Keith K. Colburn

Abnormalities of Serum Antielastin Antibodies in Connective Tissue Diseases

Background Antibodies (Abs) to α-elastin (elastin breakdown product) and tropoelastin (elastin precursor) are found in the serum of all human subjects and correlate with their respective serum peptide levels; however, peptide levels vary with age and some disease states. This study was undertaken to determine if serum elastin Abs, peptides, and elastin metabolism were altered in autoimmune diseases by detecting a changing ratio of serum anti-α:tropoelastin Ab levels. Methods Serum from patients with a variety of connective tissue diseases, including 28 with systemic lupus erythematosus (SLE), 24 with scleroderma, 18 with rheumatoid arthritis (RA), 10 with polymyositis, and 39 with vasculitis, was compared with serum from 19 age-matched healthy subjects for levels of antitropoelastin and anti-α-elastin Abs. Results We found an increase in IgG anti-α-elastin and a decrease in antitropoelastin Abs in the sera of patients with scleroderma (p < .02 and .00005) and SLE (p < .006 and .011). There was also a marked increase in anti-α-elastin Abs in patients with polyarteritis nodosa (p < .0005) and decreases in antitropoelastin Abs in patients with RA (p < .05), polymyositis (p < .01), and a variety of other vasculidities (p < .0003). Conclusions Abnormal variations in elastin metabolism may be detected in several connective tissue diseases by measuring ratios of α- and tropoelastin IgG Abs as markers of elastin degradation and synthesis.

Differences in Mouse and Human Nonmemory B Cell Pools

Identifying cross-species similarities and differences in immune development and function is critical for maximizing the translational potential of animal models. Coexpression of CD21 and CD24 distinguishes transitional and mature B cell subsets in mice. In this study, we validate these markers for identifying analogous subsets in humans and use them to compare the nonmemory B cell pools in mice and humans, across tissues, and during fetal/neonatal and adult life. Among human CD19+IgM+ B cells, the CD21/CD24 schema identifies distinct populations that correspond to transitional 1 (T1), transitional 2 (T2), follicular mature, and marginal zone subsets identified in mice. Markers specific to human B cell development validate the identity of marginal zone cells and the maturation status of human CD21/CD24 nonmemory B cell subsets. A comparison of the nonmemory B cell pools in bone marrow, blood, and spleen in mice and humans shows that transitional B cells comprise a much smaller fraction in adult humans than mice. T1 cells are a major contributor to the nonmemory B cell pool in mouse bone marrow, in which their frequency is more than twice that in humans. Conversely, in spleen, the T1:T2 ratio shows that T2 cells are proportionally ∼8-fold higher in humans than in mice. Despite the relatively small contribution of transitional B cells to the human nonmemory pool, the number of naive follicular mature cells produced per transitional B cell is 3- to 6-fold higher across tissues than in mice. These data suggest differing dynamics or mechanisms produce the nonmemory B cell compartments in mice and humans.

Antiguanosine Antibodies: A New Marker for Procainamide-Induced Systemic Lupus Erythematosus

Antinuclear antibodies are present in most patients receiving procainamide. To ascertain whether IgG antiguanosine antibodies are associated with the development of the symptoms of systemic lupus erythematosus, we compared the levels of these antibodies in the sera of 65 patients receiving procainamide: 18 with procainamide-induced symptoms and 47 asymptomatic patients. Antinuclear antibodies measured by immunofluorescence were present in the 18 patients with drug-induced symptoms but also in 24 asymptomatic patients. Similarly, elevated serum levels of antibodies to single-stranded DNA were found in 15 patients with symptoms and in 20 asymptomatic patients. In contrast, levels of IgG antiguanosine antibodies were elevated in 15 patients with drug-induced symptoms, but in only 3 asymptomatic patients. Antiguanosine antibodies binding to single-stranded DNA were found primarily in patients with arthritis, pleuritis, and pericarditis. These results suggest a strong association between IgG antiguanosine antibodies and major manifestations of procainamide-induced systemic lupus erythematosus.

BRAF drives synovial fibroblast transformation in rheumatoid arthritis.

Synovial fibroblasts destroy articular cartilage and bone in rheumatoid arthritis, but the mechanism of fibroblast transformation remains elusive. Because gain-of-function mutations of BRAF can transform fibroblasts, we examined BRAF in rheumatoid synovial fibroblasts. The strong gain-of-function mutation, V600R, of BRAF found in melanomas and other cancers was identified in first passage synovial fibroblasts from two of nine rheumatoid arthritis patients and confirmed by restriction site mapping. BRAF-specific siRNA inhibited proliferation of synovial fibroblasts with V600R mutations. A BRAF aberrant splice variant with an intact kinase domain and partial loss of the N-terminal autoinhibitory domain was identified in fibroblasts from an additional patient, and fibroblast proliferation was inhibited by BRAF-specific siRNA. Our finding is the first to establish mechanisms for fibroblast transformation responsible for destruction of articular cartilage and bone in rheumatoid arthritis and establishes a new target for therapeutic intervention.

