Changing trends in serious extra-articular manifestations of rheumatoid arthritis among United State veterans over 20 years.

OBJECTIVES: The purpose of this study was to examine prevalence trends of serious extra-articular manifestations (EAMs) in a data set representing both hospitalized and ambulatory patients with RA. METHODS: This retrospective cohort study used serial cross-sectional data to examine the prevalence of serious EAMs in patients with RA from 1985 to 2006 across the United States (US) Veteran's Health Administration system. Serious EAMs included rheumatoid carditis, RA lung disease, FS and pooled EAM rates included previously reported vasculitis prevalence as queried by ICD-9 searches. Statistical analysis employed auto-regression and time series analysis using the Chow and Durbin-Watson tests to detect breakpoints and linear time-trends. RESULTS: Among 3 million veterans, including >35,000 RA patients annually, we noted declining RA hospitalizations emphasizing the importance of examining both the inpatient and outpatient settings to assess EAM prevalence. Individual EAM trends varied, demonstrating linear declines in FS, increases in RA lung disease and significant breakpoint declines in carditis and pooled serious EAMs. Pooled EAM prevalence dropped around 2000, from an early linear trend peak of 10% among inpatients, to <7% among both inpatients and outpatients by 2006. CONCLUSIONS: Overall, serious EAMs of RA have declined among US veterans in both the inpatient and outpatient settings, with the exception of RA lung disease likely reflecting improved detection. Breakpoints in pooled EAM prevalence appear to demonstrate consistent, true declines in severe RA extra-articular disease around 2000. Future work should explore the relationship between temporal EAM trends and specific RA therapies including adoption of biological agents.

Rheumatoid vasculitis: vanishing menace or target for new treatments?

Rheumatoid vasculitis is a rare but serious complication of rheumatoid arthritis. Herein we examine the pathophysiology, epidemiology, clinical diagnosis, and treatment of rheumatoid vasculitis. Seropositivity, specific HLA variations, and tobacco use are among the genetic and environmental predictors of rheumatoid vasculitis. Fortunately, recent reports have noted declines in the prevalence of rheumatoid vasculitis. Nevertheless, proper recognition of systemic manifestations may assist in pathologically confirming the diagnosis, determining the extent of disease, and guiding treatment. Contemporary treatment reports are discussed in the context of the ongoing debate regarding whether new agents may trigger, treat, or even prevent rheumatoid vasculitis. Evolving genetic, histopathologic, and immunologic studies partnered with ongoing clinical experience with biologics offer promise to inform future prevention and treatment of rheumatoid vasculitis.

Disordered Antigens and Epitope Overlap Between Anti-Citrullinated Protein Antibodies and Rheumatoid Factor in Rheumatoid Arthritis.

OBJECTIVE: Anti-citrullinated protein antibodies (ACPAs) and rheumatoid factor (RF) are commonly present in rheumatoid arthritis (RA) without a clear rationale for their coexistence. Moreover, autoantibodies develop against proteins with different posttranslational modifications and native proteins without obvious unifying characteristics of the antigens. We undertook this study to broadly evaluate autoantibody binding in seronegative and seropositive RA to identify novel features of reactivity. METHODS: An array was created using a total of 172,828 native peptides, citrulline-containing peptides, and homocitrulline-containing peptides derived primarily from proteins citrullinated in the rheumatoid joint. IgG and IgM binding to peptides were compared between cyclic citrullinated peptide (CCP)-positive RF+, CCP+RF-, CCP-RF+, and CCP-RF- serum from RA patients (n = 48) and controls (n = 12). IgG-bound and endogenously citrullinated peptides were analyzed for amino acid patterns and predictors of intrinsic disorder, i.e., unstable 3-dimensional structure. Binding to IgG-derived peptides was specifically evaluated. Enzyme-linked immunosorbent assay confirmed key results. RESULTS: Broadly, CCP+RF+ patients had high citrulline-specific IgG binding to array peptides and CCP+RF- and CCP-RF+ patients had modest citrulline-specific IgG binding (median Z scores 3.02, 1.42, and 0.75, respectively; P < 0.0001). All RA groups had low homocitrulline-specific binding. CCP+RF+ patients had moderate IgG binding to native peptides (median Z score 2.38; P < 0.0001). The highest IgG binding was to citrulline-containing peptides, irrespective of protein identity, especially if citrulline was adjacent to glycine or serine, motifs also seen in endogenous citrullination in the rheumatoid joint. Highly bound peptides had multiple features predictive of disorder. IgG from CCP+RF+ patients targeted citrulline-containing IgG-derived peptides. CONCLUSION: Disordered antigens, which are frequently citrullinated, and common epitopes for ACPAs and RF are potentially unifying features for RA autoantibodies.

