Failure of combined chloroquine and High-Dose primaquine therapy for plasmodium vivax malaria acquired in Guyana, South America

The presence of chloroquine-resistant Plasmodium vivax malaria in the New World has been suspected but not confirmed. We report the cases of three patients who acquired vivax malaria in Guyana, South America, and for whom standard chloroquine therapy (25 mg/kg) failed despite therapeutic blood levels. The optimal treatment of chloroquine-resistant P. vivax malaria is unknown, but recent studies suggest that a combination of chloroquine (25 mg/kg) and high-dose primaquine (2.5 mg/kg over 48 hours) is effective therapy. Two of our patients had recurrences of P. vivax malaria 6–8 weeks after receiving directly observed therapy with this combination. These cases confirm the presence of chloroquine-resistant P. vivax in Guyana and emphasize the need for better treatment regimens for chloroquine-resistant and primaquine-resistant P. vivax malaria

Patient-reported outcomes from a phase III study of baricitinib in patients with conventional synthetic DMARD-refractory rheumatoid arthritis

Objectives: To evaluate the effect of baricitinib on patient-reported outcomes (PROs) in patients with active rheumatoid arthritis (RA) and an inadequate response or intolerance to conventional synthetic disease-modifying antirheumatic drugs. Methods: In this phase III study, patients were randomised 1:1:1 to placebo (N=228), baricitinib 2 mg once daily (QD, N=229) or baricitinib 4 mg QD (N=227). PROs included the Health Assessment Questionnaire-Disability Index (HAQ-DI), Patient's Global Assessment of Disease Activity (PtGA), patient's assessment of pain, measures from patient electronic daily diaries (duration and severity of morning joint stiffness (MJS), Worst Tiredness, Worst Joint Pain), Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), SF-36, EuroQol 5-D index scores and visual analogue scales (VAS) and the Work Productivity and Activity Impairment Questionnaire-RA. The primary time point for the study was week 12. Treatment comparisons were assessed with logistic regression for categorical measures and analysis of covariance for continuous variables. Results: Statistically significant improvements were observed for both baricitinib groups versus placebo in HAQ-DI, PtGA, pain, daily diary measures, EuroQoL index scores and SF-36 physical component score at week 12 and for those measures when assessed at week 24. Baricitinib 2 mg and baricitinib 4 mg were statistically significantly improved versus placebo for the EuroQoL VAS and FACIT-F, respectively, at week 24. Conclusions: Baricitinib 2 or 4 mg provided significant improvement versus placebo in PROs across different domains of RA, including physical function, MJS, fatigue, pain and quality of life

The Relationship Between Function and Disease Activity as Measured by the HAQ and DAS28 Varies Over Time and by Rheumatoid Factor Status in Early Inflammatory Arthritis (EIA). Results from the CATCH Cohort§

Objective: To investigate the relationship between function and disease activity in early inflammatory arthritis (EIA). Methods: Canadian Early Arthritis Cohort (CATCH) (n=1143) is a multi-site EIA cohort. Correlations between the Health Assessment Questionnaire Disability Index (HAQ) and DAS28 were done at every 3 months for the first year and then at 18 and 24 months. We also investigated the relationship between HAQ and DAS28 by age (<65 versus ≥65) and RF (positive vs negative). Results: Mean HAQ and DAS28 scores were highest at the initial visit with HAQ decreasing over 24 months from a baseline of 0.94 to 0.40 and DAS28 scores decreasing from 4.54 to 2.29. All correlations between HAQ and DAS28 were significant at all time points (p<0.01). The correlations between HAQ and DAS28 were variable over time. The strongest correlation between HAQ and DAS28 occurred at initial visit (most DMARD naive) (n=1,143) and 18 months (r=0.57, n=321) and 24 months (r=0.59, n=214). The baseline correlation between HAQ and DAS28 was significantly different than correlations obtained at 3, 6, and 12 months (p=0.02, 0.01, and 0.01, respectively). Age did not change the association between HAQ and DAS28 {<65 years old (r=0.50, n=868) versus ≥65 (r=0.48, n=254), p=0.49}. The correlation between HAQ and DAS28 was stronger with RF+ patients (r=0.63, n=636) vs RF negative (r=0.47, n=477), p=0.0043 Conclusion: Over 2 years in EIA, HAQ and DAS both improved; correlations at time points were different over 2 years and RF status affected the correlations

New insights into the impact of neuro-inflammation in rheumatoid arthritis.

