Effect of Adherence to Protocolized Targeted Intensifications of Disease-modifying Antirheumatic Drugs on Treatment Outcomes in Rheumatoid Arthritis: Results from an Australian Early Arthritis Cohort.

OBJECTIVE: To investigate the association between adherence to treat-to-target (T2T) protocol and disease activity, functional outcomes, and radiographic outcomes in early rheumatoid arthritis (RA). METHODS: Data from a longitudinal cohort of patients with early RA were used. Adherence was determined at each followup visit over 3 years according to predefined criteria. The primary endpoint was remission according to Disease Activity Score in 28 joints (DAS28) and Simplified Disease Activity Index (SDAI) criteria. Functional and radiographic outcomes measured by modified Health Assessment Questionnaire and modified total Sharp score, respectively, were secondary endpoints. RESULTS: A total of 198 patients with 3078 clinic visits over 3 years were included in this analysis. After adjusting for relevant variables, although there was no significant association between adherence to T2T and remission rate after 1 year, the associations reached significance after 3 years for both DAS28 (OR 1.71, 95% CI 1.16-2.50; p = 0.006) and SDAI criteria (OR 1.94, 95% CI 1.06-3.56; p = 0.033). After 3 years, adherence was also associated with improvement in physical function (ß=0.12, 95% CI 0.06-0.18; p < 0.0001). None of the radiographic outcomes were associated with adherence after either 1 or 3 years, although there was a trend for higher adherence to be associated with less radiographic progression at the end of the study (p = 0.061). CONCLUSION: Increased adherence to T2T was associated with better longterm disease activity and functional outcomes, which suggests that the benefit of a T2T protocol may be enhanced by ensuring adequate adherence.

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.

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.

Polymorphisms in cytochrome P450 2C19 enzyme and cessation of leflunomide in patients with rheumatoid arthritis.

INTRODUCTION: Rational selection of disease modifying anti-rheumatic drugs in the treatment of rheumatoid arthritis (RA) has many potential advantages, including rapid disease control, reduced long-term disability and reduced overall cost to the healthcare system. Inter-individual genetic differences are particularly attractive as markers to predict efficacy and toxicity, as they can be determined rapidly prior to drug selection. The aims of this study, therefore, were to investigate the association between differences in genes associated with the metabolism, clearance and efficacy of leflunomide with its cessation in a group of rheumatoid arthritis patients who were treated with an intensive contemporary, treat-to-target approach. METHODS: This retrospective cohort study identified all individuals who received leflunomide and were enrolled in the Early Arthritis inception cohort at the Royal Adelaide Hospital between 2001 and July 2011. Inclusion criteria were age (>18) and a diagnosis of rheumatoid arthritis. Patients were excluded if a DNA sample was not available, if they withdrew from the cohort or if clinical data were insufficient. Subjects were followed for 12 months or until either another disease modifying antirheumatic drug was added or leflunomide was ceased. The following single nucleotide polymorphisms (SNPs) were determined: CYP2C19*2 (rs4244285), CYP2C19*17 (rs12248560), ABCG2 421C>A (rs2231142), CYP1A2*1F (rs762551) and DHODH 19C>A (rs3213422). The effects of variables on cessation were assessed with Cox Proportional Hazard models. RESULTS: Thirty-three of 78 (42.3%) patients ceased leflunomide due to side effects. A linear trend between cytochrome P450 2C19 (CYP2C19) phenotype and leflunomide cessation was observed, with poor and intermediate metabolizers ceasing more frequently (adjusted Hazard Ratio = 0.432 for each incremental change in phenotype, 95% CI 0.237 to 0.790, P = 0.006). Previously observed associations between cytochrome P450 1A2 (CYP1A2) and dihydro-orotate dehydrogenase (DHODH) genotype and toxicity were not apparent, but there was a trend for ATP-binding cassette sub-family G member 2 (ABCG2) genotype to be associated with cessation due to diarrhea. CONCLUSIONS: CYP2C19 phenotype was associated with cessation due to toxicity, and since CYP2C19 intermediate and poor metabolizers have lower teriflunomide concentrations, it is likely that they have a particularly poor risk:benefit ratio when using this drug.

Recruitment and proliferation of CD4+ T cells in synovium following adoptive transfer of adjuvant-induced arthritis.

