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The Addressing Lupus Pillars for Health Advancement (ALPHA) Project is a global consensus effort to identify, prioritise and address top barriers in lupus impacting diagnosis, care, treatment and research. To conduct this process, the ALPHA Project convened a multistakeholder Global Advisory Committee (GAC) of lupus experts and collected input from global audiences, including patients. In phase I, the ALPHA Project used expert interviews and a global survey of lupus experts to identify and categorise barriers into three overarching pillars: drug development, clinical care and access to care. In phase II, reported here, the GAC developed recommended actionable solutions to address these previously identified barriers through an in-person stakeholder meeting, followed by a two-round scoring process. Recommendations were assessed for feasibility, impact and timeline for implementation (FIT), where potential FIT component values were between 1 and 3 and total scores were between 3 and 9. Higher scores represented higher achievability based on the composite of the three criteria. Simplifying and standardising outcomes measures, including steroid sparing as an outcome (drug development) and defining the lupus spectrum (clinical care) ranked as the highest two priority solutions during the GAC meeting and received high FIT scores (7.67 and 7.44, respectively). Leveraging social media (access to care) received the highest FIT score across all pillars (7.86). Cross-cutting themes of many solutions include leveraging digital technology and applying specific considerations for special populations, including paediatrics. Implementing the recommendations to address key barriers to drug development, clinical care and access to care is essential to improving the quality of life of adults and children with lupus. Multistakeholder collaboration and guidance across existing efforts globally is warranted.

Objective Due to an aging population, increasing prevalence of rheumatic disease, and a growing supply and demand gap of rheumatology providers, innovative solutions are needed to meet the needs of persons with rheumatic conditions. Nurse practitioners (NPs) and physician assistants (PAs) have been identified as a group of health professionals who could help address the workforce shortage. The Executive Committee of the Association of Rheumatology Health Professionals (ARHP), a division of the American College of Rheumatology (ACR), charged a task force to facilitate the preparation of NPs/PAs to work in a rheumatology practice setting. Methods The task force, consisting of private practice and academic rheumatologists, and NPs and PAs, from both adult and pediatric settings, conducted a needs assessment survey of current NPs and PAs to identify mechanisms for acquiring rheumatology knowledge. Through face-to-face and webinar meetings, and incorporating stakeholder feedback, the task force designed a rheumatology curriculum outline to enrich the training of new NPs and PAs joining rheumatology practice. Results Informed by the needs assessment data and stakeholders, an NP/PA rheumatology curriculum outline was developed and endorsed by the ACR Board of Directors for use by community-based and academic rheumatology practices, whether pediatric or adult, who desire to add NPs and PAs to their practice setting. Conclusion As rheumatology is facing workforce shortages, the ACR/ARHP rheumatology curriculum outline can be utilized to train NPs and PAs and create more efficient integration of NPs and PAs into rheumatology practice.

Objective Reactive arthritis (ReA) is an inflammatory disorder occurring several weeks after gastrointestinal or genitourinary infections. HLA-B27 positivity is considered a risk factor, though not necessarily predictive of disease incidence. Among non-genetic factors, the intestinal microbiome may play a role in disease susceptibility. The objective of this study was to characterize the gut microbiota and host gene interactions in ReA and post-infectious spondyloarthritis. Methods Adult peripheral spondyloarthritis and control subjects with preceding infections that did not develop arthritis were prospectively recruited from a highly prevalent geographic region. Clinical variables, HLA status, and 16S rRNA gene sequencing of intestinal microbiota were analyzed. Results ReA subjects showed no significant differences from controls in gut bacterial richness or diversity. However, there was a significantly higher abundance of Erwinia and Pseudomonas, and increased prevalence of typical enteropathogens associated with ReA. Subjects with ultrasound evidence of enthesitis were enriched in Campylobacter, while subjects with uveitis and radiographic sacroiliitis were respectively enriched in Erwinia and unclassified Ruminococcaceae, and both enriched in Dialister. Host genetics, particularly HLA-A24, were associated with differences in gut microbiota diversity irrespective of disease status. We determined several co-occurring taxa that were also predictive of HLA-A24 status. Conclusion This is the first culture-independent study characterizing the gut microbial community of post-infectious arthritis. Although bacterial factors correlated with disease presence and clinical features of ReA, host genetics also appeared to be a major independent driver of intestinal community composition. Understanding of these gut microbiota host-genetic relationships may further clarify the pathogenesis of post-infectious spondyloarthropathies. This article is protected by copyright. All rights reserved.

The objective of the study is to determine the risk factors for the development of reactive arthritis (ReA) and examine the factors associated with the persistence of symptoms. Patients with a new diagnosis of ReA and controls with a gastrointestinal (GI), urogenital, or sexually transmitted infection in the 3-6 months prior to study entry were prospectively enrolled in Guatemala City. ReA patients fulfilled the Assessment in Spondyloarthritis International Society criteria for peripheral spondyloarthropathy (SpA). Patients underwent history, examination, Achilles tendon ultrasound, and blood draw. Human leukocyte antigen (HLA) type and serum biomarkers were measured. t tests and nonparametric equivalents were used to examine the association of clinical, laboratory, and imaging factors with ReA. Patients were contacted 2 years later to assess for persistence of symptoms. Study subjects included patients with ReA (N = 32) and controls (N = 32). ReA patients were most frequently infected in April whereas controls were most frequently infected in August. Two ReA patients and two controls were HLA-B27-positive. Serum cathepsin K and C-reactive protein were higher in ReA patients compared to controls (p = 0.03 for both), while total cholesterol and low-density lipoprotein were lower (p = 0.008 and 0.045, respectively). Among those with ReA, 15 (47%) patients had continued symptoms at 2 years. These patients had a lower matrix metalloproteinase-3 level at diagnosis than patients for whom ReA resolved (p = 0.004). HLA-B27 was not associated with development of ReA in Guatemala; however, the month of infection was associated with ReA. The most striking finding was the persistence of arthritis at 2 years in nearly half of the patients.

Preview Although systemic lupus erythematosus affects primarily young and middle-aged women, a percentage of cases occur in all age-groups and both sexes. That fact, coupled with the diversity of clinical presentations, can make diagnosis a challenge. This article discusses epidemiologic and pathogenetic factors and describes the many manifestations of the disease. A brief overview of current treatment is presented.

