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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., Competing Interests: Competing interests: SCR is an employee of the Lupus Foundation of America (LFA). SS, LB, TF and DZ are consultants of Faegre Drinker Consulting, a division of Faegre Drinker Biddle & Reath, a law and consulting firm that represents patient advocacy organisations and sponsors developing drugs. INB receives grant/research support from Genzyme Sanofi, GSK and UCB; is a consultant of Eli Lilly, AstraZeneca, UCB, Iltoo and Merck Serono; and affiliated with speakers bureaus for UCB and AstraZeneca. EC-S is an employee of Mallinckrodt (former). KHC receives grant/research support from Merck and is a consultant of AstraZeneca. BD is an employee of Aurinia (former). TD receives grant/research support from Janssen, Novartis, Roche and UCB; is a consultant of Abbvie, Celgene, Eli Lilly, Roche, Janssen and EMD; and affiliated with speakers bureaus for Eli Lilly, Roche, Samsung and Janssen. KK receives grant/research support from UCB, Novartis and Resolve; and is a consultant of AstraZeneca, Viela Bio, Genentech/Roche, Biogen, Iltoo, GSK, BMS, Janssen, Abbvie, Amgen, Eli Lilly, Kyowa Kirin, Equillium Bio and Celgene. AHK is an employee of EMD Serono. EFM receives grant/research support from AstraZeneca, BMS, Eli Lilly, GSK, Janssen and Merck-Serono; is a consultant of AbbVie, Amgen, AstraZeneca, Biogen, BMS, Eli Lilly, GSK, Janssen, Neovacs and Sandoz; and is affiliated with speaker bureaus for AstraZeneca and Novartis. BHR is a consultant for GSK, Aurinia, AstraZeneca, Novartis, Alexion and BMS. LES receives grant/research support from Sobi, BMS, CARRA Inc.; is a consultant of Aurinia, UCB (DSMB), Sanofi (DSMB) and Sobi. VPW receives grant/research support from Biogen, Celgene, Gilead, Janssen and Viela; and is a consultant of Biogen, Gilead, Janssen, Abbvie, GSK, Resolve, AstraZeneca, Amgen, Eli Lilly, EMD Serono, BMS, Viela and Kyowa Kirin. JMVF is a shareholder and employee of GSK (former). KT and LMH are employees of the LFA (former). SE and AWD are LFA patient ambassadors., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: Lupus 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., Methods: A 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., Results: Expert 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., Conclusions: ALPHA 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., Competing Interests: Competing interests: IB is an NIHR Senior Investigator and is funded by Arthritis Research UK, the National Institute for Health Research Manchester Biomedical Research Unit and the NIHR/Wellcome Trust Manchester Clinical Research Facility. IB has received grants and/or honoraria and/or consultancy fees from Genzyme Sanofi, GSK, UCB, AstraZeneca, Medimmune, Eli Lilly, Merck Serono and ILTOO. KC receives research support to study lupus from the NIH (R01 AR057327 and K24 AR066109), Merck and AstraZeneca. KC has received consulting honoraria < $5000 from AstraZeneca. TD has received grants for study conduct and/or honoraria and /or consultancy fees from Janssen, GSK, Roche/Genentech, Eli Lilly, UCB, Merck Serono, AbbVie and Boston Pharmaceuticals. SM has received grants and/or honoraria and/or consultancy fees from Exagen Diagnostics, GSK, UCB and AstraZeneca. EM has received grants for study conduct and/or honoraria and/or consultancy fees from AbbVie, Sanofi, GSK, UCB, AstraZeneca, Eli Lilly, Merck Serono and Janssen. BR has received grants and/or honoraria and/or consultancy fees from Aurinia, EMD Serono, Janssen and MedImmune. BR is also a Principal Investigator on research projects for EMD Serono Research and Development Institute Inc. (Collaborated by Merck KGaA); Human Genome Sciences Inc, a GSK Company; NIH and RILITE Foundation. LES receives research support from CARRA and PCORI. LES is also on Data and Safety Monitoring Boards for UCB and Sanofi. VPW has received grants and/or honoraria from Celgene, Janssen, Biogen, Gilead, Viela, Medimmune, Pfizer, Resolve, AstraZeneca, Kyowa Hakko Kirin, Eli Lilly.

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., (© 2018, American College of Rheumatology.)

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/m(2)) and total fat mass index (kg/m(2)), as well as the peripheral quantitative computed tomography measures of the lower leg muscle and fat cross-sectional area (CSA; cm(2)) 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.

