Harlan Sayles

Bio: Harlan Sayles is an academic researcher from University of Nebraska Medical Center. The author has contributed to research in topics: Medicine & Population. The author has an hindex of 26, co-authored 127 publications receiving 2219 citations.

Porphyromonas gingivalis and Disease-Related Autoantibodies in Individuals at Increased Risk of Rheumatoid Arthritis

Abstract: Objective. To examine the relationship of Porphyromonas gingivalis to the presence of autoantibodies in individuals at risk of rheumatoid arthritis (RA). Methods. Study participants included the following: 1) a cohort enriched in subjects with HLA–DR4 and 2) subjects at risk of RA by virtue of having a first-degree relative with RA. None of the study subjects satisfied the American College of Rheumatology 1987 classification criteria for RA. Autoantibodies measured included anti–citrullinated protein antibody (ACPA; by second-generation anti–cyclic citrullinated peptide

Rheumatoid factor as a potentiator of anti-citrullinated protein antibody-mediated inflammation in rheumatoid arthritis.

Abstract: Objective The co-occurrence of rheumatoid factor (RF) and anti–citrullinated protein antibody (ACPA) positivity in rheumatoid arthritis (RA) is well described. However, the mechanisms underlying the potential interaction between these 2 distinct autoantibodies have not been well defined. The aim of this study was to evaluate the epidemiologic and molecular interaction of ACPAs and RF and its association with both disease activity and measures of RA-associated inflammation. Methods In a cohort of 1,488 US veterans with RA, measures of disease activity and serum levels of cytokines and multiplex ACPAs were compared between the following groups of patients: double-negative (anti–cyclic citrullinated peptide [anti-CCP]−/RF−), anti-CCP+/RF−, anti-CCP−/RF+, or double-positive (anti-CCP+/RF+). Additional studies were performed using an in vitro immune complex (IC) stimulation assay in which macrophages were incubated with ACPA ICs in the presence or absence of monoclonal IgM-RF, and tumor necrosis factor α production measured as a readout of macrophage activation. Results Compared with the double-negative subgroup (as well as each single-positive subgroup), the double-positive subgroup exhibited higher disease activity as well as higher levels of C-reactive protein and inflammatory cytokines (all P < 0.001). In vitro stimulation of macrophages by ACPA ICs increased cytokine production, and the addition of monoclonal IgM-RF significantly increased macrophage tumor necrosis factor α production (P = 0.003 versus ACPA ICs alone). Conclusion The combined presence of ACPAs and IgM-RF mediates increased proinflammatory cytokine production in vitro and is associated with increased systemic inflammation and disease activity in RA. Our data suggest that IgM-RF enhances the capacity of ACPA ICs to stimulate macrophage cytokine production, thereby providing a mechanistic link by which RF enhances the pathogenicity of ACPA ICs in RA.

Validation of the rheumatic disease comorbidity index.

Abstract: Objective There is no consensus on which comorbidity index is optimal for rheumatic health outcomes research. We compared a new Rheumatic Disease Comorbidity Index (RDCI) with the Charlson-Deyo Index (CDI), Functional Comorbidity Index (FCI), Elixhauser Total Score (ETS), Elixhauser Point System (EPS), and a simple comorbidity count (COUNT) using a US cohort of rheumatoid arthritis (RA) patients. Methods Using administrative diagnostic codes and patient self-reporting, we tested predictive values of the RDCI, CDI, FCI, ETS, EPS, and COUNT for 2 outcomes: all-cause mortality and physical functioning. Indices were compared using 3 models: bare (consisting of age, sex, and race), administrative (bare plus visit frequency, body mass index, and treatments), and clinic (administrative plus erythrocyte sedimentation rate, nodules, rheumatoid factor positivity, and patient activity scale). Results The ETS and RDCI best predicted death, with FCI performing the worst. The FCI best predicted function, with ETS and RDCI performing nearly as well. CDI predicted function poorly. The order of indices remained relatively unchanged in the different models, though the magnitude of improvement in Akaike's information criterion decreased in the administrative and clinic models. Conclusion The RDCI and ETS are excellent indices as a means of accounting for comorbid illness when the RA-related outcomes of death and physical functioning are studied using administrative data. The RDCI is a versatile index and appears to perform well with self-report data as well as administrative data. Further studies are warranted to compare these indices using other outcomes in diverse study populations.