Objective To quantify muscle outcomes, independent of fat mass, in rheumatoid arthritis (RA) patients compared to healthy controls. Methods Quantitative computed tomography scans measured calf muscle and fat cross-sectional area (CSA) and muscle density (an index of intramuscular adipose tissue), and isometric dynamometry was used to measure ankle muscle strength in 50 participants with RA ages 18–70 years and 500 healthy controls. Multivariable linear regression models assessed muscle deficits in RA after adjusting for group differences in adiposity and assessing for an altered muscle–fat association. Associations between RA disease characteristics and fat-adjusted muscle outcomes were also assessed. Results Compared to controls, RA subjects had significantly greater body mass index (BMI) and fat area, and lower muscle area, muscle density, and muscle strength (P < 0.001 for all). Strength deficits were eliminated with adjustment for the smaller muscle area. The magnitude of muscle deficits, relative to controls, was significantly greater (P < 0.03 for interaction) in participants with lower fat area and BMI. Among those in the lower tertiles of adiposity, RA subjects demonstrated more significant deficits compared to controls with similar adiposity. In contrast, among those in the highest tertile for adiposity, RA was not associated with muscle deficits. Among RA, greater Sharp/van der Heijde scores were associated with lower muscle CSA and muscle density. Greater disease activity and disability were associated with low muscle density. Conclusion Deficits in muscle area and muscle density are present in RA patients compared to controls and are most pronounced in subjects with low fat mass. Greater joint destruction is associated with greater muscle deficits.

ObjectiveLupus is a complex, heterogeneous autoimmune disease that has yet to see significant progress towards more timely diagnosis, improved treatment options for short-term and long-term outcomes, and appropriate access to care. The Addressing Lupus Pillars for Health Advancement (ALPHA) project is the first step in establishing global consensus and developing concrete strategies to address the challenges limiting progress.MethodsA Global Advisory Committee of 13 individuals guided the project and began barrier identification. Seventeen expert interviews were conducted to further characterise key barriers. Transcripts were analysed using Nvivo and a codebook was created containing a list of thematic ‘nodes’ (topics) and their descriptions. Findings were used to develop a final survey instrument that was fielded to a diverse, international stakeholder audience to achieve broad consensus.ResultsExpert interviews identified lupus heterogeneity as the primary barrier hindering advancement. Subsequent barriers were categorised into three areas: (1) Drug development. (2) Clinical care. (3) Access and value. The global survey received 127 completed responses from experts across 20 countries. Respondents identified barriers as high priority including the lack of biomarkers for clinical and drug development use, flawed clinical trial design, lack of access to clinicians familiar with lupus, and obstacles to effective management of lupus due to social determinants of care. Respondents also identified 30 autoimmune conditions that may be lupus-related based on overlapping features, shared autoantibodies and pathophysiology.ConclusionsALPHA is a comprehensive initiative to identify and prioritise the continuum of challenges facing people with lupus by engaging a global audience of lupus experts. It also explored views on lupus as a spectrum of related diseases. Conclusions from this effort provide a framework to generate actionable approaches to the identified high-priority barriers.

Purpose Diagnostic errors in medicine are common and costly. Cognitive bias causes are increasingly recognized contributors to diagnostic error but remain difficult targets for medical educators and patient safety experts. The authors explored the cognitive and contextual components of diagnostic errors described by internal medicine resident physicians through the use of an educational intervention. Method Forty-one internal medicine residents at University of Pennsylvania participated in an educational intervention in 2010 that comprised reflective writing and facilitated small-group discussion about experiences with diagnostic error from cognitive bias. Narratives and discussion were transcribed and analyzed iteratively to identify types of cognitive bias and contextual factors present. Results All residents described a personal experience with a case of diagnostic error that contained at least one cognitive bias and one contextual factor that may have influenced the outcome. The most common cognitive biases identified by the residents were anchoring bias (36; 88%), availability bias (31; 76%), and framing effect (23; 56%). Prominent contextual factors included caring for patients on a subspecialty service (31; 76%), complex illness (26; 63%), and time pressures (22; 54%). Eighty-five percent of residents described at least one strategy to avoid a similar error in the future. Conclusions Residents can easily recall diagnostic errors, analyze the errors for cognitive bias, and richly describe their context. The use of reflective writing and narrative discussion is an educational strategy to teach recognition, analysis, and cognitive-bias-avoidance strategies for diagnostic error in residency education.

Objective This study examined adherence, discontinuation, and switching of rheumatoid arthritis (RA) biologics over a 1-year period after initiation of the biologic treatment in Medicaid patients with RA. Methods The study sample consisted of Medicaid patients with RA in California, Florida and New York who had newly initiated etanercept (n = 1359), anakinra (n = 267), or infliximab (n = 1012) between January 1, 2000 and December 31, 2002. Adherence (proportion of days covered (PDC) ≥ 0.80), discontinuation (90-day continuous gap), and switching (initiation of second biologic within 90 days of discontinuation date of index biologic) were measured during the 12-month postindex biologic initiation. Sensitivity analyses were conducted by varying the thresholds to define these measures. Logistic regressions examined the factors associated with RA biologic adherence and discontinuation. Results Anakinra users had the lowest mean PDC (0.36) and percent adherent patients (11%) followed by etanercept users (mean PDC: 0.57; % adherent: 32%) and infliximab users (mean PDC: 0.64; % adherent: 43%). All three groups had high discontinuation rates (41% etanercept, 76% anakinra, and 41% infliximab). Few patients who discontinued the index biologic switched to another biologic. Logistic regressions found that patients in Florida had lower odds of being adherent and higher odds of discontinuing their index biologic than patients in California. Anakinra users had lower odds and infliximab users had higher odds of being adherent than etanercept users. Anakinra users had higher odds of discontinuation than etanercept users. Conclusion This study highlights the poor adherence to and premature discontinuation without concurrent switching of RA biologics that should raise concern for clinicians as well as payers.