Background: Trends in medical education have reflected the patient safety movement's initial focus on systems. While the role of cognitive-based diagnostic errors has been increasingly recognised among safety experts, literature describing strategies to teach about this important problem is scarce., Methods: 48 PGY-2 internal medicine residents participated in a three-part, 1-year curriculum in cognitive bias and diagnostic error. Residents completed a multiple-choice test designed to assess the recognition and knowledge of common heuristics and biases both before and after the curriculum. Results were compared with PGY-3 residents who did not receive the curriculum. An additional assessment in which residents reviewed video vignettes of clinical scenarios with cognitive bias and debiasing techniques was embedded into the curriculum., Results: 38 residents completed all three parts of the curriculum and completed all assessments. Performance on the 13-item multiple-choice knowledge test improved post-curriculum when compared to both pre-curriculum performance (9.26 vs 8.26, p=0.002) and the PGY-3 comparator group (9.26 vs 7.69, p<0.001). All residents correctly identified at least one cognitive bias and proposed at least one debiasing strategy in response to the videos., Conclusions: A longitudinal curriculum in diagnostic error and cognitive bias improved internal medicine residents' knowledge and recognition of cognitive biases as measured by a novel assessment tool. Further study is needed to refine learner assessment tools and examine optimal strategies to teach clinical reasoning and cognitive bias avoidance strategies.

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., (Copyright © 2013 by the American College of Rheumatology.)

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 naïve 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 (<20 ng/mL)., 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 <.001) in adjusted models., 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., (Copyright © 2012 Elsevier Inc. All rights reserved.)

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.

Objectives: Vitamin D deficiency is a potential risk factor for autoimmunity. Prior studies of the association between vitamin D levels and rheumatoid arthritis (RA) disease activity have yielded conflicting results., Methods: Serum 25(OH)vitamin D levels were measured at baseline in 499 participants with active RA, ages 18-85 years, enrolled in a randomised clinical trial of golimumab (Go-Before Trial). Subjects were methotrexate and biologic therapy naïve. Multivariable linear regression was used to assess associations between vitamin D levels and disease activity scores (DAS28), van der Heijde-Sharp (vdHS) erosion scores, and serum inflammatory markers. Generalised estimating equations were used to evaluate the associations between vitamin D status and the response to therapy over 52 weeks, using the DAS28 and ACR response., Results: Forty-eight percent of participants were vitamin D deficient, defined as serum 25(OH)vitamin D <20 ng/mL. Deficiency was not associated with greater DAS28 (β-0.021 [95% CI -0.22, 0.18]), adjusted for age, race, sex, BMI, disease duration and glomerular filtration rate. Vitamin D deficiency was not associated with baseline vdHS scores or inflammatory markers in adjusted or unadjusted models. There was no association between baseline vitamin D deficiency and change in DAS28 (β = -0.024 [-0.30, 0.25]), proportion meeting ACR response (OR 0.82 [0.56, 1.20]), or radiographic progression at 52 weeks (OR 0.91 [0.59-1.40])., Conclusions: Vitamin D levels were not associated with RA disease activity, inflammatory markers, or vdHS scores at baseline. Furthermore, there was no association between baseline vitamin D level and response to therapy or radiographic progression.

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 naïve. 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 χ 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.

The Lupus Foundation of America (LFA) convened an international working group to obtain a consensus definition of disease flare in lupus. With help from the Paediatric Rheumatology International Trials Organization (PRINTO), two web-based Delphi surveys of physicians were conducted. Subsequently, the LFA held a second consensus conference followed by a third Delphi survey to reach a community-wide agreement for flare definition. Sixty-nine of the 120 (57.5%) polled physicians responded to the first survey. Fifty-nine of the responses were available to draft 12 preliminary statements, which were circulated in the second survey. Eighty-seven of 118 (74%) physicians completed the second survey, with an agreement of 70% for 9/12 (75%) statements. During the second conference, three alternative flare definitions were consolidated and sent back to the international community. One hundred and sixteen of 146 (79.5%) responded, with agreement by 71/116 (61%) for the following definition: "A flare is a measurable increase in disease activity in one or more organ systems involving new or worse clinical signs and symptoms and/or laboratory measurements. It must be considered clinically significant by the assessor and usually there would be at least consideration of a change or an increase in treatment." The LFA proposes this definition for lupus flare on the basis of its high face validity.