Adjuvant-induced arthritis can be transferred to naive Dark Agouti (DA) strain (DA.CD45.1) rats by thoracic duct (TD) lymphocytes. Disease can be re-induced in convalescent rats by further transfer of arthritogenic cells, suggesting that resolution of the adoptive disease is not due to active regulation. To examine whether resolution is due to exhaustion of effector cells, we transferred the disease to DA.CD45.1 recipients, using CD4+ T cells from DA.CD45.2 donors. At the height of the adoptively transferred disease, donor cells comprised only 5-10% of recirculating CD4+ T cells but they accounted for approximately 40% of the CD4+ T cells in synovium-rich tissues of the hind paws. Approximately 65% of the donor cells in the synovium expressed a marker of proliferation (Ki-67 antigen). Division of CD4+ T cells continued in shielded paws after suppression of the recirculating pool of lymphocytes by selective irradiation. Intravenously injected CD4+ TD T lymphoblasts from arthritic donors were recruited to normal paws and, in greater numbers, to paws of animals with existing arthritis. Survival of the [125I]iodo-deoxyuridine-labeled lymphoblasts was greater in animals with existing arthritis. We conclude that effector CD4+ T cells in target tissues can proliferate in response to autoantigens and exhibit enhanced survival. However, without a continuous supply, adoptively transferred effector cells do not produce autonomous local disease, due to limits to their lifespan and ability to replicate indefinitely.

Blockade of IFN-gamma does not affect the arthritogenicity of T cells generated during the induction of adjuvant arthritis but exacerbates the polyarthritis produced by adoptive transfer of arthritogenic effector cells.

IFN-gamma production is prominent in some models of autoimmune disease, including adjuvant arthritis (AA), but the role of IFN-gamma in the pathogenesis of these diseases is uncertain. Experimental manipulation (administration of cytokine, blocking cytokine action with specific antibody, disruption of genes encoding the cytokine or its receptor) has revealed both pro- and anti-inflammatory effects, depending on the nature of the manipulation and the timing of the treatment. We examined separately the effects of cytokine blockade during the afferent and efferent phases of AA in Dark Agouti rats, using an adoptive transfer system. Effects of IFN-gamma on the efferent phase were investigated by treating recipients with mAb DB-1, which blocks the activity of rat IFN-gamma. When treatment was commenced before cell transfer, the resulting polyarthritis was more severe than in controls treated with normal IgG. Commencing treatment after the adoptively transferred disease had become established caused neither amelioration nor exacerbation, but did cause some delay in resolution. In contrast, treatment of donors did not appear to affect the generation of arthritogenic cells. The main effect of IFN-gamma appears to be modulation of the arthritogenicity of the migratory effector T cells that can transfer AA.

Temporal changes in the distribution of thoracic duct lymphoblasts to synovium and other tissues of rats with adjuvant-induced arthritis.

The distribution of lymphoblasts(lymphocytes in cell cycle) obtained from the central lymph of donor rats and transferred adoptively to syngeneic recipients has been shown previously to be influenced by the presence of arthritis in either donor or recipient rats. The intent of the present study was to examine patterns of distribution of lymphoblasts in the early period after transfer, when extravasation of donor lymphoblasts was expected to occur. Thoracic duct lymphoblasts labelled in vitro with [125I]-iododeoxyuridine were detected in recipient rats by external radiometry and autoradiography. Irrespective of donor status, fewer donor lymphoblasts accumulated in the feet of normal recipients when compared to arthritic recipients at 15 min, 2 h and 24 h after cell transfer.When recipients of similar disease status were compared, the percentages of injected lymphoblasts from normal and arthritic donors recovered in the feet were similar at 15 min and 2 h after transfer. The proportions of lymphoblasts recovered in the feetat 24 h after injection declined in normal recipients and arthritic recipients of cells from normal donor rats. Importantly,this decline did not occur when both the donor and the recipient were arthritic. In the hindpaws, donor lymphoblasts were located predominantly in the bone marrow, except in transfers between arthriticrats, when at 24 h they were predominantly in the synovium. At 15 min, lymphoblasts were detected within the lumen of vessels within synovium, whereas by 2 h extravasation of these cells was evident. In conclusion, lymphoblasts accumulate more readily in hindfeet that are inflamed. In the early hours after injection, lymphoblasts from normal and arthritic donors are recruited equally, but these early levels are only maintained for 24 hin the combination of arthritic donor and arthritic recipient. Adramatic change in the proportion of lymphoblasts located in synoviumat this later time suggests that a dynamic process of relocation,retention and/or local cell division maintains the numbers of arthritic donor cells in the latter combination.