Malondialdehyde-acetaldehyde adducts and anti-malondialdehyde-acetaldehyde antibodies in rheumatoid arthritis.

Abstract: Objective Malondialdehyde-acetaldehyde (MAA) adducts are a product of oxidative stress associated with tolerance loss in several disease states. This study was undertaken to investigate the presence of MAA adducts and circulating anti-MAA antibodies in patients with rheumatoid arthritis (RA). Methods Synovial tissue from patients with RA and patients with osteoarthritis (OA) were examined for the presence of MAA-modified and citrullinated proteins. Anti-MAA antibody isotypes were measured in RA patients (n = 1,720) and healthy controls (n = 80) by enzyme-linked immunosorbent assay. Antigen-specific anti–citrullinated protein antibodies (ACPAs) were measured in RA patients using a multiplex antigen array. Anti-MAA isotype concentrations were compared in a subset of RA patients (n = 80) and matched healthy controls (n = 80). Associations of anti-MAA antibody isotypes with disease characteristics, including ACPA positivity, were examined in all RA patients. Results Expression of MAA adducts was increased in RA synovial tissue compared to OA synovial tissue, and colocalization with citrullinated proteins was found. Increased levels of anti-MAA antibody isotypes were observed in RA patients compared to controls (P < 0.001). Among RA patients, anti-MAA antibody isotypes were associated with seropositivity for ACPAs and rheumatoid factor (P < 0.001) in addition to select measures of disease activity. Higher anti-MAA antibody concentrations were associated with a greater number of positive antigen-specific ACPA analytes (expressed at high titer) (P < 0.001) and a higher ACPA score (P < 0.001), independent of other covariates. Conclusion MAA adduct formation is increased in RA and appears to result in robust antibody responses that are strongly associated with ACPAs. These results support speculation that MAA formation may be a cofactor that drives tolerance loss, resulting in the autoimmune responses characteristic of RA.

Cause-Specific Mortality in Male US Veterans with Rheumatoid Arthritis

Abstract: Objective There has been limited investigation into cause-specific mortality and the associated risk factors in men with rheumatoid arthritis (RA). We investigated all-cause and cause-specific mortality in men with RA, examining determinants of survival. Methods Men from a longitudinal RA registry were followed from enrollment until death or through 2013. Vital status and cause of death were determined using the National Death Index. Crude mortality rates and standardized mortality ratios (SMRs) were calculated for all-cause, cardiovascular disease (CVD), cancer, and respiratory mortality. Associations with all-cause and cause-specific mortality were examined using multivariable Cox proportional hazards and competing-risks regression. Results There were 1,652 men with RA and 332 deaths. The leading causes of death were CVD (31.6%; SMR 1.77 [95% confidence interval (95% CI) 1.46–2.14]), cancer (22.9%; SMR 1.50 [95% CI 1.20–1.89]), and respiratory disease (15.1%; SMR 2.90 [95% CI 2.20–3.83]). Factors associated with all-cause mortality included older age, white race, smoking, low body weight, comorbidity, disease activity, and prednisone use. Rheumatoid factor concentration and nodules were associated with CVD mortality. There were no associations of methotrexate or biologic agent use with all-cause or cause-specific mortality. Conclusion Men in this RA cohort experienced increased all-cause and cause-specific mortality, with a 3-fold risk of respiratory-related deaths compared to age-matched men in the general population. Further studies are needed in order to examine whether interventions targeting potentially modifiable correlates of mortality might lead to improved long-term survival in men with RA.

Implementing an Antibiotic Stewardship Program: Guidelines by the Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America

Abstract: Evidence-based guidelines for implementation and measurement of antibiotic stewardship interventions in inpatient populations including long-term care were prepared by a multidisciplinary expert panel of the Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America. The panel included clinicians and investigators representing internal medicine, emergency medicine, microbiology, critical care, surgery, epidemiology, pharmacy, and adult and pediatric infectious diseases specialties. These recommendations address the best approaches for antibiotic stewardship programs to influence the optimal use of antibiotics.

