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Objective Rheumatoid arthritis (RA) conveys an increased risk of cardiovascular disease (CVD), making it imperative that traditional CVD risk factors are well controlled. This study compared blood pressure (BP) trends over 13 years among patients with seropositive RA and patients without RA who received care within a large health care system in Minnesota. Methods This retrospective cohort study compared 774 patients with seropositive RA and 3254 patients without RA who were matched on sex and year of birth (±5 years) and observed between 2005 and 2017. Generalized estimating equation models were used for longitudinal analyses, with adjustment for demographics, body mass index, smoking status, Charlson Comorbidity Index, number of BP measurements, and number of antihypertensive and oral glucocorticoid medications. Results Patients both with and without RA had a mean age of 55 and were predominately female (78% with RA; 79% without RA). The mean follow‐up was 6.3 (SD 3.4) years for patients with RA and 7.2 (SD 3.3) years for patients without RA. Overall, systolic BP, diastolic BP, and the number of prescribed antihypertensive medications did not differ between groups. Patients with RA were more likely to be current smokers compared with patients without RA (23% vs 11%; P < 0.01) and were less likely to have serum lipid measurements (75% vs 85%; P < 0.01). Conclusion BP was similarly controlled in patients with seropositive RA and patients without RA. However, diastolic BP in patients with RA was trending up in most recent years. Patients with RA were also more likely to smoke compared with controls and were less likely to have serum lipid measurements.

Objective Anti-citrullinated protein antibodies (ACPAs) have proven highly useful as biomarkers for rheumatoid arthritis (RA). However, composition and functionality of the associated autoreactive B cell repertoire have not been directly assessed. We aimed to selectively investigate citrullinated autoantigen-specific B cell receptors (BCRs) involved in RA and initiate studies on their pathogenicity. Methods Blood samples were obtained from patients in a University of Minnesota cohort with ACPA-positive RA (n = 89). Tetramer sets bearing citrullinated filaggrin peptide cfc1 or citrullinated α-enolase peptide were constructed to specifically capture autoreactive B cells from the unaltered, polyclonal repertoire in RA patients. Citrullinated peptide tetramer-bound B cells were subjected to flow cytometric cell sorting and single-cell IGH, IGK, and IGL gene sequencing for B cell lineage determinations. BCR gene sequences were also expressed as recombinant monoclonal antibodies (mAb) for direct evaluation of citrullinated autoantigen binding and effector functionality. Results Using citrullinated peptide tetramer enrichment to investigate single autoreactive blood B cells, we identified biased V-region gene usage and conserved junction arrangements in BCRs from RA patients. Parsimonious clustering of related immunoglobulin gene nucleotide sequences revealed clonal expansions of rare individual B cell clades, in parallel with divergent sequence mutations. Correspondingly, recombinant mAb generated from such BCR lineages demonstrated citrulline-dependent cross-reactivity extending beyond the citrullinated peptides used for B cell capture. A pair of citrullinated autoantigen-specific mAb with cross-reactive binding profiles also promoted arthritis in mice. Conclusion Our findings suggest that broad ACPA specificities in RA arise from a restricted repertoire of evolving citrulline-multispecific B cell clades with pathogenic potential.

As magnesium mediates bone and muscle metabolism, inflammation, and pain signaling, we aimed to evaluate whether magnesium intake is associated with knee pain and function in radiographic knee osteoarthritis (OA).We investigated the associations between knee pain/function metrics and magnesium intake from food and supplements in 2548 Osteoarthritis Initiative cohort participants with prevalent radiographic knee OA (Kellgren-Lawrence score ≥2). Magnesium intake was assessed by Food Frequency Questionnaire (FFQ) at baseline. WOMAC and Knee Injury and Osteoarthritis Outcome Score (KOOS) scores were reported annually with total follow up of 48 months. Analyses used linear mixed models.Among participants with baseline radiographic knee OA the mean total magnesium intake was 309.9 mg/day (SD 132.6) for men, and 287.9 mg/day (SD 118.1) for women, with 68% of men and 44% of women below the estimated average requirement. Subjects with lower magnesium intake had worse knee OA pain and function scores, throughout the 48 months (P 0.001). After adjustment for age, sex, race, body mass index (BMI), calorie intake, fiber intake, pain medication use, physical activity, renal insufficiency, smoking, and alcohol use, lower magnesium intake remained associated with worse pain and function outcomes (1.4 points higher WOMAC and 1.5 points lower KOOS scores for every 50 mg of daily magnesium intake, P 0.05). Fiber intake was an effect modifier (P for interaction0.05). The association between magnesium intake and knee pain and function scores was strongest among subjects with low fiber intake.Lower magnesium intake was associated with worse pain and function in knee OA, especially among individuals with low fiber intake.