A phase I study of immunization using particle-mediated epidermal delivery of genes for gp100 and GM-CSF into uninvolved skin of melanoma patients.

PURPOSE: We examined in vivo particle-mediated epidermal delivery (PMED) of cDNAs for gp100 and granulocyte macrophage colony-stimulating factor (GM-CSF) into uninvolved skin of melanoma patients. The aims of this phase I study were to assess the safety and immunologic effects of PMED of these genes in melanoma patients. EXPERIMENTAL DESIGN: Two treatment groups of six patients each were evaluated. Group I received PMED with cDNA for gp100, and group II received PMED with cDNA for GM-CSF followed by PMED for gp100 at the same site. One vaccine site per treatment cycle was biopsied and divided for protein extraction and sectioning to assess transgene expression, gold-bead penetration, and dendritic cell infiltration. Exploratory immunologic monitoring of HLA-A2(+) patients included flow cytometric analyses of peripheral blood lymphocytes and evaluation of delayed-type hypersensitivity to gp100 peptide. RESULTS: Local toxicity in both groups was mild and resolved within 2 weeks. No systemic toxicity could be attributed to the vaccines. Monitoring for autoimmunity showed no induction of pathologic autoantibodies. GM-CSF transgene expression in vaccinated skin sites was detected. GM-CSF and gp100 PMED yielded a greater infiltration of dendritic cells into vaccine sites than did gp100 PMED only. Exploratory immunologic monitoring suggested modest activation of an antimelanoma response. CONCLUSIONS: PMED with cDNAs for gp100 alone or in combination with GM-CSF is well tolerated by patients with melanoma. Moreover, pathologic autoimmunity was not shown. This technique yields biologically active transgene expression in normal human skin. Although modest immune responses were observed, additional investigation is needed to determine how to best utilize PMED to induce antimelanoma immune responses.

Creating champions for health care quality and safety.

Patient safety and quality of care are public concerns that demand personal responsibility at all levels of the health care organization. Senior residents in our graduate medical education program took responsibility for a capstone quality improvement project designed to transform them into champions for health care quality. Residents (n = 26) participated alone or in pairs in a 1-month faculty-mentored rotation at the Veterans Administration Hospital during the 2007-2008 academic year. They completed a Web-based curriculum, identified a quality-of-care issue, applied Plan-Do-Study-Act cycles, authored a report, and engaged colleagues in their innovations during a department-wide presentation. Results indicated that residents demonstrated significantly enhanced knowledge and attitudes about patient safety and quality improvement and provided consistently positive faculty and rotation evaluations. In addition, residents generated 20 quality improvement project proposals with a 50% rate of hospital-wide implementation, leading to meaningful changes in the systems that affect patient care.

Standards for autoantibody testing; addressing future needs for autoimmune disease and cancer diagnosis.

It is widely held that determination of increased levels of serum autoantibodies can play an important role in the diagnosis and, in some cases, management of many autoimmune diseases. It is also widely held that such testing is fraught with problems relating to accuracy and detection of clinically relevant autoantibodies. Attempts to standardize autoantibody testing by making available standard reference sera, have helped to some degree to improve the testing. Nevertheless, problems still exist and may be causing the delayed diagnosis of severely debilitating and sometimes fatal autoimmune diseases. This paper discusses current practice, as well as, possible new approaches intended to make more robust, autoantibody determinations in all fields of medicine.