Evan Beckman

Genome-Wide Association Scan Identifies Candidate Polymorphisms Associated with Differential Response to Anti-TNF Treatment in Rheumatoid Arthritis

The prediction of response (or non-response) to anti-TNF treatment for rheumatoid arthritis (RA) is a pressing clinical problem. We conducted a genome-wide association study using the Illumina HapMap300 SNP chip on 89 RA patients prospectively followed after beginning anti-TNF therapy as part of Autoimmune Biomarkers Collaborative Network (ABCoN [Autoimmune Bio-markers Collaborative Network]) patient cohort. Response to therapy was determined by the change in Disease Activity Score (DAS28) observed after 14 wks. We used a two-part analysis that treated the change in DAS28 as a continuous trait and then incorporated it into a dichotomous trait of “good responder” and “nonresponder” by European League Against Rheumatism (EULAR) criteria.We corrected for multiple tests by permutation, and adjusted for potential population stratification using EIGENSTRAT. Multiple single nucleotide polymorphism (SNP) markers showed significant associations near or within loci including: the v-maf musculoaponeurotic fibrosarcoma oncogene homolog B (MAFB) gene on chromosome 20; the type I interferon gene IFNk on chromosome 9; and in a locus on chromosome 7 that includes the paraoxonase I (PON1) gene. An SNP in the IL10 promoter (rs1800896) that was previously reported as associated with anti-TNF response was weakly associated with response in this cohort. Replications of these results in independent and larger data sets clearly are required. We provide a reference list of candidate SNPs (P < 0.01) that can be investigated in future pharmacogenomic studies.

Effects of BG9719 (CVT-124), an A1-Adenosine receptor antagonist, and furosemide on glomerular filtration rate and natriuresis in patients with congestive heart failure

OBJECTIVES To determine the effects of furosemide and the selective A1 adenosine receptor BG9719 on renal function in patients with congestive heart failure (CHF). BACKGROUND Studies suggest that adenosine may affect renal function by various mechanisms, but the effects of blockade of this system in humans is unknown. In addition, the effects of a therapeutic dose of furosemide on glomerular filtration rate (GFR) and renal plasma flow (RPF) in heart failure patients are controversial. METHODS On different days, 12 patients received placebo, BG9719 and furosemide. Glomerular filtration rate, RPF and sodium and water excretion were assessed immediately following drug administration. RESULTS Glomerular filtration rate was 84 +/- 23 ml/min/1.73m2 after receiving placebo, 82 +/- 24 following BG9719 administration and a decreased (p < 0.005) 63 +/- 18 following furosemide. Renal plasma flow was unchanged at 293 +/- 124 ml/min/1.73m2 on placebo, 334 +/- 155 after receiving BG9719 and 374 +/- 231 after receiving furosemide. Sodium excretion increased from 8 +/- 8 mEq following placebo administration to 37 +/- 26 mEq following BG9719 administration. In the six patients in whom it was measured, sodium excretion was 104 +/- 78 mEq following furosemide administration. CONCLUSIONS Natriuresis is effectively induced by both furosemide and the adenosine A1 antagonist BG9719 in patients with CHF. Doses of the two drugs used in this study did not cause equivalent sodium and water excretion but only furosemide decreased GFR. These data suggest that adenosine is an important determinant of renal function in patients with heart failure.

Lymphotoxin-LIGHT Pathway Regulates the Interferon Signature in Rheumatoid Arthritis

A subset of patients with autoimmune diseases including rheumatoid arthritis (RA) and lupus appear to be exposed continually to interferon (IFN) as evidenced by elevated expression of IFN induced genes in blood cells. In lupus, detection of endogenous chromatin complexes by the innate sensing machinery is the suspected driver for the IFN, but the actual mechanisms remain unknown in all of these diseases. We investigated in two randomized clinical trials the effects on RA patients of baminercept, a lymphotoxin-beta receptor-immunoglobulin fusion protein that blocks the lymphotoxin-αβ/LIGHT axis. Administration of baminercept led to a reduced RNA IFN signature in the blood of patients with elevated baseline signatures. Both RA and SLE patients with a high IFN signature were lymphopenic and lymphocyte counts increased following baminercept treatment of RA patients. These data demonstrate a coupling between the lymphotoxin-LIGHT system and IFN production in rheumatoid arthritis. IFN induced retention of lymphocytes within lymphoid tissues is a likely component of the lymphopenia observed in many autoimmune diseases. ClinicalTrials.gov NCT00664716.