Abnormalities of Serum Anti-Elastin Antibodies in Patients with Polymyalgia Rheumatica

Background: Antibodies [Abs] to alpha-elastin [elastin breakdown product] and tropoelastin [elastin precursor] are found in serum of all human subjects and correlate with their respective serum peptide levels. Serum elastin peptide levels vary with age and some disease states. Vascular damage is thought to be a possible mechanism in the pathogenesis of polymyalgia rheumatica [PMR] and in the closely related condition of giant cell arteritis. Damage to elastin is a characteristic of giant cell arteritis. This study was undertaken to determine if the levels of serum Abs against elastin were altered in patients with PMR by measuring the ratio of serum anti-alpha elastin to anti-tropoelastin Abs compared to age matched controls. Methods: Sera from 37 elderly patients with PMR were compared with sera from 45 age-matched, otherwise healthy osteoarthritis subjects using an enzyme-linked immunosorbent assay that measured levels of anti-alpha and anti-tropoelastin Abs. Results: We found a decrease in anti-tropoelastin and an increase in anti-alpha-elastin immuno-globulin G Abs and in the sera of patients with PMR that were significantly different than the control levels [P < 0.008 [anti-tropoelastin] and 0.005 [anti-alpha-elastin]]. The ratio of anti-tropoelastin [synthesis] to anti-alpha-elastin [degradation] was 1.98 [PMR] versus 3.40 [control] [P < 0.001]. Conclusions: Variations in elastin metabolism were detected in PMR by the ratio of anti-tropoelastin to anti-alpha-elastin immunoglobulin G Abs that represents elastin synthesis and degradation, respectively. This study suggests that there was a decrease in elastin production as well as an increase in elastin destruction in patients with PMR that may be reflecting disease pathology.

Triple therapy versus biologic therapy for Active Rheumatoid Arthritis a cost-effectiveness analysis

BackgroundnThe RACAT (Rheumatoid Arthritis Comparison of Active Therapies) trial found triple therapy to be noninferior to etanercept-methotrexate in patients with active rheumatoid arthritis (RA).nnnObjectivenTo determine the cost-effectiveness of etanercept-methotrexate versus triple therapy as a first-line strategy.nnnDesignnA within-trial analysis based on the 353 participants in the RACAT trial and a lifetime analysis that extrapolated costs and outcomes by using a decision analytic cohort model.nnnData SourcesnThe RACAT trial and sources from the literature.nnnTarget PopulationnPatients with active RA despite at least 12 weeks of methotrexate therapy.nnnTime Horizonn24 weeks and lifetime.nnnPerspectivenSocietal and Medicare.nnnInterventionnEtanercept-methotrexate first versus triple therapy first.nnnOutcome MeasuresnIncremental costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICERs).nnnResults of Base-Case AnalysisnThe within-trial analysis found that etanercept-methotrexate as first-line therapy provided marginally more QALYs but accumulated substantially higher drug costs. Differences in other costs between strategies were negligible. The ICERs for first-line etanercept-methotrexate and triple therapy were

Abnormally Low Antibody Markers of Elastin Synthesis in Patients with Fibromyalgia Syndrome

2.7 million per QALY and

Surface APRIL Is Elevated on Myeloid Cells and Is Associated with Disease Activity in Patients with Rheumatoid Arthritis

0.98 million per QALY over 24 and 48 weeks, respectively. The lifetime analysis suggested that first-line etanercept-methotrexate would result in 0.15 additional lifetime QALY, but this gain would cost an incremental

BRAF splice variants in rheumatoid arthritis synovial fibroblasts activate MAPK through CRAF.

77xa0290, leading to an ICER of

A conserved anti-DNA antibody idiotype associated with nephritis in murine and human systemic lupus erythematosus.

521xa0520 per QALY per patient.nnnResults of Sensitivity AnalysisnConsidering a long-term perspective, an initial strategy of etanercept-methotrexate and biologics with similar cost and efficacy is unlikely to be cost-effective compared with using triple therapy first, even under optimistic assumptions.nnnLimitationnData on the long-term benefit of triple therapy are uncertain.nnnConclusionnInitiating biologic therapy without trying triple therapy first increases costs while providing minimal incremental benefit.nnnPrimary Funding SourcenThe Cooperative Studies Program, Department of Veterans Affairs Office of Research and Development, Canadian Institutes for Health Research, and an interagency agreement with the National Institutes of Health-American Recovery and Reinvestment Act.