Background In the current climate of increasing demands on a disproportionately small number of senior female faculty, we implemented a brief curriculum vitae (CV) review session as an opportunity to expand the professional network of junior women faculty and provide them with additional formal career advice. Methods For 3 years, junior (mentees) and senior (mentors) faculty from different departments were paired in half-hour CV review sessions, as part of an annual conference focused on professional development for faculty women. Participating faculty received questionnaires to assess their experience with the sessions, and their feedback was combined over all 3 years and compared using c 2 and Fisher’s tests. Results During the 3 years, there were 93 CV review sessions. Although 84% of the mentees reported having a mentor, only 62% of mentees reported that any previous mentoring experience was helpful. Most (90%) participated in the CV review to determine if their career was ‘on track.’ The men-tees reported that the CV review session was helpful (93%), provided new information (87%), and identified that they were ‘on track’ for promotion (75%). The mentors felt that their mentees were progressing appropriately in their career (78%) and provided specific recommendations for the men-tees (100%). The majority (78%) of mentors felt comfortable mentoring junior faculty outside their department. Conclusions Brief interventions, such as a CV review session, can provide additional counsel to junior faculty, helping them assess their career progress as part of a mosaic of mentorship.

BACKGROUND: Women with the AA genotype at the (−2518)A>G promoter polymorphism of CCL-2, which encodes the potent pro-inflammatory chemokine monocyte chemoattractant protein 1 (MCP-1), may be at increased risk for having offspring affected by spina bifida. As the A allele at this locus has been associated with decreased transcription of MCP-1 mRNA relative to the G allele, the observed genetic association suggests that the risk of spina bifida may be increased in the offspring of women with low MCP-1 levels. The present study was undertaken to identify potential determinants of MCP-1 levels in women of reproductive age. METHODS: A small cohort of Caucasian and African-American women of reproductive age was recruited to participate in an exploratory investigation of the determinants of several disease-related, biochemical phenotypes, including MCP-1. Subjects completed a brief questionnaire and provided a fasting blood sample for biochemical and genetic studies. Potential biochemical, genetic, and lifestyle factors were assessed for their association with MCP-1 levels using linear regression analyses. RESULTS: In this cohort, MCP-1 levels were significantly higher in Caucasians as compared to African-Americans. Further, among women of both races, there was evidence that MCP-1 levels were associated with smoking status, MTHFR 677C>T genotype, and red blood cell tetrahydrofolate levels. CONCLUSIONS: The results of these analyses indicate that, if maternal CCL-2 genotype is related to the risk of spina bifida, this relationship is likely to be more complex than initially hypothesized, perhaps depending upon folate intake, MTHFR 677C>T genotype, the distribution of folate derivatives, and immune/inflammatory activity. Birth Defects Research (Part A) 82:736–741, 2008. © 2008 Wiley-Liss, Inc.

The economic, social and personal burdens of osteoporosis carry a heavy toll. Despite this, it is significantly under-recognized and under-treated. Complete evaluation includes work-up and recognition of secondary causes of osteoporosis in addition to biochemical marker and bone densitometry testing. Recognition of factors contributing to falls is a critical part of prevention of fragility fractures in the elderly. Nutraceutical treatments include calcium and vitamin D. Pharmacologic treatments include bisphosphonates, raloxifene, estrogen, testosterone, strontium ranelate, calcitonin and parathyroid hormone (recombinant 1–34 and 1–84). Although bisphosphonates are generally considered first-line therapy, therapies such as raloxifene and zoledronate have unique benefits. Nonpharmacologic interventions include weight-bearing exercise and behavioral counseling for modification of risk factors such as smoking and alcohol use. Fall and fracture prevention with hip protectors and balance training have also been used. The ideal duration of therapy is not well established. Treatment failure should raise concerns about compliance and secondary causes of fractures/osteoporosis.

Objective.Rheumatoid arthritis (RA) is associated with low muscle mass and density. The objective of our study was to evaluate associations between 2 serum biomarkers [insulin-like growth factor 1 (IGF-1) and adiponectin] and skeletal muscle in RA.Methods.Whole-body dual energy X-ray absorptiometry measures of the appendicular lean mass index (ALMI; kg/m2) and total fat mass index (kg/m2), as well as the peripheral quantitative computed tomography measures of the lower leg muscle and fat cross-sectional area (CSA; cm2) and muscle density (an index of fat infiltration) were obtained from 50 participants with RA, ages 18–70 years. Multivariable linear regression analyses evaluated associations between body composition and levels of adiponectin and IGF-1, adjusted for age, sex, and adiposity.Results.Greater age was associated with higher adiponectin (p = 0.06) and lower IGF-1 (p = 0.004). Eight subjects had IGF-1 levels below the reference range for their age and sex. These subjects had significantly lower ALMI and muscle CSA in multivariable models. Lower IGF-1 levels were associated with greater clinical disease activity and severity, as well as low ALMI, muscle CSA, and muscle density (defined as 1 SD below normative mean). After adjusting for age and sex, greater adiponectin levels were associated with lower BMI (p = 0.02) as well as lower ALMI, and lower muscle CSA, independent of adiposity (p < 0.05). Only greater Health Assessment Questionnaire scores were significantly associated with lower adiponectin levels.Conclusion.Low IGF-1 and greater adiponectin levels are associated with lower muscle mass in RA. Lower IGF-1 levels were seen in subjects with greater disease activity and severity.

To establish the value of immunologic and serologic testing in patients with Ménière's disease.Prospective cohort.University-based, tertiary care balance center.Patients with active unilateral or bilateral Ménière's disease underwent testing, including antinuclear antibodies, anti-DNA antibodies, rheumatoid factor, complement levels, anti-Sjögren syndrome A and B antibodies, sedimentation rate, antiphospholipid antibodies, Western blot for anticochlear antibodies (anti-heat shock protein 70), microhemagglutination test for Treponema pallidum, and Lyme titers.Results of laboratory tests.In patients with unilateral Ménière's disease (n = 40), 27% demonstrated elevated antiphospholipid antibody titers (population norm, 6-9%). The majority of these patients manifested negative assays on the other tests listed above. In patients with bilateral Ménière's disease (n = 18), elevations in antinuclear antibody titers (38%) were the most notable finding. As part of a broader study of patients with progressive hearing loss, four patients with positive syphilis titers were identified; however, none of these patients complained of vertigo.In general, the results of this study do not support the hypothesis that immune or infectious pathologies are involved in the pathogenesis of unilateral Ménière's disease. In particular, Lyme disease does not seem to cause labyrinthine disease. However, the potential role of the thrombogenic antiphospholipid antibodies must be further investigated. Patients with bilateral Ménière's disease may be more likely to have a systemic autoimmune process.