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, B(12), 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, B(12), and polymorphisms in MTR, TYMS, methionine synthase reductase (MTRR), and reduced folate carrier1 (RFC1). In Caucasians, folate derivative levels were associated with vitamin use, B(12), 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.

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 chi2 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 mentees 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 mentees (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.

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-CH(3)-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-CH(3)-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-CH(3)-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.

Objective: To 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., Methods: We 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 ss-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&#95;78., Results: Homocysteine 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., Conclusion: Polymorphisms in folate/homocysteine metabolizing enzymes do not predict higher homocysteine levels or CAC scores in patients with SLE.

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., (Copyright 2008 Wiley-Liss, Inc.)

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 [(13)C(5)]-5-formyltetrahydrofolate. The resulting [(13)C(5)]-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 <5%; 5,10-MTHF <5%), type II (5-MTHF <95%; THF 5% to 20%; 5,10-MTHF <5%), type III (5-MTHF >55%; THF >20%; 5,10-MTHF >5%), and type IV (5-MTHF <55%; THF >20%; 5,10-MTHF >5%)., (Copyright (c) 2008 John Wiley & Sons, Ltd.)

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.

Objective: 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., Methods: 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., Results: 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, p < 0.0001). 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 (p < 0.0001), 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.

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 approximately 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.

Objective: To search for molecular evidence of Chlamydial infection in systemic lupus erythematosus (SLE) subjects and to assess if there is an association of this infectious agent with coronary artery calcification (CAC), a marker of total atherosclerotic burden., Methods: 28 SLE subjects had blood samples drawn and DNA extracted from peripheral blood mononuclear cells (PBMC) and an electron beam computed tomography (EBCT) scan. Polymerase chain reaction (PCR) analysis was performed for Chlamydia trachomatis 16srRNA and major outer membrane protein (MOMP) and for C. pneumoniae 16srRNA, MOMP, as well as nested PCR for MOMP., Results: Four of 28 subjects (14.2%) had evidence of C. pneumoniae nucleic acid in PBMC. The 16srRNA primers detected C. pneumoniae in one patient (3.57%) and the nested PCR MOMP primers in 3 subjects (10.71%). None were positive for Chlamydia trachomatis. Two of the 4 subjects with C. pneumoniae DNA had abnormal EBCT scans and 2/11 (18.3%) subjects with abnormal EBCT were positive for C. pneumoniae. There were significant associations of C. pneumoniae DNA with smoking (OR = 3) and corticosteroid use. The odds ratio for subjects with abnormal CAC and detectable C. pneumoniae was 1.67., Conclusion: This pilot study demonstrates for the first time that C. pneumoniae DNA can be identified in the PBMC of some SLE subjects and there may be an association with CAC. Smoking may be an additional risk factor for infection in this population. Determination of pathogenicity of this organism in atherosclerotic coronary vascular disease in SLE will require further study.

Osteoarthritis is treated with a variety of pharmacologic therapies, including acetaminophen, traditional nonsteroidal anti-inflammatory drugs, cyclo-oxygenase-2 inhibitors, intra-articular steroids, viscosupplements, glucosamine, chondroitin sulfate, capsaicin, and vitamins. In this review, we describe the clinical efficacy and side effects of these pharmaceuticals. Except for vitamins, each of these therapies is effective over the short-term when compared with placebo in controlled clinical trials. Risk-benefit analysis should be considered when prescribing these medications, as side effects are relatively common, and long-term efficacy is variable. In this review, we also examine current and future research on new medications--particularly matrix metalloproteinases and inducible nitric oxide synthase inhibitors--that may modify osteoarthritis.

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 establish the value of immunologic and serologic testing in patients with Ménière's disease., Study Design: Prospective cohort., Setting: University-based, tertiary care balance center., Intervention: 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., Outcome Measures: Results of laboratory tests., Results: 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., Conclusion: 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.

Behçet'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.

Medical treatment of low back pain is at best palliative. While no drugs are specifically labeled for back pain treatment, analgesics, muscle relaxants, and corticosteroids are used in practice to augment rest and exercise programs. Invasive therapy remains contentious. This article reviews the available literature on the various pharmacologic therapies. In addition, newly postulated outcome measures for future back pain studies are discussed.

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 from 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.

In most western countries, scurvy has become a rare clinical entity. However, it may still be encountered in selected situations. It can mimic connective tissue disease, because of multiorgan involvement. Panniculitis has not previously been described in association with scurvy.