Objective To develop an evidence-based guideline for the comprehensive management of osteoarthritis (OA) as a collaboration between the American College of Rheumatology (ACR) and the Arthritis Foundation, updating the 2012 ACR recommendations for the management of hand, hip, and knee OA. Methods We identified clinically relevant population, intervention, comparator, outcomes questions and critical outcomes in OA. A Literature Review Team performed a systematic literature review to summarize evidence supporting the benefits and harms of available educational, behavioral, psychosocial, physical, mind-body, and pharmacologic therapies for OA. Grading of Recommendations Assessment, Development and Evaluation methodology was used to rate the quality of the evidence. A Voting Panel, including rheumatologists, an internist, physical and occupational therapists, and patients, achieved consensus on the recommendations. Results Based on the available evidence, either strong or conditional recommendations were made for or against the approaches evaluated. Strong recommendations were made for exercise, weight loss in patients with knee and/or hip OA who are overweight or obese, self-efficacy and self-management programs, tai chi, cane use, hand orthoses for first carpometacarpal (CMC) joint OA, tibiofemoral bracing for tibiofemoral knee OA, topical nonsteroidal antiinflammatory drugs (NSAIDs) for knee OA, oral NSAIDs, and intraarticular glucocorticoid injections for knee OA. Conditional recommendations were made for balance exercises, yoga, cognitive behavioral therapy, kinesiotaping for first CMC OA, orthoses for hand joints other than the first CMC joint, patellofemoral bracing for patellofemoral knee OA, acupuncture, thermal modalities, radiofrequency ablation for knee OA, topical NSAIDs, intraarticular steroid injections and chondroitin sulfate for hand OA, topical capsaicin for knee OA, acetaminophen, duloxetine, and tramadol. Conclusion This guideline provides direction for clinicians and patients making treatment decisions for the management of OA. Clinicians and patients should engage in shared decision-making that accounts for patients' values, preferences, and comorbidities. These recommendations should not be used to limit or deny access to therapies.

Objective To describe epidemiologic characteristics and associations with increased healthcare utilization in US adults with chronic low back pain (cLBP).

Oral glucosamine sulfate (GS) and chondroitin sulfate (CS), while widely marketed as joint-protective supplements, have limited intestinal absorption and are predominantly utilized by gut microbiota. Hence the effects of these supplements on the gut microbiome are of great interest, and may clarify their mode of action, or explain heterogeneity in therapeutic responses. We conducted a systematic review of animal and human studies reporting the effects of GS or CS on gut microbial composition. We searched MEDLINE, EMBASE, and Scopus databases for journal articles in English from database inception until July 2018, using search terms microbiome, microflora, intestinal microbiota/flora, gut microbiota/flora and glucosamine or chondroitin. Eight original articles reported the effects of GS or CS on microbiome composition in adult humans (four articles) or animals (four articles). Studies varied significantly in design, supplementation protocols, and microbiome assessment methods. There was moderate-quality evidence for an association between CS exposure and increased abundance of genus Bacteroides in the murine and human gut, and low-quality evidence for an association between CS exposure and an increase in Desulfovibrio piger species, an increase in Bacteroidales S24-7 family, and a decrease in Lactobacillus. We discuss the possible metabolic implications of these changes for the host. For GS, evidence of effects on gut microbiome was limited to one low-quality study. This review highlights the importance of considering the potential influence of oral CS supplements on gut microbiota when evaluating their effects and safety for the host.