The Oral Contraceptives part of the Safety of Estrogens in Lupus Erythematosus National Assessment (OC-SELENA) study was a prospective, randomized, double-blind trial carried out at 15 U.S. centers that examined the effects of oral contraceptives on disease activity in 183 premenopausal women with systemic lupus erythematosus. Initially, disease was inactive in 76% of participants and active but stable in the remaining 24%. Participants were assigned to receive 35 μg triphasic ethinyl estradiol plus 0.5, 0.75, or 1 mg norethindrone, or placebo, for 12 28-day cycles. None of the subjects had moderate to high titers of anticardiolipin antibodies, lupus anticoagulant, or a history of thrombosis. Just over one third of patients in each group failed to comply throughout the 12-month study. Only seven of 91 women given oral contraceptives and seven of 92 placebo recipients had a severe flare of disease during the study. Two flares in the active treatment group occurred when the study drug was omitted. On Cox proportional-hazards analysis, the relative risk (RR) of a severe flare occurring during OC treatment, compared with placebo, was 0.93 (95% confidence interval [CI], 0.33-2.65). The estimated difference was less than the maximum clinically acceptable difference. Participants in both groups who had active disease at the outset were likelier than those whose disease was inactive to have a severe flare. The estimated RR, adjusted for treatment, was 3.5 (95% CI, 1.23-9.99). Rates of moderate or mild flares were similar in the treatment and placebo groups. The likelihood of having at least one flare of any degree during 12 months of follow up was 76% for actively treated patients and 69% for those in the placebo group (RR, 1.09; 95% CI, 0.76-1.55). One OC-treated patient had deep venous thrombosis (DVT) and one had a clotted graft. In the placebo group, there was one case each of DVT, ocular thrombosis, and superficial thrombophlebitis, and one woman died after the trial ended. These findings endorse the use of oral contraceptives, including estrogen, as a birth control measure by women having inactive or active but stable systemic lupus erythematosus. These patients are at relatively low risk of developing thrombosis.

Objective. To evaluate the utility of polymerase chain reaction (PCR) amplification in detecting DNA from venereal-associated microorganisms in the synovial fluid of patients with inflammatory arthritis. Methods. Oligonucleotide primers were developed for nested PCR based on Chlamydia, Ureaplasma, and Neisseria DNA sequences. PCR products were detected by gel electrophoresis and dot-blot hybridization. Primers specific for the target bacterial DNA were used to search for bacterial DNA in 61 synovial fluid specimens from patients with inflammatory arthritis, including several clinically associated with venereal infection. Results. Five of the 61 synovial fluid specimens were positive for Neisseria gonorrhoeae DNA. Four of the 5 patients had clinical diagnoses of gonococcal arthritis; the other patient had an unexplained monarthritis. One specimen from a patient with a clinical diagnosis of gonococcal arthritis was negative for N gonorrhoeae. Three of the 61 specimens were positive for Chlamydia DNA. Two were derived from patients with clinical diagnoses of reactive arthritis or Reiter's syndrome, and 1 was from a patient with unexplained monarthritis. One of the 61 specimens was positive for Ureaplasma DNA; this sample was from a patient with a clinical diagnosis of Reiter's syndrome. In an additional patient with Reiter's syndrome, Ureaplasma DNA was also found in prostate biopsy tissue and a urine sample obtained after prostate massage (synovial fluid not available). Conclusion. These data support the classification of these 3 venereal-associated arthritides as infectious processes, and suggest that PCR for bacterial DNA is a useful method for detecting infectious agents in synovial fluid.

Systemic lupus erythematosus (SLE) is a multisystem disease that predominantly affects women. Probable causative factors include genetic predisposition, complement deficiencies, persistence of antigen, drugs, and environmental factors. The widely varying presentations of SLE include skin, musculoskeletal, cardiovascular, renal, pulmonary, gastrointestinal, neuropsychiatric, systemic, hematologic, and immunologic manifestations. Milder symptoms can be managed with nonsteroidal anti-inflammatory drugs and antimalarial agents. Corticosteroids and cytotoxic drugs are given in more severe disease.

Objective Web-based patient education materials and printed pamphlets are frequently used by providers to inform patients about their rheumatic disease. Little attention has been given to the readability and appropriateness of patient materials. The objective of this study was to examine the readability and suitability of commonly used patient education materials for osteoarthritis (OA), rheumatoid arthritis, systemic lupus erythematosus, and vasculitis. Methods Five or 6 popular patient resources for each disease were chosen for evaluation. Readability was measured using the Flesch-Kincaid reading grade level and suitability was determined by the Suitability Assessment of Materials (SAM), a score that considers characteristics such as content, graphics, layout/topography, and cultural appropriateness. Three different reviewers rated the SAM score and means were used in the analysis. Results Twenty-three resources written on the 4 diseases were evaluated. The education material for all 4 diseases studied had readability above the eighth-grade level and readability did not differ among the diseases. Only 5 of the 23 resources received superior suitability scores, and 3 of these 5 resources were written for OA. All 4 diseases received adequate suitability scores, with OA having the highest mean suitability score. Conclusion Most patient education materials for rheumatic diseases are written at readability levels above the recommended sixth-grade reading level and have only adequate suitability. Developing more appropriate educational resources for patients with rheumatic diseases may improve patient comprehension.

In many autoimmune diseases autoantibodies are intimately involved in disease manifestations. Molecular characterization of these autoantibodies should provide insights into the pathogenesis of these diseases, as well as suggest novel avenues for development of therapeutics. While some prior studies suggest that DNA binding may be a characteristic of individual heavy chain variable regions, the ability of these V regions to bind DNA in isolation has not been investigated. We have utilized a bacterial vector for cloning and expressing isolated antibody heavy chain variable regions. RNA was extracted from peripheral blood mononuclear cells of patients with active SLE, cDNA synthesized and heavy chain V regions amplified with VHspecific oligonucleotide primers. The VHfragments were cloned into a bacterial expression plasmid including the pelB leader peptide to direct appropriate expression. Recombinant antibodies were screened for binding to32P-labeled double-stranded plasmid DNA and later also characterized for binding to single-stranded DNA. Binding was confirmed by standard ELISA methodology. Sequence analysis of seven DNA binding VHfragments revealed that they utilized the VHgene family previously described to be associated with autoimmune responses, with a JH6 segment. On VHsequence analysis only one residue substitution in the consensus sequence is needed to form a VH4 germline gene. Potential contact residues with DNA were delineated by three-dimensional structure analysis. We concluded that the DNA binding characteristics of VHregions can be examined in the absence of light chain. DNA binding specificity appears to be a property of the germline VH4 gene. Analysis of such V regions can aid in the identification of hypervariable region contact residues important for DNA binding.