Rheumatoid arthritis (RA) is considered to be, in many respects, an archetypal autoimmune disease that causes activation of pro-inflammatory pathways resulting in joint and systemic inflammation. RA remains a major clinical problem with the development of several new therapies targeted at cytokine inhibition in recent years. In RA, biologic therapies targeted at inhibition of tumor necrosis factor alpha (TNFα) have been shown to reduce joint inflammation, limit erosive change, reduce disability and improve quality of life. The cytokine TNFα has a central role in systemic RA inflammation and has also been shown to have pro-inflammatory effects in the brain. Emerging data suggests there is an important bidirectional communication between the brain and immune system in inflammatory conditions like RA. Recent work has shown how TNF inhibitor therapy in people with RA is protective for Alzheimer's disease. Functional MRI studies to measure brain activation in people with RA to stimulus by finger joint compression, have also shown that those who responded to TNF inhibition showed a significantly greater activation volume in thalamic, limbic, and associative areas of the brain than non-responders. Infections are the main risk of therapies with biologic drugs and infections have been shown to be related to disease flares in RA. Recent basic science data has also emerged suggesting that bacterial components including lipopolysaccharide induce pain by directly activating sensory neurons that modulate inflammation, a previously unsuspected role for the nervous system in host-pathogen interactions. In this review, we discuss the current evidence for neuro-inflammation as an important factor that impacts on disease persistence and pain in RA

High remission and low relapse with prolonged intensive DMARD therapy in rheumatoid arthritis (PRINT): A multicenter randomized clinical trial

Objectives: To determine whether prolonged intensive disease-modifying antirheumatic drug (DMARD) treatment (PRINT) leads to high remission and low relapse rates in patients with severe rheumatoid arthritis (RA). Methods: In this multicenter, randomized and parallel treatment trial, 346 patients with active RA (disease activity score (28 joints) [DAS28] (erythrocyte sedimentation rate [ESR]) &gt; 5.1) were enrolled from 9 centers. In phase 1, patients received intensive treatment with methotrexate, leflunomide, and hydroxychloroquine, up to 36 weeks, until remission (DAS28 ≤ 2.6) or a low disease activity (2.6 &#60; DAS28 ≤ 3.2) was achieved. In phase 2, patients achieving remission or low disease activity were followed up with randomization to 1 of 2 step-down protocols: leflunomide plus hydroxychloroquine combination or leflunomide monotherapy. The primary endpoints were good European League Against Rheumatism (EULAR) response (DAS28 (ESR) &#60; 3.2 and a decrease of DAS28 by at least 1.2) during the intensive treatment and the disease state retention rate during step-down maintenance treatment. Predictors of a good EULAR response in the intensive treatment period and disease flare in the maintenance period were sought. Results: A good EULAR response was achieved in 18.7%, 36.9%, and 54.1% of patients at 12, 24, and 36 weeks, respectively. By 36 weeks, 75.4% of patients achieved good and moderate EULAR responses. Compared with those achieving low disease activity and a high health assessment questionnaire (HAQ &gt; 0.5), patients achieving remission (DAS28 ≤ 2.6) and low HAQ (≤ 0.5) had a significantly higher retention rate when tapering the DMARDs treatment (P = 0.046 and P = 0.01, respectively). There was no advantage on tapering to combination rather than monotherapy. Conclusions: Remission was achieved in a proportion of patients with RA receiving prolonged intensive DMARD therapy. Low disease activity at the start of disease taper leads to less subsequent flares. Leflunomide is a good maintenance treatment as single treatment

High frequency of antidrug antibodies and association of random drug levels with efficacy in certolizumab pegol-treated patients with rheumatoid arthritis: results from the BRAGGSS cohort

Objectives: To evaluate (i) the association between random certolizumab drug levels, antidrug antibodies (ADAbs) and treatment response in patients with rheumatoid arthritis (RA); (ii) longitudinal factors associated with ADAbs and certolizumab drug levels. Methods: This prospective cohort included 115 patients with RA treated with certolizumab. Serum samples were collected at 3, 6 and 12 months following treatment initiation. Drug levels and ADAbs were measured using ELISA and radioimmunoassay, respectively, at 3, 6 and 12 months. Disease Activity Score in 28 joints (DAS28) were measured at each visit and 12 months European League Against Rheumatism (EULAR) response was calculated. Patient self-reported adherence was collected longitudinally. Ordinal logistic regression and generalised estimating equation were used to test the association: (i) between drug levels, from serum sampled and treatment response; (ii) between ADAbs and drug levels; (iii) patient-centred factors and drug levels. Results: ADAbs were detected in 37% (42/112 patients by 12 months). The presence of ADAbs were significantly associated with lower drug levels over 12 months (β=−0.037, 95% CI −0.055 to 0.018, p<0.0001) but not independently with 12 months EULAR response (β=0.0013 (95% CI −0.0032 to 0.00061), p=0.18). Drug level was associated with 12 months EULAR response (β=0.032 (95% CI 0.0011 to 0.063), p=0.042). In the multivariate model, ADAb level and adherence were significantly associated with drug concentrations. Conclusions: This is the first study to demonstrate that higher certolizumab drug levels are associated with better 12 months EULAR response. ADAbs in certolizumab-treated patients with RA were detected at higher levels than previous studies and help determine the aetiology of a low drug level