Summary Diet is a key determinant of human gut microbiome variation. However, the fine-scale relationships between daily food choices and human gut microbiome composition remain unexplored. Here, we used multivariate methods to integrate 24-h food records and fecal shotgun metagenomes from 34 healthy human subjects collected daily over 17 days. Microbiome composition depended on multiple days of dietary history and was more strongly associated with food choices than with conventional nutrient profiles, and daily microbial responses to diet were highly personalized. Data from two subjects consuming only meal replacement beverages suggest that a monotonous diet does not induce microbiome stability in humans, and instead, overall dietary diversity associates with microbiome stability. Our work provides key methodological insights for future diet-microbiome studies and suggests that food-based interventions seeking to modulate the gut microbiota may need to be tailored to the individual microbiome. Trial Registration: ClinicalTrials.gov: NCT03610477 .

Many classes of medications have been evaluated in chronic low back pain (cLBP), however their utilization in the community remains unclear. We examined patterns of prescription medication use among Americans with cLBP in a nationally representative, community-based sample. The Back Pain Survey was administered to a representative sample of U.S. adults aged 20 to 69 years (N = 5,103) during the 2009 to 2010 cycle of the National Health and Nutrition Examination Survey. cLBP was defined as self-reported pain in the area between the lower posterior margin of the ribcage and the horizontal gluteal fold on most days for at least 3 months (N = 700). Home-based interviews with pill bottle verification were used to capture commonly prescribed medications for chronic pain. Among the sample of U.S. adults with cLBP aged 20 to 69 years, 36.9% took at least 1 prescription pain medication in the past 30 days; of them, 18.8% used opioids, 9.7% nonsteroidal anti-inflammatory drugs, 8.5% muscle relaxants, and 6.9% gabapentin or pregabalin. Nonpain antidepressants and hypnotics were used by 17.8% and 4.7%, respectively. Opioids were used long-term in 76.9% of cases (median = 2 years) and were frequently coadministered with antidepressants, benzodiazepines, or hypnotics. Ninety-four percent of prescription opioids in the cLBP population were used by individuals with less than a college education. Opioids were the most widely used prescription analgesic class in community-based U.S. adults with cLBP and were often coadministered with other central nervous system-active medications. Opioid use was highly prevalent among less educated Americans with cLBP. Perspective Because prescription opioid use is an issue of national concern, we examined pain-related prescription medication use in community-dwelling U.S. adults with cLBP. Opioids were the most common prescription pain medication, typically used long-term, in combination with other central nervous system-active agents, and disproportionately among individuals with less than a college education.

Objective. Persistent infectious agents have been implicated in chronic and recurrent inflammation, which may trigger or worsen many types of arthritis. Our objective was to determine whether exposure to herpes simplex virus (HSV) and human papillomavirus (HPV) is associated with self-reported arthritis among US adults. Methods. We used data from two consecutive cycles of the National Health and Nutrition Examination Survey (NHANES) from 2009 until 2012 (N of examined adults ages 20-69 = 9483). Participants were classified as having arthritis by self-report. Viral serology for HSV-1 and HSV-2 and HPV PCR studies from oral rinse and vaginal swabs were available for analysis. We compared HSV-1 and HSV-2 seropositivity as well as oral and vaginal HPV DNA positivity between participants with self-reported arthritis vs. those without, adjusting for age, gender, race, income, education, BMI, and the use of immunosuppressive medications. We used three comparator outcomes, gout, kidney stones, and hypertension, to evaluate whether the associations were specific or not to arthritis. Results. Arthritis was associated with older age, female gender, non-Hispanic White and Non-Hispanic Black race, higher BMI, and lower socioeconomic status. HSV-2 seropositivity, but not HSV-1 seropositivity, was independently associated with arthritis after adjustment for age, gender, race, income, education, BMI, and the use of immunosuppressive medications: AOR 1.48 (1.10-1.99). Oral HPV DNA positivity was also independently associated with arthritis: AOR 1.63 (1.17-2.28). After adjustment, there was no statistically significant difference in vaginal HPV DNA positivity between those with vs. those without arthritis: AOR 1.22 (0.90-1.66). There were no significant associations between viral exposures and any of the comparator outcomes. Conclusions. HSV-2 seropositivity and oral HPV DNA positivity were associated with self-reported arthritis and not with comparator outcomes, after adjustment for multiple potential confounders. These findings should be confirmed in longitudinal studies.