We report a 64-year-old man with arthritis and nodules to describe that this picture can be caused by normo-lipidemic xanthomas. Light and electron microscopy (EM) plus polymerase chain reaction (PCR) studies were performed for diagnosis and investigation. These showed features typical of xanthomas plus PCR and EM evidence of possible infection with Chlamydia pneumoniae as a pathogenetic mechanism deserving consideration. With such rare diseases, any clues to possible mechanisms seem important to record and thus to encourage future investigations. This uncommon cause of arthritis and nodules had been confused with rheumatoid arthritis by others in this case.

Purpose Vitamin D deficiency is a potential risk factor for cardiometabolic disease. We investigated the associations between vitamin D and dyslipidemia and the metabolic syndrome in patients with rheumatoid arthritis, a group at high risk for cardiovascular disease. Methods Serum 25(OH)vitamin D and lipoprotein levels were measured at baseline in a random sample of 499 participants, ages 18-85 years, enrolled in a randomized trial of golimumab (GOlimumab Before Employing methotrexate as the First-line Option in the treatment of Rheumatoid arthritis of Early onset or GO-BEFORE Trial). Participants had rheumatoid arthritis with active disease, and were naive to methotrexate and biologic therapies. Multivariable linear regression was performed to assess associations between vitamin D levels and lipoprotein fractions. Multivariable logistic regression was performed to determine the odds of hyperlipidemia and the metabolic syndrome in participants with vitamin D deficiency ( Results In multivariable linear regression, vitamin D levels (per 10 ng/mL) were associated inversely with low-density lipoprotein (β: −0.029 [−0.049, −0.0091], P =.004) and triglyceride (β: −0.094 [−0.15, −0.039] P =.001) levels, adjusted for demographic, cardiovascular, and disease-specific variables. Vitamin D and high-density lipoprotein levels were not associated in univariate or multivariate analyses. Vitamin D deficiency was associated independently with an increased odds of hyperlipidemia (odds ratio 1.72; 95% confidence interval, 1.10-2.45; P =.014) and metabolic syndrome (odds ratio 3.45; 95% confidence interval, 1.75-6.80; P Conclusions In conclusion, vitamin D deficiency was associated with the metabolic syndrome and dyslipidemia in rheumatoid arthritis, suggesting a potential role in cardiovascular disease risk. Large-scale, prospective studies are needed to determine if vitamin D supplementation improves lipoprotein levels and reduces cardiovascular risk in rheumatoid arthritis.

Objective To evaluate the association between BMI and radiographic joint damage (RJD) in RA. Methods van der Heijde-Sharp (vdHS) erosion scores were determined in 499 participants with RA, ages 18-85 years, while enrolled in a clinical trial of golimumab (GO-BEFORE trial). Subjects were MTX and biologic therapy naive. Multivariable logistic regressions determined the odds of prevalent RJD (defined as vdHS score >10) according to BMI category. Longitudinal analyses evaluated the association between BMI category and progression of vdHS score over 52 weeks. Analyses in a subset of 100 participants examined the association between adipokines and vdHS scores. Results At enrolment and 52 weeks, 37.6 and 43.6% of participants had RJD. Compared with normal weight, obese subjects had lower odds of RJD [0.40 (95% CI 0.22, 0.74); P = 0.003], and underweight subjects had greater odds [3.86 (95% CI 1.66, 9.00); P = 0.002] at baseline, adjusted for demographic and disease characteristics. The baseline associations between BMI category and RJD were greater among participants with multiple risk factors for bone loss (female >50 years, smoking, glucocorticoid exposure and vitamin D deficiency); test for interaction P = 0.05. Adjustment for adiponectin levels did not attenuate the association between BMI and vdHS scores. Baseline BMI and change in weight did not independently predict radiographic progression (P > 0.1). Conclusions Higher BMI was independently associated with less RJD and was greatest in participants with risk factors for bone loss. Future studies are needed to examine the associations between RJD, obesity, weight loss and osteoporosis.

Objective.To evaluate levels of resistin in female subjects with systemic lupus erythematosus (SLE) compared to age and race-matched controls and to determine the relationship between resistin and systemic inflammation, disease measures, and coronary artery calcification (CAC).Methods.Resistin levels were measured on stored samples from 159 women with SLE and 70 controls as an extension of a previous cross-sectional study. Spearman correlations and multivariable regressions were used to examine whether resistin levels were associated with SLE, disease-specific and inflammatory markers, insulin resistance, and CAC.Results.In a multivariable linear regression model, a diagnosis of SLE was significantly associated with higher resistin levels independent of age, race, renal function, body mass index (BMI), high-sensitivity CRP (hsCRP), hypertension, diabetes, and steroid use. In SLE, resistin levels correlated positively with Systemic Lupus International Collaborating Clinics Damage Index, glomerular filtration rate (GFR), hsCRP, erythrocyte sedimentation rate, homocysteine, and disease duration (all p < 0.03). Resistin level did not correlate with markers of insulin resistance or body adiposity, including homeostatic model assessment or BMI. Resistin levels were significantly elevated in SLE cases with CAC compared to cases without CAC (16.58 vs 13.10 ng/ml, respectively; p = 0.04). In multivariate logistic regression, the association was not present after adjustment for age, race, and GFR.Conclusion.SLE was independently associated with higher resistin levels. Among subjects with SLE, higher resistin level correlated positively with renal dysfunction, inflammatory markers, and disease damage but not with insulin resistance or BMI. SLE cases with CAC had higher resistin levels than cases without CAC; however, this relationship was dependent on other established risk factors.