Internet, phone, mail and mixed-mode surveys: the tailored design method: reseña

Abstract: Resena de la obra de Don A. Dillman, Jolene D. Smyth y Leah Melani Christian: Internet, Phone, Mail and Mixed-Mode Surveys. The Tailored Design Method. New Jersey: John Wiley and Sons

Diagnosis and Management of Rheumatoid Arthritis: A Review.

Abstract: Importance Rheumatoid arthritis (RA) occurs in about 5 per 1000 people and can lead to severe joint damage and disability. Significant progress has been made over the past 2 decades regarding understanding of disease pathophysiology, optimal outcome measures, and effective treatment strategies, including the recognition of the importance of diagnosing and treating RA early. Observations Early diagnosis and treatment of RA can avert or substantially slow progression of joint damage in up to 90% of patients, thereby preventing irreversible disability. The development of novel instruments to measure disease activity and identify the presence or absence of remission have facilitated new treatment strategies to arrest RA before joints are damaged irreversibly. Outcomes have been improved by recognizing the benefits of early diagnosis and early therapy with disease-modifying antirheumatic drugs (DMARDs). The treatment target is remission or a state of at least low disease activity, which should be attained within 6 months. Methotrexate is first-line therapy and should be prescribed at an optimal dose of 25 mg weekly and in combination with glucocorticoids; 40% to 50% of patients reach remission or at least low disease activity with this regimen. If this treatment fails, sequential application of targeted therapies, such as biologic agents (eg, tumor necrosis factor [TNF] inhibitors) or Janus kinase inhibitors in combination with methotrexate, have allowed up to 75% of these patients to reach the treatment target over time. New therapies have been developed in response to new pathogenetic findings. The costs of some therapies are considerable, but these costs are decreasing with the advent of biosimilar drugs (drugs essentially identical to the original biologic drugs but usually available at lower cost). Conclusions and relevance Scientific advances have improved therapies that prevent progression of irreversible joint damage in up to 90% of patients with RA. Early treatment with methotrexate plus glucocorticoids and subsequently with other DMARDs, such as inhibitors of TNF, IL-6, or Janus kinases, improves outcomes and prevents RA-related disability. A treat-to-target strategy aimed at reducing disease activity by at least 50% within 3 months and achieving remission or low disease activity within 6 months, with sequential drug treatment if needed, can prevent RA-related disability.

NETs Are a Source of Citrullinated Autoantigens and Stimulate Inflammatory Responses in Rheumatoid Arthritis

Abstract: The early events leading to the development of rheumatoid arthritis (RA) remain unclear, but formation of autoantibodies to citrullinated protein antigens (ACPAs) is considered a key pathogenic event. Neutrophils isolated from patients with various autoimmune diseases display enhanced neutrophil extracellular trap (NET) formation, a phenomenon that exposes autoantigens in the context of immunostimulatory molecules. We investigated whether aberrant NETosis occurs in RA, determined its triggers, and examined its deleterious inflammatory consequences. Enhanced NETosis was observed in circulating and RA synovial fluid neutrophils compared to neutrophils from healthy controls and from patients with osteoarthritis (OA). Further, netting neutrophils infiltrated RA synovial tissue, rheumatoid nodules, and skin. NETosis correlated with ACPA presence and levels and with systemic inflammatory markers. RA sera and immunoglobulin fractions from RA patients with high levels of ACPA and/or rheumatoid factor significantly enhanced NETosis, and the NETs induced by these autoantibodies displayed distinct protein content. Indeed, during NETosis, neutrophils externalized the citrullinated autoantigens implicated in RA pathogenesis, and anti–citrullinated vimentin antibodies potently induced NET formation. Moreover, the inflammatory cytokines interleukin-17A (IL-17A) and tumor necrosis factor–a (TNF-a) induced NETosis in RA neutrophils. In turn, NETs significantly augmented inflammatory responses in RA and OA synovial fibroblasts, including induction of IL-6, IL-8, chemokines, and adhesion molecules. These observations implicate accelerated NETosis in RA pathogenesis, through externalization of citrullinated autoantigens and immunostimulatory molecules that may promote aberrant adaptive and innate immune responses in the joint and in the periphery, and perpetuate pathogenic mechanisms in this disease.