was estimated by extrapolation between the clearance curves for the 2 rest periods., Results: Cycling and walking increased the clearance rate, straight leg raising had no effect, and flexion decreased the clearance rate., Conclusion: Our results suggest that some dynamic exercises can increase the rate of synovial blood flow in joints with effusions. This outcome may be beneficial in inflamed joints which are chronically hypoxic due to elevated intraarticular pressure and consequent chronic synovial ischemia.

A female subject dependent on long-term total parenteral nutrition developed an aversion and noncompliance to a prescribed weekly lipid infusion designed to meet essential fatty acid (EFA) requirements. Fatty acids (FA) in the subject's plasma and isolated peripheral blood neutrophils were analyzed in search of biochemical evidence of EFA deficiency. Neutrophil 5-lipoxygenase metabolism was examined to assess the possible effects of EFA deficiency on neutrophil eicosanoid metabolism. EFA deficiency was confirmed by marked depletion of linoleic acid (18:2n-6) and accumulation of eicosatrienoic acid (ETrA; 20:3n-9) in plasma and neutrophil phospholipids. In the neutrophils, ETrA comprised 5.2% of phospholipid FA (normal reference values < 0.1%), and arachidonic acid (AA; 20:4n-6) comprised 8.6% of phospholipid FA (normal reference range 10-16%). When stimulated by A23187 in vitro on three separate occasions, the subject's neutrophils displayed impaired synthesis of leukotriene B4 (LTB4), but produced normal amounts of 5-hydroxy-eicosatetraenoic acid and all-trans isomers of LTB4 formed nonenzymatically from leukotriene A4 (LTA4). This pattern of synthesis suggested inhibition of LTA hydrolase and was also seen in neutrophils from healthy subjects by addition of exogenous ETrA in vitro. Comparative studies of the effects of ETrA and eicosapentaenoic acid (20:5n-3) on neutrophils in vitro suggested that ETrA is the more potent inhibitor. Accumulation of ETrA, rather than depletion of AA, appears principally responsible for the observed impairment of neutrophil LTB4 synthesis seen in this EFA-deficient subject.

Objective: To examine the effect of methotrexate (MTX) administered in vivo on the production of the 5-lipoxygenase (5-LO) metabolites of arachidonic acid by neutrophils from subjects with rheumatoid arthritis., Methods: Neutrophils were isolated from peripheral blood samples taken 12 h before and 12 h after the ingestion of an oral dose of MTX and stimulated in vitro by calcium ionophore A23187. Lipid extracts of cell suspensions were assayed for leukotriene B4 (LTB4), the all-trans isomers of LTB4, 20-hydroxy LTB4 and 5-hydroxyeicosatetraenoic acid by high pressure liquid chromatography., Results: An increase in the production of all measured 5-LO metabolites was seen between the pre and postdose assessments., Conclusion: Our results do not support the putative inhibitory effect of MTX on 5-LO metabolism.