Objective: The objective of the study was to develop and test a survey of gout patients regarding their level of disease-related knowledge, to identify potential targets for patient education. Methods: A 10-item questionnaire with readability at a Flesch-Kincaid grade level of 4.6 and Flesch reading ease of 83.9% was designed to address parameters considered important for patient participation in the management of gout. The questionnaire was primarily evaluated at the Veterans Affairs (VA) Medical Center in Philadelphia, but was also secondarily performed at 2 Chinese hospitals, the Sun Yat-sen Memorial Hospital of Zhong Shan University, Guangdong Province (GZ), and the Qingdao Municipal Hospital, Qingdao City, Shandong Province (QD). Demographic and questionnaire data by institution were evaluated using descriptive statistics, and significant differences were identified by χ2 and Fisher exact tests. Patient responses were displayed by each individual question and by the distribution of total scores. Kruskal-Wallis tests of significance were used for nonparametric or skewed data. Intraclass correlations (ICCs) were performed within the VA population to determine internal consistency of the individual questions. A high score was defined as greater than 7 (the median value). Multivariate regression models using demographic and clinical characteristics attempted to identify factors associated with correct answers to each question. Results: Total correct score for individual patients varied widely at each institution with a mean (SD) and median (interquartile range [IQR]) scores in all 3 hospitals of 6.15 (2.25) and 7 (5-8), respectively. The average numbers of correct responses for each institution were 4.38 (SD, 3.04) (median, 4 [IQR, 2-7]) at GZ; 7.05 (SD, 1.37) (median, 8 [IQR, 6-8]) at QD; 6.21 (SD, 1.74) (median, 7 [IQR, 6-7]) at VA; P = 0.0010. Two questions (Q4 and Q10) were identified as difficult to understand by patients and showed poor ICC (ICC = 0.0000, P > 0.5) at the VA. Questions that were more difficult to answer were (1) Q3: What inside the joint causes attacks of gout? (GZ, 28.6%; QD, 7.7%; VA, 72.4%; P = 0.000); (2) Q8: How long should patients continue with serum uric acid-lowering drugs? (GZ, 19.1%; QD, 10.3%; VA, 82.7%; P = 0.000); (3) Q6: The ideal serum uric acid to aim at during treatment? (GZ, 42.8%; QD, 89.7%; and VA, 17.2%; P = 0.000); and (4) Q5: Which drugs can lower serum uric acid? (GZ, 61.9%; QD, 89.7%; VA, 51.7%; P = 0.002). Conclusions: This study describes an easy-to-read 10-item questionnaire that can identify important knowledge gaps in patients with gout. This can be the first step in designing educational interventions to improve patient understanding and improve clinical care.

Circulating endothelial progenitor cells (EPCs) are reduced in patients with systemic lupus erythematosus (SLE). A reduced number of EPCs are associated with the presence of atherosclerosis in other populations. We sought to determine whether the reduction in EPC numbers in SLE is dependent on the presence of advanced coronary artery calcification (CAC). Patients with SLE had previous coronary calcium scores which placed them in either the >75th percentile or

BACKGROUND Low folate and high homocysteine (Hcy) concentrations are associated with pregnancy-related pathologies such as spina bifida. Polymorphisms in folate/Hcy metabolic enzymes may contribute to this potentially pathogenic biochemical phenotype. METHODS The study comprised 26 Caucasian and 23 African-American premenopausal women. Subjects gave fasting blood samples for biochemical phenotyping and genotyping. Total Hcy (tHcy) and both plasma and red blood cell (RBC) folate derivatives (i.e. tetrahydrofolate [THF], 5-methylTHF [5-MTHF], and 5,10-methenylTHF [5,10-MTHF]) were measured using stable isotope dilution liquid chromatography, multiple reaction monitoring, and mass spectrometry. Eleven polymorphisms from nine folate/Hcy pathway genes were genotyped. Tests of association between genetic, lifestyle, and biochemical variables were applied. RESULTS In African American women, tHcy concentrations were associated (p < 0.05) with total RBC folate, RBC 5-MTHF, B12, and polymorphisms in methionine synthase (MTR) and thymidylate synthase (TYMS). In Caucasian women, tHcy concentrations were not associated with total folate levels, but were associated (p < 0.05) with RBC THF, ratios of RBC 5-MTHF:THF, and polymorphisms in 5,10-methylenetetrahydrofolate reductase (MTHFR) and MTR. In African Americans, folate derivative levels were associated with smoking, B12, and polymorphisms in MTR, TYMS, methionine synthase reductase (MTRR), and reduced folate carrier1 (RFC1). In Caucasians, folate derivative levels were associated with vitamin use, B12, and polymorphisms in MTHFR, TYMS, and RFC1. CONCLUSIONS Polymorphisms in the folate/Hcy pathway are associated with tHcy and folate derivative levels. In African American and Caucasian women, different factors are associated with folate/Hcy phenotypes and may contribute to race-specific differences in the risks of a range of pregnancy-related pathologies. Birth Defects Research (Part A), 2010. © 2010 Wiley-Liss, Inc.

To describe obstacles to optimum management of gout by primary care physicians and to propose educational interventions to improve care.In the past, gout education has been hampered by infrequency of continuing medical education courses, loss of excitement for a disease in which therapies have not changed (until recently), insufficient evidence-based medicine, and the lack of motivation by physicians to re-learn this disease once in active practice. We identify 10 common myths that impede appropriate treatment of gout, identify gaps in evidence-based medicine that perpetuate those myths, and propose opportunities to improve education on these myths. It is through better gout-centered education that quality of care in gout can be enhanced. Residency may be one of the key points of intervention. As more evidence-based medicine publications address the optimum management of gout, national re-education can occur. More outreach by community rheumatologists to primary care physicians through educational programs and improved referral letters can help re-educate practitioners. Lastly, an often overlooked engine to change physician practices is consumer education, but current patient education programs are lacking.Novel education interventions for physician trainees, primary care physicians, and patients are proposed to improve the care of patients with gout.