Development of EULAR recommendations for the reporting of clinical trial extension studies in rheumatology

Objectives: Our initiative aimed to produce recommendations on post-randomised controlled trial (RCT) trial extension studies (TES) reporting using European League Against Rheumatism (EULAR) standard operating procedures in order to achieve more meaningful output and standardisation of reports. Methods: We formed a task force of 22 participants comprising RCT experts, clinical epidemiologists and patient representatives. A two-stage Delphi survey was conducted to discuss the domains of evaluation of a TES and definitions. A ‘0–10’ agreement scale assessed each domain and definition. The resulting set of recommendations was further refined and a final vote taken for task force acceptance. Results: Seven key domains and individual components were evaluated and led to agreed recommendations including definition of a TES (100% agreement), minimal data necessary (100% agreement), method of data analysis (agreement mean (SD) scores ranging between 7.9 (0.84) and 9.0 (2.16)) and reporting of results as well as ethical issues. Key recommendations included reporting of absolute numbers at each stage from the RCT to TES with reasons given for drop-out at each stage, and inclusion of a flowchart detailing change in numbers at each stage and focus (mean (SD) agreement 9.9 (0.36)). A final vote accepted the set of recommendations. Conclusions: This EULAR task force provides recommendations for implementation in future TES to ensure a standardised approach to reporting. Use of this document should provide the rheumatology community with a more accurate and meaningful output from future TES, enabling better understanding and more confident application in clinical practice towards improving patient outcomes

MRI assessment of suppression of structural damage in patients with rheumatoid arthritis receiving rituximab: results from the randomised, placebo-controlled, double-blind RA-SCORE study

Objective To evaluate changes in structural damage and joint inflammation assessed by MRI following rituximab treatment in a Phase 3 study of patients with active rheumatoid arthritis (RA) despite methotrexate (MTX) who were naive to biological therapy. Methods Patients were randomised to receive two infusions of placebo (n=63), rituximab 500 mg (n=62), or rituximab 1000 mg (n=60) intravenously on days 1 and 15. MRI scans and radiographs of the most inflamed hand and wrist were acquired at baseline, weeks 12 (MRI only), 24 and 52. The primary end point was the change in MRI erosion score from baseline at week 24. Results Patients treated with rituximab demonstrated significantly less progression in the mean MRI erosion score compared with those treated with placebo at weeks 24 (0.47, 0.18 and 1.60, respectively, p=0.003 and p=0.001 for the two rituximab doses vs placebo) and 52 (−0.30, 0.11 and 3.02, respectively; p<0.001 and p<0.001). Cartilage loss at 52 weeks was significantly reduced in the rituximab group compared with the placebo group. Other secondary end points of synovitis and osteitis improved significantly with rituximab compared with placebo as early as 12 weeks and improved further at weeks 24 and 52. Conclusions This study demonstrated that rituximab significantly reduced erosion and cartilage loss at week 24 and week 52 in MTX-inadequate responder patients with active RA, suggesting that MRI is a valuable tool for assessing inflammatory and structural damage in patients with established RA receiving rituxima

Identification of the NF-κB activating protein-like locus as a risk locus for rheumatoid arthritis

Objective: To fine-map the NF-κB activating protein-like (NKAPL) locus identified in a prior genome-wide study as a possible rheumatoid arthritis (RA) risk locus and thereby delineate additional variants with stronger and/or independent disease association. Methods: Genotypes for 101 SNPs across the NKAPL locus on chromosome 6p22.1 were obtained on 1368 Canadian RA cases and 1471 controls. Single marker associations were examined using logistic regression and the most strongly associated NKAPL locus SNPs then typed in another Canadian and a US-based RA case/control cohort. Results: Fine-mapping analyses identified six NKAPL locus variants in a single haplotype block showing association with p≤5.6×10−8 in the combined Canadian cohort. Among these SNPs, rs35656932 in the zinc finger 193 gene and rs13208096 in the NKAPL gene remained significant after conditional logistic regression, contributed independently to risk for disease, and were replicated in the US cohort (Pcomb=4.24×10−10 and 2.44×10−9, respectively). These associations remained significant after conditioning on SNPs tagging the HLA-shared epitope (SE) DRB1*0401 allele and were significantly stronger in the HLA-SE negative versus positive subgroup, with a significant negative interaction apparent between HLA-DRB1 SE and NKAPL risk alleles. Conclusions: By illuminating additional NKAPL variants with highly significant effects on risk that are distinct from, but interactive with those arising from the HLA-DRB1 locus, our data conclusively identify NKAPL as an RA susceptibility locus