Renal effects of BG9719, a specific A1 adenosine receptor antagonist, in congestive heart failure

A1 adenosine receptors mediate renal afferent arteriolar vasoconstriction when distal tubular Na+ concentrations increase (tubuloglomerular feedback, TGF). A1 adenosine receptor stimulation also increases both proximal and distal tubular Na+ reabsorption. Thus, an A1 adenosine receptor antagonist might produce natriuresis while maintaining renal blood flow and glomerular filtration. BG9719 (also known as CVT‐124) is a selective A1 adenosine receptor antagonist. Its natriuretic properties have been demonstrated both in healthy volunteers and in patients with congestive heart failure (CHF) in double‐blind, two‐period crossover studies of similar design. In each study, subjects received a single intravenous dose of BG9719 (0.30 mg/kg) or matching placebo on separate days. BG9719 increased Na+ excretion in both volunteers and CHF patients; the effects were proportionately greater in CHF. In volunteers, mean Na+ excretion during the first 3 h after BG9719 was more than double that after placebo (151.5 mEq vs. 63.8 mEq; P < 0.01); whereas in CHF patients, the increase was nearly fourfold (54.5 mEq vs. 15.0 mEq; P < 0.05). In contrast, effects on K+ excretion were small. In volunteers, mean K+ excretion was 22.7 mEq on BG9719 vs. 19.3 mEq on placebo (P < 0.05); in CHF, these values were 11.8 mEq vs. 7.5 mEq, respectively (P = 0.06). Uric acid was not retained and creatinine clearance was not affected in either group. Mean Cmax was similar in volunteers and CHF patients, but clearance of the drug was reduced in CHF, resulting in a longer half‐life. Increases in Na+ excretion with minimal urinary K+ losses suggest inhibition of both proximal tubular Na+ reabsorption and distal Na+‐K+ exchange by BG9719. A stable creatinine clearance despite natriuresis is consistent with TGF interruption. These properties may render BG9719 especially useful in diuretic‐resistant patients with CHF complicated by renal dysfunction. Drug Dev. Res. 45:166–171, 1998.

Biological Significance of Anti–Cyclic Citrullinated Peptide Antibody in Rheumatoid Arthritis

TO THE EDITOR: We read with great interest the thorough meta-analysis and review by Nishimura and colleagues (1) on the diagnostic accuracy of anticyclic citrullinated peptide (CCP) antibody in rheumatoid arthritis (RA). The authors conclude that although anti-CCP antibodies are more specific than rheumatoid factor, their sensitivity is only 67%. However, we believe that anti-CCP may in fact define a biologically distinct subset of RA, and therefore a simple assessment of its sensitivity for RA in general may be misleading. Emerging data show that the presence of anti-CCP antibodies interacts with genetic risk factors, such as the shared epitope in the human leukocyte antigen locus (2); environmental risk factors, such as smoking (3, 4); and response to treatment (5). Therefore, anti-CCP positivity may not be as important for diagnosing RA as for being the first of a new generation of biomarkers that allow us to redefine RA according to biological and genetic categories rather than purely phenotypic ones. Such a transition has already begun in oncology, where lymphomas have been reclassified according to biomarker status rather than histology, leading to better definition of prognosis and treatment responses (6). Thus, in the future, we should be thinking not about the sensitivity and specificity of CCP for RA, but rather about anti-CCPpositive versus anti-CCPnegative RA.