Background Osteoarthritis pain appears to be caused, at least in part, by alterations in peripheral and/or central nociceptive pathways.[1] As magnesium is a known mediator of nociception, we hypothesized that low magnesium intake may be associated with increased pain in radiographic knee OA. Objectives To evaluate whether magnesium intake is associated with knee pain in radiographic knee osteoarthritis. Methods We investigated the associations between knee pain and magnesium intake from food and supplements in 2549 participants with prevalent radiographic knee OA (Kellgren-Lawrence score ≥2) in the Osteoarthritis Initiative cohort.[2] WOMAC pain scores in the affected knee were reported annually with total follow up period of 48 months. Magnesium intake was assessed at baseline by food frequency questionnaire and dietary supplement questionnaire, and expressed in gender-specific calorie-adjusted quintiles. Analyses used generalized linear mixed effects models with repeated measures. Results Among participants with baseline radiographic knee OA the mean total magnesium intake was 310 mg/day (SD 133) for men, and 288 mg/day (SD 118) for women, with 68% of men and 44% of women below the estimated average requirement (EAR). The mean WOMAC pain score at 0, 12, 24, 36, and 48 months of follow up was 3.5 (SD 3.8), median score 2 (IQR 0; 6). After adjustment for age, gender, BMI, caloric intake, physical activity, smoking status, alcohol use, renal insufficiency, and the use of analgesics, subjects in the lowest gender-specific quintile of magnesium intake (Q1) had, on average, 1 point higher WOMAC knee pain scores than subjects in the highest quintile (Q5): Q1 β (95% CI) 1.00 (0.61–1.39), Q2 0.69 (0.32–1.06), Q3 0.25 (-0.12–0.62), Q4 0.25 (-0.14–0.64); p Conclusions In a cohort of adults with prevalent radiographic knee osteoarthritis, magnesium intake overall was below recommended. Low magnesium intake at baseline was associated with increased pain in the affected knee over 48 months of follow up. These findings may be of growing importance as the average dietary magnesium intake for humans is declining.[3] References Thakur M, Dickenson AH, Baron R. Osteoarthritis pain: nociceptive or neuropathic? Nat Rev Rheumatol. 2014;10(6):374–380. doi: 10.1038/nrrheum.2014.47. Fawaz-Estrup F. The osteoarthritis initiative: an overview. Med Health R I. 2004;87(6):169–171. Rosanoff A, Weaver CM, Rude RK. Suboptimal magnesium status in the United States: are the health consequences underestimated? Nutr Rev. 2012;70(3):153–164. doi:10.1111/j.1753–4887.2011.00465.x. Disclosure of Interest None declared

Background Handoff is the process in which patient care is transitioned from one provider to another. In teaching hospitals, handoffs are frequent, and resident duty hour restrictions have increased the use of night float staff. To date, few studies have focused on long-term sustainability and effectiveness of a handoff quality improvement project. Objective The objective of our resident-driven quality improvement project was to evaluate the effectiveness and sustainability of a standardized template for handoff quality in a community hospital internal medicine program. Methods We used a multistep continuous quality improvement approach. Problems in the handoff process were identified through process mapping and anonymous needs assessment of the residents. A group of residents and faculty identified problems during biweekly discussions, created a standardized template, and adopted a new handoff process. We audited handoffs and surveyed residents at 3 and 9 months after implementation to assess effectiveness and sustainability. Results Before the intervention, only 40% of residents reported regular morning handoff. Using the standardized template, statistically significant, sustained improvements were seen in morning handoff frequency (59% preintervention, 90% at 3 months, 89% at 9 months), along with decreases in unreported overnight events (84% preintervention, 58% at 3 months, 50% at 9 months) and uncertainty about decisions because of poor handoffs (72% preintervention, 49% at 3 months, 37% at 9 months). Statistically significant decreases in missed content (69%–46%) and copy-and-paste behavior (78%–38%) at 3 months were not sustained. Conclusions We demonstrated sustained improvements in unreported events and uncertainty caused by poor handoffs. Initial improvements in missed content and copy-and-paste behavior that were not sustained suggest a need for ongoing reinforcement and monitoring of handoff quality.