Objectives A low folate/high homocysteine phenotype is associated with several pathologies, including spina bifida and cardiovascular disease. Folate and total homocysteine (tHcy) measurements are used clinically to assess risk and the need for folic acid supplementation and in research to investigate the metabolic basis of disease. Red blood cell (RBC) folate, the best indicator of long-term folate status, is usually measured as “total” folate. However, different folate derivatives support distinct biochemical functions, suggesting a need to develop more precise methods. This study was designed to evaluate a method based on stable isotope dilution liquid chromatography-multiple reaction monitoring/mass spectrometry (LC-MRM/MS). Design and methods We used LC-MRM/MS to quantify the RBC folate derivatives 5-methyltetrahydrofolate (5-CH3-THF), tetrahydrofolate (THF), and 5,10-methenyltetrahydrofolate (5,10-methenylTHF) in pre-menopausal women. The concentration of each folate derivative was assessed for utility in predicting tHcy levels, and compared to folate and tHcy measurements derived by routine clinical laboratory methods. Results LC-MRM/MS was qualitatively and quantitatively superior to routine clinical laboratory methods for determining folate and tHcy concentrations. RBC 5-CH3-THF had a reciprocal relationship with tHcy (p = 0.0003), whereas RBC THF and RBC 5,10-methenylTHF had direct relationships (p = 0.01, 0.04 respectively). In combination, these three variables accounted for 42% of the variation in tHcy. Conclusions Robust methods for measuring RBC 5-CH3-THF would improve the utility of folate/homocysteine phenotyping in patient management. The use of LC-MRM/MS would allow studies of hyperhomocysteinemia and diseases associated with a low folate/high homocysteine phenotype to be performed with less measurement error and greater statistical power to generate data with the potential to elucidate the etiologic mechanisms of complex diseases and traits.

Cardiovascular morbidity and mortality in SLE is increased in patient with established disease, and SLE itself has been determined to be an independent risk factor for cardiovascular events. Autopsy studies have demonstrated that the coronary vessels of SLE patients have atherosclerotic plaque, and most cardiovascular events are not attributable to active vasculitis. It is believed that patients with inflammatory disease, including SLE, are more likely to have vulnerable plaque rupture, accounting for more frequent events. Elevated homocysteine levels have been associated with the presence and progression of atherosclerotic plaque. Enzyme polymorphisms involved in the folatehomocysteine pathway do not seem to contribute to differences in homocysteine concentration or atherosclerotic plaque. Recently, endothelial dysfunction has been identified as an early abnormality in ASCVD, and has been demonstrated in the vessels of SLE patients. Premature cardiovascular disease in SLE patients is likely attributable to the consequences of inflammation. There is preliminary evidence that type I interferons maybe the initial stimulation of the cascade of atherosclerotic development, starting with endothelial damage, and abnormal vascular repair.

ObjectiveTo determine if functional polymorphisms of folate/homocysteine pathway enzymes are associated with homocysteine concentrations and/or coronary artery calcification (CAC) scores in patients with systemic lupus erythematosus (SLE) and controls.MethodsWe investigated 163 SLE patients and 160 controls. Functional polymorphisms in 6 genes in the folate/homocysteine pathway were genotyped: 5,10-methylenetetrahydrofolate reductase (MTHFR) 677C>T, MTHFR 1298A>C, cystathionine β-synthase (CBS) 844ins68, methionine synthase (MTR) 2756A>G, methionine synthase reductase (MTRR) 66A>G, thymidylate synthase (TYMS) 1494del6, and dihydrofolate reductase (DHFR) c.86+60_78.ResultsHomocysteine levels were higher in African American SLE patients than Caucasian patients and African American controls. Genotype distributions were significantly different in African American and Caucasian controls for 6 of the 7 polymorphisms. Genotype distributions for each polymorphism did not differ significantly between SLE patients and controls even after stratification by race. Glomerular filtration rate was strongly negatively correlated to homocysteine levels, and was therefore adjusted for as a covariate in the models of the effects of the polymorphisms on homocysteine levels. In SLE patients none of the 7 polymorphisms was associated with homocysteine concentrations. In Caucasian controls only MTHFR 677C>T and 1298A>C showed effects on homocysteine similar to what would be expected from the literature. There were no genotypic associations with median CAC scores in SLE patients or controls with and without stratification by race.ConclusionPolymorphisms in folate/homocysteine metabolizing enzymes do not predict higher homocysteine levels or CAC scores in patients with SLE.

Red blood cell (RBC) folate levels are established at the time of erythropoiesis and therefore provide a surrogate biomarker for the average folate status of an individual over the preceding four months. Folates are present as folylpolyglutamates, highly polar molecules that cannot be secreted from the RBCs, and must be converted into their monoglutamate forms prior to analysis. This was accomplished using an individual’s plasma pteroylpolyglutamate hydrolase by lysing the RBCs in whole blood at pH 5 in the presence of ascorbic acid. Quantitative conversion of formylated tetrahydrofolate derivatives into the stable 5,10-methenyltetrahydrofolate (5,10-MTHF) form was conducted at pH 1.5 in the presence of [13C5]-5-formyltetrahydrofolate. The resulting [13C5]-5,10-MTHF was then used as an internal standard for the formylated forms of tetrahydrofolate that had been converted into 5,10-MTHF as well any 5,10-MTHF that had been present in the original sample. A stable isotope dilution liquid chromatography-multiple reaction monitoring/mass spectrometry method was validated and then used for the accurate and precise quantification of RBC folic acid, 5-methyltetrahydrofolate (5-MTHF), tetrahydrofolate (THF), and 5,10-MTHF. The method was sensitive and robust and was used to assess the relationship between different methylenetetrahydrofolate reductase (MTHFR) 677C>T genotypes and RBC folate phenotypes. Four distinct RBC folate phenotypes could be identified. These were classified according to the relative amounts of individual RBC folates as type I (5-MTHF >95%; THF 55%; THF >20%; 5,10-MTHF >5%), and type IV (5-MTHF 20%; 5,10-MTHF >5%).

To determine (1) whether the A(-2518)G polymorphism of CCL-2, the gene encoding monocyte chemoattractant protein-1 (MCP-1), is associated with disease, MCP-1 concentration, nephritis, or coronary artery calcification (CAC) in systemic lupus erythematosus (SLE); and (2) whether MCP-1 and homocysteine (Hcy) concentrations are correlated.Statistical tests were applied to determine the relationships between CCL-2 A(-2518)G genotypes, plasma MCP-1 concentrations, and clinical variables in Caucasian and African American patients with SLE and controls.The CCL-2 (-2518)G allele was not significantly associated with SLE in the whole study sample (p = 0.07). Among Caucasians, but not African Americans, G allele carriers had significantly increased risk of SLE (OR 4.2, 95% CI 1.8-9.6, p0.0001). Genotype was not associated with nephritis, CAC, or MCP-1 concentrations when all patients or all controls were considered; however, among recently diagnosed patients, G allele carriers had significantly higher MCP-1 concentrations than AA homozygotes (p = 0.02). SLE patients had higher MCP-1 concentrations than controls (p0.0001), African American patients had higher concentrations than Caucasian patients (p = 0.006), and patients with nephritis had higher concentrations than those without nephritis (p = 0.02). Although not associated with CAC, MCP-1 concentrations were significantly positively correlated with Hcy. CONCLUSION. CCL-2 A(-2518)G genotype is a significant risk factor for SLE among Caucasians but not African Americans, suggesting that genetically mandated differences in MCP-1 expression contribute to SLE etiology in the former. The positive correlation between MCP-1 and Hcy concentrations is consistent with the hypothesis that active inflammation and hyperhomocysteinemia are etiologically linked.

Cardiovascular and cerebrovascular events, the third leading cause of death in patients with systemic lupus erythematosus (SLE), are disproportionately common by age and gender. Risk factors for atherosclerotic cardiovascular disease (ASCVD) cannot reliably predict subsets of patients at risk for events. Coronary electron beam computed tomography (EBCT), a noninvasive imaging technique that quantifies ASCVD by measuring calcium deposition in the walls of coronary arteries, has been demonstrated to be a marker of ASCVD in traditional populations. A pilot group of 13 SLE patients (ages, 33-48 years) with two or more traditional risk factors for cardiovascular disease were studied by EBCT. Five of these SLE patients had calcification scores in the 70th percentile or higher, as compared with age-matched women without known coronary artery disease, and three had scores in the 90th percentile. Four of these five patients had antiphospholipid antibodies currently or in the past. These data suggest that EBCT may be able to detect premature ASCVD in SLE patients and may be a useful noninvasive tool as more attention is directed to ASCVD as a major complication of SLE.

Objective To compare the incidence and extent of coronary artery calcification (CAC) as measured by electron beam computed tomography (EBCT) in patients with systemic lupus erythematosus (SLE) and controls, and to identify variables associated with CAC in patients with SLE. Methods Female patients with SLE and matched controls were recruited; EBCT of the coronary arteries was performed, and laboratory values (including the homocysteine concentration, the lipid level, the high-sensitivity C-reactive protein [hsCRP] concentration, the glomerular filtration rate [GFR], and the level of soluble CD154 [sCD154]) were determined. For patients, the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index and the SLE Disease Activity Index scores were recorded. Tests of association between the CAC score and the above-mentioned variables were performed. Results The incidence of CAC was higher in patients with SLE than in controls (P = 0.009), and patients had a higher mean raw CAC (rCAC) score (87.9 versus 9.6 in controls; P = 0.02). In particular, more CAC-positive patients than CAC-positive controls had rCAC scores above the 75th percentile (P = 0.003). Among both patients and controls, those with CAC were ∼10 years older than those without CAC. In addition to age, a significant determinant of positive CAC status in both groups was the number of cardiovascular risk factors. In patients with SLE, CAC was associated with a higher homocysteine concentration, a lower GFR, and longer disease duration. In controls, the total cholesterol level correlated positively with CAC. When multivariate logistic regression methods were applied to candidate explanatory variables, homocysteine concentration, age, and disease duration (but not the levels of sCD154 or hsCRP) contributed significantly to CAC status. The methylenetetrahydrofolate reductase C677T genotype was not a predictor of hyperhomocysteinemia or CAC status. Conclusion Among patients with SLE, the homocysteine concentration, the GFR, age, and disease duration were associated with CAC. CAC occurred more frequently and was more extensive in patients with SLE than in controls, suggesting that EBCT could be used to detect premature atherosclerosis in the former group. An elevated homocysteine concentration might identify patients with SLE who are likely to have premature atherosclerosis and who would benefit from evaluation of CAC by EBCT.

Behcet's disease (BD) is a systemic inflammatory disease of unknown etiology. The disease is strongly associated with the human leukocyte antigen (HLA) B51. BD has a chronic course with periodic exacerbations and progressive deterioration. There are no specific diagnostic laboratory tests, although recurrent oral ulceration is an obligatory manifestation for diagnosis. The treatment, which includes local, systemic, or surgical therapies, is based on the severity of the illness; the most appropriate management requires a multidisciplinary approach. This paper summarizes all aspects of BD with particular emphasis on the latest immunologic and treatment aspects.

Several syndromes involving antiphospholipid antibodies have been described in the literature. Although the varied clinical manifestations have been well delineated, the vascular pathophysiology in patients with these antibodies remains unclear. Vascular damage is often described as a vasculopathy; however, several case reports have described an associated vasculitis. We report two patients with manifestations of antiphospholipid antibody syndrome (APLS) and concurrent vasculitis. The first patient, a 42-year-old man, presented with abdominal pain and fevers. The second patient, a 39-year-old man, presented with fever and testicular pain. Both were ultimately felt to have polyarteritis nodosa associated with APLS. Their complicated hospital courses and difficulties we encountered in diagnosing and treating them are discussed. The literature describing other cases of vasculitis associated with antiphospholipid antibody syndrome is reviewed. Whether the presence of antiphospholipid antibodies favors the development of vasculitis or vice versa is not clear. Further studies are needed to address this question and to determine optimal therapeutic regimens in these critically ill patients.

The increase in the incidence of HIV-1 infection in women of child bearing age has resulted in a surge in the number of cases of pediatric AIDS. The World Health Organization (WHO) has estimated that the number of cases of pediatric AIDS worldwide will be at least 10 million by the year 2000. This alarming statistic underscores the need for accurate prediction and diagnosis of pediatric HIV-1 infection which is of paramount importance for the initiation of effective therapeutic interventions. Since circulating maternal anti-HV-1 antibody persists in the baby for up to 21 months, early conventional serological diagnosis of infection is not possible. Other methods for diagnosis of HIV-1 infection in a child less than 2 years of age have been utilized including the polymerase chain reaction (PCR), measurements of the HIV-1 p24 core protein and anti-HIV-1 IgA, as well in vitro measurements of antibody producing cells. In addition, the ability to predict HIV-1 infection in the child based upon maternal humoral immune responses to the envelope glycoprotein has also been suggested. This review summarizes the recent serological, biological and molecular methodologies used to predict and diagnose pediatric HIV-1 infection and AIDS. © 1994 Wiley-Liss, Inc.