A population-based cross-sectional survey.The aim of this study was to compare the prevalence of illicit drug use among US adults with and without chronic low back pain (cLBP).Although addictive medications, such as opioids and benzodiazepines, are frequently prescribed to patients with cLBP, little is known about illicit drug use among Americans with cLBP.We used data from the back pain survey, administered to a representative sample of US adults aged 20 to 69 years (N = 5103) during the 2009 to 2010 cycle of the National Health and Nutrition Examination Survey (NHANES). Participants with pain in the area between the lower posterior margin of the ribcage and the horizontal gluteal fold for at least 3 months were classified as having cLBP (N = 700). The drug use questionnaire was self-administered in a private setting, and included data on lifetime and current use of marijuana or hashish, cocaine, heroin, and methamphetamine. Chi-square tests, one-way analysis of variance, and logistic regression, adjusted for age, gender, race, and level of education, were used for comparisons.About 46.5% of US adults with cLBP used marijuana versus 42% of those without cLBP [Adjusted odds ratio (aOR) 1.36, 95% confidence interval (95% CI) 1.06-1.74]. About 22% versus 14% used cocaine (aOR 1.80, 95% CI 1.45-2.24), 9% versus 5% used methamphetamine (aOR 2.03, 95% CI 1.30-3.16), and 5% versus 2% used heroin (aOR 2.43, 95% CI 1.44-4.11). Subjects with cLBP who reported lifetime illicit drug use were more likely to have an active prescription for opioid analgesics than those without illicit drug use history: 22.5% versus 15.3%, P = 0.018.cLBP in community-based US adults was associated with higher odds of using marijuana, cocaine, heroin, and methamphetamine. Prescription opioid analgesic use was more common in cLBP sufferers with a history of illicit drug use.2.

Background and objectives Presence of autoantibodies targeting citrullinated proteins (ACPA) and clinical response from anti-CD20 Rituximab therapy indicate a critical role for B cells in rheumatoid arthritis (RA). Due to the difficulty of reliably tracking rare B cells with a defined specificity, the composition of the autoreactive B cell repertoire contributing to ACPA + RA has not been analysed. We previously developed a tetramer enrichment strategy for capturing autoreactive B cells. We now employ cyclic citrullinated peptide (CCP) tetramers for cloning and expressing citrulline-specific immunoglobulin (Ig) from single blood B cells in RA. Materials and methods We analysed B cells specific for two previously described CCP, which are citrullinated epitopes from human filaggrin (Cfc1) and alpha-enolase (CEP-1). Antigen-specific B cells were detected by flow cytometry – with fluorescent CCP tetramer for citrulline-specific capture and non-citrullinated peptide decoy tetramer for distinguishing B cells that bind irrelevant epitopes on the tetramer complex. Tetramers were subsequently used to sort single B cells from RA patient (n = 3) blood. Reverse transcription-PCR generated Ig cDNA from the cells. Ig was amplified, cloned, and expressed as monoclonal antibody (mAb). Results Single B cells sorted by either CCP tetramer (Cfc1 or CEP-1) from RA patients’ peripheral blood have highly mutated Ig sequences and show preferential use of the VH4 gene family. When expressed as mAb, 9 of 25 tetramer-sorted clones demonstrated high reactivity towards the targeted CCP epitope, as opposed to 0 of 21 randomly selected memory B cells isolated from the same patient samples. All of the highly citrulline-specific clones further exhibited cross-reactivity to citrullinated epitopes from other proteins and unique binding patterns to these autoantigens on peptide array. The mAb generated from tetramer-selected cells also induced osteoclastogenesis and bone erosion in vitro . Conclusions Single B cells selected by CCP tetramers have highly mutated Ig sequences and receptors with citrulline-specific reactivity. Efficient isolation of mAb clones from the autoreactive B cell repertoire by this strategy will be used to better understand the pathogenesis of autoimmunity. By re-engineering the expressed Ig Fc domain towards blocking or immunosuppressive functions, mAb with defined disease-associated specificities could also offer intriguing possibilities in targeted therapeutic design for RA and other conditions.